Tuberculosis

TUBERCULOSIS

CONTENTS

Preface Neil W. Schluger Global Epidemiology of Tuberculosis Dermot Maher and Mario Raviglione

ix

167

This article provides an overview of the current scale of the global tuberculosis epidemic. It describes the global tuberculosis situation as measured by reported and estimated cases and deaths. The increasing threats of HIV-related tuberculosis and drug-resistant tuberculosis receive particular attention. There is a brief review of the extent of implementation of effective tuberculosis control using the directly observed treatment, short-course (DOTS) strategy. The article ends with a summary of the approaches needed to accelerate progress in global tuberculosis control.

Epidemiology of Tuberculosis in the United States Eileen Schneider, Marisa Moore, and Kenneth G. Castro

183

After decades of decline, an unprecedented resurgence in tuberculosis occurred in the late 1980s and early 1990s. Deterioration of tuberculosis program infrastructure, the HIV/AIDS epidemic, drug-resistant tuberculosis, and tuberculosis among foreignborn persons contributed to the resurgence. Since then, tuberculosis case numbers have declined, but the decline in 2003 was the smallest since the resurgence. Key challenges remain, and efforts must focus on identifying and targeting interventions for high-risk populations, active involvement in the global effort against tuberculosis, developing new tools, and maintaining adequate resources.

The DOTS Strategy for Controlling the Global Tuberculosis Epidemic Thomas R. Frieden and Sonal S. Munsiff

197

This article reviews the principles, scientific basis, and experience with implementation of the directly observed treatment, short-course (DOTS) strategy for tuberculosis. The relevance of DOTS in the context of multidrug-resistant tuberculosis and the HIV epidemic also is discussed.

The Origin and Evolution of Mycobacterium tuberculosis Serge Mostowy and Marcel A. Behr

207

This article introduces the tools and terminology used for the classification of specific isolates of the Mycobacterium tuberculosis complex (MTC). The utility of these tools and

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terminology is illustrated by discussing work from independent laboratories that have established a genome-based phylogeny for the MTC. It considers the use of these markers to distinguish atypical isolates not conforming to attributes of traditional MTC members. Finally, it discusses the current genomic evidence regarding the origin and evolution of M. tuberculosis in the context of its relevance for tuberculosis control in humans and other mammalian hosts.

Molecular Epidemiology: A Tool for Understanding Control of Tuberculosis Transmission Charles L. Daley

217

One of the primary goals of tuberculosis control programs is to interrupt the transmission of Mycobacterium tuberculosis. The development of several genotyping tools has allowed tracking of strains of M. tuberculosis as they spread through communities. Studies that have combined the use of genotyping with conventional epidemiologic investigation have increased the understanding of the transmission and pathogenesis of tuberculosis. This article reviews some of the lessons learned using these new epidemiologic tools.

Genetic Susceptibility to Tuberculosis Richard Bellamy

233

Host genetic factors are important in determining susceptibility and resistance to Mycobacterium tuberculosis. The etiology of tuberculosis is complex, and several host genes have been shown to contribute to the development of clinical disease. The success of the strategies used to investigate host genetic susceptibility to mycobacterial infections can serve as a model for the investigation of host susceptibility to other infectious diseases.

The Diagnosis of Tuberculosis Daniel Brodie and Neil W. Schluger

247

Diagnostic testing for tuberculosis has remained unchanged for nearly a century, but newer technologies hold the promise of a true revolution in tuberculosis diagnostics. New tests may well supplant the tuberculin skin test in diagnosing latent tuberculosis infection in much of the world. Tests such as the nucleic acid amplification assays allow more rapid and accurate diagnosing of pulmonary and extrapulmonary tuberculosis. The appropriate and affordable use of any of these tests depends on the setting in which they are employed.

Treatment of Active Tuberculosis: Challenges and Prospects Behzad Sahbazian and Stephen E. Weis

273

This article reviews the basic principles of drug treatment of tuberculosis, individual pharmacologic agents, current treatment recommendations, and several special situations that clinicians are likely to encounter in medical practice.

Issues in the Management of HIV-Related Tuberculosis William J. Burman

283

This article focuses on the ways in which HIV infection and the associated immunodeficiency affect the management of active tuberculosis. Controversies in the management of HIV-related tuberculosis can be grouped into issues about tuberculosis treatment itself and

vi

CONTENTS

issues posed by the use of combination antiretroviral therapy. The author reviews these controversies and makes recommendations for the management of HIV-related tuberculosis.

Tuberculosis in Children Kristina Feja and Lisa Saiman

295

The epidemiology of pediatric tuberculosis (TB) is shaped by risk factors such as age, race, immigration, poverty, overcrowding, and HIV/AIDS. Once infected, young children are at increased risk of TB disease and progression to extrapulmonary disease. Primary disease and its complications are more common in children than in adults, leading to differences in clinical and radiographic manifestations. Difficulties in diagnosing children stem from the low yield of mycobacteriology cultures and the subsequent reliance on clinical case definitions. Inadequately treated TB infection and TB disease in children today is the future source of disease in adults.

Treatment of Latent Tuberculosis Infection: Challenges and Prospects Kelly E. Dooley and Timothy R. Sterling

313

This article reviews the treatment of latent tuberculosis infection in HIV-seropositive and HIV-seronegative persons.

New Drugs for Tuberculosis: Current Status and Future Prospects Richard J. O’Brien and Mel Spigelman

327

This article reviews two classes of compounds that have advanced into phase II and III clinical trials, long-acting rifamycins and fluoroquinolones, and a number of other drugs that have entered or may enter clinical development in the near future.

The Global Alliance for Tuberculosis Drug Development—Accomplishments and Future Directions Charles A. Gardner, Tara Acharya, and Ariel Pablos-Méndez

341

The Global Alliance for Tuberculosis Drug Development (TB Alliance) aims to stop the spread of tuberculosis by developing new, faster-acting, and affordable tuberculosis drugs. The TB Alliance is a public–private partnership, a not-for-profit enterprise, that draws upon the resources of both private and public institutions to help address this urgent health need. This article summarizes some of the achievements of the TB Alliance to date and outlines potential future directions.

Index

CONTENTS

349

vii

Clin Chest Med 26 (2005) 349 – 353

Index Note: Page numbers of article titles are in boldface type.

A

tuberculosis in, 295 – 312 diagnosis of smear for acid-fast bacilli and mycobacterial culture, 306 epidemiology of, 295 – 297 extrapulmonary, 300 – 302 in newborns, 302 – 303 latent clinical and radiographic manifestations of, 299 – 303 diagnosis of, 303 – 306 infectious, 299 risk factors for, 297 – 298 treatment of, 306 – 309 pathogenesis of, 298 – 299 prevalence of, 295 public health aspects of, 309 – 310 pulmonary, 299 – 300 tuberculous disease, 299

Age as factor in tuberculosis, 186 Aminoglycoside(s) for active tuberculosis, 277 Amplification phage in pulmonary tuberculosis diagnosis, 261 – 262 Antimycobacterial agents for active tuberculosis, 274 – 277 Antiretroviral therapy with tuberculosis treatment challenges of, 286 – 292

B Bacille Calmette-Guerin vaccination effect on tuberculin skin test, 306 Bronchoscopy fiberoptic in pulmonary tuberculosis diagnosis, 256 – 257

Culture(s) in pulmonary tuberculosis diagnosis, 257 – 258

D Diarylquinolones (R207910) for tuberculosis, 333 Dihydroimidazo-oxazoles (OPC-67683) for tuberculosis, 335

C Chemotherapy for active tuberculosis axioms of, 273 – 274 standardized short-course in DOTS strategy for controlling global tuberculosis epidemic, 198 – 199 Children latent Mycobacterium tuberculosis infection in treatment of, 322

1,25-Dihydroxyvitamin D3 in genetic susceptibility to tuberculosis, 238 Directly observed treatment, short-course (DOTS) strategy for controlling global tuberculosis epidemic, 197 – 205 administrative commitment to, 197 drug quality in, 199 for multi-drug resistant TB, 200 – 201 HIV infection and, 201 – 202

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/S0272-5231(05)00042-0

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political commitment to, 197 results of, 200 sputum microscopy of patients attending health facilities, 198 standardized short-course chemotherapy, 198 – 199 systemic monitoring and accountability, 200 DOTS. See Directly observed treatment, short-course (DOTS) strategy. Drug(s) for tuberculosis, 327 – 340 new agents. See also specific drug and Tuberculosis, treatment of, drugs in. tuberculosis resistant to, 175 – 176 Drug resistance in pulmonary tuberculosis diagnosis rapid detection of, 261 – 262 tuberculosis effects of transmission- and pathogenesis-related, 222

Global Alliance for Tuberculosis Drug Development, 341 – 347 described, 341 – 342 future directions for, 346 global product development public – private partnerships, 346 strategy of, 342 – 345 Global product development public – private partnerships in Global Alliance for Tuberculosis Drug Development, 345 – 346

H HIV. See Human immunodeficiency virus (HIV) infection. HLA-DR2 in genetic susceptibility to tuberculosis, 238 Human immunodeficiency virus (HIV) infection tuberculosis and. See Tuberculosis, HIV-related.

I E Ethambutol for active tuberculosis, 276 Ethnicity as factor in tuberculosis, 186

F Fiberoptic bronchoscopy in pulmonary tuberculosis diagnosis, 256 – 257 Fingerprinting patterns in Mycobacterium tuberculosis complex study, 208 Fluoroquinolones for active tuberculosis, 276 – 277

Interferon gamma signaling pathway in genetic susceptibility to tuberculosis, 237 – 238 Isoniazid for active tuberculosis, 275 for latent Mycobacterium tuberculosis infection, 316 – 319 rifampin with for latent Mycobacterium tuberculosis infection, 320 – 321

L Large-sequence polymorphisms in Mycobacterium tuberculosis complex study, 210 Line probe assays in pulmonary tuberculosis diagnosis, 261 LL3858 for tuberculosis, 335

G

Luciferase reporter phages in pulmonary tuberculosis diagnosis, 262

Genetic susceptibility to tuberculosis, 233 – 246. See also Tuberculosis, genetic susceptibility to.

M

Genome(s) sequenced in Mycobacterium tuberculosis complex study, 208

Macrolide(s) for tuberculosis, 335 – 336 Mannan-binding lectin (MBL) in genetic susceptibility to tuberculosis, 238

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INDEX

MBL. See Mannan-binding lectin (MBL). Molecular beacons in pulmonary tuberculosis diagnosis, 261 Moxifloxacin for tuberculosis, 331 – 333 Mycobacterium tuberculosis dissemination of, 226 geographic distribution of, 226 origin and evolution of, 207 – 216 Mycobacterium tuberculosis complex characteristics of, 207 deletions from, 212 – 214 genetic resources in study of, 207 – 210 fingerprinting patterns, 208 large-sequence polymorphisms, 210 sequenced genomes, 208 single-nucleotide polymorphisms, 208 – 210 origin and evolution of chronologic, 211 – 212 ecologic, 211 – 212 genomic deletions and, 210 – 211 geographic, 211 – 212 Mycobacterium tuberculosis infection latent diagnosis of, 223 treatment of, 313 – 326 challenges of, 322 – 323 difficulties with, 322 – 323 implementation-related issues in, 323 importance of, 314 in children, 322 in contacts of persons with drug-resistant tuberculosis, 322 in special situations, 322 indications for, 313 – 314 isoniazid in, 316 – 319 with rifampin, 320 – 320 monitoring for toxicity in, 323 prospects for improvements in, 323 regimens in, 314 – 316 rifampin in, 321 with pyrazinamide, 319 – 320 TNF-a antagonists and, 322 treatment completion rates in, 322 – 323 treatment initiation problems in, 322

N National tuberculosis surveillance system, 184 Natural resistance – associated macrophage protein in genetic susceptibility to tuberculosis, 235 – 237

Newborn(s) tuberculosis in, 302 – 303 Nitroimidazopyran(s) (PA-824) for tuberculosis, 333 – 335 Nucleic acid amplification assays in pulmonary tuberculosis diagnosis, 258 – 260

O OPC-67683 for tuberculosis, 335 Oxazolidinones for tuberculosis

P PA-284 for tuberculosis, 333 – 335 Phage(s) lucifer reporter in pulmonary tuberculosis diagnosis, 262 Phage amplification in pulmonary tuberculosis diagnosis, 261 – 262 Polymorphism(s) large-sequence in Mycobacterium tuberculosis complex study, 210 single-nucleotide in Mycobacterium tuberculosis complex study, 208 – 210 Pyrazinamide for active tuberculosis, 277 rifampin with for latent Mycobacterium tuberculosis infection, 319 – 320 Pyrrole (LL3858) for tuberculosis, 335

R R207910 for tuberculosis, 333 Race as factor in tuberculosis, 186 Rifampin for latent Mycobacterium tuberculosis infection, 321

352

INDEX

isoniazid with for latent Mycobacterium tuberculosis infection, 320 – 321 pyrazinamide with for latent Mycobacterium tuberculosis infection, 319 – 320 Rifamycins for active tuberculosis, 275 – 276 Rifapentine for tuberculosis, 328 – 331

S Single-nucleotide polymorphisms in Mycobacterium tuberculosis complex study, 208 – 210 Sputum in pulmonary tuberculosis diagnosis, 255 – 256 SQ109 for tuberculosis, 336 – 338

T TNF-a antagonists. See Tumor necrosis factor-a (TNF-a) antagonists. Tuberculin skin test bacille Calmette-Guerin vaccination effects on, 306 in active tuberculosis diagnosis, 255 in latent tuberculosis diagnosis, 248 – 251 in latent tuberculosis in children, 305 – 306 Tuberculosis active diagnosis of tests in, 254 – 255 treatment of, 273 – 282 aminoglycosides in, 277 antimycobacterial agents in pharmacology and toxicity of, 274 – 277 chemotherapy in axioms of, 273 – 274 ethambutol in, 276 fluoroquinolones in, 276 – 277 guidelines in, 277 – 280 in special situations, 279 – 280 isoniazid in, 275 pyrazinamide in, 277 rifamycins in, 275 – 276

control of, 214 diagnosis of, 247 – 271 rapid detection of drug resistance in, 261 – 262 drug-resistant, 175 – 176 contacts of persons with latent Mycobacterium tuberculosis infection treatment in, 322 in U.S. epidemiology of, 189 – 190 genetic susceptibility to, 233 – 246 1,25-dihydroxyvitamin D3 and, 238 HLA-DR2 and, 238 host genetics in, 234 – 235 identification of, 235 interferon gamma signaling pathway and, 237 – 238 MBL and, 238 natural resistance – associated macrophage protein and, 235 – 237 global epidemic of control of acceleration in progress of, 179 – 180 DOTS strategy in, 197 – 205. See also Directly observed treatment, shortcourse (DOTS) strategy, for controlling global tuberculosis epidemic. status of, 178 – 179 deaths due to, 170 – 171, 175 epidemiology of, 167 – 182 new cases, 176 – 178 prevalence of, 170 – 171, 172 – 174 review of, 167 – 178 HIV-related, 171 – 172, 190 – 191 DOTS strategy in control of, 201 – 202 treatment of adherence to, 287 antiretroviral therapy with, 286 – 292 drug – drug interactions in, 288 immune reconstitution inflammatory events in, 289 – 290 issues in, 283 – 294 optimal duration of therapy in, 284 – 286 overlapping adverse event profiles in, 287 – 288 recommendations in, 286, 292 in children, 295 – 312. See also Children, tuberculosis in. in U.S. elimination of, 192 epidemiology of, 183 – 195 age and, 186 foreign-born persons and, 186 – 189 historical background of, 183 – 184 post-resurgence, 185 – 192

353

INDEX

treatment of diarylquinolones (R207910) in, 333 dihydroimidazo-oxazoles (OPC-67683) in, 335 drug development for, 328 Global Alliance for, 341 – 347. See also Global Alliance for Tuberculosis Drug Development. drug(s) in new, 327 – 340 pipeline of, 333 – 338 macrolides in, 335 – 336 moxifloxacin in, 331 – 333 nitroimidazopyrans (PA-284) in, 333 – 335 oxazolidinones in, 336 pyrrole (LL3858) in, 335 rifapentine in, 328 – 331 SQ109 in, 336 – 338 widely spaced intermittent, 328 – 331

race/ethnicity factors, 186 resurgence, 184 – 185 latent diagnosis of beyond tuberculin skin test in, 251 – 254 tests in, 248 – 254 tuberculin skin test in, 248 – 251 multi-drug resistant global epidemic of control of DOTS strategy in, 200 – 201 new tools for, 191 – 192 pathogenesis of drug resistance effects on, 222 lessons learned regarding, 219 – 226 pulmonary diagnosis of cultures in, 257 – 258 fiberoptic bronchoscopy in, 256 – 257 line probe assays in, 261 luciferase reporter phages in, 262 methods in, 255 – 260 molecular beacons in, 261 nucleic acid amplification assays in, 258–260 phage amplification in, 261 – 262 sputum in, 255 – 256 tuberculin skin test in, 255 in children, 299 – 300 transmission of community epidemiology and, 224 contact investigations, 222 – 223 control of genotyping methods in, 217 – 219 molecular epidemiology and, 217 – 231 future of, 226 drug resistance effects on, 222 exogenous reinfection and, 220 – 222 infectiousness of patients and, 219 – 220 lessons learned regarding, 219 – 226 mixed infection and, 220 – 222 outbreak investigations, 222 – 223 risk factors for clustering in, 224

Tuberculosis control program performance of measurement of, 224 – 226 Tuberculosis disease case definitions of, 303 – 305 Tuberculosis infection latent treatment of, 313 – 326. See also Mycobacterium tuberculosis infection, latent, treatment of. Tuberculosis/HIV coinfection, 190 – 191 Tumor necrosis factor-a (TNF-a) antagonists latent Mycobacterium tuberculosis infection treatment and, 322

V Vaccination(s) bacille Calmette-Guerin effect on tuberculin skin test, 306

Clin Chest Med 26 (2005) 183 – 195

Epidemiology of Tuberculosis in the United States Eileen Schneider, MD, MPHa,*, Marisa Moore, MD, MPHa,b, Kenneth G. Castro, MDa a

Division of Tuberculosis and Elimination, Centers for Disease Control and Prevention, 1600 Clifton Road, MS E-10, Atlanta, GA 30333, USA b TB Control Program, San Diego County Health and Human Services, Department of Public Health Services, 3851 Rosecrans Street, MS P511D, San Diego, CA 92110, USA

Historical background The epidemiology of tuberculosis (TB) in the United States has changed remarkably over the last 2 centuries. In the nineteenth century, TB was the leading cause of death. As the nineteenth century progressed, TB mortality decreased, partly because of improved socioeconomic conditions [1,2], especially in urban settings, and partly owing to the natural behavior of epidemics [3]. After the tubercle bacillus was identified as the causative agent of TB by Robert Koch in 1882, the approach to TB control changed greatly, and the concepts of public health, prevention, and segregation of TB patients gained more acceptance. As a result, in industrialized countries, the prescribed treatment of rest, isolation, nutrition, and fresh air for TB patients was achieved with long stays in sanatoria [1,2]. By the late 1800s, TB was more than ever considered a public health issue, even though there were few well established local or state public health departments [1,2,4]. More resources became available, and public health programs dedicated to TB control were established. In 1904, the first voluntary health agency dedicated to TB, the National Tuberculosis Association (now the American Lung Association), was organized [1,5]. TB surveillance and

This work was funded by the Division of Tuberculosis and Elimination, Centers for Disease Control and Prevention. * Corresponding author. E-mail address: [email protected] (E. Schneider). 0272-5231/05/$ – see front matter. Published by Elsevier Inc. doi:10.1016/j.ccm.2005.02.007

data collection was a priority for the National Tuberculosis Association. As the mortality rate continued to decrease, attention focused on TB case finding. Armed with a new diagnostic tool, the chest roentgenogram, mass chest radiograph screenings were conducted beginning in the early 1930s and continuing into the 1950s, enabling the diagnosis of TB patients before they became symptomatic [2]. The need to expand data collection to include TB morbidity in addition to TB mortality was acknowledged [1,2]. Reliable and complete morbidity data would allow TB experts to measure more accurately the magnitude of the TB problem and the effectiveness of control efforts. In 1920, the National Tuberculosis Association published its first Diagnostic Standards and Classifications of TB to assist health care providers and standardize diagnostic criteria [5,6]. National TB mortality and morbidity data, coordinated by the National Tuberculosis Association, became available in 1933. In 1944, a United States Public Health Service Act mandated the creation of a national TB control program [1]. With the introduction of the therapeutic agents streptomycin (1947), p-aminosalicylic acid (1949), isoniazid (1952), and pyrazinamide (1952) TB mortality rates decreased dramatically. Between 1930 and 1960, the mortality rate decreased by 92%, from 71 to 6 deaths per 100,000 population. Because of the widespread use of chemotherapy, long hospitalizations for TB were no longer needed, and TB sanatoria and hospitals began to close [1,2,5]. Having a standard definition for a reportable case of TB for surveillance purposes became paramount [7],

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and in 1951, a committee consisting of state TB control officers and sanatoria directors published recommendations for TB case reporting and counting procedures [8]. In 1952, the United States Public Health Service (USPHS) Tuberculosis Control Program instituted procedures to report new cases of TB. Not until 1953, through the cooperation of the states, did the USPHS receive reports from the entire United States, heralding the birth of the national TB surveillance system [1,2]. National tuberculosis surveillance system Since 1953, the national TB surveillance system has been modified several times to monitor and respond better to changes in TB morbidity. Data are collected on TB cases that have been verified and have met the Centers for Disease Control and Prevention (CDC) public health surveillance case definition for TB [9,10]. TB is a reportable disease in each state [11]. In 1985, the national TB surveillance system changed: originally collecting aggregate data, the CDC began collecting individual case reports on a form called the Report of Verified Case of Tuberculosis (RVCT). Currently, data are collected by reporting areas (the 50 states, the District of Columbia, New York City, Puerto Rico, and jurisdictions in the Pacific and Caribbean) using the RVCT. An RVCT is completed for each reported new TB disease case and contains patient demographic, clinical, and laboratory information. An RVCT is completed by the health department for each confirmed TB case and transmitted to the CDC to be included in the national TB surveillance database. The CDC annually publishes a report summarizing national TB statistics [10]. Also included in this annual report are the ‘‘Recommendations for Counting Reported TB Cases,’’ which were last revised in 1997. The CDC has maintained a computer database on TB surveillance data since 1985. State and local TB programs have been able to collect, manage, and transfer TB surveillance data (i.e., RVCT) electronically to the CDC first through software for expanded TB surveillance (SURVS-TB, 1993 – 1997) and currently through the Tuberculosis Information Management System (TIMS, 1998 – present). In 1993, the RVCT was expanded to collect additional information (eg, drug resistance, HIV infection) in response to the TB epidemic of the mid-to-late 1980s and early 1990s. The most recent modification was implemented in January 2003 to meet federal standards for the classification of race and ethnicity. Additional changes for the national TB surveillance system are on the horizon with a revision of the RVCT.

Reporting of RVCT data to the CDC also will be modified with the transitioning of the TIMS to the Web-based National Electronic Disease Surveillance System.

Tuberculosis resurgence Noting that extraordinary strides against TB have been made both in treatment and surveillance since the 1950s, many TB experts have believed that TB elimination in the United States is within reach [1,2]. In 1959, the historic Arden House Conference, sponsored by the National Tuberculosis Association and the USPHS Tuberculosis Control Program, brought together TB experts to formulate a plan on how to eliminate TB; this plan served as a basis for future TB control efforts [12]. TB incidence continued to decrease. From 1953 through 1985, TB case numbers decreased by 74%, from 84,304 to 22,201 cases, and the case rate decreased by 82%, from 53.0 to 9.3 cases per 100,000 population. As a result, many no longer considered TB to be a major problem. In the early 1970s, federal funding allocated for TB control began to decrease, and, as a result, many TB control services were dismantled [13,14]. Although TB funds were decreasing, the cost of treating TB was increasing. In 1981, only $3.7 million was appropriated to the CDC to fight TB nationally. In 1987, the Advisory Committee (now Council) for Elimination of Tuberculosis (ACET) was established, and its membership was directed to develop a strategic plan for TB elimination [15]. The ACET and the CDC published this plan, proposing a TB incidence interim goal for the year 2000 of 3.5 or fewer TB cases per 100,000 population and an elimination target of less than 1 TB case per million population by 2010. In the mid-to-late 1980s, however, the longstanding downward trend in TB incidence was interrupted. In 1986, a 2.6% annual increase in the case number was documented, signaling the beginning of the TB resurgence (Fig. 1). In the late 1980s, after decades of decreasing TB incidence, TB once again became a major threat. The resurgence had a significant impact on TB control strategies in the United States. Because of newly identified risk groups, the focus of many TB control strategies had to be shifted, and many programs needed to be overhauled. CDC researchers concluded that the resurgence had resulted in an estimated 52,100 excess TB cases from 1985 through 1992 [16]. Several factors have been linked to the resurgence, including the deterioration of the TB program infrastructure, the HIV/AIDS epidemic,

epidemiology of tuberculosis in the united states

185

Number of TB Cases

28,000 26,000 24,000 22,000 20,000 18,000 16,000 14,000 12,000 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003

Year Fig. 1. Reported tuberculosis cases in the United States from 1981 to 2003.

drug-resistant TB, TB among foreign-born persons, and an increase in transmission, especially in congregate and institutional settings [16 – 19]. The degree to which each of these factors affected TB control at the local level varied, but two of these factors, the HIV/AIDS epidemic and TB among foreign-born persons, strongly influenced the TB resurgence in the United States. HIV infection is considered to be the greatest risk factor known today for TB. Several large outbreaks of multidrug-resistant TB (MDR-TB) (ie, TB resistant to at least isoniazid and rifampin) among persons infected with HIV were documented in Florida and New York City [20 – 22]. In 1991, 41% of culture-positive TB patients in New York City were also infected with HIV, and 19% had MDR-TB [23]. Early diagnosis of TB among persons infected with HIV was difficult because of the lack of specific clinical findings, such as a positive tuberculin skin test result and an abnormal chest radiograph. Ineffective isolation precautions also contributed to nosocomial transmission of MDR-TB among patients and health care providers [24 – 26]. HIV-related TB outbreaks were also documented in other congregate settings [27] such as correctional facilities [28] and homeless shelters [29,30]. Another important factor fueling the TB resurgence was the immigration of persons from countries that have high rates of TB [19]. The proportion of reported TB cases among foreign-born persons increased from 22% in 1986 (the first year birthplace data were collected by the national TB surveillance system) to 30% in 1993. In the early 1990s, the newly established Federal Tuberculosis Task Force revaluated existing TB strategies and formulated the National Action Plan to Combat MDR-TB [31]. In the United States, a monumental public health effort to control TB was initiated [32,33]. Federal funding was increased and used to rebuild the TB infrastructure, strengthen sur-

veillance, augment case finding and contact investigations, advance laboratory capacity (eg, drugsusceptibility testing and new diagnostic tools), and ensure each patient completed therapy through the use of directly observed therapy (DOT).

After the tuberculosis resurgence, 1993 – 2003 During the resurgence, the national TB incidence peaked in 1992 at 26,673 cases (10.5 cases per 100,000 population). The aggressive attack on TB in the United States resulted in the annual TB case number and case rate decreasing in 1993 to 25,108 cases, 9.7 cases per 100,000 population. Tuberculosis became more localized to well-defined risk groups and geographic areas [34,35]. In response, strategic plans were revised to help prioritize efforts and outline updated recommendations for TB elimination in the United States [36,37]. From 1993 to 2002, the average year-to-year decrease in TB rate was 6.9%. In 2003, however, the CDC reported the smallest annual decrease in the TB rate (1.9%) and TB case numbers (184) since the resurgence, raising concern about a possible slowing of the progress against TB. For 2003, 14,874 TB cases were reported in the United States, with a rate of 5.1 per 100,000 population that remains higher than the national interim goal of 3.5 cases per 100,000 population set for 2000. Moreover, despite the decline in TB nationwide, rates have increased in certain states, and elevated TB rates continue to be reported in certain populations (eg, foreign-born persons and racial/ethnic minorities). In 2003, 12 states and the District of Columbia reported case rates above the national average, and 20 states reported increases in case number compared with 2002 [10].

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Age The distribution of TB cases and case rates among age groups remained relatively stable. In 2003, 34.2% of TB patients were 25 to 44 years old, 28.9% were 45 to 64, 20.2% were 65 years and older, 10.6% were 15 to 24 years, and 6.2% were children under 15 years. In contrast, 2003 TB case rates (cases per 100,000 population) were highest (8.4) among persons 65 years and older, followed by a rate of 6.3 for those 45 to 64, 6.0 for those 25 to 44 years, 3.8 for those 15 to 24 years, and 1.5 for children under 15. Although TB case rates among children under 15 are low, certain groups of children (eg, younger children, racial and ethnic minorities, and foreign-born children) are at higher risk for TB [38]. Children pose unique challenges to TB control: 1. TB in children is considered a sentinel event, usually indicating recent transmission. 2. TB diagnosis in children, especially in children under 5 years of age, can be more difficult because they often have nonspecific signs and symptoms and fewer positive bacteriologic tests because of the paucity of mycobacteria. 3. Children, especially infants, are at an increased risk for progressing from latent TB infection (LTBI) to active and sometimes severe TB disease [38]. Race/ethnicity Disparities in TB rates persist among racial and ethnic minority populations (Table 1). Overall, the highest TB rates are seen among Asian/Pacific Islanders, in large part because of the high proportion of foreign-born persons in this population. Among foreign-born persons, non-Hispanic blacks had the highest case rate in 2003 and were the only group with an increase in case rate from 1998 to 2003. In 2003, among TB patients born in the United States, case rates for non-Hispanic blacks and for American Indian/Alaska Natives were 7.7 and 6.8 times, respectively, that of non-Hispanic whites. Local, state, and federal public health partners, including the CDC and the ACET, are collaborating to develop effective strategies to reduce racial disparities in TB [39]. Foreign-born tuberculosis patients National TB surveillance for patient country of birth began in 1986, when 4925 (21.8%) new cases were reported among foreign-born persons. The pro-

portion of foreign-born TB patients remained relatively stable at 22% to 23% until 1990, when the proportion and number of cases among foreign-born persons began to increase (Fig. 2). Since then, the proportion has increased steadily, with foreign-born persons accounting for 53.4% of the national case total in 2003. This trend results from the relatively stable case count in foreign-born persons since the mid 1990s, with 7902 cases reported in 2003, coupled with the significant decrease in cases among US-born persons (Fig. 3). In 1992, 19,225 cases among US-born persons were reported in the United States; this number decreased to 6903 in 2003. TB case rates among foreign-born persons have been consistently higher than among US-born persons [40]. The 2003 TB rate among all foreign-born persons (23.6 cases per 100,000 population) was 8.8 times greater than that among US-born persons (2.7 cases per 100,000 population). Six birth countries of foreign-born TB patients have consistently accounted for approximately 60% of the foreignborn TB cases reported in the United States annually. In 2003, Mexico accounted for 25.6% of foreignborn patients; the Philippines, 11.5%; Viet Nam, 8.4%; India, 7.6%; China 4.8%; and Haiti 3.3%. The number of states reporting 50% or more of their TB cases among foreign-born persons has also been increasing, from two states in 1986, to 14 states in 1998, and to 25 states in 2003 (Fig. 4). Five states have consistently reported the most foreign-born TB patients: California, New York, Texas, Florida, and New Jersey. In 2003, these states combined reported almost two thirds of the total cases in foreignborn TB persons (California, 30.6%; New York, 12.4%; Texas, 9.0%; Florida, 5.9%; and New Jersey, 4.4%). Within each state, the birth-country composition often varies. In 2003, the most common birth country for reported foreign-born TB patients from California and Texas was Mexico; for New York, it was China; for Florida, it was Haiti; and for New Jersey, it was India. In addition, TB patients from certain countries were concentrated in certain states. For example, in 2003, New York reported 63.5% of the national total of TB patients born in the Dominican Republic and 55.7% of those born in Ecuador. Florida reported 60.0% of the TB patients born in Cuba and 49.2% of those born in Haiti; California reported 52.0% of the TB patients born in the Philippines and 48.6% of the patients born in Laos; and Minnesota reported 55.2% of TB patients born in Somalia. This diversity poses unique challenges to state and local TB control programs and must be addressed to facilitate case finding and contact investigations and to ensure completion of therapy.

US-born 1998 Race/ethnicitya Hispanic Non-Hispanic Black Asian/Pacific Islanderc Asian Native Hawaiian and Other Pacific Islander White American Indian/Alaska Native Totald a

No.

Totalb

Foreign-born 2003 Rate

No.

Rate

1282

6.6

1015

4.3

4968 213 ... ...

16.0 5.8 ... ...

3086 204 155 49

3914 248 10,633

2.1 12.6 4.3

2358 173 6903

% change 1998 – 2003

1998

2003

% change 1998 – 2003

1998 No.

2003 Rate

No.

Rate

% change 1998 – 2003

No.

Rate

No.

Rate

33.8

2785

26.0

3073

19.6

24.7

4091

13.5

4115

10.5

22.2

9.2 5.4 4.4 15.7

42.6 6.9 ... ...

841 3411 ... ...

48.5 55.4 ... ...

1048 3288 3252 36

52.0 41.2 41.1 48.6

7.2 25.6 ... ...

5816 3637 ... ...

17.8 36.9 ... ...

4145 3510 3425 85

11.7 29.8 30.0 22.1

34.4 19.3 ... ...

1.2 8.1 2.7

40.6 36.3 38.2

550 ... 7598

8.5 ... 30.2

427 ... 7902

6.1 ... 23.6

27.7 ... 21.8

4473 254 18,287

2.3 12.7 6.8

2790 176 14,874

1.4 8.1 5.1

38.6 36.2 24.4

In 2003, two modifications were made to the tuberculosis report form: (1) multiple race entries were allowed, with 0.3% selecting more than one race, and (2) the previous category of Asian/Pacific Islander was divided into ‘‘Asian’’ and ‘‘Native Hawaiian or Other Pacific Islander.’’ b Persons included for whom country of birth was unknown: 56 in 1998 and 69 in 2003. c For comparison with 1998, data for 2003 Asian/Pacific Islander = Asian plus Native Hawaiian and Other Pacific Islander. d Persons included for whom race/ethnicity was unknown: 16 for all, 8 for US-born, and 5 for foreign-born persons in 1998; 101 for all, 58 for US-born, and 35 for foreign-born persons in 2003. In 2003, persons included who selected multiple races: 37 for all, 9 for US-born, 28 for foreign-born persons.

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Table 1 Number and rate per 100,000 population of tuberculosis cases in the United States in 1998 and 2003

187

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schneider et al Number of Foreign-born TB Cases

Percentage of Foreign-born TB Cases

10,000

60

8,000

50 40

6,000 30 4,000 20 2,000

10

0

0 1986

1988

1990

1992

1994

1996

1998

2000

2002

Year Number of Foreign-born TB Cases

Percentage of Foreign-born TB Cases

Fig. 2. Trends in tuberculosis cases in foreign-born persons in the United States from 1986 to 2003.

requirements for persons seeking permanent residency in the United States [43]. TB among foreign-born persons is a major component of TB morbidity in the United States [40] and reflects the global TB situation, defined in 1993 by the World Health Organization (WHO) as a global emergency [44,45]. The WHO estimated that in 2002 there were 8.8 million new cases of TB (141 cases per 100,000 population) [46]. Among the 22 high-burden countries, India and China accounted for 46% of the total. Among the 15 countries that have the highest TB rates (>400 cases per 100,000 population), 13 are in Africa, and 12 of these had high TB/HIV incidence rates (>100 cases per 100,000 population) among adults 15 to 49 years

Most TB cases among foreign-born persons are caused by Mycobacterium tuberculosis complex infections acquired abroad [41]. Among foreign-born children, aged younger than 15 years, who had TB, 60% were diagnosed within 18 months of arrival in the United States [38]. Prompt evaluation of foreignborn persons for TB following their arrival in the United States can help identify persons who have LTBI and are eligible for preventive therapy; prompt evaluation can prevent development of active TB disease [41,42]. Foreign-born TB patients are also more likely to have drug resistance and are less likely to be HIV infected than US-born TB patients [40]. The lower proportion of foreign-born TB patients infected with HIV results in part from HIV screening

Number of US-born TB Cases

Percentage of US-born TB Cases

100

20,000

90 80

15,000

70 60 50

10,000

40 30

5,000

20 10

0

0 1986

1988

1990

1992

1994

1996

1998

2000

2002

Year Number of US-born TB Cases

Percentage of US-born TB Cases

Fig. 3. Trends in tuberculosis cases in persons born in the United States from 1986 to 2003.

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Number of states with ≥50% TB cases in foreign-born persons

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30 25 22

23

22

20 15

2

2

3

3

4

4

5

15

10

9

10

14

6

2

0 1986

1988

1990

1992

1994

1996

1998

2000

2002

Year

Fig. 4. Number of states with 50% or more of tuberculosis cases in foreign-born persons in the United States from 1986 to 2003.

old, highlighting the magnitude of the TB/HIV epidemic and the influence of HIV/AIDS on TB [46]. Therefore, immigration from regions that have high rates of drug-resistant TB (eg, Eastern Europe) as well as from regions that have high rates of HIV infection (eg, sub-Saharan Africa) substantially affect the epidemiology of TB in the United States. The CDC is collaborating with partners such as the US Agency for International Development, the International Union Against TB and Lung Disease (IUATLD), the KNCV TB Foundation (formerly the Royal Netherlands Tuberculosis Association), and WHO to assist countries that have high burdens of TB. Collaborations have focused on building program capacity, operational research, and programmatic evaluation to address problems such as TB/HIV and drug resistance in TB patients. TB screening among immigrant and refugee visa applicants is being improved through the development of new diagnostic tools [47] and updated medical screening guidelines [43]. In addition, because Mexico contributes the largest number of foreign-born TB patients in the United States, the CDC has been collaborating with partners in the United States and Mexico to help control TB along the United States – Mexico border. These efforts include an innovative new initiative that uses a binational health card to track and manage binational TB patients who cross the border to ensure continuity of TB care and completion of treatment [48,49]. Worldwide, TB is a recognized cause of morbidity and mortality in children. A renewed interest by domestic and international health agencies has focused on mobilizing and strengthening global efforts to improve surveillance, and to promote program and research initiatives to reduce the burden of TB on children [50,51].

Drug-resistant tuberculosis Drug-resistant TB, especially MDR-TB, places an increased burden on all aspects of TB control, including diagnosis, case management, treatment, and cost [52 – 54]. MDR-TB is defined as resistance to at least isoniazid and rifampin, two of the most effective antituberculosis agents in the TB arsenal. When used in conjunction with other antituberculosis agents, rifampin can significantly shorten the treatment course of TB. Although many factors have been associated with the development of drug resistance, including naturally occurring spontaneous mutations, two of the most commonly encountered and preventable factors are nonadherence to therapy and inappropriate use of antituberculosis drugs. Poor infection-control practices within hospitals caring for patients who have drug-resistant TB have also played an important role in the nosocomial transmission of MDR-TB [20 – 22]. Collection of drug-susceptibility results became part of routine national TB surveillance in 1993, in part because of the recommendations outlined by the National Action Plan to Combat MDR-TB [31]. Before 1993, several regional and national drug susceptibility surveys on TB patients were conducted [52]. In 1991, findings of a nationwide survey revealed 14.2% of cases were resistant to at least one drug and 3.5% were resistant to at least isoniazid and rifampin (MDR-TB) [55]. The strongest risk factor for drug resistance was geographic location. New York City had the highest MDR-TB rate (13%) and accounted for 61% of the total MDR-TB cases reported in the United States. Analysis of national TB surveillance data collected from 1993 through 1996 revealed a 13.5%,

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incidence of resistance to at least one drug, and the incidence of MDR-TB was 2.2% [56]. Higher drugresistance rates were seen among TB patients who have had a previous episode of TB, foreign-born persons, HIV-infected persons, and persons residing in specific geographic areas (eg, New York City). In the mid-to-late 1990s, several outbreaks involving highly drug-resistant strains of M. tuberculosis (ie, strain W) were investigated [57 – 59]. These strains share a common drug resistance to first-line antituberculosis medications (eg, isoniazid, rifampin, ethambutol, and, at that time, streptomycin) as well as resistance to some second-line medications, making treatment difficult and costly. The majority of strain W TB cases were reported by New York City [57,59], although outbreaks have occurred elsewhere, including one that was attributed to bronchoscope contamination in South Carolina [58]. To facilitate early detection of strain W isolates, the CDC began recommending that health departments notify the CDC of all M. tuberculosis isolates that have strain W – resistance patterns [59]. Since 1998, overall multidrug resistance among culture-positive TB patients, who do not have a prior history of TB, has been relatively stable (~1%) (Fig. 5), although outbreaks and regional differences continue to occur. Historically, overall drugresistance rates among those who have a previous history of TB have been higher than for those who do not have a previous history of TB. In 2003, among TB patients who had a prior history of TB, 12.6% had resistance to at least isoniazid and 3.6% had MDR-TB, whereas 7.9% of TB patients who did not have a prior history of TB had resistance to

at least isoniazid and 0.9% had MDR-TB. Additionally, drug resistance (MDR-TB and resistance to at least isoniazid) has been seen more commonly in foreign-born TB patients (2003: MDR-TB, 1.2%; isoniazid, 10.6%) than in US-born TB patients (2003: MDR-TB, 0.6%; isoniazid, 4.6%). Knowledge of drug-resistance rates worldwide is critical to controlling the global epidemic and has direct implications for TB control in the United States [60,61]. A more comprehensive understanding of global drug resistance was made possible with the formation of the Supranational Reference Laboratory Network in 1994 and the WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Newly released data reveal that TB patients in parts of Eastern Europe and Central Asia are 10 times more likely to have MDR-TB than patients in the rest of the world, with some MDR-TB incidence rates higher than 10% (Israel, 14.2%; Kazakhstan,14.2%; Tomsk Oblast [Russian Federation], 13.7%; Uzbekistan, 13.2%; Estonia, 12.2%; and Liaoning [China], 10.4%) [61]. Tuberculosis/HIV coinfection Today, any discussion about TB is incomplete without a discussion about HIV/AIDS. Knowing a TB patient’s HIV status is critical to management, treatment, contact investigation, and prevention [62 – 67]. The CDC recommends that all TB patients, independent of risk factors, should undergo voluntary HIV counseling, testing, and referral [64,65,67]. Nonetheless, HIV status is not reported nationally for many TB patients in the United States. This in-

Number of MDR TB Cases

Percentage of MDR TB Cases

450

3.0

400 350 300

2.0

250 200 150

1.0

100 50 0.0

0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

Year Number of MDR TB Cases

Percentage of MDR TB Cases

Fig. 5. MDR-TB among persons without a history of tuberculosis in the United States from 1993 to 2003. MDR-TB is defined as resistance to at least isoniazid and rifampin.

epidemiology of tuberculosis in the united states

complete reporting of HIV status probably reflects several factors including concerns about confidentiality, interpretation of laws and regulations in certain states and local jurisdictions, and reluctance by health care providers to report HIV test results to the TB surveillance program staff [10]. Information on HIV status was added to the national TB surveillance system in 1993, in response to the TB resurgence. HIV test results (ie, negative, positive, or indeterminate) were reported for 45.7% of TB patients aged 25 to 44 years in 1993 and for 65.3% in 2002. In this group, positive HIV test results were reported for 29.1% in 1993 and for 15.9% in 2002. Historically, reported TB/HIV coinfection rates and case numbers have been relatively high in a few states and urban areas. In 2002, 60% of the positive HIV test results among TB patients aged 25 to 44 years were reported from five areas: California, Florida, Georgia, New York City, and Texas. Crossmatching of state TB registries and HIV/AIDS registries in 1993 and 1994 revealed that 14% (range, 0% – 31%) of persons reported to have TB in the United States were also listed in HIV/AIDS registries [68]. TB-AIDS cases were more likely to be in persons aged 25 to 44 years, male, culture-positive for M. tuberculosis, and USborn. In geographic areas where the prevalence rates of HIV-infected persons were high, drug resistance, especially MDR-TB (6%) and rifampin monoresistance (3%), was reported among TB-AIDS patients. HIV coinfection has several key implications for the overall treatment and management of TB. HIV infection increases the risk of (1) TB disease progression among persons who have LTBI, (2) rapid progression of those newly infected with M. tuberculosis to active TB disease, and (3) reinfection with M. tuberculosis [67,69]. Many of the TB outbreaks among persons infected with HIV that occurred during the resurgence were complicated by high drug-resistance rates and resulted in mortality rates reaching 70% [21 – 23]. TB outbreaks among HIVinfected persons have illustrated the continued need for appropriate treatment and monitoring of this population [70 – 73]. The use of antiretroviral therapy has significantly decreased mortality and morbidity, including the development of opportunistic infections (eg, TB) among HIV-infected persons. New concerns have developed, however, concerning the potential for drug – drug interactions, development of resistance to rifamycin, and paradoxical reactions. Drug – drug interactions, primarily between rifamycin and protease inhibitors and nonnucleoside reverse transcriptase inhibitors, have resulted in new treatment guidelines and recommendations [66,66a]. Acquired rifampin monoresistance has been docu-

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mented in HIV-infected patients who have low CD4+ T-lymphocyte counts, extrapulmonary disease, and concomitant antifungal therapy [74,75]. Clinicians treating TB-HIV – coinfected persons should be familiar with current diagnostic, management (eg, DOT), and treatment modalities to maximize therapeutic success and minimize TB transmission, drug resistance, adverse effects, and treatment failures [64,67]. Globally, the HIV/AIDS epidemic has had an immense impact on TB control, especially in subSaharan Africa, where an estimated two thirds of persons who have HIV/AIDS live, and has contributed significantly to TB morbidity and mortality [76 – 78]. In these countries, TB incidence and case fatality are strongly associated with HIV prevalence. The prevalence of drug-resistant TB is expected to increase greatly as the HIV epidemic spreads to areas of the world where drug-resistant TB is more prevalent (eg, Asia, Eastern Europe) [61,76]. The scaling up of treatment programs providing antiretroviral therapy will require patient and health care provider education and close monitoring to optimize therapy, reduce transmission, and reduce drugresistant TB [79]. Development of new tools An important component of disease control is the development of new diagnostic tests, pharmacologic agents, and vaccines. The resurgence of TB in the mid-to-late 1980s to 1992 was associated with delays in the diagnosis and identification of drug resistance. This situation generated renewed interest in the development of several new diagnostic tools and the subsequent genomic sequencing of M. tuberculosis. During the past few years, TB diagnostic capabilities have improved through new techniques for the rapid detection of M. tuberculosis complex (eg, nucleic acid amplification tests) [80], identification of M. tuberculosis (eg, nucleic acid probe), rapid detection of latent TB infection (eg, whole-blood interferon gamma assay [QuantiFERON (Cellestis Inc., Valencia, California)]) [81,82], the investigational enzyme-linked immunospot test (ELISPOT) [83], and differentiation of M. tuberculosis strains (eg, DNA fingerprinting) [84,85]. In the 1990s, molecular genetic typing (genotyping) of M. tuberculosis strains became a commonly used tool to understand outbreaks and transmission dynamics. In 1996, the CDC established the National TB Genotyping and Surveillance Network to determine the usefulness of molecular genotyping in more routine TB control settings using the IS6110-based restriction fragment length polymorphism (RFLP)

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technique supplemented with spacer oligonucleotide typing (spoligotyping) on M. tuberculosis isolates [86,87]. Genotyping, in conjunction with epidemiologic investigation, has proven a useful adjunct to epidemiologic investigations in tracing the chain of transmission [88]. The techniques are particularly useful in outbreaks and institutional settings, identifying groups at risk for TB (eg, homeless persons), identifying contacts and social networks, understanding exogenous reinfection, and confirming laboratory cross-contamination [89,90]. To refine the understanding of TB transmission and epidemiology and to advance TB control, the CDC has launched the National TB Genotyping Program, which provides the capacity to genotype M. tuberculosis isolates from all culture-positive TB patients in the United States. Two polymerase chain reaction – based genotyping tests (spoligotyping, mycobacterial interspersed repetitive units analysis) will be supplemented with IS6110 RFLP testing for selected specimens [91]. The goal of this program is to improve the characterization of TB transmission dynamics and to use the results to improve the efficiency of public health interventions. In 1995, following a several-year hiatus in the USPHS-sponsored clinical trials, the CDC reinstated clinical TB research, creating the TB Trials Consortium (TBTC). The TBTC currently is coordinating several studies, including efficacy trials for the use of moxifloxcin as a first-line drug in the treatment of TB disease. Information gained from the earliest of these studies contributed to the Food and Drug Administration licensure of rifapentine, a longacting rifampin and the first anti-TB drug approved in 25 years [92]. Additional studies include a comparison of several generations of QuantiFERON with the tuberculin skin test in the diagnosis of LTBI [81]. In 2001, the CDC established the TB Epidemiologic Studies Consortium to conduct multicenter epidemiologic, behavioral, and operational research studies. Furthermore, recognizing the need for TB prevention globally, a renewed interest, fueled by generous funding has resulted in actively revisiting vaccine development [93,94]. Numerous organizations, both in the public and private sectors, are conducting major research efforts to develop a safe and effective TB vaccine.

Elimination of tuberculosis in the United States: remaining challenges After decades of decline, an unprecedented resurgence in TB began in 1986 and continued through

1992, with case numbers increasing by 20%. Following an intensive campaign and mobilization of new resources, TB cases once again began to decline. Remarkable gains have been made since the early 1990s, with efforts being concentrated on maintaining control of TB, speeding the decline of TB, and developing new tools [37]. Key TB epidemiologic features that have been identified include an increasing proportion of TB cases among persons born in countries where TB is endemic, racial and ethnic disparities, and localized unique epidemiologic profiles in areas throughout the United States. Development of new tools, such as vaccines, antituberculosis drugs, and rapid diagnostic tests have also been identified as vital measures needed to eliminate TB in the United States. The smallest decline since the resurgence was seen in 2003, raising the concern about a possible slowing of the progress against TB or even a reversal of the decline. Despite increasing health care costs and demands for increased programmatic and operational efforts, funding for TB control has not increased [95]. The elimination of TB in the United States will require sustained efforts such as identifying and targeting populations at high risk for TB, remaining actively involved in the global effort against TB, and maintaining adequate resources.

Acknowledgments The authors thank the state and local tuberculosis control officials in health departments throughout the United States who collected and reported the national surveillance data presented in this article, the surveillance staff at the Division of TB Elimination, Centers for Disease Control and Prevention, who maintain the database, Ann H. Lanner for her editorial review of the manuscript, and Dr. Thomas Navin and Dr. Michael Iademarco for their critical review of the manuscript.

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protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Available at: http://www.cdc.gov/ nchstp/tb/TB_HIV_Drugs/TOC.htm. Accessed September 1, 2004. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR Morb Mortal Wkly Rep 1998;47(RR-20): 1 – 58. Moore M, McCray E, Onorato IM. Cross-matching TB and AIDS registries: TB patients with HIV coinfection, United States, 1993 – 1994. Public Health Rep 1999;114:269 – 77. Shafer RW, Singh SP, Larkin C, Small PM. Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in an immunocompetent person. Tuber Lung Dis 1995;76:575 – 7. Centers for Disease Control and Prevention. Drugsusceptible tuberculosis outbreak in a state correctional facility housing HIV-infected inmates – South Carolina, 1999 – 2000. MMWR Morb Mortal Wkly Rep 2000;49(46):1041 – 4. Centers for Disease Control and Prevention. Tuberculosis outbreaks in prison housing units for HIVinfected inmates – California, 1995 – 1996. MMWR Morb Mortal Wkly Rep 1999;48(4):79 – 82. Spradling P, Drociuk D, McLaughlin S, et al. Drugdrug interactions in inmates treated for human immunodeficiency virus and Mycobacterium tuberculosis infection or disease: an institutional tuberculosis outbreak. Clin Infect Dis 2002;35:1106 – 12. 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 – 12. Vernon A, Burman W, Benator D, et al for the TB Trials Consortium. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Lancet 1999; 353:1843 – 7. Sandman L, Schluger NW, Davidow AL, et al. Risk factors for rifampin-monoresistant tuberculosis. Am J Respir Crit Care Med 1999;159:468 – 72. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis. Arch Intern Med 2003;163: 1009 – 21. Corbett EL, Steketee R, ter Kuile FO, et al. HIV-1/ AIDS and the control of other infectious diseases in Africa. Lancet 2002;359:2177 – 87. Joint United Nations Programme on HIV/AIDS. 2004 Report on the global AIDS epidemic. UNAIDS/04. 16E. Geneva (Switzerland)7 UNAIDS; 2004. Gupta R, Irwin A, Ravigilone MC, et al. Scaling-up treatment for HIV/AIDS: lessons learned from multidrug-resistant tuberculosis. Lancet 2004;363:320 – 4. American Thoracic Society Board of Directors. Rapid

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diagnostic tests for tuberculosis. Am J Respir Crit Care Med 1997;155:1804 – 14. Mazurek GH, LoBue PA, Daley CL, et al. Comparison of a whole-blood interferon-gamma assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection. JAMA 2001;286(14):1740 – 7. Centers for Disease Control and Prevention. Guidelines for using QuantiFERON1-TB Test for diagnosing latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep 2003;52(RR-2):15 – 8. Lalvani A, Pathan AA, McShane H, et al. Rapid detection of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Am J Respir Crit Care Med 2001;163:824 – 8. Barnes PF, Cave MD. Molecular epidemiology of tuberculosis. N Engl J Med 2003;349(12):1149 – 56. Woods GL. The mycobacteriology laboratory and new diagnostic techniques. Infect Dis Clin North Am 2002; 16(1):127 – 45. Castro KG, Jaffe HW. Rationale and methods for the national tuberculosis genotyping and surveillance network. Emerg Infect Dis 2002;8(11):1188 – 91. Crawford JT, Braden CR, Schable BA, et al. National tuberculosis genotyping and surveillance network: design and methods. Emerg Infect Dis 2002;8(11): 1192 – 6. Small PM, Hopewell PC, Singh SP, et al. The epidemiology of tuberculosis in San Francisco. N Engl J Med 1994;330(24):1703 – 9. Small PM, McClenny NB, Singh SP, et al. Molecular strain typing of Mycobacterium tuberculosis to confirm cross-contamination in the mycobacteriology laboratory and modification of procedures to minimize occurrence of false-positive cultures. J Clin Microbiol 1993;31(7):1677 – 82. Braden CR, Templeton GL, Stead WW, et al. Retrospective detection of laboratory cross-contamination of Mycobacterium tuberculosis cultures with use of DNA fingerprint analysis. Clin Infec Dis 1997;24:35 – 40. Rosenblum LS, Navin TR, Crawford JT. Molecular epidemiology of tuberculosis. N Engl J Med 2003; 349(24):2364. The TB Trials Consortium. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 2002;360:528 – 34. Centers for Disease Control and Prevention. Development of new vaccines for tuberculosis. MMWR Morb Mortal Wkly Rep 1998;47(RR-13):1 – 6. Reed SG, Alderson MR, Dalemans W, et al. Prospects for a better vaccine against tuberculosis. Tuberculosis 2003;83:213 – 9. National Coalition for Elimination of Tuberculosis. Tuberculosis elimination: the federal funding gap. National Coalition for Elimination of Tuberculosis; 2004. p. 1 – 19.

Clin Chest Med 26 (2005) 233 – 246

Genetic Susceptibility to Tuberculosis Richard Bellamy, MRCP, DPhil James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, UK

Genetic factors are important contributors to the development of a wide range of complex or multifactorial diseases. For example, if one has a close relative who died of ischemic heart disease, one will be at increased risk of developing ischemic heart disease oneself. It is not inevitable that one will develop the same condition, because other factors such as cigarette smoking, diet, exercise, and ‘‘bad luck’’ also contribute to the risk of developing ischemic heart disease. A positive family history simply indicates that one is at increased risk of developing heart disease compared with a person of the same age and sex who does not have a positive family history. Patients and their doctors recognize the importance of family history for a wide range of multifactorial, noncommunicable diseases such as cancer, cardiovascular disease, and diabetes mellitus. Much of the clustering in families that occurs in these conditions, however, probably results from shared environmental risk factors. Although there is much debate about the importance of nature versus nurture, few scientists would dismiss the importance of host genetics in the development of chronic noncommunicable diseases. In contrast, host genetic factors are often given little attention in infectious disease. The familial clustering that is frequently observed for infectious diseases is commonly dismissed as the result of transmission of infection among household members. This assumption is unfair, because host genetic factors are probably at least as important in determining the outcome of infection as they are in other complex diseases. Studies on adoptees are sometimes used to help eliminate the effects of shared environment when

E-mail address: [email protected]

considering the contribution of genetic factors to observed familial clustering of disease. In a study of almost 1000 adoptees, Sorensen et al [1] found that the host genetic component of susceptibility to premature death from infection was greater than for cancer or cardiovascular disease. This finding does not mean that if one’s father dies of tuberculosis, one inevitably will succumb to the same disease. Rather, it indicates that a person who has such a family history has a higher probability of dying from tuberculosis than a person who does not have a positive family history. Thus the statement that host genetic factors make a person susceptible to a particular infectious disease simply means that the risk of developing the disease is higher than for someone who has not inherited the genetic risk factor (ie, who can be described as resistant). Someone whose genetic constitution makes him or her susceptible to Mycobacterium tuberculosis will not necessarily develop clinical disease after exposure to the microorganism. Conversely someone whose genetic constitution makes him or her resistant to M. tuberculosis may still develop clinical disease after exposure. The term ‘‘susceptible’’ simply indicates a genetic make-up with a higher risk of developing tuberculosis than a resistant one. In 1949, Haldane [2] suggested that microorganisms have been the main agents of natural selection among human populations for the past 5000 years. He believed that the recent evolution of the human genome was driven primarily by the need to resist pathogens because infectious diseases were the most important cause of premature death. This hypothesis proposes that most of the genetic diversity found within human populations has been selected for and maintained by pathogenic microorganisms. Until recently, progress in identifying the host genes con-

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ferring resistance to infectious diseases was limited to malaria. Geographic variations in the prevalence of malaria facilitated the identification of several gene variants conferring resistance to malaria, including sickle cell hemoglobin, a- and b-hemoglobin, and glucose-6-phosphate dehydrogenase deficiency [3,4]. Genetic mutations conferring malaria resistance are common in populations originating in areas where malaria is endemic and are rare among populations where malaria does not occur. Historically, tuberculosis has not shown the marked geographic variation shown by malaria. This lack of variation has made the task of identifying the host genes conferring tuberculosis susceptibility and resistance more difficult to identify. It has been estimated that M. tuberculosis was responsible for more than one fifth of all deaths in Western Europe after the industrial revolution [5]. It is therefore logical to expect that M. tuberculosis would have been among the microorganisms that have had the most important effects on the evolution of the human genome. It has been estimated that approximately one third of the world’s population is infected with mycobacteria, but among those infected only about 10% will ever develop clinical disease [6]. Much scientific research has focused on proving that host genetic factors are important in determining why only a minority of those infected by M. tuberculosis develops clinical disease. This article provides a brief summary of this research and describes the strategies that have been used to identify the host genes involved in tuberculosis resistance.

Evidence showing the importance of host genetics in tuberculosis susceptibility In 1926, in Lubeck, Germany, a tragic accident occurred during the bacille Calmette-Guerin (BCG) vaccination program: 249 babies were injected with the same live dose of virulent M. tuberculosis bacteria. Seventy-six babies died; 173 babies survived [7]. This experience showed that there is wide variation in the degree of innate immunity against M. tuberculosis. The babies who died presumably had weaker resistance to M. tuberculosis than the babies who managed to clear the infection. This difference in host immunity could not have resulted from variation in acquired resistance to M. tuberculosis, because the babies were too young to have had significant prior exposure to mycobacteria, and they had not previously been vaccinated with BCG. The difference could also not be explained by variation in virulence or infectivity of the bacteria, because all the infants

received direct inoculation with the same dose of the same strain of M. tuberculosis. Therefore the difference in outcome of the infection is probably explained by host genetic factors. It has been suggested that a population’s resistance to M. tuberculosis is determined by its history of previous exposure [8]. Resistance is built up over a number of generations by selection pressure in favor of mycobacteria-resistant gene variants. When the selection pressure is strong, gene variants conferring disease-resistance can rise to high population frequencies in relatively short periods of time. The most striking example of a population acquiring resistance to tuberculosis has been described by Motulsky [9]. At the end of the nineteenth century the Qu’Appelle Indians suffered their first cases of tuberculosis. The disease spread rapidly through the population and caused the deaths of 10% of the total population annually. After two generations (40 years), half of the families had been lost, but the annual death rate from tuberculosis had fallen to 0.2% [9]. This striking reduction in tuberculosis-specific mortality is believed to have resulted from the strong selection pressure in favor of M. tuberculosis – resistant gene variants [9]. Tuberculosis has been a major cause of premature death in Europe since the Industrial Revolution. In Africa it is believed that tuberculosis did not become widespread until the start of the twentieth century [10 – 12], when the building of densely populated towns and cities facilitated the spread of M. tuberculosis. Haldane’s theory would therefore predict that present-day people of European origin would have greater resistance to tuberculosis than people of African origin. A study of 25,000 nursing home residents in Arkansas confirmed that black residents were twice as likely to become infected with M. tuberculosis as white residents of the same nursing homes [13]. This difference could not be explained by environmental or social factors, indicating that it was most likely caused by host genetics [13]. Twin studies are the most reliable method of determining whether genetic factors are involved in determining who will develop a particular disease. Monozygotic twins inherit identical genomes, whereas dizygotic twins share only 50% of the genes they inherit. If monozygotic twins have higher concordance for a disease than dizygotic twins, this finding indicates that genetic factors are important in the etiology of the disease. Several studies have compared the concordance for tuberculosis in monozygotic twins with that in dizygotic twins. These studies have shown concordance rates among monozygotic twins to be approximately twice as high as

genetic susceptibility to tuberculosis

concordance rates among dizygotic twins [14 – 16]. This evidence that host genes are important in determining susceptibility/resistance to tuberculosis has led to the development of several strategies to attempt to identify the genes involved.

Strategies to identify host genes determining tuberculosis susceptibility Identifying the genes influencing susceptibility to multifactorial diseases is a complex process. No single strategy could identify all of the genes of interest, because each study design has advantages and limitations. Genome-wide linkage studies are used to identify regions of the genome that contain major diseasesusceptibility loci. This approach involves typing a large number of genetic markers (usually more than 300) covering the whole human genome. Sibling-pair families that contain two or more siblings affected by the disease of interest are usually used in studies of multifactorial diseases. These families are preferred to large, extended families (which are generally used for single-gene Mendelian disorders), because they are believed to be more representative of the disease in the general population. Large numbers of sibling-pair families must be typed to provide sufficient power to detect genes exerting a large effect on population-wide disease risk. The approach is systematic and comprehensive and in theory should detect any genomic region that contains a major disease-susceptibility locus. This approach has relatively low power, however, and it cannot detect gene loci that confer only a moderate effect on population-wide disease risk. For example if a disease-susceptibility allele has a frequency of 0.5 (ie, 50% of the alleles in the population are of this type) and exerts a twofold increased risk of disease compared with the resistant wild-type allele, 2498 sibling-pair families are required to provide an 80% probability of identifying this effect by linkage analysis [17]. It would be difficult to collect and type this number of families in a genomewide screen. Association-based candidate gene studies have much greater power. Only 340 cases are required to have the power to detect the effect of the diseasesusceptibility locus described previously [17]. Association-based candidate gene studies can therefore detect genetic effects that would be overlooked in a genome-wide linkage study. The simplest form of association study is the case-control study, but more

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complex, family-based designs are also occasionally used. Association studies generally involve typing individual gene variants that are believed to be potentially important because of previous work on animal models of the disease or for theoretical reasons. Association between a genetic marker and a disease can be caused by either the genetic variant itself conferring disease susceptibility/resistance or the genetic variant being in linkage disequilibrium with the true disease-susceptibility locus. Linkage disequilibrium occurs only when two gene variants are located close together (within 1 centi-Morgan) on the same chromosome. A genome-wide association study would require typing more than 3000 genetic markers; this approach would be time-consuming and expensive and therefore generally is not feasible. Because association studies are usually restricted to candidate genes, this approach cannot be used alone. Regardless of how many candidate genes are typed, the genes that exert the largest effects on population-wide disease risk could be overlooked. Candidate gene studies and genome-wide linkage studies are therefore complementary, and both are generally required when investigating a multifactorial disease. Animal models have several advantages for the study of multifactorial diseases. Animal models can be used in breeding experiments, targeted gene disruption can be performed, and the animals can be challenged with pathogens. Identifying genes that confer susceptibility to individual pathogens in animal species is a useful strategy for identifying candidate genes for case-control studies in human populations. Human patients who suffer from extreme susceptibility to specific opportunistic infections can also provide insight into the host immune response to common infectious disease. For example, individuals who have developed overwhelming infection following BCG infection or who have developed disseminated atypical mycobacterial infections have provided insight into host resistance to M. tuberculosis. This article describes how several of these methods have been used to identify some of the host genes involved in susceptibility to tuberculosis.

Natural resistance – associated macrophage protein More than 20 years ago, innate susceptibility to infection with M. bovis BCG was shown to be determined by a single genetic factor in inbred strains of mice [18]. Gros and colleagues [18] named this putative gene Bcg. Following a single inoculation

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with BCG-Montreal, mice carrying the resistant allele (Bcgr ) had between 100- and 1000-fold fewer splenic colony-forming units than mice carrying the susceptible gene variant (Bcgs ) [19]. The Bcgr allele was found to be dominant over the Bcgs allele [18]. The Bcg locus was mapped to murine chromosome 1 by linkage analysis [20]. Linkage analysis also showed that Bcg was the same gene that determined resistance to Leishmania, salmonella, and other mycobacterial species such as M. lepraemurium and M. intracellulare [21 – 28]. In vitro studies showed that macrophages from mice carrying the Bcgs allele had decreased ability to restrict the growth of mycobacteria, salmonella, and Leishmania compared with Bcgr macrophages [29 – 32]. As a result, Bcgs mice had impaired ability to control the initial stage of mycobacterial infection, but the genetic susceptibility does not affect the later stages of an infection, which are determined by the acquired immune response [19]. A high-resolution linkage map of murine chromosome 1 enabled the Bcg locus to be pin-pointed to a 0.3 – centi-Morgan region [33,34]. The search for the Bcg gene itself was then vigorously pursued by Gros’ group. They produced a 400 – kg-base (kb) bacteriophage and cosmid contig of the region surrounding the Bcg gene [35] and used a molecular method called exon trapping to isolate potential candidate genes for Bcg [36]. One gene was expressed solely in macrophage populations and encoded a polypeptide with characteristics suggestive of a transport protein. This gene was believed to be the Bcg gene, because it contained a nonconservative base change (glycine to aspartic acid at position 169: designated G169D) in the Bcgs strains studied [36]. The group named this gene the natural resistanceassociated macrophage protein gene (Nramp, later re-named Nramp1) [36]. Three experiments were then performed to demonstrate that Nramp1 is the putative Bcg gene. Twenty inbred strains of mice with the Bcgr phenotype and seven inbred strains of mice with the Bcgs phenotype were typed for the Nramp1 G169D variant [37]. All 20 strains with the Bcgr phenotype were found to be Nramp1G169/G169 wildtype homozygotes, and all seven Bcgs strains were Nramp1D169/D169 gene-variant homozygotes [37]. The second experiment involved the production of an Nramp1 gene-disrupted knock-out mouse [38]. This knock-out mouse, designated Nramp1
/
, was mated with the homozygous gene-variant mouse Nramp1 D169/D169 . The resulting offspring all had the compound genotype Nramp1D169/- [38]. If the Nramp1D169 allele is a nonfunctional (or null) allele, mice with the genotypes Nramp1D169/D169 ,

Nramp1D169/
, and Nramp1
/
should have identical phenotypes. Gros’ group found that mice with these three Nramp1 genotypes had indistinguishable resistance to mycobacteria, confirming that Nramp1D169 is a null allele [38]. In the third experiment the normal Nramp1G169 allele was transferred onto the background of a mouse with the homozygous Nramp1D169/D169 genotype [39]. Macrophages from this transgenic mouse expressed the Nramp1 protein, and the BCG-resistant phenotype was restored [39]. These experiments proved beyond doubt that Nramp1 is the putative Bcg gene. The Nramp1 gene consists of 15 exons spanning 11.5 kb. The gene encodes a 90- to 100-kiloDalton membrane-bound protein containing 12 hydrophobic transmembrane domains [36,40,41]. Macrophages from Nramp1D169/D169 mice do not produce detectable Nramp1 protein [42]. The human homolog of Nramp1 was originally designated NRAMP1 but has now been renamed Slc11a1 (solute carrier family 11 member 1). In this article the name NRAMP1 is retained to avoid confusion. NRAMP1 maps to chromosome 2q35, contains 15 exons spanning 12 kb of DNA, and encodes a polypeptide consisting of 550 amino acids [43,44]. There are several Nramprelated proteins in humans, mice, and many other species. In mice, Nramp2 and Nramp-rs have been mapped to chromosomes 15 and 17, respectively [45, 46]. The human homologue of Nramp2 (NRAMP2) has been cloned and mapped to chromosome 12q13 [47,48]. Evidence is now accumulating to suggest that the NRAMP1 protein is a transmembrane iron transporter. It was first suggested in 1996 that Nramp1 may be a metal cation transporter because of its structural similarity to a known manganese transporter in Saccharomyces cerevisiae [49]. A missense mutation in the Nramp2 gene (glycine to arginine at position 185; G185D) was subsequently found to be responsible for microcytic anemia in a murine model [50]. The same Nramp2G185D mutation is also responsible for microcytic anemia in the Belgrade rat [51]. Murine Nramp2 and human NRAMP2 are integral membrane glycoproteins located at the plasma membrane and at recycling endosomes [52,53]. In contrast, Nramp1 is localized to the late endosomal compartment of resting macrophages and is recruited to the phagosome on phagocytosis [54]. In the presence of excess iron, macrophages from Nramp1D169/D169 mice have the same ability to limit intracellular M. avium replication as macrophages from wild-type Nramp1G169/G169 mice [55]. This finding suggests that Nramp1 may be an iron transporter that becomes saturated at high concentration.

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genetic susceptibility to tuberculosis

Nramp2 function in epithelial

Nramp1 function in macrophages

and other cells Iron

Iron Bacteria

Transferrin receptor

Nramp2

H+ Nramp2

Iron

H+

Iron Nramp1 Iron Iron

Nramp2

H+

Nramp1

H+

Fig. 1. Nramp1 and Nramp2 function as hypothesized by Gruenheid et al [52]. The ubiquitous Nramp2 is a membrane glycoprotein that becomes internalized to endosomes with iron. Acidification of the endosome activates Nramp2 resulting in the transport of iron and protons into the cytoplasm. Nramp1 is recruited to the macrophage phagosome after bacteria and iron are ingested. Following acidification, Nramp1 transports iron and protons out of the phagosome into the macrophage cytoplasm. Presumably mycobacterial Mramp competes with Nramp1 for the available intraphagosomal iron.

M. tuberculosis possesses a member of the Nramp protein family called Mramp [56]. Mramp is a transporter of iron and other divalent metal cations [56]. Mycobacterial Mramp is probably competing with host Nramp for control of the iron concentration within the host phagosome (Fig. 1). The identification of several polymorphisms in the human NRAMP1 gene [57] has enabled linkage and association studies to be used to study the importance of the NRAMP1 gene in explaining individual variability in susceptibility to tuberculosis in human populations. Weak evidence of linkage was found between NRAMP1 polymorphisms and tuberculosis in 98 Brazilian families [58] and 173 African sibling-pairs [59]. Strong evidence of linkage between NRAMP1 and tuberculosis was found in a single large aboriginal Canadian family [60]. These results suggested that NRAMP1 is involved in susceptibility to tuberculosis in humans, but that the effect is too small for NRAMP1 to be the major gene involved. Association studies have greater power than linkage studies to evaluate the effects of a candidate gene on disease susceptibility. Association-based case-control studies are therefore more useful than linkage-based family studies for assessing the effects of NRAMP1 on the population-wide variability in risk of tuber-

culosis. In a case-control study of more than 800 persons from Gambia, West Africa, individuals that had tuberculosis had more than four times the odds of carrying the disease-associated NRAMP1 genotype than ethnically matched controls [61]. The association between NRAMP1 polymorphisms and tuberculosis has since been confirmed in further patient populations from Gambia [62], Japan [63], Korea [64, 65], and Guinea-Conakry [66]. One of the NRAMP1 polymorphisms, a (GT)n repeat in the 50-untranslated region, influences gene expression following lipopolysaccharide or interferon gamma (IFNg) stimulation [67]. Persons who possess the less actively expressed allele are more likely to develop tuberculosis. Although these studies confirm that NRAMP1 influences susceptibility to tuberculosis in human populations, it is likely that NRAMP1 accounts for only a small proportion of the total genetic component of tuberculosis susceptibility.

Interferon gamma signaling pathway In 1995, Levin et al [68] described four children from a village in Malta who had suffered from severe

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and recurrent infections with the atypical mycobacteria M. fortuitum, M. chelonae, and M. aviumintracellulare. Three of the children were related, suggesting that they had inherited the same genetic immune defect [68]. Leukocytes from the affected children had impaired IFNg production in response to mycobacterial antigens [68]. A genome-wide screen identified a single region of homozygosity on chromosome 6q in the three related children [69]. The region identified contains the gene encoding the IFNg receptor ligand binding chain (IFNgR1). Sequencing the IFNcR1 gene identified a single-base transversion at position 395 of the coding sequence, which produced a premature stop codon. The three related children were all homozygous for this single-base transversions, and the IFNgR protein was absent from the children’s leukocytes. This finding established that IFNgR1 deficiency could be a cause of increased susceptibility to mycobacterial infections. Independently of Levin’s group, Casanova and colleagues [70] identified IFNgR1 deficiency as a cause of disseminated BCG infection. They identified 121 French children who developed disseminated BCG infection following vaccination. Sixty-one of the children had an identifiable underlying immune defect such as severe combined immune deficiency, chronic granulomatous disease, Di George syndrome, or HIV infection. Casanova and colleagues attempted to find an underlying immune deficiency in the remaining 60 children. They screened a number of candidate genes and found that autosomal recessively inherited mutations in the IFNcR1 gene could lead to disseminated BCG infection following vaccination [71]. Complete IFNgR1 deficiency is caused by gene mutations that abolish receptor expression [69, 71 – 76] or binding of the receptor to IFNg [77,78]. There are two reports of dominant IFNcR1 gene mutations in patients suffering from disseminated atypical mycobacterial infections [79,80]. There is also a report of partial IFNgR1 deficiency in two siblings, one of whom developed disseminated BCG infection and the other tuberculosis [81]. This report led to speculation that the existence of other common gene variants of the IFNcR1 gene might explain the population variability in susceptibility to tuberculosis. When six common IFNcR1 gene polymorphisms were typed in a case-control study of 640 persons from Gambia, however, no association with tuberculosis was found [82]. Mutations in four other genes in the interleukin-12 (IL-12) – IFNg signaling pathway have been found to lead to disseminated mycobacterial infections. Patients have been identified who have complete or partial deficiency of the IFNgR signal transduction

chain (IFNgR2) because of IFNcR2 gene mutations [83,84]. Deficiency of signal transducer and activator of transcription-1 (STAT-1) protein can lead to decreased response to IFNg stimulation [85]. A patient was described who had a dominant mutation in the STAT1 gene causing partial STAT1 deficiency resulting in impaired immunity to atypical mycobacteria [85]. Some patients who have disseminated atypical mycobacterial infections have been found to have abnormal IFNg production in response to IL-12 stimulation but normal cellular responses to IFNg. This result can be caused by complete deficiency of the IL-12 receptor b1 chain (IL12Rb1) caused by recessive mutations in the IL12Rb1 gene [86 – 91] or by deficiency of the IL-12 p40 subunit caused by mutations in the IL12B gene [92,93]. Patients inheriting one of the gene mutations causing abnormal IL-12 – IFNg signaling suffer recurrent infections with mycobacteria that are usually nonpathogenic, such as M. bovis BCG, M. aviumintracellulare, M. kansasii, M. chelonae, and M. smegmatis [94]. The immune deficiency is relatively specific, because, although recurrent salmonella infections occur, there does not seem to be increased susceptibility to a wider range of pathogens [94]. Mendelian susceptibility to mycobacterial infections is rare. Most persons who develop tuberculosis do not have a recognized IL-12 – IFNg signaling pathway defect. Although common gene variants in the IFNcR1 gene were not found to be associated with tuberculosis [82], mutations in other IL-12 – IFNg signaling pathway genes might partly explain population variation in susceptibility to tuberculosis [95]. Lio et al [96] genotyped 45 Sicilian patients who had tuberculosis and 97 controls for a single nucleotide polymorphism in the INFc gene and found the genotype associated with high IFNg production was under-represented among the tuberculosis patients. Case-control studies of the same gene variant in tuberculosis patients from Spain [97] and South Africa [98] found results consistent with this finding, indicating it is unlikely to result from chance. The population-wide effect of the IFNc gene polymorphism on susceptibility to tuberculosis is comparable to that of NRAMP1 [99]. Therefore these gene variants can explain only a small percentage of the total genetic component of the host variability in susceptibility to tuberculosis. A provisional association has also been described between common IL-12Rb1 gene variants and tuberculosis in Japanese patients [100]. It is therefore possible that several genes in the IL-12 – IFNg signaling pathway may contribute to the population-wide variability in tuberculosis susceptibility.

genetic susceptibility to tuberculosis

Other candidate genes Several genes have now been suggested to have a role in host variability in susceptibility to tuberculosis. This section focuses on the gene loci for which there is the most convincing evidence. Mannan-binding lectin (MBL) is an important component of the innate immune system. MBL is a calcium-dependent C-type lectin that forms a bouquetlike structure similar to C1q [101]. The lectin domain of MBL can bind to repetitive carbohydrate structures on microorganisms. This action activates complement independently of the classic and alternative pathways and promotes opsonophagocytosis [102]. Deficiency of MBL has been described as the world’s most common immune deficiency [103]. It is caused by one of three nonconservative singlenucleotide polymorphisms at codons 52, 54, or 57 of the gene encoding MBL protein, which is called mbl2 [104 – 106]. These polymorphisms produce variant MBL polypeptides that are unstable and nonfunctional [104 – 106]. MBL deficiency does not have a close relationship with susceptibility to specific pathogens [107]. Rather, it seems to confer an increased risk of susceptibility to a wide range of pathogens during infancy [108,109] and possibly also during adulthood [110,111]. If MBL deficiency predisposes a person to a large number of potentially fatal diseases, there must be some selective advantage in carriage of the variant alleles to explain their high population frequency. The most plausible explanation is that heterozygote carriers of mbl2 variant alleles have some protection against mycobacterial infections [112]. This theory has been given support from case-control studies of tuberculosis [113 – 116], leprosy [112], and M. avium [117]. There is also, however, some limited contradictory evidence that MBL deficiency is a risk factor for tuberculosis [118,119]. Further work is required to confirm whether mbl2 variant alleles confer resistance against tuberculosis and other mycobacterial infections. 1,25 Dihydroxyvitamin D3 (1,25(OH)2D3) is an important immunomodulatory hormone that activates monocytes and suppresses lymphocyte proliferation, immunoglobulin production, and cytokine synthesis [120 – 122]. In vitro, 1,25(OH)2D3 enhances the ability of human monocytes to restrict the growth of M. tuberculosis [120,123,124]. Epidemiologic evidence suggests that vitamin D deficiency may be a risk factor for tuberculosis [125 – 127]. Vitamin D exerts its effects through the vitamin D receptor (VDR), which is present on monocytes and on activated T and B lymphocytes [128,129]. If vitamin D

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deficiency is a risk factor for tuberculosis, VDR gene polymorphisms could contribute to genetic variability in susceptibility to tuberculosis. VDR gene polymorphisms were analyzed in the Gambian case-control study in which NRAMP1 variants were found to be associated with tuberculosis. The VDR genotype that produces higher circulating levels of 1,25(OH)D3 [130] was significantly underrepresented among patients who had tuberculosis compared with ethnically matched controls [131]. VDR gene polymorphisms were also found to be associated with tuberculosis among Gujerati Indians in London [132] and with leprosy type in patients from India [133]. Further work is required to investigate the association between VDR gene polymorphisms, vitamin D intake, and host susceptibility to tuberculosis. The class II HLA DR2 has been found to be associated with tuberculosis and leprosy in several populations [134 – 137], but HLA-DR2 has not been associated with tuberculosis in all populations studied [138]. In Cambodia, a provisional association has been described between HLA-DQB1*0503 and tuberculosis [139]. In India, multidrug-resistant tuberculosis also has been found to be associated with HLA-DQB1*0503 as well as with HLADQB1*0502 and HLA-DRB1*14 [140]. In a further case-control study, Indian patients who had pulmonary or miliary tuberculosis were found to be more likely to possess HLA-A3 – like peptide-binding motifs [141]. The mechanisms underlying these associations are uncertain. HLA associations with tuberculosis could be explained by particular HLA types being more effective at recognizing specific mycobacterial antigens. Alternatively, the observed associations may be cause by linkage disequilibrium with other genes in the major histocompatibility complex region of chromosome 6, such as the gene for tumor necrosis factor-a. Genome-wide linkage studies are an effective way of screening for the genes that exert the greatest population-wide effect on variability in susceptibility to a multifactorial disease. A genome-wide screen on 173 sibling-pairs from Gambia and South Africa found evidence suggestive of linkage to tuberculosis for markers on chromosomes 15q11-13 and Xq26 [59]. The size of the observed linkage effect would suggest that the putative tuberculosissusceptibility genes in these regions would exert a much greater population-wide effect than that caused by NRAMP1 or IFNg signaling pathway gene variants. Ongoing studies are attempting to identify the tuberculosis-susceptibility genes in these regions [142].

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Table 1 Putative mycobacteria-susceptibility genes/loci Description of genetic variation associated with disease

Source of information suggesting the gene is involved in susceptibility to tuberculosis or other mycobacterial infections

Relevance to susceptibility to tuberculosis or other mycobacterial infections

NRAMP1

Several polymorphisms described function of these remains uncertain

Studies of inbred strains of mice with increased susceptibility to mycobacterial infections

Common gene polymorphisms are associated with susceptibility to tuberculosis

[61 – 66]

IFNcR1

Gene mutations result in severe deficiency of the protein

Maltese family with Mendelian susceptibility to mycobacterial infections and rare individuals with disseminated BCG infections

The rare condition of partial or complete deficiency leads to disseminated infections with BCG and atypical mycobacteria

[69,71 – 81]

IFNcR2

Gene mutations result in severe deficiency of the protein

Rare individuals with disseminated BCG and atypical mycobacterial infections

The rare condition of partial or complete deficiency leads to disseminated infections with BCG and atypical mycobacteria

[83,84]

STAT1

Gene mutations result in severe deficiency of the protein

Single individual with disseminated atypical mycobacterial infection

The rare condition of partial deficiency leads to disseminated infections with atypical mycobacteria

[85]

IL12Rb1

Gene mutations result in severe deficiency of the protein

Rare individuals with disseminated BCG and atypical mycobacterial infections

The rare condition of partial or complete deficiency leads to disseminated infections with BCG and atypical mycobacteria

[86 – 91]

IL12B

Gene mutations result in severe deficiency of the protein

Rare individuals with disseminated BCG and atypical mycobacterial infections

The rare condition of partial or complete deficiency leads to disseminated infections with BCG and atypical mycobacteria

[92,93]

Referencesa

bellamy

Gene or chromosome region

Gene polymorphism described, function of this remains uncertain

Rare individuals with IFNgR1 deficiency suggested IFNg is important in tuberculosis

A common gene polymorphism is associated with susceptibility to tuberculosis

[96 – 98]

Mbl2

Gene mutations result in severe deficiency of the protein

Children with recurrent infections and inability to opsonize Baker’s yeast

Carriers of MBL-variant alleles have been found to have increased resistance to tuberculosis, leprosy and M. avium

[112 – 117]

VDR

Several polymorphisms described function of these remains uncertain

Epidemiologic and in vitro data suggested vitamin D is important in immunity to tuberculosis

Common gene polymorphisms are associated with susceptibility to tuberculosis

[131 – 133]

HLA class II

Large number of different HLA types

Case-control studies performed because the HLA system is known to be a key component of the acquired immune system

HLA-DR2 associated with tuberculosis and leprosy in several populations

[134 – 137]

HLA class I

Large number of different HLA types

Case-control studies performed because the HLA system is known to be a key component of the acquired immune system

Several different HLA class I types have been found to be associated with tuberculosis

[139 – 141]

X chromosome

Minisatellite markers on chromosome Xq26

Genome-wide linkage analysis carried out on sibling-pair families with tuberculosis

Suggestive evidence of linkage to tuberculosis for Xq26 in Africans

[59]

Chromosome 15

Minisatellite markers on chromosome 15q11-13

Genome-wide linkage analysis carried out on sibling-pair families with tuberculosis

Suggestive evidence of linkage to tuberculosis for 15q11-13 in Africans

[59]

Abbreviations: BCG, bacille Calmette-Guerin; IFNgR1, interferon-g receptor ligand binding chain; MBL, mannan-binding lectin. a Studies assessing the relevance of the gene to susceptibility to tuberculosis or to other mycobacterial infections.

genetic susceptibility to tuberculosis

IFNc

241

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Summary The development of disease following infection with M. tuberculosis depends on a complex interaction between the host, the pathogen, and environmental factors. Many host genes are likely to be involved in the complex etiology of clinical tuberculosis. Substantial progress has already been made in advancing the understanding of genetic susceptibility to tuberculosis (Table 1). The host genes identified to date, however, account for only a small part of the total component of the genetic variability in individual susceptibility to tuberculosis. It is likely that there are many more tuberculosis-susceptibility genes remain to be identified, and several of these may have much greater importance than those that have been discovered to date.

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and variation in the vitamin D receptor gene. J Infect Dis 1999;179(3):722 – 4. Wilkinson RJ, Llewelyn M, Toossi Z, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis amongst Gujarati Asians in west London. Lancet 2000;355(9204):618 – 21. Roy S, Frodsham A, Saha B, et al. Association of vitamin D receptor genotype with leprosy type. J Infect Dis 1999;179(1):187 – 91. Singh SPN, Mehra NK, Dingley HB, et al. Human leukocyte antigen (HLA)-linked control of susceptibility to tuberculosis and association with HLA-DR types. J Infect Dis 1983;148(4):676 – 81. Bothamley GH, Beck JS, Schreuder GMT, et al. Association of tuberculosis and tuberculosis-specific antibody levels with HLA. J Infect Dis 1989;159(3): 549 – 55. Todd JR, West BC, McDonald JC. Human leukocyte antigen and leprosy: study in Northern Louisiana and review. Rev Infect Dis 1990;12(1):63 – 74. Brahmajothi V, Pitchappan RM, Kakkanaiah VN, et al. Association of pulmonary tuberculosis and HLA in South India. Tubercle 1991;72(2):123 – 32. Cox RA, Downs M, Neimes RE, et al. Immunogenetic analysis of human tuberculosis. J Infect Dis 1988;158(6):1302 – 8. Goldfeld AE, Delgado JC, Thim S, et al. Association of an HLA-DQ allele with clinical tuberculosis. JAMA 1998;279(3):226 – 8. Sharma SK, Turaga KK, Balamurugan A, et al. Clinical and genetic risk factors for the development of multi-drug resistant tuberculosis in non-HIV infected patients at a tertiary care center in India: a casecontrol study. Infect Genet Evol 2003;3(3):183 – 8. Balamurugan A, Sharma SK, Mehra NK. Human leukocyte antigen supertypes influence susceptibility and severity of tuberculosis. J Infect Dis 2004;189(5): 805 – 11. Campbell SJ, Sabeti P, Fielding K, et al. Variants of the CD40 ligand gene are not associated with increased susceptibility to tuberculosis in West Africa. Immunogenet 2003;55(7):502 – 7.

Clin Chest Med 26 (2005) 167 – 182

Global Epidemiology of Tuberculosis Dermot Maher, BM, BCh, DM, Mario Raviglione, MD* Stop TB Department, World Health Organization, Avenue Appia, CH1211 Geneva 27, Switzerland

In 1993, the World Health Organization (WHO) declared tuberculosis a global emergency because of the scale of the epidemic and the urgent need to improve global tuberculosis control [1,1a]. Since then, WHO has promoted the strategy for global tuberculosis control known as DOTS (a name derived originally from directly observed treatment, shortcourse) [2,3] and its adaptations (eg, as part of a strategy of expanded scope where HIV prevalence is high [4] and as DOTS-Plus in areas where the prevalence of multidrug-resistant [MDR] tuberculosis is high) [5]. This article provides an overview of the current scale of the global tuberculosis epidemic. It describes the global tuberculosis situation as measured by reported and estimated cases and deaths. The increasing threats of HIV-related tuberculosis and drug-resistant tuberculosis receive particular attention. There is a brief review of the extent of implementation of effective tuberculosis control using the DOTS strategy. The article ends with a summary of the approaches needed to accelerate progress in global tuberculosis control.

Review of the global tuberculosis epidemic As part of the description of the global tuberculosis epidemic, the size of the burden of tuberculosis indicates progress in tuberculosis control and draws attention to the scale of the problem, thereby helping to mobilize resources for tuberculosis control.

* Corresponding author. E-mail address: [email protected] (M. Raviglione).

The size of the burden of tuberculosis Tuberculosis case notifications and reported deaths Tuberculosis notification data are important and are routinely reported by WHO [6]. At the country level, a system of recording and reporting tuberculosis cases and their treatment outcomes (including death) is an intrinsic part of the DOTS strategy (Box 1). Therefore as the number of countries implementing the DOTS strategy increases, routine national tuberculosis program (NTP) data on tuberculosis cases and deaths are becoming more widely available [6]. Notification data reflect health service coverage and the efficiency of case-finding and reporting activities of NTPs. Thus, in the developing countries where tuberculosis incidence is generally high, where access to health services may be limited, and where NTP performance may be suboptimal, notification data often represent only a fraction of the true incident cases. In addition, because case definitions vary among countries (eg, when some countries’ notification data include all cases, both new and re-treatment cases), comparisons of case notification data from different countries are difficult. In industrialized countries, however, where tuberculosis incidence is generally low, where health service coverage is generally universal, and where NTPs are effective, notifications of cases often closely approximate to the true incidence of tuberculosis. In any country, under stable program conditions, case notifications may provide useful data on the trend of incidence and a means for obtaining rates by age, sex, and risk group. Despite the limitations of tuberculosis case notifications, WHO has since 1997 published worldwide data provided by its member states, most recently referring to the 4.1 million cases reported in 2002 [6].

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.02.009

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Box 1. The five elements of the directly observed treatment, short-course strategy for tuberculosis control  Sustained government commitment

to tuberculosis control  Diagnosis based on quality-assured

sputum-smear microscopy mainly among symptomatic patients presenting to health services  Standardized short-course chemotherapy for all cases of tuberculosis, under proper casemanagement conditions including direct observation of treatment  Uninterrupted supply of qualityassured drugs  A standard recording and reporting system enabling program monitoring by systematic assessment of treatment outcomes of all patients registered Data from Refs. [2,3].

Table 1 shows tuberculosis case notifications and rates by WHO region. Three regions dominate the worldwide distribution of notified cases: the SouthEast Asian Region (36% of cases), the African Region (24% of cases), and the Western Pacific Region (20% of cases). The three other regions have much smaller proportions of the cases notified worldwide: the Region of the Americas (9%), the Eastern Mediterranean Region (6%), and the European Region (5%). Fig. 1 shows tuberculosis case notification rates by country in 2002 [6]. In industrialized countries, case notifications generally approximate the true incidence of tuberculosis more closely than in developing countries. Tuberculosis case notifications steadily declined throughout most of the twentieth century in industrialized countries, beginning before the introduction of antituberculosis chemotherapy, largely because of socioeconomic improvements and possibly also because of the isolation of infectious cases in sanatoria. The effective application of chemotherapy in the latter half of the twentieth century further accelerated the decline. From the mid-1980s onwards, however, several countries saw a failure of the expected continued decline, and others saw the trend reversed, with case notifications increasing for the first time in many years. For example, in the United States, after

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30 years of previous steady decline, tuberculosis incidence increased regularly between 1985 and 1992 [7]. Factors responsible for the reversal of the previous trend included increased poverty among marginalized groups in inner city areas, immigration from countries with high tuberculosis prevalence, the impact of HIV, and, most importantly, the failure to maintain the necessary public health infrastructure under the mistaken belief that tuberculosis was a problem of the past. Many countries in Europe, including Denmark, the Netherlands, Sweden, and the United Kingdom, also reported a failure of the expected continued decline or even a steady rise in tuberculosis cases [8]. The high proportion of cases in the foreign-born (eg, 24% in France, 51% in the Netherlands, 54% in Sweden, 68% in Switzerland) indicated immigration as the main cause of this change in trend [9]. Annual case rates in foreign-born populations often exceed 50 per 100,000 and may even exceed 100 per 100,000 (eg, in the Netherlands), in contrast to annual case rates usually below 15 per 100,000 in indigenous populations [9]. In Western Europe, the impact of HIV on tuberculosis has been largely limited to certain countries (eg, Spain, Portugal) and cities (eg, Paris, Amsterdam) [10]. In most countries in Western Europe, the proportion of AIDS cases diagnosed with tuberculosis is low; two notable exceptions are Spain and Portugal [11], where the overlap between the population infected with HIV and the population infected with Mycobacterium tuberculosis is greater than in the other countries of Western Europe. Tuberculosis incidence rates in Japan are still high, at about 40 per 100,000, but

Table 1 Tuberculosis case notifications and rates by World Health Organization region in 2002

WHO region

No. of Proportion Rate cases notified of global (per 100,000 (all forms) total (%) population)

African 992,054 Americas 233,648 Eastern 188,458 Mediterranean European 373,497 Southeast Asia 1,487,985 Western Pacific 806,112 Global 4,081,754

24 9 6

148 27 37

5 36 20 —

43 94 47 66

Data from World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/HTM/TB/2004.331. Geneva (Switzerland): World Health Organization; 2004. p. 21.

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Fig. 1. Tuberculosis case notification rates by country in 2002. 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, or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement. [From World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/HTM/TB/ 2004.331. Geneva (Switzerland): World Health Organization; 2004. p. 218, fig. 4; with permission.]

are declining [12]. In other industrialized countries, including Australia, New Zealand, and Canada, rates have leveled off during the past few years below 10 per 100,000. The proportion of cases in the foreign-born is about 70% in Australia and about 50% in Canada [12]. The implication of the high proportion of cases in the foreign-born in most industrialized countries is that tuberculosis control in these settings depends on tuberculosis control globally. Tuberculosis case notification rates are still high in the countries of the former Soviet Union [6]. In many countries the previous continued decline in case notifications stopped or reversed from the early 1990s onwards. For example, annual notification rates doubled in Russia from 1990 to 2002, with an increased proportion of cases in young adults [6]. Dramatic social changes following the end of the Soviet Union engendered a combination of factors responsible for the reversal of the previous trend, probably through increased susceptibility to infection and increased breakdown to disease after infection. These factors include increased poverty and poor

living conditions (resulting in malnutrition, crowding, and stress) and in some cases civil conflicts and wars, deteriorating health services, and lack of drugs, resulting in decreased rates of cure of tuberculosis patients and continued transmission in the community. The spread of HIV in some countries, particularly the Russian Federation and Ukraine, has the potential, if unchecked, to fuel the tuberculosis epidemic further. Data on tuberculosis deaths are reported through national vital registration systems and through the routine standard NTP recording and reporting system. Few developing countries have comprehensive vital registration systems for the accurate reporting of deaths. Routine NTP data on tuberculosis deaths are becoming more widely available in developing countries [6]. NTPs report these tuberculosis-cohort deaths (the number and proportion of tuberculosis patients dying during treatment) without specifying cause, because the cause of death can rarely be determined in countries where income is low and the prevalence of tuberculosis is high [13]. Inaccurate

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routine NTP reporting of cohort deaths and incomplete NTP coverage of all incident cases in many countries limit the extent to which tuberculosis cohort deaths reflect tuberculosis mortality.

Estimated tuberculosis cases and deaths Because of the limitations of tuberculosis notifications and the difficulties in directly measuring the numbers of cases and deaths, the size of the tuberculosis disease burden must be estimated. WHO estimates of tuberculosis incidence and deaths are based on a variety of inputs, including surveys of prevalence of tuberculosis infection and disease, vital registration data, and independent assessments of quality of surveillance systems [14,15]. In 2002 there were an estimated 8.8 million new cases of tuberculosis worldwide, with an incidence rate of 141 per 100,000 population [6]. The global incidence rate of tuberculosis is growing at approximately 1.1% per year, although this overall global trend is fueled by and hides much faster increases in sub-Saharan Africa and in countries of the former Soviet Union

[6]. Table 2 summarizes tuberculosis incidence and mortality estimates in 2002 by WHO regions [6,14]. Fig. 2 shows estimated tuberculosis incidence by country for 2002 [6]. The ranking of countries by number of tuberculosis cases draws attention to the 22 countries that account for roughly 80% of the world’s tuberculosis burden (Table 3). Developing countries suffer the brunt of the tuberculosis epidemic. Overall, it is estimated that 95% of the world’s tuberculosis cases and 98% of the tuberculosis deaths occur in the developing world [12], and that tuberculosis causes more than 25% of avoidable adult deaths in the developing world [16]. The importance of the tuberculosis problem for individual countries is expressed as the annual incidence (absolute number of cases occurring yearly) and as the incidence rate (cases per 100,000 population). Fig. 3 shows estimated tuberculosis incidence rates by country in 2002 [6]. Tuberculosis incidence rates are generally much lower in industrialized countries than in developing countries. Among the 15 countries with the highest estimated tuberculosis incidence rates, 13 are in subSaharan Africa, and in most of these countries the

Table 2 Summary of tuberculosis estimates by World Health Organization region in 2002 WHO region AFRa Population (millions) New cases of TB (all forms) No. of incident cases (thousands) Incidence rate (per 100,000) Change in incidence rate 1997 – 2000 (%/y) HIV prevalence in new adult cases (%) Attributable to HIV (thousands) Attributable to HIV (% of adult cases) New SS+ cases of TB No. of incident cases (thousands) Prevalence rate of SS+ TB (per 100,000) Prevalent SS+ cases HIV+ (%) Deaths from TB No. of deaths from TB (thousands) Deaths from TB (per 100,000) Deaths from TB in HIV-positive adults (thousands) Adult AIDS deaths caused by TB (%) TB deaths attributable to HIV (%)

AMR

EMR

EUR

SEAR

WPR

Global

857

507

877

1591

1718

6222

2354 350 5.9 37.0 506.0 31.0

370 43 3.6 5.5 11.0 5.0

622 123 0.7 2.8 9.8 2.5

472 54 1.9 3.6 10.0 3.3

2890 182 2.1 3.5 56.0 2.9

2090 122 0.2 1.2 14.0 1.1

8798 141 1.1 12.0 656.0 11.0

1000 224 6.9

165 25 1.0

279 102 0.4

211 34 0.7

1294 166 0.5

939 104 0.2

3888 112 1.8

556 83.0 208.0 15.0 34.0

53 6.2 3.7 5.4 6.5

143 28.0 4.8 20.0 3.2

73 8.3 3.0 13.0 3.9

625 39.0 26.0 7.6 3.8

373 22.0 5.5 14.0 1.4

1823 29.0 251.0 13.0 13.0

672

Abbreviations: adult, 15 – 49 years old; AFR, African; AMR, Americas; EMR, Eastern Mediterranean; EUR, European; SEAR, Southeast Asia; SS+, sputum smear-positive; TB, tuberculosis; WPR, Western Pacific. a WHO African region comprises sub-Saharan Africa and Algeria. The remaining North African countries are included in the WHO Eastern Mediterranean region. Data from World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/HTM/TB/2004.331. Geneva (Switzerland): World Health Organization; 2004; and 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 – 21.

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Fig. 2. Estimated tuberculosis incidence by country in 2002. 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, or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement. [From World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/HTM/TB/ 2004.331. Geneva (Switzerland): World Health Organization; 2004; with permission.]

prevalence of HIV infection among tuberculosis patients is high [6]. In conclusion, worldwide notification data and estimates suggest a steady decline in the tuberculosis burden in many regions except in sub-Saharan Africa and the former Soviet Union. The reasons for the persisting global tuberculosis burden include (1) poverty and the widening gap between rich and poor in various populations (eg, developing countries, inner city populations in developed countries); (2) previous neglect of tuberculosis control (inadequate case detection, diagnosis, and cure); (3) changing demography (increasing world population and changing age structure); and (4) the impact of the HIV pandemic [17].

HIV-related tuberculosis Through potent immunocompromise of infected hosts, HIV has emerged as the most important risk

factor for progression of dormant M. tuberculosis infection to clinical tuberculosis disease [18]. A short overview of HIV epidemiology is useful because HIV is such an important force driving the tuberculosis epidemic in sub-Saharan Africa and has the potential to drive the tuberculosis epidemic in other regions wherever HIV transmission spreads unchecked. HIV surveillance systems in most countries with generalized epidemics rely on tracking HIV prevalence among pregnant women attending antenatal clinics. These antenatal clinic data, supplemented by data from other sources such as blood donors and sex workers, are used to obtain national estimates of HIV prevalence among men and women and to assess trends. By the end of 2003, an estimated 38 million adults and children worldwide had HIV infection or AIDS [19]. Of these, 25 million (66%) were in subSaharan Africa, and 6.5 million (17%) were in South and South-East Asia. In 2003, 4.8 million adults and children were newly infected with HIV. An estimated 2.9 million adults and children died from HIV/AIDS

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Table 3 Ranking of countries by estimated number of tuberculosis cases Number estimated All cases

Rank

Country

1 2 3 4 5 6 7 8 9 10

Smear-positive cases

Population (thousands)

No. (thousands)

Rate (per 100,000 population)

1,049,549 1,294,867 217,131 120,911 143,809 149,911 68,961 78,580 44,759 51,201

1761 1459 557 368 318 272 255 251 250 196

168 113 256 304 221 181 370 320 558 383

787 656 250 159 143 122 110 113 102 85

75 51 115 132 99 81 159 144 227 167

20 37 43 47 51 54 57 60 62 65

No. (thousands)

Rate (per 100,000 population)

Cumulative incidence (%)

India China Indonesia Nigeria Bangladesh Pakistan Ethiopia Philippines South Africa Democratic Republic of the Congo 11 Russian Federation 12 Kenya 13 Vietnam 14 United Republic of Tanzania 15 Brazil 16 Uganda 17 Zimbabwe 18 Mozambique 19 Thailand 20 Afghanistan 21 Cambodia 22 Myanmar High-burden countries

144,082 31,540 80,278 36,276

182 170 155 132

126 540 192 363

81 70 69 56

56 223 86 155

67 69 70 72

176,257 25,004 12,835 18,537 62,193 22,930 13,810 48,852 3,892,274

110 94 88 81 80 76 76 75 7005

62 377 683 436 128 333 549 154 180

49 41 35 34 35 34 33 33 3100

28 164 271 182 57 150 242 68 80

73 74 75 76 77 78 79 80 80

Global total

6,219,011

8797

141

3887

63

100

The top 22 countries account for roughly 80% of the world’s tuberculosis burden. Data from World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/HTM/TB/2004.331. Geneva (Switzerland): World Health Organization; 2004. p. 22.

during 2003. Roughly 2.2 million (76%) of these deaths occurred in sub-Saharan Africa. Sub-Saharan Africa is the region with the highest overall HIV prevalence rate in the general adult (15 – 49 years) population, 7.5% at the end of 2003. Of 20 countries in the world with an adult HIV prevalence rate in 2003 above 5%, 19 are in subSaharan Africa (the other is Haiti). In seven countries in southern Africa, adult HIV prevalence is 15% or above. Although the countries that have the highest rates of HIV infection are in Africa, certain countries in South-East Asia and Latin America are also badly affected, with an adult HIV prevalence of 1% to 5%. Although the rise in HIV prevalence seems now to be decelerating or even decreasing in parts of Eastern and Southern Africa, it is still increasing rapidly in

some other large populations, for example in the Russian Federation.

Tuberculosis cases The HIV pandemic has dramatically fuelled tuberculosis in populations where there is overlap between those infected with M. tuberculosis and those infected with HIV. Table 4 shows the number of M. tuberculosis- and HIV-coinfected adults (15 – 49 years) in WHO regions and globally by the end of 2000 [14]. Of the 11.4 million adults coinfected with M. tuberculosis and HIV worldwide by the end of 2000, 70% were in sub-Saharan Africa (Table 4) [14]. The estimated national HIV prevalence in tuberculosis patients reflects the extent of the overlap

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Fig. 3. Estimated tuberculosis incidence rates by country in 2002. 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, or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement. [From World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/HTM/TB/ 2004.331. Geneva (Switzerland): World Health Organization; 2004. p. 215, fig. 1; with permission.]

Table 4 Number and global percentage of Mycobacterium tuberculosis- and HIV-coinfected adults (15 – 49 years) in World Health Organization regions by the end of 2000

WHO region African Americas Eastern Mediterranean European Southeast Asia Western Pacific Total

No. of people coinfected with M. tuberculosis and HIV (thousands)

Proportion of global total (%)

7979 468 163 133 2269 427

70 4 1 1 20 4

11,440

100

Data from 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 – 21.

between the population infected with M. tuberculosis and the population infected with HIV in that country. Fig. 4 shows the estimated HIV prevalence in tuberculosis patients by country in 2002. The estimated HIV prevalence in tuberculosis patients is greater than 20% in nearly all of the countries of subSaharan Africa and is greater than 50% in most of the countries of the southern cone. Haiti is the only country outside sub-Saharan Africa where the estimated HIV prevalence in tuberculosis patients is greater than 20%. The largest share of the global burden of HIV-related tuberculosis falls on subSaharan Africa, where 31% of new cases of tuberculosis (all forms) and 34% of tuberculosis deaths are attributable to HIV, and where HIV is now the most important single predictor of tuberculosis incidence (Fig. 5) [14]. The increasing spread of HIV, especially in Eastern and Southern Africa, resulting in an increased population of M. tuberculosis- and HIV-coinfected

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Fig. 4. Estimated HIV prevalence in tuberculosis cases by country in 2002. 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, or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement. [From World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2004. Document WHO/ HTM/TB/2004.331. Geneva (Switzerland): World Health Organization; 2004. p. 216, fig. 2; with permission.]

Estimated TB incidence (per 100,000 population)

1000 800 600 400 200 0

0

10

20

30

40

Estimated HIV prevalence, adults 15-49 yrs (%)

Fig. 5. Estimated tuberculosis incidence in relation to estimated HIV prevalence for 42 countries in the WHO African Region. (From 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; 163:1018; with permission.)

people, has driven the incidence of tuberculosis upwards in sub-Saharan Africa [6]. From 1997 to 2002, the tuberculosis incidence rate in the WHO African region grew at approximately 4% per year, and at 6% per year in Eastern and Southern Africa, faster than on any other continent and considerably faster than the 1% per year global increase. In several African countries, including those with well-organized control programs [20,21], annual tuberculosis case notification rates have risen more than fivefold since the mid 1980s, reaching more than 400 cases per 100,000 population [6]. Because HIV infection rates are higher in women than men, more tuberculosis cases are also being reported among women, especially those aged 15 to 24 years. Although tuberculosis case notifications typically show a male gender predominance, in several African countries with high rates of HIV infection, the majority of notified tuberculosis cases are now women [6].

global epidemiology of tuberculosis

Tuberculosis deaths The aims of tuberculosis control are to reduce tuberculosis mortality, morbidity, and disease transmission while preventing the development of drug resistance [13]. Tuberculosis deaths are not related to the public health objective of cutting the cycle of disease transmission, but, as an adverse outcome for tuberculosis patients and their families, they are an important indicator of NTP performance and of progress toward reaching the global health targets agreed as part of the United Nations Millennium Development Goals (MDGs) [22]. These considerations are particularly important in countries with high HIV prevalence where the advent of the HIV epidemic has dramatically increased both the incidence of tuberculosis and tuberculosis deaths. It is useful to consider briefly tuberculosis case fatality (the proportion of tuberculosis cases that die within a specified time) in the pre-HIV era (before and after the introduction of effective antituberculosis chemotherapy) before turning to the HIV era (ie, from the 1980s onwards). Tuberculosis case fatality was high before the introduction of effective antituberculosis chemotherapy. For example, survival analysis of confirmed pulmonary tuberculosis patients diagnosed between 1925 and 1934 in a large town in Denmark showed that the probability of dying ranged between 17% and 29%, 32% and 43%, and 42% and 55% 1 year, 3 years, and 5 years after tuberculosis diagnosis, respectively [23]. In an observational study of sputum-positive tuberculosis patients diagnosed between 1928 and 1938 in the United Kingdom, 40% of patients died in the first year after they were diagnosed with tuberculosis [24]. A reduction in tuberculosis deaths usually quickly followed the introduction of antituberculosis chemotherapy. Data on tuberculosis case fatality in the prechemotherapy era in sub-Saharan Africa are lacking, but data from clinical trials of combination chemotherapy in Eastern Africa in the 1970s showed a low case fatality [25]. HIV has dramatically increased tuberculosis case fatality as measured in clinical trials and as reflected by tuberculosis cohort deaths reported by NTPs. Risk of death during and after tuberculosis treatment is higher among HIV-positive than among HIV-negative patients who have smear-positive pulmonary tuberculosis and is higher still among HIV-positive patients who have smear-negative tuberculosis (probably reflecting their greater degree of immunosuppression) [26]. In sub-Saharan Africa, up to 30% of HIV-infected tuberculosis patients die within 12 months of starting treatment [27]. Even with treatment regimens that are highly effective in HIV-

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negative pulmonary tuberculosis patients, cohort deaths for HIV-positive pulmonary tuberculosis patients in some sub-Saharan African countries are now as high as 20% for sputum smear – positive cases and 50% for sputum smear – negative cases [26]. Tuberculosis cohort deaths are linked closely to HIV prevalence, both within countries (ie, in many countries tuberculosis cohort deaths have increased as adult HIV seroprevalence has increased) and in wider areas (tuberculosis cohort deaths and national HIV seroprevalence in sub-Saharan Africa are strongly correlated) [26]. The increase in tuberculosis deaths in populations with high HIV prevalence in subSaharan Africa may change the popular perception of tuberculosis as a curable disease and threaten the reputation of NTPs. This experience may have an adverse influence on the willingness of tuberculosis suspects to come forward for diagnosis and on the ability of the NTPs to ensure that tuberculosis patients complete treatment. Measures to prevent tuberculosis deaths in countries with high HIV prevalence include [27] 1. Antiretroviral therapy (likely to have the greatest impact) 2. Tuberculosis treatment regimens of proven effectiveness 3. Preventive therapy for HIV-related diseases other than tuberculosis (eg, co-trimoxazole to prevent common bacterial infections) 4. Improved tuberculosis and HIV control services 5. Improved general health services with better diagnosis and treatment of HIV-related diseases Implementing these measures will need increased financial and human resources for the general health services and for tuberculosis and HIV programs and more effective collaboration between tuberculosis and HIV/AIDS programs [4].

Drug-resistant tuberculosis Drug resistance and eventually MDR (ie, resistance to at least isoniazid and rifampicin) are expected to occur wherever there is inadequate application of antituberculosis chemotherapy [28]. An assessment of the number and distribution of drug-resistant tuberculosis cases is important for planning tuberculosis control, because the treatment of resistant cases is more costly and more complex when second-line drugs are used, with more frequent failures and deaths. The distinction between resistance among new cases (previously known as

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primary resistance) and resistance among previously treated cases (previously known as acquired resistance) is important because of their different implications for NTPs. Three rounds of surveys coordinated by WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) between 1996 and 2002 have yielded data on antituberculosis drug resistance among new and previously treated cases. The third round of surveys included new data from 77 settings or countries collected between 1999 and 2002 and gave the following results for resistance among new and previously treated cases [29]. New cases Data on new cases were available for 75 settings. In total, 55,779 patients were surveyed. The prevalence of resistance to at least one antituberculosis drug (any resistance) ranged from 0% in some Western European countries to 57.1% in Kazakhstan (median, 10.2%). Median prevalences of resistance to specific drugs were as follows: streptomycin, 6.3%; isoniazid, 5.9%; rifampicin, 1.4%; and ethambutol,

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0.8%. Prevalence of MDR ranged from 0% in eight countries to 14.2% in Kazakhstan (51/359) and Israel (36/253) (median, 1.1%). Fig. 6 shows by participating country the prevalence of MDR-tuberculosis among new tuberculosis cases. Other high prevalences of MDR were observed in Tomsk Oblast (Russian Federation) (13.7%), Karakalpakstan (Uzbekistan) (13.2%), Estonia (12.2%), Liaoning Province (China) (10.4%), Lithuania (9.4%), Latvia (9.3%), Henan Province (China) (7.8%), and Ecuador (6.6% on preliminary data). Trends in drug resistance in new cases were determined in 46 settings (20 with two data points and 26 with at least three). Significant increases in prevalence of any resistance were found in Peru, Botswana, New Zealand, Poland, and Tomsk Oblast, (Russian Federation). Cuba, Hong Kong SAR, and Thailand reported significant decreases over time. Tomsk Oblast (Russian Federation) and Poland showed significantly increased prevalences of MDR. Decreasing trends in MDR were observed in Hong Kong SAR, Thailand, and the USA.

Fig. 6. Prevalence of MDR-tuberculosis among new tuberculosis cases, 1994 – 2002. 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, or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dashed lines represent approximate border lines for which there may not yet be full agreement. [From World Health Organization. Anti-tuberculosis drug resistance in the world. Report no. 3. The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 1999 – 2002. Document WHO/HTM/TB/2004.343. Geneva (Switzerland): World Health Organization; 2004. p. 47; with permission.]

global epidemiology of tuberculosis

Previously treated cases Data on previously treated cases were available for 66 settings. In total, 8405 patients were surveyed. The median prevalence of resistance to at least one drug (any resistance) was 18.4%, with the highest prevalence, 82.1%, in Kazakhstan (262/319). Median prevalences of resistance to specific drugs were as follows: isoniazid, 14.4%; streptomycin, 11.4%; rifampicin, 8.7%; and ethambutol, 3.5%. The median prevalence of MDR was 7.0%. Fig. 7 shows by participating country the prevalence of MDR tuberculosis among previously treated tuberculosis cases. The highest prevalences of MDR were reported in Oman (58.3%; 7/12) and Kazakhstan (56.4%; 180/ 319). Among countries of the former Soviet Union, the median prevalence of resistance to the four drugs was 30%, compared with a median of 1.3% in all other settings. Given the small number of subjects tested in some settings, prevalence of resistance among previously treated cases should be interpreted with caution. Drug-resistance trends in previously treated cases were determined in 43 settings (19 with two data

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points and 24 with at least three data points). A significant increase in the prevalence of any resistance was observed in Botswana. Cuba, Switzerland, and the United States showed significant decreases. The prevalence of MDR significantly increased in Estonia, Lithuania, and Tomsk Oblast (Russian Federation). Decreasing trends were significant in Slovakia and the United States. More representative geographic coverage of global antituberculosis drug resistance surveillance, with further data from longitudinal studies, will enable more accurate and comprehensive monitoring of global trends in the spread of MDR tuberculosis. Increases in prevalence of resistance can be caused by poor or worsening tuberculosis control, immigration of patients from areas of higher resistance, outbreaks of drug-resistant disease, and variations in surveillance methodologies. In conclusion, although drug-resistant tuberculosis is present in all settings surveyed, the prevalence of MDR is high only in certain settings. Because good tuberculosis control practices are generally associated with lower or decreasing levels of resistance, the findings of the WHO/IUATLD Global Project

Fig. 7. Prevalence of MDR-tuberculosis among previously treated tuberculosis cases, 1994 – 2002. 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, or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dashed lines represent approximate border lines for which there may not yet be full agreement. [From World Health Organization. Anti-tuberculosis drug resistance in the world. Report no. 3. The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 1999 – 2002. Document WHO/HTM/TB/2004.343. Geneva (Switzerland): World Health Organization; 2004. p. 53; with permission.]

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emphasize the vital importance of strengthening tuberculosis control worldwide, by expanding and improving the quality of implementation of the DOTS strategy, to prevent the emergence of further drug resistance. National programs need to manage MDR tuberculosis cases, regardless of prevalence, through application of the DOTS-Plus strategy [30].

Status of global tuberculosis control The scale of the tuberculosis epidemic, as described previously, and the human rights approach to tuberculosis demand effective and urgent action [31]. WHO has promoted the DOTS strategy to control tuberculosis primarily by the interruption of transmission through the rapid identification and cure of infectious cases. By 2002, the number of countries and territories implementing the DOTS strategy was 180 (of 210), with an estimated 69% of the world’s population living in administrative areas of countries where the DOTS strategy was being implemented [6]. In practice, however, the proportion of the population with access to the DOTS strategy is less than this administrative figure because of several possible barriers to access, including geographic, financial, and cultural impediments, within the administrative area. Relying on currently available methods of diagnosis and treatment, the DOTS strategy is effective, affordable, and adaptable in different settings (eg, as part of a strategy of expanded scope where HIV prevalence is high [4], as DOTS-Plus in areas where the prevalence of MDR tuberculosis is high [5], and as public-private mix [PPM] DOTS where the majority of tuberculosis suspects consult private practitioners) [32]. WHO coordinates a global tuberculosis monitoring and evaluation project in which countries report annual progress in implementation of the DOTS strategy [33]. The World Health Assembly (WHA) has set global targets for tuberculosis control through the implementation of the DOTS strategy [34]. The choice of these global targets reflected the need to achieve a significant epidemiologic impact by reaching targets that field experience had demonstrated were feasible in countries with a high incidence of tuberculosis. These targets are to detect at least 70% of all new infectious cases and to cure at least 85% of those detected by 2005 [35]. A 70% case detection rate and an 85% cure rate eventually would reduce both the prevalence of infectious tuberculosis cases and the number of infected contacts by about 40% [36] and would lead to an expected decline in annual

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tuberculosis incidence rate of 6% to 7% per year [37]. The epidemiologic impact on the global tuberculosis epidemic of sustained achievement of these targets is expressed in the MDG relevant to tuberculosis (Goal 6, Target 8), ‘‘to have halted and begun to reverse incidence by 2015’’ [22]. The epidemiologic interpretation of this goal set by politicians is to decrease tuberculosis prevalence and deaths by half by 2015. The following section summarizes the most recent assessment of progress in implementation of the DOTS strategy toward achieving the cure rate and case detection targets as set out in the 2004 WHO Report, which reports on the cases detected in 2002 and the outcomes of treatment of patients detected in 2001 [6]. Cases detected and notified Through the global tuberculosis monitoring and evaluation project coordinated by WHO, countries report annually the number and type of tuberculosis cases detected, reported, and treated under DOTS and non-DOTS programs [6]. In 2002, approximately 3 million patients who were newly diagnosed with tuberculosis, 1.4 million of whom were smearpositive, were reported in DOTS programs. A total of 13.3 million tuberculosis patients and 6.8 million smear-positive patients were treated in DOTS programs between 1995 and 2002. Regarding new cases of sputum smear – positive pulmonary tuberculosis, for the calculation of case detection rate in each country, the numerator is the number of annual cases detected and reported under the DOTS strategy, and the denominator is the estimated annual incidence of cases in that country. The numerator is derived annually from country reports of registered cases (ie, cases detected and reported under the DOTS strategy). The denominator is an estimate based on a variety of inputs, as outlined earlier. One of the challenges in improving the accuracy of measurement of the case detection rate is ensuring that all cases detected by different care providers (eg, private practitioners) and treated in line with the DOTS strategy are reported through the NTP. The 1.4 million smear-positive cases reported globally by DOTS programs in 2002 represent 37% of the estimated incidence, a little more than half of the 70% target. Treatment success The cure rate is reported by each country through cohort analysis of standard treatment outcomes of registered patients (Table 5) [13]. Because practice varies considerably among countries in documenting

global epidemiology of tuberculosis Table 5 Standard treatment outcomes in patients who have sputum smear-positive pulmonary tuberculosis Outcome

Patient characteristics

Cure

Patient who is sputum smear-negative in the last month of treatment and at least on one previous occasion Patient who has completed treatment but who does not meet the criteria to be classified as a cure or a failure Patient who is sputum smear-positive at 5 months or later during treatmentb Patient who dies for any reason during the course of treatment Patient whose treatment was interrupted for 2 consecutive months or more Patient who has been transferred to another recording and reporting unit and for whom the treatment outcome is not known

Treatment completeda Treatment failure Died Default Transfer out

a Treatment success is defined as the sum of patients cured and those who have completed treatment. b Also a patient who was initially smear-negative before starting treatment and became smear-positive after completing the initial phase of treatment. Data from World Health Organization. Treatment of tuberculosis: guidelines for national programmes. 3rd edition. Document WHO/CDS/TB/2003.313. Geneva (Switzerland): World Health Organization; 2003. p. 55.

negative sputum smears on completion of treatment, for practical purposes the treatment success rate (cure plus treatment completion) is used as a proxy for cure rate. Treatment success under DOTS for the 2001 cohort was 82% on average. As in previous years, treatment success was substantially below average in the WHO African Region (71%) and in the former Soviet Union (70%). Low treatment success in these two regions is attributable, in part, to NTPs failing to cope with the increased caseload fuelled by HIV and the problem of drug resistance, respectively. All indicators of treatment outcome were much worse in non-DOTS areas, although the true outcome of treatment is unknown for a high proportion of patients in non-DOTS areas because of the lack of use of standardized definitions and lack of systematic reporting when programs are weak. Fatal outcomes were most common in Africa (7.2%), where a higher percentage of cases is HIV-positive, and in Europe (5.9%), where a higher percentage of cases occurs among the elderly. Treatment interruption (default) was most frequent in the WHO African Region (10.3%), Eastern Mediterranean Region (7.2%), and South-East Asia Region (6.7%). Transfer without follow-up was also especially high in Africa (6.6%).

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Treatment failure was conspicuously high in the European region (8.1%), mainly because of high failure rates in the former Soviet Union, most likely resulting from the high prevalence of MDR tuberculosis. In summary, the global case detection rate for patients who had sputum smear – positive tuberculosis was 37% in 2002, half of the 70% target, whereas treatment success under the DOTS strategy for the 2001 cohort was 82% on average, close to the 85% target. Although this progress toward the WHA 2005 targets of 70% case detection and 85% treatment success represents a considerable gain, making an impact on the global tuberculosis burden as expressed in the 2015 MDGs will require speeding progress toward meeting and then sustaining the 2005 WHA targets.

Approaches needed to accelerate progress in global tuberculosis control A global alliance named the Stop TB Partnership provides the means for international partners and the governments of countries with high tuberculosis incidence to intensify efforts to accelerate progress in global tuberculosis control [38]. The development of new tools for tuberculosis control (eg, a more effective vaccine [39], better diagnostic tests [40], and improved preventive [41] and therapeutic [42] approaches) holds out the prospect of rapid progress in tuberculosis control in the future. In the meantime, the challenge in maximizing the impact of currently available methods of diagnosis and treatment lies in implementing the DOTS strategy and its adaptations as effectively and as widely as possible. In coordination with a global network of partners known as the DOTS Expansion Working Group (DEWG), WHO is committed to implementing the DOTS strategy as effectively and as widely as possible [43]. WHO published the Global DOTS Expansion Plan (GDEP) in 2001 [44]. The GDEP is based on two pillars: the preparation in each country of a mid-term (at least 5-year) DOTS expansion plan, and the establishment of a mechanism for interagency coordination ensuring that all relevant partners contribute to the implementation of the national plan. Effective development and implementation of the national plan depends on the engagement of the full range of health providers under NTP stewardship: government services, whether Ministry of Health (nationally and locally administrated services) or not (eg, social security schemes, prisons, military), and nongovernment services (eg, NGOs, community

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groups [45], private practitioners [32], and employers [46]). In practice, all health providers should refer patients to public health facilities delivering tuberculosis care under the DOTS strategy or deliver tuberculosis care consistent with the DOTS strategy in collaboration with the NTP. The failure of providers to deliver care consistent with the DOTS strategy compromises the achievements of NTPs and the chances of successful tuberculosis control. Governments should consider reform of legislative and regulatory frameworks to engage the full range of health providers and will need to invest in developing human resource capacity (for strengthened NTP stewardship and service delivery) [47]. Three of the main adaptations of the DOTS strategy are as part of a strategy of expanded scope where HIV prevalence is high [4], as DOTS-Plus in areas where the prevalence of MDR tuberculosis is high [5], and as PPM DOTS where the majority of tuberculosis suspects consult private practitioners [32]. Until recently, the efforts to control tuberculosis among HIV-infected people have focused mainly on identifying and curing infectious tuberculosis cases among patients presenting to general health services. This approach targets the final step in the sequence of events by which HIV fuels tuberculosis, namely the transmission of M. tuberculosis infection by infectious tuberculosis cases. The strategy of expanded scope for tuberculosis control in populations with high HIV prevalence comprises interventions against tuberculosis (the DOTS strategy and tuberculosis preventive treatment) and interventions against HIV (and therefore indirectly against tuberculosis) (eg, condoms, treatment of sexually transmitted infections, safe injecting drug use, and highly active antiretroviral treatment) [4]. DOTS-Plus is the programmatic approach to the diagnosis and treatment of MDR tuberculosis within the context of DOTS programs. Management involves the diagnosis of MDR tuberculosis through quality-assured culture and drug-susceptibility testing and treatment with second-line drugs under proper case management conditions. In response to the seriousness of MDR tuberculosis as a global public health problem, the DOTS-Plus Working Group was established in 1999 to promote improved management of MDR tuberculosis in resource-limited countries. The Working Group aims to assess the feasibility and cost effectiveness of the use of secondline antituberculosis drugs in DOTS-Plus projects. Since 2000, the Working Group’s Green Light Committee has successfully negotiated with the pharmaceutical industry to obtain substantial concessionary prices for second-line drugs that otherwise

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were unaffordable in poor settings. As a result, prices of the most expensive regimens have dropped by 95%. PPM-DOTS is the means of engaging private practitioners in collaboration with the NTP in the delivery of tuberculosis care consistent with the DOTS strategy. This approach is necessary where large numbers of tuberculosis suspects seek care from private practitioners rather than from public health services. Recent studies indicate the success of the PPM approach in achieving high rates of case detection, notification, and cure [48]. A global subgroup of the DEWG concerned with PPM-DOTS is promoting the scaling up of this approach, accompanied by the necessary strengthening of the NTP stewardship and leadership roles. Lessons learned from PPM-DOTS are applicable to engaging the contributions of a wide range of public providers who in many countries are providing tuberculosis care independently of the NTP (eg, in prisons and social security programs). Accelerating progress in global tuberculosis control depends on developments in the specific field of tuberculosis control and on strengthening health systems. In 2003, the Stop TB Partnership convened a second ad hoc committee on the tuberculosis epidemic to seek solutions to the health system constraints to more rapid progress in global tuberculosis control and to make recommendations to overcome those constraints [49,50]. The committee made recommendations under seven headings (many of which cut across the different aspects of tuberculosis control) [49]: 1. Consolidate, sustain, and advance achievements 2. Enhance political commitment (and its translation into policy and action) 3. Address the health workforce crisis 4. Strengthen health care systems, particularly primary care delivery 5. Accelerate the response to the TB/HIV emergency 6. Mobilize communities and the corporate sector 7. Invest in research and development to shape the future. Implementation of these recommendations depends on coordination between the health care sector and other sectors to deliver effective tuberculosis control covering all populations in need.

Summary In 2002 there were an estimated 8.8 million new cases of tuberculosis worldwide, and the global

global epidemiology of tuberculosis

incidence rate was growing at approximately 1.1% per year. The scale of the global tuberculosis epidemic indicates the huge challenge for tuberculosis control, which is complicated by the impact of HIV and drug-resistant tuberculosis. Global efforts to implement the DOTS strategy widely and effectively have resulted in a global case detection rate of 37% in 2002, more than half of the target of 70%, and treatment success for the 2001 cohort of 82%, on average, close to the target of 85%. Faster progress toward global targets depends on future development of new drugs, diagnostics, and vaccines, meanwhile overcoming health system constraints to intensified implementation of the DOTS strategy and to its adaptations in areas with high prevalence of HIV or MDR tuberculosis or where not all care providers deliver the internationally recommended standard of care.

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[9] Rieder HL, Zellwegger J-P, Raviglione MC, et al. Tuberculosis control in Europe and international migration. Report of European Task Force. Eur Respir J 1994;7:1545 – 53. [10] Raviglione MC, Sudre P, Esteves K, et al. Tuberculosis – Western Europe, 1974 – 1991. MMWR Morb Mortal Wkly Rep 1993;42:628 – 31. [11] European Centre for the Epidemiological Monitoring of AIDS. HIV/AIDS surveillance in Europe: quarterly report no. 46, 30 June 1995. [12] Raviglione MC, Snider D, Kochi A. Global epidemiology of tuberculosis: morbidity and mortality of a worldwide epidemic. JAMA 1995;273(3):220 – 6. [13] World Health Organization. Treatment of tuberculosis: guidelines for national programmes. 3rd edition. Document WHO/CDS/TB/2003.313. Geneva (Switzerland)7 World Health Organization; 2003. [14] 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 – 21. [15] Dye C, Scheele S, Dolin P, et al for the WHO Global Surveillance and Monitoring Project. Global burden of tuberculosis: estimated incidence, prevalence and mortality by country. JAMA 1999;282:677 – 86. [16] Murray CJL, Styblo K, Rouillon A. Tuberculosis in developing countries: burden, intervention and cost. Bull Int Union Tuberc Lung Dis 1990;65:6 – 24. [17] Raviglione MC, Luelmo F. Update on the global epidemiology of tuberculosis. Curr Issues Public Health 1996;2:192 – 7. [18] Rieder HL, Cauthen GM, Comstock GW, et al. Epidemiology of tuberculosis in the United States. Epidemiol Rev 1989;11:79 – 98. [19] Joint United Nations Programme on HIV/AIDS (UNAIDS). 2004 report on the global AIDS epidemic. Geneva (Switzerland)7 UNAIDS; 2004. [20] Kenyon TA, Mwasekaga MJ, Huebner R, et al. Low levels of drug-resistance amidst rapidly increasing tuberculosis and human immunodeficiency virus coepidemics in Botswana. Int J Tuberc Lung Dis 1999;3: 4 – 11. [21] Harries AD, Nyong’Onya Mbewe L, Salaniponi FM, et al. Tuberculosis programme changes and treatment outcomes in patients with smear-positive pulmonary tuberculosis in Blantyre, Malawi. Lancet 1996;347: 807 – 9. [22] United Nations Statistics Division. Millennium Indicators Database. Available at: http://unstats.un.org/ unsd/mi/mi_goals.asp. Accessed August 4, 2004. [23] Buhl K, Nyboe J. Epidemiological basis of tuberculosis eradication. Changes in the mortality of Danish tuberculosis patients since 1925. Bull World Health Organ 1967;37:907 – 25. [24] Thompson BC. Survival rates in pulmonary tuberculosis. BMJ 1943;2:721. [25] Second East African/British Medical Research Council Kenya Tuberculosis Survey follow-up 1979. Tuberculosis in Kenya: follow-up of the second (1974)

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maher national sampling survey and a comparison with the follow-up data from the first (1964) national sampling survey. An East African and British Medical Research Council co-operative investigation. Tubercle 1979;60: 125 – 49. Mukadi YD, Maher D, Harries AD. Tuberculosis case fatality rates in high HIV prevalence populations in sub-Saharan Africa. AIDS 2001;15:143 – 52. 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 – 23. Crofton J, Chaulet P, Maher D. Guidelines for the management of drug-resistant tuberculosis. Document WHO/TB/1996.210. Geneva (Switzerland)7 World Health Organization; 1997. World Health Organization. Anti-tuberculosis drug resistance in the world. Report number 3. The WHO/ IUATLD Global project on anti-tuberculosis drug resistance surveillance 1999 – 2002. Geneva (Switzerland)7 World Health Organization; 2004. World Health Organization. Guidelines for establishing DOTS-plus pilot projects for the management of multidrug-resistant tuberculosis. Document WHO/ CDS/TB/2000.278. Geneva (Switzerland)7 World Health Organization; 2000. World Health Organization. Guidelines for social mobilization: a human rights approach to tuberculosis. Document WHO/CDS/TB/2001.9. Geneva (Switzerland)7 World Health Organization; 2001. Murthy KJR, Frieden TR, Yazdani A, et al. Publicprivate partnership in tuberculosis control: experience in Hyderabad, India. Int J Tuberc Lung Dis 2001;5: 354 – 9. Raviglione MC, Dye C, Schmidt S, et al. Assessment of worldwide tuberculosis control. Lancet 1997;350: 624 – 9. World Health Organization. Forty-fourth World Health Assembly. Resolutions and decisions. Resolution WHA 44.8. WHA44/1991/REC/1. Geneva (Switzerland)7 World Health Organization; 1991. World Health Organization. Fifty-third World Health Assembly. Resolutions and decisions. Resolution WHA 53.1. Geneva (Switzerland)7 World Health Organization; 2000. Styblo K., Bumgarner J.R. Tuberculosis can be controlled with existing technologies: evidence. Tuberculosis Surveillance Research Unit Progress Report (The Hague, The Netherlands) 1991;2:60 – 72. Dye C, Williams BG. Criteria for the control of drugresistant tuberculosis. Proc Natl Acad Sci USA 2000; 97:8180 – 5.

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raviglione [38] Stop TB Partnership. Annual Report 2001. Document WHO/CDS/STB/2002.17. Geneva (Switzerland)7 World Health Organization; 2001. [39] Young DB. Current tuberculosis vaccine development. Clin Infect Dis 2000;30(Suppl 3):S254 – 6. [40] Perkins MD. New diagnostics for tuberculosis. Int J Tuberc Lung Dis 2000;4(12):S182 – 8. [41] Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR Morb Mortal Wkly Rep 1998;47(No. RR-20):1 – 58. [42] Barry III CE, Slayden RA, Sampson AE, et al. Use of genomics and combinatorial chemistry in the development of new antimycobacterial drugs. Biochem Pharmacol 2000;59:221 – 31. [43] World Health Organization. Report on DOTS Expansion Working Group meeting, Montreal, Canada, in October 2002 [internal document]. Geneva (Switzerland)7 World Health Organization; 2002. [44] World Health Organization. Global DOTS expansion plan—progress in TB control in high-burden countries 2001, 1 year after the Amsterdam Ministerial Conference. Document WHO/CDS/TB/2003.312. Geneva (Switzerland)7 World Health Organization; 2001. [45] World Health Organization. Community contribution to TB care: practice and policy. Document WHO/CDS/ TB/2003.312. Geneva (Switzerland)7 World Health Organization; 2003. [46] World Health Organization and International Labour Office. Guidelines for workplace TB control activities. Document WHO/CDS/TB/2003.323. Geneva (Switzerland)7 World Health Organization; 2003. [47] World Health Organization. Good practice in legislation and regulations for TB control: an indicator of political will. Document WHO/CDS/TB/2001.290. Geneva (Switzerland)7 World Health Organization; 2001. [48] Lo¨nnroth K, Uplekar M, Arora VK, et al. Publicprivate mix for improved TB control—what makes it work? Bull World Health Organ 2004;82(8):580 – 6. [49] World Health Organization. Report on the meeting of the second ad hoc committee on the TB epidemic. Montreux, Switzerland, 18 – 19, 2003. Recommendations to Stop TB partners. Document WHO/HTM/ STB/2004.28. Geneva (Switzerland)7 World Health Organization; 2004. [50] World Health Organization. Background document prepared for the meeting of the second ad hoc committee on the TB epidemic. Document WHO/HTM/ STB/2004.27. Geneva (Switzerland)7 World Health Organization; 2004.

Clin Chest Med 26 (2005) 283 – 294

Issues in the Management of HIV-Related Tuberculosis William J. Burman, MDa,b,* a

Division of Infectious Diseases, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA b Infectious Diseases Clinic, Denver Department of Public Health, 605 Bannock Street, Denver, CO 80204, USA

The HIV pandemic poses major problems for the tuberculosis control program and for the individual clinician treating HIV-related tuberculosis. HIVrelated immunosuppression is the single most potent risk factor for progression from latent tuberculosis infection to active tuberculosis [1]. As a result, HIV is major factor driving the global resurgence of tuberculosis; incidence rates of tuberculosis in countries with high prevalence of HIV infection have increased up to fivefold [2]. Severe immunosuppression also results in marked changes in the clinical, radiographic, and histopathologic presentation of tuberculosis [3]. This article does not review all aspects of HIV-related tuberculosis; the dramatic effects of HIV on the epidemiology, presentation, and diagnosis of tuberculosis have been reviewed elsewhere recently [2,3]. This article focuses on the ways in which HIV infection and the associated immunodeficiency affect the management of active tuberculosis. Controversial topics are highlighted, followed by a suggested strategy for management while awaiting additional data. There are a number of unique challenges in the treatment of HIV-related tuberculosis, but the basic principles of tuberculosis treatment developed over the past 50 years are applicable to HIV-related tuberculosis. Drug-susceptible tuberculosis is treated most efficiently with regimens including an initial intensive phase—2 months of isoniazid, rifampin or

This work was supported in part by the Tuberculosis Trials Consortium, Centers for Disease Control and Prevention, Atlanta, GA. The author has had research contracts with Roche Laboratories, Merck, Glaxo-Smith Kline, and Bristol Myers-Squibb. * 605 Bannock Street, Denver, CO 80204. E-mail address: [email protected]

rifabutin, pyrazinamide, and ethambutol—followed by a 4-month continuation phase of isoniazid and rifampin or rifabutin. A remaining challenge for the treatment of active tuberculosis among HIV-infected and uninfected persons is finding efficient and programmatically relevant ways to identify patients at increased risk for relapse and targeting them for prolonged or otherwise altered treatment [4,5]. Adherence to multidrug therapy is difficult, particularly when it must be sustained for at least 6 months. Directly observed therapy, the most effective way of promoting adherence to tuberculosis treatment [6], is all the more important in the management of HIVrelated tuberculosis [7]. There is little margin for error in the treatment of tuberculosis in a severely immunocompromised person.

Issues in the treatment of HIV-related tuberculosis When these basic principles are observed, the outcomes of treatment of active tuberculosis among persons with HIV infection are similar to those of HIV-negative patients with tuberculosis [5,8 – 14]. The rates of treatment failure (a positive culture at or beyond 4 months of treatment) and relapse are low. Whether the rates of treatment failure and relapse are somewhat higher among patients with HIV coinfection and how the rate of treatment failure should affect the management of HIV-related tuberculosis remain subjects of controversy. One key difference is that the risk of death during tuberculosis treatment is much higher among persons with HIV-related tuberculosis. For example, in a study from South Africa the risk of death during tuberculosis treatment was 13.7% among HIV-infected miners versus 0.5%

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.02.002

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among HIV-negative miners [11]. After the first few weeks of tuberculosis treatment, nearly all the excess mortality is related to complications of AIDS other than tuberculosis [10,15]. Combination antiretroviral therapy markedly reduces new opportunistic infections and death among persons with AIDS [16] and seems to do so among persons with HIV-related tuberculosis [17 – 19]. The use of combination antiretroviral therapy in persons being treated with tuberculosis poses a number of challenges for the patient and clinician, however. To summarize, the controversies in the management of HIV-related tuberculosis can be grouped into issues about tuberculosis treatment itself and issues posed by the use of combination antiretroviral therapy. The issues related to tuberculosis treatment are the uncertainties about the optimal duration of therapy and the adequacy of intermittent dosing of tuberculosis therapy (dosing less frequently than daily). Use of combination antiretroviral therapy during tuberculosis treatment is complicated by (1) the adherence challenge of polypharmacy, (2) overlapping side-effect profiles of the antituberculosis drugs, antiretroviral therapy, and drugs used to prevent or treat other opportunistic infections, (3) drug – drug interactions, and (4) the occurrence of immune reconstitution inflammatory syndromes following the institution of effective antiretroviral therapy. These four issues lead to uncertainties about the optimal timing of antiretroviral therapy during tuberculosis treatment.

Issues related to tuberculosis treatment Optimal duration of therapy Early in the HIV pandemic, it became clear that some opportunistic infections required prolonged, if not lifelong, treatment in persons with advanced HIV disease. For example, cryptococcal meningitis can be cured in a high percentage of immunocompetent patients with 6 weeks of treatment [20], but

patients with advanced HIV disease (in the era before combination antiretroviral therapy) required lifelong therapy to prevent recurrent meningitis [21]. Such experience suggested that treatment of tuberculosis might also have to be longer among patients with advanced HIV disease. Despite the importance of the question, there have been no definitive studies of the optimal duration of treatment for HIV-related tuberculosis. A large study performed in Zaire randomly assigned patients to 6 or 12 months of therapy and found a higher rate of recurrent tuberculosis among patients treated with 6 months of therapy [22]. High losses to follow-up and the inability to distinguish infection with a new strain of Mycobacterium tuberculosis (re-infection) from relapse of the initial infecting strain make this study difficult to interpret. In an area with high tuberculosis case rates, re-infection can be a common cause of recurrent tuberculosis, particularly among HIV-infected persons [23,24]. A trial in the United States comparing 6 versus 9 months of therapy showed low relapse rates in both arms (<3%), but the study was inadequately powered to be definitive [25]. The results of published observational cohort studies of standard 6-month regimens (isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for 4 months) given by directly observed therapy to patients with and without HIV coinfection are shown in Table 1. Most studies have shown similar rates of treatment failure and relapse among HIV-positive and HIVnegative persons [5,13,14,23]. The one study that found a much higher risk of recurrent tuberculosis among HIV-infected patients was done in a setting of high rates of tuberculosis (gold mines in South Africa) [23]. Notably, this study used DNA fingerprinting of initial and relapse isolates and showed that the higher rate of recurrent tuberculosis in HIVinfected patients resulted entirely from an increased risk of re-infection. These cohort studies do not offer a definitive answer to the question whether patients with HIV-

Table 1 Comparison of the outcomes of tuberculosis treatment by HIV serostatus in cohort studies using directly-observed, 6-month, rifampin-containing regimens HIV positive

HIV negative

Study [reference]

Treatment failure (%)

Relapse (%)

Treatment failure (%)

Relapse (%)

Haiti (n = 427) [14] South Africa (n = 403) [13] Baltimore (n = 407) [5] South Africa (n = 385) [23]

2.0 3.0 0 5.3

5.4 5.0 8.3 21.5

3.0 7.0 0 8.1

2.8 5.0 1.7 13.0

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related tuberculosis might require longer or more intensive therapy. The size of the cohorts evaluated (approximately 400) is not been adequate to evaluate the optimal duration of therapy, particularly in key subgroups, such as patients with advanced HIV disease (CD4 cell count <200/mm3). Cohort studies and clinical trials suggest that patients with advanced HIV disease are at increased risk of treatment failure and relapse [5,18,25,26]. These studies also demonstrated that a surprisingly high percentage of M. tuberculosis isolates from cases of treatment failure and relapse among patients with advanced HIV disease and tuberculosis had acquired rifamycin resistance. Before making provisional recommendations about duration of treatment for HIV-related tuberculosis, it is important to review the factors associated with acquired rifamycin resistance. One of the key advantages of directly observed therapy is that it prevents selective drug taking (ie, a patient takes some, but not all, medications in a multidrug regimen). Among HIV-negative patients, this feature of directly observed therapy almost completely prevents acquired drug resistance among the 2% to 5% of patients whose tuberculosis relapses [27 – 29]. There is, however, increasing evidence that

directly observed therapy does not prevent acquired drug resistance among patients with advanced HIV disease. The clearest demonstration of the association between HIV infection and acquired drug resistance despite use of directly observed therapy comes from a clinical trial evaluating once-weekly rifapentine and isoniazid during the last 4 months of therapy for drug-susceptible tuberculosis. Among 30 HIVinfected patients treated with this regimen, 5 relapsed, 4 of whom had isolates with acquired drug resistance [30], whereas there were no cases of acquired drug resistance among the 502 HIV-negative patients treated with the same regimen [4]. In all cases, the drug class to which resistance was acquired was the rifamycin class, and all patients with acquired rifamycin resistance had advanced HIV disease (CD4 cell counts <200/mm3) [30]. Subsequent clinical trials and observational cohort studies have confirmed and extended the findings from the trial evaluating once-weekly rifapentine-based therapy (Table 2). Acquired rifamycin resistance is clearly associated with HIV coinfection. Among patients with HIV-related tuberculosis, the consistent associations are advanced HIV disease (CD4 counts in cases of acquired rifamycin resistance have

Table 2 Summary of studies of acquired rifamycin resistance in studies using directly observed therapy treatment of HIV-related tuberculosis Dosing frequency Study [reference]

Rifamycin used

Intensive phase (first 8 weeks)

Continuation phase

TBTC 23 [18]

Rifabutin

Twice weekly

TBTC 22 [30]

Rifapentine

Daily for 2 weeks, then daily or intermittent Daily for 2 weeks, then daily or intermittent Daily for 2 weeks, then daily or intermittent Daily for 2 weeks, then thrice weekly 5 d/wk for 3 weeks, then twice weekly 5 d/wk for 3 weeks, then twice weekly 5 d/wk

Rifampin

CPCRA/ ACTG [25] Baltimore [5]

Rifampin Rifampin Rifabutin

South Africa [23]

Rifampin

Rate of treatment failure/ relapse 5.3% (9/169)

Once weekly

16.7% (5/30)

Twice weekly

10.0% (3/30)

Twice weekly

3.0% (3/101)

Twice weekly

11.1% (9/81)

Twice weekly

0% (0/27)

5 d/wk

Rate of acquired rifamycin resistance 4.7% (8/169)

13.3% (4/30)

CD4 cell counts of cases of acquired rifamycin resistance 4 – 55

8, 8, 23, 188

0%

Not applicable

2.0% (2/101)a

17, 26

3.7% (3/81)

Median, 61

0%

Not applicable

0% (0/151)b

Not applicable

Abbreviations: CPCRA/ACTG, Community Programs for Clinical Research on AIDS/AIDS Clinical Trials Group; TBTC, Tuberculosis Trials Consortium. a One patient was thought to have re-infection with rifamycin-monoresistant tuberculosis, based on DNA fingerprinting of the relapse isolate. b Cases of treatment failure and relapse occurred in the cohort study, but none had acquired rifamycin resistance.

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all been <200 cells/mm3 and usually <50 cells/mm3) and the use of highly intermittent therapy (once or twice weekly) [5,18,23,25,26,30]. The timing of the use of intermittent therapy may also be important. The greatest risk of acquired rifamycin resistance seems to be among patients who received twiceweekly therapy during the intensive phase (the first 2 months of treatment) [18,26]. Despite the appeal of the hypothesis that acquired rifamycin resistance might be caused by the pharmacokinetic mismatch between isoniazid (half-life of 1 – 3 hours) and the long-acting rifamycins, rifabutin and rifapentine (half-lives of 33 and 15 hours, respectively) [31,32], it is clear that acquired rifamycin resistance can occur with twice-weekly rifampin-based therapy (half-life of rifamycin, 2 – 3 hours) [5,25,26]. Recommendations for tuberculosis treatment The current recommendation for the duration of therapy for HIV-related tuberculosis is to use standard 6-month regimens with extension of therapy to 9 months for patients with a delayed clinical or microbiologic response (continued symptoms or sputum culture-positive at 2 months) [33]. Given the lack of data that patients with HIV-related tuberculosis require longer durations of treatment, the recommendation for 6-month regimens is reasonable and has the programmatic advantage of having consistent recommendations for HIV-infected and HIV-uninfected patients. If a subgroup is to be targeted for longer therapy, it seems that criteria derived from studies of HIV-uninfected patients, such as 2-month sputum culture positivity and pulmonary cavitation [4], may not be appropriate for HIV-related tuberculosis. The key patient-related risk factor for treatment failure and relapse among patients with HIV coinfection is advanced immunodeficiency, not 2-month sputum culture results [5,18,25,30]. A high percentage of cases of treatment failure and relapse among patients with HIV-related tuberculosis are cases of acquired rifamycin resistance (Table 2). Therefore, the question whether to treat HIV-related tuberculosis differently from tuberculosis among immunocompetent patients devolves to considerations of how to avoid acquired rifamycin resistance. There have been no randomized trials of different dosing frequencies of tuberculosis therapy among HIV-coinfected patients, so all recommendations for avoiding or reducing acquired rifamycin resistance are derived from comparisons of cohort studies and expert opinion. Given the consistency of the association between acquired rifamycin resistance and highly intermittent dosing, it is prudent to follow

the current recommendation that patients with advanced HIV disease (CD4 cell count <200/mm3) should receive daily (5 days/week) tuberculosis treatment, at least for the first 2 months of treatment. The choice of rifamycin (rifampin or rifabutin) should be based on the drug interactions with the planned antiretroviral treatment regimen. The available data suggest that rifampin and rifabutin are equally effective for tuberculosis treatment [34 – 36]. Whether caused by re-infection or relapse, the high rates of recurrent tuberculosis among HIVcoinfected patients in areas of the world with endemic tuberculosis are worrisome. Possible interventions to decrease the risk of recurrent tuberculosis in these areas include changes in tuberculosis treatment and the use of combination antiretroviral therapy. A longer duration of multidrug tuberculosis treatment [22] or the use of isoniazid after completion of the standard 6-month multidrug regimen may decrease the risk of recurrent tuberculosis [37,38], probably by decreasing rates of re-infection. Use of potent antiretroviral therapy seems to decrease the rate of initial progression to active tuberculosis [39,40] and may decrease the risk of recurrent tuberculosis after completion of tuberculosis treatment. Randomized trials are underway to evaluate some of these possibilities. If available, the most promising intervention seems to be use of potent antiretroviral therapy, because it should protect against the many complications of AIDS, not only prevent recurrent tuberculosis.

Challenges of using antiretroviral therapy during tuberculosis therapy Combination antiretroviral therapy has revolutionized the treatment of advanced HIV disease, dramatically decreasing rates of death and opportunistic infection. Because patients with HIV-related tuberculosis have relatively high rates of HIV disease progression (death or a new opportunistic illness) during the 6-month period of tuberculosis treatment [15,25], antiretroviral therapy should markedly improve the outcome of patients with HIV-related tuberculosis. Despite its promise, the use of antiretroviral therapy during tuberculosis treatment is complex for both patient and clinician. Therefore, it is important that use of antiretroviral therapy be targeted to those at substantial risk of HIV disease progression during tuberculosis treatment. As is true for all persons with HIV infection, the short-term (6 – 12 month) risk of HIV disease progression among persons with HIV-related tuberculosis is related closely to the de-

management of hiv-related tuberculosis

gree of immunodeficiency at the time of tuberculosis diagnosis (as measured by CD4 cell count or CD4 cell percentage) [10,11,25]. Therefore, it is reasonable to use the standards for initiating combination antiretroviral therapy among patients with concomitant tuberculosis that are used for all patients with HIV disease: start combination antiretroviral therapy for those with clinical or laboratory evidence of advanced HIV disease (presence of an opportunistic illnesses or a CD4 cell count <200/mm3) [41]. Given the lack of clear evidence that, in general, patients having CD4 cell counts higher than 200 to 250/mm3 benefit from earlier initiation of antiretroviral therapy, it seems prudent to avoid the substantial difficulties of using antiretroviral therapy during tuberculosis treatment for the subset with concomitant active tuberculosis. Those with higher CD4 cell counts can be re-evaluated during and after tuberculosis treatment. It is also noteworthy that tuberculosis treatment itself results in substantial increases in CD4 cell counts among coinfected patients [42]. Adherence to treatment of HIV and tuberculosis Combination antiretroviral treatment regimens have become simpler during the past few years. Most regimens can now be given twice daily with food, and a number of potent combinations can be given once daily without regard to food. Even so, adherence to any long-term therapy is a tremendous challenge, and adherence remains one of the most important determinants of survival among patients with advanced AIDS [43]. Therefore, it is important to consider how the adherence challenge of concomitant multidrug therapy for tuberculosis treatment might affect the success of antiretroviral therapy. Adherence to antiretroviral therapy seems to decrease with increasing number of pills per day and increasing overall complexity of the regimen (number of different medications, number of different doses per day) [44]. The patient’s readiness to start combination antiretroviral therapy is also a determinant of outcomes [45]. There are no published studies of how tuberculosis treatment affects adherence to antiretroviral therapy, but studies of adherence in the general HIV-infected population suggest that, to promote readiness to begin antiretroviral treatment, it is important to take the time to deal with the psychologic reactions to the diagnoses of tuberculosis and advanced HIV disease, as well as the social issues—poverty, homelessness, substance abuse— that are commonly present among patients with HIV-related tuberculosis. Programs focusing on the

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importance of adherence and behavioral techniques to promote adherence are associated with better response to antiretroviral therapy [46]. Finally, it may be possible to use the team that provides directly observed treatment for tuberculosis to promote adherence to antiretroviral therapy [47]. This cooperation is one of many benefits that can come from close collaboration between HIV and tuberculosis care providers. Overlapping adverse event profiles Adverse clinical events are common among patients with HIV-related tuberculosis [18,48], and it may be difficult to ascribe a specific cause to many adverse events (Table 3). The severe immunosuppression of advanced HIV disease may lead to additional opportunistic illnesses or direct complications of HIV itself (eg, HIV-related thrombocytopenia). Although tuberculosis treatment is generally well tolerated, there are a host of common bothersome side effects (eg, nausea from pyrazinamide) and occasional serious side effects (eg, hepatitis from isoniazid or pyrazinamide). Antiretroviral drugs have many of the same side effects as drugs used to treat tuberculosis or other opportunistic infections (eg, efavirenz, pyrazinamide, and cotrimoxacole all commonly cause skin rash). Finally, the immune reconstitution following successful antiretroviral therapy may cause clinical events that may mimic drug side effects (eg, rising hepatic transaminases in a patient with chronic viral hepatitis). Even an experienced clinician may have great difficulty determining the cause of a specific clinical event, such as skin rash in a patients with HIV-related tuberculosis who has recently started multidrug tuberculosis treatment, cotrimoxazole, and efavirenzbased antiretroviral therapy. Laboratory testing is seldom helpful in these situations; the temporal sequence of events is often the best clinical tool for ascribing a cause to the many clinical events in patients with HIV-related tuberculosis. Therefore, the implication of overlapping adverse event profiles is that, as much as possible, the clinician should initiate one intervention at a time, allowing time to gauge the success and tolerability of that intervention. The attempt to start tuberculosis treatment, opportunistic infection prophylaxis, and antiretroviral therapy in a short period may result in adverse events that lead to the discontinuation of all drug therapy while awaiting resolution or stabilization of the adverse event. The first-line tuberculosis drugs should not be discontinued permanently without clear evidence that they are causing a serious side effect. Despite the fre-

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Table 3 The challenge of attributing adverse events to a specific cause among patients with HIV-related tuberculosis Possible causes

Adverse event

Antituberculosis drugs

HIV disease

Medications other than antiretroviral drugs

Skin rash

Pyrazinamide, rifampin, rifabutin, isoniazid

Folliculitis, severe asteatosis

Cotrimoxazole

Nausea, vomiting

Pyrazinamide, rifampin, rifabutin, isoniazid

Other opportunistic infections

Cotrimoxazole

Hepatitis

Pyrazinamide, rifampin, rifabutin, isoniazid

Leukopenia, anemia, thrombocytopenia

Rifabutin, rifampin

Cotrimoxazole

HIV-related bone marrow dysplasia

quency of adverse events, experienced clinicians can complete tuberculosis treatment with the first-line drugs in a high percentage of cases [18,49]. Drug – drug interactions Clinically significant interactions are common between drugs for tuberculosis and HIV treatment [50]. Absorption interactions have been described, such as the marked decrease in fluoroquinolone exposure if given with the buffered formulation of didanosine [51], but these interactions are uncommon and are easily managed by spacing the ingestion of these two medications several hours apart. The more common and problematic interactions between drugs used to treat tuberculosis and HIV disease occur in the process of hepatic and gut-wall metabolism. The rifamycins increase the synthesis of a number of hepatic enzyme systems involved in drug metabolism. Particularly important in drug interactions with the antiretroviral drugs is the effect of the rifamycins on the cytochrome P450 3A (CYP3A) enzyme system. Rifampin administration results in marked decreases in the concentrations of antiretroviral drugs predominantly metabolized by CYP3A. The magnitude of this interaction is such that rifampin cannot be used with the HIV-1 protease inhibitors other than relatively high-dose ritonavir (400 – 600 mg twice daily) [50]. Rifabutin also increases the expression of CYP3A, but the effect is much less marked, so rifabutin can be given with the protease inhibitors (other than unboosted saquinavir). Both rifamycins

Cotrimoxazole, valganciclovir

Antiretroviral drugs Nevirapine, delavirdine, efavirenz, abacavir Zidovudine, ritonavir, amprenavir, indinavir Nevirapine, HIV-1 protease inhibitors Zidovudine

Immune reconstitution inflammatory syndrome

Immune reconstitution intraabdominal adenitis or pancreatitis Immune reconstitution in patients with chronic viral hepatitis

can be given with the non-nucleoside reversetranscriptase inhibitor efavirenz and probably with nevirapine, as well. Antiretroviral drugs can also affect the concentrations of the rifamycins, particularly rifabutin. Concentrations of rifabutin and its metabolites are markedly increased by the protease inhibitors [52], and this increased concentration can lead to increased rifabutin toxicity [53]. Conversely, concentrations of rifabutin are substantially decreased by efavirenz [54]. Therefore, the clinician caring for the patient with HIV-related tuberculosis must be aware of both sides of the possible interactions between HIV and tuberculosis drugs: the effect of the rifamycins on antiretroviral drugs and the effect of antiretroviral drugs on rifabutin. Recommendations for dosing of the rifamycins and antiretroviral therapy are provided in Tables 4 and 5 [55]. Because this field is rapidly changing, the clinician should use a regularly updated source of information on the interactions between tuberculosis drugs and antiretroviral drugs, such as the website sponsored by the Centers for Disease Control and Prevention (http://www.cdc.gov/nchstp/tb/TB_HIV_ Drugs/TOC.htm). Other ways to avoid major drug – drug interactions (Box 1) include ongoing communication between HIV and tuberculosis care providers and awareness of the need to readjust doses of drugs that have been altered because of an interaction when the use of an interacting drug has been stopped (eg, decreasing the dose of methadone back to baseline when rifampin is discontinued).

management of hiv-related tuberculosis

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Table 4 Recommendations for coadministering protease inhibitors and non-nucleoside reverse transcriptase inhibitors with rifabutin – United States, 2003 Drug

Antiretroviral dose change

Rifabutin dose change

Comments

Non-nucleoside reverse-transcriptase inhibitors Efavirenz None

Nevirapine Delavirdine Single protease inhibitors Amprenavir

" to 450 – 600 mg/d or Rifabutin AUC # by 38%; effect of efavirenz + 600 mg 2 – 3 /wk protease inhibitor(s) on rifabutin concentration has not been studied None 300 mg/d or 3 /wk Rifabutin and nevirapine AUC not significantly changed Rifabutin and delavirdine should not be Delavirdine AUC # by 80%; used together rifabutin AUC " by 100%

# to 150 mg/d or 300 mg 3 /wk fos-Amprenavir None # to 150 mg/d or 300 mg 3 /wk Atazanavir None # to 150 mg every other day or 3 /wk Indinavir " to 1000 every # to 150 mg/d or mg q 8 h 300 mg 3 /wk Nelfinavir None # to 150 mg/d or 300 mg 3 /wk Saquinavir Rifabutin and saquinavir should not be used together Dual-protease inhibitor combinations Lopinavir/ritonavir (Kaletra) None # to 150 mg every other day or 3 /wk None # to 150 mg every Ritonavir (any dose) other day or 3 /wk with saquinavir, indinavir, amprenavir, fos-amprenavir, or atazanavir None

Rifabutin AUC " by 193%; no change in amprenavir concentration

Rifabutin AUC " by 250% Rifabutin AUC " by 204%; indinavir AUC # by 32% Rifabutin AUC " by 207%; insignificant change in nelfinavir concentration Saquinavir AUC # by 43%

Rifabutin AUC " by 303%; 25-O-des-acetyl rifabutin AUC " by 47.5 fold

Abbreviation: AUC, area under the curve.

Immune reconstitution inflammatory events The improvement in immune function following antiretroviral therapy clearly has tremendous benefits. Restoration of immunity, however, can also cause markedly increased inflammation in tuberculosis lesions and result in a significant worsening of clinical symptoms and signs [56]. The clinical spectrum of these immune reconstitution inflammatory events ranges from fevers and mild increased adenopathy [57] to life-threatening complications such as the expansion of intracranial tuberculomas [58]. The occurrence of severe immune reconstitution inflammatory events needs to be considered in decisions about use of antiretroviral therapy in patients being treated for tuberculosis. Common clinical manifestations of immune reconstitution inflammatory events include fever, adenopathy, increased pulmonary infiltrates, and serositis (pleural or pericardial effusions, ascites)

[57,59,60]. Less common manifestations include worsening meningitis, enlargement of central nervous system tuberculomas, soft tissue and bone abscesses, and diffuse skin lesions [60]. These manifestations are often at sites of previously evident tuberculosis but can also occur at sites that were not previously known to be involved. The diagnosis of an immune reconstitution inflammatory event may be difficult in that its clinical manifestation may be similar to those of other infections, drug side effects, or failure of tuberculosis treatment. There is much to be learned about immune reconstitution inflammatory events following antiretroviral therapy, but early studies have shown a number of consistent features to this syndrome. The time of onset is often within days of starting antiretroviral therapy, earlier than one might expect significant restoration of immune function. The median time from starting antiretroviral therapy to the onset of the immune reconstitution inflammatory

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Table 5 Recommendations for coadministering protease inhibitors and non-nucleoside reverse transcriptase inhibitors with rifampin – United States, 2003 Drug

Antiretroviral dose change

Single protease inhibitors Ritonavir None

Rifampin dose change None (600 mg/d)

Amprenavir

Rifampin and amprenavir should not be used together

fos-Amprenavir Atazanavir

Rifampin and fos-amprenavir should not be used together Rifampin and atazanavir should not be used together

Indinavir Rifampin and indinavir should not be used together Nelfinavir Rifampin and nelfinavir should not be used together Saquinavir Rifampin and saquinavir should not be used together Dual protease-inhibitor combinations Saquinavir/ritonavira Saquinavir 400 mg + None (600 mg/d) ritonavir 400 mg twice daily Boosted lopinavir/ Lopinavir/ritonavir (Kaletra) 3 capsules + None (600 mg/d) ritonavir (Kaletra) 300 mg ritonavir twice daily Lopinavir/ritonavir Rifampin and unboosted lopinavir/ritonavir (Kaletra) should not (Kaletra) be used together Non-nucleoside reverse transcriptase inhibitors Efavirenz None or " to 800 mg/d None (600 mg/d)

Nevirapine

Consider " to 300 mg twice dailyb

Delavirdine

Rifampin and delavirdine should not be used together

None (600 mg/d)

Comments Use with caution. Ritonavir AUC # by 35%; no change in rifampin concentration. Monitor for antiretroviral activity of ritonavir Amprenavir AUC # by 82%, Cmin # by 92% See amprenavir Interaction studies not performed, but marked decrease in atazanavir concentrations predicted Indinavir AUC # by 89% Nelfinavir AUC # 82% Saquinavir AUC # by 84% Limited clinical experience Limited clinical experience Lopinavir AUC # by 75% and Cmin # by 99% Efavirenz AUC # by 22%; no change in rifampin concentration Nevirapine AUC # 37% – 58% and Cmin # 68% with 200 mg 2 /d dose Delavirdine AUC # by 95%

Abbreviation: AUC, area under the curve. a In a recent drug interaction study among healthy volunteers, there was a high and unacceptable rate of hepatoxicity during treatment with saquinavir, ritonavir, and rifampin. The FDA and Roche Laboratories advise that this combination not be used. b No safety data available; limited data on antiretroviral efficacy.

event in a large series of patients with HIV-related tuberculosis was 11 days [61], with some events beginning within 2 days [57]. On the other hand, other patients can have the onset of an immune reconstitution event months after starting antiretroviral therapy [62]. The most consistent risk factor for immune reconstitution inflammatory events seems to be severity of immunosuppression; patients with very low CD4 cell counts, and hence those in greatest need of effective antiretroviral therapy, seem to be at highest risk of an immune reconstitution inflammatory event [57,58,63,64]. The potency of the antiretroviral regimen seems to be related to the risk of an immune reconstitution inflammatory event; such events were infrequently reported in the era of single-

drug therapy but are common in the era of potent combination antiretroviral therapy (being reported in 11% to 35% of patients starting potent antiretroviral therapy) [18,57,61,63]. Finally, the timing of antiretroviral therapy may also be important; earlier initiation of antiretroviral therapy may increase the risk and severity of immune reconstitution inflammatory event [61,64]. Summary of issues involved in the use of combination antiretroviral therapy The use of antiretroviral therapy during tuberculosis treatment seems to reduce markedly the risk of death and opportunistic infections among patients

management of hiv-related tuberculosis

Box 1. Principles for anticipating and managing drug – drug interactions in the treatment of HIV-related tuberculosis 1. Frequent communication between the tuberculosis control program and the HIV primary care provider is necessary. 2. Avoid the use of delavirdine, ketoconazole, and itraconazole when using rifabutin. 3. Rifampin probably causes more clinically significant interactions than any other drug. Have a regularly updated reference for drug interactions and look for possible as well as documented interactions every time rifamycin-containing tuberculosis treatment is started. 4. When using a fluoroquinolone, avoid the use of the buffered tablet formulations of didanosine. Antacids, iron, zinc, or vitamins containing these substances should not be given within 2 hours of the dose of directly observed tuberculosis treatment. 5. If a drug dose is increased to compensate for the effect of a rifamycin, it must be decreased when the rifamycin is discontinued.

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with advanced HIV disease [17 – 19]. For example, the rate of death within the 12 months of tuberculosis diagnosis among patients in a recent study in which most patients received combination antiretroviral therapy was 5%, compared with 20% among patients with similar baseline characteristics in a study conducted before the availability of potent antiretroviral therapy [18,25]. Other studies have shown comparable early outcomes of antiretroviral therapy among patients who did and did not have concomitant tuberculosis [19]. The optimal timing of antiretroviral therapy during tuberculosis treatment remains controversial. Some experts [48] recommend that antiretroviral therapy be started within 2 weeks of the initiation of tuberculosis treatment for patients with severe immunosuppression (CD4 cell count <100 cells/mm3). Others recommend that antiretroviral therapy be delayed until after 2 months of tuberculosis treatment [65]. The issues are complex, and a randomized trial is needed to clarify how the timing of antiretroviral therapy affects the competing risks of HIV disease progression versus those of drug side effects or a severe immune reconstitution event. For now, decisions about the timing of antiretroviral therapy should be individualized using the considerations outlined in Table 6 [33]: adherence demands and the patient’s readiness for antiretroviral therapy, overlapping adverse event profiles, severe immune reconstitution events, and the risk of HIV disease progression. The author’s practice is to wait until the first 2 months of tuberculosis treatment have been completed. At this point, tuberculosis treatment can

Table 6 Possible advantages and disadvantages of early versus delayed initiation of antiretroviral therapy during tuberculosis treatment

Adherence demands Ability to determine the cause of adverse events

Drug – drug interactions Severe immune reconstitution inflammatory events HIV disease progression (new opportunistic infection or death) Abbreviation: TB, tuberculosis.

Early antiretroviral therapy (before 8 weeks of tuberculosis treatment)

Delayed antiretroviral therapy (after 8 weeks of tuberculosis treatment)

Problematic with use of four-drug therapy for TB and multidrug therapy for HIV Complex because of the large number of medications started in a short time period and overlapping side effect profiles Problematic Risk may be increased

Less problematic because fewer drugs necessary for TB treatment Simpler because the number of drugs for TB treatment is less and there has been more time to evaluate response to tuberculosis treatment Problematic Risk may be decreased

Risk may be decreased

Risk may be increased

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usually be simplified (to a rifamycin plus isoniazid), the patient has had sufficient time to prepare for antiretroviral therapy, and the risk of a severe immune reconstitution inflammatory event may be lower.

Summary of recommendations HIV-related tuberculosis in patients with relatively high CD4 cell counts (>200/mm3) can be managed much like tuberculosis in HIV-negative patients. Standard 6-month regimens given as directly observed therapy are effective. The risk of acquired rifamycin resistance seems to be low, so intermittent therapy can be used. The risk of HIV disease progression during tuberculosis treatment is low, so the author recommends observation of antiretroviral therapy. HIV disease should be appropriately monitored using CD4 cell count and HIV-RNA level, and treatment of tuberculosis alone will probably result in an increase in immune function, as judged by CD4 cell count [42,66]. Patients with lower CD4 cell counts do well with standard 6-month regimens, but the risk of acquired rifamycin resistance becomes significant. Therefore, patients should be treated with daily tuberculosis treatment, at least for the first 2 months of therapy. Patients with baseline CD4 cell counts lower than 200/mm3 seem to benefit from antiretroviral therapy during tuberculosis treatment, but the initiation of antiretroviral therapy should be approached methodically and not considered an emergency. Even in the presence of advanced HIV disease (CD4 cell count <50/mm3), the clinician should do one intervention at a time. The first priority is the initiation of fourdrug tuberculosis treatment and the assessment of its tolerability and its success in decreasing the clinical manifestations of tuberculosis. Prevention of pneumocystosis is often the next priority, because these patients have advanced immunodeficiency. Many patients are diagnosed with tuberculosis and advanced HIV disease at the same time, and it is important to take the time to help them adjust to these two life-changing diagnoses. Successful antiretroviral therapy requires a high level of adherence (>95%), and it is critical to allow sufficient time to manage psychosocial issues and help the patient prepare for long-term adherence. Immune reconstitution inflammatory events are common, and patients should be counseled about the frequency and management of such an event. After these critical initial steps have been completed, it is appropriate to start combination antiretroviral therapy.

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Clin Chest Med 26 (2005) 217 – 231

Molecular Epidemiology: A Tool for Understanding Control of Tuberculosis Transmission Charles L. Daley, MD Division of Mycobacterial and Respiratory Infections, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA

One of the primary goals of tuberculosis control programs is to interrupt the transmission of Mycobacterium tuberculosis. The most effective way to accomplish this goal is to identify and treat individuals who have active tuberculosis. Even in effective tuberculosis control programs, however, M. tuberculosis continues to be transmitted to others, largely because most transmission occurs before diagnosis and initiation of therapy. The ability to track specific strains of M. tuberculosis as they spread through a community would greatly increase the understanding of the transmission and pathogenesis of tuberculosis, but, until recently, the only means of distinguishing different strains of M. tuberculosis were drugresistance patterns and mycobacterial phage typing, both of which have significant limitations. Fortunately, several molecular genotyping techniques available now allow differentiation of isolates of M. tuberculosis for tracking strains in the community. Epidemiologic investigations that incorporate genotyping of M. tuberculosis have provided important information about the spread of tubercle bacilli by identifying factors related to transmission and rapid progression to disease. This article reviews how these genotyping tools have increased the understanding of the transmission and pathogenesis of M. tuberculosis.

E-mail address: [email protected]

Genotyping methods and methodologic considerations Several nucleic acid – based genotyping methods have been developed that allow different strains of M. tuberculosis to be distinguished. The most widely used method of genotyping, referred to as restriction fragment-length polymorphism (RFLP) analysis, uses restriction endonucleases to cleave the mycobacterial DNA at the sites of specific repetitive sequences, producing DNA restriction fragments of different lengths that can be separated by gel electrophoresis (Fig. 1) [1]. Only the genomic DNA restriction fragments that are complementary to and hybridize with specific probes are visible, resulting in an easily readable band pattern. Most laboratories use a standardized protocol for RFLP genotyping of the M. tuberculosis complex that takes advantage of a specific, well-characterized, repetitive element, insertion sequence 6110 (IS6110) [1]. Despite its widespread use, there are several disadvantages with IS6110-based RFLP genotyping. First, it can be done only on cultures of M. tuberculosis. Second, it is a slow, labor-intensive, and technically demanding technique. Finally, it has relatively poor discriminatory power for isolates that have six or fewer copies of IS6110 and should be supplemented with other methods such as polymorphic guanine-cytosine – rich genotyping or spoligotyping [2]. Spoligotyping is a polymerase chain reaction (PCR)-based method that interrogates a direct repeat sequence comprising a repetitive 36 – base-pair element separated by short, unique, nonrepetitive se-

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.02.005

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Chromosomal DNA

M. tuberculosis 1

2

1

2

Extract DNA

Digest DNA

IS6110 site

1

Digested DNA

Separate by gel electrophoresis

2

1

3 2

Hybridization performed with labeled IS6110

4

Fig. 1. IS6110-based restriction fragment length polymorphisms analysis. Depicted are two strains of Mycobacterium tuberculosis, labeled 1 and 2. The location and number of the insertion sequence IS6110 is noted by the small black rectangles. Step 1: Chromosomal DNA is extracted. Step 2: Extracted DNA is cleaved with a restriction endonuclease (Pvu-II). (In reality, thousands of fragments are created.) Step 3: After digestion, the DNA fragments are separated according to molecular weight by gel electrophoresis. (In reality, this process results in thousands of bands that are nearly confluent on the gel.) Step 4: Hybridization with probe for IS6110 results in a gel with bands containing only the IS6110 element. The two strains can be seen to differ in the number of bands (ie, the number of IS6110 copies in the genome) and the location of the bands.

quences [3]. By using one set of primers, all the unique, nonrepetitive sequences, or spacers, between the direct repeats can be amplified simultaneously. Individual strains are differentiated by the number and position of the spacers that are missing from the complete spacer set. Spoligotyping has at least two advantages over IS6110-based genotyping: (1) smaller amounts of DNA are needed so the procedure can be performed on clinical samples or on strains of M. tuberculosis shortly after inoculation into liquid culture, and (2) the spoligotyping results can be expressed in a digital format [4]. Spoligotyping can be used as either a secondary genotyping method or as a primary genotyping method followed by another genotyping method that has greater discriminatory power [5,6]. A promising PCR-based method is a highresolution genotyping technique that characterizes the number and size of the variable number tandem repeats (VNTR) in each of 12 independent mycobacterial interspersed repetitive units (MIRUs) [7,8]. MIRU-VNTR profiling is appropriate for strains regardless of their IS6110 RFLP copy number, can be automated for large-scale genotyping, and permits rapid comparison of results from independent laboratories using a 12-digit classification system [9,10].

The Centers for Disease Control and Prevention (CDC) will use this methodology, along with spoligotyping, for all initial isolates of M. tuberculosis in the United States as part of a national genotyping program. More studies are needed, however, to understand better the role of MIRU typing in the molecular epidemiology of tuberculosis. In a recent study from Quebec, Canada, 302 clinical isolates were evaluated with three different genotyping methods: IS6110-based genotyping noted that 27% of the isolates were clustered, MIRU noted clustering in 61%, and spoligotyping noted clustering in 77% [11]. When all three methods were used, only 14% were clustered, closer to the percentage that would have been expected in the population. This study provided some insight into the evolution of genotypes in endemic areas and the potential for false clustering when the wrong genotyping methodologies are used. The genotyping method used depends on several factors including technical capacity and the speed with which results are needed. The genotyping methods vary in the reproducibility of the tests and in their ability to differentiate individual strains of M. tuberculosis. An interlaboratory comparative study compared several genotyping techniques [12]. Of the seven PCR-based assays, only mixed linker

molecular epidemiology Table 1 Reproducibility and differentiating capabilities of common genotyping methods Method

Reproducibility (%)

No. of different genotypes (%)

IS6110 RFLP IS6110 mixed linker PCR PGRS RFLP Spoligotyping Variable number tandem repeats

100 100

84 81

100 94 97

70 61 56

Study analyzed 90 strains of Mycobacterium tuberculosis and 10 nontuberculous strains. Abbreviations: IS6110, insertion sequence 6110; PCR, polymerase chain reaction; PGRS, polymorphic guanine–cytosinerich sequence; RFLP, restriction fragment length polymorphisms. Data from Kremer K, van Soolingen D, Frothingham R, et al. Comparison of methods based on different molecular epidemiological markers for typing of Mycobacterium tuberculosis complex strains: interlaboratory study of discriminatory power and reproducibility. J Clin Microbiol 1999;37:2607 – 18.

PCR and VNTR typing were highly reproducible (Table 1). Only mixed linker PCR had discriminatory power similar to IS6110-based RFLP analysis. Other studies [10] showed VNTR-MIRU typing to be slightly more discriminatory than spoligotyping. The combination of MIRU-VNTR, IS6110 RFLP, and spoligotyping has demonstrated the highest specificity [9]. Regardless of the genotyping method used, interpretation of the results is based on the assumption that epidemiologically related strains will have the same genotype pattern and epidemiologically unrelated strains will have different patterns. Clustering has often been equated with recent or ongoing transmission, and the factors associated with clustering have been sought as a means to identify and target subpopulations that have substantial ongoing transmission [13]. In contrast, patients whose isolates of M. tuberculosis have genotype patterns that do not match any other isolates in the community are considered to be unique and likely represent disease caused by reactivation of a latent tuberculosis infection (LTBI). Thus, genotyping allows tuberculosis resulting from recent or ongoing infection to be distinguished from reactivation of LTBI and makes it possible to estimate the proportion of ongoing tuberculosis transmission in a community. There is not always an epidemiologic link between patients whose isolates have identical genotype patterns. Some studies have demonstrated that clus-

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tered cases often have no discernible contact or other epidemiologic links among themselves, even in relatively stable populations [14,15], whereas other studies have shown that most patients do have epidemiologic links [16]. The amount of transmission represented by genotypic clustering depends on the sampling strategy and the duration of the study [17,18]. Undersampling can bias the estimates of the proportion of tuberculosis cases that were likely caused by recent or ongoing transmission, and it can bias the estimates of the risk factors associated with clustering. Two population-based cohort studies in San Francisco, California [19], and the Netherlands [20] reported that the percentage of clustered strains was high during the first 2 years and declined thereafter. Thus, clustering based on less than 2 years of sampling will probably underestimate the amount of ongoing transmission. Despite its limitations, genotyping has provided investigators and tuberculosis control programs new tools in which to uncover the transmission of M. tuberculosis in our communities.

Lessons learned regarding the transmission and pathogenesis of tuberculosis Molecular genotyping has revolutionized the ability to track strains of M. tuberculosis as they spread through a community. Studies using genotyping techniques in combination with standard epidemiologic investigations have provided insights into the transmission and pathogenesis of M. tuberculosis and in the process have provided important lessons for tuberculosis control. Infectiousness of patients Several studies that have assessed tuberculin skin test reactivity among contacts to cases of pulmonary tuberculosis have documented the variation in infectivity among source cases based on the bacteriologic status of the source, the extent of disease, and the frequency of cough [21]. These studies have documented that patients who have more extensive pulmonary tuberculosis, as evidenced by cavitary changes on the chest radiograph or the identification of acid-fast bacilli on sputum smear examination, are more likely to transmit M. tuberculosis to contacts. Molecular epidemiology studies have confirmed the variation in infectivity that exists among patients who have tuberculosis and highlighted the infectivity of patients who have smear-positive pulmonary tuberculosis. For example, a single patient who had smear-positive pulmonary tuberculosis was directly

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or indirectly responsible for 6% of the tuberculosis cases in San Francisco during a 2-year period [22]. In another report, investigators showed that a single homeless tuberculosis patient who had highly infectious pulmonary tuberculosis and was a regular patron of a neighborhood bar probably infected 42% (41/97) of the contacts who were regular customers and employees of the bar and caused disease in 14 (34%) of them. All 12 patients whose isolates of M. tuberculosis were available had identical IS6110 RFLP band patterns [23]. Most infection-control policies and recommendations prioritize smear-positive pulmonary tuberculosis over smear-negative cases, leading to the false assumption that smear-negative cases are not infectious. Several studies have demonstrated that patients who have sputum smears that are negative for acidfast bacilli but culture-positive for M. tuberculosis can transmit infection to others in the community. Behr and colleagues [24] reported that patients who have smear-negative culture-positive pulmonary tuberculosis were probably responsible for 17% of cases in San Francisco. In a recent study from Vancouver, British Columbia [25], investigators reported that a similar proportion of cases resulted from smearnegative source cases. In this study, the authors also included extrapulmonary cases of tuberculosis and noted that the proportion of episodes of transmission from smear-negative clustered cases increased to at least 25%, suggesting that some transmission was occurring from extrapulmonary cases. Pulmonary tuberculosis apparently was not ruled out in all of these cases, so transmission probably occurred through more traditional means of spread. As an illustration of this point, investigators in San Francisco reported that patients who have pleural tuberculosis combined with negative sputum cultures were unlikely to generate secondary cases of tuberculosis [26]. Although the frequency of cough has been shown to correlate with skin test reactivity among contacts [21], genotyping has provided conflicting results regarding the importance of symptoms in transmission. Investigators in Harris County, Texas, reported no association between the duration of symptoms and the size of molecularly defined clusters [27]. Cronin and colleagues [28], however, reported that the time from symptom onset to diagnosis was twice as long for patients who were considered to be transmitters than for nontransmitters. These latter data support the belief that reducing diagnostic delays can prevent transmission of M. tubeculosis. The studies reviewed here have demonstrated that the potential for transmitting tuberculosis should be considered in all pulmonary tuberculosis patients/

suspects, particularly in settings and environments that facilitate transmission, such as shelters, hospices, health care facilities, prisons, and other institutional or crowded settings [13]. It would be prudent to treat smear-negative pulmonary tuberculosis suspects for some period before removing them from isolation or sending them into high-risk settings such as jails and prisons. In addition, pulmonary tuberculosis should be carefully ruled out in patients who have extrapulmonary diseases. Although international guidelines for the diagnosis and treatment of tuberculosis prioritize the detection and treatment of infectious sputum smear – positive patients [29], timely diagnosis and treatment of sputum smear – negative cases should be considered when resources permit. Exogenous reinfection and mixed infection Molecular genotyping can determine whether a patient who has a recurrent episode of tuberculosis has a relapse with the previous strain of M. tuberculosis or exogenous reinfection with a new strain. Although exogenous reinfection was reported before the availability of genotyping [30], these techniques have made the identification of reinfection easier and more specific. Exogenous reinfection has been reported in both immunocompromised and immunocompetent persons (Table 2) [31 – 34]. In Cape Town, South Africa, where there is a high incidence of tuberculosis and ongoing transmission, 16 of 698 patients had more than one episode of tuberculosis. Twelve of these 16 (75%) had pairs of isolates of M. tuberculosis with different genotyping patterns [34]. Exogenous reinfection is relatively uncommon in areas that have a low incidence of tuberculosis, such as Switzerland [35] and the Netherlands [36], compared with high- to moderate-incidence regions [37 – 45]. In Houston, Texas, among 100 patients who have recurrent tuberculosis and have completed therapy for a first episode of tuberculosis, exogenous reinfection was reported to cause a surprisingly high 24% to 31% of the second episodes of tuberculosis [46]. Some cases of suspected exogenous reinfection might be caused by initial infections that include more than one strain. These instances would represent repeated infections over time that lead to a mixed infection with different strains of M. tuberculosis. Multiple infections were demonstrated in a patient in San Francisco [47], in two patients who worked in a medical-waste processing plant in Washington State [48], and among prisoners in Spain [49]. In South Africa, a country that has a reportedly high frequency of exogenous reinfection [34], mixed infections are

Table 2 The frequency of exogenous reinfection in selected studies by tuberculosis incidence rates

First author/date [reference]

Study location

Bandera, 2001 [45] Caminero, 2001 [38] Kru¨u¨ner, 2002 [41] Garcia de Viedma, 2002 [40]

Lombardy, Italy Gran Canaria Island, Spain Tartu, Estonia Madrid, Spain

El Sahly, 2004 [46] Houston, TX High incidence areas (100 per 100,000 population) Godfrey-Faussett, 1994 [42] Nairobi, Kenya Das, 1995 [37] Madras, India Van Rie, 1999 [34] Sonnenberg, 2000 [43] Lourenco, 2000 [39] Fitzpatrick, 2002 [44]

Cape Town, South Africa Gauteng Province, South Africa Rio de Janeiro, Brazil Kampala, Uganda

AIDS patients with positive culture for >1 y or increasing drug resistance HIV cohort with two isolates HIV-infected Spanish inmates who remained culture positive for >4 mo TB recurrences separated >6 mo Two positive cultures >12 mo apart Treatment failures HIV+ and HIV cases with two isolates >100 d apart TB recurrences TB recurrences Recurrence or isolated positive culture Recurrent TB HIV+ and HIV gold miners HIV+ patients with multiple isolates HIV+ and HIV TB recurrences

No. of patients who have genotyping

No. of patients who have reinfection (%)

17 31 20 11

6 11 20 9

0 4 2 2

(0) (36) (10) (22)

NA 23 35 172

32 18 11 43

5 (16) 8 (44) 11 (100) 14 (33)

100

100

NA 30 32 48 57 12 NA

4 30 32 16 48 12 40

. . . (24 – 31)

molecular epidemiology

Low and moderate incidence areas (<100 per 100,000 population) Small, 1993 [31] King’s County Hospital, New York City, NY Sudre, 1999 [32] Switzerland Chaves, 1999 [49] Madrid, Spain

Study population

No. of patients who have two episodes TB or two isolates

1 (20) 11 (37) 29 (91) 12 (75) 2 (4) 3 (25) 9 (23)

Abbreviations: HIV , sero-negative for HIV; HIV+, seropositive for HIV; NA, not available; TB, tuberculosis.

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common. Warren and colleagues [50], using a PCRbased method of strain classification reported that 19% of all patients were simultaneously infected with Beijing and non-Beijing strains and that 57% of patients infected with Beijing strains also were infected with a non-Beijing strain. These observations indicate that simultaneous infections with multiple strains of M. tuberculosis occur and may be responsible for conflicting drug-susceptibility results [51] or episodes of recurrence caused by exogenous reinfection.

few years, this strain was documented to have disseminated widely in the community. Because poor tuberculosis control and underlying HIV infection are common in many areas, drug resistance may disseminate locally despite the diminished propensity of drug-resistant strains to cause disease. In addition, it is possible that some organisms could experience a subsequent mutation that increases its virulence back to its pre – drug-resistant state [60].

Contact and outbreak investigations Impact of drug resistance on transmission and pathogenesis Before the advent of genotyping, studies suggested that isoniazid-resistant strains of M. tuberculosis were less likely to result in disease in animals [52 – 54]. Mutations or deletions within the katG gene of isoniazid-resistant strains of M. tuberculosis have been associated with a decrease in the pathogenicity in animal models [55]. Several molecular epidemiologic studies have reported that patients who have drug-resistant strains were less likely to be in clusters, suggesting that drug-resistant strains might be less predisposed to being transmitted or to cause active tuberculosis [20,56,57]. The spread of tuberculosis involves a three-step process: transmission of bacteria, establishment of infection, and progression to disease. Because genotyping studies require the development of active tuberculosis, they cannot determine whether drug resistance influences only one, two, or all three of the processes. Burgos and colleagues [58] recently reported that the number of secondary cases generated by isoniazid-resistant cases of tuberculosis was significantly less than the drug-susceptible cases. This difference in the generation of secondary cases was noted regardless of HIV status and place of birth. These findings support the hypothesis that drugresistant strains are less likely than drug-susceptible strains to result in disease. There are, however, populations in which drug resistance is neither detected nor treated effectively and where the longer duration of infectiousness for patients who have drugresistant organisms treated with standard regimens might offset the bacterium’s diminished capacity to cause secondary cases [58]. In areas that have high prevalence rates of HIV, the increased host susceptibility, even to strains that have diminished virulence, may offset bacterial differences. For example, one multidrug-resistant strain of M. tuberculosis, strain W, caused several nosocomial outbreaks in New York City in the early 1990s [59]. Over the next

Conventional tuberculosis contact investigations use the stone-in-the-pond or concentric circle approach to collect information and to screen household contacts, coworkers, and increasingly distant contacts for tuberculosis infection and disease [61]. Studies in low-incidence areas such as San Francisco [22] and Amsterdam [62] demonstrated that a relatively small proportion (5% – 10%) of tuberculosis cases that had identical IS6110 -based genotyping patterns were named as a contact by the source case. One explanation for these findings is that unsuspected transmission of M. tuberculosis occurred and was not easily detected by conventional contact tracing investigations. In a 5-year, population-based study in the Netherlands, contact investigations of persons in five of the largest clusters identified epidemiologic links among them based on time, place, and risk factors [20]. Tuberculosis transmission also occurred through only short-term, casual contact that was not easily identified in routine contact investigations. In a more recent study [16] from the Netherlands, patients were divided into one of five transmission groups based on the results of contact investigations, genotyping, and, in some cases, a second interview: 1. Clear epidemiologic links, confirmed by genotyping and contact tracing (24%) 2. Clear epidemiologic links, confirmed by genotyping and second interview but not by contact tracing (6%) 3. Initially unclear epidemiologic links that became likely after genotyping and second interview (55%) 4. No epidemiologic links but genotyping indicated clustering 5. Patients who were part of a different cluster other than expected (1%) Combining groups 1 and 2 would suggest that at best contact investigations could identify about 30% of the clustered cases. Fifty-five percent of

molecular epidemiology

the clustered cases had an epidemiologic link identified after the genotyping results became available and a second interview was performed. These data suggest that as newer, more rapid amplificationbased genotyping methods become available, this approach might be able to improve contact investigations [63]. Genotyping has also demonstrated that even when another case is identified through a contact investigation, the contact case may be unrelated to the index case. For example, Marcel Behr and colleagues [64] in San Francisco reported that 30% of case – contact pairs had different strains of M. tuberculosis. Unrelated strains were more common among foreignborn, particularly Asian, contacts. Of 538 similar case pairs in a study [65] involving seven sites in the United States, 29% did not have matching genotype patterns, similar to the finding in San Francisco. Case pairs from the same household were no more likely to have confirmed transmission than those linked elsewhere. Among patients younger than 5 years of age, 15% of culture-confirmed cases and their suspected source patient had different genotype patterns [66]. In a recent study from South Africa, investigators evaluated 129 households in which genotyping data were available for more than one patient [67]. They identified 313 patients of whom 145 (46%) had a genotype pattern matching that of another member of the household. These studies suggest that contact investigations should not focus solely on the household but all settings frequented by the index case. Even when the essential elements of tuberculosis control are in place, ongoing transmission of M. tuberculosis will continue until tuberculosis is diagnosed and therapy is initiated. In a populationbased molecular epidemiologic study in an urban community in the San Francisco Bay area, 75 (33%) of 221 cases had the same strain of M. tuberculosis [68]. Thirty-nine (53%) of the 73 patients developed tuberculosis because they were not identified as contacts of source-case patients; 20 case patients (27%) developed tuberculosis because of delayed diagnosis of their sources; 13 case patients (18%) developed tuberculosis because of problems associated with the evaluation or treatment of contacts; and one case patient (1%) developed tuberculosis because of delays identifying the person as a contact. Contact tracing in the community can be ineffective in tuberculosis outbreaks if patients do not live in stable settings and either do not know or are unwilling to reveal the names and locations of contacts. Fortunately, studies that incorporate genotyping are able to provide information about the chains of transmission in these groups [69 – 71]. A prospective

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study of tuberculosis transmission in Los Angeles, California, identified 162 patients who had culturepositive tuberculosis and interviewed the patients to identify their contacts and whereabouts [72]. Traditional contact investigations did not reliably identify patients infected with the same strain of M. tuberculosis: only 2 of the 96 clustered cases named others in the cluster as contacts. The degree of homelessness and the use of daytime services at three shelters were independently associated with clustering, however. This study demonstrated that locations where the homeless congregate are important sites of tuberculosis transmission. Several studies support the idea that specific locations can be associated with recent or ongoing transmission of M. tuberculosis. In a 30-month prospective, city-wide study of all tuberculosis cases in Baltimore, Maryland, using traditional contact investigations and IS6110-based genotyping, 46% (84/182) of initial isolates were clustered, and 32% (58/182) of the cases were considered to have tuberculosis that was recently transmitted [73]. Only 24% (20/84) of clustered cases had an identifiable epidemiologic link of recent contact with an infectious tuberculosis patient. Using geographic information system data, the 20 clustered cases, which have epidemiologic links in geographic areas of the city that have low socioeconomic status and high drug use, were spatially aggregated. Therefore, in some populations, location-based control efforts may be more effective than traditional concentric circle – based contact tracing for early identification of cases. Genotyping has been particularly useful in identifying otherwise unsuspected and undetected transmission in the community [13]. Molecular epidemiologic studies have confirmed suspected and unsuspected transmission of tuberculosis in places such as residential care facilities [74], bars [23,75 – 77], crack houses [78], sites of illegal floating card games [79], schools [80,81], hospitals [82,83], and jails and prisons [84 – 87]. Tuberculosis transmission also has been demonstrated among groups such as church choirs [88], interstate transgender social networks [89], renal transplant patients [90], from patient to health care providers [91], and from health care provider to patients [92,93]. Processing contaminated medical waste resulted in transmission of M. tuberculosis to at least one worker in a medical waste treatment facility [94]. Genotyping was also used to document unsuspected bronchoscopy-related transmission and the cross-contamination of patients [95,96]. Without the availability of genotyping, it would have been difficult to confirm that transmission had occurred in such settings.

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Community epidemiology and risk factors for clustering Tuberculosis develops by rapid progression from a recently acquired infection, from LTBI, or from exogenous reinfection. Most molecular epidemiology studies have assumed that the proportion of clustered isolates in a population estimates the amount of recent or ongoing transmission of M. tuberculosis. The frequency of clustering has ranged from 7% to 32% in low-incidence areas such as Canada [97 – 100] to 34% to 46% in urban areas in the United States [22,28,73,101] and Europe [20,102 – 104]. Among gold miners in South Africa, 50% of tuberculosis patients were in clusters [15], and in Botswana 42% of the cases were clustered [105]. Whether or not clustered cases represent tuberculosis caused by recent transmission has remained a controversial point. A recent study from the Netherlands suggests that clustered cases do, in fact, represent recent transmission and rapid progression. Of 481 patients who had tuberculosis, 29% were clustered, suggesting recent transmission in 20% (using the n-1 approach to calculate recent transmission). The authors reported that 86% of the cases had epidemiologic links consistent with recent transmission [16]. In high-incidence areas, the frequency of clustering has ranged from 25% in Hong Kong [106], to 38% in India [107], to 42% to 72% in various African populations [57,67,105]. Conventional epidemiologic methods can be used in combination with molecular genotyping techniques to identify the risk factors associated with recent infection and rapid progression to disease (Table 3). In studies in low-incidence areas, young age, being in an ethnic minority group, homelessness, and substance abuse have been associated with recent infection and rapid progression to disease [22,62, 73,101]. In New York City, birth outside the United States, age of 60 years or older, and diagnosis after 1993 were factors independently associated with having a unique strain; homelessness was associated with clustering or recent transmission [108]. Tuberculosis among foreign-born persons was more likely to result from recent transmission among those who were HIV-infected and more likely to result from LTBI among those who were not infected with HIV. These data suggest that tuberculosis prevention and control strategies need to be targeted to the large number of foreign-born persons in New York City who have latent tuberculosis infection. Among foreign-born patients who have tuberculosis in Hamburg, Germany, risk factors for recent infection included a history of contact tracing, intravenous

drug use, alcohol dependence, asylum stay, and unemployment [109]. Thus, the risk factors associated with recent infection and rapid progression to disease have varied from study to study, partly because of differences in populations, methodologies, and definitions. Unfortunately, there are few population-based studies from high-incidence areas. In a study of South African gold miners, tuberculosis patients who had not responded to treatment at entry to the study were more likely to be in clusters (adjusted odds ratio [OR] = 3.41). Patients who have multidrug-resistant tuberculosis were more likely not to have responded to tuberculosis treatment but were less likely to be clustered than those who have a drug-susceptible strain (OR = 0.27) [15]. HIV infection, although common (53.6%), was not associated with clustering. Apparently, persistently infectious individuals who had previously not responded to treatment were responsible for one third of the tuberculosis cases in this population. In a study from Cape Town, 72% of cases were clustered, suggesting high rates of transmission in the community [110].

Measuring the performance of a tuberculosis control program As noted previously, tuberculosis can develop through three mechanisms: recent transmission and rapid progression to disease, reactivation of latent infection, or exogenous reinfection. Because clustering is considered a measure of recent transmission, a decline in the rate of clustering could be used to evaluate interventions aimed at reducing recent transmission [111]. In an evaluation of tuberculosis transmission over a seven-year period in San Francisco, the number and proportion of clustered tuberculosis cases declined, particularly among the native-born population [19]. This decline was attributed to the implementation of targeted tuberculosis prevention and control programs such as screening high-risk populations and implementing directly observed therapy to ensure high cure rates. A recent study in New York City showed that as tuberculosis case rates fell from recent high levels, the proportion of tuberculosis cases caused by recent transmission dropped from 63.2% in 1993 to 31.4% in 1999 [108]. Tuberculosis was unlikely to result from recent transmission in persons born outside the United States. Investigators in Denver, Colorado [112], used clustering to measure the impact of a skin testing program among homeless persons and showed that clustering decreased from 49% during the implemen-

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molecular epidemiology Table 3 Frequency of clustering and risk factors for clustering in selected studies by tuberculosis incidence rate First author/date [reference]

Study location

Study population

Low and moderate incidence areas (<100 per 100,000 population) Alland, 1994 [101] New York, NY Hospital-based

N ever clustered (%) 104 (38)

Risk factors for clustering HIV seropositive Hispanic ethnicity Younger age Drug-resistant disease Low income AIDS Born in the United States Intravenous drug use Male gender Urban residence Dutch and Surinamese nationality Long-term residence in The Netherlands Canadian-born aboriginals Canadian-born nonaboriginals Injection drug users Haitian birth

Small, 1994 [22]

San Francisco, CA

Community-based

473 (40)

Bishai, 1998 [73] van Soolingen, 1999 [20]

Baltimore, MD The Netherlands

Community-based Country-based

182 (46) 4266 (46)

Hernandez-Gardun˜o, 2002 [97]

Vancouver, BC, Canada

Community-based

793 (17)

Kulaga, 2002 [98]

Montreal, QC, Canada Hamburg, Germany

Community-based

243 (25)

Community-based

423 (34)

Fitzgerald, 2003 [99]

Western Canada

Regionally-based

944 (32)

Blackwood, 2003 [100]

MB, Canada

Province-based

629 (7)

Vokovic, 2003 [103]

Belgrade, Central Serbia Slovenia

Random sample

176 (31)

Country-based

306 (38)

Younger age Alcohol abuse Homelessness

Gold miners

419 (50)

Community-based Community-based

301 (42) 378 (38)

Community-based

702 (25)

Community-based

797 (72)

Treatment failure Time spent working in mines Imprisonment Identified by house-to-house survey Permanent residents Recent travel to mainland China Smear positive Defaulted retreatment cases Specific community

Diel, 2002 [102]

Zolnir-Dove, 2003 [104]

High incidence areas (100 per 100,000 population) Godfrey-Faussett, South Africa 2000 [57] Lockman, 2001 [105] Botswana Narayanan, 2002 [107] Tiruvallur District, India Chan-Yeung, 2003 [106] Hong Kong, China Verver, 2004 [110]

Capetown, South Africa

Alcohol abuse History of contact tracing Unemployment Younger age Male gender Pulmonary disease Living in shelter Drug-susceptible disease Predisposing factors Prior contact Prior skin test Male gender Younger age Treaty aboriginals Living on reserve land Multidrug-resistant disease

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tation of the program to 14% in the 4-year period after the program. By contrast, an 8-year study in Greenland showed that the annual incidence of tuberculosis doubled from 1990 to 1997, and the percentage of culturepositive tuberculosis cases in RFLP-defined clusters increased to 85%, reflecting microepidemics among adults and young children in small, isolated settlements [113]. Thus, genotyping was a useful indicator of changes in the proportion of cases that resulted from recent transmission and rapid progression to disease. Geographic distribution and dissemination of Mycobacterium tuberculosis Genotyping has permitted the tracking of strains of M. tuberculosis as they spread both locally and globally. Population-based data from the San Francisco Bay area suggest that M. tuberculosis does not rapidly transmit and spread across geographic boundaries and that tuberculosis control programs should focus on transmission within well-defined areas [114]. In fact, most clusters (66%) from the National Tuberculosis Genotyping and Surveillance Network in the United States were restricted to a single site [115]. Some strains of M. tuberculosis are widely dispersed both geographically and temporally, however, suggesting the strains are either older, more transmissible, or are more likely than other strains to cause disease. Data from the Genotyping Network found that 25% of the clusters were in two sites, 5% were in three, 2% were in four, and 1% each were in five and six sites [115]. Further research is needed to determine why some strains seem to be more disseminated than others. The Beijing family of strains has been detected in high proportions among the strains in China [116], other parts of Asia [117], the former Russian Federation [87], Estonia [118], Europe [119 – 121], and South Africa [122] and has been associated with large outbreaks, febrile responses [123], treatment failure and relapse [124,125], and drug resistance [126]. The W strain, a multidrug-resistant strain of M. tuberculosis that caused many cases of tuberculosis among patients and health care workers in nosocomial outbreaks and other institutional settings in New York City [59,127 – 130], is a member of the Beijing family [128]. It is unclear why the Beijing family strains are so widely disseminated [131]. It is possible that the Beijing genotype has a selective advantage and is more readily aerosolized, can establish infection more effectively, or can progress more rapidly from infection to disease [4,132]. On the other hand,

it is also possible that the Beijing genotype was introduced into multiple locations before other strains and had more time to spread.

The future of molecular epidemiology Molecular genotyping, in combination with conventional epidemiologic investigations, has contributed greatly to the understanding of the transmission and pathogenesis of tuberculosis and has identified inadequacies in tuberculosis control programs. The development of new tools, such as real-time amplification-based genotyping, should improve the ability to genotype strains of M. tuberculosis and conduct effective, timely, contact and outbreak investigations. Other technologies based on the genome of M. tuberculosis may eventually make it possible s to differentiate strains based on important phenotypic characteristics such as transmissibility and pathogenicity. For these new tools to be used effectively, they must be used in combination with conventional epidemiologic investigations. With time, genotyping should be integrated with new surveillance systems that will allow more rapid responses to potential outbreaks of tuberculosis. The integration of genotyping and new approaches to surveillance will be particularly important in low-incidence areas of the United States where resources are limited and early detection of outbreaks is difficult. The CDC-funded national genotyping network should help with the integration of genotyping tools into standard tuberculosis control practices and pave the way for tuberculosis control in the future.

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Clin Chest Med 26 (2005) 327 – 340

New Drugs for Tuberculosis: Current Status and Future Prospects Richard J. O’Brien, MDa,*, Mel Spigelman, MDb a b

Foundation for Innovative New Diagnostics, Case Postale 93, 1216 Cointrin/Geneva, Switzerland Global Alliance for TB Drug Development, 80 Broad Street, 31st Floor, New York, NY 10004, USA

Following nearly 3 decades of neglect, there is now renewed interest in the development of new drugs for the treatment and prevention of tuberculosis [1]. Three reasons are usually given for needing new tuberculosis drugs: (1) to improve current treatment of active tuberculosis by shortening the total duration of treatment or by providing for more widely spaced intermittent therapy; (2) to improve the treatment of multidrug-resistant tuberculosis (MDR-TB), and (3) to provide more effective treatment of latent tuberculosis infection (LTBI) in low-incidence countries where this intervention is a component of the control strategy. Of these, the first is most compelling. Despite the great decrease in tuberculosis incidence throughout the latter half of the twentieth century in industrialized countries, the disease remains a significant global health problem, particularly among adults in developing countries [2]. In countries affected by the AIDS epidemic, notably those in subSaharan Africa, rates of tuberculosis have increased dramatically, overwhelming control programs [2]. The World Health Organization (WHO) has recently promoted the directly observed treatment, short course (DOTS) strategy as an effective intervention that will lead to reduced tuberculosis transmission and decreasing numbers of tuberculosis cases [3]. This strategy has been shown to be among the most cost-effective global health interventions available today [4]. An important component of that strategy is the provision

* Corresponding author. E-mail address: [email protected] (R.J. O’Brien).

of high-quality drugs in standardized regimens of short-course, rifampin-based treatment given under direct supervision. The current treatment regimens, however, suffer from a number of drawbacks. With the combination of available drugs, the duration of treatment required for curing patients cannot be reduced below 6 months without a significant increase in relapses. When given under suboptimal conditions, these regimens are associated with high rates of patient nonadherence, with the consequence of increased mortality and creation of chronic, infectious, drug-resistant cases [5]. It is recommended that treatment be directly observed by a health care provider, especially during the first 2 months and whenever rifampin is used. The infrastructure required is cumbersome, labor intensive, and expensive. Thus, shorter treatment regimens or those that could be administered once or twice a week would significantly improve treatment outcome. Development of drug resistance is far more likely when supervised treatment is not given, when recommended regimens are not used, and when drugs with poor bioavailability are used. All these factors are frequently present in countries where DOTS has not been established. WHO has documented an increasing problem of MDR-TB that threatens to undermine recent progress in global efforts to control the disease [6]. The second-line drugs that are used for treatment of MDR-TB are much more expensive, more toxic, or less effective than first-line drugs. Although the development of more effective therapy for MDR-TB would not alone solve the problem, providing better treatment would be an important personal health benefit for those afflicted by MDR-

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.02.013

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TB and would improve the effectiveness of the WHO-supported MDR-TB treatment programs known as DOTS-Plus [7]. The resurgence of tuberculosis in the United States beginning in the late 1980s, coupled with the outbreaks of MDR-TB largely associated with HIV infection, led to increased federal support for both domestic and global tuberculosis control [8]. That support has resulted in continued declines in tuberculosis in the United States beginning in 1993 and a renewed call for the elimination of tuberculosis as a public health problem [9]. An important component of the tuberculosis elimination strategy in the United States is the treatment of individuals who have LTBI and are at increased risk of developing active TB [10]. The most widely used LTBI treatment regimen, 9 months of isoniazid, is associated with significant nonadherence, however. Thus, a more easily administered LTBI treatment regimen is a priority in a number of low-incidence countries.

Clinical Trials Program of the International Union Against Tuberculosis and Lung Disease. With support from the European Community, the European and Developing Countries Clinical Trials Partnership aims to provide A600 million over 5 years to perform clinical trials and to establish capacity for the conduct of high-quality clinical trials, including those for tuberculosis, throughout Africa [12]. Underpinning all this effort is the Global Alliance for TB Drug Development (TB Alliance), a recently established organization that is forging public – private partnerships with the objective of building a portfolio of new tuberculosis drugs and bringing a major new tuberculosis drug to market in the next decade [13]. This article reviews two classes of compounds that have advanced into phase II and III clinical trials, long-acting rifamycins and fluoroquinolones, and a number of other drugs that have entered or it is hoped will enter clinical development in the near future.

Tuberculosis drug development—a changing environment

Rifapentine: the search for widely spaced intermittent treatment

Increased resources directed toward tuberculosis drug development are now being marshaled from both the public and private sectors. Governmental organizations, such as the United States National Institutes of Health (NIH), are investing in basic research aimed at the identification of new drug targets and a better understanding of the phenomena of mycobacterial latency. Foundations, such as the Bill and Melinda Gates Foundation, are supporting research and development to enhance the understanding of the basic biology of tuberculosis and to develop new tuberculosis drugs. A number of small biotech companies have programs focused on the identification of new chemical entities with antimycobacterial activities that could become lead compounds in the drug-development process. Several large pharmaceutical companies, such as GlaxoSmithKline (Brentford, United Kingdom), AstraZeneca (London, United Kingdom), and Novartis (Basel, Switzerland), have launched programs directed at the discovery and development of new tuberculosis drugs. Other companies, notably Aventis and Bayer, have made compounds available for clinical studies. At the same time, the clinical trials infrastructure, which had been greatly eroded beginning in the early 1980s, is being reestablished with the formation of groups such as the United States Tuberculosis Trials Consortium (TBTC) [11] sponsored by the Centers for Disease Control and Prevention (CDC) and the

Rifampin is the cornerstone of modern shortcourse tuberculosis treatment, but rifampin-based regimens must be administered for at least 6 months for optimal effectiveness. Although this treatment is also highly effective when given three times per week throughout the course of treatment [14], more widely spaced regimens are less effective and may be associated with acquired drug resistance in HIVinfected patients, even when properly taken. A number of rifamycin derivatives with much longer serum half-lives than that of rifampin (2 – 4 hours) have been evaluated in regimens given intermittently. The first of these compounds to undergo clinical investigation was rifabutin [15]. The initial clinical trials of the drug focused on the prevention of Mycobacterium avium complex (MAC) infection in HIV-infected patients [16]. Although the drug was approved for MAC prophylaxis in the United States and for the treatment of tuberculosis in several other countries, it now is used primarily as a substitute for rifampin in patients who cannot use that drug because of drug – drug interactions [17]. A TBTC trial of a rifabutin-containing regimen given twice weekly in HIV-infected patients found high rates of acquired rifamycin resistance among patients who had more advanced immunosuppression, leading to CDC recommendations against the use of widely spaced treatment of tuberculosis with rifamycin regimens in such patients [18].

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Another long-acting rifamycin derivative, rifalazil, has an even longer half-life and potent activity in animal models suggesting that it might be used in ultrashort treatment regimens [19]. One attractive feature of the compound is its rather low potential for enzyme induction and drug interactions [20]. Initial phase I tolerability studies, however, found relatively high rates of side effects manifesting as a flulike syndrome when the drug was administered as a single 50-mg dose [21]. The hypothesized mechanism causing the dose limiting side effect is release of cytokines with evidence for increased interleukin-6 levels in the serum. Following an early bactericidal activity (EBA) study that did not demonstrate drug activity of once-weekly rifalazil (at 10- and 25-mg doses) plus isoniazid given for 2 weeks [22], further clinical development stopped. It is believed that closely related compounds can be identified that are better tolerated and lack the propensity for enzyme induction. Currently, there is significant interest in the use of rifalazil for the treatment of chlamydia infections [23]. The greatest interest and investment in long-acting rifamycins has been in rifapentine, a cyclopentylsubstituted rifampin with a half-life of 14 to 18 hours in normal adults. Following a 600-mg dose, serum levels in excess of the minimum inhibitory concentration (MIC) persist beyond 72 hours, suggesting that the drug might be useful in intermittent regimens (Fig. 1). A series of experimental studies in mice found that a once-weekly continuation phase of rifapentine and isoniazid for 4 months following a standard 2-month induction phase with daily isoniazid, rifampin, and pyrazinamide was as effective as stan-

dard therapy given daily for 6 months [24]. These studies provided the scientific underpinning for the large phase III trial that was begun by CDC in 1995 and subsequently became known as TBTC Study 22. Study 22 was an unmasked clinical trial that randomly assigned adults who had newly diagnosed, drug-susceptible pulmonary tuberculosis to a 4-month (16-week) continuation-phase regimen of either once-weekly rifapentine-isoniazid or twiceweekly rifampin-isoniazid following successful completion of a standard 2-month induction phase [25]. The primary study end points were treatment failure and relapse and safety and tolerability of rifapentine. The rifamycins were dosed at 600 mg and isoniazid at 900 mg. Although the trial focused on HIV-negative patients, HIV-positive patients were also enrolled initially to gain experience with this important subset of patients. Enrollment of HIV-positive patients was stopped early in the trial, however, following the finding of a high rate of relapse with acquired rifampin monoresistance among HIV-positive patients assigned to the rifapentine arm [26]. A total of 1003 HIV-negative patients were enrolled into the completed study. The crude rate of failure and relapse was significantly higher in the rifapentine arm (9.2% versus 5.6%, P = 0.04). In a multivariate analysis, the factors statistically associated with an adverse outcome were the presence of cavitary disease on chest radiograph, sputum culture positivity at study entry (ie, at the end of the intensive phase of therapy), white race, and weight less than 90% of ideal body weight at time of the diagnosis of tuberculosis. The treatment regimen was not associ-

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Fig. 2. Tuberculosis Trials Consortium study 22. Relapse rate by arm, cavitary chest radiograph, and 2-month culture. (Adapted from Tuberculosis Trials Consortium. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 2002;360:528 – 34; with permission.)

ated with an adverse outcome. Cavitary disease and culture positivity after 2 months were also predictors of an adverse outcome among patients in the rifampin arm (Fig. 2). Among patients who had noncavitary tuberculosis and negative 2-month sputum cultures, the relapse rate was low in both arms. Rifapentine was well tolerated, and rates of adverse events were similar in both treatment groups, with 3% of patients in both groups discontinuing treatment because of a drug-related adverse event. These results were similar to those from a study in Hong-Kong that used Chinese-manufactured rifapentine of inferior bioavailability [27] and with those from a companysponsored trial that enrolled patients largely from Africa [28]. The TBTC study results led to new recommendations for the use of the rifapentine-isoniazid continuation-phase regimen for HIV-negative adults who have drug-susceptible, noncavitary tuberculosis and negative acid-fast bacillus (AFB) smears at 2 months [29]. This category includes approximately 40% of patients in the United States who have newly diagnosed pulmonary tuberculosis. The regimen provides substantial cost savings for these patients, because encounters for directly observed treatment during the continuation phase are reduced by 50% [30]. Rifapentine-based treatment is not recommended for patients who have more advanced tuberculosis or patients who have HIV infection. Pharmacokinetic studies undertaken as part of Study 22 indicated that low levels of isoniazid and rapid isoniazid acetylation were associated with relapse, suggesting that a more effective companion drug might improve onceweekly treatment [31]. Experimental studies have also suggested that, in addition to a better companion drug, higher doses of rifapentine might also result in more effective treatment [24].

Following the completion of Study 22, the TBTC undertook a large phase II trial of higher rifapentine doses. In Study 25, 150 HIV-negative patients who had drug-susceptible pulmonary tuberculosis and completed initial-phase treatment were randomly assigned to 600, 900, and 1200 mg rifapentine given once weekly with isoniazid for 16 weeks. The rifapentine dose was masked with the use of dummy tablets of rifapentine. The primary study end points were adverse events and drug discontinuation. All regimens were well tolerated, and only one patient assigned to the 1200-mg dose stopped treatment because of a possible drug-related adverse event [32]. Because the results of Study 22 were known when this study began, the protocol was modified to provide extended treatment for an additional 3 months (or 12 weeks) for patients who had cavitary disease and had positive sputum cultures at entry (ie, at 2 months). Twenty such patients were enrolled, received extended treatment, and were followed prospectively for relapse. Only one patient who was assigned to the 600-mg dose relapsed. The relapse rate of 5%, when compared with historical data from Study 22 (22%), suggests that extended treatment and higher rifapentine doses may provide more effective treatment for patients who are at increased risk of relapse [33]. The results also suggest that the 900-mg rifapentine dose would be appropriate to use in subsequent trials. Experimental studies have also suggested that once-weekly rifapentine and isoniazid for as short a period as 3 months may provide effective treatment for LTBI, comparable to that conferred by 6 months of daily isoniazid or by 2 months of daily rifampin and pyrazinamide [34]. Based on these findings, the TBTC has embarked on an ambitious study of rifapentine/isoniazid for LTBI treatment, intending to enroll and randomly assign 8000 patients to either

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followed by twice-weekly isoniazid and rifampin for 1 and 2 months, respectively. These results suggest that fluoroquinolones might permit substantial shortening of tuberculosis treatment from the current minimum of 6 months. Recent experimental data also suggest that fluoroquinolones may be potent sterilizing drugs that could allow shortened regimens for the treatment of active tuberculosis, including MDR-TB, and be effective against LTBI. Thus, newer fluoroquinolones have the potential to achieve all three objectives of a new tuberculosis drug. Several fluoroquinolones with markedly enhanced in vitro activity against M. tuberculosis are now available. Of these, the most potent are moxifloxacin and gatifloxacin. The MICs of these two agents are fourfold lower than that of levofloxacin, the fluoroquinolone that is currently preferred for the treatment of drug-resistant tuberculosis [37,38]. Moxifloxacin also has excellent activity against M. tuberculosis in animal models [39,40]. A recent evaluation of fluoroquinolones in a model of mycobacterial persistence found that moxifloxacin had the greatest sterilizing activity [41]. The pharmacokinetic profile of moxifloxacin, with a relatively long half-life and high area under the time concentration curve, also suggests that this agent may be an ideal antimycobacterial drug [42]. A series of studies of moxifloxacin in mouse models of acute tuberculosis have also contributed to the interest in this drug. The initial study, in which infected mice were treated for 1 month with several fluoroquinolones, found that moxifloxacin has the greatest bactericidal activity, comparable to that of isoniazid (Fig. 3) [39]. A second study suggested that

9 months of daily self-administered isoniazid or 12 doses of once-weekly rifapentine/isoniazid. Because of the large sample size required and the capacity of the TBTC sites to enroll eligible patients, study completion is not expected before 2008.

Moxifloxacin: the next treatment-shortening drug? During the past decade, fluoroquinolone antibiotics have become the most important second-line drugs for treating patients who have MDR-TB. Until recently, however, these drugs have not been considered for the treatment of drug-susceptible disease, in part because the few randomized, controlled trials of fluoroquinolones for drug-susceptible tuberculosis that have been conducted have not demonstrated a benefit. This perspective began to change with the publication of a clinical trial conducted by the Tuberculosis Research Centre in Chennai, India. This study, which did not have a standard control group, randomly assigned patients who had newly diagnosed pulmonary tuberculosis to one of four ofloxacincontaining regimens [35]. Rates of 2-month sputum culture conversion, a marker of the sterilizing activity of tuberculosis drug regimens [36], ranged from 92% to 98%, which compares favorably to an expected rate of approximately 80% with standard four-drug treatment [25]. Rates of relapse during the 2 years following completion of treatment were 2% and 4% in patients randomly assigned to 3 months of daily isoniazid, rifampin, pyrazinamide, and ofloxacin,

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Fig. 4. Experimental study of moxifloxacin-containing regimens in murine tuberculosis. (Adapted from Nuermberger EL, Yoshimatsu T, Tyagi S, et al. Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am J Respir Crit Care Med 2004;169:334 – 5; with permission.)

moxifloxacin also has potent sterilizing activity and might substantially improve the efficacy of onceweekly rifapentine treatment, replacing isoniazid that has been shown in clinical studies to be a poor companion drug [43]. The most recent study found that the combination of rifampin, pyrazinamide, and moxifloxacin had substantially greater sterilizing activity than the standard regimen, again suggesting the possibility that the drug would permit significant shortening of treatment (Fig. 4) [44]. The results of two small EBA studies have demonstrated that moxifloxacin has bactericidal activity superior to that of rifampin and perhaps comparable to that of isoniazid, the most potent bactericidal drug in EBA studies [45,46]. The only other published experience with moxifloxacin treatment of tuberculosis is a small case series that indicated good tolerability to chronic administration of the drug [47]. The next step in the clinical development of moxifloxacin for TB is the conduct of a series of phase II clinical trials in which moxifloxacin replaces various drugs in the initial 2-month phase of TB treatment and where sputum culture conversion at 2 months is the primary study end point [48]. Data from such studies, which have historically taken 2 years to complete, are usually required to proceed to the larger and more costly phase III trials that commonly take much longer to complete. To develop clinical data that would justify larger phase III efficacy trials of moxifloxacin, the TBTC has embarked on a phase II trial of the drug, Study 27. This study randomly assigns newly diagnosed, AFB-positive, HIV-positive and -negative patients who have suspected pulmonary tuberculosis to

one of four 2-month intensive-phase regimens: two standard-treatment regimens given either daily or three times weekly or similar regimens in which moxifloxacin replaces ethambutol, with assignment masked by placebo moxifloxacin and ethambutol. The primary study end points are 2 month sputum culture conversion and withdrawal because of adverse events. Investigators from Johns Hopkins University are working with colleagues from Rio de Janeiro on a similar study that is supported by the United States Food and Drug Administration Office of Orphan Products Development (R. Chaison, personal communication, 2004). A product development team supported by the United Nations Childrens Fund/United Nations Development Program/World Bank/WHO Special Program for Research and Training in Tropical Diseases and the European Commission is embarking on several studies of a gatifloxacin fixed-dose combination product for the treatment of drug-susceptible tuberculosis. These efforts include preclinical pharmacology and toxicology studies and a phase I study designed to compare the drug – drug/pharmacokinetic interactions of gatifloxacin and isoniazid, rifampin, and pyrazinamide. A phase II study is being conducted in Durban, South African, randomly assigning newly diagnosed patients to one of three fluoroquinolone-containing regimens (ofloxacin, moxifloxacin, and gatifloxacin) in combination with isoniazid, rifampin, and pyrazinamide during the first 2 months of treatment. A variety of bacteriologic markers are being evaluated as potential surrogate markers of treatment response. A large phase III trial of gatifloxacin included in a 4-month regimen that intends

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to enroll over 2000 patients at centers in five countries in sub-Saharan Africa was expected to begin in late 2004 (C. Lienhardt, personal communication, 2004).

The emerging tuberculosis drug pipeline In addition to the rifamycin derivatives and fluoroquinolones, a variety of other compounds or classes of compounds are under investigation as potential antimycobacterial drugs. These include a diarylquinoline (R207910), a nitroimidazopyran (PA-824), a nitro-dihydroimidazo-oxazole (OPC 67,683), a pyrrole (LL3858), macrolides, oxazolidinones, and a diamine (SQ109).

Diarylquinolines (R207910) The diarylquinolines, under investigation by Johnson & Johnson (New Brunswick, New Jersey), have been shown to have potent in vitro activity against M. tuberculosis and seem promising in an animal model [49]. The lead compound, R207910, is currently in clinical testing in phase I studies. R207910 is equally active against drug-sensitive M. tuberculosis (MIC 0.03 mg/mL) and strains resistant to a variety of commonly used drugs such as isoniazid, rifampin, streptomycin, ethambutol, pyrazinamide, and fluoroquinolones. Similar potency was also found against other mycobacteria, such as M. smegmatis, M. bovis, M. avium, and M. fortuitum, but the compound is not active against several other bacterial species, such as Nocardia asteroides, Escherichia coli, Staphylococcus aureus, Enterococcus faecium, and Hemophillis influenzae. Two resistant M. smegmatis isolates were not crossresistant to a wide range of antibiotics, including the fluoroquinolones. Thus, the mechanism of action of R207910 seems to be unique among the commonly used antimicrobials. In addition to the in vitro activity of R207910, the compound has also shown excellent in vivo activity in mouse models of established and nonestablished disease. When R207910 was administered by gavage 5 days/week from day 1 to day 28 after intravenous inoculation of Swiss mice with 7-log colony forming units (CFU) of strain H37Rv M. tuberculosis (nonestablished infection model), the compound was able to prevent mortality at the lowest dosage used (1.5 mg/kg), prevent gross lesions at 6.5 mg/kg, and reduce CFU counts in lungs and

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spleens at 12.5 mg/kg to the same extent as isoniazid (25 mg/kg). When therapy was started on day 14 after inoculation and continued until day 70 (established infection model), 12.5 mg/kg of R207910 was at least as active in decreasing CFU count in lung as was isoniazid (25 mg/kg) or rifampin (10 mg/kg). At a dose of 25 mg/kg, R207910 was even more active than at 12.5 mg/kg, reducing lung CFU count from 6 to 0.4 log. The combination of R207910 with any two of the three commonly used drugs (isoniazid, rifampin, and pyrazinamide) was more effective than the standard regimen of isoniazid, rifampin, and pyrazinamide. In fact, the combination of R207910, isoniazid, and pyrazinamide and the combination of R207910, rifampin, and pyrazinamide both resulted in negative spleen and lung cultures after 8 weeks of therapy. Pending results of the phase I studies, the ability of R207910 to shorten the therapy of active TB will be tested.

Nitroimidazopyrans (PA-824) The TB Alliance is developing PA-824, a novel nitroimidazopyran with a molecular weight of 359, for first-line therapy of active tuberculosis and for the treatment of MDR-TB. The history of the nitroimidazoles goes back to the 1970s, when Ciba-Geigy (Basel, Switzerland) explored a novel series of nitroimidazole compounds as radiosensitizing agents for use in cancer therapy. Subsequent studies described these compounds’ antimicrobial activity, including activity against M. tuberculosis. Ciba-Geigy halted development when their lead compound (CGI-17341) was found to be mutagenic in the Ames assay. In the 1990s, PathoGenesis (Seattle, Washington) decided this class of compounds warranted further exploration for potential tuberculosis therapy and synthesized more than 700 novel compounds. They determined that the nitroimidazopyran PA-824 was the most active of these compounds against M. tuberculosis in a murine infection model [50]. Following Chiron’s (Seattle, Washington) purchase of PathoGenesis in 2000, development of PA-824 was halted because of the company’s decision to focus on other therapeutic areas. In 2002, the TB Alliance and Chiron signed an exclusive license agreement granting the TB Alliance worldwide rights to PA-824 and nitroimidazole derivatives. Since then, the TB Alliance has continued the development of PA-824. A series of in vitro pharmacology studies indicate that PA-824 may be efficacious against both drug-

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sensitive and drug-resistant tuberculosis. In vitro studies demonstrate that the MIC of PA-824 against a variety of drug-sensitive tuberculosis isolates (
0.015 – 0.25 mg/mL) is similar to that of isoniazid (0.03 – 0.06 mg/mL). PA-824 is highly selective, with potent activity only against bacille Calmette-Guerin (BCG) and M. tuberculosis among the mycobacterial species tested, and without significant activity against a broad range of gram-positive and gram-negative bacteria (with the exception of H. pylori and some anaerobes). In vitro studies using anaerobic culture models indicate that PA-824 has activity against nonreplicating bacilli, whereas isoniazid does not have activity in these models. Finally, PA-824 has been shown to have activity against strains of tuberculosis with known resistance to standard antituberculosis therapies, indicating a novel mechanism of action. To evaluate in vivo activity, PathoGenesis tested PA-824 in a mouse model of tuberculosis, employing an M. tuberculosis reporter strain expressing firefly luciferase. PA-824 was administered orally at 25, 50, and 100 mg/kg/day in mice for 10 days, with isoniazid used in the control arm. Administration of PA-824 at all doses significantly reduced M. tuberculosis levels in both spleen and lung compared with controls and demonstrated a linear dose response. In longer-term studies, PA-824 at 50 mg/kg/day demonstrated reductions in bacillary burden similar to isoniazid at 25 mg/kg/day in murine lungs, and all mice treated with PA-824 survived infection, whereas all untreated control animals died by day 35. Daily oral administration of PA-824 at 37 mg/kg/day for 35 days in a guinea pig aerosol infection model also caused statistically significant reductions of M. tuberculosis in lungs and spleens compared with controls, reductions comparable to those caused by isoniazid. The activity of PA-824 against MDR-TB isolates and against both replicating (aerobic) and nonreplicating (anaerobic) M. tuberculosis bacilli indicates this compound has a novel mechanism of action. PA-824 seems to inhibit significantly both protein and lipid synthesis but does not affect nucleic acid synthesis. PA-824 produces an accumulation of hydroxymycolic acid with a concomitant reduction in ketomycolic acids, suggesting inhibition of an enzyme responsible for the oxidation of hydroxymycolate to ketomycolate. Unlike the Ciba-Geigy lead compound, CGI17341, PA-824 has not demonstrated mutagenicity in the Ames test (with or without S9 activation), and initial toxicity studies indicated the doses needed for therapeutic activity in murine and guinea pig infec-

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tion models are below the acute and chronic toxic thresholds observed for PA-824 in mice. More recent studies by Grosset et al [51] have indicated that, in a murine model, the minimum effective dose (defined as the minimum dose which prevents the development of gross lung lesions and splenomegaly) of PA-824 is 12.5 mg/kg/day, that the absence of lung lesions on gross inspection correlates well with bacteriostatic activity measured by CFU count, that the minimum bactericidal dose (defined as the minimum dose which reduces the long colony forming unit counts by 99%) is 100 mg/kg/day, and that the activity of PA-824 at 100 mg/kg is comparable to the activity of isoniazid at 25 mg/kg. The potential genotoxicity of PA-824 was examined further with chromosomal aberration, mouse micronucleus, and mouse lymphoma tests. The results indicate that PA-824 is not genotoxic. Furthermore, in vitro studies indicate that PA-824 neither inhibits nor is metabolized by major P450 enzyme isoforms. Pharmacokinetic studies have been performed in the rat, dog, and monkey, because the systemic exposure in dogs is low for both males and females secondary to poor absorption and rapid metabolism. Results of the single-dose studies indicate that the half-life of PA-824 is approximately 2 to 5 hours in male rats and monkeys and trends toward a longer half-life in female rats (8 – 9 hours). The half-life in dogs is shorter (1 – 2 hours). In monkeys, single doses of PA-824 are rapidly absorbed with a time to maximal concentration (Tmax) of 3.33 hours or less, whereas Tmax in the rat ranges up to 8 hours. There was no significant effect of sex on rate of absorption in any species. There was not a significant food-effect on PA-824 pharmacokinetics in the rat. The pharmacokinetics of PA-824 was determined in plasma, heart, liver, kidney, spleen, and lung following a single 100-mg/kg oral dose of PA-824 in rats. The time to reach maximal concentrations of PA-824 in these tissues was 4 hours as compared with 6 hours in plasma. Exposure (area under the curve) in tissues was approximately three- to eightfold higher than that in plasma. These data suggest that, in the rat model, penetration of PA-824 into lung, spleen, and other tissues is extensive. In repeated dose studies, there was no evidence of accumulation in the rat or monkey. Two 14-day good – laboratory practice toxicology studies, one in the rat and one in the monkey, have been completed. The results of these studies indicate that toxicity is observed when exposures at or above approximately 500 mg/hour/mL are achieved. Phase I

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studies of PA-824 are planned for the first quarter of 2005.

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antituberculous drugs, LL3858 sterilizes lungs and spleens of infected animals in a shorter timeframe than conventional therapy.

Dihydroimidazo-oxazoles (OPC-67683) Macrolides OPC-67683 is a newly synthesized nitro-dihydroimidazo-oxazole derivative under development by Otsuka Pharmaceutical Company (Tokyo, Japan) for the treatment of tuberculosis and is currently in phase I study in normal volunteers (Otsuka Pharmaceutical Company, personal communication, 2004). The compound has potent in vitro antimicrobial activity against M. tuberculosis, with MICs against H37Rv and 67 clinically isolated strains ranging from 0.006 to 0.024 mg/mL. Furthermore, OPC-67683 shows no cross-resistance with any of the currently used first-line tuberculosis drugs, most likely indicating a novel mechanism of action. Therefore the compound may be of benefit both in shortening duration of therapy in the treatment of active disease and in the treatment of MDR-TB. In vivo studies using a chronic mouse model of tuberculosis have demonstrated the efficacy of OPC67683 to be superior to that of the currently used tuberculosis drugs. In the mouse model, the dose that provided the effective plasma concentration of 0.100 mg/mL was 0.625 mg/kg, confirming the remarkable in vivo potency of OPC-67683. In other nonclinical in vitro and in vivo studies, OPC-67683 does not have any antagonistic activity with other first-line tuberculosis drugs when used in combination. Combinations with other first-line therapeutic drugs reveal synergistic, additive, or no appreciable interactions. Pyrrole (LL3858) Pyrrole derivatives were first described by Deidda et al [52] as having fairly potent antimycobacterial activities against several strains of M. tuberculosis. The MICs were between 0.7 and 1.5 mg/mL for the most potent derivative, 1,5-diaryl-2-methyl-3(4-methylpiperazin-1-yl) methyl-pyrrole (BM212). The activity of BM212 against various drug-resistant strains of M. tuberculosis was similar to its activity against sensitive strains, probably indicating a novel mechanism of action. Although some nontuberculosis mycobacterial strains seemed to be sensitive, the MICs were higher than for M. tuberculosis. A novel pyrrole compound, LL3858, is currently in development for tuberculosis by Lupin Limited (Mumbai, India). This compound has submicromolar MICs and seems to be very active in a mouse model of tuberculosis. In combination with currently used

The Institute for Tuberculosis Research, College of Pharmacy at the University of Illinois at Chicago, in conjunction with the TB Alliance, is currently studying the potential for macrolide antibiotics in the treatment of tuberculosis. Among approved antimicrobial agents that do not include tuberculosis as an indication, the macrolides are one of the more promising to yield a clinically useful tuberculosis drug. This potential is based on their oral bioavailability and distribution to the lungs, low toxicity, infrequent adverse reactions, extensive intracellular concentration and activity, anti-inflammatory activity, and, perhaps most importantly, demonstrated clinical utility and bactericidal activity in infections caused by several pathogenic and opportunistic mycobacteria, including M. avium, M. leprae, M chelonei, and M. fortuitum. Erythromycin, the first-generation prototypical macrolide, is a natural product derived from Streptomyces erythreus. The compound interferes with protein synthesis and possesses most of the favorable properties mentioned previously but suffers from a short serum half-life and acid lability, which results in gastric motility – based discomfort. In addition, activity is restricted to gram-positive bacteria. Therefore, second-generation macrolides with superior acid stability and serum half-life were developed. Clarithromycin, roxithromycin, and azithromycin represent the most successful second-generation macrolides. It quickly became apparent that the second-generation macrolides were, along with rifabutin, the most active clinical agents against the MAC. With the exception of azithromycin (an azalide that possesses a spectrum of activity different from that of other macrolides), these compounds also were found to possess potent activity against M. leprae in macrophages and mice and were shown to be effective in clinical trials. Clarithromycin is currently recommended by the WHO for treatment of leprosy in cases of rifampin resistance or intolerance. Other studies demonstrated low MICs or clinical utility of second-generation macrolides against M. kansasii, M. marinum, M. xenopi, and other opportunistic mycobacterial pathogens. The impressive activity of second-generation macrolides unfortunately did not include M. tuberculosis. The third-generation macrolides, represented largely by the ketolides, were developed with the

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intention of overcoming the ribosome-modification and efflux-resistance mechanisms found in grampositive cocci. Telithromycin was the first such agent to be brought to market. A comparative study of the antimycobacterial activity of clarithromycin versus telithromycin (as well as the fluorinated analogue of telithromycin) revealed the superior activity of clarithromycin for both the moderately clarithromycinsusceptible mycobacteria M. bovis BCG, M. avium, M. ulcerans, and M. paratuberculosis, and the clarithromycin-resistant mycobacteria M. tuberculosis, M. bovis, M. africanum, and M. simiae [53]. Thus, although the general resistance mechanisms to macrolides of gram-positive cocci and mycobacteria seem to be similar, there are significant differences in their structure – activity relationships. Studies conducted several years ago confirmed that clarithromycin was the most active antimycobacterial macrolide among 15 first- and secondgeneration macrolides (S. Franzblau, personal communication, 2004). The most potent of the commercially available macrolides, cethromycin, still has a MIC that is higher than the maximum plasma concentration (Cmax) that is obtainable in man. Further testing of modifications of the substituents on the macrolide structure have produced much more potent antimycobacterial compounds with low toxicity. These compounds form the basis for the ongoing work in optimizing the macrolide structure for activity against M. tuberculosis. Oxazolidinones Oxazolidinones represent a relatively new class of antimicrobial agents, initially discovered by scientists at DuPont (Wilmington, Delaware) in the 1970s [54,55]. They act by inhibiting protein synthesis by binding to the 70S ribosomal initiation complex [56,57]. The spectrum of activity of the oxazolidinones includes anaerobic and gram-positive aerobic bacteria, such as methicillin-resistant S. aureus and S. epidermidis, the enterococci, and also mycobacteria [58,59].

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Linezolid is the first commercially available oxazolidinone antibiotic. Although not approved for use in mycobacterial disease, there are convincing in vitro data that the drug is active against M. tuberculosis. A few oxazolidinones have been evaluated for their activity in murine in vivo systems. The most active compound seems to be PNU-100480, the activity of which seems to be similar to that of isoniazid or rifampicin [59]. Because of the lack of effective therapeutic options for patients who have MDR disease, linezolid has been used sporadically in patients who have MDR-TB. Although all reports are anecdotal, linezolid does seem to have biologic activity as evidenced by sputum culture conversion [60]. Somewhat distressing, however, is the reported occurrence of peripheral and optic neuropathy associated with prolonged use of linezolid [61]. Overall, the class of oxazolidinones seems to hold promise for the treatment of tuberculosis. Unfortunately, there has not yet been a truly concerted effort to optimize activity of the oxazolidinones for M. tuberculosis. In the meantime, the evidence for potential neuropathies associated with long-term use of linezolid will require careful use of this drug as it becomes used more commonly in the treatment of MDR-TB. SQ109 N- adamantan-2-yl-N 0-( 3,7-dimethylocta-2,6dienyl)-ethane-1,2-diamine (SQ109) was originally developed as a second-generation antibiotic from a first-line tuberculosis drug, ethambutol, to improve efficacy of the drug against M. tuberculosis and lower its toxicity. Although SQ109 is a diamine, its structural dissimilarity to ethambutol and differences in its intracellular target(s) suggest that it is a new antimycobacterial agent, not an ethambutol analogue (Fig. 5). In collaboration with Dr. Clifton Barry at the NIH, Sequella, Inc. (Rockville, Maryland) synthesized a diverse combinatorial library of compounds with the

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1,2-diamine pharmacophore of ethambutol and tested them for activity against M. tuberculosis using an MIC- and target-based (cell wall) reporter highthroughput screening assay [62]. These efforts found 2796 mostly lipophilic compounds to be active against M. tuberculosis in vitro, and 26 demonstrated in vitro activity equal to or greater than (up to 14-fold) ethambutol. Sixty-nine of the most potent hit compounds were later studied in a sequential set of in vitro and in vivo tests: MIC followed by cytotoxicity screen, followed by activity in infected macrophages, followed by permeability evaluation, followed by in vivo efficacy testing, followed by pharmacokinetic studies. SQ109 was identified as the most potent compound in the series and was then subjected to intensive pharmacokinetic/ pharmacodynamic testing. SQ109 is a lipophilic, nonsymmetric derivative of 1,2-ethylenediamine with unsaturated geranyl and bulky adamantane fragments present. SQ109 has been synthesized as a stable dihydrochloride salt on a multikilogram scale with high chemical purity (99.7%). The formulation to be used in clinical development, hard gelatin capsules, has been developed. SQ109 has an MIC against M. tuberculosis in the range of 0.1 to 0.63 mg/mL (broth microdilution, Alamar blue, BACTEC [Becton Dickinson, Franklin Lakes, New Jersey]). The compound is bactericidal with 99% inhibition of M. tuberculosis growth in macrophages at its MIC. When tested in vivo (in mice), SQ109 is able to reduce infection in lungs and spleen by 2 to 2.5 log. It is active against MDR strains of M. tuberculosis in vitro. SQ109 has a low mutational frequency in M. tuberculosis in vitro (2.18  109) and demonstrates enhanced antimycobacterial activity in vitro and in vivo when used in combination with rifampicin and isoniazid (rapid mouse model and chronic infection model).

The mechanism of action of SQ109 seems to be that of a cell wall inhibitor because, like the cell wall – targeting antibiotics (ethambutol, isoniazid, ethionamide, and thiacetazone), it induces a promoter, Rv0341, that was employed in the original luciferase high-throughput screening assay. Because the Rv0341 luciferase reporter responds with light production to inhibition of a wide variety of enzyme targets involved in cell wall construction, the specific target of SQ109 is not known. To address the issue, a proteomic study was initiated to identify proteins in H37Rv M. tuberculosis that are affected by the drug in comparison with ethambutol and isoniazid. The results of this study suggest that most of the 44 distinct proteins whose expression is increased (ESAT-6 and others) or decreased (MPT64 and others) by SQ109 were similar to those affected by ethambutol. Only two gene products whose functions are unknown were regulated differently by ethambutol and SQ109. Similarly, two different genes were affected, but in opposite directions, by exposure of M. tuberculosis to SQ109 or ethambutol [63]. The pharmacokinetic/pharmacodynamic profiles of SQ109 were evaluated in three species (mice, rats, and dogs). Single-dose pharmacokinetic studies in mice indicate that SQ109 has 4% oral bioavailability as measured by drug concentration in plasma. The high potency of SQ109 in vivo at low doses (1 mg/kg) combined with tissue distribution data argue, however, that, despite low bioavailability, SQ109 antimicrobial effects can be attributed to effective concentrations achieved at the sites of bacterial infection. Although blood concentrations remain low, SQ109 distributes into lungs and spleen (target sites of the bacterial infection), greatly exceeding the MIC (Fig. 6). Oral administration of SQ109, 30 to 75 mg/m2 (10 – 25 mg/kg in mice)

A

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Fig. 6. Tissue levels of SQ109 after intravenous administration of 3 mg/kg (A) and oral administration of 25 mg/kg (B) to mice.

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one time per day maintains drug levels above the MIC without accumulation of the drug in the target tissues. The liver may have a first-pass effect on SQ109 metabolism, resulting in low content of the drug in plasma after oral dosing. P450 reaction phenotyping suggests exclusive involvement of CYP2D6 and CYP2C19 in SQ109 metabolism; analysis of metabolites formed upon incubation of SQ109 with human, mouse, dog, and rat microsomes suggest similar metabolism of the drug in all tested species. SQ109 is undergoing formal preclinical 90-day pharmacology and toxicology studies in preparation for human clinical trials. In summary, SQ109 is a novel 1,2-diamine-based drug candidate with in vitro and in vivo activity against M. tuberculosis. It has pharmacokinetic/ pharmacodynamic properties that are characterized by a rapid and broad distribution into various tissues (ie, lungs) that is advantageous for tuberculosis infection.

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[3]

[4]

[5]

[6]

[7]

[8]

[9]

Summary During the recent decade, significant progress has been made in reinvigorating the almost nonexistent pipeline of novel agents for the treatment of tuberculosis and in reestablishing the infrastructure for the conduct of clinical trials of new tuberculosis drugs and treatment regimens. Recent studies of long-acting rifamycin derivatives and potent fluoroquinolone antibiotics are leading to improved regimens for the treatment of active and latent tuberculosis. A number of other compounds in late preclinical and early clinical development show great promise. The rapid increase in knowledge of mycobacterial pathogenesis is leading to the identification of new drug targets, including those believed to play a role in latent infection or in the phenomenon of persistence. A major challenge will be to sustain and increase funding for continued developmental and clinical work if the promise of tuberculosis elimination, or at least significant lessening of the global tuberculosis epidemic, is to be achieved.

[10]

[11]

[12]

[13] [14]

[15]

[16]

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spigelman [55] Gregory WA, Brittelli DR, Wang C-LJ, et al. Antibacterials, synthesis and structure-activity studies of 3-Aryl-2-oxooxazolidinones. 1. The ‘‘B’’ group. J Med Chem 1989;32:1673 – 81. [56] Birmingham MC, Rayner CR, Meagher AK, et al. Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate use program. Clin Infect Dis 2003;36c: 159 – 68. [57] Eustice DC, Feldman PA, Zajac PA, et al. Mechanism of action of DuP 721: inhibition of an early event during initiation of protein synthesis. Antimicrob Agents Chemother 1988;32:1218 – 22. [58] Slee AM, Wuonola MA, McRipley RJ, et al. Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721. Antimicrob Agents Chemother 1987;31:1791 – 7. [59] Cynamon MH, Kelmens SP, Sharpe CA, et al. Activities of several novel oxazolidinones against Mycobacterium tuberculosis in a murine model. Antimicrob Agents Chemother 1999;43:1189 – 91. [60] Dworkin F, Winters SS, Munsiff C, et al. Use of linezolid in treating multidrug-resistant tuberculosis in New York City. Am J Respir Crit Care Med 2004; 169(Suppl):A233. [61] Bressler AM, Zimmer SM, Gilmore JL, et al. Peripheral neuropathy associated with prolonged use of linezolid. Lancet Infect Dis 2004;4:528 – 31. [62] Lee R, Protopopova M, Crooks E, et al. Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates. J Comb Chem 2003;5:172 – 87. [63] Boshoff HI, Myers TG, Copp BR, et al. The transcriptional responses of, M. tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. J Biol Chem 2004;279:40174 – 84.

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The Diagnosis of Tuberculosis Daniel Brodie, MD, Neil W. Schluger, MD* Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Medical Center, 622 West 168th Street, PH 8 East, Room 101, New York, NY 10032, USA

Tuberculosis is transmitted from person to person by respiratory droplets. Although some people develop active tuberculosis disease after infection, almost all tuberculosis infections are asymptomatic and remain latent. Latent tuberculosis infection (LTBI) itself progresses to active disease in approximately 5% to 10% of infected persons. The rate of progression is much greater in immunocompromised individuals. The estimated 2 billion people living with LTBI represent a vast reservoir of potential cases of tuberculosis around the world. This reservoir of LTBI is therefore a major barrier to the ultimate control and elimination of tuberculosis. Strategies to combat tuberculosis in regions that are resource-rich aim, first, to identify and treat persons who have active disease; second, to find and treat contacts of cases of active disease who develop LTBI, and, third, to screen high-risk populations and treat LTBI [1]. Diagnosis and treatment of LTBI are crucial in this effort. In most of the world, however, resources are devoted exclusively to the highest priorities of tuberculosis control: identification and treatment of active disease [1]; for lack of resources, LTBI is neither diagnosed nor treated. Diagnostic testing for both LTBI and active disease has changed little during the last century. Because of limitations in available tests, there has long been a clear need for better diagnostic tests. LTBI, until very recently, has been diagnosed exclusively by the tuberculin skin test (TST). The TST is fraught with problems including relatively poor sensitivity

* Corresponding author. E-mail address: [email protected] (N.W. Schluger).

and specificity. Newer tests for LTBI offer the promise of greatly improved diagnostic accuracy. Tools for the diagnosis of active disease include clinical suspicion, response to treatment, chest radiographs, staining for acid-fast bacilli (AFB), culture for mycobacteria, and, more recently, nucleic acid amplification (NAA) assays. AFB smears lack both sensitivity and specificity, and culture is very slow to produce results, limiting the ability to diagnose active disease effectively. NAA assays and several other experimental diagnostic tools can add significantly to the active disease diagnostic armamentarium. The suitability of newer diagnostic tests in a given population varies according to the resources available to pay for and implement those tests, however [2]. In resource-poor countries, where options are limited, current approaches, such as relying almost exclusively on the sputum smear for the diagnosis of active disease, leave a significant number of cases undetected [3 – 6]. This approach may be the only economically feasible strategy given the initial costs involved in the widespread use of other diagnostic modalities. Although smear-positive cases are the most infectious, neglecting smear-negative disease (approximately half of cases overall) increases the morbidity and mortality of the disease in those patients and does not account for the significant burden of transmission attributable to these smear-negative cases (17% of all transmission in one study using molecular epidemiology techniques) [6]. The increased likelihood of smear-negative tuberculosis in HIV patients, particularly those who have advanced immunosuppression [7], makes this diagnostic approach especially problematic, because the regions most afflicted by tuberculosis are similarly inundated with HIV infection.

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.02.012

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Meanwhile, in resource-rich countries, underdiagnosis is less an issue than overdiagnosis with its attendant costs (the production of specimens, the surveillance of cultures—most of which will ultimately be negative—use of isolation rooms, empiric therapy for tuberculosis, and expensive or invasive diagnostic testing) [8]. In part, the need is for more rapid diagnosis, allowing for earlier treatment of cases, decreased transmission of active disease, and decreased expenditure of resources. There is also a need for increased sensitivity of testing so that cases do not go unrecognized, and for increased specificity and negative predictive value to decrease the cost of having a high suspicion for this disease. An ideal test for active tuberculosis would produce rapid results (available within 1 day), would have high sensitivity and specificity, low cost, and robustness (ability to provide reproducible results in a variety of settings), would be highly automated or easily performed without the need for excessive sample preparation or technical expertise, and would be able to provide drug-susceptibility data. Ideally, such a test would also be able to distinguish between LTBI and active disease. For LTBI, such a test would distinguish true infection from bacille CalmetteGuerin (BCG) vaccination and infection with nontuberculous mycobacteria (NTM). In cases of active disease, it would be valuable to be able to determine infectiousness, follow response to therapy, distinguish Mycobacterium tuberculosis from NTM in AFBpositive specimens and obtain drug-susceptibility information. No test performs all these functions at present, but several new tests are being used or are currently under study that incorporate many of these features and offer the possibility of improved diagnosis of LTBI and of active disease.

Tests for latent tuberculosis infection The tuberculin skin test Tuberculin, a broth culture filtrate of tubercle bacilli, was first described in detail by Robert Koch in 1891, a year after he introduced it as a potential cure for tuberculosis [9]. Although its purported curative properties proved unfounded, Koch observed that subcutaneous inoculation of tuberculin led to a characteristic febrile reaction in patients who had tuberculosis but not in those who did not have tuberculosis, giving rise to its use in the diagnosis of the disease. The technique was refined over the next 2 decades so that cutaneous or intradermal inoculation restricted the reaction to the skin. Subsequently, a standardized version of tuberculin, the purified protein derivative (PPD), was introduced in 1934 [9]. In 1939, the batch of PPD known as PPD-S was produced by Seibert and Glenn [3]. This batch remains the international standard for PPD to this day. In the early years of the TST, the assumption that tuberculin reactions resulted solely from tuberculosis infections went virtually unchallenged [9]. By the mid-1930s, however, mounting evidence suggested that tuberculin reactions might not be restricted to such infections. In addition, investigators noted that if the dose of PPD were increased enough, almost everyone tested positive, including infants unlikely to have been exposed to tuberculosis [9]. These findings called into question the specificity of the TST, highlighting its limitations for the first time. The current state of knowledge about the utility of tuberculin skin testing derives in large measure from a series of trials performed in epidemiologically welldefined populations of persons who have known 5 TU PPD-S

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Fig. 2. Frequency distribution of skin test reaction with 5-TU PPD-S (solid line) and 2-TU PPD RT 23 (dotted line) among Eskimo children and United States Navy recruits. TU, tuberculin units. (From Reider H. The epidemiologic basis of tuberculosis control. Paris: International Union Against Tuberculosis and Lung Disease; 1999. p. 33; with permission.)

tuberculosis disease, those at extremely low likelihood of having latent infection, and those likely to be close contacts of persons who have active tuberculosis. Reider [10] has described these trials in detail. The dosing of tuberculin for use in skin testing was determined in studies such as one done in Ohio, in which skin testing was performed on tuberculosis patients and a group of children in orphanages who had little chance of tuberculosis exposure. At a dose of 10 4 mg of tuberculin, a clear distinction could be made between the two groups (Fig. 1). Refinements in dosing and criteria for positivity were achieved by

using standardized preparations of PPD made by the Statenseruminstitut in Amsterdam and testing them in groups of Eskimo children (a group that has a high likelihood of latent infection acquired from close contact with active cases and very little exposure to environmental mycobacteria) and US Navy recruits who have little chance of contact with active tuberculosis but have frequent exposure to environmental mycobacteria (Fig. 2). Testing of 5440 tuberculosis patients revealed a normal distribution of extent of induration, with a mean of 16 to 17 mm (Fig. 3). Finally, a massive survey of more than 700,000 US military recruits, of whom 400,000 had no known

Fig. 3. Frequency distribution of tuberculin skin test results (5 – tuberculin unit PPD S) among 5544 tuberculosis patients in the United States. (From Reider H. The epidemiologic basis of tuberculosis control. Paris: International Union Against Tuberculosis and Lung Disease; 1999. p. 35; with permission.)

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Fig. 4. Frequency distribution of tuberculin skin test results in United States Navy recruits with (dashed line) or without (dotted line) tuberculosis. The solid line shows the difference between the two groups. (From Reider H. The epidemiologic basis of tuberculosis control. Paris: International Union Against Tuberculosis and Lung Disease; 1999. p. 36; with permission.)

contact with tuberculosis patients and 10,000 had definite contacts, provided meaningful data on which to base recommendations for interpretation of skin tests that are still useful today (Fig. 4). Although the TST has been in widespread use for a century and is the only universally accepted test for the diagnosis of LTBI, it suffers from significant inherent limitations. To understand these limitations, it is useful to review the mechanism of the TST. Infection with M. tuberculosis results in a cellmediated immune response giving rise to sensitized T lymphocytes (both CD4+ and CD8+ [11]) targeted to M. tuberculosis antigens. Stimulation by M. tuberculosis antigens causes these T cells to release interferon-gamma (IFN-g). The TST functions by eliciting this response in previously sensitized individuals. In such individuals, an intradermal injection of PPD evokes a delayed-type hypersensitivity response mediated by sensitized T cells and results in cutaneous induration. PPD, however, is a precipitate of M. tuberculosis culture supernatant which contains roughly 200 antigens, many of which are shared by other mycobacteria including many NTM and M. bovis BCG [12,13]. A response to PPD may signify infection with M. tuberculosis or, just as readily, infection with NTM [14 – 18] or vaccination with BCG [18 – 22]. This cross-reactivity seriously limits the specificity of the TST in many populations [23]. Given that one quarter to one half of the burden of tuberculosis in developed countries is found in foreign-born immigrants from high-prevalence countries, and this population is made up precisely of those who are likely to be BCG-vaccinated and to have been exposed to NTM, the TST is least reliable in those most in need of screening. Specificity is a major shortcoming of the TST. In addition, sensitivity of the TST may also be poorest in patients at high

risk for developing tuberculosis. Anergy caused by an immunocompromised state (especially with HIV infection or medication-induced immunosuppression) may lead to false-negative results [24]. False-negative results also may occur up to about 10 weeks after infection with M. tuberculosis [25 – 27]. False negatives, particularly in the HIV population where the implications of active disease are most pressing [3,28,29], greatly limit the utility of this test. The exact sensitivity and specificity of the TST for LTBI is impossible to know with certainty, given the lack of a reference standard for diagnosis. In that context, estimates of the global burden of LTBI are especially problematic. Estimates indicate that the problem is enormous, but these estimates are based on the performance of the TST, and such estimates, particularly in developing countries, are notoriously unreliable [30,31]. Studies of the prevalence of LTBI in India, for instance, have yielded prevalence rates ranging from 9% [32] to more than 80% in various populations [33]. A more accurate epidemiologic tool would greatly facilitate a better estimation of the true scope of the problem. The TST is limited further by the subjectivity of its interpretation [34], in particular, by problems with interreader and intrareader reliability [25,35 – 37] and digit preference [38,39]. Also, the existence of the booster phenomenon [24,25,39 – 41], poor standardization of PPD preparations [31], and, logistically, the need for a return visit to have the test read make the TST a highly imperfect diagnostic tool. That it does not distinguish between LTBI and active disease also limits its usefulness. Whether the extent of induration resulting from tuberculin skin testing can predict the development of tuberculosis in a linear (or at least dependent fashion) has also been the subject of considerable discussion

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and investigation. Recently, Horsburgh [42] has provided a well-reasoned and -supported data set that gives guidance in this area. Alternatives to the TST are lacking. Serologic tests for the diagnosis of M. tuberculosis have been disappointing [43,44]. Although an antibody response to M. tuberculosis antigens occurs, there is great individual variability in the number and type of serologically reactive antibodies [44], making this diagnostic tool too unreliable. Because no serologic tests for tuberculosis are remotely good enough to be used clinically at present, they are not discussed further in this article. Despite its many limitations, the TST by necessity remains in widespread use. In 2000, the Centers for Disease Control and Prevention (CDC), the American Thoracic Society (ATS), and the Infectious Disease Society of America (IDSA) issued updated guidelines for the use of the TST in screening for LTBI [24]. These guidelines stress that in general one should not place a TST unless treatment would be offered in the event of a positive test. In addition, cut-off points of induration (5, 10, or 15 mm) for determining a positive test vary by the pretest risk category into which a patient falls. This approach may further decrease the specificity of the test, but it increases the sensitivity for capturing those at highest risk for developing active disease in the short term. Continued focus on this century-old test highlights its continued importance, but the need for a more accurate diagnostic tool is evident.

Beyond the tuberculin skin test Development of novel diagnostic tests for LTBI is hampered by the lack of a true reference standard for diagnosis. Without such a standard, the best approach might be to apply a new test to a population in a controlled study, observe all patients positive by the novel and reference tests, and determine which test more accurately predicts the development of active disease. This approach, however, is limited by ethical and practical considerations. Demonstrating that any test is better than the TST is therefore difficult. Studies of the magnitude of those cited by Reider [10] for the development of tuberculin skin testing are unlikely to be repeated. What approach, then, might be taken? It is well documented that the greater the proximity to the source case of active disease and the greater the duration of exposure to that case, the more likely it is that a person will develop LTBI. Although the risk of LTBI cannot be precisely quantified for all degrees of

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contact, the risk of LTBI may be expressed as an increasing likelihood of infection with increasing exposure to the source case or increasing amounts of high-risk behavior. It is against this standard that the sensitivity of any new diagnostic test must be compared with the TST itself. A test that is superior to the TST in sensitivity would be more likely to be positive given a greater degree of contact with the source case. Specificity must similarly be gleaned from the expectation that only infection with M. tuberculosis and not with NTM or M. bovis BCG would give a positive result. A test would be superior in specificity if its results seemed to be independent of NTM exposure and BCG vaccination status. Recently, a new generation of tests for LTBI has been developed. They are the QuantiFERON-TB and QuantiFERON-TB Gold (QFN-Gold) tests (Cellestis Limited, St. Kilda, Australia) and the T SPOT-TB test (Oxford Immunotec, Oxford, UK) The basis of these tests is the detection in serum of either the release of IFN-g on stimulation of sensitized T cells by M. tuberculosis antigens in vitro (QuantiFERON) or detection of the T cells themselves (T SPOT-TB). In 1990, Wood and colleagues [45] developed a wholeblood assay for the detection of IFN-g in response to a specific antigen, PPD, intended for diagnosing bovine tuberculosis. Later that year, Rothel and colleagues [46] introduced a sandwich enzyme immunoassay for bovine IFN-g that streamlined the assay, making it more practical for widespread testing. This assay was shown to be both sensitive and specific in field comparisons with the intradermal tuberculin test [46 – 48] and later was accredited in Australia for use in the diagnosis of bovine tuberculosis [49]. In 1995, the test was successfully used in the diagnosis of M. tuberculosis and M. avium complex infection in humans [50,51]. Similar to the TST, the QuantiFERON-TB test detects cell-mediated immunity to tuberculin. In contrast to intradermal injection of PPD, however, whole blood is incubated overnight with PPD from M. tuberculosis, and the IFN-g that is released from sensitized lymphocytes is subsequently quantified by ELISA [38]. As discussed previously, PPD antigens are shared across mycobacterial species, including M. bovis BCG [13,52]. A positive response to the whole-blood IFN-g assay for PPD therefore, like the TST itself, lacks specificity for M. tuberculosis infection and may reflect infection with NTM or vaccination with BCG [18]. Early studies were nonetheless encouraging [38,49,53 – 56], demonstrating decreased false-positive results relative to the TST in BCGvaccinated individuals [38] and those exposed to NTM [38], with equal or better apparent sensitivity

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and specificity than the TST in multiple studies [38,49,53,56], including in populations of intravenous drug users and HIV-positive patients [54,55]. Few studies purported to demonstrate the superiority of the TST for LTBI [57,58]. The discovery of M. tuberculosis – specific antigens opened the way to improving the specificity of the assay. In 1986, Harboe and colleagues [59] reported the first M. tuberculosis – specific antigen, MPB-64 (later known as MPT-64). In 1995, Andersen and colleagues [60] reported the highly immunogenic antigen target of the cellular immune response to tuberculosis in mice, known as the early secreted antigenic target 6 (ESAT-6). Subsequently, in 1998, Berthet and colleagues [61] described culture filtrate protein (CFP-10) [61], another highly immunogenic antigen. MPT-64 has been studied extensively [62 – 66], but, because it is present in some strains of BCG and is a less potent target of the immune response, it has limited utility [62,63,67]. On the other hand, ESAT-6 [61 – 64,68 – 70] and CFP-10 [61,71] have demonstrated great potential. In 1998, the complete genome sequence of M. tuberculosis was determined [72]. An earlier comparison of the M. tuberculosis genome with the genomic composition of M. bovis and M. bovis BCG in 1996 by subtractive genomic hybridization [68] and, subsequently, in 1999, by comparative hybridization experiments on a DNA microarray [73] led to the identification of a genomic region known as RD1. The gene products of RD1 are found only in M. tuberculosis, in pathogenic M. bovis strains [64, 68,73], and in four NTM (M. kansasii, M. szulgai, M. flavescens, and M. marinum) [69,70]. Because, of these, only M. kansasii overlaps clinically with M. tuberculosis, and because M. kansasii infection is uncommon, the RD1 region encodes antigens that are essentially specific to M. tuberculosis. Among these antigens are, of course, ESAT-6 and CFP10, as well as MPT-64. ESAT-6 and CFP-10 are secreted by M. tuberculosis into the extracellular environment and are potent targets of the cell-mediated immune response [61 – 63,71,74]. ESAT-6, which has been shown to be highly immunogenic in animals [66, 75 – 78], readily discriminated between bovine tuberculosis and cattle sensitized to environmental mycobacteria [75]. CFP-10 also has demonstrated utility in diagnosing bovine tuberculosis because of its significant specificity [78]. The melding of the ELISA-based QuantiFERONTB test and the RD1 antigens, ESAT-6 and CFP-10, led to a more specific test, now known as the QFNGold. Similarly, the T SPOT-TB test employs the RD1 antigens but links them to an ELISPOT assay

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that identifies ESAT-6 – or CFP-10 – specific IFN-g – secreting CD4+ T cells. Studies of the IFN-g release assays employing ESAT-6 or CFP10 in humans have been promising [79 – 88]. ESAT-6 is a major target of the cellular immune response in humans [62,63]. Early on, assays employing ESAT-6 were shown to be more specific although less sensitive than PPD-based assays for active disease [79,82,89 – 91]. This improved specificity over PPD with loss of sensitivity was later shown by Arend and colleagues [80,81] to hold true in LTBI as well. More importantly, they also demonstrated improved specificity over the TST. They reported loss of sensitivity with respect to the TST, but, because the TST was used as the reference standard for LTBI, this result probably reflected the improved specificity rather than poorer sensitivity [80]. The improved specificity over the QuantiFERON-TB assay for PPD and over the TST was confirmed in a study by Johnson et al [79] of 60 Australian medical students who did not have BCG vaccination or known exposure to M. tuberculosis or NTM. The specificity of both the QuantiFERON-TB for PPD and the TST were reduced after BCG vaccination was administered to the students, but the QuantiFERON-TB for ESAT-6 was unaffected [79]. Brock and colleagues [85] also demonstrated improved specificity for both the ESAT-6 and CFP-10 over PPD in BCG-vaccinated versus nonvaccinated subjects. Recently, Brock and colleagues [88] published an outbreak study based on a case of active disease in a Danish high school student and the student’s mostly non – BCG-vaccinated contacts. The TST was used as the reference standard for LTBI in this population, and there was excellent agreement between the TST and the QuantiFERON-TB ESAT-6/ CFP-10 assay (94%) [88]. Superiority of the assay could not be established in this study, because the TST was itself the reference standard. Nonetheless, significant specificity with regard to BCG status was suggested by the findings in subjects who were BCGvaccinated. Of these, 50% in the high-exposure group had a positive assay, compared with 53% of high-exposure subjects who did not have BCG vaccination. In the low-exposure group, 5% of BCGvaccinated persons were assay positive, similar to the 6% of those who did not have BCG vaccination [88]. Finally, Mori and colleagues [87] studied a group of 216 Japanese student nurses who had no identified risk for M. tuberculosis exposure, all of whom had been vaccinated with BCG [87]. In this group 64.6% of the subjects had a TST response measuring 10 mm or more, yielding a specificity of 35.4% for the TST if it is assumed that none had true LTBI using exposure

the diagnosis of tuberculosis

history as the reference standard. The QuantiFERONTB ESAT-6/CFP-10 assay, on the other hand, yielded a specificity of 98.1% in this group, far superior to the TST. The sensitivity of the assay, 89.0%, was determined in a separate group of patients who had culture-proven active disease. Extrapolating the sensitivity for LTBI from the sensitivity for active disease is problematic, however, because both IFN-g activity and TST reactivity are reduced in active disease; extrapolation probably underestimates the sensitivity for LTBI [12,92,93]. Ajit Lalvani and colleagues [94] have adapted the ELISPOT technique, an ex vivo T-cell – based assay for the detection of cell-mediated immunity, for use in detecting M. tuberculosis. The technique detects and enumerates peripheral blood IFN-g – secreting T cells that respond to ESAT-6 or CFP-10. In 2001, Lalvani and colleagues [94] established a sensitivity of 96% in active disease (100% in the subpopulation that had extrapulmonary tuberculosis) as compared with 69% sensitivity for the TST. In healthy BCG-vaccinated controls, the ELISPOT was not confounded by BCG. In TST-positive household contacts of a case of active disease (expected cases of LTBI), 85% were ELISPOT positive, suggesting a sensitivity for LTBI of 85% if the TST is taken to be the reference standard [94]. In 2001, Pathan and colleagues [92] also examined a low-exposure population of mostly BCGvaccinated subjects. None of the 32 healthy controls were positive on ELISPOT. That year, Lalvani and colleagues [95] also reported on an outbreak study [95]. The odds ratio (OR) of a positive ELISPOT with increasing proximity and duration of exposure to the index case was 9.0, whereas the OR of a positive TST (by Heaf test, a less well-standardized approach to skin testing than the tuberculin test) was only 1.9. Another study published in 2001 by Lalvani and colleagues [12] looked at 40 healthy controls in the United Kingdom, 82% of whom were BCGvaccinated and all of whom were ELISPOT negative. Another study in the United Kingdom similarly found that none of 40 healthy controls were ELISPOT positive [96]. In 2003, Ewer and colleagues [97] published a meticulously investigated outbreak study that evaluated the ESAT-6/CFP-10 – based ELISPOT assay for LTBI. Two years earlier, in the United Kingdom, a secondary school student had been diagnosed with sputum smear – positive cavitary pulmonary tuberculosis. The health authority screened 1128 students at the school with the TST (HEAF test). Screening detected 69 cases of active disease and 254 cases of LTBI, 87% of whom had been vaccinated with BCG.

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Five hundred thirty-five representative students were enrolled in the study and underwent ELISPOT testing. The significance of the study derives from the detailed contact information available for each student by virtue of their mandatory, scheduled daily activities. Degree of exposure to the source case could be readily quantified and grouped as (1) same class, same year, with regularly shared lessons; (2) same year with only weekly shared events; and (3) other years. Using ORs, the authors provide an estimate of the increase in odds of a positive ELISPOT for each increase in level of exposure. The ELISPOT correlated significantly better than the TST with increasing exposure across each group. The relative risk (RR) of direct exposure to the index case if one was both TST and ELISPOT positive was 17.6. If one was ELISPOT positive but TST negative, it was 11.7. If one was ELISPOT negative and TST positive, the RR was only 2.97. Also, TST positivity was significantly associated with BCG vaccination status and with birth in a region of high prevalence for NTM, whereas no significant association was found for the ELISPOT. The superior correlation with degree of exposure strongly suggests improved sensitivity with the ELISPOT. The lack of confounding by BCG or NTM suggests improved specificity with the ELISPOT. The role of IFN-g – or T-cell – based assays in the diagnosis of LTBI is being defined. These tests show promise as replacements for the TST in diagnosing LTBI among persons at risk for infection in the developed world. Both the QFN-Gold and T SPOTTB tests are approved for diagnostic use throughout the European Union. In addition, the QFN-GOLD was approved by the United States Food and Drug Administration (FDA) in December 2004. Clinical experience with these tests should accumulate rapidly. The less accurate original QuantiFERON-TB is approved for use in the United States by the FDA, but guidelines for its use are confusing, and the test has not been widely adopted in clinical settings. The improved sensitivity of these tests over the TST would capture a cohort of patients who otherwise would go without treatment of LTBI. Within that cohort, those that would have progressed to active disease would be spared the attendant morbidity and mortality. The future contacts of those destined to progress to active disease would likewise be spared. This cohort would be overrepresented by those most likely to have false-negative TST results, namely immunosuppressed individuals. This population is precisely the one in which it is most important to identify LTBI because of their increased risk for developing active disease [3]. Unanswered is whether

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there is something different about this cohort that gives positive results on these assays and negative results on the TST and whether their risk for developing active disease is less than that of those who are also TST positive. The TST has predictive value for the subsequent development of active disease in both HIV-negative [9,25] and HIV-positive patients [98]: a stronger skin test response indicates an increased risk of developing active disease [99,100]. Longitudinal studies linking positive assays with risk for development of active disease are ongoing and are crucial to demonstrating the true role of these tests. If they demonstrate a high degree of accuracy, treatment of LTBI might, under the right conditions, become a viable strategic component of tuberculosis control efforts in high- and low-prevalence countries [97]. One small study of 24 healthy household contacts of persons who had smear-positive pulmonary tuberculosis in Ethiopia looked at QuantiFERON-TB ESAT-6 responses at the initial visit and approximately 2 years later. The subjects were not treated for LTBI. Seven of 24 patients went on to develop pulmonary active disease. The subjects who responded to ESAT-6 at study entry were significantly more likely to develop active disease than those who were not responsive [101]. The improved specificity would decrease unnecessary treatment in those who are not truly infected, thereby avoiding the costs to the health care system for medication, follow-up, and management of complications. It would also spare the individual patient these same costs. Costs would also likely be reduced by the increased capture of cases of LTBI, because their identification would eliminate the future—much greater—costs of treating an outbreak of active disease. Costs also might be reduced by the decreased number of clinic visits required, because the TST requires a follow-up visit for reading the TST and may require a second skin test to overcome the booster phenomenon. At present, LTBI is neither diagnosed nor treated in most high-burden, resource-poor countries, except in certain situations, such as young children who are close contacts of active cases. The expense of a novel diagnostic test must be justified in terms of the cost savings realized from treating LTBI. Such savings could accrue by reducing the number of cases of active disease that develop from the vast reservoir of LTBI that exists in the developing world. Overall, the potential advantages of the IFN-g – release and T-cell – based assays over the TST in diagnosing LTBI seem to include improved specificity (lack of confounding by BCG and NTM) and

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improved sensitivity. Operator bias and inter- and intrareader variability are significantly reduced. Only a single patient visit is required. There is no booster effect. The results are obtained rapidly, within 24 hours. There may well be cost savings to the health care system. The assays have proven to be robust in different populations and in different settings, in both the developed and developing worlds. The technology for running the assays has improved so that requirements for equipment and technical expertise are reasonable. Further study is needed. Longitudinal data, as mentioned previously, are critical. To date there are no large-scale trials of these assays, and few studies have employed the Mantoux test while using current ATS/CDC/IDSA criteria for a positive TST. Study of the effect of treatment on assay results in LTBI may provide the data necessary to monitor therapy for LTBI, allowing the clinician, for example, to distinguish response to therapy from lack of response caused by noncompliance or isoniazid resistance. Another area of interest would be the ability to distinguish past exposure to M. tuberculosis without ongoing infection from true ongoing LTBI. It may be that detection of T cells specific for ESAT-6 or CFP-10 suggests that tubercle bacilli continue to secrete these antigens [12]. Identification of an antigen that is expressed either during LTBI or during active disease, but not during both, and that could distinguish these two states would greatly enhance the role of the assays in active disease and would increase the specificity for LTBI. Finally, the point after infection at which the RD1 antigens become detectable has yet to be defined precisely and has significant implications for testing in contact investigations and for reducing false-negative results soon after infection with M. tuberculosis.

Tests for tuberculosis disease The reference standard for diagnosing active disease remains largely clinical: documented response to appropriate therapy. Of course, establishing a microbiologic diagnosis is preferable. AFB smear, mycobacterial culture, and NAA assays may all be used in confirming a diagnosis of active disease (both pulmonary and extrapulmonary). In the case of pulmonary tuberculosis, the method of obtaining a sample greatly affects the sensitivity of testing. Extrapulmonary tuberculosis frequently poses a diagnostic challenge because specimens may be difficult to obtain. After identifying M. tuberculosis, the most pressing issue is drug-susceptibility testing, in which

the diagnosis of tuberculosis

traditional culture techniques are giving way to more advanced technologies that produce rapid results.

Mode of diagnosis of pulmonary tuberculosis Is there a role for the tuberculin skin test in the diagnosis of active disease? The TST was originally a test for active disease [9]. It is unsuited for that purpose because its specificity is limited by cross reactions with NTM and M. bovis BCG, and, more importantly, by its detection of LTBI itself, and by alterations in general immune responsiveness that may occur in cases of active tuberculosis. The sensitivity of the TST for active disease varies considerably, from 65% to 94% [31,34,58,87,89,94]. A study of 3600 hospitalized patients done by the World Health Organization in the 1950s found a sensitivity of 93% for reactions of 10 mm or more and a sensitivity of 78% when a cut-off of 14 mm or more was used [31]. The sensitivity is decreased in certain populations (eg, to less than 50% in critically ill patients who have disseminated tuberculosis) [25]. Lacking both specificity and sensitivity for active disease, the TST is not particularly useful in this setting.

Sputum-based diagnosis To establish a diagnosis of pulmonary tuberculosis, respiratory samples are submitted to the laboratory for microscopy (AFB smear) and for mycobacterial culture. NAA assays may also be used in the diagnostic algorithm, as discussed later. The technique used to obtain the respiratory sample strongly influences the ability to detect pulmonary tuberculosis. Expectorated sputum is generally the starting point. Three samples are collected on three separate days and stained for AFB [102,103]. Although, the utility of collecting three samples has been questioned [104], the overall yield for smear and culture is superior to collecting fewer specimens [105,106]. Samples are generally sent simultaneously for smear and culture, because culture data are essential for confirmation of the diagnosis. In resourcepoor countries, the cost of culture is often too great, resulting in reliance solely on AFB smears. The sensitivity of sputum AFB smears for detecting pulmonary tuberculosis is limited by the need for 5000 to 10,000 bacilli per milliliter to be present in a specimen to allow detection [3]. The sensitivity

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of expectorated sputum ranges from 34% to 80% [3 – 5,104,107 – 116]; the sensitivity tends to be highest in patients who have cavitary disease and lowest in patients who have weak cough or less advanced disease. In no way does a negative sputum smear eliminate the diagnosis of active tuberculosis, particularly if the clinical suspicion is high. Instituting therapy in such cases often is warranted while awaiting culture results. If a patient is suspected of having pulmonary tuberculosis but is smear negative on expectorated sputum or is unable to produce sputum for testing (30% of patients in one series [117]), further diagnostic testing may be warranted. The options include sputum induction (SI), fiberoptic bronchoscopy (FOB), and perhaps gastric washings (GW). The following discussion refers specifically to patients who are expectorated sputum smear negative or who cannot produce an expectorated sputum sample.

Sputum induction SI in the diagnosis of active disease was first described in 1961 by Hensler and colleagues [117]. They adapted an earlier technique used to obtain sputum for cytology in diagnosing lung cancer. Early studies compared SI with the well-established method of gastric aspiration [117 – 119]. In patients unable to expectorate or who had smear-negative sputum samples, SI was superior to GW in obtaining a suitable sample for culture, although the two techniques were noted to be complementary [119]. GW probably adds to overall diagnosis, and, according to one author, its value has been underestimated in recent years [120]. The role of GW in adults is probably quite limited, however. SI, on the other hand, has proven effective in patients clinically suspected of having pulmonary tuberculosis who are either unable to produce sputum or are sputum smear negative. SI has performed well in resource-poor countries with little added cost [121 – 123]. In South Africa, SI performed on 51 patients yielded a suitable sample in 36 [123]. Fifteen of the 36 patients (42%) were smear positive, 12 of whom were ultimately culture positive as well. In Malawi, Parry and colleagues [122] were able to obtain SI specimens in 73 of 82 patients. Eighteen of the 73 (25%) were smear positive, and 30 of 73 (42%) were culture positive. Similarly, of 1648 patients in China, 558 (34%) were smear positive on SI samples. The direct cost per SI in that study was 37 cents [121]. In these studies, SI provided appropriate samples for diagnosis and increased the early diagnostic yield significantly. SI also seems to be cost-effective in the resource-poor setting.

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Conversely, in a retrospective review of 114 patients who had culture-positive M. tuberculosis infection at an urban hospital in New York, SI added little to overall diagnosis and was deemed costly by the investigators [124]. In 1 year, they performed 1566 SIs yielding only 16 positive smears in 10 patients. At a cost of $28.65 per SI, the annual cost of $45,000 would indeed be difficult to justify [124]. A study in the United Kingdom confirmed a low yield but suggested there might be a role for SI [125]. Is there a role for SI in resource-rich countries? A large, prospective study from Montreal, Canada, assessed 500 patients who were either smear negative (5%) or could not produce sputum (95%) with repeated SI [126]. An adequate sample was obtained in 99.8% of patients. The cumulative yield of SI for smear-positive samples with successive attempts was 64%, 81%, 91%, and, after four inductions, 98%. The culture yield also increased with each attempt from 70% to 91% to 99% to 100%. This study suggests that the use of repeated SI has a high yield in this setting and that repeated SI should be considered seriously in this subset of patients [126]. Sputum induction versus fiberoptic bronchoscopy How does SI compare with FOB in the diagnosis of pulmonary tuberculosis in expectorated-sputum smear-negative patients or patients unable to produce sputum? A study by McWilliams and colleagues [127] from New Zealand compared repeated SI with FOB, which was performed if at least two SIs were smear negative. They prospectively studied 129 patients who underwent both procedures. Each successive SI, up to three in total, increased the yield for culture-positive samples significantly. SI was performed without difficulty in 96% of patients and had an overall yield of 96.3% after three tests, confirming the utility of repeated SIs. By contrast, the yield of FOB was only 51.9%, making SI significantly more sensitive in this population. The authors also noted that the overall cost of FOB was three times that of doing three SIs. They offered several strategies for diagnosis: FOB alone was too insensitive, whereas SI alone was sensitive (missed only one case) and cost effective. Although the combination of SI and FOB would have captured all culture-confirmed cases of pulmonary tuberculosis, it would have done so at four times the cost. The preferred strategy, according to the authors, would employ SI followed by FOB only in patients who were negative on SI but had features of pulmonary tuberculosis on chest radiograph. This strategy missed no cases and was only 2.5 times the cost of SI alone [127]. This strategy may be

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worthwhile in resource-rich settings but may be less applicable in resource-poor settings where repeated SI alone would diagnose most of the cases at a substantially reduced cost. Anderson [128] prospectively compared SI and FOB with bronchoalveolar lavage (BAL) in 101 patients who had suspected pulmonary tuberculosis in Montreal. SI yielded a positive smear in 19% of cases; the yield of FOB smear was 12%. The yield was much higher in obtaining culture-positive samples: 87% with SI, as compared with 73% for FOB. Overall, SI performed better than FOB, and direct costs of FOB were more than eight times those of SI [128]. A Brazilian study compared SI with FOB in HIV-positive and HIV-negative patients [129]. One hundred forty-three patients were diagnosed with pulmonary tuberculosis, 17% of whom were HIV positive. The sensitivity of SI smear was 33.8%, and that of FOB was 38.1% in HIV-negative patients. In HIV-positive patients, the sensitivities were similar: 36% for SI smear and 40% for FOB smear. SI produced an adequate sample in 97% of patients in this study [129]. SI performs well in both resource-poor and resource-rich countries, is useful in HIV-positive and -negative patients and compares favorably with FOB in diagnostic yield and cost. Some authors argue that neither SI nor FOB should be performed unless absolutely necessary, given the risk of exposure of health care workers and other patients to the aerosolgenerating procedures [130]. This warning, however, applies mostly to environments where proper respiratory protective equipment and exhaust ventilation devices or appropriate isolation rooms are in short supply [130].

The role of fiberoptic bronchoscopy FOB encompasses BAL, bronchial washings (BW), bronchial brushings (BB), transbronchial biopsy (TBB), and postbronchoscopy sputum collection (PBS). FOB has been studied by several investigators (although usually in relatively small studies) in pulmonary tuberculosis suspects who are smear negative or unable to produce a sputum sample. The utility of FOB (or SI) in this setting is twofold. First, generating a sample in patients who do not have spontaneous sputum creates the potential for making a diagnosis. Second, rapid diagnosis (by positive smear or histopathology) in either subset of patients provides the potential for earlier intervention and treatment while awaiting culture results.

the diagnosis of tuberculosis

In 1988, Chawla and colleagues [131] at the University of Delhi in India prospectively studied 50 pulmonary tuberculosis suspects who were smear negative or unable to produce sputum. Overall, cultures of M. tuberculosis from FOB were positive in 90%. More significantly, a rapid diagnosis was made in fully 72% of cases. Smear-positive samples were obtained in 28% of PBS specimens, 24% of BW specimens, and 56% of BB specimens. In the case of BB specimens, 10 patients (20% of those studied) were rapidly diagnosed exclusively by this means. PBS and BW each provided the exclusive diagnosis for 6% of patients. TBB was performed in 30 patients, and histopathology was positive in 9 (3 were exclusively diagnosed on biopsy). The authors comment that the high yield from the BB smears was a result of brushing caseous material in the bronchi when visible [131]. In a study from Hong Kong in 1982, So and colleagues [132] also prospectively examined the capability of FOB for rapid diagnosis. They performed FOB in 65 pulmonary tuberculosis suspects. Overall, rapid diagnosis was achieved in 42 of 65 (65%). TBB gave a rapid diagnosis in 33 of the 57 patients in whom it was performed (58%) and was the exclusive means of rapid diagnosis in 12% [132]. Willcox and colleagues [133] conducted a study in Cape Town, South Africa, in 1982 that looked at 275 pulmonary tuberculosis suspects. Seventy-nine were diagnosed with pulmonary tuberculosis. FOB made the culture diagnosis in 60 of 79 (76%). BB gave a rapid diagnosis in 33%, and TBB did so in 43%. Similarly, Sarkar and colleagues [134] prospectively performed FOB in 30 pulmonary tuberculosis suspects in Rajasthan, India. Rapid diagnosis was made in 22 of 30 persons (73%). In a retrospective review of 41 patients who had culture-proven pulmonary tuberculosis and underwent FOB, a rapid diagnosis was obtained in 34% of patients [135]. Finally, Mehta and colleagues [112] looked retrospectively at 30 patients who had culturepositive pulmonary tuberculosis and a negative sputum smear or no sample. FOB (BW and BB) made a rapid diagnosis in 18 of 30 patients (60%). The potential utility of BAL and TBB for rapid diagnosis in HIV-positive and HIV-negative patients was demonstrated in a study by Kennedy and colleagues [136]. They retrospectively reviewed 67 HIVpositive and 45 HIV-negative patients who had culture-proven pulmonary tuberculosis. Of those who had smear-negative sputum, BAL provided a rapid diagnosis in 24% of HIV-positive and 8% of HIV-negative patients. BAL was the exclusive means of diagnosis in seven HIV-positive patients and in one

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HIV-negative patient. TBB yielded a rapid diagnosis in 16% of HIV-positive and 42% of HIV-negative patients. Overall, TBB provided the exclusive early diagnosis in 10% of patients [136]. Although not all studies report such high yields from FOB [137 – 142], it definitely has utility [103]. The ability to achieve rapid diagnosis—a crucial step in the management of pulmonary tuberculosis—with FOB generally ranges from around 30% to 70%, and the overall yield of culture from FOB specimens is much higher [112,113,131,132,134 – 136,143 – 147]. Although the yield of the different techniques varied significantly among studies, each one clearly contributed to the overall yield of FOB. The most productive use of FOB is in pulmonary tuberculosis suspects who produce no sputum or who are smear negative and in patients in whom there is considerable diagnostic uncertainty, where lung biopsy may produce an alternative diagnosis. These benefits must always be weighed against the costs of the procedure, concerns regarding infection control, and the risk of TBB in any given patient. Cultures Cultures of mycobacteria require only 10 to 100 organisms to detect M. tuberculosis. As a result, the sensitivity of culture is excellent, ranging from 80% to 93% [3,107]. Moreover, the specificity is quite high, at 98% [3]. Cultures increase the sensitivity for diagnosis of M. tuberculosis and allow speciation, drug-susceptibility testing, and, if needed, genotyping for epidemiologic purposes [3]. Therefore, all specimens should be cultured. There are three types of culture media: solid media, which includes egg-based media (LowensteinJensen) and agar-based media (Middlebrook 7H10 and 7H11), and liquid media (Middlebrook 7H12 and other broths). Solid media, long the standard for culturing mycobacteria, are slower than liquid media, which now are widely used alongside solid media to increase sensitivity and decrease recovery time [148, 149]. In fact, Lowenstein-Jensen 7H10 and 7H11 media may detect mycobacteria in less than 4 weeks [148,150,151], but they require incubation for as long as 6 to 8 weeks before they can be classified as negative. In contrast, broth media combined with DNA probes for rapid species identification typically provide results in less than 2 weeks with smearpositive samples and somewhat longer with smearnegative samples [148,151,152]. Broth media formulations include both manual and automated systems using radiometric or colorimetric methods for detection of mycobacteria. Examples of broth media

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include the BACTEC 460TB and BACTEC MB9000 radiometric methods, the Mycobacterial Growth Indicator Tube or MGIT nonradiometric method, and the manual Septi-Chek AFB system (all from Becton Dickinson Microbiology Systems, Franklin Lakes, NJ), the MB/Bac T (Biomerieux, Durham, NC), Extra Sensing Power (ESP) and Myco-ESPculture System II (Trek Diagnostic Systems, Cleveland, OH), and BacT/ALERT MB Susceptibility Kit (Organon Teknika, Durham, NC). Broth media also may allow more rapid determination of drug susceptibilities, particularly if direct susceptibility testing is used. Direct susceptibility testing may be done with smear-positive samples that are simultaneously inoculated into bottles lacking and containing antibiotics. With this technique, drug susceptibilities can be known at the same time as culture results. Newer culture technologies are in development. One such product is TK Medium (Salubris, Inc., Cambridge, MA). TK Medium uses multiple-color dye indicators to identify M. tuberculosis rapidly. It can also be used for drug-susceptibility testing and can differentiate a contaminated specimen. Information is available at www.salubrisinc.com.

Nucleic acid amplification assays NAA assays amplify M. tuberculosis – specific nucleic acid sequences using a nucleic acid probe. NAA assays enable direct detection of M. tuberculosis in clinical specimens. Such assays complement the conventional laboratory approach to the diagnosis of active disease. Whereas AFB smears are rapid but lack sensitivity and specificity, and culture is both sensitive and specific but may take from 2 to 8 weeks to produce results, NAA assays allow rapid, sensitive, and specific detection of M. tuberculosis. The sensitivity of the NAA assays currently in commercial use is at least 80% in most studies, and these assays require as few as 10 bacilli from a given sample under research conditions [3]. Although the sensitivity of these assays in AFB smear-negative samples is lower than for smear-positive samples, newer assays perform much better in this regard than earlier versions, increasing the sensitivity for smearnegative specimens as well as overall sensitivity [4,108]. NAA assays are also quite specific for M. tuberculosis, with specificities in the range of 98% to 99%. At present two FDA-approved NAA assays are widely available for commercial use: the AMPLICOR M. tuberculosis (Roche Diagnostic Systems,

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Inc., Branchburg, NJ), and the Amplified Mycobaterium Tuberculosis Direct (MTD) Test (Gen-Probe, Inc., San Diego, CA). The AMPLICOR assay uses DNA polymerase chain reaction (PCR) to amplify nucleic acid targets. The FDA approved its use in smear-positive respiratory specimens in December 1996. The COBAS AMPLICOR is an automated version of the AMPLICOR MTB. The MTD assay is an isothermal strategy for detection of M. tuberculosis rRNA. The FDA approved its use for use with smear-positive respiratory specimens in December 1995. A reformulated MTD (AMTDII or E-MTD, for enhanced MTD) was approved by the FDA in May 1998 for smear-positive specimens and in September 1999 for detection of M. tuberculosis in both smear-positive and smearnegative respiratory specimens. In clinical and laboratory studies, the original MTD assay ranged in sensitivity from 83% to 98% for smear-positive respiratory samples [107,153 – 160] and from 70% to 81% for smear-negative respiratory samples. In a recent study in Zambia (one of relatively few studies in a resource-poor country), the sensitivity was only 64% [116]. The specificity in these studies was 98% to 99%. The AMPLICOR assay performed similarly. The sensitivity was 74% to 92% for smear-positive respiratory samples [5,107,109, 157,161 – 166] and 40% to 73% for smear-negative samples [5,107,161,164 – 166]. Specificity ranged from 93% to 99%. In Switzerland, Laifer and colleagues [167] recently tested the AMPLICOR assay in 3119 war refugees from Kosovo and found a sensitivity of only 64% for pulmonary tuberculosis [167]. They noted, however, that the negative predictive value of three consecutive PCRs (in two sputa and one BAL) was 100%. In studies where MTD and AMPLICOR have been compared directly, MTD has consistently had a small advantage [107, 157,159]. The E-MTD brings with it an improved sensitivity [4,108,153,168], especially in smear-negative specimens [4,108]. Bergmann and colleagues [4] investigated the E-MTD in a 1999 study of Texas prison inmates [4]. One thousand four respiratory specimens from 489 inmates tested with E-MTD were compared with culture, smear, and clinical course. Twenty-two inmates were diagnosed with pulmonary tuberculosis (10 smear-positive and 12 smear-negative.) Overall, the E-MTD had a sensitivity of 95.2% and a specificity of 99.1%. In smear-positive patients, the sensitivity and specificity were both 100%. In smearnegative patients, the sensitivity was 90.2%, and the specificity was 99.1% [4]. A 1999 study from the Central Public Health Laboratory in Etobicoke,

the diagnosis of tuberculosis

Ontario, looked at 823 specimens (616 respiratory) over a 1-year period [108]. Using clinical diagnosis as the reference standard, the specificity approximated 100%, and the sensitivity for either smearpositive or smear-negative respiratory samples was 100%, an exceptionally high value, especially for the smear-negative specimens. Specimens that were smear negative were preselected for testing with the E-MTD based on a clinical determination that the patients were at high risk for tuberculosis. Preselection no doubt contributed to the high sensitivity and specificity in this study, but results indicate there is great utility in selecting appropriate patients for testing [108]. An investigation of the E-MTD with particular clinical relevance was undertaken by Catanzaro and colleagues [169] who evaluated the performance of the E-MTD in a multicenter, prospective trial. In this study, the E-MTD was evaluated against the backdrop of a patient’s clinical suspicion for pulmonary tuberculosis, which was stratified into low, intermediate, or high risk as determined by physicians who had expertise in evaluating patients for tuberculosis. Clinical investigators determined the risk for 338 patients. The specificity of the E-MTD was high in all groups. The sensitivities were 83%, 75%, and 87% respectively. The positive predictive value, however, was low in the low-risk group (59%, as compared with 100% in the other two groups). The negative predictive value was especially high in the low-risk group (99%) and remained high (91%) in the intermediate- and high-risk groups. These results compared favorably with the AFB smear, which had positive predictive values of 36% (low), 30% (intermediate), and 94% (high), respectively, and negative predictive values of 96% (low), 71% (intermediate), and 37% (high), respectively. This study demonstrates the clear utility of the E-MTD 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 [169]. Other NAA assays have been tested, such as a ligase chain-reaction – based test (LCx test; Abbott Diagnostics Division, Abbott Park, IL), and the strand displacement amplification (SDA) test known as the BDProbeTec ET Mycobacterium tuberculosis Complex Direct Detection Assay (DTB) (Becton Dickinson Biosciences, Sparks, MD). DTB is a 1-hour assay that couples SDA to a fluorescent energy-transfer detection system. DTB performs similarly to the E-MTD [170,171]. A variety of less standardized PCR assays have been developed and tested [172 – 175]. Real-time PCR assays have com-

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pared favorably with AMPLICOR [174,175] and E-MTD [173]. None of these tests has been approved for use in the United States. In 2000, the CDC updated its recommendations for use of NAA tests for the diagnosis of active disease [176]. The CDC now recommends that AFB smear and NAA be performed on the first sputum smear collected. If smear and NAA are both positive, pulmonary tuberculosis is diagnosed with near certainty. 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 M. tuberculosis and repeating the assay. If inhibitors are not detected, the process is repeated on additional specimens. If the sputum remains smear positive without inhibitors and NAA negative, the patient can be assumed to have NTM. If a sputum sample is smear negative but E-MTD positive (only the E-MTD is approved for smearnegative specimens), the CDC recommends testing additional samples. If further samples are E-MTD positive, the patient can be assumed to have pulmonary tuberculosis. If both the smear and E-MTD are negative, an additional specimen should be tested by E-MTD. If negative, the patient can be assumed not to have infectious pulmonary tuberculosis. The recommendations conclude by noting that clinicians must always rely on clinical judgment and that, ultimately, definitive diagnosis rests on response to therapy and culture results [176]. Although they have a certain logic, these recommendations are expensive and based on few published data. Overall, a reasonable use of NAA assays for rapid diagnosis of pulmonary tuberculosis is as follows: NAA assays should be used to confirm that a positive AFB smear does indeed represent M. tuberculosis. If both smear and NAA are positive, pulmonary tuberculosis 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 [177]. 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 observers [169,178,179]), NAA should be performed on a sputum sample, and a presumptive diagnosis of tuberculosis is 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 [169, 179,180]. Testing should also be limited to those who have not been treated recently for active disease [177].

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Cost is the main consideration limiting the use of the NAA assays, particularly in the developing world. A study in Nairobi, Kenya, compared the costeffectiveness of AMPLICOR and that of an AFB smear [181]. The AFB smear was 1.8 times as costeffective. The authors, however, concluded that AMPLICOR could be cost-effective if ‘‘the largest contributing component, the costs of the PCR-kit, can be reduced substantially.’’ 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 smearpositive specimens [182]. Extending this assay to smear-negative specimens may be possible when g the E-MTD is used, however, because of its superior sensitivity in smear-negative patients who have pulmonary tuberculosis. Furthermore, centralized laboratories offer the ability to invest in technology, conduct batch testing, develop expertise, and benefit from economies of scale. In such settings, regular NAA testing may be economically feasible [108,183]. A major limitation of NAA tests is that they give no drug-susceptibility information. In addition, they are able to detect nucleic acids from both living and dead organisms and may be falsely positive for active disease in patients who have a recent history of infection and have been adequately treated [156, 184 – 186]. In contrast to NAAs that employ DNA or rRNA, the use of an assay to detect M. tuberculosis mRNA, with a half-life of only minutes, offers an indicator of the viability of M. tuberculosis. Assays that detect mRNA remain positive only while viable mycobacteria persist and therefore are useful as sensitive indicators of adequate treatment and for rapid determination of drug susceptibility [187]. This technology is under study.

Extrapulmonary tuberculosis Diagnosing extrapulmonary tuberculosis presents the clinician with many challenges. In most cases, the samples are paucibacillary, decreasing the sensitivity of diagnostic tests. Testing for extrapulmonary tuberculosis follows the same principles as for pulmonary tuberculosis, but, because accuracy of diagnosis is attenuated in extrapulmonary tuberculosis, clinicians must rely more heavily on clinical judgment and response to treatment to diagnose extrapulmonary tuberculosis. Meanwhile, the increased incidence of extrapulmonary tuberculosis in HIV patients makes it all the more urgent to improve diagnostic strategies for this entity.

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AFB smear and culture are used but generally are less sensitive in nonrespiratory samples. Respiratory samples are sometimes of benefit in extrapulmonary tuberculosis. In the case of pleural tuberculosis, the finding of M. tuberculosis in the sputum is diagnostic of tuberculosis in patients who have an effusion. Such patients may not easily give expectorated sputum samples, however. In this setting, IS has been shown to have a sensitivity of 52% for M. tuberculosis [188], compared with the 60% to 80% sensitivity of the more invasive pleural biopsy [189]. In the case of miliary tuberculosis, sputum smears are warranted, but if smears are negative, FOB may play a significant role. FOB was performed in 41 patients who had miliary tuberculosis and smearnegative sputum [190]. Diagnosis was obtained in 34 patients (83%). BB captured 57% of cases, and TBB was diagnostic in 73% of cases. A rapid diagnosis was made in 27 of 34 patients [190]. In a separate study, 22 patients who had smear-negative miliary tuberculosis underwent FOB with brushings, aspirate, and TBB. Tuberculosis was diagnosed in 16 of the 22 patients (73%). A rapid diagnosis was made in 14 of 16, from brush smears alone in 3 patients, aspirate alone in 1, and biopsy alone in 7 [191]. Sampling multiple sites may also be of benefit in miliary tuberculosis. There is clearly a role for NAA assays in the diagnosis of extrapulmonary tuberculosis, although this role needs to be better defined. The overall sensitivity in nonrespiratory specimens for the MTD or E-MTD ranges from 67% to 100% [108,153 – 155, 160,168,170,192]. In smear-negative samples, the sensitivity was 52% in one study [160] and 100% in another [108]. The AMPLICOR had a similar sensitivity [162,193], and the specificity of both assays remains high in nonrespiratory samples. The assays do not perform equally well in all sample types; for example, they are much more sensitive in cerebrospinal fluid [192,194] than in pleural fluid [154]. The sensitivities vary significantly among studies, as shown in recent meta-analyses of the use of NAA tests in tuberculous meningitis [195] and tuberculous pleuritis [196]. In one study, the combination of AFB smear and MTD in cerebrospinal fluid had a sensitivity of 64%, which increased to 83% by the third sample tested [197]. The DTB system delivers sensitivity similar to the E-MTD in nonrespiratory samples [170,198,199]. The use of adenosine deaminase (ADA) levels, especially in pleural fluid samples, to diagnose extrapulmonary tuberculosis has shown great promise. A recent meta-analysis of 40 studies investigating ADA for the diagnosis of tuberculous pleuritis yielded the

the diagnosis of tuberculosis

summary measure of test characteristics derived from the receiver operator characteristic curve where sensitivity equaled specificity at 92.2% [200]. Similarly, a meta-analysis of 31 studies on ADA in pleural tuberculosis yielded a joint sensitivity and specificity of 93% [201]. The performance of ADA in diagnosing pleural tuberculosis is inconsistent across studies, however. In one study, the sensitivity and specificity were both 55% [202]; in another, they were 88% and 85.7%, respectively [203]. Some authors report the need to combine ADA determination with PCR analysis, yielding a combined sensitivity of 87.5% [204], but others argue that ADA alone is superior to ADA combined with PCR [205]. ADA use outside the pleural space has been explored as well. ADA may be of limited value in diagnosing tuberculous meningitis [206] but was sensitive for tuberculous pericarditis in one study [207]. Another test that has received some attention for the diagnosis of pleural and pericardial tuberculosis is pleural or pericardial fluid IFN-g, which has proven comparable to or even better than ADA in some studies [201,203,207]. Finally, there may be a role for the serum IFN-g assays, discussed earlier, in the diagnosis of extrapulmonary tuberculosis [81,208].

Rapid detection of drug resistance Multidrug-resistant (MDR) tuberculosis poses a major public health problem in many parts of the world. Traditional methods of drug-susceptibility testing rely on cultures of M. tuberculosis inoculated with antibiotics and can take weeks for results to be known. The ability to detect drug resistance rapidly would be vitally important to tuberculosis-control efforts, enabling expeditious administration of appropriate treatment and a decrease in transmission of the MDR strain. The detection of rifampin resistance may be used as a surrogate for uncovering multidrug resistance, because most rifampin-resistant isolates are also isoniazid-resistant [209,210]. Rifampin resistance signals the need for treatment with secondline drugs. It is currently feasible to detect rifampin resistance rapidly. One approach takes advantage of genotypic abnormalities by identifying mutations primarily in the region of the M. tuberculosis rpoB gene associated with most rifampin-resistant strains of M. tuberculosis. Coupling a variety of assays that identify genetic mutations (line probe assays and molecular beacons, for instance) to PCR or related technologies allows rapid detection of the drugresistant mutations from smear-positive respiratory

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specimens or from culture specimens [209,211 – 215]. Another approach detects actual phenotypic resistance seen as persistence of the organism in a rifamycin-containing medium (eg, luciferase reporter phage assays.) Line probe assays Line probe assays use PCR and reverse hybridization with specific oligonucleotide probes fixed to nitrocellulose strips in parallel lines. These assays may be used for the detection and identification of mycobacterial species or for rapid identification of mutations in the rpoB gene. The INNO-LiPA MYCOBACTERIA v2 (Innogenetics, Ghent, Belgium) and GenoType Mycobacterium (Hain Diagnostika, Nehren, Germany) are line probe assays for the simultaneous detection and identification of mycobacteria; both are very sensitive [216]. The INNO-LiPA Rif.TB assay detects M. tuberculosis and is very sensitive for detecting rifampin resistance [213 – 215,217,218]. 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 fluoresce only when bound to their targets, so that a mutation—even a single-nucleotide substitution—prevents fluorescence. A PCR assay using molecular beacons can identify drug resistance in sputum samples in less than 3 hours and is both sensitive and specific [219]. Lin and colleagues [211] designed a set of molecular beacons for the detection of isoniazid- and rifampin-resistant mutations in M. tuberculosis organisms from both cultureand smear-positive respiratory specimens [211]. The sensitivity and specificity for detection of isoniazid resistance were 82.7% and 100%, respectively, and for rifampin resistance were 97.5% and 100%, respectively. Piatek et al [220] previously reported similar findings. Phage amplification Phage amplification uses a bacteriophage to detect M. tuberculosis in a given sample within 48 hours. FASTPlaqueTB (Biotec, Ipswich, Suffolk, UK) uses phage amplification technology to detect viable M. tuberculosis in sputum samples and has had mixed results with excellent specificity (96% – 99%) but lesser overall sensitivity (70% – 87%) [116,221 – 223].

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It detected 48.8% of smear-negative cases in one study [223]. The FASTPlaqueTB-MDRi or FASTPlaqueTB-RIF uses the phage amplification technology to determine rifampin resistance in culture or sputum specimens. Albert and colleagues [224] demonstrated a sensitivity of 100% and a specificity of 97% for identifying rifampicin-resistant strains in solid culture media and in a separate study demonstrated similar results using a liquid culture system [210]. A more recent study by Albert and colleagues [225] showed a 100% sensitivity and specificity for determining rifampin resistance directly from smearpositive sputum, with results also available within 48 hours. Luciferase reporter phages Firefly luciferase catalyzes the reaction of luciferin with ATP to generate photons efficiently and thereby emit light. Mycobacteriophages expressing the firefly luciferase gene may be introduced into viable mycobacteria [226]. The presence of cellular ATP in viable mycobacteria causes visible light to be emitted when exogenous luciferin is added. The emitted light is measured by a luminometer or on film (eg, with the Bronx box [227,228]). In the presence of adequate antimycobacterial therapy, mycobacteria are rendered nonviable, and the light is extinguished. Drug-resistant strains of M. tuberculosis continue to produce light in the presence of antimycobacterial therapy, revealing their resistance. This method can determine drug susceptibility in 1 to 4 days, and it is also a sensitive and specific means for identifying M. tuberculosis [228 – 232]. Cost and the need for advanced technology and laboratory skills limit the applicability of most of these technologies. Efforts to reduce costs and simplify the technology may make these tests practical for widespread use in the near future in resource-rich and, perhaps, even in resource-poor countries.

Summary Diagnostic testing for tuberculosis remained unchanged for nearly a century, but newer technologies hold the promise of a true revolution in tuberculosis diagnostics. The IFN-g release and T-cell – based assays may well supplant the TST in diagnosing LTBI in much of the world. NAA assays are proving their worth in more rapidly diagnosing both pulmonary and extrapulmonary tuberculosis with great sensitivity and specificity. The role of line probe assays, molecular beacons, phage amplification, and

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luciferase reporter phages in diagnosing tuberculosis and rapidly detecting drug resistance is still being defined. These tests are likely to play an everincreasing role in the coming years. Ultimately, the appropriate and affordable use of any of these tests depends on the setting (low or high prevalence of active disease, low or high clinical suspicion in a given patient, available resources, and laboratory capabilities) in which they are employed.

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Clin Chest Med 26 (2005) 197 – 205

The DOTS Strategy for Controlling the Global Tuberculosis Epidemic Thomas R. Frieden, MD, MPHa,*, Sonal S. Munsiff, MDa,b a

New York City Department of Health and Mental Hygiene, 125 Worth Street, New York, NY 10013, USA b Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, GA, USA

In 1997, the Director General of the World Health Organization (WHO) called the directly observed treatment, short-course (DOTS) strategy ‘‘the most important health breakthrough of the decade in terms of the number of lives it will save’’ [1]. DOTS is nothing new; Karel Styblo developed the essential principles of DOTS in the 1980s [1a]. The five principles of the WHO-recommended DOTS strategy [2] are: 1. Political and administrative commitment. 2. Case detection, primarily by microscopic examination of sputum of patients presenting to health facilities. 3. Standardized short-course chemotherapy given under direct observation. 4. Adequate supply of good-quality drugs. 5. Systematic monitoring and accountability for every patient diagnosed. This article reviews the principles, scientific basis, and experience with implementation of DOTS and discusses the relevance of DOTS in the context of

This article is adapted from: Frieden TR. Directly observed treatment, short course (DOTS): the strategy that ensures cure of tuberculosis. In: Sharma SK, Mohan A, editors. Tuberculosis. 2nd edition. New Delhi: Jaypee Brothers Medical Publishers; 2005 [in press]; with permission. * Corresponding author. E-mail address: [email protected] (T.R. Frieden).

multidrug-resistant tuberculosis (MDR-TB) and the HIV epidemic.

Political and administrative commitment By any measure, the global burden of tuberculosis is staggering. There are nearly 9 million new cases and 2 million deaths from tuberculosis worldwide every year [3,4]. More than 100 million people have died of tuberculosis since the tubercle bacillus was discovered by Koch in 1882 [5]. Cases are likely to increase, particularly in parts of the world with a poorly controlled HIV epidemic. Tuberculosis disproportionately affects young adults, impoverishes families, and undermines economic development [6]. Despite the heavy burden of disease, tuberculosiscontrol efforts are often inadequately funded and supported. Shortages of drugs and equipment are common, and key posts within tuberculosis-control programs suffer from low prestige or high turnover and are often vacant. Physicians, in their role as community leaders, are responsible for promoting the existence of effective tuberculosis-control programs and for supporting and coordinating their own efforts with these programs. Although tuberculosis control is a core government function, it cannot be accomplished by any one individual or sector. It requires communication and collaboration among local and national health authorities, the primary health care system, hospitals, medical schools, private physicians, nongovernmental organizations, and others.

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.02.001

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Diagnosis by sputum microscopy of patients attending health facilities Two important concepts are combined in this aspect of the DOTS strategy: first, diagnosis should be based primarily on microscopy rather than on chest radiograph, clinical examination, or culture; and second, case finding should be done primarily among patients presenting at health facilities and not by active case finding in the community. Sputum microscopy is a highly specific test and should be the primary tool for diagnosis. In contrast, the unreliability of chest radiograph is well documented; 30% or more of patients classified as having active tuberculosis on the basis of chest radiograph, even by experts, are found not to have tuberculosis [7 – 10]. The acid-fast bacillus (AFB) smear also correlates with severity of disease, infectiousness, and mortality [11,12] and is a low-cost, appropriate technology that can be done reliably even in remote areas [13]. Decisions based on the standard WHOrecommended diagnosis algorithm [14] are often more rapid than those based on culture [15]. Technical and logistic requirements make culture unsuitable as a primary diagnostic tool in developing countries. Serologic and amplification tests on sputum samples are currently more expensive and less informative than the AFB smear and are not of proven utility in global tuberculosis control; amplification techniques can be useful in areas with low tuberculosis prevalence. Future developments in this area may further facilitate diagnosis, particularly of smearnegative and extrapulmonary tuberculosis cases [16]. The second component of this aspect of the DOTS strategy is the approach to case finding. Active tuberculosis case finding in the community should not be undertaken; it usually results in low cure rates and is of limited or no value in tuberculosis control [17]. Most patients with active tuberculosis seek care, especially if care is provided free of charge, and the few who do not seek care are less likely to complete treatment [11,18]. In countries or regions with generalized HIV epidemics, however, programs for intensified tuberculosis case finding should be implemented in all HIV counseling and testing settings [19].

Standardized short-course chemotherapy given in a program of directly observed treatment This principle also has two aspects, both of which are crucial. The efficacy of short-course, intermittent treatment has been conclusively demonstrated in

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numerous controlled clinical trials, [20 – 24] and is effective for extrapulmonary tuberculosis [25,26]. Standard short-course regimens can cure more than 95% of cases of new, drug-susceptible tuberculosis [27]. Most recommended treatment regimens have two phases: an initial intensive phase with four drugs lasting 2 months, followed by a 4-month continuation phase with at least two drugs. Corticosteroids have been shown to be useful in patients with pericardial and meningeal tuberculosis and are recommended in these situations [14,28]. Attempts to reduce the length of treatment to less than 6 months have failed, indicating that as of 2005 no practical regimen shorter than 6 months using currently available medications is effective for patients with smearpositive tuberculosis [29,30]. Patients previously treated for tuberculosis may require a more intensive treatment regimen. In areas where drug-susceptibility testing is not available, the WHO re-treatment regimen should be used [14]. In areas where drug susceptibility can be determined, the susceptibility results of the isolate should guide the treatment regimen [28]. It is now well documented that intermittent treatment given two or three times a week is, in general, as effective as daily therapy. This finding should not be surprising, because Mycobacterium tuberculosis doubles in 18 to 24 hours, compared with 12 to 20 minutes for most bacteria [31]. In fact, in one animal model, intermittent treatment was more effective than daily treatment [32]. Supervised intermittent short-course therapy for tuberculosis is shown to be highly effective and extremely well tolerated in patients whether or not they are HIV infected [24]. Intermittent treatment should be given only in a program of direct treatment observation [33]. Once- or twice-weekly dosing with rifamycins in HIV-infected tuberculosis patients with CD4 cell counts less than 100/mm3 has been associated with the development of acquired rifamycin resistance [34]. The Centers for Disease Control (CDC) and American Thoracic Society (ATS) now recommend that patients with HIV-associated tuberculosis not be treated with once-weekly regimens and that those with CD4 cell counts of less than 100/mm3 not be treated with any highly intermittent (ie, once- or twice-weekly) regimens. The CDC and ATS now recommend that such patients receive daily therapy during the intensive phase and daily or thrice-weekly therapy during the continuation phase, regardless of whether they are also receiving antiretroviral drugs. The international relevance of this recommendation is unclear and should be further examined; thriceweekly regimens in the intensive phase are recom-

the dots strategy for controlling tuberculosis

mended by the WHO and the International Union Against TB and Lung Disease (IUATLD) and are of proven efficacy for tuberculosis treatment regardless of HIV status. If rifabutin is used, its dose may need to be adjusted depending on the antiretroviral medications used [28,35]. Drugs can be effective only if they are taken [36]. Virtually all clinical studies of short-course chemotherapy were conducted using directly observed therapy [37], and it can be argued that unobserved use of rifampicin-containing regimens is experimental and potentially dangerous. In particular, the initial phase of treatment regimens that include rifampicin should always be directly observed to ensure adherence and prevent emergence of resistance to rifampicin [37]. Direct observation is the standard of care for tuberculosis in most countries [38]. About one third of patients do not take medications regularly as prescribed, and it is not possible to predict accurately which patients will not adhere to treatment [33,36, 39 – 42]. Nonadherence is not related to adverse effects, dosage, or prior receipt of supervised treatment [40,43] and is as high with placebo as with active drugs. Surprise home visits revealed a much greater degree of nonadherence than did pill counts or urine tests, despite ongoing efforts to obtain and maintain the cooperation of patients and their families during the full course of chemotherapy [44]. Directly observed therapy is the most difficult and most controversial aspect of the DOTS strategy. (DOTS is the comprehensive five-point tuberculosiscontrol strategy; directly observed therapy is one essential component of that strategy.) Observation must be done by a person who is accessible and acceptable to the patient and who is accountable to the health system [14]. In some countries, directly observed therapy is given in hospital for the first 2 months [45]. In other countries, health staff [46 – 48], community volunteers [49,50], members of nongovernmental organizations [51], religious leaders [52], and combinations of health staff and a broad cross-section of community workers or volunteers [53] have given directly observed therapy. Each community has particular leaders, and the challenge in implementing this aspect of the DOTS strategy is to identify and enlist the support of these leaders. Even in the unstable environment of a refugee camp, directly observed therapy has been shown to be feasible [54]. Directly observed therapy involves more than merely watching patients as they take medications. Rather, direct observation succeeds by building a human bond between the patient and the health care worker or community volunteer and acknowledging

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the value of treatment success to patients and to their communities. It also implies recognition of the responsibility of the program and of the community to ensure successful treatment through showing respect for the patient and by providing treatment at convenient times and in appropriate facilities [55]. It may be impossible to arrange directly observed therapy for some patients, but directly observed therapy should be possible in more than 90% of cases in a well-functioning program. When directly observed treatment is impossible, the patient may need to be given self-administered treatment, in which a family member may be able to assist the patient. Assistance by a family member is unreliable, however [39,56]. There are no examples of successful large-scale DOTS programs in which immediate family members have been used as primary providers of directly observed therapy. Organizing DOTS, including directly observed therapy, may not be simple, but it is the only method that can ensure a high cure rate on a program basis.

Adequate supply of good-quality drugs Because long-term treatment with a combination of drugs is required [57], it is important that sufficient supplies of all necessary antituberculosis drugs are available so that patients can complete the prescribed treatment. In addition, it is important that drugs are of good quality, with adequate bioavailability. Of particular concern are the bioavailability of rifampicin in combination tablets, particularly when combined with pyrazinamide, and the stability of ethambutol, which may be compromised by poor-quality packaging or excessive humidity during storage. Combination tablets of proven bioavailability have the theoretical advantage of preventing monotherapy. Fixed-dose combination (FDC) tablets incorporate two or more medications into the same tablet and prevent providers and patients from using a single antituberculosis drug. This precaution should reduce the likelihood of development of drug resistance and the possibility of physician prescription error or patient medication error. FDCs can also simplify treatment for patients and logistics for program managers. FDCs of low bioavailability could result in treatment failure and drug resistance, however, and FDCs generally have a shorter shelf life and increase the cost of antituberculosis drugs [14]. The benefits of FDCs on a program basis are difficult to document, and, of course, FDCs still cannot ensure that the drugs are taken.

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Systematic monitoring and accountability Although record keeping is often seen as unimportant, an effective system of registering patients is the heart of the DOTS strategy because it ensures accountability. The information system designed by Styblo [1a] and recommended by WHO is simple but remarkably robust, allowing effective program management as well as operational research. At each microscopy center, a good-quality microscope and reagents are supplied, and the laboratory technician is trained, supervised, and included in a quality control network. Every patient whose sputum is examined is recorded in the tuberculosis laboratory register. Every patient whose sputum is found positive for AFB and started on treatment is recorded in the tuberculosis register, with all patient outcomes recorded. Quarterly reporting of diagnosed cases allows simple but revealing analysis of diagnostic quality and the descriptive epidemiology of tuberculosis. Smear-positive patients are monitored for sputum conversion to negative at the end of the intensivetreatment phase, and this conversion rate is monitored as an early indicator of program effectiveness. Finally, treatment outcomes are systematically recorded in one of six strictly defined categories [14]. The global target for successful treatment of new smear-positive patients is 85% or more [2]. Information in the tuberculosis laboratory register and the tuberculosis register can be easily checked for internal consistency and consistency between records and can also be externally verified by reviewing sputum slides, interviewing patients and health workers, and monitoring consumption of drugs and supplies.

Results of the directly observed treatment, short course strategy The DOTS strategy has been implemented successfully in many countries and contexts. Through 2003, DOTS has been implemented in 182 of 211 countries, covering 77% of the world’s population [3]. In 132 countries, including most of the industrialized world, DOTS is available to more than 90% of their populations [3]. Average treatment success among all national DOTS programs is 82%, close to the 85% global target [3]. By 2005, more than 20 million patients have been treated under DOTS, with an expected case detection rate of close to 50% [3]. While the case detection rate has been increasing over the past decade, it is still below the 70% target [3].

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In Baltimore, Maryland, DOTS achieved a marked reduction in case rates despite a high rate of HIV infection [58]. In New York City, by 1991, half of tuberculosis patients were HIV-infected, and one in five had MDR-TB; [59]; DOTS, in addition to an MDR-TB control program, resulted in a rapid decrease in both tuberculosis and in multidrug resistance [60]. Application of universal directly observed therapy and subsequent adoption of shortcourse chemotherapy were associated with a substantial decline in tuberculosis in Beijing, China, and in Cuba to levels below those of some industrialized countries [47,61]. In Peru, where DOTS was introduced in 1990, high rates of case detection and cure have decreased the incidence of pulmonary tuberculosis by at least 6% per year [62]. In China, prevalence of smear-positive tuberculosis fell 32% more between 1990 and 2000 in areas where DOTS was implemented than in non-DOTS areas [63]. Effective DOTS programs have been established and have functioned well even in the context of civil war [45,46]. In addition, DOTS has been shown to be highly cost effective [45,64].

Multidrug-resistant tuberculosis The emergence of drug resistance is a symptom of ineffective tuberculosis control [65]. If patients take appropriately prescribed antituberculosis treatment, development of resistance is extremely rare. In contrast, in situations where prescribing practices, case holding, or both are poor, drug resistance can emerge. Effective treatment programs can prevent drug resistance [66,67] and may even result in a decrease in drug resistance if it has emerged [60, 68 – 74]. Treatment of MDR-TB is difficult, expensive, and often unsuccessful. Treatment of MDR-TB may be important for tuberculosis control in some contexts, but it should be undertaken only with the appropriate expertise and resources [65]. In most contexts, preventing development of MDR-TB by ensuring cure of new smear-positive patients is a much higher public health priority than treatment of MDR-TB. Low cure rates among new tuberculosis cases will result in the creation of drugresistant cases at a faster rate than these cases can be cured, even if unlimited resources are available [75]. For disease control, if multidrug resistance is present in congregate facilities (eg, prisons, hospitals) where immunosuppressed (eg, HIV-infected or malnourished) individuals are present, it is essential to diagnose patients with MDR-TB promptly and to treat them effectively to avoid rapid spread of the disease.

the dots strategy for controlling tuberculosis

Where resources permit (eg, targets for case detection and treatment success are met and resources are in place to continue DOTS implementation), treatment of MDR-TB can save lives and prevent further spread of disease. There were an estimated 273,000 cases of MDRTB worldwide (3.1% of all tuberculosis cases) in 2000. Most MDR-TB is estimated to be concentrated in 10 countries [76]. These data may underestimate the number of MDR-TB cases worldwide, however, because MDR-TB has been found in most regions of the world that have been surveyed [77]. Systematic surveys of several areas of the world with high tuberculosis incidence, such as most parts of subSaharan Africa and most of Asia, have not yet been done. Resources need to be directed at areas with the highest burden of this disease. There is limited experience treating MDR-TB in resource-limited settings, but successful programs can be implemented [78]. International collaboration and resources probably will be required to implement such programs [79]. Although MDR-TB can be successfully treated in a variety of settings, including community-based treatment by trained community health workers [78], treatment should be given only under a program of directly observed therapy in conjunction with clinicians who are expert in the management of MDR-TB. All attempts should be made to obtain susceptibility results so that regimens can be tailored for individual patients. Most studies of MDR-TB treatment have used individualized regimens [80]. Patients must be treated with a regimen of at least three to five antituberculosis medications to which the strain is known or likely to be susceptible, including an injectable agent and a fluoroquinolone [14,81]. Although longer use of injectable medications is associated with significant adverse effects, longer-term injectable therapy increases culture conversion and survival rates in persons with MDR-TB [82]. Intermittent regimens should not be used. The drugs for treating MDR-TB are much more expensive and have markedly more adverse effects than standard drugs [83]. The duration of treatment is 18 to 24 months; patients need to be monitored carefully, because the risk of default can be high.

HIV Infection with HIV is the most potent known risk factor for progression to active tuberculosis among adults [84]. In outbreaks of tuberculosis in wards for AIDS patients in the United States, the median time

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from tuberculosis exposure to disease was 3 months, and in some outbreaks more than one third of exposed patients developed tuberculosis [85]. The HIV epidemic is a stress test for tuberculosiscontrol programs and can relentlessly reveal program weaknesses. The increase in tuberculosis incidence in Africa is strongly associated with the prevalence of HIV infection [86]. Tuberculosis case rates increased approximately twice as fast in countries with high HIV infection rates, but the increase was lower in countries with good-quality tuberculosis-control services. Improving the quality of national tuberculosis programs can mitigate HIV-associated tuberculosis [87]. Where prevalence of HIV infection is high, tuberculosis treatment alone cannot reverse the rise in tuberculosis incidence. At present, the most effective way to address HIV-associated tuberculosis is through a sound DOTS program coupled with comprehensive, effective HIV prevention and care that incorporates active case finding in settings where HIV counseling and testing are offered [19,88 – 92]. In settings with high incidences of HIV and tuberculosis, diagnosing active tuberculosis in HIVinfected persons is challenging. Sputum smearnegative and extrapulmonary tuberculosis are more common in HIV-infected persons [90,93]. In such settings, consideration should be given to using radiographs and, if feasible, mycobacterial cultures to assist the clinician in diagnosing tuberculosis if sputum smears are negative. Recommended treatment regimens are similar for all tuberculosis patients, whether HIV-infected or uninfected [27], and patients with HIV respond well to standard antituberculosis treatment and do not need additional drugs [90,94,95]. Death during antituberculosis treatment is more common in HIV-infected individuals but is primarily from non – tuberculosisassociated causes [33]. Patients with HIV infection and tuberculosis survive longer if given short-course chemotherapy with rifampicin-containing regimens than if given non – rifamycin-containing regimens [96] and longer still if short-course chemotherapy is given in a program of directly observed therapy [97,98]. In addition, antituberculosis regimens containing rifampicin can be administered safely with several effective, highly active antiretroviral drugs, making it easier to deliver simultaneous treatment for tuberculosis and HIV [35,90,99]. Rifabutin, a more expensive alternative to rifampicin, can be used with most antiretroviral regimens with some dose adjustments [35]. Tanzania and Malawi have had DOTS programs for more than 10 years. Despite high rates of HIV infection (which is present in more than 60% of tu-

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berculosis patients in some sub-Saharan African countries, including Malawi, Zimbabwe, Ethiopia, and Botswana [3]), there has been no evidence of an increased rate of relapse among HIV-infected patients, and rates of drug resistance remain low [66,67]. Avoiding the creation of drug-resistant tuberculosis is the best way to prevent the spread of such strains.

Summary The technology to control tuberculosis has been known for decades. The DOTS strategy can double cure rates. Successful global implementation of DOTS could save millions of lives over the next 10 years. Success will require effective governmental programs along with active communication, collaboration, and participation on the part of the health care system and governmental and nongovernmental sectors.

References [1] WHO calls for immediate use of new tuberculosis breakthrough [press release WHO/24, 1997]. Geneva (Switzerland)7 World Health Organization; March 21, 1997. [1a] Murray CJ, DeJonghe E, Chum HJ, et al. Cost effectiveness of chemotherapy for pulmonary tuberculosis in three sub-Saharan African countries. Lancet 1991; 338(8778):1305 – 8. [2] An expanded DOTS framework for effective tuberculosis control. WHO/CDS/TB/2002.297. Geneva (Switzerland)7 World Health Organization Global Tuberculosis Programme; 2002. [3] Global tuberculosis control: surveillance, planning, financing. WHO Report 2005. WHO/HTM/TB/ 2005.49. Geneva (Switzerland)7 World Health Organization; 2005. [4] The world health report 2004: changing history. Geneva (Switzerland)7 World Health Organization; 2004. [5] TB deaths reach historic levels [press release WHO/22, 1996]. Geneva (Switzerland)7 World Health Organization; March 21, 1996. [6] Groups at risk: WHO report on the tuberculosis epidemic 1996. WHO/TB/96.198. Geneva (Switzerland)7 World Health Organization; 1996. [7] Newell RR, Chamberlain WE, Rigler L. Descriptive classification of pulmonary shadows: a revelation of unreliability in the roentgenographic diagnosis of tuberculosis. Am Rev Tuberc 1954;69(4):566 – 84. [8] Garland LH. Studies on the accuracy of diagnostic procedures. Am J Roentgenol Radium Ther Nucl Med 1959;82(1):25 – 38.

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munsiff [71] Ledru S, Cauchoix B, Yameogo M, et al. Impact of short-course therapy on tuberculosis drug resistance in South-West Burkina Faso. Tuber Lung Dis 1996; 77(5):429 – 36. [72] Zhang LX, Kan GQ, Tu DH, et al. Trend of initial drug resistance of tubercle bacilli isolated from new patients with pulmonary tuberculosis and its correlation with the tuberculosis programme in Beijing. Tuber Lung Dis 1995;76(2):100 – 3. [73] 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(17):1179 – 84. [74] Weyer K, Kleeberg HH. Primary and acquired drug resistance in adult black patients with tuberculosis in South Africa: results of a continuous national drug resistance surveillance programme involvement. Tuber Lung Dis 1992;73(2):106 – 12. [75] Sterling TR, Lehmann HP, Frieden TR. Impact of DOTS compared with DOTS-plus on multidrug resistant tuberculosis and tuberculosis deaths: decision analysis. BMJ 2003;326(7389):574 – 9. [76] Dye C, Espinal MA, Watt CJ, et al. Worldwide incidence of multidrug-resistant tuberculosis. J Infect Dis 2002;185(8):1197 – 202. [77] Anti-tuberculosis drug resistance in the world: report no. 3, prevalence and trends. WHO/HTM/TB/2004. 343. Geneva (Switzerland)7 World Health Organization; 2004. [78] 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 – 28. [79] Guidelines for establishing DOTS-PLUS pilot projects for the management of multidrug-resistant tuberculosis (MDRTB). WHO/CDS/TB/2000.279. Geneva (Switzerland)7 World Health Organization; 2000. [80] Mukherjee JS, Rich ML, Socci AR, et al. Programmes and principles in treatment of multidrug-resistant tuberculosis. Lancet 2004;363(9407):474 – 81. [81] Thorpe LE, Frieden TR, Laserson KF, et al. Seasonality of tuberculosis in India: is it real and what does it tell us? Lancet 2004;364(9445):1613 – 4. [82] Frieden TR, Sherman LF, Maw KL, et al. A multiinstitutional outbreak of highly drug-resistant tuberculosis: epidemiology and clinical outcomes. JAMA 1996;276(15):1229 – 35. [83] Nathanson E, Gupta R, Huamani P, et al. Adverse events in the treatment of multidrug-resistant tuberculosis: results from the DOTS plus initiative. Int J Tuberc Lung Dis 2004;8(11):1382 – 4. [84] 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 – 50. [85] Dooley SW, Villarino ME, Lawrence M, et al. Nosocomial transmission of tuberculosis in a hospital unit for HIV-infected patients. JAMA 1992; 267(19):2632 – 4. [86] Corbett EL, Steketee RW, ter Kuile FO, et al.

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Clin Chest Med 26 (2005) 341 – 347

The Global Alliance for Tuberculosis Drug Development—Accomplishments and Future Directions Charles A. Gardner, PhDa,*, Tara Acharya, PhD, MPHa, Ariel Pablos-Me´ndez, MD, MPHb a

The Rockefeller Foundation, 420 Fifth Avenue, New York, NY 10018, USA The World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland

b

Nearly 2 billion people, one third of the world’s population, are infected with tuberculosis (TB). Eight million of these people develop active TB every year, leading to 2 million deaths annually [1]. Although an effective vaccine against active disease would be key in ultimately eradicating TB as a public health problem, there is, as yet, no satisfactory vaccine for the disease. The commonly used bacille CalmetteGue´rin vaccine is reasonably effective when administered to infants but is much less effective against the pulmonary form of TB in adults. Despite a recent increase in vaccine research, ongoing efforts to develop a new, more effective vaccine are not expected to yield results for at least a decade, and an effective vaccine would not substantially diminish the TB epidemic for several decades after that. Both effective drugs and an effective vaccine will probably be needed for many decades to come, until the pool of current TB patients and latently infected individuals is eliminated. Drugs that improve or shorten therapy, in contrast, would affect treatment of current patients almost immediately upon their adoption. The World Health Organization’s directly observed treatment, short course (DOTS) strategy is an effective TB control strategy but reaches only one third of the people who need it [2]. Moreover, it is expensive, labor-intensive, and usually involves a 6- to 12-month, four-drug combination regimen consisting

The views expressed by the authors do not necessarily reflect the views of their institutions. * Corresponding author. E-mail address: [email protected] (C.A. Gardner).

of isoniazid, rifampin, pyrazinamide, and ethambutol. Patients find it difficult to adhere to this complicated regimen, leading to an increase in drug-resistant strains [3]. Second-line drugs for multidrug-resistant tuberculosis (MDR-TB) are expensive and more toxic than the standard treatment. It has been more than 30 years since a novel TB drug has been introduced into clinical practice. The estimated costs of discovery and development of a new TB drug (including the costs of failure) are between $115 million and $240 million [4]. Adopting a portfolio approach, the Global Alliance for TB Drug Development (TB Alliance) expects to pursue multiple candidate drugs. The global TB market could reach $700 million by 2010 but is concentrated in developing countries, and the pharmaceutical industry, guided by the perception that the TB market remains too small and diverse to guarantee return on investment, has not driven a comprehensive development program for new TB drugs.

The Global Alliance for Tuberculosis Drug Development In response to these challenges, and with initial support from the Rockefeller Foundation and other international organizations, the TB Alliance [5] was established in 2000 with a mission to accelerate the discovery and development of new drugs to fight TB and to ensure their affordability and accessibility. The initiative was born at a pivotal meeting in Cape Town, South Africa [6], and soon gained substantial support from the Bill and Melinda Gates Foundation.

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.02.008

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As one of a new breed of nonprofit productdevelopment public – private partnerships (PD PPPs), the TB Alliance draws on strengths of the public and private sector to achieve its objectives—new and better TB treatments that  Shorten or significantly simplify the treatment

of active tuberculosis  Provide effective treatment of MDR-TB  Improve the treatment of latent tuberculosis

The TB Alliance operates like a nonprofit company based on an innovative partnership designed to share risks and incentives. The range of organizations that partner with the TB Alliance includes academic institutions, government research laboratories and public health institutions, nongovernmental organizations, the pharmaceutical industry, and contract research organizations worldwide. Its headquarters are in New York, but it also maintains offices in Cape Town, South Africa, and Brussels, Belgium.

fined and measurable milestones, and clear go/no-go decision points. So far, the TB Alliance has assembled a portfolio of projects that are in various phases—lead identification, lead optimization, and preclinical development (Fig. 1). Since 2000, the TB Alliance has catalyzed the expansion of the TB drug pipeline. In 2005, up to seven compounds are expected to be in or to enter clinical trials, many of them with novel modes of action. For comparison, in 2000 only two TB candidate drugs were in development, and these products represented only slight modifications to existing molecules. The sequencing of the genome of Mycobacterium tuberculosis is expected to yield useful results for drug discovery, although not before substantial investment by the global research community. Examples of compound families reviewed by the TB Alliance for drug candidacy over the last several years include  Nitroimidazoles, with potentially sterilizing ac-

tivity and effectiveness against MDR-TB  Fluoroquinolones and quinolizine derivatives

The strategy of the Global Alliance for Tuberculosis Drug Development



The TB Alliance has five strategic objectives: 1. Identify and access promising compounds 2. Oversee the preclinical development of candidate drugs 3. Spearhead clinical trials and drive regulatory approval 4. Ensure affordability, adoption, and access (AAA strategy) 5. Mobilize expertise and resources for tuberculosis drug development







These objectives and selected accomplishments for each objective are outlined below [5]. Objective 1: identify and access promising compounds Through proactive business development and periodic requests for proposals from public, private, and academic institutions, the TB Alliance selects, assembles, and manages a portfolio of promising candidate drugs. The TB Alliance collaborates with or outsources (and provides funding for) the development of these candidates to public and private partners but retains overall responsibility for these projects, with dedicated project management, prede-



that may hold the key to significantly shorter treatment regimens Longer-acting rifamycins for more widely spaced intermittent treatment that have a potential for avoiding cross-resistance to other rifamycins and antiretroviral drug interactions Macrolides, an excellent antibiotic class with significant potential to yield a tuberculosis drug because of its excellent pharmacologic features and its promising antibacterial activity against M. tuberculosis Oxazolidinones, broad-spectrum antimicrobials, which may have substantial antimycobacterial activity; Pleuromutilins, a novel class of antibiotics of a natural product origin, which have tuberculosis efficacy in early tests, do not have crossresistance with other antibiotics, and seem to produce resistance very slowly Pyrroles, a previously largely unexplored class of compounds with antimycobacterial activity in vitro and in preclinical animal models, with a novel mechanism of action.

Selected lead compounds in the Global Alliance for Tuberculosis Drug Development portfolio A lead compound in the portfolio, the nitroimidazopyran PA-824, has successfully passed established milestones and is expected to be in clinical trials by the first half of 2005. PA-824 was the first compound acquired by the TB Alliance, in June

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global alliance for tuberculosis drug development

Compounds, Analogs and Derivatives

Discovery

Preclinical

Clinical Testing

Nitroimidazole Analogs (TB Alliance, Novartis Institute for Tropical Diseases, NIAID)

Nitroimidazole PA-824 (TB Alliance, Chiron)

Moxifloxacin (TB Alliance, Bayer Pharmaceuticals)

Carboxylates (TB Alliance, Wellesley College)

Pyrrole LL-3858 (LupinLimited)

Diarylquinoline R207910 (Johnson & Johnson)

Quinolones (TB Alliance, KRICT/Yonsei University)

Diamine SQ-109 (Sequella, Inc.)

Proprietary Compound (PrivateSector Company)

Macrolides (TB Alliance, University of Illinois at Chicago)

Gatifloxacin (OFLOTUB – TDR)

Pleuromutilins (TB Alliance, GlaxoSmithKline) Isocitrate Lyase (ICL) (TB Alliance, GlaxoSmithKline) InhA (TB Alliance, GlaxoSmithKline) Focused Screening (TB Alliance, GlaxoSmithKline) Methyltransferase inhibitors (AnacorPharmaceuticals) Screening and Target Identification (AstraZeneca)

Fig. 1. Global tuberculosis drug pipeline, March 2005. (Courtesy of the Global Alliance for TB Drug Development, New York, NY; with permission.)

2002, through an exclusive license agreement with Chiron Corporation (Emeryville, California). The compound has bactericidal activity similar to isoniazid and sterilizing activity that rivals that of rifampicin. During the discovery stage, PA-824 and its analogues demonstrated activity against both drugsensitive and MDR strains of TB. Preclinical development results so far have demonstrated the feasibility of increasing synthesis for animal and clinical trials. In preliminary toxicology testing, PA-824 did not demonstrate teratogenic or toxic effects on normal metabolic or hormonal systems. Additional animal studies to assess the safety and efficacy of PA-824 have also yielded encouraging results. As a result, PA-824 will be entering phase I clinical trials in the first half of 2005. The TB Alliance is also working to optimize the synthesis of PA-824 to reduce production costs. To ensure further development of this promising class of drug candidates, the TB Alliance is pursuing research into analogues of PA-824. To this end, the Alliance has also launched a partnership with Novartis Institute of Tropical Diseases in Singapore to explore new avenues within the nitroimidazole class, working closely with the National Institutes of Allergy and Infectious Diseases (NIAID), among others. Moxifloxacin is a quinolone that has shown high levels of activity against M. tuberculosis in vitro and has generated significant interest from the TB community for its potential to become the first major advance in TB therapy since the 1965 introduction

of rifampicin. Developed by Bayer AG (Leverkusen, Germany), the drug currently has been approved by the Food and Drug Administration (FDA) for treatment of skin and upper respiratory tract infections and pneumonia. In vivo experiments using a murine model at the Center for Tuberculosis Research at Johns Hopkins University and funded by the TB Alliance have affirmed moxifloxacin’s early promise for shortening therapy. Support from the TB Alliance helps ensure that this murine model, one of the TB Alliance’s platform technologies, will continue to be available for the development of other TB drugs. The Johns Hopkins team substituted moxifloxacin in various combinations to replace or enhance aspects of existing treatment. Substitution of moxifloxacin for isoniazid significantly increases efficacy, and studies have suggested that inclusion of moxifloxacin in a combination regimen can shorten the time of TB treatment [7]. The next step is to confirm these results in clinical trials. To that end, the TB Alliance is working with Bayer and several partners, including the Centers for Disease Control and Prevention (CDC), Johns Hopkins University, and University College, London (with funding from the European and Developing Countries Clinical Trials Program), to formulate and support a global clinical development plan for moxifloxacin in the treatment of TB. This undertaking would build on an existing Cooperative Research and Development Agreement between

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Bayer AG and the CDC that the TB Alliance facilitated in 2002. As part of this plan, the CDC TB Trials Consortium is conducting phase II clinical trials in Spain, North America, and Africa to evaluate the safety and efficacy of a regimen in which moxifloxacin is substituted for ethambutol in the treatment of patients who have newly diagnosed TB. Objective 2: oversee the preclinical development of drug candidates The TB Alliance has established an effective process and enabling technologies to develop candidate drugs. It has developed a comprehensive management plan, created a diverse network of outsourced, global expertise, and established go/nogo decision gates to advance candidates along the development pipeline. A research plan and development timeline is established for each compound or project selected for the portfolio. The development plan requires a series of tests, each designed to provide a go/no-go decision point for continued development. At preclinical stages, a comprehensive program of safety and toxicology pharmacologic investigations is performed. Because TB drugs must be designed to optimize combination therapy, the cornerstone of resistance control, these safety considerations must include drug – drug interactions with companion antiTB medications. Furthermore, because an increasing percentage of TB patients are also infected with HIV, it is critical to determine the compatibility with antiretroviral treatments and in particular to ensure the lack of induction or metabolism by cytochrome P450 enzymes. Objective 3: spearhead clinical trials and drive regulatory approval The TB Alliance is working to ensure that there is adequate capacity for clinical trials to test the compounds that successfully pass preclinical milestones. These facilities must meet the highest regulatory standards, including those of the FDA and European Medicines Agency. The aim is to reduce unnecessary regulatory hurdles to ensure that new drugs are made available to patients as soon as possible. Therefore, the TB Alliance is also working to harmonize regulatory approval processes to expedite the inclusion of new products in standardized treatment. As in any drug discovery and development program, general delays or setbacks are expected in the process of TB drug development. The TB Alliance hopes to reduce these risks by maintaining

a diverse portfolio and working with countries to build capacity for drug development. For instance, the TB Alliance is working with the International Union Against Tuberculosis and Lung Disease to build clinical trials capabilities at international locations in Africa, South America, and Asia. The TB Alliance is exploring multiple approaches to streamlining clinical development, including simultaneous rather than sequential testing of new compounds and validation of novel surrogate markers. Objective 4: ensure affordability, adoption, and access In developing countries, the TB Alliance is working to ensure the AAA strategy for the products it develops. Affordability of the final product depends on both technical and business factors. The costs of production and development of potential compounds are evaluated, and all agreements are structured to limit royalties in countries where TB is endemic and to include licensing provisions and manufacturing rights to keep prices low. The TB Alliance is also working with the World Health Organization and national TB control programs to ensure early adoption of a new product in existing programs and therapeutic regimens. Access ensures that medicines reach all patients, particularly the poorest of the poor. As part of the AAA strategy, the TB Alliance is exploring innovative intellectual-property strategies to balance access and incentives. The TB Alliance hopes to retain the ability to deliver new anti-TB drugs equitably to those areas most in need while helping to maintain incentives for the pharmaceutical industry to develop new TB medicines. The costs of production and development of potential compounds are evaluated, and all agreements are structured to limit royalties in endemic countries and to include licensing provisions and manufacturing rights to keep prices low. The TB Alliance is also working with the World Health Organization, the Stop TB Partnership, and national TB control programs to ensure early adoption of a new product in existing programs and therapeutic regimens. Unlike PD PPPs developing novel prevention tools lacking any existing distribution mechanisms, the TB Alliance will be able to rely on a decade of investments in DOTS programs and their drug procurement and distribution mechanisms such as the Global Drug Facility. Although further improvements in access to DOTS are imperative, these mechanisms are in place, and the TB Alliance can rely on them for the distribution of the new drugs in combination therapy.

global alliance for tuberculosis drug development

Objective 5: mobilize expertise and resources for tuberculosis drug development Following initial funding by the Rockefeller and The Bill and Melinda Gates Foundations, the TB Alliance has secured further public funding from the United States Agency for International Development and the Dutch Ministry of Development Cooperation and in-kind support from the NIAID. The TB Alliance has leveraged this funding to position itself as the catalyst in developing new TB drugs. The TB Alliance has mobilized worldwide expertise and resources by establishing solid relationships with pharmaceutical and biotechnology companies, proactively seeking new sources of support, and actively participating in global forums to promote its mission. For example, the TB Alliance is the lead agency of the Stop TB Partnership Working Group on TB Drug Development, which coordinates a forum to facilitate research and development collaborations worldwide for new TB drugs. While building its own portfolio through the partnerships described previously, the TB Alliance has helped catalyze the global TB drug pipeline by engaging all relevant industry entities and by enhancing technologies to support drug development in general. The TB Alliance has taken both advisory and advocacy roles to support corporate efforts for TB, such as those currently underway at Novartis, Anacor, AstraZeneca, Lupin, GlaxoSmithKline, and other companies. For example, AstraZeneca has committed $25 million over 5 years at its newly established research facility in Bangalore, India [8], and Novartis has established a $122 million tropical disease research institute in Singapore to focus on tuberculosis and dengue fever [9]. Moreover, the TB Alliance Scientific Advisory Committee includes drug discovery and TB experts from GlaxoSmithKline, Pfizer, and Johnson & Johnson. Additionally, to enhance the scope and depth of the global pipeline, the TB Alliance has invested in platform technologies that expedite, support, and lower hurdles in TB drug development. One essential platform technology is the mouse model for preclinical testing, which has been instrumental in affirming preclinical efficacy of lead compounds. Others include the establishment of a worldwide inventory of preclinical and clinical capacity/expertise and clinical trial site standardization in selected countries to ensure the necessary clinical infrastructure as portfolio compounds advance to clinical trials. In this context, the involvement of endemic countries is central to the mission of the TB Alliance. On the drug development front, these countries may have compounds to expand the

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portfolio and could offer their laboratories’ preclinical capacity to develop the portfolio. For instance, in April 2003 the TB Alliance signed a 2-year agreement with the Korea Research Institute of Chemical Technology, where scientists will synthesize more than 400 compounds, including novel quinolones, pyridones, and quinolizines. This project aims to yield up to three lead candidates for the TB Alliance portfolio and is the TB Alliance’s first research and development partnership in Asia as well as the first in a country that has a significant TB burden. Patient enrollment plays a central role in the clinical development stage. Because of TB’s global impact, most patients reside in developing countries, where clinical trial infrastructure is limited but where reasonable cost structures help fulfill the ultimate goal of affordability. Furthermore, DOTS infrastructure, expanded during the last 10 years, offers an excellent starting point for clinical trial capacity building. The TB Alliance is also working closely with other PD PPPs with similar goals, such as Medicines for Malaria Venture, the Malaria Vaccine Initiative, the International AIDS Vaccine Initiative, the International Partnership for Microbicides, and others, to coordinate overall activities and to strengthen the incentive for investment in new tools to solve global health problems. The TB Alliance has welcomed the creation of a new research effort, the Foundation for Innovative New Diagnostics (FIND) to develop better diagnostic tests for infectious diseases, with an initial emphasis on TB [10]. The TB Alliance and FIND plan to work together to encourage the development of new tools for tuberculosis.

Global product development public – private partnerships Globally based nonprofit PD PPPs emerged in the 1990s as a way to 1. Link public-sector goals with private-sector expertise as a means of accelerating drug and vaccine development for neglected diseases 2. Raise awareness of global health inequities and attract substantial new funding to the field 3. Promote culture change, incorporating methods and models from the private sector into publicsector practice and encouraging more private entities to enter the field of neglected diseases [11] In many ways, PD PPDs can be seen as notfor-profit companies.

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Building on its history, mission, and comparative advantages, The Rockefeller Foundation provided social venture capital toward the creation of the International AIDS Vaccine Initiative, Medicines for Malaria Venture, the TB Alliance, International Partnership for Microbicides, and Pediatric Dengue Vaccine Initiative [12]. At the same time, other organizations established a Malaria Vaccine Initiative, Aeras Global TB Vaccine Foundation, Foundation for Innovative New Diagnostics, Drugs for Neglected Diseases Initiative, Institute for One World Health, and others. Most of these PD PPPs, including the TB Alliance, owe their continued financial well being to donors—principally the Bill and Melinda Gates Foundation—along with other philanthropies, government development agencies, and multilateral organizations. The Rockefeller Foundation based its diseaseproduct priorities (eg, in the creation of the TB Alliance) on expert assessment of a combination of high social demand and maturity of the science. The Foundation pushed for pharmacoeconomic analyses, business plans, and scientific blueprints for the organizations with which it was involved, and these approaches have now become the norm. Like private for-profit companies, PD PPPs use business practices in staffing and in managing a portfolio of candidate products. Most have explicit policies affecting portfolio turnover, including a guillotine strategy based on milestones in the project’s business plan and criteria for acquiring new product candidates. Go/no-go decisions are based on advice from a scientific advisory board made up of experts in the field. Thus, for some donors, PD PPPs represent a way to delegate the tough decisions to professional experts. Each PD PPP seeks to deliver products that will be cheaper and easier to supply than existing interventions [13]. The quintessential example would be a vaccine, just as the polio vaccine replaced the iron lung half a century ago. A shorter-course TB treatment regimen to replace the existing 6- to 12-month regimen represents a similar breakthrough goal. Such products will make access to better health more attainable. In addition, PD PPPs focus directly on ensuring that their products will be affordable and accessible to the poor. Criteria for acquisition of new candidate products include low manufacturing cost (often with manufacture in developing countries), ease of delivery in tropical conditions, and advantageous intellectual-property arrangements that entice private-sector participation and help ensure fulfillment of the AAA strategy in endemic countries. It is important that a series of strategic partnerships be established to deliver products to the neediest.

Together, these organizations provide a true, new, and coherent field of initiatives designed to bridge the gap between basic research and product development, aligning public health goals with private-sector expertise to develop essential new products to prevent, control, and treat diseases of the poor. The field is still young. Sufficient time has not yet passed to determine whether PD PPPs will achieve their ultimate goals. A recent analysis of interim indicators and organizational best-practice benchmarks gives room for hope, even enthusiasm [14]. Impressive new public-sector support has arisen, and productdevelopment pipelines have expanded significantly both within and outside of PD PPP portfolios. To build on this progress successfully, still more resources will be needed to carry the work forward to the next stages including regulatory approvals, clinical trials, manufacturing, and distribution.

Future directions for the Global Alliance for Tuberculosis Drug Development Among the TB Alliance’s achievements to date are the rapid scaling-up of their project portfolio, securing of endorsements at the highest national and international levels, and enlisting the assistance of leading global pharmaceutical and biotechnology companies. Most significantly, the TB Alliance is developing a growing, robust pipeline, a quantum leap from the situation 5 years ago when TB drug development was at a standstill. The ideal scenario in the next decade is one in which the TB Alliance successfully creates and manages a portfolio of therapeutic alternatives and develops a novel anti-TB drug regimen that is as effective or more effective than the current treatment and that shortens the duration of treatment to less than 2 months. The reduction in the duration of treatment would represent a significant reduction in the cost and complexity of DOTS. A drug that simplifies the regimen and shortens treatment by 3 months would also have a significant, positive impact (although not as dramatic as the previous scenario). In either case, the benefits of a new, faster-acting TB regimen would go beyond the direct impact on TB incidence and prevalence and the indirect effect on the global economy. The success of the TB Alliance could encourage donors, mobilizing more funding for additional projects. Demonstration of the success of the PD PPP model could spur support for other PD PPPs. Other institutions might apply the TB Alliance’s platform technologies and lessons learned during the process of TB drug development to

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their own objectives. Finally, a success from one of the PD PPPs might energize the entire field of global health.

Acknowledgments The authors thank Ann Ginsberg, Gwynne Oosterbaan, Melvin Spigelman, and Joelle Tanguy at the TB Alliance for their valuable comments.

References [1] World Health Organization Fact sheet no 104, revised March 2004. Geneva (Switzerland)7 World Health Organization; 2004. [2] Me´decins sans Frontie`res. Campaign for access to essential medicines Running out of breath? Available at: http://www.doctorswithoutborders.org/publications/ reports/2004/tbreport_2004.pdf. Accessed March 4, 2005. [3] World Health Organization. WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 1999 – 2002 Anti-tuberculosis drug resistance in the world (third global report). Available at: http:// www.tballiance.org/MDR_report/WHO_MDRTB_ report.pdf. Accessed March 4, 2005. [4] Global Alliance for TB Drug Development. The economics of TB drug development, October 2001. New York: Global Alliance for TB Drug Development; 2001.

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[5] Global Alliance for TB Drug Development. Overview of the TB Alliance program. Available at: http//www. tballiance.org. Accessed March 4, 2005. [6] Pablos-Me´ndez A for the Working Alliance for TB Drug Development. The declaration of Cape Town. Int J Tuberc Lung Dis 2000;4(6):489 – 90. [7] Nuermberger EL, Yoshimatsu T, Tyagi S, et al. Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am J Respir Crit Care Med 2004;169(3):421 – 6. [8] Astrazeneca. Astrazeneca opens multi-million dollar Indian research facility to find new treatments for tuberculosis [press release, June 2, 2003]. Available at: http://www.astrazeneca.com/pressrelease/497.aspx. Accessed March 4, 2005. [9] Novartis. Novartis Institute for Tropical Diseases opens in Singapore’s state-of-the-art Biopolis research facility. Novartis special report. Available at: http://www. novartis.com/special/nitd_opening_pr.shtml. Accessed March 4, 2005. [10] Foundation for Innovative New Diagnostics (FIND). Available at: http://www.finddiagnostics.org. [11] Internal strategic planning document. New York7 The Rockefeller Foundation; 1998. [12] Evans TG. Health-related global public goods: initiatives of the Rockefeller Foundation 2002. Available at: http://www.undp.org/ods/monterrey-papers/evans.pdf. Accessed March 4, 2005. [13] Wheeler C, Berkley S. Initial lessons from publicprivate partnerships in drug and vaccine development. Bull World Health Organ 2001;79(no. 8):728 – 34. [14] The Rockefeller Foundation. Partnering to develop new products for diseases of poverty—one donor’s perspective 2004. Available at: http://www.rockfound.org. Accessed March 8, 2005.

Clin Chest Med 26 (2005) 207 – 216

The Origin and Evolution of Mycobacterium tuberculosis Serge Mostowya, Marcel A. Behr, MDa,b,* b

a McGill University Health Centre, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada Division of Infectious Diseases and Medical Microbiology, A5-156, Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada

With tuberculosis (TB) having plagued mankind for centuries, there can be no doubt that Mycobacterium tuberculosis, the causative agent of human TB, has been successful in adapting for human infection. M. tuberculosis belongs to the Mycobacterium tuberculosis complex (MTC), itself comprised of bacterial agents responsible for TB or TB-like disease. Members of the MTC are known to infect mammalian hosts, and the extent and consequence of this infection is gaining greater recognition in part because of the availability of diagnostic tools to classify specific isolates appropriately. This article introduces the tools and terminology used for this classification and illustrates their utility by discussing work from independent laboratories that have established a genome-based phylogeny for the MTC [1 – 5]. Next, it considers the use of these markers to distinguish atypical isolates not conforming to attributes of traditional MTC members [6,7]. Finally, it discusses the current genomic evidence regarding the origin and evolution of M. tuberculosis in the context of its relevance for TB control in humans and other mammalian hosts.

* Corresponding author. Division of Infectious Diseases and Medical Microbiology, A5-156, Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada. E-mail address: [email protected] (M.A. Behr).

Characteristics of the Mycobacterium tuberculosis complex The MTC consists of bacteria that genetically share identical 16S rRNA sequence and greater than 99.9% nucleotide identity. M. tuberculosis, M. africanum, M. microti, and M. bovis have been regarded as the four traditional species of the MTC, although the extent of MTC speciation is not yet resolved. In this article, MTC organisms are referred to as members, and the nomenclature provided in the most recent literature is used. Members characteristically differ in their host range, epidemiology, clinical presentation in humans, and laboratory phenotype, although little is known about these differences or why these differences have evolved. The human form (M. tuberculosis sensu stricto) and the bovine form (M. bovis) have been nominally distinct for more than a century; other members have been identified more recently (Table 1). The members classically were described by their biochemical properties or by targeting their specific genetic regions. Genomic insights now show a new approach to MTC speciation outside the scope of these more traditional tools [8].

Genetic resources to study the Mycobacterium tuberculosis complex With the availability of complete sequence information, several methodologies have developed to understand the MTC genetically. These methods can

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.02.004

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Table 1 Myobacterium tuberculosis complex members Virulence MTC member

Natural host

Mouse

Guinea pig

Rabbit

Unique attribute

M.canettii

Human?

+

+ + + + + +

+

+ +

+ +

Most ancestral recognized MTC member, anecdotal isolation Predominant cause of human TB Reclassified as atypical M. tuberculosis Rarely isolated Phenotypically heterogeneous Closely related to M. microti Attenuated, used as live vaccine in humans More attenuated than M. microti Only described in Europe? Dynamic pathogen with wildlife reservoirs? Family of laboratory adapted strains of M. bovis used as live vaccine

M. tuberculosis a M. africanum subtype II b M. africanum subtype I (a) c M. africanum subtype I (b) M. pinnipedii M. microti Dassie bacillus M. caprae M. bovis M. bovis BCG

Human Human Human? Human? Pinnipeds Vole Dassie Goat Cow None

+ + + + +

+ +

Abbreviations: +, animal typically succumbs to infection; , animal typically survives infection. a Although previously suggested as a unique member of the MTC, M. africanum subtype II isolates cannot be genomically distinguished from M. tuberculosis [7]; and throughout this article, M. africanum subtype II is included within the M. tuberculosis lineage. b Refers to the genotype ‘(a)’ of M. africanum subtype I having deleted RD9, but not RD7, RD8, and RD10. c Refers to the genotype ‘(b)’ of M. africanum subtype I having deleted RD9, RD7, RD8, and RD10. Data from Refs. [38,39,42,43,62,63].

be categorized as genetically fast or slow and as having phenotypic consequences or not. Each methodology has advantages and disadvantages. Whereas each methodology has proven useful, a tool is only as informative as the question toward which it is applied. Responsible contributions ideally should draw information from all available typing methods to conclude with the most parsimonious scenario. Fingerprinting patterns The use of DNA fingerprinting patterns, in which samples are genotyped by restriction-fragment-length polymorphisms using genetic attributes specific to the MTC as markers, has proven valuable for tracking MTC disease [9]. Molecular epidemiologic markers used include the MTC-specific insertion sequence IS6110 [10], polymorphic glycine- and cytosine-rich sequences [11], the direct-repeat region [12], spaceroligonucleotide typing (spoligotyping) [13,14], and variable-number tandem repeats of genetic elements termed mycobacterial interspersed repetitive units [15,16]. Although these genetic markers are known to mutate at rates suitable for tracing a chain of disease transmission, their patterns of change are potentially too common to act as reliable markers over longer periods of evolutionary time. Therefore, they do not seem to be reliable for phylogenetic studies and speciation of clinical isolates.

Sequenced genomes A wealth of genomic insight for the Mycobacterium genus is available through whole-genome sequence information for several species (Table 2), including six entire MTC genomic sequences completed or in progress. These are M. tuberculosis H37Rv [17], M. tuberculosis CDC1551 [18], M. tuberculosis 210 [18a], M. microti OV254 [19], M. bovis 2122 [20], and M. bovis bacille CalmetteGuerin (BCG) Pasteur [20a]. Mycobacteria sequenced or being sequenced outside the MTC include M. leprae [21], M. ulcerans [22], M. avium 104 [51], M. paratuberculosis K10 [22a], M. marinum [22b], and the relatively fast-growing M. smegmatis MC2 155 [18a]. Even the most distant of these sequenced mycobacterial genomes are minimally related by 60% DNA/DNA homology, and comparative genomic analysis has shown that gene loss is a significant part of the ongoing evolution of the slow-growing mycobacterial pathogens [23]. Single-nucleotide polymorphisms Single-nucleotide polymorphisms (SNPs) can result in a silent amino acid substitution in which the protein coding sequence remains unchanged (synonymous) or can alter the protein-coding sequence (nonsynonymous) and hence act as a substrate for

Table 2 Overview of mycobacterial genome sequencing projects First author/date [reference]

Genome size (base pairs)

No. of proteincoding genes

G + C nucleotide content (%)

M. tuberculosis H37Rv M. tuberculosis CDC1551

Cole, 1998 [17] Fleischmann, 2002 [18]

4,411,532 4,403,836

3995 4249

65.6 65.6

M. tuberculosis 210

The Institute for Genomic Research [18a] Garnier, 2003 [20] Brodin, 2002 [19] Sanger Institute [20a] Sanger Institute [22b]

4,400,000a

NA

NA

4,345,492 4,400,000a 4,083,000a 6,636,827

3951 NA NA NA

65.6 64.0a NA 65.73%

M. ulcerans M. leprae M. avium avium 104

Stinear, 2004 [22] Cole, 2001 [21] Semret, 2004 [51]

6,032,000a 3,268,203 5,475,491

NA 1604 4480

65.0a 57.8 69

M. avium paratuberculosis K10 M. smegmatis MC2 155

GenBank [22a] The Institute for Genomic Research [18a]

4,829,781 7,000,000a

4350 NA

69.3 NA

M. M. M. M.

bovis 2122 microti bovis BCG Pasteur marinum

Insight from sequencing project First sequenced mycobacterial genome Polymorphisms among M. tuberculosis strains more extensive than initially anticipated Describes hyper-virulence of ‘Beijing’ strain family? M. bovis is derivative compared to M. tuberculosis Loss of RD1 contributed to attenuation of M. microti Describes live vaccine administered to humans Describes causative agent of TB-like disease in fish and ‘fish tank granuloma’ of humans Plasmid-encoded toxin responsible for Buruli ulcer Massive gene decay in the leprosy bacillus Extensive genomic polymorphism among M. avium sub-species Describes causative agent of Johne’s disease in cattle Describes fast growing, model organism for mycobacteria

mycobacterium tuberculosis complex evolution

Species

Mycobacteria are listed is the order of 16S rRNA sequence relatedness to M. tuberculosis [64]. Abbreviations: G + C, guanine plus cytosine; NA, not available. a Parameter estimates.

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evolutionary selection. Both types of mutations have been applied toward differentiation and diagnostics of MTC members [24 – 26]. In a landmark study, a first sequence analysis of MTC isolates revealed that allelic polymorphism is impressively rare, occurring on the order of 1 in 10,000 base pairs (bp), suggesting that the complex could be dated to about 15,000 to 20,000 years of age [24]. Genomic comparison of multiple sequenced MTC strains has made possible the identification of SNP markers for studies of evolution, pathogenesis, and epidemiology in clinical M. tuberculosis [27] and M. bovis [20], supporting a clonal evolution of the MTC without detectable lateral gene exchange. The ratio of SNP types within a genome can act as a molecular clock [28] in which the high ratio of nonsynonymous to synonymous mutations across coding sequences within MTC genomes suggests a recent divergence of M. bovis and M. tuberculosis [20]. Large-sequence polymorphisms Unlike other mycobacterial species in which horizontal gene transfer has been demonstrated [22], this mode of generating genomic diversity has not been observed for the obligately intracellular MTC. Genomic comparisons for the MTC reveal a prominent role of genomic deletions relative to the sequenced strains of M. tuberculosis. For example, the complete genome sequence of M. bovis 2122 contains 66,037 bp less than M. tuberculosis H37Rv, and no genomic region exclusive to M. bovis but consistently absent from M. tuberculosis has been detected [20]. To uncover deletions in nonsequenced strains efficiently, one can hybridize whole genomic DNA of a MTC member against a spotted array [29] or an Affymetrix GeneChip (Santa Clara, California) [30] representative of the entire M. tuberculosis H37Rv genome [17]. Regions of the prototype strain that seem to be absent from the test strain are then confirmed by performing polymerase chain reaction (PCR) with primers approximating the deleted region, to amplify across the deletion. This amplicon is then sequenced to define the deletion point precisely. Isolates are said to share a genomic deletion when sequencing shows the deletion occurs in different isolates at exactly the same cut point [2]. Because independently arisen chromosomal rearrangements sometimes involve the same strategically located elements, only upon exact description of the specific genomic event (ie, genomic location within a reference strain) can one determine with confidence whether genomic deletions behave as unidirectional

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event polymorphisms (UEPs). These UEPs, which represent one-time events in the evolution of the organism, can serve as robust markers of clonal organisms, useful for determining phylogenetic classification. A valuable use of these genomic deletions pertains to their application in defining specific MTC members and accurately assessing their prevalence in clinical specimens [8,26]. Unlike biochemical testing, which for individual results had imperfect sensitivity and specificity, the use of genomic events in these studies provided unambiguous classification, thereby simplifying the process considerably. To explore the basis for the previously observed biochemical attributes used for MTC speciation, an association was sought between deleted sequences and phenotypic results for isolates assigned as M. africanum. Results indicate that convergent biochemical profiles can be independently obtained in different MTC members. For instance, organisms presenting the distinct deletion profile of M. africanum and M. bovis can manifest the same biochemically based profile [7]. These results confirm the limitations of biochemically derived speciation and, by extension, challenge the taxonomic divisions currently in place for classifying members of the MTC. Beyond diagnostics, different studies have all supported the potential value of most MTC genomic deletions (with the exception of mycobacteriophage DNA) as evolutionary markers. In separate genomic studies of M. bovis BCG vaccine strains, it has been documented that BCG-specific deletions superimpose perfectly on the historical record [3,29]. In studies of genomic deletions within clinical isolates of M. tuberculosis [31,32], mycobacterial clones shared the same genomic deletions, again suggesting that deletions can be used to reconstruct phylogenetic trees. Finally, a recent analysis of 100 M. tuberculosis clones from San Francisco has again confirmed that these deletions are UEPs [5], and therefore genomic deletions can effectively brand a particular clone [33]. A practical use of this approach will be to provide a secure genomic definition for prominent strains, such as the Beijing [34] and Manila [35] strains of M. tuberculosis, and to assess their prevalence through space and time.

Genomic deletions and the origin and evolution of the Mycobacterium tuberculosis complex The long-recognized presence of a human TB bacillus and a closely related bovine form has given rise to speculation that TB originally came to humans as a zoonotic infection from cattle [36]. In

mycobacterium tuberculosis complex evolution

retrospect, this view was probably influenced by the types of M. tuberculosis isolates available for study, biased toward hosts (namely cattle and humans) for which a diagnosis of TB would lead to microbiologic investigation. To explore the evolutionary relationship of members of the MTC, the presence or absence of deletions was tested within complex isolates derived from different hosts and from isolates in various geographic locales [1,2]. Analysis revealed a stepwise accumulation of genomic deletions among isolates interrogated, but the distribution of genomic deletions argued against present-day M. bovis as the evolutionary precursor of M. tuberculosis, making it improbable that human TB originated with the domestication of cattle. Instead, a number of MTC organisms, both long established and more recently described, present genomic profiles that seem to be intermediate between the ancestor of modern M. tuberculosis and that of present-day M. bovis. The availability of improved laboratory tools has facilitated the description of a number of novel variants of the MTC, including M. canettii [37,38], M. caprae [39,40], M. pinnipedii [41,42], and the dassie bacillus [2,43] (Table 1). Before these tools were available, MTC members had presented a well-established host range, presumably biased by expectations: M. tuberculosis (and sometimes M. africanum) is classically isolated from humans, M. microti from voles, and M. bovis from a broad range of hosts including (but not limited to) cows. More careful study, however, has revealed a wider range of host animals. A practical issue arising from these studies involves the generally held belief that M. bovis infects an extensive range of animal species, including the badger, opossum, elk, cougar, and buffalo. Until recently, M. caprae and M. pinnipedii were considered to be forms of M. bovis [40,42]. Although M. bovis might be versatile enough to accommodate such a dynamic host range, the inclusion of such organisms probably overestimates the true host range of M. bovis. Detailed genomic analysis of isolates from unusual hosts is underway, with the expectation that results will continue to challenge accepted notions of MTC speciation and taxonomy [2]. Just as genomic deletions have proven unique to isolates of M. tuberculosis affecting only human hosts [5,30], deletions unique to these other MTC members permit resolution of their phylogenetic situation (Fig. 1) [1,2]. A first observation from this distribution of organisms is that the MTC affects a number of undomesticated and domesticated mammals, both terrestrial and aquatic. M. marinum can be

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considered a piscine/amphibian mycobacterium [44] and M. avium an avian mycobacterium [45]. The MTC is a relatively broad-ranging mammalian mycobacterium. Organisms of the four most ancestral lineages (M. canettii, M. tuberculosis, and both genotypes of M. africanum subtype I) have been cultured predominantly from humans. Because isolation of M. canettii has been extremely rare [37,38], an unrecognized nonhuman reservoir might exist, with humans representing an accidental or circumstantial host. The next three MTC lineages (M. microti, M. pinnipedii, and the dassie bacillus) affect undomesticated mammals irrespective of their geographic location. M. microti, first identified in Europe, infects the field vole [19], the dassie bacillus infects the dassie and the surikat from Africa [6,43], and M. pinnipedii globally infects a variety of seals and sea lions from Oceania to South America [4,42]. Finally, more derivative forms of the MTC are seen in goats (M. caprae) and subsequently cattle (classic M. bovis), suggesting that the organism was introduced into livestock in the order of their domestication. More recently, spillover of M. bovis from farms has been seen in the case of badgers in the United Kingdom [46] and the brushtail opossum in New Zealand [46a]. Far from suggesting that human TB originated with livestock, the genomic record suggests that, directly or indirectly, humans were responsible for bringing MTC to the farm, with secondary foci of spread now observed in animals associated with this setting.

Geographic, chronologic, and ecologic origins of the Mycobacterium tuberculosis complex An absolute chronology of the TB epidemic is difficult to discern by genomic deletions, because they do not evolve on a predictable time scale. The genetic record can potentially point to the geographic origins, however, because the ancestral form M. canettii [1,4,25] has been isolated only in persons living in Africa [37,38]. If the origins of human TB are situated in the same the continent as the origins of man, it is conceivable that the organism spread with humans during the paleomigration, explaining the presence of MTC DNA in 5000-year-old samples from Egypt [47] and pre-Columbian mummies from Ecuador [48]. Because more derivative organisms are found in hosts domesticated 10,000 to 12,000 years ago, these clues suggest that the organism accessed humans before that era and subsequently spread to other hosts, either from man directly or through an unrecognized vector.

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Ancestral tubercle bacillus Deletions unique to M. canettii

M. canettii

Deletions unique to M. tuberculosis

M. tuberculosis (including M. africanum subtype II)

Deletions unique to M. africanum (a)

M. africanum (a)

Deletions unique to M. africanum (b)

M. africanum (b)

RD9

RD7 RD8 RD10

Deletions unique to M. pinnipedii Deletions unique to M. microti RD5 RD12 RD13 N-RD25

Deletions unique to dassie bacillus

M. pinnipedii M. microti dassie bacillus

Deletions unique to M. caprae

M. caprae

Deletions unique to M. bovis

M. bovis

RD4

Deletions unique to M. bovis BCG

Tubercle bacillus of other mammalian hosts?

M. bovis BCG

Fig. 1. Deletion-based phylogeny of the MTC based on deleted regions demonstrated through genomic analysis. The vertical axis presents the stepwise accumulation of unidirectional evolutionary polymorphisms (RDs and N-RD) previously characterized among members of the MTC [1,2]. Clustered along each horizontal axis are organisms for which one or more genomic deletions specific to this evolutionary branch have been revealed in supporting citations [4,6,7,19,32,58] and unpublished observations. N-RD, new deletions. (Serge Mostowy, Marcel Behr, MD, unpublished data, 2005.)

Using deletions to assign directionality to the MTC phylogeny, one can employ sequence-based analysis to estimate the chronology of this scenario and refine the previous nucleotide-based analysis that suggested a 20,000-year divergence between M. tuberculosis and M. bovis [24]. Another approach to date these events uses testing for genomic regions directly on paleo-DNA samples [49] (Mostowy et al, unpublished data). Because these samples can be carbon dated independently, it is possible to provide genomic signatures for samples of human or nonhuman provenance and to derive minimal estimates for the ages of genomic events portrayed in Fig. 1. Turning to the ecologic origins of the MTC, a livestock source seems to be unlikely, because human forms diverged before the modern caprine and bovine forms. Although it is attractive to consider another mammalian host as the ancestral niche, observations for other mycobacteria suggest that nonmammalian

reservoirs such as plant or insects deserve consideration [50]. With the ability to test rapidly for genomic deletions by PCR, one can test putative wildlife reservoirs for variants of the MTC to find the natural host of relatively ancestral forms such as M. canettii.

What is being deleted from the Mycobacterium tuberculosis complex? When compared with other bacterial species, members of the MTC present relatively little genomic diversity. Estimates of large-sequence polymorphism diversity among MTC members [32], in agreement with similar conclusions drawn from estimates of SNPs [25], have been consistently described as low in comparison with other microbes. Nonetheless,

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genomic flexibility does seem to exist within the MTC for specific host adaptation, and a similar potential is beginning to reveal itself among other mycobacterial complexes. Although the amount of diversity revealed within the Mycobacterium avium complex is 10-fold more than that of the MTC [51], host-specific genomic contents are being observed there as well (M. Semret and M. Behr, unpublished data). Taken together, these data highlight a comparative genomics approach to understanding an evolutionary potential of mycobacterium pathogenesis, in which genomic content can suggest DNA features for host-specific adaptation. Genomic deletions and virulence With host-specific MTC extending beyond a domesticated setting, how TB spreads from host to host is difficult to ascertain. From what is known about humans and cows with TB, it is reasonable to expect that transmission would occur through aerosols from a diseased animal to a contact animal. If so, a requisite of host adaptation is a certain degree of virulence in that host. Although greater virulence might facilitate transmission, too much virulence could be detrimental if host mortality is excessive or if the organism causes an invasive form of TB that is generally nontransmissible (such as TB meningitis). Thus, optimal transmissibility requires some degree of virulence (ie, pulmonary pathology) but a sufficiently contained disease process to generate the agents required for spread (ie, aerosols). Support for this notion comes from studying the content of the genomic regions that have been deleted in different MTC members. A general observation is that although each deletion noted in Fig. 1 is unique to the bp, both genomic regions and the predicted function of implicated genes are nonrandom. Several regions of difference (RD) seem to be prone to genomic deletion, with different specific deletions having occurred near the same locus [6,7]. Most prominent among these is RD1, a series of nine genes implicated in the attenuation of M. bovis BCG strains, that has suffered three distinct genomic deletions. Although this confluence of deletions might point to genetic instability at this locus, a study of 100 circulating M. tuberculosis clones documenting 176 deletions failed to detect a single deletion in this region, arguing against an inherently elevated mutation rate [32]. The absence of RD1 was first observed for BCG vaccines [51a]; subsequently, targeted disruption of RD1 from M. tuberculosis was shown to decrease bacterial replication and educe pulmonary pathology in a mouse model [52,53]. More recently,

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M. microti and the dassie bacillus also were shown to have deletions in the RD1 region; notably, both have been characterized as having low virulence in animal models [19,43]. More detailed analysis of the RD1 region revealed it contains genes encoding a novel secretion system of two important secreted antigens (CFP-10, ESAT-6) [53,54]. Presumably a metabolically expensive process, the loss of this region in BCG was probably advantageous with no selective pressure in favor of synthesizing and secreting antigenic proteins in vitro. Although the independent loss of CFP-10 and ESAT-6 in M. microti and the dassie bacillus explains their attenuated phenotype, the selective pressures for their deletion in vivo are more speculative. Given the documented impact of the RD1 region on virulence, the observation of its deletion in both the vole and dassie hosts is provocative. Nothing evident points to why the genetically distant vole (a rodent) and dassie (closely related to the elephant) would share some unique immunologic susceptibility. A more likely explanation might involve social conditions and transmissibility [55], given that voles and dassies congregate in high-density underground communities, unlike other MTC hosts that predominantly live aboveground in open-air conditions. Such congregate living settings would be extremely favorable for TB transmission, and an organism of lesser virulence might be successful in such burrowing hosts so long as host populations remain sufficiently abundant [56]. Conversely, conditions for transmission aboveground between goats and seals are less ideal and would probably require an organism of relatively high virulence to optimize transmissibility. Summary of catalogued deletions From Fig. 1, deletions represented along the vertical line of the phylogeny preceded spread of the bacillus into new hosts; those along the horizontal axes arose during coevolution of the organism with new hosts. Evidence supporting this scenario is that organisms lacking RD7, RD8, RD9, and RD10 have been recovered from the entire MTC host range, whereas the precise deletions seen along the horizontal lineages are observed in only restricted, one-host settings. To derive a scenario for the loss of genomic regions in vivo, genes lost on the vertical axis and those lost along horizontal lineages can be directly compared, pointing to nonrandom distinction between the functional classification of these two sets of deleted genes. Although such studies generate hypotheses regarding the evolution of MTC members in different hosts, these studies are naturally biased

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to successful pathogenic strains, as opposed to those that caused infection but not disease. In this light, an examination of BCG vaccines provides telling insights into MTC evolution when the selective pressures for virulence were absent in the host and limited to the culture media employed. Remarkably, the sheer volume of genomic disturbance incurred by BCG vaccines during a half-century of laboratory evolution is on the same order as observed among virulent M. tuberculosis isolates that have been circulating through the human hosts through millennia [3]. Here, the preponderant message is that BCG evolution has favored the elimination of regulatory elements and antigens. These results reinforce the notion that the capacity to engage the host immune system is selected for during in vivo conditions, consistent with MTC members being professional pathogens [57]. More practically, the absence of numerous antigens from BCG vaccines may in part explain its limitations as an immunizing agent [58].

Summary and concluding thoughts: lessons for tuberculosis control M. tuberculosis has probably been with humans for millennia and thus probably became adapted to humans during times of low population density and predominantly outdoor living. Unlike diseases such as HIV that rapidly spread in epidemic form soon after introduction into humans, the TB epidemic peaked in Western Europe during the nineteenth century and has arguably yet to peak in certain parts of the world. Although it is possible that the organism has evolved toward greater virulence in recent centuries, it seems more probable that that social changes brought about by industrialization were paramount in altering the transmission dynamics. This argument would also apply to M. bovis, in which an organism that evolved to persist in free-ranging cattle would predictably wreak havoc in the environment provided by modern-day factory farming. Finally, whereas tuberculous animals in the wild might normally succumb to predation, the increasing protection of these hosts in wildlife refuges and zoos should provide a greater chance for progression to TB, as attested to by reports of TB in farmed deer [59], zoo tigers [60], and seal-trainers [61]. Although these cases are generally rare, these anecdotes do serve notice that MTC has the capacity to adapt to the immunologic environment it engages and suggest that nonhuman reservoirs may become pertinent to human TB control.

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Treatment of Active Tuberculosis: Challenges and Prospects Behzad Sahbazian, DOa, Stephen E. Weis, DOb,* a

John Peter Smith Hospital, Viola Pitts/Como Community Health Clinic, 4701 Bryant Irvin Road, Fort Worth, TX 76107, USA b Department of Medicine, University of North Texas Science Center, Texas College of Osteopathic Medicine, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA

In the past 5 years, the Tuberculosis Trials Consortium (TBTC) of the Centers for Disease Control and Prevention has completed several large studies that have improved the understanding of pharmacotherapy of tuberculosis. Insights gained from these studies have resulted in major changes in drug therapy of tuberculosis in HIV-infected and noninfected individuals [1 – 5]. These advances require that tuberculosis drug therapy now be individualized. Recommended treatment regimens are based on a patient’s risk profile that is determined by a combination of hematologic, microbiologic, clinical, and radiographic findings [6]. These studies have resulted in substantial changes in the treatment guidelines. Although they are more complicated than the previous guidelines, they allow treatment to be refined so that it can be extended in patients at high risk for treatment failure and allow shorter, more convenient treatment regimens in patients who can be identified as being at very low risk for failure [2]. This article reviews the basic principles of drug treatment of tuberculosis, individual pharmacologic agents, current treatment recommendations, and several special situations that clinicians are likely to encounter in medical practice.

Axioms of chemotherapy of tuberculosis Effective tuberculosis drug therapy requires not one but at least two effective drugs. This axiom

* Corresponding author. E-mail address: [email protected] (S.E. Weis).

emerged from the first studies of drug therapy of tuberculosis initiated in the late 1940s. These studies evaluated monotherapy with streptomycin and subsequently para-aminosalicylic acid (PAS) [7 – 9]. They demonstrated that drug resistance developed frequently in persons treated with monotherapy. During 3 months of monotherapy with streptomycin, 92% of persons who remained culture-positive developed streptomycin resistance [3]. Resistance also developed commonly during monotherapy with PAS and was found in approximately one third of patients during 4 months of treatment [9]. It was also observed that resistance was much less common in persons treated with the combination of streptomycin and PAS, and that many more patients treated with the two-drug regimen became bacteriologically negative with 4 months of therapy [9]. Ten percent or less of persons treated simultaneously with streptomycin and PAS developed streptomycin resistance [7,8]. It also was observed that development of resistance was associated with a worse prognosis and with more severe disease [3]. From these early observations came the principle that tuberculosis treatment must include simultaneous treatment with at least two effective drugs. The microbiologic basis for these early observations was not identified until the early 1960s and remains as important today to understand the design of current treatment regimens [10]. Persons with cavitary disease are estimated to have bacterial populations of approximately 108 organisms in each cavity [10,11]. During division, Mycobacterium tuberculosis bacilli mutate from drug-susceptible to drugresistant status spontaneously, randomly, and at a predictable rate [12]. The proportion of naturally oc-

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curring organisms that are resistant to antituberculosis drugs is variable, approximately 10 5 for ethambutol, 10 6 for isoniazid and streptomycin, and 10 8 for rifampin [8]. The probability of a single organism mutating simultaneously and becoming resistant to two drugs is the product of individual probabilities of mutation. It can therefore be estimated that the likelihood of an organism having mutations simultaneously for isoniazid and rifampin is approximately [(1  10 6)  (1  10 8)] or (1  10 14), and the bacillary burden in human tuberculosis is several orders less than this [13]. This mutation rate is the basis for the observation that successful drug therapy requires that at least two drugs be given concurrently to prevent selection of drug-resistant organisms. If a single drug is used for treatment, selection of the resistant organisms occurs, and the patient rapidly becomes resistant to that drug. This mutation rate is also the basis for designing regimens with an intensive initial phase that uses more medications and a less intense continuation phase that uses fewer medications. Corollaries of the treatment axiom that tuberculosis treatment must include simultaneous treatment with at least two effective drugs are important for designing effective tuberculosis regimens and tuberculosis control programs. Because of the possibility of resistance, a single drug is never added to a failing drug-treatment regimen. Optimal design of re-treatment regimens should include at least two medications to which the patient is naı¨ve, and clinicians designing initial treatment regimens must consider prevailing tuberculosis-susceptibility patterns in the community where the infection probably was acquired. It is equally important to successful treatment that the patient actually take the two probably effective drugs. The only way to ensure that a patient actually takes drug therapy as prescribed is direct observation of therapy. If three separate drugs are prescribed for a patient with tuberculosis, the patient may, for many reasons, take a single drug at a time. Short-term single-drug therapy in a person with high bacillary burden can lead to emergence of drug resistance [7 – 9]. If a patient happens to be initially resistant to one drug and takes a combination of two drugs, including the one to which he or she is resistant, drug resistance to the second drug will emerge. Similarly, if the patient is resistant to two drugs and takes these two drugs and a single effective drug, resistance to the third will emerge. Therefore, poor adherence, inadequate prescribing, or both may result in the development of multidrug resistance. Although these axioms may seem selfevident, the growing number of persons worldwide

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with drug-resistant tuberculosis is testimony that these principles are not being implemented successfully [14]. The last 50 years of tuberculosis drug treatment can be summarized succinctly. First, it was demonstrated that proper chemotherapy and the cooperation of the patient are the most important factors influencing response to treatment [15]. Second, it has been proven that the social factors such as those corrected during sanatoria treatment of tuberculosis (which provided bed rest, airy accommodations, a well-balanced diet, good nursing care, and psychologic balance) have had no effect on outcome in persons prescribed drug therapy and cooperating with treatment [15]. Third, a few new antituberculosis drugs have been developed. For the most part, however, progress has been made in learning to use available drugs more effectively, with treatment regimens becoming refined to the current treatments that are shorter, have fewer side effects, and are more convenient [6].

Pharmacology and toxicity of antimycobacterial agents The current drugs approved by the Food and Drug Administration (FDA) for the treatment of tuberculosis include isoniazid, pyrazinamide, rifampin, rifapentine, ethambutol, cycloserine, ethionamide, capreomycin, PAS, and streptomycin. Drugs that commonly are recommended by expert panels for use in the treatment of tuberculosis but are not FDA approved include rifabutin, the aminoglycosides including amikacin, kanamycin, and the fluoroquinolones including ciprofloxacin, moxifloxacin, and levofloxacin. Of the approved drugs, isoniazid, rifampin, ethambutol, and pyrazinamide are considered first-line antituberculosis drugs. Rifapentine and rifabutin can also be considered first-line drugs under special conditions discussed later. The others are categorized as second-line drugs, which are used when the first-line drugs are unsuitable because of drug intolerance or infection with drug-resistant tuberculosis. Additionally clarithromycin, amoxicillin/clavulanate, and linezolid have been used in the treatment of patients with drug-resistant tuberculosis. Drug-level monitoring is not routinely an important aspect of treatment in a patient with active tuberculosis. Therapeutic drug monitoring is most useful when there is a direct relationship between serum concentrations and therapeutic response and when serum concentrations serve as a surrogate for drug concentrations at the site of action. Therapeutic

treatment of active tuberculosis

drug monitoring is also important when there is a narrow range of concentrations that are effective and safe and when toxicity or lack of effectiveness puts the patient at great risk [16,17]. Examples of situations in which therapeutic drug monitoring is useful for safety include persons treated with aminoglycosides and persons treated with ethambutol or cycloserine with renal impairment.

Isoniazid Isoniazid is used for the treatment of both latent and active tuberculosis and works primarily by inhibiting cell wall synthesis. It is usually administered orally but has been given successfully intramuscularly or intravenously [6]. Isoniazid is cleared predominantly through the liver by acetylation. A patient’s acetylation status and the associated differences in plasma isoniazid concentrations are not associated with isoniazid-induced liver injury [18]. Additionally, no association was found between plasma isoniazid concentrations and isoniazid-induced liver injury [19]. Isoniazid is distributed throughout the body with peak concentrations occurring within 1 to 2 hours after the administration of an oral dose [20]. The usual dose for isoniazid is 3 to 5 mg/kg body weight/day in adults with a maximum dose of 300 mg/day [6]. Isoniazid generally is well tolerated. Hepatic side effects are perhaps the best known of the untoward effects associated with isoniazid use. Less well known is the asymptomatic elevation of liver aminotransferases of up to five times the upper limits of normal, which occurs in approximately 20% of patients receiving isoniazid. This asymptomatic mild elevation of liver aminotransferases is not progressive, is not an indication of progressive liver toxicity, and when asymptomatic does not require discontinuation of isoniazid treatment [6]. Isoniazid-induced hepatitis does occur, but recent studies indicate it is less common than previously thought. Isoniazidinduced hepatitis is estimated to occur in 0.15% of those starting and in 0.15% of those completing treatment for latent tuberculosis infection [21]. The rate of isoniazid-induced hepatitis is higher when isoniazid is combined with rifampin [22]. It is also more common in older persons, heavy alcohol consumers, and persons with underlying liver disease [23]. Based on a large survey, the risk of isoniazidinduced fatal hepatitis is much lower than previously thought—0.001%—when patients are monitored routinely for liver toxicity [24,25]. The risk increases slightly in patients over the age of 35 years.

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Peripheral neuropathy also is associated occasionally with use of isoniazid. Neuropathy occurs more commonly among persons who have other risks for neuropathy. Persons at increased risk of peripheral neuropathy include those who are nutritionally deficient, alcoholics, diabetics, pregnant women, breastfeeding mothers, and patients with renal disease. Vitamin B6 (pyridoxine) supplements usually are given with isoniazid to prevent development of peripheral neuropathy [6]. Hypersensitivity reactions including arthralgias, irritability, seizures, and lupuslike syndrome have also been reported in patients receiving isoniazid. Although as many as 20% of patients treated with isoniazid develop a positive antinuclear antibody test, systemic lupus rarely occurs [26]. Isoniazid has clinically important reactions with other concomitantly used medications. Isoniazid can affect the levels of certain antiseizure medications, such as phenytoin and carbamazepine. Levels of these medications must be monitored during isoniazid therapy [6].

Rifamycins The rifamycins, which include rifampin, rifabutin, and rifapentine, work by interfering with RNA synthesis, even in bacilli with minimal metabolic activity [27]. The rifamycins are variable inducers of the cytochrome P450 system. Rifampin, rifabutin, and rifapentine are each first-line drugs for the treatment of tuberculosis in different circumstances. Rifampin generally is given orally, but formulations are available for parenteral therapy. The usual dose for rifampin in adults is 10 mg/kg to a maximum of 600 mg daily. It is distributed well throughout the body and reaches effective concentrations in all tissues [6]. Rifampin is a necessary component of all short-course regimens [6]. Rifampin is generally a well-tolerated drug. The most common side effect of rifampin use is an orange discoloration of the urine, tears, and other body fluids. The change in the color of the urine or other body fluids can be disconcerting to persons treated with rifampin if they are not warned. This discoloration has been associated with discoloration of soft contact lenses and clothing. This staining must be rare, however, because the author and colleagues have treated many contact lens wearers with rifampin and never have had a complaint of discoloration of contacts lens, even though they routinely warn patients of this potential side effect. Rifampin can also cause pruritus [28]. Gastroin-

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testinal upset, including diarrhea, nausea, and abdominal pains, can occur but rarely require drug discontinuation and are usually self limiting [29]. Transient elevation of serum bilirubin may be observed during rifampin administration. Hepatitis is more common when rifampin is administered with isoniazid [30]. A more serious side effect of rifampin use is an influenzalike syndrome. Symptoms often mistaken by patients and physicians for influenza, including fevers, chills, faintness, headaches, myalgia, and arthralgia, occur alone or in combination. This hypersensitivity syndrome seems to be immune mediated and develops primarily when rifampin is given intermittently or in larger doses than are currently recommended. It most commonly develops after 3 to 6 months but can occur at any time during treatment [31]. Among persons receiving once-weekly rifampin as part of the antituberculosis regimen, 35% to 57% of persons who received 1200 to 1800 mg rifampin developed a flulike syndrome; the rates were 22% to 31% among those receiving 900 mg/week and 10% among persons taking 600 mg/week [32]. In contrast, for persons who received twice-weekly rifampin, a flulike syndrome was reported in 8% of those receiving 900 mg/week and in 4% of those receiving 600 mg/week. Symptoms usually appear 1 to 2 hours after administration of the drug and last up to 8 hours [31,32]. The hypersensitivity syndrome can be accompanied by other manifestations that may be severe and, rarely, life threatening. The incidence of individual adverse drug reactions included in the hypersensitivity syndrome is not well described for persons treated for tuberculosis. A study of 20,667 patients treated for leprosy with rifampin, 600 mg/day for 3 months, noted the following incidence rates: rash (0.07%), acute renal failure (0.1%), thrombocytopenia (0.01%), and hypotension (0.01%) [33]. Rifabutin use is also associated with rare immune-related reactions. These reactions tend to be hematologic, such as leukopenia and thrombocytopenia [33,34]. Rifampin can interact with a large number of medications because it is a potent inducer of several enzymes. Rifampin induction of hepatic enzymes can reduce serum concentrations of oral contraceptives, resulting in pregnancy, and women relying on hormonal methods of contraception need to use additional means of contraception. Rifampin can increase the metabolism of methadone and glucocorticoids, resulting in narcotic withdrawal syndrome and adrenal insufficiency or exacerbation of the illness being treated by glucocorticoid. The interactions of rifampin with other drugs are so extensive that all

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concurrent medications must be checked for interactions with rifampin. Ethambutol Ethambutol is used in combination with isoniazid and rifampin in the initial treatment of active tuberculosis and has been proven effective in primary treatment of pulmonary tuberculosis [35]. Ethambutol is used with isoniazid and rifampin to prevent selecting resistant organisms when resistance to one of the primary drugs is present. Like isoniazid, ethambutol inhibits cell wall synthesis. It is available only in the oral form. Because it is secreted through the kidneys, it can accumulate in patients with renal insufficiency. The usual dose for ethambutol is 15 to 20 mg/kg/day or 50 mg/kg two times per week. Ethambutol generally is very well tolerated, but, rarely, it can cause retrobulbar neuritis. This syndrome first manifests as decreased red-green color discrimination and visual acuity. Although it can result in irreversible vision loss, recognition of the symptoms and prompt discontinuation of the drug usually results in return of normal vision. Reducing the dose of ethambutol to 15 mg/kg/day can minimize the risk [36]. Fluoroquinolones Levofloxacin, moxifloxacin, and gatifloxacin all are active against mycobacterium tuberculosis [37,38]. Although they are not approved by the FDA for the treatment of tuberculosis, they are used frequently in treating drug-resistant tuberculosis or when patients are intolerant of first-line agents [39,40]. The adult dose for levofloxacin is 500 to 1000 mg/day orally. Moxifloxacin is administered at 400 mg/day. Central nervous system (CNS) concentrations of fluoroquinolones have been found to be around 16% to 20% of serum after administration of a standard dose of levofloxacin [41]. Microbial resistance to fluoroquinolones is common in the community setting; therefore it is imperative that fluoroquinolones be used only when appropriate. The most common side effects reported with the use of this group of antimicrobials are gastrointestinal symptoms such as nausea, anorexia, dyspepsia, abdominal pain, followed by CNS disturbances (headache, dizziness, drowsiness, abnormal vision) and liver enzyme abnormalities [42]. Fluoroquinolones were not developed with the expectation that they would be used for months; however most experts in the field of TB have reported a good safety profile and tolerability with long-term use. Controlled stud-

treatment of active tuberculosis

ies are in progress by CDC/TBTC to look at fluoroquinolones as there is a dearth of information on the efficacy of long-term fluoroquinolone treatment (either daily or intermittently) as is required for multidrug resistant TB. Pyrazinamide Pyrazinamide is the primary drug used in the initial intensive phase of active tuberculosis therapy to reduce the total length of therapy. It has a sterilizing effect and helps eliminate potential persisters and consequently is used in the first two months of intensive therapy to reduce the total length of therapy [43]. It is administered orally and is first broken down by the liver. The remaining metabolites are excreted through the kidney [44]. It is more hepatotoxic than isoniazid; therefore, liver function tests should be monitored. It can exacerbate gout and arthralgias by elevating serum uric acid levels [45]. The adult dose for pyrazinamide, based on estimated lean body weight, is 25 mg/kg for daily oral administration orally, 37.5 mg/kg for trice-weekly administration, and 50 mg/kg for twice-weekly administration [6]. Aminoglycosides Amikacin [46], kanamycin [47], and capreomycin are three aminoglycosides that are second-line agents used in treatment of patients who have resistant tuberculosis. They are available for both intramuscular and intravenous administration. All three are administered at 15 mg/kg/day (maximum, 1.0 g/day). Sensitivity tests have shown incomplete crossresistance between amikacin and capreomycin but complete cross-resistance between amikacin and kanamycin [48]. Adverse effects most commonly associated with the use of these drugs are ototoxicity and nephrotoxicity. Patients receiving these medications should have regular audiograms, vestibular and Romberg testing, and monitoring of renal function.

Treatment guidelines Tuberculosis treatment guidelines for the United States have been prepared by and endorsed by the American Thoracic Society, the Infectious Diseases Society of America, and the Centers for Disease Control and Prevention. These regimens are, for the most part, evidence based. These guidelines rate treatments according to the strength of the evidence supporting their use, using a system developed by the

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Box 1. Infectious Diseases Society of America/United States Public Health Service rating system for treatment recommendations based on quality of evidence Strength of the recommendation A. Preferred; should generally be offered B. Alternative; acceptable to offer C. Offer when preferred or alternative regimens cannot be given D. Should generally not be offered E. Should never be offered Quality of evidence supporting the recommendation I. At least one properly randomized trial with clinical end points II. Clinical trials that either were not randomized or were conducted in other populations III. Expert opinion From Gross PA, Barrett TL, Dellinger EP, et al. Purpose of quality standards for infectious diseases. Infectious Diseases Society of America. Clin Infect Dis 1994;18: 421; with permission.

United States Public Health Service and the Infectious Diseases Society of America (Box 1) [6]. The guidelines recommend four regimens for treating persons with drug-susceptible tuberculosis [6]. These regimens contain recommendations for regimen modification under circumstances determined by a combination of hematologic, microbiologic, clinical, and radiographic findings [6]. Each regimen has an initial intensive phase of 2 months followed by several options for the continuation phase of 4 or 7 months’ duration. These regimens, together with the number of doses specified by the regimen, are described in Table 1. The initial phases are denoted by a number (1, 2, 3, or 4), and the continuation phases associated with the initial phase are denoted by the number of the initial phase plus a letter designation for the continuation phase (a, b, or c). The continuation phase can be given daily, two times per week, or three times per week with iso-

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Table 1 Drug regimens for culture-positive pulmonary tuberculosis caused by drug-susceptible organisms Initial phase

Continuation phase Regimen

Drugs

Interval and dosesc,d (minimal duration)

1

INH RIF PZA EMB INH RIF PZA EMB INH RIF PZA EMB INH RIF EMB

7 d/wk for 56 doses (8 wk) or 5 d/wk for 40 doses (8 wk)e

1a

INH/RIF

1b 1cg 2a 2bg

INH/RIF INH/RPT INH/RIF INH/RPT

7 d/wk for 128 doses (18 wk) or 5 d/wk for 90 doses (18 wk)c 2/wk for 36 doses (18 wk) 1/wk for 18 doses (18 wk) 2/wk for 36 doses (18 wk) 1/wk for 18 doses (18 wk)

3a

INH/RIF

3/wk for 54 doses (18 wk)

4a

INH/RIF

4b

INH/RIF

7 d/wk for 217 doses (31 wk) or 5 d/wk for 156 doses (31 wk)c 2/wk for 62 doses (31 wk)

2

3

4

7 d/wk for 14 doses (2 wk), then 2/wk for 12 doses (6 wk) or 5 d/wk for 10 doses (2 wk)e then 2/wk for 12 doses (8 wk) 3/wk for 24 doses (8 wk)

7 d/wk for 56 doses (8 wk) or 5 d/wk for 40 doses (8 wk)e

Range of total doses (minimal duration)

HIV

HIV+

A (I)

A (II)

A (I) B (I) A (II) B (I)

A (II)f E (I) B (II)f E (I)

B (I)

B (II)

273 – 195 (39 wk)

C (I)

C (II)

118 – 102 (39 wk)

C (I)

C (II)

182 – 130 (26 wk) 92 – 76 74 – 68 62 – 68 44 – 40

(26 (26 (26 (26

wk) wk) wk) wk)

78 (26 wk)

Abbreviations: EMB, Ethambutol; HIV , HIV-negative; HIV+, HIV-positive; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RPT, rifapentine. a Definitions of evidence ratings: A, preferred; B, acceptable alternative; C, offer when A and B cannot be given; E, should never be given. b Definitions of evidence ratings: I, randomized clinical trial; II, data from clinical trials that were not randomized or were conducted in other populations; III, expert opinion. c When directly observed therapy is used, drugs may be given 5 d/wk and the necessary number of doses adjuated accordingly. Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice. d Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31 wk; either 217 doses [7/wk] or 62 doses [2/wk]) continuation phase. e Five d/wk administration is always given by DOT. Rating for 5 d/wk regimens is A III. f Not recommended for HIV-infected patients with CD4+ cell counts <100 cells/ml. g Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time of completion of 2 months of therapy and who do not have cavitation on initial chest radiograph (see text). For patients started on this regimen and found to have a positive culture from 2-month specimen, treatment should be extended an extra 3 months. From American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003; 52(RR-11):3.

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Interval and dosesc (minimal duration)

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Regimen

Ratinga (evidence)b

treatment of active tuberculosis

niazid and rifampin. It can also be given, more conveniently for patients and staff, once weekly using isoniazid and rifapentine in patients with tuberculosis without cavitation on the chest radiograph. This group is estimated to represent 40% of persons with tuberculosis in the United States [3]. Persons who have cavitation on the initial or follow-up chest radiograph or who are culture positive at the end of initial phase of therapy (usually completed after 2 months) have an unacceptably high risk of treatment failure [3,6]. For these patients, the continuation phase should be extended for an additional 3 months [6]. It is critically important to have sputum cultures at the time of completion of the initial phase of treatment to identify patients at increased risk of relapse. The treatment of tuberculosis in persons with HIV is discussed elsewhere in this issue. Treatment of tuberculosis may be delayed for many reasons. The current treatment guidelines defined completion of adequate therapy by the number of doses ingested as well as by the duration of treatment administration [6]. The minimum goal for adequate therapy is delivery of the full number of doses in no more than 150% of the expected delivery duration [6]. Special situations Central nervous system tuberculosis is one of the most devastating presentations of human tuberculosis. Disability and death occur despite antituberculosis therapy [49]. The best antimicrobial agents for the treatment of central nervous system tuberculosis have not been validated by well-designed, randomized, clinical trials. Isoniazid and pyrazinamide penetrate the meninges in all stages of inflammation. Rifampin, ethambutol, and aminoglycosides penetrate the blood – brain barrier in the presence of meningeal inflammation but poorly in its absence. The use of glucocorticoids in an attempt to reduce mortality and morbidity has been controversial [50]. Recently, a large trial of dexamethasone adjunct therapy for persons 14 years of age and older with tuberculous meningitis has clarified the role of glucocorticoids [51]. Dexamethasone treatment was started as soon as possible after starting antituberculosis treatment. Patients were stratified by Glasgow Coma Scale and given intravenous dexamethasone for 4 weeks for severe disease and for 2 weeks for mild disease. Subsequently, all patients were given tapering doses of dexamethasone orally for an additional 4 weeks. Dexamethasone adjunctive treatment improved survival. Adverse and severe adverse events were reduced significantly in the dexamethasone-

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therapy group. There was no demonstrable improvement in the broader prespecified combined end points of death or severe disability after 9 months [52]. There have been many reports of an increased risk of tuberculosis in patients receiving tumor necrosis factor- alpha (TNF-a) antagonists [53,54]. These agents, which include infliximab, etanercept, and adalimumab, are used for the treatment of an expanding group of diseases and work by blocking TNF-a; an inflammatory cytokine. TNF-a is expressed by activating macrophages, T cells, and other immune cells and is an important part of the host response against M. tuberculosis and other intracellular organisms. Current expert opinion on this emerging problem in tuberculosis treatment is that the TNF-a antagonist should be discontinued if tuberculosis develops during TNF-a antagonist therapy. The optimal time for resuming TNF-a antagonist therapy is undetermined. It is recommended that TNF-a antagonist therapy be withheld at least until treatment with the tuberculosis regimen has been started, and the patient’s condition has improved [54]. Tuberculosis occurring in pregnancy is a danger to the pregnant woman and her child, and treatment should not be delayed because of the pregnancy. Infants born to women with untreated tuberculosis may be of lower birth weight than those born to women without tuberculosis and can acquire congenital tuberculosis [55 – 57]. Of the first-line medications, pyrazinamide is not recommended for general use in pregnant women in the United States because of insufficient data to determine safety. Aminoglycosides should not be used to treat tuberculosis in pregnancy, because they are associated with birth defects [6]. There is little information about the safety of second-line antituberculosis drugs during pregnancy. The recommended initial treatment regimen in pregnancy should consist of isoniazid, rifampin, and ethambutol [6]. If the organism is confirmed to be susceptible to isoniazid and rifampin, the ethambutol may be discontinued and isoniazid and rifampin continued for a minimum of 9 months [6]. It is recommended that pregnant women receiving isoniazid also be given pyridoxine (25 mg/day) [6]. Breastfeeding should not be discouraged for women being treated with first-line agents, because the small concentrations of these drugs in breast milk do not produce toxic effects in the nursing infant [58]. Renal insufficiency increases the risk for developing tuberculosis, and treatment of the two conditions concurrently is a complex and common situation. Isoniazid and rifampin are metabolized in the liver, and dosages need not be changed in persons with chronic renal failure [59 – 61]. Metabolites of

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pyrazinamide are excreted renally and can accumulate in patients with renal insufficiency [61]. Approximately 80% of ethambutol is cleared by the kidneys, so ethambutol may accumulate in patients with renal insufficiency [59,61]. Reducing the dosage may avoid toxicity, but the peak serum concentrations achieved may be too low to be effective. Therefore increasing the dosing interval is recommended [60]. For patients undergoing hemodialysis, administering all drugs for tuberculosis after dialysis is a way to facilitate directly observed treatment and simultaneously to avoid removal of drugs such as pyrazinamide [6]. To avoid toxicity, it is important to monitor serum drug concentrations in persons with renal failure who are taking aminoglycosides, cycloserine, or ethambutol [60]. Data are unavailable for the effect of peritoneal dialysis on the clearance of antituberculosis drugs. The challenges facing patients with tuberculosis and underlying liver disease are great. Clinicians must choose antituberculosis agents that, with a few exceptions, are metabolized by the liver and can potentially cause additional liver damage [62 – 64]. This damage can be life threatening for a person with marginal hepatic function [62 – 65]. Hepatic dysfunction can also alter absorption and distribution of drugs that are metabolized or excreted by the liver [65]. In the setting of severe liver disease, it is reasonable to include fewer hepatotoxic medications and to extend the period of treatment [6,65]. This change can be accomplished using a single hepatotoxic drug, generally rifampin, in combination with ethambutol, a quinolone, and an aminoglycoside. Isoniazid can be substituted for rifampin, if rifampin cannot be given [6]. For these complicated patients, expert opinion should be obtained [6].

Summary Insights gained from studies done by the TBTC have resulted in major changes in the recommendations for drug therapy of tuberculosis in HIV-infected and noninfected individuals [1 – 5]. Although the goals for the treatment of tuberculosis remain the same, these advances require that tuberculosis drug therapy now be more individualized. Treatment regimens are based on a patient’s risk profile based on a combination of hematologic, microbiologic, clinical, and radiographic findings [6]. Although they are more complicated than the previous guidelines, they allow treatment to be refined so that it can be extended in patients at high risk for treatment failure and allow shorter, more convenient treatment regi-

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mens in patients who can be identified as being at very low risk for failure [2].

Acknowledgments The authors acknowledge Thaddeus Miller’s work in editing this article.

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Clin Chest Med 26 (2005) 313 – 326

Treatment of Latent Tuberculosis Infection: Challenges and Prospects Kelly E. Dooley, MD, MPHa, Timothy R. Sterling, MDb,* a

Department of Medicine, Providence Portland Medical Center, 4805 NE Glissan Street, Portland, OR 97213, USA b Division of Infectious Diseases, Department of Medicine and Center for Health Services Research, Vanderbilt University Medical Center, A4103 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232, USA

It is estimated that one third of the global population, or 2 billion people, are infected with Mycobacterium tuberculosis [1]. Among infected persons, approximately 10% progress to the clinically important (and infectious) stage of active tuberculosis over their lifetime [2,3]. The risk is higher in persons with concomitant HIV infection (>20%), evidence of old healed tuberculosis on chest radiograph (>20%), or recent M. tuberculosis infection (10% to 20%) [4]. In most infected persons, the host immune response contains the replication of M. tuberculosis and prevents the development of disease [5]. Among infected persons who develop active disease, progression occurs either shortly after initial infection (progressive primary disease) or subsequent to the initial infection, when there is a breakdown in the host immune response. A person is at greatest risk of progressing to active disease during the first 2 years after infection with M. tuberculosis [2]. In addition to HIV infection and recent M. tuberculosis infection, other risk factors for progression to active tuberculosis include silicosis, diabetes mellitus, chronic renal failure, malnutrition, weight loss, leukemia, lymphoma, cancer of the head, neck, and lung, gastrectomy, and jejunoileal bypass surgery [6].

This work was supported by the National Institutes of Allergy and Infectious Diseases K23 AI01654 (TRS). * Corresponding author. E-mail address: [email protected] (T.R. Sterling).

Diagnosis of latent Mycobacterium tuberculosis infection As discussed elsewhere in this issue, the diagnosis of latent M. tuberculosis infection relies primarily on the tuberculin skin test, an intradermal test that utilizes purified protein derivative (PPD). Because the mycobacterial proteins in PPD are not specific for M. tuberculosis, persons infected with other mycobacteria (eg, environmental mycobacteria such as M. avium intracellulare and M. bovis, the organism in the tuberculosis vaccine bacille Calmette-Guerin) may result in a false-positive test. Conversely, the tuberculin skin test has low sensitivity, particularly in immunocompromised persons. Because of these limitations, the definition of a positive tuberculin skin test varies according to the person’s risk of tuberculosis infection and risk of progressing to active disease if infected (Box 1) [6]. The different criteria for a positive test increase its sensitivity in high-risk persons and specificity in low-risk persons.

Indications for treatment of Mycobacterium tuberculosis infection All persons with evidence of latent M. tuberculosis infection should be evaluated for the presence of active disease. The evaluation should include an assessment of the signs and symptoms of tuberculosis and a chest radiograph; in persons with symptoms or an abnormal chest radiograph, sputum for acid-

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.02.003

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Box 1. Criteria for a positive tuberculin skin test based on millimeters of induration after intradermal placement of five tuberculin units of purified protein derivative (Mantoux technique) 5 mm induration  HIV seropositive  Recent contact with a cultureconfirmed tuberculosis case  Fibrotic changes on chest radiograph consistent with prior tuberculosis  Chronic immunosuppression (eg, prednisone 15 mg/day for at least 30 days) 10 mm induration  Immigration from a highprevalence country within the last 5 years  Injection drug use  Residents and employees of highrisk settings: prisons, jails, nursing homes, and other long-term care facilities, hospitals, residential facilities for AIDS patients, homeless shelters  Mycobacteriology laboratory personnel  Persons at increased risk of developing active tuberculosis: those with silicosis, diabetes mellitus, chronic renal failure, leukemia, lymphoma, cancer of the head, neck or lung, weight loss of more than 10% of ideal body weight, gastrectomy, jejunoileal bypass  Children younger than 4 years old 15 mm induration  Persons with no risk factors for tuberculosis From 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):S234; with permission.

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fast smear and culture should also be obtained. Once active disease has been excluded, all persons at increased risk of progressing to active tuberculosis (see Box 1) should receive treatment for latent infection.

Importance of treatment of Mycobacterium tuberculosis infection to decrease the global tuberculosis burden Most cases of active tuberculosis arise from persons with latent M. tuberculosis infection; treatment of such persons is therefore necessary to achieve tuberculosis elimination. The focus should be on those persons at high risk of progressing to active disease. The strategy of targeted tuberculin skin testing among high-risk groups and treatment of all such persons with a positive tuberculin skin test is recommended in the United States [6,7]. Infection with M. tuberculosis is often termed latent because of the absence of clinical manifestations, the slower replication rate of M. tuberculosis, and the lower burden of organisms compared with active disease [8]. Because of the relatively low burden of organisms, treatment of latent infection requires fewer drugs than active disease to facilitate cure and prevent the development of drug resistance. Use of a single antituberculosis agent is sufficient for latent infection but not for active disease. As detailed later, treatment of latent M. tuberculosis infection dramatically decreases the risk of developing active tuberculosis.

Regimens to treat Mycobacterium tuberculosis infection Each of the regimens available to treat latent M. tuberculosis infection is reviewed here, with emphasis on both the effectiveness and toxicity of the regimens. The review is limited to studies conducted in adults and published in the English peerreviewed literature; studies reported only in abstract form are not included. The authors are unaware of studies of the effectiveness of short-course therapy conducted among children. Because the risk of active tuberculosis is substantially higher in HIVseropositive persons than in HIV-seronegative persons, and because the effectiveness of many regimens has been assessed separately according to HIV serostatus, the data are presented separately for HIVseropositive and HIV-seronegative persons. Toxicity of therapy may also differ according to HIV sero-

Table 1 Randomized, controlled trials of isoniazid for the treatment of latent Mycobacterium tuberculosis infection among HIV-seronegative persons First author/date [reference]

Randomization unit

United States Public Health Service trials Mount, 1962 [67] Family Family

Ferebee, 1963 [68]

Ward

Comstock, 1967 [69]

Household

International trials Chiba, 1963 [70]

Household

Nyboe, 1963 [71]

City blocks

Egsmose, 1965 [72]

Household

DelCastillo, 1965 [73]

Household

Horwitz, 1966 [74]

Village

Veening, 1968 [75]

Individual

IUAT, 1982 [9]

Individual

Follow-up

Regimen

Contacts of known active cases PPD+ and Household contacts of new active TB 39 US communities, PPD+ and Mental institutions PPD+ and Alaskan Eskimos in Bethel area Most not PPD tested

4 years

INH 5 mg/kg/d Placebo INH 5 mg/kg/d Placebo INH 5 mg/kg/d Placebo INH 5 mg/kg/d Placebo

Osaka, Japan Household contacts of new active TB Suburb of Tunis City

3 years 5 years 6 years

for 1 year for 1 year for 1 year for 1 year

2 years

INH 5 mg/kg/d for 1 year

1 year

INH (very erratic pill taking) Placebo INH 5 – 10 mg/kg/d for 1 year Placebo INH Placebo INH 400 mg 2 /wk for total 52 doses Placebo INH 600 mg  4 mo, 400 mg  8 mo Placebo INH 300 mg/d for 12 weeks INH 300 mg/d for 24 weeks INH 300 mg/d for 52 weeks Placebo

Rural northern Kenya PPD+ contacts of new active cases Philippines Contacts of active cavitary TB Greenland villagers

4 years

Royal Netherlands Navy New PPD+ after exposure to index case 7 European countries PPD+ patients with fibrotic lesions

4 years

2 years 6 years

5 years

Active TB n/N (%)

Reduction (%)

6/1463 (0.41) 12/1351 (0.89) 29/12439 (0.23) 97/12594 (0.77) 35/12884 (0.27) 89/12326 (0.72) 58/3047 (1.9) 141/3017 (4.67)

54

8/1142 (0.7) 11/1096 (1.0) 18/7769 (0.23) 25/8141 (0.31) (1.04) (1.6) 8/97 (8.2) 18/129 (14.0) 238/4174 (5.7) 323/3907 (8.3) 2/133 (0.38) 12/128 (9.4) 76/6956 (1.1) 34/6965 (0.49) 24/6919 (0.35) 97/6990 (1.4)

70 62 59

30 25 35 41 31

treatment of latent tuberculosis infection

Ferebee, 1962 [17]

Population

96 21 65 75

Abbreviations: INH, isoniazid; IUAT, International Union Against Tuberculosis; PPD, purified protein derivative; TB, tuberculosis.

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status, so tolerability data are also presented according to HIV serostatus. Recommended doses of specific drugs have been published previously [6].

Isoniazid Effectiveness HIV-seronegative persons Isoniazid is the best-studied regimen for the treatment of latent M. tuberculosis infection. More than 20 randomized, controlled trials have been conducted, which together enrolled more than 100,000 persons. Most of these studies were conducted in the 1950s and 1960s and therefore enrolled only HIVseronegative persons. These trials are summarized in Table 1. Most of the studies assessed the effectiveness of 12 months of isoniazid versus placebo. The trial conducted by the International Union Against Tuberculosis (IUAT) assessed 3 versus 6 versus 12 months of therapy and found that 6 months of isoniazid was less effective (65%) than 12 months (75%) [9]. George Comstock [10] subsequently performed an analysis of previously conducted clinical trials and found that 6 months of isoniazid provided insufficient protection; 9 to 10 months of isoniazid seemed to provide optimal protection. Based on these findings, the American Thoracic Society (ATS), Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) guidelines recommend 9 months of isoniazid [6]. A 9-month regimen of isoniazid has never been compared with a 6- or 12-month course of isoniazid in a clinical trial, however. HIV-seropositive persons Isoniazid effectiveness has also been studied in HIV-seropositive persons, although not as extensively as in HIV-seronegative persons. The randomized, controlled trials of treatment of latent M. tuberculosis infection in HIV-infected persons are summarized in Table 2, and the randomized, placebo-controlled trials of isoniazid are summarized in Table 3. Among tuberculin skin-test – positive persons, isoniazid is clearly more effective than placebo in preventing tuberculosis; this finding has been confirmed in a metaanalysis [11]. Isoniazid has been associated with improved survival in some studies [12 – 14], but not in all [11,15,16]. Although there has not been a direct comparison of 6 versus 9 versus 12 months of isoniazid, 6 months seems to be less effective than 12 months. Based on the rationale used for

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HIV-seronegative persons, and to ensure uniformity of recommendations, the ATS/CDC/IDSA guidelines recommend 9 months of isoniazid for HIVseropositive persons [6]. Although HIV-infected persons are at increased risk of having a negative tuberculin skin test, particularly with advanced immunosuppression, isoniazid is not substantially more effective than placebo in preventing tuberculosis in such persons, and therefore is not recommended (Table 3) [11]. Toxicity HIV-seronegative persons In the initial studies of isoniazid, drug discontinuation rates were low and did not differ from rates among persons receiving placebo [17]. Subsequent studies, however, have noted higher rates of drug discontinuation, as summarized in Tables 4 and 5. Few of these studies have been placebo-controlled. Isoniazid can cause elevated hepatic transaminases [18], but these liver function abnormalities are often transient and are not representative of clinically significant hepatitis. In studies in which serum transaminases were monitored regularly regardless of symptoms, 10% to 22% of participants had at least one elevated transaminase level during the course of therapy [19 – 25]. Rates of clinically significant hepatitis are lower. In a surveillance study of the US Public Health Service, 236 of 13,838 persons (1.7%) who received isoniazid developed hepatitis. When considering only those persons in whom the hepatitis was probably or possibly related to isoniazid, the rate was 174 in 13,838 (1.3%) [26]. Hepatitis risk increased with age and concomitant alcohol consumption. In another study, a 7-year survey from one public health clinic, 11 of 11,141 patients (0.10%) who started isoniazid developed hepatotoxicity [27]. Isoniazid-associated hepatotoxicity can be fatal, and the risk of death increases with age. It is estimated that the hepatotoxicity-associated casefatality rate per 10,000 persons initiating isoniazid treatment is 0 for ages 20 to 34 years, 2 for ages 35 to 49 years, and 4 for ages 50 to 64 years [24,26,28,29]. Although never tested in a trial, rates of hepatotoxicity may be lower when there is regular monitoring of signs and symptoms of hepatitis [27,28]. In the United States it is currently recommended that patients receiving isoniazid undergo monthly clinical assessments for adverse effects. They should also be evaluated whenever symptoms develop. Patients should be educated regarding the signs and symptoms of hepatotoxicity and instructed to discontinue the medicine and seek clinical evaluation if symptoms

Table 2 Randomized, controlled trials of treatment of latent Mycobacterium tuberculosis infection among HIV-seropositive persons First author/date [reference] INH versus placebo trials Pape, 1993 [12]

Gordin, 1997 [77]

Fitzgerald, 2001 [78]

Multiregimen trials Whalen, 1997 [15]

Mwinga, 1998 [41]

Gordin, 2000 [36]

Halsey, 1998 [40]

Compliance/follow-up

118

33 months

No loss to follow-up

INH 300 mg/d for 6 months

684

20 months

70% follow-up

US, mostly NYC Anergic patients

INH 300 mg/d for 6 months

517

33 months

63% completed therapy; 6% INH and 7% placebo lost to follow-up

Haiti PPD

INH 300 mg/d for 12 months

237

2.5 years

77% followed to death or study end

Uganda (1) PPD+

PPD+: INH 300 mg/d for 6 months or INH 300 mg/d and RIF 600 mg/d for 3 months or INH 300 mg/d, RIF 600 mg/d, and PZA 2000 mg/d for 3 months Anergic: INH 300 mg/d for 6 months INH 900 mg 2 /wk for 6 months or RIF 600 mg and PZA 3500 mg 2 /wk for 3 months INH 300 mg/d for 12 months or RIF 600 mg and PZA 20 mg/kg/d for 2 months

2018

15 months

75% urine tests and 80% – 89% completed the trials

718 1053

1.8 years

81% placebo, 66% INH, and 75% RIF/PZA were >80% compliant

1583

37 months

80% RIF/PZA and 69% INH completed therapy

750

2.5 years

55% INH and 74% RIF/PZA had >80% compliance

Population

Regimens

Randomized Double-blind Placebo-controlled

Haiti New HIV diagnosis PPD+ or Kenya PPD+ or

INH 300 mg/d for 12 months

Block-randomized Double-blind Placebo-controlled Randomized Double-blind Placebo-controlled Randomized Blinding unclear Placebo-controlled Block-randomized Double-blind Placebo-controlled

Block-randomized Double-blind Placebo-controlled Randomized Open-label No placebo arm Randomized Unmasked Partly supervised No placebo arm

(2) Anergic Zambia

US, Mexico, Haiti, Brazil PPD+ Haiti PPD+

INH 600 – 800 mg 2 /wk for 6 months or RIF 450 – 600 mg and PZA 1500 – 2000 mg 2 /wk for 2 months (weight-based)

N

treatment of latent tuberculosis infection

Hawken, 1997 [76]

Mean follow-up

Trial type

Abbreviations: INH, isoniazid; PPD, purified protein derivative; PZA, pyrazinamide; RIF, rifampin. 317

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Table 3 Results of randomized, controlled trials of isoniazid for the treatment of latent Mycobacterium tuberculosis infection among HIV-seropositive persons First author/date [reference] PPD positive Pape, 1993 [12] Hawken, 1997 [76] Whalen, 1997 [15] PPD+ cohort Mwinga, 1998 [41] PPD negative Gordin, 1997 [77] Fitzgerald, 2001 [78] Hawken, 1997 [76] Pape, 1993 [12] Whalen, 1997 [15] anergic cohort Mwinga, 1998 [41]

Rx n/N (%) INH

Control n/N (%) placebo

RR

95% Confidence interval

Reduction (%)

2/38 (5.2) 5/67 (7.5) 7/536 (1.3)

6/25 (24.0) 8/69 (11.6) 21/464 (4.5)

0.22 0.64 0.29

0.05, 1.00 0.22, 1.87 0.12, 0.67

78 36 71

6/101 (5.9)

11/60 (18.3)

0.32

0.13, 0.83

68

(2.3) (3.6) (3.6) (14.3) (3.1)

0.66 1.32 1.31 0.70 0.74

0.19, 0.38, 0.54, 0.15, 0.30,

34 32 31 30 26

17/166 (10.2)

0.75

0.42, 1.34

4/260 6/126 11/235 2/20 9/395

(1.5) (4.8) (4.7) (10.0) (2.3)

27/351 (7.7)

6/257 4/111 8/224 5/35 10/323

2.31 4.56 3.20 3.28 1.79

25

Results are presented according to the tuberculin skin test status of study patients. Abbreviations: INH, isoniazid; PPD, purified protein derivative; RR, relative risk.

occur. Routine laboratory monitoring is recommended for persons with abnormal baseline liver function tests, persons at increased risk of hepatotoxicity (eg, HIV infection, liver disease, alcoholism, pregnancy), and persons who develop symptoms while on therapy. [6] Isoniazid can also cause peripheral neuropathy, but the risk is lower with concomitant use of vitamin B6 (pyridoxine) [30,31]. HIV-seropositive persons The rates of isoniazid-associated toxicity requiring drug discontinuation in HIV-seropositive persons are summarized in Table 5. Although the data are not as extensive as in HIV-seronegative persons, isoniazid is generally well tolerated in this patient population. Table 4 Toxicity of isoniazid for treatment of latent Mycobacterium tuberculosis infection in HIV-seronegative patients

First author/date [reference] Scharer, 1969 [18] Byrd, 1972 [22] Bailey, 1973 [79] Byrd, 1977 [80] Byrd, 1979 [24] Stuart, 1999 [25]

Toxicity requiring discontinuation of therapy INH n/N (%)

Placebo n/N (%)

2/90 16/160 18/427 10/120 64/1000 26/83

No placebo No placebo No placebo 1/60 (1.7) No placebo No placebo

(2.2) (10) (7.3) (8.3) (6.4) (31.3)

arm arm arm arm arm

Toxicity is defined as adverse events resulting in discontinuation of therapy. Abbreviation: INH, isoniazid.

Hepatitis C virus and isoniazid-associated hepatotoxicity Hepatitis C virus (HCV) infection has been associated with an increased risk of hepatotoxicity among persons receiving combination antituberculosis therapy for active disease, particularly HIVinfected persons [32]. HCV infection is common in injection drug users [33], who are also at high risk of progressing to active tuberculosis if latently infected with M. tuberculosis. Two studies have assessed the risk of isoniazid-associated hepatotoxicity in persons with underlying HCV. In a study of 146 injection drug users with M. tuberculosis infection and normal baseline hepatic transaminases, 138 were HCV seropositive; 32 (22%) developed hepatic transaminases levels more than three times the upper limit of normal, and 11 (8%) required drug discontinuation [34]. These rates are comparable to those reported in populations with lower HCV seroprevalence (see preceding discussion and Table 5). In a second study of 415 drug users, of the 214 that were HCV-antibody – positive, 16 (7.5%) developed hepatotoxicity (defined as drug discontinuation in the setting of hepatic transaminase elevation more than five times the upper limit of normal in the presence of symptoms or as transaminase elevation alone on two occasions at least 1 week apart) [35]. On multivariate analysis, HCV infection was not independently associated with hepatotoxicity. Both studies suggest that isoniazid is safe in persons with HCV infection and is not associated with significantly higher rates of hepatotoxicity than in persons without HCV.

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treatment of latent tuberculosis infection Table 5 Toxicity of isoniazid for treatment of latent Mycobacterium tuberculosis infection in HIV-seropositive patients Toxicity requiring discontinuation of therapy First author/date [reference]

INH n/N (%)

Placebo n/N (%)

RR

Pape, 1993 [12] Gordin, 1997 [77] Hawken, 1997 [76] Whalen, 1997 [15] PPD+ Anergic Mwinga, 1998 [41]

0/58(0) 24/260 (9.2) 11/342 (3.2) 3/536 (0.6) 0/395 26/703 (3.7)

0/60 (0) 24/257 (9.3) 5/342 (1.5) 1/464 (0.2) 0/323 3/350 (0.9)

0 0.99 2.2 2.60 0 4.31

95% Confidence interval 0.58, 1.69 0.77, 6.26 0.27, 24.88 1.32, 14.16

Toxicity is defined as adverse events resulting in discontinuation of therapy. Abbreviations: INH, isoniazid; PPD, purified protein derivative; RR, relative risk.

Although the efficacy of isoniazid in preventing tuberculosis exceeds 90% among persons who adhere to therapy [9], the effectiveness of isoniazid is lower because of low rates of adherence to the long duration of therapy. This problem of adherence has led to the assessment of regimens that require a shorter course of treatment. These regimens are summarized here.

Rifampin plus pyrazinamide for 2 months Effectiveness Among available short-course regimens for the treatment of latent M. tuberculosis infection, the regimen with the shortest duration, and therefore the greatest potential for improved adherence, is the 2-month regimen of rifampin plus pyrazinamide. HIV-seronegative persons Effectiveness of rifampin plus pyrazinamide has not been studied in HIV-seronegative persons. Because of high rates of hepatotoxicity in tolerability studies (see later discussion), it is unlikely that effectiveness will ever be studied in HIVseronegative persons.

HIV-seropositive persons The effectiveness of the 2-month rifampin plus pyrazinamide regimen has been studied entirely in HIV-seropositive persons. Because the risk of tuberculosis without treatment of latent infection is substantially higher in HIV-seropositive persons than in HIV-seronegative persons, much smaller sample sizes were required to study effectiveness in the former. The results of the studies are summarized in Table 6. In the largest of the studies, the effectiveness of daily rifampin plus pyrazinamide for 2 months was nearly identical to 12 months of daily isoniazid [36]. Toxicity HIV-seronegative persons After the effectiveness and tolerability of 2 months of rifampin plus pyrazinamide were demonstrated in HIV-seropositive adults, the regimen was recommended in the United States for both HIVseropositive and -seronegative adults [6]. Shortly thereafter, however, there were reports of severe hepatotoxicity and death among persons treated with this regimen [37,38]. When such cases continued to be reported, the CDC began collecting retrospective surveillance data on the number of persons treated

Table 6 Randomized, controlled trials of the effectiveness of pyrazinamide plus rifampin for the treatment of latent Mycobacterium tuberculosis infection in HIV-seropositive persons First author/date [reference] PPD positive Gordin, 2000 [36] Halsey, 1998 [40] Mwinga, 1998 [41] PPD negative Mwinga, 1998 [41]

Rx n/N (%) RIF/PZA

Control n/N (%) INH

RR

95% Confidence interval

28/791 (3.5) 19/380 (5.0) 2/49 (4.1)

29/792 (3.7) 14/370 (3.8) 4/52 (7.7)

0.97 1.32 0.53

0.58, 1.61 0.67, 2.56 0.10, 2.77

3 32 47

13/173 (7.5)

14/178 (7.9)

0.96

0.46, 1.96

4

Reduction (%)

Results are presented according to the tuberculin skin test status of study patients. Abbreviations: INH, isoniazid; PPD, purified protein derivative; PZA, pyrazinamide; RIF, rifampin; RR, relative risk.

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Table 7 Toxicity of rifampin plus pyrazinamide for treatment of latent Mycobacterium tuberculosis infection in HIV-seronegative patients Toxicity requiring discontinuation of therapy First author/date [reference]

RIF/PZA n/N (%)

INH n/N (%)

a

13/168 12/589 28/307 26/148

No INH arm No INH arm 8/282 (2.8) No INH arm

Bock, 2001 [58] a Chaisson, 2002 [81] Jasmer, 2002 [60] a Lee, 2002 [82] a McNeill, 2003 [83] a Stout, 2003 [84] Van Hest, 2004 [85]

(7.7) (2.0) (9.1) (17.6)

8/114 (7.0) 14/166 (8.4)

No INH arm 17/528 (3.2)

Hepatotoxicity requiring discontinuation of therapy RR

3.21

2.62

RIF/PZA n/N (%)

INH n/N (%)

1/168 (0.6) 10/589 (1.7) 12/207 (5.8) 11/148(7.4) 14/110 (12.7) 6/114 (5.3) 14/166 (8.4)

No INH arm No INH arm 2/204 (1.0) No INH arm 5/114 (4.4) No INH arm 18/528 (3.4)

RR

5.91 2.90 2.47

Toxicity is defined as adverse events resulting in discontinuation of therapy. Abbreviations: INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RR, relative risk. a In these studies, the patient population was predominantly HIV-seronegative, with a small minority of HIVseropositive patients.

with this regimen so that the risk of toxicity could be determined [39]. Data were collected for persons initiating therapy between January 2000 and June 2002 and reported to CDC by June 6, 2003. Of the 7737 persons reported to have started rifampin plus pyrazinamide treatment during the survey period, 204 persons developed aspartate aminotransferase concentrations more than five times the upper limit of normal (2.6/100 treatment initiations), and an additional 146 patients discontinued therapy because of symptoms of hepatitis (1.9/100 treatment initiations). There were 48 cases of severe hepatotoxicity (defined as resulting in hospitalization or death); 11 patients died. The estimated rate of death caused by hepatotoxicity was 0.9 per 1000 treatment initiations [39]. The estimates were limited because data were obtained retrospectively, and the risk associated with isoniazid was not determined concurrently. Nonetheless, the risk of severe hepatotoxicity and death seemed to be approximately 10 times greater than the risk associated with isoniazid, and it was therefore recommended that rifampin plus pyrazinamide should generally not be offered for treatment of latent tuberculosis infection [39]. The toxicity data from clinical trials are summarized in Table 7.

HIV-seropositive persons The regimen was very well tolerated in all of the clinical trials conducted among HIV-seropositive persons (Table 8) [36,40,41], even upon repeat analysis specifically addressing hepatotoxicity [42]. Because of the relatively small sample sizes of the studies, and an event rate of severe hepatotoxicity of approximately 1 per 1000, it is possible that such serious events were not detected in these studies. The CDC therefore recommends that rifampin plus pyrazinamide should generally not be offered, regardless of HIV serostatus [39].

Isoniazid plus rifampin for 3 months Effectiveness There are few studies of isoniazid plus rifampin for the treatment of latent M. tuberculosis infection. In the only study among HIV-seronegative adults, the efficacy among adherent patients of 3 months of isoniazid plus rifampin was 41% [43]. Among HIVseropositive adults, the regimen was 59% effective in

Table 8 Toxicity of rifampin plus pyrazinamide for treatment of latent Mycobacterium tuberculosis infection in HIV-seropositive patients Toxicity leading to discontinuation of therapy First author/date [reference]

RIF/PZA n/N (%)

INH n/N (%)

RR

95% Confidence interval

Halsey, 1998 [40] Mwinga, 1998 [41] Gordin, 2000 [36,42] Narita, 2003 [86]

0/380 14/351 75/791 5/135

0/370 12/352 48/792 0/25

1.17 1.56

0.55, 2.50 1.09, 2.22

(0) (4.0) (9.5) (3.7)

(0) (3.4) (6.1) (0)

Toxicity is defined as adverse events resulting in discontinuation of therapy. Abbreviations: INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RR, relative risk.

treatment of latent tuberculosis infection

preventing tuberculosis [15]. Extensive programmatic experience with the regimen among children in Great Britain suggests its effectiveness, but there are no clinical trial data [44]. In the United States, this regimen is not among the recommended treatment regimens, perhaps because of the limited available data [6].

Toxicity The regimen has been well tolerated, although relatively few studies have been conducted to date. In the study among HIV-seronegative adults, 8 of 167 persons (5%) discontinued therapy because of adverse drug reaction [43]; the rate among HIVseropositive adults was 13 of 556 (2.3%) [15]. In a pooled analysis of 6105 persons who received isoniazid plus rifampin, 156 (2.5%) developed hepatitis [45].

Rifampin for 4 months Effectiveness Among persons who are intolerant of isoniazid, or among close contacts of tuberculosis cases in which the isolate of M. tuberculosis is resistant to isoniazid, rifampin can be used to treat latent M. tuberculosis infection. There are, however, only limited data from randomized clinical trials and uncontrolled observational studies regarding the effectiveness and tolerability of the regimen. Given the importance of rifampin in the treatment of active tuberculosis, it is particularly important to exclude active disease before treating for latent M. tuberculosis infection, because treatment of undiagnosed active tuberculosis with rifampin monotherapy will lead to rifampin resistance.

HIV-seronegative persons The only randomized trial to evaluate the effectiveness of rifampin was conducted in Hong Kong among persons with latent M. tuberculosis infection and silicosis. Among all persons initiating therapy, 20 of 165 (12.1%) randomly assigned to receive rifampin for 3 months developed tuberculosis, compared with 36 of 159 persons (22.6%) who received placebo, for an effectiveness of 46% [43]. Among persons who completed the 5-year study, rates were 17 of 103 (17%) and 34 of 99 (34%), respectively, for

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an effectiveness of 50% [43]. In an observational study among homeless persons with documented tuberculin skin-test conversion during an epidemic of tuberculosis resistant to isoniazid and streptomycin, 49 persons received rifampin. The average duration of therapy was 6.4 months. None of the 49 persons developed tuberculosis, compared with 6 of 71 persons (8.6%) who received no therapy [46]. In a study of 157 tuberculin skin-test – positive adolescent close contacts of persons with isoniazid-resistant tuberculosis, all were treated with a 6-month course of rifampin; none developed tuberculosis during the 2-year evaluation period [47]. Although the effectiveness of 4 months of rifampin has never been studied, it is the currently recommended duration in the ATS/ CDC/IDSA guidelines [6].

HIV-seropositive persons There are no studies of the effectiveness of rifampin for the treatment of latent M. tuberculosis infection among HIV-seropositive persons. Because of the lack of studies, and because active disease is more difficult to exclude in persons with HIV, one should use rifampin in this patient population with much caution, if at all.

Toxicity HIV-seronegative persons Although data on the tolerability of rifampin are limited, it seems to be well tolerated. In the randomized trial conducted in Hong Kong, 6 of 172 patients (3.5%) discontinued therapy during the study because of adverse drug reaction. None of these patients developed hepatotoxicity [43]. In the study among homeless persons in Boston, 7 of 49 persons (14%) developed adverse effects requiring discontinuation of therapy, but there were no reports of hepatotoxicity [46]. Of the 157 adolescents who received rifampin, 18 (11.5%) interrupted therapy temporarily, and 2 (1.3%) permanently discontinued therapy [47]. In a recent study of persons randomly assigned to receive either 4 months of rifampin or 9 months of isoniazid, 2 of 58 persons (3%) receiving rifampin developed adverse events requiring permanent drug discontinuation; none developed hepatitis [48].

HIV-seropositive persons There are no data on the safety of this regimen in HIV-seropositive persons.

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Special situations Pregnant/breastfeeding women Pregnancy does not increase the risk of progression from latent infection to active disease. Because of the morbidity associated with tuberculosis in the pregnant mother and neonate, treatment of latent M. tuberculosis infection is recommended for pregnant women at high risk of progression to active disease (ie, those with recent M. tuberculosis infection or with coinfection with M. tuberculosis and HIV) [6]. Given the proven effectiveness of isoniazid and its safety in pregnancy, it is the preferred regimen. Because of the low levels of isoniazid in breast milk, its use is not contraindicated in breastfeeding women.

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mab, etanercept, and adalimumab, are used to treat autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. Use of these drugs increases the risk of progressing from latent M. tuberculosis infection to active disease in persons with either remote or recent M. tuberculosis infection [53 – 55]. Before initiating the use of a TNF-a antagonist, patients should be evaluated for latent M. tuberculosis infection and, if symptomatic, for active tuberculosis. In immunocompromised persons, induration of 5 mm or greater is considered a positive tuberculin skin test (see Box 1). Treatment of latent infection may be considered in persons with an induration of less than 5 mm if epidemiologic and clinical circumstances suggest recent M. tuberculosis infection [54,55]. Treatment for latent M. tuberculosis infection should be initiated (and preferably completed) before starting treatment with the TNF-a antagonist [55].

Children The only treatment regimen that has been extensively studied in children is isoniazid. Isoniazid may be more effective in children than in adults, with a reported effectiveness of 70% to 90% [49,50]. Because the effectiveness of short-course regimens has not been studied in children, such regimens are not recommended by the ATS/CDC/IDSA [6]. Contacts of persons with drug-resistant tuberculosis If persons are infected with a strain of M. tuberculosis that is resistant to rifampin but susceptible to isoniazid, isoniazid is effective for treatment. For persons exposed to a case of tuberculosis resistant to isoniazid, treatment with rifampin is recommended, as discussed previously [6]. The optimal treatment is unknown for persons with evidence of latent M. tuberculosis infection who have been exposed to multidrug-resistant tuberculosis (MDR-TB), defined as resistance to at least isoniazid plus rifampin. No clinical studies have assessed the effectiveness of specific regimens, and such studies will probably never be conducted because of the difficulty in enrolling a sufficient sample size. Recommended regimens include a fluoroquinolone plus pyrazinamide or ethambutol plus pyrazinamide [51]. The optimal duration of these regimens is unknown, although 6 to 12 months is recommended. They often are poorly tolerated [52]. Tumor necrosis factor-alpha antagonists Drugs that block the inflammatory cytokine tumor necrosis factor-alpha (TNF-a), such as inflixi-

Difficulties and challenges of treatment of latent Mycobacterium tuberculosis infection Low rates of treatment initiation Not all persons who are eligible for treatment of latent tuberculosis infection initiate therapy. In a study of close contacts of smear-positive pulmonary tuberculosis cases, 95 HIV-infected persons were eligible for treatment of latent infection; of these, only 30 (32%) initiated therapy [56]. In another study of close contacts of tuberculosis cases, of the 630 persons with newly documented positive tuberculin skin tests (all of whom were eligible for therapy), treatment was recommended in 447 (71%), and was started in only 398 (63%) [57]. Efforts must be made to improve the use of treatment of latent infection, particularly in those at highest risk of progression to active disease, such as HIV-infected persons and close contacts. Low treatment-completion rates Among persons who start therapy, treatmentcompletion rates are low. In the second study of close contacts mentioned previously, 203 of 398 persons starting therapy (51%) completed it; 203 of 630 of those eligible for therapy (32%) completed it [57]. In a study of isoniazid treatment of latent infection in an inner-city population, 84 of 409 persons eligible for therapy (21%) completed it [58]. Low treatment-completion rates can result in continued transmission of M. tuberculosis and additional cases [59]. The low completion rates may result from a lack

treatment of latent tuberculosis infection

of understanding on the part of the patient of the importance of treatment, the absence of symptoms related to tuberculosis, the toxicity of the regimen, and the prolonged duration of therapy. Even if toxicity is relatively mild and infrequent, patients may be less likely to tolerate adverse effects because they do not have symptomatic tuberculosis disease. Shorter treatment duration may improve completion rates [36,40], but this result has not been noted uniformly [60]. Education of the patient regarding the importance of such therapy is extremely important. Direct observation of treatment of latent infection can improve adherence [61,62] but is often not feasible for tuberculosis treatment programs because of its high cost. Monitoring for toxicity As discussed previously, the potentially severe toxicity associated with the treatment of latent M. tuberculosis infection necessitates monitoring, particularly in persons at increased risk for toxicity. Routine monitoring for symptoms of toxicity is recommended. Monitoring of laboratory tests (eg, hepatic transaminases) to prevent toxicity, or at least identify toxicity in its early stages, is a reasonable approach in persons at high risk for toxicity, although the utility of such a strategy (and the optimal monitoring strategy) has never been assessed in a clinical trial.

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tine for 3 months. A study assessing the tolerability of this regimen has recently completed enrollment in Brazil, and data analysis is underway. A comparison of isoniazid plus rifapentine versus the standard regimen of daily isoniazid is underway in South Africa and in a multinational study being conducted by the Tuberculosis Trials Consortium of the CDC (US Public Health Service Study 26). If effective and well-tolerated, isoniazid plus rifapentine would provide a relatively simple short-course regimen for the treatment of latent tuberculosis infection, which could improve treatment completion rates. Data from the mouse model of tuberculosis, which has correlated closely with human tuberculosis [63,64], have demonstrated that moxifloxacin, a newer fluoroquinolone, has excellent activity against M. tuberculosis. This drug may allow shorter and more effective treatment of active tuberculosis [65,66] and may be effective for the treatment of latent tuberculosis infection. Additional studies are warranted. The Tuberculosis Epidemiologic Studies Consortium of the CDC has launched a large study of the treatment of latent tuberculosis infection in the United States (Task Order 13), including an assessment of the regimens used and the factors associated with acceptance of, adherence to, and tolerability of current treatment regimens. A better understanding of these factors will allow the development of interventions to improve the treatment of latent M. tuberculosis infection in the United States and throughout the world.

Logistical difficulties in implementing treatment of latent tuberculosis infection References Treatment of latent M. tuberculosis infection has been a cornerstone of efforts to control tuberculosis in the United States for the past several decades. This approach has been possible because of the relatively low number of tuberculosis cases and available public health resources in the United States. In areas of the world where tuberculosis case rates are substantially higher and resources are more limited, treatment of latent M. tuberculosis infection is limited; the focus in these countries is to identify and treat cases of active tuberculosis.

Prospects for improvements in the treatment of latent Mycobacterium tuberculosis infection There is clearly a need for safe and effective shortcourse treatment of latent M. tuberculosis infection. Studies are underway to assess the tolerability and effectiveness of once-weekly isoniazid plus rifapen-

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Clin Chest Med 26 (2005) 295 – 312

Tuberculosis in Children Kristina Feja, MD, MPH, Lisa Saiman, MD, MPH* Department of Pediatrics, College of Physicians and Surgeons, Columbia University, 622 West 168th Street, PH4West, New York, NY 10032, USA

Tuberculosis (TB) accounts for significant morbidity and mortality in children and adolescents worldwide, with the majority of cases of latent TB infection (LTBI) and disease occurring in developing countries. Pediatric TB, or childhood TB, defined by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) as TB in children less than 15 years of age, presents health care providers with unique challenges. In contrast to adults and older adolescents, the clinical manifestations of TB disease in children are usually related to primary tuberculosis. Diagnostic and therapeutic challenges arise because children have less specific signs and symptoms of disease, have fewer positive mycobacterial cultures, are at increased risk for progression of disease once infected, and are at an increased risk of disseminated disease. Pediatric TB is considered a sentinel event reflecting recent transmission from an undiagnosed infectious source case in the community. Performing contact investigations in adults with infectious TB to detect other cases of TB or LTBI is an important means of diagnosing or preventing TB in children. Public health efforts vary according to country and available resources. Developed countries focus on identification and treatment of LTBI as well as active disease. Children who have LTBI represent the reservoir for future disease. In resource-poor countries, identification and treatment of TB disease, using the strategy of directly observed therapy (DOT), if available, are the primary public health efforts. This article

* Corresponding author. E-mail address: [email protected] (L. Saiman).

examines aspects of TB epidemiology, pathogenesis, clinical presentations, diagnosis, treatment, and public health issues unique to children.

Epidemiology of childhood tuberculosis The knowledge of the global epidemiology of TB in children is somewhat limited. In 1990, approximately 7,500,000 TB cases occurred worldwide, of which 650,000 occurred in children [1]. In 2002, the WHO estimated that 8,800,000 TB cases occurred worldwide, based on data from 209 countries with an estimated mean case rate of 145 per 100,000 population (range, 2 – 1067 cases) [2]. Although estimates, these numbers can be particularly useful when assessing the effectiveness of TB control programs. Currently, the WHO reports only acid-fast bacillus (AFB) smear – positive cases stratified by age. Therefore, age-specific estimates of all cases (smearnegative and smear-positive) are unavailable. Data from the WHO reflecting 2002 regional notification rates of smear-positive cases among children ranged from 0 per 100,000 persons in Europe to 6 per 100,000 in Africa and 43 and 45 per 100,000 in South Africa and Zambia, respectively [2]. Reporting only AFB smear – positive cases potentially has a huge impact on accurate estimates of pediatric cases, because young children have lower organism burdens than adults and adolescents, and they are less likely to be AFB smear – positive. Approximately 95% of children less than 12 years of age are AFB smear – negative [3]. Other challenges in accurately estimating the burden of TB in children include the difficulties establishing a definitive diagnosis, the increased

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prevalence of extrapulmonary disease, the lack of a standard clinical case definition, and the generally lower public health priority given to childhood TB compared with adult TB in many countries [3]. Nelson and Wells [3] reviewed recent epidemiologic studies and surveillance data describing trends in the global burden of TB in children. Childhood TB accounted for only 2% to 7% of TB cases in developed countries, compared with 15% to 40% of cases in developing countries. This difference may be explained partially by an older population structure in developed countries. Case rates in children seem to be increasing in Africa, countries of the former Soviet Union, and some countries in Europe, the Middle East, and South America such as Sweden, England, Wales, Greenland, Austria, Denmark, Israel, and Brazil. Possible reasons for this trend include increasing immigration of children or families born in countries with high case rates of TB, worsening economic conditions, rising HIV infection rates, and a weakening public health infrastructure [3,4]. Conversely, Turkey and Peru have experienced a decline in case rates among children. In Peru, the decline in case rates has been attributed to the institution of an aggressive DOT short-course program. Nelson and Wells [3,4], however, cited several limitations of these epidemiologic data which included possible reporting bias because countries with smaller TB burdens may be less likely to report cases and some studies included only hospitalized patients. Comparing rates across countries may not be feasible because of variations in case definition, case finding, and contact investigation protocols. The epidemiology of TB in the United States has undergone substantial changes during the past 20 years. After decades of decline, the United States

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experienced an increase in TB case rates in the late 1980s and early 1990s with case rates of pediatric TB increasing from 2.4 cases per 100,000 persons (1261 cases) in 1985 to 3.1 cases per 100,000 (1708 cases) in 1992 [5]. The cause of this resurgence was multifactorial. Contributing factors included the HIV epidemic, the dismantling of national TB control programs, the increased immigration of persons from countries with a high prevalence of TB, and, perhaps, improved reporting [6]. Happily, since 1993, there has been a steady decline of TB in the United States. Nelson et al [7] recently reviewed the epidemiology of 11,480 cases of childhood TB reported in the United States between 1993 and 2001 and reported that the number of childhood TB cases declined by 44%, from 1663 cases in 1993 to 931 cases in 2001, with a respective 48% decline in incidence rates from 2.9 to 1.5 cases per 100,000 persons (Fig. 1). This decline, however, is less pronounced than that seen in adults (Fig. 1). Seventy percent of all cases of pediatric TB occurred in eight states: California, Texas, New York, Illinois, Georgia, Florida, New Jersey, and Pennsylvania, and most cases presented in urban areas with populations greater than 2,500,000. In the United States, a disproportionate burden of cases is seen among younger children, racial and ethnic minorities, and those who are foreign-born (Figs. 2, 3). In 2001, case rates per 100,000 persons were 2.8, 1.0, and 0.9 in children less than 5 years of age, 5 to 9 years of age, and 10 to 14 years of age, respectively. From 1993 to 2001, 74% of pediatric TB cases occurred in Hispanic and non-Hispanic blacks and approximately 30% occurred in foreignborn children [7]. Approximately two thirds of foreign-born children with pediatric TB were born in the following countries: Mexico (39.8%), the Phil-

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Age Group (years) Fig. 1. Tuberculosis case rates (per 100,000) by age group in the United States from 1993 to 2003. (From Centers for Disease Control and Prevention. 2003 Surveillance slide sets. Available at: http://www.cdc.gov/nchstp/tb/pubs/slidesets/surv/surv2003/ default.htm. Accessed March 14, 2005.)

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Fig. 2. Pediatric tuberculosis cases by race and ethnicity from 1990 to 2002. (From Centers for Disease Control and Prevention.)

family member with LTBI, contact with a high-risk adult (eg, an adult who is infected with HIV/AIDS, homeless, incarcerated, or a user of illicit drug) and age greater than 11 years of age [8 – 11]. Approximately one third of the world’s population is infected with Mycobacterium tuberculosis. Most infected persons do not progress to disease. In the absence of treatment for LTBI, 5% to 10% of immunologically normal adults develop TB disease during their lifetimes, and half of the risk occurs in the first 2 to 3 years after infection [12]. Infected children have a comparatively higher risk of progression to active disease: 43% of infants less than 1 year of age, 24% of children 1 to 5 years old, and 15% of those 11 to 15 years old develop TB disease if not treated for LTBI [6]. Factors that increase the risk of progression from infection to disease usually affect

ippines (8.9%), Vietnam (5.7%), Somalia (4.4%), Russia and the former countries of the Soviet Union (3.5%), and Haiti (3.3%). Approximately 60% of foreign-born cases were reported from three states: California (38.5%; n = 1070), New York (11.4%; n = 317), and Texas (8.9%; n = 247) [7].

Risk factors for latent tuberculosis infection and progression to tuberculosis disease Several recent studies have assessed the risk factors for LTBI among children in the United States. Risk factors varied somewhat from study to study but generally included close contact with a TB case, birth in a country with high prevalence of TB, travel to or a household visitor from a high-prevalence country, a

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Fig. 3. Pediatric tuberculosis cases by birth country from 1990 to 2002. (From Centers for Disease Control and Prevention.)

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the immune system and include immunosuppressive therapy, HIV coinfection, malnutrition, medical conditions (eg, renal and liver failure, diabetes mellitus, or cancer), TB infection within the past 2 years, age of 4 years or younger, or intercurrent viral infections such as measles [6,12,13].

Pathogenesis The pathogenesis of pediatric TB is largely similar to that described for adults and older adolescents, but subtle differences in pathogenesis can lead to differences in clinical presentations. As in adults, more than 98% of infections in children occur when M. tuberculosis bacilli enter the lungs through aerosolized droplets expelled when an infectious adult coughs, sneezes, or sings [6]. Other less common portals of entry include the gastrointestinal tract, the skin, mucous membranes, and conjunctiva. When inhalation is the route of infection, the organisms multiply in alveolar macrophages, thus creating a small area of inflammatory reaction known as the primary focus [14]. Early in infection, tubercle bacilli may also spread to the regional lymph nodes or disseminate through the bloodstream. The primary focus, regional lymph nodes, and adjoining lymphatics are collectively known as the primary tuberculous complex. The pathology of the primary complex is the same, regardless of the site of infection. Cellular immunity develops, usually 2 to 12 weeks after infection, and manifests as delayed hypersensitivity to tuberculin, that is, a positive tuberculin skin test (TST). At this time, the primary focus becomes encapsulated, and perifocal inflammation increases and manifests as a granuloma, which may be visible on chest radiograph. Radiographic evidence of perifocal infiltration is most common in younger children [13]. In most cases, cellular immunity controls the spread of infection. The pathologic events associated with this process include caseous necrosis, fibrosis, and healing of the primary complex components with or without calcification. The extent of calcification depends on the relative degree of necrosis and caseation [13] and occurs sooner after infection in infants. Although this sequence of events occurs in LTBI [14], the resolution of infection may not be complete, and viable M. tuberculosis may persist for many years, potentially reactivating and causing TB disease months to years later. Primary tuberculosis, defined as disease progression of any part of the primary complex, is most common in younger children. Disease from a primary pulmonary source may extend to the adjacent lung

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or disseminate further. Progression within the lung, pulmonary primary disease, is the most common manifestation of primary TB and presents as enlargement of the affected regional lymph nodes. The primary focus may be smaller and may not be visualized radiographically. Lymphadenopathy may lead to further spread of disease by partial or complete bronchial obstruction, by erosion of the bronchial wall resulting in endobronchitis, or by external compression of the bronchus resulting in segmental lesions caused by localized hyperinflation and atelectasis of the adjacent lung tissue. Local progression in the lung may also occur from the primary focus, particularly if the majority of bacilli remain within this component of the primary complex. In young children, the primary focus generally continues to grow even after the development of cellular immunity and may caseate centrally, liquefy, and empty into the bronchi resulting in further spread [13]. This phenomenon is known as progressive pulmonary primary tuberculosis. Progression of disease beyond the lungs occurs more frequently in younger children [13]. Younger children are more likely to have involvement of distal lymph nodes such as the mediastinal nodes, which may also compress or invade bronchi, blood vessels, or lymphatics. Occasionally disease progression occurs by local spread to the pleural space, mediastinum, esophagus, or pericardium. Progression to these sites most often occurs through the bloodstream, however. Mycobacteria disseminated by the bloodstream can cause extrapulmonary disease (eg, superficial lymphadenopathy generally of the cervical nodes, miliary TB, meningitis, or osteoarticular TB). Meningitis develops when caseating lesions on the cerebral cortex invade the meninges and disseminate into the subarachnoid space. Tuberculomas, a less frequent manifestation of central nervous system disease, form when caseous foci within the brain enlarge and become encapsulated. Miliary TB occurs when large numbers of bacilli disseminate through the bloodstream and cause simultaneous disease in two or more organs [13]. The pathogenesis of different forms of childhood TB may be viewed as a continuum in which host factors play an important role in controlling the extent of disease. Immunologic control of TB infection is a function of macrophages and dendritic cells, manifested by a Th1-type T-cell immunity characterized by strong CD8-positive cell response with production of interferon gamma by CD4-positive cells. Children have a relative deficiency of macrophage and dendritic cell function, however, and, in contrast with adults, tend to develop Th2-type T-cell responses to

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mycobacterial infection characterized by lack of CD8-positive cell response and interleukin (IL)-4 and IL-5 production by CD4-positive cells. Additional research is needed to determine the exact role of each immune factor in the pathogenesis of TB disease in children. Such knowledge might facilitate the development of a more effective vaccine [15].

Clinical and radiographic manifestations of latent tuberculosis infection and tuberculosis in children Latent tuberculosis infection In both adults and children, LTBI is defined as infection with M. tuberculosis as evidenced by a positive TST and lack of clinical or radiographic signs or symptoms of TB disease. Radiographs are usually normal but may show evidence of healed primary complex in the form of dense nodules (with or without calcifications), calcified nonenlarged regional lymph nodes, or pleural thickening [16,17]. CT scans are generally not indicated in children with LTBI unless a chest radiograph is equivocal. Lateral views are particularly useful in detecting hilar adenopathy, and both frontal and lateral views should be obtained to assess children for pediatric TB [18,19]. Tuberculous disease The clinical presentation of TB disease depends on the site of infection, bacillary load, patient age, and host immunity. TB in children often presents with nonspecific symptoms and may be indolent.

Fig. 4. Bilateral hilar adenopathy in a 16-month-old known contact of an infectious TB case (posterior-anterior view).

Fig. 5. Hilar adenopathy in a 16-month-old known contact of an infectious TB case (lateral view).

The diagnosis may be delayed as alternative disease entities are considered. Thus, the diagnosis of TB requires a high index of suspicion. Children, especially young children, tend to develop primary disease or extrapulmonary TB as early complications of initial infection, whereas these entities are less common in adults and older adolescents [13]. United States data from 1993 to 2001 describing 11,480 childhood TB cases demonstrated that 76.9% of cases were pulmonary, 15.5% lymphatic, 2.1% meningeal, 1.1% miliary TB, 1.1% pleural, and 1.4% osteoarticular [7]. Pulmonary tuberculosis The most common presenting symptoms of pulmonary primary TB are cough, fever, wheezing, decreased appetite, and fatigue [13,20]. Weight loss and night sweats are far less common than in adults. Children with pulmonary primary TB may be asymptomatic despite abnormal radiographic findings; infants are more likely than older children to be symptomatic [21]. Physical findings may be relatively mild compared with the extent of radiographic findings and may include rales, wheezing, or decreased breath sounds, but respiratory distress is infrequent [20]. Pediatric patients with TB are usually not infectious; they lack cavities with a large number of bacilli, and the relatively weak cough of young children is not conducive to the airborne transmission of organisms. Radiographic manifestations of pulmonary primary TB include intrathoracic lymphadenopathy of the hilar, mediastinal, and subcarinal nodes and parenchymal changes (Figs. 4, 5) [21]. In some

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Fig. 6. Segmental atelectasis of the right upper lobe with hyperinflation of right middle and lower lobe caused by ballvalve effect in an 8-month-old girl demonstrating partial obstruction of the bronchus intermedius by hilar adenopathy (anteroposterior view).

patient populations, isolated hilar adenopathy has increased in frequency during the past 2 decades, possibly because of more efficient contact investigations of infectious TB cases and subsequent detection of disease in children at an earlier stage of illness [22]. The most common parenchymal findings include segmental hyperinflation and atelectasis caused by bronchial obstruction (Fig. 6), alveolar consolidation, interstitial densities, and, occasionally, bronchiectasis (Fig. 7) [21].

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Fig. 8. CT scan demonstrating bilateral upper lobe cavities and infiltrates in a 14-year-old girl.

Progressive pulmonary primary TB presents with weight loss or failure to gain weight, anorexia, fatigue, low-grade fevers, and intermittent cough. Rales may persist for days to weeks after the onset of initial symptoms [13]. Advanced disease may result in the development of a cavity or endobronchial spread [13]. Chronic pulmonary TB or adult-type reactivation disease is seen most commonly in adolescents whose primary infection occurred after 7 years of age [13]. Like adults, such patients present with fever, weight loss, a productive cough, hemoptysis, and night sweats. Radiographic findings include cavitary lesions, typically in the upper lobes (Fig. 8). An atlas of radiographic images of intrathoracic TB disease in children is available at www.iuatld.org/pdf/iuatld_ atlas.pdf. Recent United States data indicated that, when compared with younger children, children 10 to 14 years of age had significantly higher rates of cavitary disease (11.8% versus 3.5%; P< 0.001), AFB smear – positive sputum (10.3% versus 1.7%; P< 0.001), and culture-positive sputum (21.3% versus 4.2 – 5.0%; P< 0.001) [7]. Extrapulmonary tuberculosis

Fig. 7. CT scan demonstrating partial right lower lobe consolidation with extensive postobstructive bronchiectasis in a 13-year-old boy.

Extrapulmonary TB occurs in 9% to 23% of pediatric TB cases [7,20,23]. Superficial lymphadenitis is the most common site of extrapulmonary TB followed by pleural, meningeal, osteoarticular, and miliary TB in varying frequency depending on the patient population. Superficial lymphadenitis is responsible for 44% to 67% of cases of extrapulmonary disease [7,20,23], is more common in children (15.5%) than adults (6.8%) [7], usually affects the

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Fig. 9. CT scan demonstrating right sided cervical lymphadenopathy with central necrosis and right jugular vein thrombosis in a 2-year-old with HIV/AIDS.

anterior cervical and submandibular nodes, and may be caused by M. bovis (Fig. 9). Superficial lymphadenitis usually presents within 6 months of infection [13] in children with a median age of 31 to 36 months [20,23]. Firm, nontender or minimally tender enlarged lymph nodes without generalized symptoms are the most common presentation [13,23]. As evidence of the relatively indolent presentation of this entity, among 48 children diagnosed with superficial TB lymphadenitis, symptoms occurred a median of 35 days before hospitalization, and 47 of the 48 had lymph node enlargement as the only symptom [23]. Concurrent chest radiographic findings were noted in 23 of the 48 patients, however, and included enlarged hilar lymph nodes (n = 21) and calcified nodules (n = 2) [23]. In a smaller study, only 2 of 11 children with cervical TB lymphadenitis had concurrent chest radiograph abnormalities [20]. In advanced disease, matting of the nodes, adherence to the overlying skin with dark discoloration of the skin, and subsequent drainage of caseous material occur [13]. Cosmetic deformities may result if adequate treatment is not administered. In the United States, tuberculous pleural effusions are found in 1.1% to 3.6% of children with active disease [7,20], accounting for 5% of cases of extrapulmonary disease [7]. Merino et al [24] found pleural effusions in 39 of 175 children (22%) less than 18 years of age with pulmonary TB [24]. Most cases occur 3 months after primary infection [25] in older children (mean age, 13.5 years) [24]. The most common clinical manifestations include fever, fatigue, respiratory distress, and chest pain. Diminished breath sounds and dullness to percussion are the most common physical findings. Radiographic find-

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ings include unilateral pleural effusion in most cases and associated parenchymal findings in approximately half of patients [24]. Prognosis is excellent, although residual pleural thickening occurs [24]. Miliary and meningeal TB develop after hematogenous dissemination of M. tuberculosis, usually within 3 to 6 months of initial infection [13,25]. Frequently these two entities present together, especially in children less than 5 years of age [7,26]. Tuberculous meningitis is the most severe complication of TB disease and in the United States accounts for 2.1% of pediatric cases and 9.1% of extrapulmonary TB cases [7]. Studies of childhood TB meningitis cite a median age of 17 to 23 months of age in the United States [20,27] and 30 to 48 months of age among children presenting in other countries [23,26]. As with other forms of TB, the clinical presentation is usually indolent, with symptoms present 1 to 4 weeks before diagnosis [27]. The most common presenting symptoms are high-grade fever, vomiting, lethargy, headache, and seizures. Seizures are especially common in children less than 2 years of age [13,27]. Physical findings include nuchal rigidity, cranial nerve findings caused by exudates on the cerebral base leading to obstructive hydrocephalus, and hemiparesis caused by vascular occlusion. The clinical course is divided into stages that have both therapeutic and prognostic significance: stage I (nonspecific symptoms such as fever, irritability, headache, sleepiness, or malaise with no focal neurologic findings), stage II (nonspecific symptoms with neurologic findings), and stage III (marked decrease in mental status with neurologic findings) [13]. Evidence of hydrocephalus detected by CT of the brain is usually present, whereas parenchymal disease, such as tuberculoma, is evident only in 20% to 37% of cases (Fig. 10). In addition, 40% to 86% of chest radiographs are abnormal [20,26,27]. Risk factors for poor outcome are associated with stage III disease at the time of admission, patient age of 3 years or less, miliary disease, or delay in initiation of treatment [28]. Infants have more rapid disease progression and poorer outcome than older children [13,23]. Before effective antituberculosis drugs were available, the mortality rate among children with TB meningitis was 100%. With effective therapy, the mortality rate has decreased to less than 10% [26,27]. TB meningitis still causes significant long-term morbidity such as mental retardation, seizure disorders, and hemiparesis. In a study of 30 children conducted during the 1980s, 70% were reported to have major neurologic sequelae [27]. Miliary TB accounts for 1.1% and 4.7% of all pediatric cases and extrapulmonary cases, respec-

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pericardium, skin, or middle ear, rarely occur in children and account for less than 2% of all pediatric TB cases in the United States [7]. Tuberculosis in newborns Several unique manifestations of TB disease may present in neonates either because of intrauterine infection causing congenital disease or postnatal transmission of M. tuberculosis from a mother or other caregiver with active tuberculosis.

Fig. 10. MRI scan demonstrating ring-enhancing lesions in cerebellum bilaterally in a 13-year-old girl (T1-weighted coronal postcontrast views).

tively [7]. Miliary TB is similar to TB meningitis in its pathogenesis, time of onset after infection, indolent presentation, severity, and disproportionate effect on infants and young children. The median age of presentation is 6 to 11 months [23,29]. Miliary TB may occasionally present acutely, but, in most cases, weeks of fever, cough, weight loss, anorexia, and malaise are present before diagnosis. Hepatosplenomegaly and generalized lymphadenopathy develop in 50% to 70% of cases. Bilateral diffuse micronodular pulmonary consolidations develop in 90% of cases manifest as respiratory distress, diffuse rales, or wheezing [29,30]. During the 1980s, the case fatality rate for miliary TB was 14% among 94 children in South Africa [29]. Osteoarticular TB accounts for 1.4% of all cases of pediatric TB and 5.9% of cases of extrapulmonary TB in children compared with 2.2% of total cases in adults [7]. The onset of disease usually occurs 6 to 18 months after primary infection [13]. The median age of onset was 6 years of age in a case series of 102 children conducted from 1982 to 1998 [23]. The vertebrae, followed by knee, hip, and elbow, are the bones most commonly affected. Presenting signs and symptoms may include localized inflammation, pain, swelling, fever, and decreased movement and limited range of motion of the affected bone or joint [23,30,31]. Radiographic evidence of spondylitis, arthritis, and osteomyelitis may occur, and chest radiograph abnormalities are noted in 50% of cases [32]. Additional presentations, such as tuberculosis of the gastrointestinal tract, eyes, genitourinary tract,

Maternal tuberculosis and impact on infants The proportion of pregnant women who have active TB seems to be increasing [33], but there is no evidence that pregnancy is a risk factor for progression from LTBI to active disease. Although the clinical presentations of TB in pregnant women are similar to those noted in nonpregnant adults, nonspecific signs such as fatigue and malaise may be attributed to pregnancy and thus cause a delay in diagnosis in this population. Increased obstetric morbidity and neonatal mortality were associated with delayed treatment [34]. In a case-control study, infants born to women with pulmonary TB were significantly more likely to be of low birth weight (< 2500 g), small for gestation, or premature and had increased rates of perinatal mortality when compared with infants born to women without TB of similar age, parity, and socioeconomic status [35]. Adverse outcomes were increased with late maternal diagnosis, incomplete or irregular treatment, or advanced pulmonary lesions. Furthermore, pregnant women with nonlymphatic extrapulmonary TB had higher rates of antenatal hospitalization, and their infants had Apgar scores of 6 or lower and low birth weight. Pregnant women with TB lymphadenitis and their infants had outcomes similar to those in a healthy control group [36]. Congenital tuberculosis is a rare entity, with approximately 300 cases reported in the literature [37]. Infection of the fetus may occur by hematogenous dissemination through the placenta (50% of cases) or by aspiration or ingestion of infected amniotic fluid. The former leads to primary complex formation in the liver or lungs, whereas the latter leads to primary disease in the lungs or gastrointestinal tract [37]. Previously, surgery or autopsy was used to diagnose the site of the primary complex and thereby identify the mode of transmission. Today, CT findings and the time course of the development of lesions may be used to distinguish the modes of transmission [38]. In 1994, Cantwell et al [37] proposed revised criteria for congenital TB. These criteria include proven tuber-

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culous lesions in the infant, exclusion of postnatal transmission by thorough contact investigation of close contacts including health care workers, and one of the following:

cations in the lung parenchyma, nonenlarged regional lymph node, or both The lack of the previously described clinical signs or symptoms of disease

Lesions in the first week of life Primary complex in the liver or caseating hepatic granulomas TB infection of the maternal genital tract or placenta

In recent years, a paradigm shift to targeted tuberculin skin testing has taken place in the United States. This concept suggests that children should be screened for known risk factors for TB, elicited on a risk factor questionnaire. Only children with one or more risk factors should be skin tested, thereby increasing the sensitivity and specificity of the TST (Box 2). Current recommendations for screening, diagnosis, and treatment of LTBI in children are found in a consensus document prepared by the Pediatric Tuberculosis Collaborative Group entitled Targeted Tuberculin Skin Testing and Treatment of Latent Tuberculosis Infection in Children and Adolescent [19].

Congenital TB most often presents in the second to third week of life and may mimic other congenital infections such as syphilis, cytomegalovirus, or neonatal sepsis. Hepatosplenomegaly, respiratory distress, fever, lymphadenopathy, and abdominal distention are the most common signs and symptoms [37]. Most infants have abnormal chest radiographs, usually showing a miliary pattern, hilar and mediastinal lymphadenopathy, or parenchymal infiltrates [33, 37,38], and, less commonly, multiple rim-enhancing pulmonary nodules with central hypodense areas [38]. In many cases, infants require mechanical ventilation. Delayed diagnosis and onset of treatment contribute to the approximately 40% mortality [37]. Perinatal TB is acquired from postnatal transmission from the mother, adult caregiver, health care worker, or other infectious source and presents later than congenital TB. Clinical manifestations may be similar to those noted in congenital TB. Of 38 South African infants (including 7 cases of congenital TB) who were less than 3 months of age when diagnosed with TB, 87% had cough, 82% had tachypnea, 66% had hepatomegaly, and 53% had splenomegaly [39]. Other common findings are pneumonia, fever, and lymphadenopathy [40].

Diagnosis of pediatric latent tuberculosis infection and tuberculosis The diagnosis of TB infection or disease rests on the basic components of history (eg, previous TB or contact with infectious case, signs, and symptoms), TST results including the precise millimeters of induration, chest or other radiographic findings, and mycobacteriology smear and culture results. LTBI is relatively simple to diagnose in children. Criteria for diagnosis are A positive TST as interpreted based on stratification of risk factors (Box 1) Normal chest radiograph or radiographic signs of primary complex with granulomas or calcifi-

Case definitions for tuberculosis disease Although AFB smears and culture remain the cornerstones of diagnosing TB among adults, children are often diagnosed clinically based on a positive TST, clinical and radiographic findings suggestive of TB, or a history of contact with an adult with TB [21,41]. Both the WHO and the CDC employ laboratory-confirmed or clinician-diagnosed case definitions. In the United States, the laboratory case definition consists of (1) isolation of M. tuberculosis complex (ie, M. tuberculosis, M. bovis, and M. africanum) from a clinical specimen; (2) demonstration of M. tuberculosis from a clinical specimen using nucleic acid amplification (NAA) test; or (3) demonstration of AFB from a clinical specimen when culture is unavailable. In the absence of laboratory confirmation, the clinical case definition is fulfilled by all of the following criteria [42]: 1. Positive TST 2. Signs or symptoms of TB disease, such as abnormal, unstable chest radiograph or clinical evidence of current disease (eg, fever, night sweats, cough, weight loss, hemoptysis) 3. Treatment with two or more anti-TB drugs 4. A completed diagnostic evaluation A case will also be reported and counted by the CDC if the these criteria are not met but a provider diagnosis is given by a state or local health department following a thorough review of the patient’s medical record. For example, in New York City, the

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Box 1. Definitions of positive tuberculin skin test results in children using three cut-off levels Induration 5 mm Children in close contact with known or suspected contagious cases of tuberculosis disease Children suspected to have tuberculosis disease because of  Findings on chest radiograph consistent with active or previously active tuberculosis  Clinical evidence of tuberculosis disease Children receiving immunosuppressive therapy or with immunosuppressive conditions, including HIV infection Induration 10 mm Children at increased risk of disseminated disease:  Those younger than 4 years of age  Those with other medical conditions, including Hodgkin’s disease, lymphoma, diabetes mellitus, chronic renal failure, or malnutrition Children with increased exposure to tuberculosis disease:  Those born, or whose parents were born, in high-prevalence regions of the world  Those frequently exposed to adults who are HIV-infected, homeless, users of illicit drugs, residents of nursing homes, incarcerated or institutionalized, or migrant farm workers  Those who travel to high-prevalence regions of the world Induration 15 mm Children 4 years of age or older without any risk factors From American Academy of Pediatrics. Tuberculosis. In: Red book: 2003 report of the committee on infectious diseases. 25th edition. Elk Grove (IL): Pickering LK; 2003. p. 642 – 60; with permission.

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Box 2. Risk assessment questionnaire All Risk Assessment Questionnaires should ask the following questions (adolescents can be asked these questions directly): 1. Was your child born outside the United States? If yes, this question would be followed by where was your child born? If the child was born in Africa, Asia, Latin America, or Eastern Europe, a tuberculin skin test should be placed. 2. Has your child traveled outside the United States? If yes, this question would be followed by where did the child travel, with whom did the child stay, and how long did the child travel. If the child stayed with friends or family members in Africa, Asia, Latin America, or Eastern Europe, for 1 week or longer, cumulatively, a tuberculin skin test should be placed. 3. Has your child been exposed to anyone with TB disease? If yes, this question should be followed by questions to determine if the person had TB disease or LTBI, when the exposure occurred, and the nature of the contact. If the child’s exposure to someone with suspected or known TB disease is confirmed, a tuberculin skin test should be placed, and the local health department should be notified per local reporting guidelines. 4. Does your child have a close contact with a person who has a positive TB skin test? If yes, see question 3 follow-up questions. Risk Assessment Questionnaires can include the following based on local epidemiology and priorities: 1. Does your child spend time with anyone who has been in jail (or prison), a shelter, who uses illegal drugs, or who has HIV? 2. Has your child drunk raw milk or eaten unpasteurized cheese? 3. Does your child have a household member who was born outside the United States? 4. Does your child have a household member who has traveled outside the United States? From Pediatric Tuberculosis Collaborative Group. Targeted tuberculin skin testing and treatment of latent tuberculosis infection in children and adolescents. Pediatrics 2004; 114(4):1175 – 201; with permission.

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provider diagnosis is fulfilled if the patient is being treated with two or more anti-TB drugs determined to be medically justified by the TB Control Surveillance Unit [43]. In the past decade, only 23.6% of pediatric cases fulfilled the laboratory case definition, compared with 84.3% of adult cases; 52.6% of pediatric cases fulfilled the clinical case definition; and 23.0% were given a provider diagnosis [7]. From 1985 to 1994, 41 states and the District of Columbia reported provider-diagnosed cases, but not all reporting areas used the same provider-diagnosis case definition [5]. For example, some states included additional criteria such as anergy in HIV-infected persons, an epidemiologic link to a known TB case, or clinical improvement on therapy without radiographic follow-up [5]. These different surveillance definitions can obviously affect case rates. The accuracy of surveillance data for pediatric TB may be further compromised by incomplete reporting; in a study conducted in New York City from 1993 to 1995, 20% of cases identified by an alternative surveillance method, which included gastric aspirate reports, hospital discharge codes, and physician interviews, were not reported to the health department [43].

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Tuberculin skin testing A reactive TST, an important component of the CDC’s clinical case definition, is interpreted as positive according to the individual patient’s risk factors (see Box 1). Overall, children with reported TB disease are more likely to have positive reactions (89%) than adults (54%) [7]. Approximately 20% of children with culture-proven TB may have negative TSTs at diagnosis, however, and about 5% may have persistently negative TSTs [44]. TST positivity also depends on the site of disease; for example, only 57.6% of miliary and 54.6% of meningeal cases had positive TSTs, compared with 90.6% of pulmonary cases [7]. In contrast, TST results in congenital TB are always negative but may become positive in 1 to 3 months [33]. Certain factors such as infections, live viral vaccines, certain medical conditions, drugs, technical factors, and interpretation bias are associated with both false-negative and false-positive TST reactions (Table 1) [19]. Anergy testing with control skin-test antigens is not routinely recommended by the CDC [45] and has several limitations. These limitations

Table 1 Factors associated with false-negative or false-positive tuberculin skin test reactions False-negative reactions Infections Viral illnesses (HIV, measles, varicella) Bacterial (typhoid fever, brucellosis, typhus, leprosy) Early TB infection (< 12 wk) TB disease (meningitis, miliary, pleural) Fungal (Blastomycosis) Live-virus vaccines Measles Polio Smallpox Concomitant medical conditions Metabolic abnormalities (chronic renal failure) Malignancies (Hodgkin’s disease, lymphoma, leukemia) Sarcoidosis Poor nutrition Drugs and technical factors Corticosteroids, chemotherapy Newborns and children <2 y Material: poor quality, inadequate dose (1 tuberculin unit), improper storage (exposure to heat/light), expired Administration: not injected intradermally, too long in syringe Reading: inexperienced or biased reader, recording error, read too early/late Interpretative Decreasing mm of induration

False-positive reactions Exposure to nontuberculous mycobacteria (eg, M. marinum, M. kansasii)

Bacille Calmette-Guerin vaccine

Transfusion with whole blood from donors with known positive tuberculin skin test

Inexperienced or biased reader

Increasing mm of induration

From Pediatric Tuberculosis Collaborative Group. Targeted tuberculin skin testing and treatment of latent tuberculosis infection in children and adolescents. Pediatrics 2004;114(4):1186; with permission.

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include the lack of standardization of antigens and poor reproducibility of the delayed-type hypersensitivity reaction [46], lack of association of anergy with a high risk of progression to TB disease, and no demonstrable benefit of treatment with empiric isoniazid in anergic HIV-infected individuals to prevent TB disease [47]. Effect of bacille Calmette-Guerin vaccination on tuberculin skin test results Bacille Calmette-Guerin (BCG) vaccination is used in most countries with a high incidence of TB to prevent the severe forms of TB in young children. According to the WHO, 161 member states have BCG vaccination on their immunization schedule, and global BCG vaccination coverage in 2002 among infants less than 1 year of age was 81% [48]. Thus, it is important to understand the potential effects of BCG vaccine on TST results in previously immunized children who immigrate to developed countries and undergo targeted tuberculin skin testing. Factors such as age at BCG immunization (less effect if vaccinated at birth), time since immunization (less effect if immunization occurred years before TST), exposure to nontuberculous mycobacteria (increased exposure may cause false positive TSTs), prevalence of LTBI (higher prevalence increases the positive predictive value of reactive TSTs), and type of vaccine used (larger number of viable bacilli causes larger effect) may influence TST results [19]. Children immunized with BCG at birth who were studied 12 years later and found to have a TST induration of 10 mm or more had a five- to 48-fold increased risk of developing TB disease within 4 years [49]. Thus, positive TST reactions in BCGvaccinated children from countries with high case rates of TB are likely be caused by LTBI, not immunization. It is recommended that a history of BCG immunization be ignored when planting, reading, and interpreting a TST [20]. Smear for acid-fast bacilli and mycobacterial culture Smear and culture techniques in children are similar to those in adults, but the types of specimens and their yield differs. Younger children with pulmonary TB rarely produce sputum and have a relatively low organism burden. Thus, first morning gastric aspirates have traditionally been the best clinical specimens to obtain in young children with suspected pulmonary TB. These aspirates may be positive for M. tuberculosis in 30% to 50% of all cases [21,50] and in as many as 75% of infants [51].

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Standardization of gastric aspiration techniques is critical and has been shown to increase the proportion of positive cultures [50]. Hospitalization may not be necessary to obtain gastric aspirate specimens from children with suspected TB (providing hospitalization is otherwise not clinically indicated). There was no significant difference in the yield of outpatient (37%) and inpatient (48%) gastric aspirates among 80 children [52]. In the United States, the relative yield of gastric aspirates is not reportable, but recent epidemiologic studies indicate that only 2.4% and 8.5% of all pediatric cases had smear-positive and culture-positive gastric aspirates, respectively [7]. To circumvent the low yield of positive cultures from expectorated sputum and gastric aspirates, Zar et al [53] successfully performed sputum induction in 142 of 149 children (median age, 9 months; 70% HIV-infected) in South Africa. After a 2- to 3-hour fast, pretreatment with inhaled salbutamol was followed by nebulized 5% sterile saline and chest physiotherapy. Sputum was then obtained by suctioning (90% of children) or expectoration (10% of children). Induced sputum cultures grew M. tuberculosis more frequently (11%; 15 of 142 children) than gastric aspirates (6%; 9 of 142 children). Bronchoscopy does not aid significantly in the diagnosis of pediatric TB; only 4% to 12% of bronchoalveolar lavage (BAL) cultures were positive among children with suspected or presumed pulmonary TB [54 – 56]. Furthermore, in the two studies examining a total of 70 children, the overall yield of BAL specimens was lower than that of gastric aspirates (10% – 12% versus 32% – 50%), and 83% to 100% of children with positive BAL specimens also had positive gastric aspirates [55,56]. Bronchoscopy in children may be useful to accurately diagnose endobronchial disease, however [57]. Cultures from children with extrapulmonary TB grow M. tuberculosis from the affected site in about 50% of cases [20]. A summary of diagnostic procedures and findings is found in Table 2. More recent diagnostic techniques include polymerase chain reaction, NAA, serology tests, and immunoassays based on detection of cellular responses to specific M. tuberculosis antigens.

Treatment of latent tuberculosis infection and tuberculosis disease Children with LTBI and TB are treated with the drugs used for adults, although regimens, side-effect profiles, and availability of antituberculous drugs in pediatric doses may differ. Further, recommendations

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Table 2 Diagnostic methods for obtaining specimen to assess tubercular disease in children Site

Evaluation

Findings

Pulmonary

Induced sputum Gastric aspirates Bronchoscopy Lumbar puncture Cerebrospinal fluid

May be AFB smear – negative but culture positive Role of rapid amplification tests is limited, not FDA approved for AFB-smear negative specimens Lymphocytosis, low glucose, high protein Smear usually negative Culture may be positive Rapid amplification tests are not FDA approved Lymphocytosis, low glucose, high protein Smear usually negative Culture may be positive Adenosine deaminase may be elevated Caseous granulomas with AFB on pathology Culture may be positive Smear and culture of sediment or biopsy Culture may be positive Smears usually negative

Central nervous system

Pleural, pericardial, peritoneal

Fluid samplea

Adenitis

Biopsy

Osteoarticular

Joint aspirationa Bone or synovial biopsy Urine sample Multiple samples

Renal

Abbreviations: AFB, acid-fast bacilli; FDA, Food and Drug Administration. a Greater volume and centrifugation increase yield.

for pediatric regimens and doses from national and international organizations (eg, the British Thoracic Society, American Thoracic Society, WHO) may differ. Nevertheless, the backbone of all recommended regimens for LTBI is isoniazid unless the child has been exposed to an isoniazid-resistant source case. Although the recommended regimens for TB vary somewhat, they generally include two to four of the following first-line drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. Generally, antituberculosis drugs are well tolerated by children and are better tolerated than by adults. The success of pediatric treatment regimens depends on using correct doses (Table 3) and completing a full course of therapy. Adherence to treatment is facilitated by the use of child-friendly (eg, good tasting, small volumes) drug formulations and DOT. Treatment should be started promptly in young children when infection or disease is diagnosed, because they are at increased risk for pro-

Table 3 Pediatric doses for first-line antituberculous drugs Dose mg/kg (maximum dose) First-line drugs

Daily

Isoniazid Rifampin Pyrazinamide Ethambutol

10 – 15 10 – 20 15 – 40 15 – 25

Intermittent (300 mg) (600 mg) (2 g) (1 g)

20 – 30 (900 mg) 10 – 20 (600 mg) 50 (2 g) 50 (2.5 g)

gression to disease and disseminated disease. All infants and children with LTBI and no history of previous treatment for TB should be treated with isoniazid for 9 months. When the source case has isoniazid-resistant, rifampin-susceptible M. tuberculosis, rifampin is recommended for at least 6 months [17]. In young children, especially those less than 4 years of age, with close exposure to an infectious source case, window prophylaxis is recommended in efforts to initiate preventive therapy early and potentially prevent progression to active disease [17]. If the contact investigation demonstrates that a young child’s initial TST shows no induration, and chest radiography is normal, treatment with isoniazid (or rifampin, if the source case is known to have an isoniazid-resistant, rifampin-susceptible organism) is recommended to prevent progression to active disease. A follow-up TST is performed 12 weeks after the last exposure to the infectious source case; if the induration is less than 5 mm, preventive therapy is discontinued. If the TST induration is 5 mm or greater (see Box 1), a full course for LTBI is completed. Choice of treatment regimens in children with TB disease must consider the identification of a source case and mycobacterial susceptibilities, extent of disease, empiric versus targeted therapy, and local resistance patterns. The lower bacillary load typical of primary pulmonary tuberculosis is associated with less risk of drug resistance [58]. Therefore, a 6-month regimen of isoniazid, rifampin, and pyrazinamide for

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the first 2 months (daily for at least 2 weeks) followed by 4 months of isoniazid and rifampin (daily or 2 – 3 times/week) is recommended for children with drug-susceptible intrathoracic tuberculosis [17]. Children with hilar adenopathy and no other evidence of disease may be treated with 6 months of isoniazid and rifampin if drug resistance is not a consideration [17]. If reactivation-type cavitary disease is diagnosed, an adult-type regimen is used that includes ethambutol in addition to isoniazid, rifampin, and pyrazinamide during the initial 2 months, until drug susceptibilities are determined [58]. Ethambutol also should be added during the first 2 months if isoniazid resistance is documented or suspected, particularly in regions with high rates of isoniazid resistance [17]. Most extrapulmonary disease in children can be treated like pulmonary TB with 6 months of therapy. TB meningitis, miliary, and severe disseminated disease require four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) used daily for 2 months followed by daily or twice weekly isoniazid and rifampin for a total of 9 to 12 months [17,58]. Some experts continue all four drugs to complete a full course if susceptibilities are unknown. Toxicities of first-line tuberculosis drugs Isoniazid is generally very well tolerated by children, but, rarely, hepatic, neurologic, and gastrointestinal toxicities may occur. Hepatotoxicity may manifest as asymptomatic transient elevation of transaminases (most common) to fulminant hepatitis and liver failure (very rare). Risk factors for hepatitis, such as preexisting liver disease, older age, malnutrition, excessive alcohol consumption, and the use of concomitant hepatotoxic drugs, are less frequently noted in children [19,58]. Palusci et al [59] performed a pooled analysis and calculated that 8% of 965 children developed transient abnormalities in liver function tests, but only 0.4% discontinued isoniazid. Fewer than 1% of children receiving isoniazid may develop adverse effects that include rash, nausea, vomiting, and diarrhea [60,61], but severe hepatotoxicity has been reported [59,62,63]. Thus, before initiating isoniazid therapy, a history should be obtained for risk factors, side effects with previous isoniazid, and signs or symptoms of liver disease [19]. Baseline liver function tests and further testing during therapy are recommended only in children with risk factors for hepatitis. Liver function tests should be obtained in children without risk factors if signs (scleral icterus, jaundice, brown urine, claycolored stools) or symptoms (anorexia, nausea, vomit-

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ing, malaise, fatigue, abdominal discomfort, or fever) of liver toxicity develop during treatment [19]. Furthermore, parents and children should be educated to be alert for signs and symptoms of hepatitis while the patient is receiving isoniazid. The use of isoniazid may lead to peripheral neuropathy caused by pyridoxine (vitamin B6) deficiency from increased excretion. This toxicity manifests as a tingling sensation of the fingers and toes. This phenomenon is rare in children, although factors such as diabetes, uremia, a diet deficient in milk and meat, nutritional deficiencies, symptomatic HIV infection, alcohol consumption, pregnancy, and breastfeeding may increase the risk of peripheral neuropathy. Children and adolescents with these risk factors should receive pyridoxine [17]. Additional toxicities of isoniazid include a hypersensitivity reaction such as maculopapular or morbilliform skin rashes, which may necessitate discontinuation of isoniazid. Isoniazid inhibits the P450 cytochrome isozymes and may therefore increase serum concentrations of concomitant drugs such as anticonvulsants [58]. Rifampin may cause adverse effects such as cutaneous reactions, gastrointestinal reactions, flulike syndrome with intermittent therapy, hepatotoxicity (particularly when paired with isoniazid), and, rarely, a severe immunologic reaction. In a study of 157 adolescents receiving 6 months of daily rifampin for treatment of LTBI caused by isoniazid-resistant M. tuberculosis, 26% reported anorexia, nausea, fatigue, or rash, but only 1.3% (2/157) required permanent drug discontinuation [64]. Patients should be made aware of the probable orange discoloration of body fluids (eg, urine, sweat, tears) as well as the need for additional birth control methods in adolescents taking oral contraceptives. Rifampin is a potent cytochrome P450 enzyme inducer and can decrease the serum concentration of many drugs, including oral contraceptives, HIV protease inhibitors, nonnucleoside reverse transcriptase inhibitors, corticosteroids, and phenytoin [58]. Pyrazinamide generally is well tolerated in children and rarely causes hepatotoxicity in doses of 30 mg/kg/day or less, although toxicity can be observed during treatment with multidrug regimens. Toxicities from pyrazinamide (20 – 25 mg/kg/day) were evaluated among 114 children (aged 6 months to 15 years) given 2 months of isoniazid, rifampin, and pyrazinamide followed by 4 months of isoniazid and rifampin for pulmonary TB. Adverse effects during the pyrazinamide treatment phase included fever (2.6%), gastrointestinal disturbances (4.4%), and transient asymptomatic elevation of uric acid

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(9.8%). No patients had treatment interrupted [65]. In another study, liver enzymes were monitored in 43 children receiving isoniazid, rifampin, and pyrazinamide [66]. Only 5 (12%) of the 43 developed transaminase elevations more than twice the upper limit of normal for age. One child developed jaundice requiring temporary discontinuation of medications. Most laboratory abnormalities occurred in the first 2 weeks of treatment and resolved by 14 weeks of treatment [66]. Despite the rarity of symptomatic hepatitis, pyrazinamide is not recommended for pediatric patients with underlying liver disease or isoniazid-induced hepatotoxicity [17]. Adverse reactions associated with ethambutol include retrobulbar neuritis, gastrointestinal disturbances, and hypersensitivity. Retrobulbar neuritis is usually a reversible, dose-dependent, and renal function – dependent phenomenon that manifests as decreased visual acuity or decreased red-green color discrimination. Monitoring for these signs and symptoms is recommended monthly in older children and adults [17,58]. Past guidelines have advised against using or have advised caution when using ethambutol in younger children who cannot verbalize symptoms of optic neuritis, although two reviews did not detect visual toxicity in young children [67,68]. Current recommendations of the American Academy of Pediatrics suggest consideration of the risks and benefits involved with the use of ethambutol in younger children [17]. The use of second-line drugs such as cycloserine, ethionamide, streptomycin, amikacin, kanamycin, capreomycin, p-aminosalicylic acid, and fluoroquinolones should always be reserved for the treatment of multidrug-resistant TB. Consultation with a pediatric TB specialist is required, because the associated adverse effects may be greater than with first-line drugs, because clinical experience and pharmacokinetic data are more limited in children than in adults, and because inappropriate management may lead to life-threatening consequences [58]. Corticosteroids as adjuvant therapy are indicated when the heightened inflammatory response may cause further tissue damage. High-dose steroids should always be used in conjunction with effective antituberculosis therapy and should be tapered slowly over weeks to avoid a rebound reaction. Generally, 1 to 2 mg/kg/day of prednisone (maximum, 60 mg/day) or its equivalent tapered over 6 to 8 weeks is used [17]. Prospective, randomized trials have shown that concomitant corticosteroids decreased mortality rates in children with TB meningitis [69,70] and reduced neurologic complications, neurologic sequelae [70],

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and cognitive dysfunction [69]. A prospective, randomized study of 29 children with greater than 50% bronchial obstruction caused by TB found a more rapid improvement in radiographic and bronchoscopy findings in children treated with concomitant prednisolone than in those only given anti-TB medications [71]. Although no randomized trials in children are available, corticosteroids may be used to increase reabsorption of pleural and pericardial fluids and to alleviate alveolocapillary block in severe miliary disease [17]. Optimal treatment regimens for TB in HIVinfected children have not yet been established. Prospective cohort studies have noted higher treatment failures among HIV-infected children receiving standard short-course therapy when compared with non – HIV-infected children (29%, 6/21, versus 3%, 5/156; P = 0.0004) [72]. Mortality rates also were found to be higher in HIV-infected children with pulmonary TB (41%, 22/58 HIV-positive, versus 7%, 26/459 HIV-negative; P < 0.001) or TB meningitis (30%, 3/10 HIV-positive, versus 0/30 HIV-negative, P = 0.01) [73,74]. The American Academy of Pediatrics recommends at least 9 months of therapy with isoniazid, rifampin, pyrazinamide, plus ethambutol (or an aminoglycoside) for at least 2 months pending drug-susceptibility results [17]. An expert in pediatric TB and HIV should be consulted. Rifabutin can be substituted for rifampin to avoid drug interactions in children receiving protease inhibitors as part of the HIV treatment. It is paramount to ensure successful completion of therapy. Pediatric formulations are not available for many antituberculosis drugs, and often pills or capsules must be crushed and mixed with food, frequently resulting in bitter-tasting mixtures. Despite these barriers, between 1993 and 1999, 90% of children with TB in the United States completed therapy [7]. A combination of DOT, parent/patient education, pediatric formulations, enablers (strategies to overcome logistic barriers such as funds for transportation or extended clinic hours), and incentives (strategies to enhance motivation such as snacks, food coupons, or movie tickets) can increase completion rates [19]. DOT is recommended for use in all children with TB disease and multidrugresistant LTBI and in children with drug-susceptible LTBI when resources permit [17,19,58].

Public health aspects of pediatric tuberculosis As with adults, the public health sector plays an important role in control of TB in children through a

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hierarchy of activities that range from identification and treatment of patients with TB disease to conducting public health investigations of infectious source cases and identifying and treating patients with LTBI [19]. Following recognition of an infectious adult or adolescent case, a contact investigation is performed to identify exposed persons, including children and adolescents, and evaluate them for LTBI or TB disease. Source-case investigations are conducted to identify an infectious adult from whom a child with active TB may have contracted M. tuberculosis. During this process, the close contacts of the child (including other children) are evaluated for infection and disease. Last, associate investigations evaluate household contacts of children with LTBI to find a potential source of infection and to identify others with LTBI. As previously mentioned, younger children with pulmonary TB are rarely infectious. Therefore, airborne isolation is not generally required in a health care setting. Unique situations have been described, however, in which transmission may have occurred from a young child with unrecognized congenital TB or cavitary TB. Such transmission is associated particularly with suctioning or respiratory care interventions [75,76]. More commonly, accompanying parents, relatives, or health care workers with undiagnosed pulmonary TB are the source of nosocomial transmission in pediatric health care settings [77 – 81]. Infection control measures, therefore, should focus on adults accompanying the child. Promptly evaluating of the household contacts of a child with suspected TB by chest radiograph before giving visitation rights in the hospital may avoid health care – associated transmission of TB.

Summary The epidemiology of pediatric TB continues to be shaped by risk factors such as age, race, immigration, poverty, overcrowding, and HIV/AIDS. Once infected, young children have an increased risk of TB disease and progression to extrapulmonary disease because of immunologic host factors. The pathogenesis of disease differs from that in adults, because primary disease and its complications are more common in children. This prevalence of primary disease in turn leads to differences in clinical and radiographic manifestations in pediatric TB. Difficulties in diagnosing children stem from the low yield of mycobacteriology cultures and the subsequent reliance on clinical case definitions. Inadequately treated TB infection and TB disease in children today

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are the future source of disease in adults. Therefore, close collaboration between public health services and pediatric care providers is needed to ensure successful completion of treatment. Future goals should continue to focus on developing more accurate epidemiologic data for childhood TB, supporting TB control programs to decrease morbidity and mortality in children with TB and LTBI, and developing additional pediatric formulations of antituberculosis drugs.

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[50] Pomputius WF, Rost J, Dennehy PH, et al. Standardization of gastric aspirate technique improves diagnosis of tuberculosis in children. Pediatr Infect Dis J 1997;16(2):222 – 6. [51] Vallejo JG, Ong LT, Starke JR. Clinical features, diagnosis, and treatment of tuberculosis in infants. Pediatrics 1994;94:1 – 7. [52] Lobato MN, Loeffler AM, Furst K, et al. Detection of Mycobacterium tuberculosis in gastric aspirates collected from children: hospitalization is not necessary. Pediatrics 1998;102(4):e40. [53] 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 – 8. [54] Bibi H, Mosheyev D, Shoseyov D, et al. Should bronchoscopy be performed in the evaluation of suspected pediatric pulmonary tuberculosis? Chest 2002; 122:1604 – 8. [55] 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(9):735 – 8. [56] 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(4):295 – 9. [57] Chan S, Abadco DL, Steiner P. Role of flexible fiberoptic bronchoscopy in the diagnosis of childhood endobronchial tuberculosis. Pediatr Infect Dis J 1994; 13(6):506 – 9. [58] Centers for Disease Control and Prevention. Treatment of tuberculosis, American Thoracic Socity, CDC, and Infectious Diseases Society of America. MMWR Morb Mortal Wkly 2003;52(No. RR-110):1 – 77. [59] Palusci VJ, O’Hare D, Lawrence RM. Hepatotoxicity and transaminase measurement during isoniazid chemoprophylaxis in children. Pediatr Infect Dis J 1995; 14(2):144 – 8. [60] Mount F, Ferrebee S. Preventive effects of isoniazid in the treatment of primary tuberculosis in children. N Engl J Med 1961;265:713 – 21. [61] Hsu KH. Isoniazid in the prevention and treatment of tuberculosis. A 20-year study of the effectiveness in children. JAMA 1974;229(5):528 – 33. [62] Vanderhoof JA, Ament ME. Fatal hepatic necrosis due to isoniazid chemoprophylaxis in a 15-year-old girl. J Pediatr 1976;88(5):867 – 8. [63] Moulding TS, Redeker AG, Kanel GC. Twenty isoniazid-associated deaths in one state. Am Rev Respir Dis 1989;140(3):700 – 5. [64] Villarino ME, Ridzon R, Weismuller PC, et al. Rifampin preventive therapy for tuberculosis infection: experience with 157 adolescents. Am J Respir Crit Care Med 1997;155(5):1735 – 8. [65] Sanchez-Albisua I, Vidal ML, Joya-Verde G, et al. Tolerance of pyrazinamide in short course chemotherapy for pulmonary tuberculosis in children. Pediatr Infect Dis J 1997;16(8):760 – 3.

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Clin Chest Med 26 (2005) ix – x

Preface

Tuberculosis

Neil W. Schluger, MD Guest Editor

In 1952, Selman Waksman received the Nobel Prize for his discovery of streptomycin. In his Nobel address, Waksman said: In the treatment of tuberculosis, the more controlled dosage of streptomycin and the supplementary use of PAS tended to overcome some of the limitations of the antibiotic, notably its toxicity and the development of bacterial resistance. The recent introduction of isonicotinic acid hydrazide suggests the possibility that its combined use with streptomycin will tend further to control the disease and overcome undesirable complications. The conquest of the bGreat White Plague,Q undreamt of less than 10 years ago, is now virtually in sight. [1]

That same year, Rene and Jean Dubos, in their still important and prescient book The White Plague, wrote: However useful in specialized cases, vaccination, antimicrobial drug therapy, or other therapeutic measures cannot possibly solve the social problem of tuberculosis. . .. It is only through gross errors in social organization, and mismanagement of individual life, that tuberculosis could reach the catastrophic levels that prevailed in Europe and North America during the nineteenth century, and that still prevail in Asia and much of Latin America today. [2]

culosis rates in high-burden countries is not due to lack of efficacy of drugs in those countries, but rather the confluence of medical and social factors that fuel the ongoing tuberculosis epidemic: the coepidemic of HIV; poverty; lack of a functioning public health infrastructure; the economics of tuberculosis drug development; bureaucratic and doctrinaire approaches to tuberculosis control; lack of funding to support basic research aimed at development of new drugs, diagnostics, and vaccines; and apathy. The articles in this issue of the Clinics in Chest Medicine address many of these issues. They have been written by leaders in the basic science, medical, and public health communities who have broad perspective and expertise in their fields, and who are engaged in efforts locally and globally to control the worldwide tuberculosis epidemic. I would like to dedicate this issue to all patients who have tuberculosis, in hopes that the information and knowledge offered within will improve their lives in a direct and immediate way.

Unfortunately, the Dubos’ assessment proved more accurate than Waksman’s. Despite great advances in immunology, microbiology, and drug development, tuberculosis remains among the great public health challenges of our time. The failure to reduce tuber0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.03.001

Neil W. Schluger, MD Division of Pulmonary, Allergy, and Critical Care Medicine Columbia University College of Physicians and Surgeons PH-8, Room 101 630 West 168th Street New York, NY 10032, USA E-mail address: [email protected]

chestmed.theclinics.com

x

preface

References [1] Waksman SA. Streptomycin: background, isolation, properties, and utilization [Nobel lecture; December

12, 1952]. Available at: http://nobelprize.org/medicine/ laureates/1952/waksman-lecture.html. [2] Dubos R, Dubos J. The white plague. New Brunswick (NJ)7 Rutgers University Press; 1987. p. 224.