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Pulmonology
227
Lung Biology in Health and Disease
Volume 227
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LBH_6x9_Walsworth_Template.indd
Volume
Pulmonology
227
Lung Biology in Health and Disease
Volume 227
Executive Editor: Claude Lenfant
about the book…
about the editor... JOSEPH P. LYNCH, III is Professor of Clinical Medicine in the Division of Pulmonary and Critical Care Medicine, Clinical Immunology and Allergy, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. Dr. Lynch received his M.D. from Harvard Medical School, Boston, Massachusetts, USA. He is a member and fellow of several professional organizations, including the American Thoracic Society and the American College of Chest Physicians. Dr. Lynch has been invited to speak at more than 400 seminars and lectures, and he currently serves as the editor in chief of the publication Seminars of Respiratory and Critical Care Medicine. Dr. Lynch is also on the editorial board of other publications, such as Clinical Pulmonary Medicine, Pulmonary Infections Forum, and Clinical Medicine: Respiratory and Pulmonary Medicine. From 1992–2008, he has been cited in The Best Doctors in America and from 2001–2007, he has been cited in America’s Top Doctors. Dr. Lynch is also the editor of Informa Healthcare’s Idiopathic Pulmonary Fibrosis and Lung and Heart-Lung Transplantation. Printed in the United States of America
Lynch
edited by
Joseph P. Lynch, III
DESIGNER: XX
H5342
Interstitial Pulmonary and Bronchiolar Disorders FILE NAME: XXXXX DATE CREATED: XXXXX DATE REVISED: XXXX NOTES:
The only text on the market today that deals with the entire spectrum of ILDs, this handy, one-stop reference includes: • a special focus on treatment and the proper use of treatment options, including in depth coverage of the most common and potentially dangerous means of treatment • emerging concepts in patient care • discussion of lung diseases affecting the survivors of 9/11
Interstitial Pulmonary and Bronchiolar Disorders
Removing the guesswork associated with Interstitial Lung Disorders (ILDs) and bronchiolar disorders, Interstitial Pulmonary and Bronchiolar Disorders addresses the issues faced by pulmonologists in treating these disorders. Divided into sections based on the disease type (granulomatous, pneumonias, bronchiolar disorders, vasculitis, and orphan lung disease), each disorder is covered from epidemiological, pathogenic, clinical, and radiographic perspectives.
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LUNG BIOLOGY IN HEALTH AND DISEASE
Executive Editor Claude Lenfant Former Director, National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
Immunologic and Infectious Reactions in the Lung, edited by C. H. Kirkpatrick and H. Y. Reynolds The Biochemical Basis of Pulmonary Function, edited by R. G. Crystal Bioengineering Aspects of the Lung, edited by J. B. West Metabolic Functions of the Lung, edited by Y. S. Bakhle and J. R. Vane Respiratory Defense Mechanisms (in two parts), edited by J. D. Brain, D. F. Proctor, and L. M. Reid Development of the Lung, edited by W. A. Hodson Lung Water and Solute Exchange, edited by N. C. Staub Extrapulmonary Manifestations of Respiratory Disease, edited by E. D. Robin Chronic Obstructive Pulmonary Disease, edited by T. L. Petty Pathogenesis and Therapy of Lung Cancer, edited by C. C. Harris Genetic Determinants of Pulmonary Disease, edited by S. D. Litwin The Lung in the Transition Between Health and Disease, edited by P. T. Macklem and S. Permutt Evolution of Respiratory Processes: A Comparative Approach, edited by S. C. Wood and C. Lenfant Pulmonary Vascular Diseases, edited by K. M. Moser Physiology and Pharmacology of the Airways, edited by J. A. Nadel Diagnostic Techniques in Pulmonary Disease (in two parts), edited by M. A. Sackner Regulation of Breathing (in two parts), edited by T. F. Hornbein Occupational Lung Diseases: Research Approaches and Methods, edited by H. Weill and M. Turner-Warwick Immunopharmacology of the Lung, edited by H. H. Newball Sarcoidosis and Other Granulomatous Diseases of the Lung, edited by B. L. Fanburg Sleep and Breathing, edited by N. A. Saunders and C. E. Sullivan Pneumocystis carinii Pneumonia: Pathogenesis, Diagnosis, and Treatment, edited by L. S. Young Pulmonary Nuclear Medicine: Techniques in Diagnosis of Lung Disease, edited by H. L. Atkins
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24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52.
Acute Respiratory Failure, edited by W. M. Zapol and K. J. FaIke Gas Mixing and Distribution in the Lung, edited by L. A. Engel and M. Paiva High-Frequency Ventilation in Intensive Care and During Surgery, edited by G. Carlon and W. S. Howland Pulmonary Development: Transition from Intrauterine to Extrauterine Life, edited by G. H. Nelson Chronic Obstructive Pulmonary Disease: Second Edition, edited by T. L. Petty The Thorax (in two parts), edited by C. Roussos and P. T. Macklem The Pleura in Health and Disease, edited by J. Chre´tien, J. Bignon, and A. Hirsch Drug Therapy for Asthma: Research and Clinical Practice, edited by J. W. Jenne and S. Murphy Pulmonary Endothelium in Health and Disease, edited by U. S. Ryan The Airways: Neural Control in Health and Disease, edited by M. A. Kaliner and P. J. Barnes Pathophysiology and Treatment of Inhalation Injuries, edited by J. Loke Respiratory Function of the Upper Airway, edited by O. P. Mathew and G. Sant’Ambrogio Chronic Obstructive Pulmonary Disease: A Behavioral Perspective, edited by A. J. McSweeny and I. Grant Biology of Lung Cancer: Diagnosis and Treatment, edited by S. T. Rosen, J. L. Mulshine, F. Cuttitta, and P. G. Abrams Pulmonary Vascular Physiology and Pathophysiology, edited by E. K. Weir and J. T. Reeves Comparative Pulmonary Physiology: Current Concepts, edited by S. C. Wood Respiratory Physiology: An Analytical Approach, edited by H. K. Chang and M. Paiva Lung Cell Biology, edited by D. Massaro Heart–Lung Interactions in Health and Disease, edited by S. M. Scharf and S. S. Cassidy Clinical Epidemiology of Chronic Obstructive Pulmonary Disease, edited by M. J. Hensley and N. A. Saunders Surgical Pathology of Lung Neoplasms, edited by A. M. Marchevsky The Lung in Rheumatic Diseases, edited by G. W. Cannon and G. A. Zimmerman Diagnostic Imaging of the Lung, edited by C. E. Putman Models of Lung Disease: Microscopy and Structural Methods, edited by J. Gil Electron Microscopy of the Lung, edited by D. E. Schraufnagel Asthma: Its Pathology and Treatment, edited by M. A. Kaliner, P. J. Barnes, and C. G. A. Persson Acute Respiratory Failure: Second Edition, edited by W. M. Zapol and F. Lemaire Lung Disease in the Tropics, edited by O. P. Sharma Exercise: Pulmonary Physiology and Pathophysiology, edited by B. J. Whipp and K. Wasserman
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53. 54. 55. 56.
57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82.
Developmental Neurobiology of Breathing, edited by G. G. Haddad and J. P. Farber Mediators of Pulmonary Inflammation, edited by M. A. Bray and W. H. Anderson The Airway Epithelium, edited by S. G. Farmer and D. Hay Physiological Adaptations in Vertebrates: Respiration, Circulation, and Metabolism, edited by S. C. Wood, R. E. Weber, A. R. Hargens, and R. W. Millard The Bronchial Circulation, edited by J. Butler Lung Cancer Differentiation: Implications for Diagnosis and Treatment, edited by S. D. Bernal and P. J. Hesketh Pulmonary Complications of Systemic Disease, edited by J. F. Murray Lung Vascular Injury: Molecular and Cellular Response, edited by A. Johnson and T. J. Ferro Cytokines of the Lung, edited by J. Kelley The Mast Cell in Health and Disease, edited by M. A. Kaliner and D. D. Metcalfe Pulmonary Disease in the Elderly Patient, edited by D. A. Mahler Cystic Fibrosis, edited by P. B. Davis Signal Transduction in Lung Cells, edited by J. S. Brody, D. M. Center, and V. A. Tkachuk Tuberculosis: A Comprehensive International Approach, edited by L. B. Reichman and E. S. Hershfield Pharmacology of the Respiratory Tract: Experimental and Clinical Research, edited by K. F. Chung and P. J. Barnes Prevention of Respiratory Diseases, edited by A. Hirsch, M. Goldberg, J.-P. Martin, and R. Masse Pneumocystis carinii Pneumonia: Second Edition, edited by P. D. Walzer Fluid and Solute Transport in the Airspaces of the Lungs, edited by R. M. Effros and H. K. Chang Sleep and Breathing: Second Edition, edited by N. A. Saunders and C. E. Sullivan Airway Secretion: Physiological Bases for the Control of Mucous Hypersecretion, edited by T. Takishima and S. Shimura Sarcoidosis and Other Granulomatous Disorders, edited by D. G. James Epidemiology of Lung Cancer, edited by J. M. Samet Pulmonary Embolism, edited by M. Morpurgo Sports and Exercise Medicine, edited by S. C. Wood and R. C. Roach Endotoxin and the Lungs, edited by K. L. Brigham The Mesothelial Cell and Mesothelioma, edited by M.-C. Jaurand and J. Bignon Regulation of Breathing: Second Edition, edited by J. A. Dempsey and A. I. Pack Pulmonary Fibrosis, edited by S. Hin. Phan and R. S. Thrall Long-Term Oxygen Therapy: Scientific Basis and Clinical Application, edited by W. J. O’Donohue, Jr. Ventral Brainstem Mechanisms and Control of Respiration and Blood Pressure, edited by C. O. Trouth, R. M. Millis, H. F. Kiwull-Scho¨ne, and M. E. Schla¨fke
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83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114.
A History of Breathing Physiology, edited by D. F. Proctor Surfactant Therapy for Lung Disease, edited by B. Robertson and H. W. Taeusch The Thorax: Second Edition, Revised and Expanded (in three parts), edited by C. Roussos Severe Asthma: Pathogenesis and Clinical Management, edited by S. J. Szefler and D. Y. M. Leung Mycobacterium avium–Complex Infection: Progress in Research and Treatment, edited by J. A. Korvick and C. A. Benson Alpha 1–Antitrypsin Deficiency: Biology . Pathogenesis . Clinical Manifestations . Therapy, edited by R. G. Crystal Adhesion Molecules and the Lung, edited by P. A. Ward and J. C. Fantone Respiratory Sensation, edited by L. Adams and A. Guz Pulmonary Rehabilitation, edited by A. P. Fishman Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease, edited by J.-P. Derenne, W. A. Whitelaw, and T. Similowski Environmental Impact on the Airways: From Injury to Repair, edited by J. Chre´tien and D. Dusser Inhalation Aerosols: Physical and Biological Basis for Therapy, edited by A. J. Hickey Tissue Oxygen Deprivation: From Molecular to Integrated Function, edited by G. G. Haddad and G. Lister The Genetics of Asthma, edited by S. B. Liggett and D. A. Meyers Inhaled Glucocorticoids in Asthma: Mechanisms and Clinical Actions, edited by R. P. Schleimer, W. W. Busse, and P. M. O’Byrne Nitric Oxide and the Lung, edited by W. M. Zapol and K. D. Bloch Primary Pulmonary Hypertension, edited by L. J. Rubin and S. Rich Lung Growth and Development, edited by J. A. McDonald Parasitic Lung Diseases, edited by A. A. F. Mahmoud Lung Macrophages and Dendritic Cells in Health and Disease, edited by M. F. Lipscomb and S. W. Russell Pulmonary and Cardiac Imaging, edited by C. Chiles and C. E. Putman Gene Therapy for Diseases of the Lung, edited by K. L. Brigham Oxygen, Gene Expression, and Cellular Function, edited by L. Biadasz Clerch and D. J. Massaro Beta2-Agonists in Asthma Treatment, edited by R. Pauwels and P. M. O’Byrne Inhalation Delivery of Therapeutic Peptides and Proteins, edited by A. L. Adjei and P. K. Gupta Asthma in the Elderly, edited by R. A. Barbee and J. W. Bloom Treatment of the Hospitalized Cystic Fibrosis Patient, edited by D. M. Orenstein and R. C. Stern Asthma and Immunological Diseases in Pregnancy and Early Infancy, edited by M. Schatz, R. S. Zeiger, and H. N. Claman Dyspnea, edited by D. A. Mahler Proinflammatory and Antiinflammatory Peptides, edited by S. I. Said Self-Management of Asthma, edited by H. Kotses and A. Harver Eicosanoids, Aspirin, and Asthma, edited by A. Szczeklik, R. J. Gryglewski, and J. R. Vane
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115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144.
Fatal Asthma, edited by A. L. Sheffer Pulmonary Edema, edited by M. A. Matthay and D. H. Ingbar Inflammatory Mechanisms in Asthma, edited by S. T. Holgate and W. W. Busse Physiological Basis of Ventilatory Support, edited by J. J. Marini and A. S. Slutsky Human Immunodeficiency Virus and the Lung, edited by M. J. Rosen and J. M. Beck Five-Lipoxygenase Products in Asthma, edited by J. M. Drazen, S.-E. Dahle´n, and T. H. Lee Complexity in Structure and Function of the Lung, edited by M. P. Hlastala and H. T. Robertson Biology of Lung Cancer, edited by M. A. Kane and P. A. Bunn, Jr. Rhinitis: Mechanisms and Management, edited by R. M. Naclerio, S. R. Durham, and N. Mygind Lung Tumors: Fundamental Biology and Clinical Management, edited by C. Brambilla and E. Brambilla lnterleukin-5: From Molecule to Drug Target for Asthma, edited by C. J. Sanderson Pediatric Asthma, edited by S. Murphy and H. W. Kelly Viral Infections of the Respiratory Tract, edited by R. Dolin and P. F. Wright Air Pollutants and the Respiratory Tract, edited by D. L. Swift and W. M. Foster Gastroesophageal Reflux Disease and Airway Disease, edited by M. R. Stein Exercise-Induced Asthma, edited by E. R. McFadden, Jr. LAM and Other Diseases Characterized by Smooth Muscle Proliferation, edited by J. Moss The Lung at Depth, edited by C. E. G. Lundgren and J. N. Miller Regulation of Sleep and Circadian Rhythms, edited by F. W. Turek and P. C. Zee Anticholinergic Agents in the Upper and Lower Airways, edited by S. L. Spector Control of Breathing in Health and Disease, edited by M. D. Altose and Y. Kawakami Immunotherapy in Asthma, edited by J. Bousquet and H. Yssel Chronic Lung Disease in Early Infancy, edited by R. D. Bland and J. J. Coalson Asthma’s Impact on Society: The Social and Economic Burden, edited by K. B. Weiss, A. S. Buist, and S. D. Sullivan New and Exploratory Therapeutic Agents for Asthma, edited by M. Yeadon and Z. Diamant Multimodality Treatment of Lung Cancer, edited by A. T. Skarin Cytokines in Pulmonary Disease: Infection and Inflammation, edited by S. Nelson and T. R. Martin Diagnostic Pulmonary Pathology, edited by P. T. Cagle Particle–Lung Interactions, edited by P. Gehr and J. Heyder Tuberculosis: A Comprehensive International Approach, Second Edition, Revised and Expanded, edited by L. B. Reichman and E. S. Hershfield
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145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172.
Combination Therapy for Asthma and Chronic Obstructive Pulmonary Disease, edited by R. J. Martin and M. Kraft Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Disease, edited by T. D. Bradley and J. S. Floras Sleep and Breathing in Children: A Developmental Approach, edited by G. M. Loughlin, J. L. Carroll, and C. L. Marcus Pulmonary and Peripheral Gas Exchange in Health and Disease, edited by J. Roca, R. Rodriguez-Roisin, and P. D. Wagner Lung Surfactants: Basic Science and Clinical Applications, R. H. Notter Nosocomial Pneumonia, edited by W. R. Jarvis Fetal Origins of Cardiovascular and Lung Disease, edited by David J. P. Barker Long-Term Mechanical Ventilation, edited by N. S. Hill Environmental Asthma, edited by R. K. Bush Asthma and Respiratory Infections, edited by D. P. Skoner Airway Remodeling, edited by P. H. Howarth, J. W. Wilson, J. Bousquet, S. Rak, and R. A. Pauwels Genetic Models in Cardiorespiratory Biology, edited by G. G. Haddad and T. Xu Respiratory-Circulatory Interactions in Health and Disease, edited by S. M. Scharf, M. R. Pinsky, and S. Magder Ventilator Management Strategies for Critical Care, edited by N. S. Hill and M. M. Levy Severe Asthma: Pathogenesis and Clinical Management, Second Edition, Revised and Expanded, edited by S. J. Szefler and D. Y. M. Leung Gravity and the Lung: Lessons from Microgravity, edited by G. K. Prisk, M. Paiva, and J. B. West High Altitude: An Exploration of Human Adaptation, edited by T. F. Hornbein and R. B. Schoene Drug Delivery to the Lung, edited by H. Bisgaard, C. O’Callaghan, and G. C. Smaldone Inhaled Steroids in Asthma: Optimizing Effects in the Airways, edited by R. P. Schleimer, P. M. O’Byrne, S. J. Szefler, and R. Brattsand IgE and Anti-lgE Therapy in Asthma and Allergic Disease, edited by R. B. Fick, Jr., and P. M. Jardieu Clinical Management of Chronic Obstructive Pulmonary Disease, edited by T. Similowski, W. A. Whitelaw, and J.-P. Derenne Sleep Apnea: Pathogenesis, Diagnosis, and Treatment, edited by A. I. Pack Biotherapeutic Approaches to Asthma, edited by J. Agosti and A. L. Sheffer Proteoglycans in Lung Disease, edited by H. G. Garg, P. J. Roughley, and C. A. Hales Gene Therapy in Lung Disease, edited by S. M. Albelda Disease Markers in Exhaled Breath, edited by N. Marczin, S. A. Kharitonov, M. H. Yacoub, and P. J. Barnes Sleep-Related Breathing Disorders: Experimental Models and Therapeutic Potential, edited by D. W. Carley and M. Radulovacki Chemokines in the Lung, edited by R. M. Strieter, S. L. Kunkel, and T. J. Standiford
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173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199.
Respiratory Control and Disorders in the Newborn, edited by O. P. Mathew The Immunological Basis of Asthma, edited by B. N. Lambrecht, H. C. Hoogsteden, and Z. Diamant Oxygen Sensing: Responses and Adaptation to Hypoxia, edited by S. Lahiri, G. L. Semenza, and N. R. Prabhakar Non-Neoplastic Advanced Lung Disease, edited by J. R. Maurer Therapeutic Targets in Airway Inflammation, edited by N. T. Eissa and D. P. Huston Respiratory Infections in Allergy and Asthma, edited by S. L. Johnston and N. G. Papadopoulos Acute Respiratory Distress Syndrome, edited by M. A. Matthay Venous Thromboembolism, edited by J. E. Dalen Upper and Lower Respiratory Disease, edited by J. Corren, A. Togias, and J. Bousquet Pharmacotherapy in Chronic Obstructive Pulmonary Disease, edited by B. R. Celli Acute Exacerbations of Chronic Obstructive Pulmonary Disease, edited by N. M. Siafakas, N. R. Anthonisen, and D. Georgopoulos Lung Volume Reduction Surgery for Emphysema, edited by H. E. Fessler, J. J. Reilly, Jr., and D. J. Sugarbaker Idiopathic Pulmonary Fibrosis, edited by J. P. Lynch III Pleural Disease, edited by D. Bouros Oxygen/Nitrogen Radicals: Lung Injury and Disease, edited by V. Vallyathan, V. Castranova, and X. Shi Therapy for Mucus-Clearance Disorders, edited by B. K. Rubin and C. P. van der Schans Interventional Pulmonary Medicine, edited by J. F. Beamis, Jr., P. N. Mathur, and A. C. Mehta Lung Development and Regeneration, edited by D. J. Massaro, G. Massaro, and P. Chambon Long-Term Intervention in Chronic Obstructive Pulmonary Disease, edited by R. Pauwels, D. S. Postma, and S. T. Weiss Sleep Deprivation: Basic Science, Physiology, and Behavior, edited by Clete A. Kushida Sleep Deprivation: Clinical Issues, Pharmacology, and Sleep Loss Effects, edited by Clete A. Kushida Pneumocystis Pneumonia: Third Edition, Revised and Expanded, edited by P. D. Walzer and M. Cushion Asthma Prevention, edited by William W. Busse and Robert F. Lemanske, Jr. Lung Injury: Mechanisms, Pathophysiology, and Therapy, edited by Robert H. Notter, Jacob Finkelstein, and Bruce Holm Ion Channels in the Pulmonary Vasculature, edited by Jason X.-J. Yuan Chronic Obstructive Pulmonary Disease: Cellular and Molecular Mechanisms, edited by Peter J. Barnes Pediatric Nasal and Sinus Disorders, edited by Tania Sih and Peter A. R. Clement
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200. 201. 202. 203. 204. 205. 206. 207. 208. 209. 210. 211. 212. 213. 214. 215. 216. 217. 218. 219. 220. 221. 222.
223.
224.
225.
Functional Lung Imaging, edited by David Lipson and Edwin van Beek Lung Surfactant Function and Disorder, edited by Kaushik Nag Pharmacology and Pathophysiology of the Control of Breathing, edited by Denham S. Ward, Albert Dahan and Luc J. Teppema Molecular Imaging of the Lungs, edited by Daniel Schuster and Timothy Blackwell Air Pollutants and the Respiratory Tract: Second Edition, edited by W. Michael Foster and Daniel L. Costa Acute and Chronic Cough, edited by Anthony E. Redington and Alyn H. Morice Severe Pneumonia, edited by Michael S. Niederman Monitoring Asthma, edited by Peter G. Gibson Dyspnea: Mechanisms, Measurement, and Management, Second Edition, edited by Donald A. Mahler and Denis E. O’Donnell Childhood Asthma, edited by Stanley J. Szefler and Sfren Pedersen Sarcoidosis, edited by Robert Baughman Tropical Lung Disease, Second Edition, edited by Om Sharma Pharmacotherapy of Asthma, edited by James T. Li Practical Pulmonary and Critical Care Medicine: Respiratory Failure, edited by Zab Mosenifar and Guy W. Soo Hoo Practical Pulmonary and Critical Care Medicine: Disease Management, edited by Zab Mosenifar and Guy W. Soo Hoo Ventilator-Induced Lung Injury, edited by Didier Dreyfuss, Georges Saumon, and Rolf D. Hubmayr Bronchial Vascular Remodeling In Asthma and COPD, edited by Aili Lazaar Lung and Heart–Lung Transplantation, edited by Joseph P. Lynch III and David J. Ross Genetics of Asthma and Chronic Obstructive Pulmonary Disease, edited by Dirkje S. Postma and Scott T. Weiss Reichman and Hershfield’s Tuberculosis: A Comprehensive, International Approach, Third Edition (in two parts), edited by Mario C. Raviglione Narcolepsy and Hypersomnia, edited by Claudio Bassetti, Michel Billiard, and Emmanuel Mignot Inhalation Aerosols: Physical and Biological Basis for Therapy, Second Edition, edited by Anthony J. Hickey Clinical Management of Chronic Obstructive Pulmonary Disease, Second Edition, edited by Stephen I. Rennard, Roberto Rodriguez-Roisin, Ge´rard Huchon, and Nicolas Roche Sleep in Children, Second Edition: Developmental Changes in Sleep Patterns, edited by Carole L. Marcus, John L. Carroll, David F. Donnelly, and Gerald M. Loughlin Sleep and Breathing in Children, Second Edition: Developmental Changes in Breathing During Sleep, edited by Carole L. Marcus, John L. Carroll, David F. Donnelly, and Gerald M. Loughlin Ventilatory Support for Chronic Respiratory Failure, edited by Nicolino Ambrosino and Roger S. Goldstein
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226. 227.
Diagnostic Pulmonary Pathology, Second Edition, edited by Philip T. Cagle, Timothy C. Allen, and Mary Beth Beasley Interstitial Pulmonary and Bronchiolar Disorders, edited by Joseph P. Lynch III
The opinions expressed in these volumes do not necessarily represent the views of the National Institutes of Health.
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Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 # 2008 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 1-4200-5342-6 (Hardcover) International Standard Book Number-13: 978-1-4200-5342-5 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www .copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Interstitial pulmonary and bronchiolar disorders / edited by Joseph P. Lynch III. p. ; cm. — (Lung biology in health and disease ; 227) Includes bibliographical references and index. ISBN-13: 978-1-4200-5342-5 (hardcover : alk. paper) ISBN-10: 1-4200-5342-6 (hardcover : alk. paper) 1. Interstitial lung diseases. 2. Bronchioles—Diseases. I. Lynch, Joseph P. II. Series: Lung biology in health and disease ; v. 227. [DNLM: 1. Lung Diseases, Interstitial. 2. Bronchial Diseases. W1 LU62 v.227 2008 / WF 600 I6176 2008] RC776.I56I586 2008 616.2’4—dc22 2008017204 For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue, 7th floor, New York, NY 10017. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com
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Introduction
In the second half of the last century, we saw a huge interest in lung disease which developed in several phases. The first one was undoubtedly driven by the increased knowledge in the physiology of the lung and of the respiratory system. Then, the impact of biochemistry and cell biology in lung research led to a better understanding of the pathophysiology of a number of diseases of the lung. The best example is undoubtedly the evolution of our knowledge about neonatal respiratory distress syndrome. Eventually this knowledge brought about new and effective treatments resulting in a significant decrease in mortality from this condition. Other major lung conditions benefited from the increase in research stimulated by success from neonatal respiratory distress syndrome leading to further understanding of the structure and function of the lung and the respiratory system, as well as to new therapeutic approaches for infectious and noninfectious lung diseases. Although it is too early to claim victory for many noninfectious chronic conditions, we can be reassured that the intensity of the research and its productivity will continue to bring progress to the treatment of such diseases. Examples include increased intensity of research interest in asthma and chronic obstructive pulmonary disease (COPD). Unfortunately diseases classified under the term “diffuse interstitial pulmonary and bronchiolar disorders” have not received the same attention until recently. Indeed, in the last five years or so, these conditions have attracted a new—and sometimes renewed—interest from the research community in great part because of the development of molecular and genetic disciplines and their application to the lung. This group of diseases comprise many disorders, perhaps as many as 200, characterized by inflammation and eventually scaring of the lung tissue—or fibrosis. In many instances, the pathological process begins in the most terminal segment of the bronchioles eventually affecting lung tissue as well as the bronchioles. The incidence and prevalence of all these conditions together is not known, but estimates suggest that there may be from 50 to 100 cases per 100,000 population. Many patients die at a relatively young age, for example, in the fourth decade.
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iv
Introduction
The readership of the series of monographs Lung Biology in Health and Disease know that the series has attempted to address as many pulmonary disorders as possible, but never before has a volume focused on the rare and often puzzling disorders of the interstitium and bronchiolar tissues. In 2004, the series introduced volume 185 titled Idiopathic Pulmonary Fibrosis edited by Dr. Joseph P. Lynch III to present diseases closely related to many of these diffuse disorders. However, this new volume rich with 35 chapters each addressing a different disorder presents in a comprehensive manner what we now know about Interstitial Pulmonary and Bronchiolar Disorders. Expert research scientists and clinicians from several countries shared their expertise and experience. Undoubtedly, the research community will be stimulated from reading this volume and the clinicians will be assisted in their search to provide the very best care to their patients. As the Executive Editor of the series, I am grateful to all the contributors of this volume and for the opportunity to introduce it. Claude Lenfant, M.D. Vancouver, Washington, U.S.A.
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Preface
Interstitial Pulmonary and Bronchiolar Disorders provides a comprehensive review of clinical and investigative aspects of diverse interstitial lung diseases (ILDs) and bronchiolar inflammatory disorders. Immune-mediated mechanisms have been implicated as the cause of most of these diseases. However, the etiologic agents responsible for many of these lung and bronchiolar disorders remain enigmatic. Management of these diseases is difficult, owing to the rarity of these disorders and the lack of placebo-controlled therapeutic trials for many ILDs. Most practicing clinicians have inadequate personal experience to deal with these rare and diverse disorders with confidence. This book enlists internationally recognized experts to discuss controversies and evolving concepts in the management of diffuse ILDs and bronchiolar disorders. The first five chapters address an overall approach to ILDs (chap. 1 by Drs. Collard and King), and discuss in depth radiographic (chap. 2 by Dr. Lynch et al.), and histopathological (chap. 4 by Dr. Wallace et al.) features and patterns. In chapter 3, Drs. Woodhead and du Bois explore in detail the role of genetics in specific ILDs, and the importance of genetic polymorphisms in the clinical expression of diseases. Corticosteroids and immunosuppressive and cytotoxic agents are the cornerstone of therapy for many (but not all) of these disorders. These agents have potential serious toxicities, and many clinicians lack expertise with these agents. In chapter 5, Drs. Baughman and Lower provide a comprehensive review of the diverse agents utilized to treat ILDs, indications to treat, toxicities, and appropriate monitoring strategies. All of the remaining chapters provide in-depth discussions of specific ILDs or bronchiolar disorders including epidemiology, pathogenesis, clinical features, and treatment. Within each chapter, histopathological and radiographic images (particularly computed tomographic) highlight the key features of the respective diseases. Chapters 6 to 11 review specific disorders manifesting granulomatous character. Three chapters are devoted to sarcoidosis. In chapter 6, Drs. Zissel, Prasse, and Müller-Quernheim elegantly discuss the epidemiology and immunopathogenesis of this enigmatic
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Preface
disorder. In chapter 7, Drs. Lynch, Fishbein, and White discuss the pulmonary manifestations of sarcoidosis. In chapter 8, Dr. Judson elegantly reviews the protean extrapulmonary manifestations of sarcoidosis. The remaining topics encompassed in the granulomatous section include hypersensitivity pneumonia (triggered by diverse organic and sometimes inorganic irritants/antigens) (chap. 9 by Dr. Selman et al.), berylliosis (a mimic of sarcoidosis caused by inhaled beryllium) (chap. 10 by Drs. Newman and Sackett), and other pneumoconioses (chap. 11 by Dr. Brody). The third section in the book (chaps. 12–18) reviews the idiopathic interstitial pneumonias and pulmonary complications of connective tissue disorders (CTDs). Separate chapters are included for idiopathic pulmonary fibrosis (Dr. Lynch et al.), nonspecific interstitial pneumonia (Dr. Flaherty), respiratory bronchiolitis interstitial lung disease and desquamative interstitial pneumonia (Dr. Ryu), acute interstitial pneumonia (Drs. Vourlekis and Brown), and lymphocytic interstitial pneumonia (Drs. Koss and Shigemitsu). In chapter 17, Dr. Nunes and colleagues provide an elegant and comprehensive review of ILDs complicating CTDs. In chapter 18, Dr. Strange reviews the other diverse pleuropulmonary complications of CTDs not encompassed in chapter 17. The fourth section in the book discusses diverse bronchiolar disorders (some idiopathic, some due to well-recognized causes). Organizing pneumonia (formerly termed bronchiolitis obliterans organizing pneumonia) and obliterative bronchiolitis (OB) exhibit striking differences in prognosis and responsiveness to therapy. Hence, these disorders are discussed separately by Dr. Lazor et al. and Dr. Poletti et al. in chapters 19 and 20, respectively. Additional chapters focus on the devastating complications of OB in the context of lung or heart-lung (Dr. Verleden et al.) and hematopoietic stem cell transplantation (Drs. Afessa and Peters). Recent data linked inhalation exposure among rescue personnel in New York City to diverse pulmonary and bronchiolar disorders (discussed in depth in chap. 23 by Dr. Prezant et al.). The fifth section of the book discusses vasculitic syndromes that may affect the lung. The initial chapter in this section (chap. 24 by Drs. Jennette and Falk) provides an in-depth view of epidemiology and pathogenesis of ANCA-associated vasculitides (AAV). The following chapters discuss Wegener’s granulomatosis (Dr. Silva et al.), Churg–Strauss Vasculitis (Dr. Guilpain et al.), and microscopic polyangiitis (Drs. Salama and Pusey). Each of these AAV has overlapping characteristics yet differ in important respects articulated in the individual chapters. In Chapter 28, Drs. Biddinger and Panos review anti-glomerular basement membrane disease, a rare but important cause of pulmonary hemorrhage and renal failure that mimics pulmonary vasculitis. Finally, Drs. Hajj-Ali and Langford discuss Behçet’s disease, an uncommon cause of pulmonary vasculitis with marked variability in prevalence in different countries/regions worldwide. The final section in the book discusses what have been termed “orphan lung disorders” and includes chapters on eosinophilic pulmonary disorders (Dr. Cottin et al.),
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Langerhans cell histiocytosis (Dr. Vassallo et al.), lymphangioleiomyomatosis (Dr. McCormack), pulmonary alveolar proteinosis (Dr. Wang et al.), amyloidosis (Dr. Berk), and drug-induced pulmonary disorders (Drs. Maldonado and Limper). This book assembles the best international experts in ILD and bronchiolar disorders and provides a global perspective of the current and future management of these rare and often puzzling disorders. Each of these chapters not only comprehensively outlines the salient clinical features of these diverse ILD and bronchiolar disorders but also reviews in depth the pathogenic mechanisms of these disorders, and the role of current and novel therapies. The bibliography is extensive, allowing ready access to the sentinel and original articles in the field. The book will be of great interest and value to pulmonologists, rheumatologists, immunologists, allergists, pathologists, and radiologists, as well as basic scientists with an interest in immunologically mediated pulmonary and bronchiolar disorders. Joseph P. Lynch, III
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Contributors
Bekele Afessa U.S.A.
Mayo Clinic College of Medicine, Rochester, Minnesota,
Thomas K. Aldrich Albert Einstein College of Medicine and Montefiore Medical Center, New York, New York, U.S.A. Marie Christine Aubry Minnesota, U.S.A.
Mayo Clinic College of Medicine, Rochester,
Robert P. Baughman Department of Medicine, Interstitial Lung Disease and Sarcoidosis Clinic, University of Cincinnati, Cincinnati, Ohio, U.S.A. John Belperio David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. John L. Berk Amyloid Treatment and Research Program, Department of Medicine, Boston University Medical Center, Boston, Massachusetts, U.S.A. Paul Biddinger
Medical College of Georgia, Augusta, Georgia, U.S.A.
P. Y. Brillet UPRES EA 2363, Service de Radiologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Université Paris 13, Bobigny, France Arnold R. Brody Carolina, U.S.A.
North Carolina State University, Raleigh, North
Kevin K. Brown National Jewish Medical and Research Center, Denver, Colorado, U.S.A. Angelo Carloni
Azienda Ospedaliera S. Maria, Terni, Italy
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x Gianluca Casoni
Contributors GB Morgagni Hospital, Forlì, Italy
Marco Chilosi University of Verona, Verona, Italy Harold R. Collard Department of Medicine, University of California, San Francisco, San Francisco General Hospital, San Francisco, California, U.S.A. Jean-Franc¸ois Cordier Department of Respiratory Medicine, Reference Center for Orphan Pulmonary Diseases, Hospices Civils de Lyon, Louis Pradel University Hospital, University of Lyon, Lyon, France Vincent Cottin Department of Respiratory Medicine, Reference Center for Orphan Pulmonary Diseases, Hospices Civils de Lyon, Louis Pradel University Hospital, University of Lyon, Lyon, France R. M. du Bois National Jewish Medical and Research Center, Denver, Colorado, U.S.A. Lieven J. Dupont
University Hospital Gasthuisberg, Leuven, Belgium
Ronald J. Falk University of North Carolina, Chapel Hill, North Carolina, U.S.A. Michael C. Fishbein Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. Kevin R. Flaherty Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, U.S.A. Loı¨c Guillevin Department of Internal Medicine and Referral Center for Necrotizing Vasculitides and Systemic Sclerosis, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France Philippe Guilpain Department of Internal Medicine and Referral Center for Necrotizing Vasculitides and Systemic Sclerosis, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France Rula A. Hajj-Ali Center for Vasculitis Care and Research, Cleveland Clinic, Cleveland, Ohio, U.S.A. J. Charles Jennette University of North Carolina, Chapel Hill, North Carolina, U.S.A.
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Contributors
xi
Marc A. Judson Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, South Carolina, U.S.A. M. Kambouchner Service d’Anatomie Pathologique, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Université Paris 13, Bobigny, France Michael P. Keane St. Vincent’s University Hospital and University College, Dublin, Ireland Talmadge E. King, Jr. Department of Medicine, University of California, San Francisco, San Francisco, California, U.S.A. Michael N. Koss Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A. Chi Lai Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. Carol A. Langford Center for Vasculitis Care and Research, Cleveland Clinic, Cleveland, Ohio, U.S.A. Romain Lazor Department of Respiratory Medicine, University Hospital, Bern, Switzerland, and Department of Respiratory Medicine, Reference Center for Orphan Pulmonary Diseases, Louis Pradel University Hospital, Lyon, France Stephen Levin U.S.A.
Mount Sinai School of Medicine, New York, New York,
Andrew H. Limper Minnesota, U.S.A.
Mayo Clinic College of Medicine, Rochester,
Elyse E. Lower Department of Medicine, Interstitial Lung Disease and Sarcoidosis Clinic, University of Cincinnati, Cincinnati, Ohio, U.S.A. Joseph P. Lynch, III Department of Medicine, Division of Pulmonary and Critical Care Medicine, Clinical Immunology and Allergy, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. Raja S. Mahidhara David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
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Contributors
Fabien Maldonado Minnesota, U.S.A.
Mayo Clinic College of Medicine, Rochester,
Francis X. McCormack Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio, U.S.A. Mayra Mejı´a Instituto Nacional de Enfermedades Respiratorias, Dr. Ismael Cosío Villegas, México DF, México Joachim Mu¨ller-Quernheim Department of Pneumology, University Medical Center, University Hospital Freiburg, Freiburg, Germany Lee S. Newman Department of Preventive Medicine and Biometrics, School of Medicine, University of Colorado Denver, Denver, Colorado, U.S.A. H. Nunes UPRES EA 2363, Service de Pneumologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Université Paris 13, Bobigny, France Christian Pagnoux Department of Internal Medicine and Referral Center for Necrotizing Vasculitides and Systemic Sclerosis, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France Ralph J. Panos Cincinnati VAMC and University of Cincinnati Medical School, Cincinnati, Ohio, U.S.A. Annie Pardo México
Universidad Nacional Autónoma de México, México DF,
Rajesh Patel U.S.A.
Mayo Clinic College of Medicine, Rochester, Minnesota,
Steve G. Peters U.S.A.
Mayo Clinic College of Medicine, Rochester, Minnesota,
Venerino Poletti GB Morgagni Hospital, Forlì, Italy and University of Parma, Parma, Italy Antje Prasse Department of Pneumology, University Medical Center, University Hospital Freiburg, Freiburg, Germany
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Contributors
xiii
David J. Prezant Fire Department of the City of New York (FDNY); Albert Einstein College of Medicine and Montefiore Medical Center, New York, New York, U.S.A. Charles D. Pusey Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, London, U.K. Jay H. Ryu U.S.A.
Mayo Clinic College of Medicine, Rochester, Minnesota,
Holly M. Sackett Department of Preventive Medicine and Biometrics, School of Medicine, University of Colorado Denver, Denver, Colorado, U.S.A. Alan D. Salama Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, London, U.K. Moise´s Selman Instituto Nacional de Enfermedades Respiratorias, Dr. Ismael Cosío Villegas, México DF, México Hidenobu Shigemitsu Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A. Francisco Silva Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota, U.S.A. Ulrich Specks Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota, U.S.A. Charlie Strange Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, South Carolina, U.S.A. Robert D. Suh David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. Y. Uzunhan UPRES EA 2363, Service de Pneumologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Université Paris 13, Bobigny, France D. Valeyre UPRES EA 2363, Service de Pneumologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Université Paris 13, Bobigny, France
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Contributors
E. M. Van Raemdonck Belgium Bart M. Vanaudenaerde Belgium Robert Vassallo U.S.A.
University Hospital Gasthuisberg, Leuven,
Mayo Clinic College of Medicine, Rochester, Minnesota,
Geert M. Verleden Robin Vos
University Hospital Gasthuisberg, Leuven,
University Hospital Gasthuisberg, Leuven, Belgium
University Hospital Gasthuisberg, Leuven, Belgium
Jason Vourlekis
Inova Fairfax Hospital, Falls Church, Virginia, U.S.A.
W. Dean Wallace Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. Tisha Wang David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. S. Samuel Weigt David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. A. U. Wells Interstitial Lung Disease Unit, Royal Brompton Hospital, London, U.K. Eric S. White Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, U.S.A. Felix A. Woodhead Royal Brompton Hospital and National Heart and Lung Institute, Imperial College, London, U.K. David A. Zisman David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. Gernot Zissel Department of Pneumology, University Medical Center, University Hospital Freiburg, Freiburg, Germany Maurizio Zompatori
University Hospital of Parma, Parma, Italy
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Contents
Introduction Claude Lenfant . . . . . . . iii Preface .......................... v Contributors . . . . . . . . . . . . . . . . . . . . . . ix OVERVIEW 1. Approach to the Diagnosis of Diffuse Parenchymal Lung Disease Harold R. Collard and Talmadge E. King, Jr. I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Significance of an Accurate Diagnosis . . . . . . . . . . . . . III. General Diagnostic Methods ................... IV. Physiological Testing . . . . . . . . . . . . . . . . . . . . . . . . . V. Ancillary Tests ............................. VI. Screening for Common Comorbidities . . . . . . . . . . . . . VII. Importance of a Multidisciplinary Approach ........ VIII. Conclusions ............................... References ................................ 2. Thoracic Imaging for Diffuse ILD and Bronchiolar Disorders Joseph P. Lynch, III, S. Samuel Weigt, and Robert D. Suh I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Idiopathic Interstitial Pneumonias . . . . . . . . . . . . . . III. Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Hypersensitivity Pneumonia . . . . . . . . . . . . . . . . . . V. Pulmonary Alveolar Proteinosis ............... VI. Pulmonary Langerhans Cell Histiocytosis ........ VII. Lymphangioleiomyomatosis . . . . . . . . . . . . . . . . . . References ..............................
1 1 1 3 7 8 9 10 11 11 13
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13 15 25 28 29 30 32 33
3. Genetics of ILD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Felix A. Woodhead and R. M. du Bois I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Diffuse Panbronchiolitis . . . . . . . . . . . . . . . . . . . . . . .
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Contents III. IV. V. VI. VII.
Idiopathic Interstitial Pneumonias . . . . Systemic Sclerosis . . . . . . . . . . . . . . . Sarcoidosis . . . . . . . . . . . . . . . . . . . . Hypersensitivity Pneumonitis . . . . . . . DNA Microarrays and High-Throughput Genotyping . . . . . . . . . . . . . . . . . . . . VIII. Conclusions ................... References ....................
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4. Pathology of Diffuse Interstitial Lung Disease . . . . . . . . . . . . 93 W. Dean Wallace, Chi Lai, and Michael C. Fishbein I. Interstitial Lung Disease . . . . . . . . . . . . . . . . . . . . . . 93 II. Pulmonary Fibrosis in Collagen Vascular Diseases . . . 108 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 5. Immunosuppressive and Cytotoxic Drug Therapy for Diffuse ILD .................................. Robert P. Baughman and Elyse E. Lower I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Cytotoxic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Other Agents ............................. V. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ...............................
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SPECIFIC DISEASES GRANULOMATOUS 6. Sarcoidosis: Pathogenesis and Epidemiology . . . . . . . . . . . . . Gernot Zissel, Antje Prasse, and Joachim M€ uller-Quernheim I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Epidemiology of Sarcoidosis . . . . . . . . . . . . . . . . . . . III. Immunopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . IV. Model of Granuloma Formation in Sarcoidosis . . . . . References ............................... 7. Pulmonary Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Joseph P. Lynch, III, Michael C. Fishbein, and Eric S. White I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Pulmonary Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . III. Clinical Features of Pulmonary Sarcoidosis . . . . . . . . IV. Chest Radiographic Features in Sarcoidosis . . . . . . . . V. Radiographic Classification Schema .............
163 163 164 165 176 178 189 189 189 190 190 190
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Contents VI. VII. VIII. IX. X. XI. XII. XIII. XIV. XV. XVI. XVII. XVIII. XIX. XX. XXI. XXII. XXIII. XXIV. XXV. XXVI.
xvii Clinical Prognostic Factors . . . . . . . . . . . . . . . . . . Computed Tomographic Scans . . . . . . . . . . . . . . . Pulmonary Function Tests in Sarcoidosis . . . . . . . . Influence of Pulmonary Function on Prognosis ... Laboratory Features ...................... Pathogenesis of Sarcoidosis ................. Bronchoalveolar Lavage in Sarcoidosis . . . . . . . . . Radionuclide Techniques . . . . . . . . . . . . . . . . . . . Pathology of Pulmonary Sarcoidosis . . . . . . . . . . . Diagnosis of Pulmonary Sarcoidosis . . . . . . . . . . . Specific Complications of Intrathoracic Sarcoidosis Necrotizing Sarcoid Angiitis and Granulomatosis . . Bronchostenosis ......................... Mycetomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pleural Involvement in Sarcoidosis . . . . . . . . . . . . Lung Cancer Complicating Sarcoidosis . . . . . . . . . Sarcoidosis in HIV-Infected Patients . . . . . . . . . . . Sarcoidosis Complicating Type 1 Interferon Therapy Treatment of Sarcoidosis . . . . . . . . . . . . . . . . . . . Alternatives to Corticosteroids . . . . . . . . . . . . . . . Lung Transplantation for Sarcoidosis .......... References .............................
8. Extrapulmonary Sarcoidosis Marc A. Judson I. Introduction . . . . . II. Eye ........... III. Skin . . . . . . . . . . . IV. Liver .......... V. Heart . . . . . . . . . . VI. Neurologic . . . . . . VII. Calcium Metabolism VIII. Other Organs .... IX. Summary . . . . . . . References ......
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9. Hypersensitivity Pneumonitis . . . . . . . . . . . . . . . . . . . . . . . . Moise´s Selman, Mayra Mejı´a, and Annie Pardo I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. The Promoting Factors ...................... III. Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . IV. Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Chest Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. Pulmonary Function Testing . . . . . . . . . . . . . . . . . . .
267 267 269 271 272 273 275
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Contents VII. VIII. IX. X.
Bronchoalveolar Lavage Histological Features . Diagnostic Criteria .. Treatment and Outcome References ........
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10. Berylliosis ...................................... Lee S. Newman and Holly M. Sackett I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Historical Perspective ....................... III. Exposure and Toxicology . . . . . . . . . . . . . . . . . . . . . IV. Immunopathogenesis and Disease Susceptibility . . . . . V. Clinical Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. Diagnosis of CBD . . . . . . . . . . . . . . . . . . . . . . . . . . References ...............................
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11. Silicosis and Asbestosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Arnold R. Brody I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Deposition of Inhaled Particles . . . . . . . . . . . . . . . . . III. Pathobiological Responses . . . . . . . . . . . . . . . . . . . . IV. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ...............................
289 291 291 293 295 299 306 317 317 318 319 328 328
IDIOPATHIC INTERSTITIAL PNEUMONIAS 12. Idiopathic Pulmonary Fibrosis . . . . . . . . . . . . . . . . . . . . . . . Joseph P. Lynch, III, Raja S. Mahidhara, Michael C. Fishbein, Michael P. Keane, David A. Zisman, and John Belperio I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Clinical Features of IPF . . . . . . . . . . . . . . . . . . . . . . III. Histopathological Features of Usual Interstitial Pneumonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Pathogenesis of IPF . . . . . . . . . . . . . . . . . . . . . . . . . VI. Physiological Aberrations in IPF . . . . . . . . . . . . . . . . VII. Radiographical Manifestations of IPF . . . . . . . . . . . . VIII. Ancillary Staging Techniques . . . . . . . . . . . . . . . . . . IX. Complications of IPF . . . . . . . . . . . . . . . . . . . . . . . . X. Therapy of IPF . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI. Lung Transplantation for IPF . . . . . . . . . . . . . . . . . . References ...............................
333 333 334 335 336 337 343 344 346 347 349 351 352
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Contents 13. Nonspecific Interstitial Pneumonitis (NSIP) Kevin R. Flaherty I. Introduction . . . . . . . . . . . . . . . . II. Epidemiology . . . . . . . . . . . . . . . III. Clinical Assessment and Diagnosis IV. Histopathology and Pathogenesis . V. Natural History and Prognosis . . . VI. Management and Treatment . . . . . VII. Conclusion . . . . . . . . . . . . . . . . . References .................
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14. Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RB-ILD) and Desquamative Interstitial Pneumonia (DIP) . . . Jay H. Ryu I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Respiratory Bronchiolitis–Associated Interstitial Lung Disease ............................. III. Desquamative Interstitial Pneumonia ............ IV. Conclusions .............................. References ............................... 15. Acute Interstitial Pneumonia (AIP) ................... Jason Vourlekis and Kevin K. Brown I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Historical Perspective and Current Case Definition .. III. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. Differential Diagnosis and Management .......... VII. Survival ................................. VIII. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ............................... 16. Lymphocytic Interstitial Pneumonia (LIP) and Other Pulmonary Lymphoproliferative Disorders . . . . . . . . . . . . . . . . . . . . . . . Michael N. Koss and Hidenobu Shigemitsu I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. LIP .................................... III. NLH of the Lung .......................... IV. Follicular Bronchitis/Bronchiolitis . . . . . . . . . . . . . . . V. Giant Lymph Node Hyperplasia (Castleman Disease) ........................ VI. Posttransplant Lymphoproliferative Disorders ...... References ...............................
379 379 380 382 385 385 389 389 389 390 392 392 394 395 397 397 403 403 405 413 416 418 420 421
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17. Connective-Tissue Disease-Associated Interstitial Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H. Nunes, Y. Uzunhan, D. Valeyre, P. Y. Brillet, M. Kambouchner, and A. U. Wells I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. General Concepts in CTDS-ILD . . . . . . . . . . . . . . . . III. Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . V. Sjögren’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . VI. Polymyositis/Dermatomyositis . . . . . . . . . . . . . . . . . VII. Systemic Lupus Erythematosus . . . . . . . . . . . . . . . . . VIII. Mixed Connective Tissue Disease and Overlap Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ............................... 18. Other Pleuropulmonary Complications of Connective Tissue Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Charlie Strange I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . III. Systemic Lupus Erythematosus . . . . . . . . . . . . . . . . . IV. Polymyositis/Dermatomyositis . . . . . . . . . . . . . . . . . V. Systemic Sclerosis (Scleroderma) ............... VI. Sjögren’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . VII. Lung Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. Relapsing Polychondritis ..................... IX. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ...............................
429 429 430 434 441 448 453 462 465 466 487 487 487 494 496 497 499 500 500 501 501
BRONCHIOLAR DISORDERS 19. Cryptogenic Organizing Pneumonia and Other Causes of Organizing Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . Romain Lazor, Vincent Cottin, and Jean-Franc¸ois Cordier I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Mechanisms of Intra-Alveolar Organization and Fibrosis, and its Resolution . . . . . . . . . . . . . . . . VI. Clinical and Imaging Characteristics . . . . . . . . . . . . . VII. Histopathological Diagnosis . . . . . . . . . . . . . . . . . . . VIII. Clinicopathological Diagnosis . . . . . . . . . . . . . . . . . . IX. Differential Diagnosis .......................
505 505 505 506 506 507 509 512 513 514
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Contents X. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI. Clinical Course and Outcome . . . . . . . . . . . . . . . . . . References ............................... 20. Obliterative Bronchiolitis: Classification, Causes and Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Venerino Poletti, Gianluca Casoni, Maurizio Zompatori, Angelo Carloni, and Marco Chilosi I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Anatomy and Definition . . . . . . . . . . . . . . . . . . . . . . III. Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Radiographic Findings . . . . . . . . . . . . . . . . . . . . . . . V. Pulmonary Function Impairment ............... VI. Specific Clinicopathologic Forms of Diseases Involving the Small Conducting and/or Transitional Airways . . . References ............................... 21. Obliterative Bronchiolitis Following Lung or Heart-Lung Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Geert M. Verleden, Lieven J. Dupont, Bart M. Vanaudenaerde, Robin Vos, and E. M. Van Raemdonck I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Prevalence and Clinical Presentation of OB/BOS . . . . III. Pathology of Chronic Rejection ................ IV. Risk Factors for Chronic Rejection . . . . . . . . . . . . . . V. Pathophysiology of BOS . . . . . . . . . . . . . . . . . . . . . . VI. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ............................... 22. Pulmonary Complications of Bone Marrow Transplantation . Bekele Afessa and Steve G. Peters I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Noninfectious Pulmonary Complications . . . . . . . . . . References ............................... 23. Pulmonary and Airway Complications Related to September 11th . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David J. Prezant, Stephen Levin, and Thomas K. Aldrich I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. World Trade Center Cough Syndrome . . . . . . . . . . . . III. Chronic Rhinosinusitis and Reactive Upper Airways Dysfunction Syndrome ................
xxi 515 516 517 525 525 526 526 529 532 532 540 543 543 544 546 547 548 549 551 553 554 559 559 560 569 573 573 574 578
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Contents IV. Gastroesophageal Reflux Disease . . . V. Asthma and Reactive (Lower) Airways Dysfunction Syndrome . . . . . . . . . . . VI. Interstitial Lung Diseases . . . . . . . . . VII. Diagnostic Evaluation . . . . . . . . . . . VIII. Treatment . . . . . . . . . . . . . . . . . . . . References ...................
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VASCULITIS 24. Pathogenesis and Epidemiology of ANCA-Associated Vasculitides . . . . . . . . . . . . . . . . . . . . . . . J. Charles Jennette and Ronald J. Falk I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Pathology of ANCA-Associated Vasculitis . . . . . . . . . IV. ANCA Serology ........................... V. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. Immunogenesis of the ANCA Autoimmune Response . VII. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ............................... 25. Wegener’s Granulomatosis . . . . . . . . . . . . . . . . . . . . . . . . . . Francisco Silva, Joseph P. Lynch, III, Michael C. Fishbein, and Ulrich Specks I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Historic Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. Specific Organ Manifestation . . . . . . . . . . . . . . . . . . VII. Laboratory Features ........................ VIII. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ............................... 26. Churg-Strauss Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Philippe Guilpain, Christian Pagnoux, and Loı¨c Guillevin I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Pathogenesis and Triggering Factors . . . . . . . . . . . . . III. Systemic Manifestations of CSS and Diagnosis . . . . . . IV. Pulmonary Manifestations of CSS . . . . . . . . . . . . . . . V. CSS Natural History, Classifications, and Phenotypes . VI. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
591 591 592 593 594 595 599 600 601 605 605 606 606 607 607 609 618 618 619 629 643 643 644 645 647 649 650
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Contents VII. Conclusion References
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27. Microscopic Polyangiitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alan D. Salama and Charles D. Pusey I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . V. The Spectrum of Lung Disease . . . . . . . . . . . . . . . . . VI. Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Disease Outcome and Relapse . . . . . . . . . . . . . . . . . VIII. Conclusions .............................. References ...............................
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28. Anti-GBM Antibody Disease (Goodpasture’s Syndrome) Ralph J. Panos and Paul Biddinger I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . II. Background: Basement Membrane and Type IV Collagen . . . . . . . . . . . . . . . . . . III. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . IV. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . V. Clinical Manifestations . . . . . . . . . . . . . . . . . . VI. Imaging Studies . . . . . . . . . . . . . . . . . . . . . . . VII. Laboratory Studies .................... VIII. Histopathology . . . . . . . . . . . . . . . . . . . . . . . IX. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . X. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . References ..........................
657 657 658 660 661 665 666 666 667
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29. Behc¸et’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rula A. Hajj-Ali and Carol A. Langford I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Diagnosis and Clinical Features . . . . . . . . . . . . . . . . VI. Pulmonary Manifestations .................... VII. Imaging Techniques in the Evaluation of Behçet’s-Related Pulmonary Disease . . . . . . . . . . . . . VIII. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ...............................
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ORPHAN LUNG DISEASES 30. Eosinophilic Pneumonias and Syndromes . . . . . . . . . . . . . . . Vincent Cottin, Romain Lazor, and Jean-Franc¸ois Cordier I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. The Eosinophil Leukocyte . . . . . . . . . . . . . . . . . . . . III. Histopathology of Eosinophilic Pneumonia ........ IV. Diagnosis of Eosinophilic Pneumonia . . . . . . . . . . . . V. Eosinophilic Lung Diseases of Determined Origin ... VI. Eosinophilic Pneumonia of Undetermined Origin . . . . References ............................... 31. Langerhans Cell Histiocytosis . . . . . . . . . . . . . . . . . . . . . . . . Robert Vassallo, Rajesh Patel, and Marie Christine Aubry I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Epidemiological Features . . . . . . . . . . . . . . . . . . . . . III. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Histological Characteristics ................... V. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. Pulmonary Function Impairment ............... VII. Radiographical Imaging . . . . . . . . . . . . . . . . . . . . . . VIII. Lung Biopsy and Bronchoalveolar Lavage . . . . . . . . . IX. Diagnostic Approach and Differential Diagnosis .... X. Clinical Outcomes and Prognosis . . . . . . . . . . . . . . . References ............................... 32. Lymphangioleiomyomatosis Francis X. McCormack I. Introduction . . . . . II. Discovery in LAM . III. Clinical Features . . IV. Special Issues . . . . V. Treatment . . . . . . . VI. Future Directions . References ......
707 707 707 709 709 710 715 726 733 733 733 734 735 738 739 739 740 740 742 743
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33. Pulmonary Alveolar Proteinosis . . . . . . . . . . . . . . . . . . . . . . Tisha Wang, S. Samuel Weigt, Michael C. Fishbein, and Joseph P. Lynch, III I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Pulmonary Function Tests . . . . . . . . . . . . . . . . . . . .
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Contents V. VI. VII. VIII. IX. X. XI. XII. XIII.
xxv Laboratory Studies ........... Histopathological Features . . . . . . Radiographic Features . . . . . . . . . Natural History and Clinical Course Pathogenesis . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . Exogenous GM-CSF . . . . . . . . . . Aerosolized GM-CSF ......... Other Therapies ............. References .................
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34. Pulmonary and Tracheobronchial Involvement with Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John L. Berk I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Primary Systemic (AL) Amyloidosis . . . . . . . . . . . . . IV. Secondary Amyloidosis (AA) . . . . . . . . . . . . . . . . . . V. Familial Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . VI. Senile Systemic Amyloidosis . . . . . . . . . . . . . . . . . . . VII. Dialysis-Related Amyloidosis . . . . . . . . . . . . . . . . . . VIII. Localized Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . References ............................... 35. Drug-Induced Pulmonary Disorders . . . . . . . . . . . . . . . . . . . Fabien Maldonado and Andrew H. Limper I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Chemotherapeutic Agents . . . . . . . . . . . . . . . . . . . . . IV. Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Cardiovascular Medications . . . . . . . . . . . . . . . . . . . VI. Anti-inflammatory Medications . . . . . . . . . . . . . . . . . VII. Illicit Drugs .............................. VIII. Conclusions .............................. References ............................... Index
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823
771 771 773 774 775 778 779 780 780 781 789 789 789 791 796 797 799 799 801 804 809 809 810 811 817 818 819 820 821 821
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1 Approach to the Diagnosis of Diffuse Parenchymal Lung Disease
HAROLD R. COLLARD Department of Medicine, University of California, San Francisco, San Francisco General Hospital, San Francisco, California, U.S.A.
TALMADGE E. KING, JR. Department of Medicine, University of California, San Francisco, San Francisco, California, U.S.A.
I.
Introduction
Despite our detailed knowledge of the various causes of diffuse parenchymal lung diseases (DPLD), diagnosis and classification of the disease in an individual patient remain a challenge in clinical practice (Table 1) (1–3). There are several likely reasons. First, DPLD is rare, and many providers feel uncomfortable with and inexperienced in their diagnostic approach. Second, accurate diagnosis requires knowledge beyond the field of medicine; expertise in radiology and pathology is essential. This mandates close collaboration with colleagues, which adds clinical and logistical complexity (4,5). Third, some providers continue to have a nihilistic approach to DPLD, believing that a specific diagnosis is of limited importance since prognosis and treatment response are thought to be universally poor. II.
Significance of an Accurate Diagnosis
An accurate diagnosis of DPLD is important to the management of patients. Prognosis, attention to extrapulmonary manifestations and comorbidities, choice of medication, and consideration for lung transplantation all depend on the 1
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Table 1 Selected Causes of DPLD Idiopathic interstitial pneumonia Idiopathic pulmonary fibrosis Nonspecific interstitial pneumonia Cryptogenic organizing pneumonia Desquamative interstitial pneumonia Respiratory bronchiolitis–associated interstitial lung disease Lymphocytic interstitial pneumonia Acute interstitial pneumonia
Connective tissue–associated DPLD Rheumatoid arthritis Systemic sclerosis Systemic lupus erythematosus Polymyositis/dermatomyositis Mixed connective tissue disease Undifferentiated connective tissue disease Sjogren’s syndrome Behcet’s syndrome Ankylosing spondylitis
Pneumoconiosis Selected exposures: silica, asbestos, hard metals, coal, beryllium, aluminum Hypersensitivity pneumonitis Selected exposures: animal proteins (pigeons, parakeets, budgerigars, chickens, rats), fungi and bacteria (numerous), chemicals (isocyanates, pesticides) Drug-induced DPLD Selected medications: nitrofurantoin, methotrexate, amiodarone, sulfasalazine, phenytoin, bleomycin, interferon-a, multiple chemotherapeutic agents, radiation Systemic diseases associated with DPLD Sarcoidosis Vasculitis Amyloidosis Immune deficiency (hypogammaglobulinemia, common variable immunodeficiency) Genetic diseases associated with DPLD Hermansky-Pudlak syndrome Tuberous sclerosis Neurofibromatosis Familial pulmonary fibrosis Other Chronic eosinophilic pneumonia Acute eosinophilic pneumonia Lymphangioleiomyomatosis Langerhans’ cell histiocytosis Idiopathic pneumonia syndrome Inflammatory bowel disease Cryoglobulinemia Primary biliary cirrhosis
Abbreviation: DPLD, diffuse parenchymal lung disease.
accurate diagnosis and staging of the disease. For example, making the diagnosis of idiopathic pulmonary fibrosis (IPF) portends a distinctly poor prognosis, should trigger evaluation for common comorbidities such as gastroesophageal reflux (GER) disease, acute exacerbations, and pulmonary hypertension, strongly influences one’s decision of pharmacotherapy, and mandates prompt evaluation for lung transplantation in appropriate cases. Alternatively, a diagnosis of connective tissue disease (CTD)-related DPLD requires aggressive anti-inflammatory therapy coordinated with the patient’s rheumatologist. The diagnosis of chronic hypersensitivity pneumonitis (HP) should prompt a careful search of the home and work environments for potential causative exposures. These are just a few examples of
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Figure 1 Diagnostic algorithm for approach to diffuse parenchymal lung diseases. Abbreviations: DPLD, diffuse parenchymal lung disease; H&P, history and physical examination; PFTs, pulmonary function tests; HRCT, high-resolution computed tomography; Dx, diagnosis.
why a systematic and rigorous approach to making a diagnosis in DPLD is essential. III.
General Diagnostic Methods
A number of procedures and tests are relevant to the diagnosis of DPLD. No algorithm is perfect, but a general approach is outlined in Figure 1. Below is a description of the specific components of the evaluation of DPLD and a discussion of the authors’ approach to their application. A.
History and Physical Examination
A detailed history and physical examination is essential to the evaluation of the patient with DPLD and should be routine (Table 2). The presentation of patients with DPLD usually follows several common patterns. The patient presents because of the onset of progressive breathlessness with exertion (dyspnea) or with a persistent nonproductive cough. In most instances, the patient has
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Table 2 Focused History Questions for DPLD Connective tissue disease If you have even been told you have the following conditions, answer ‘‘Yes’’ and give the year diagnosed. A. Rheumatoid arthritis & Yes & No B. Scleroderma, systemic sclerosis, or CREST & Yes & No syndrome C. Systemic lupus erythematosus & Yes & No D. Polymyositis or dermatomyositis & Yes & No E. Sjogren’s syndrome & Yes & No If you experience any of the symptoms listed below, please answer ‘‘Yes’’ and provide an approximate date the symptom started. A. Fatigue & Yes & No B. Joint stiffness, pain, or swelling & Yes & No Joints involved: & Hands/wrists & Shoulders & Knees & Ankles/feet & Other: __________ C. Difficulty swallowing or food getting stuck & Yes & No in your throat D. Persistently dry eyes or dry mouth & Yes & No E. Pain or color change (white/red) in fingers & Yes & No with cold weather F. Weight loss & Yes & No G. Heartburn, reflux, or sour taste in mouth & Yes & No after eating H. Rash & Yes & No I. Ulcers in the mouth or vagina & Yes & No Family history Does anyone in your family have a history of pulmonary fibrosis (lung scarring)? Does anyone in your family have a history of autoimmune disease (for example, rheumatoid arthritis, lupus, scleroderma)?
& Yes
& No Who: ______
& Yes
& No Who: ______
Environmental history The following questions ask about specific exposures you may have had in your environment. If you were REGULARLY OR REPEATEDLY EXPOSED to any of the following, answer ‘‘Yes.’’ A. Humidifier & Yes & No B. Air cleaner/purifier & Yes & No C. Steam sauna/steam shower & Yes & No D. Indoor hot tub & Yes & No (Continued )
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Table 2 (Continued ) E. Swamp cooler & Yes & No F. Water damage or mold/mildew in the home & Yes & No G. Asbestos & Yes & No H. Down pillows or comforters & Yes & No I. Dogs, cats, rabbits, gerbils, hamsters, & Yes & No or guinea pigs Kind: _____________ J. Pigeons, parakeets, or other birds & Yes & No Kind: _____________ Abbreviation: DPLD, diffuse parenchymal lung disease.
attributed the insidious onset of breathlessness with exertion to aging, deconditioning, obesity, or a recent upper respiratory tract illness. Other important symptoms and signs include hemoptysis, wheezing, and chest pain. Some cases are identified because of the discovery of interstitial opacities on chest X-ray examination obtained for another reason (preemployment examination). Lung disease may be suspected because of the association with another disease, such as a CTD. Occasionally, DPLD may be suspected following the finding of lung function abnormalities on simple office spirometry. In the vast majority of patients with DPLD, the symptoms and signs are chronic, i.e., months to years. In some, however, they may be acute (days to weeks) or subacute (weeks to months). These latter processes are often confused with atypical pneumonias since many have diffuse radiographic opacities, fever, or relapses of disease activity. Common diseases, such as chronic obstructive pulmonary disease (COPD), heart failure, mycobacterial and fungal disease, can mimic interstitial lung disease (ILD), and must be ruled out. Simple demographics such as the age, gender, and smoking status of the patient are relevant—young women are more likely to have CTD-related DPLD than old men. The history of tobacco use is important since some diseases occur largely among current or former smokers [Langerhans’ cell histiocytosis (LCH), desquamative interstitial pneumonitis (DIP), IPF, and respiratory bronchiolitis (RB)-associated interstitial lung disease (RB-ILD)] or among never or former smokers (sarcoidosis and HP). Active smoking can lead to complications in some processes such as Goodpasture’s syndrome, where pulmonary hemorrhage is more frequent in current smokers. Details of any potential exposure history (occupational, environmental, and medication related) should be recorded: both open-ended (‘‘What do you do in a typical work day?’’) and focused (‘‘Have you ever taken nitrofurantoin?’’) questions should be asked. A chronological listing of the patient’s employment must be sought, including specific duties and known exposures to dusts, gases,
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and chemicals. The degree of exposure, duration, latency of exposure, and the use of protective devices should be elicited. A careful review of systems should focus on connective tissue–related symptoms such as Raynaud’s phenomenon, arthralgia, dysphagia, and sicca symptoms. A family history of DPLD or CTD may suggest an underlying etiology. The physical examination should focus on identifying the extent and severity of disease, and looking for clues to an underlying etiology (e.g., CTD). Oxygen saturation, extent of adventitial sounds on auscultation, and digital clubbing can all suggest extent of disease, but are nonspecific findings. Dry conjunctiva and mucous membranes, telangiectasias, sclerodactyly, joint deformities, and proximal muscle weakness may each suggest CTD-related DPLD. Skin lesions may also suggest sarcoidosis or a systemic vasculitis. Table 3 lists other selected physical examination findings and their associated conditions.
Table 3 Selected Physical Examination Findings Finding
Condition
Head and neck Pigmented maculopapular rash Telangiectasia Loss of nasolabial fold Peridontal disease/dry mucous membrane
Sarcoidosis (lupus pernio variant) Systemic sclerosis Systemic sclerosis Sjogren’s syndrome
Extremities Clubbing Sclerodactyly Digital ulceration Nail bed capillary abnormalities (requires capillaroscopy to visualize) Joint deformity Proximal muscle weakness
CTD (most common in rheumatoid arthritis) Polymyositis
Chest Dry inspiratory (Velcro) crackles Inspiratory squeak Accentuated second heart sound
Nonspecific Nonspecific (described in organizing pneumonia) Nonspecific (suggests pulmonary hypertension)
Miscellaneous Albinism Hypomelanotic macules, angiofibromas
Hermansky-Pudlak syndrome Tuberous sclerosis
Nonspecific (most common in IPF) Systemic sclerosis Systemic sclerosis Systemic sclerosis
Abbreviations: IPF, idiopathic pulmonary fibrosis; CTD, connective tissue disease.
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Approach to the Diagnosis of DPLD IV. A.
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Physiological Testing Pulmonary Function Testing
Complete pulmonary function tests (PFTs), including spirometry, lung volumes, and diffusing capacity, should be obtained in all patients (6). While PFT abnormalities are not specific, documentation of restrictive physiology helps confirm the presence and extent of impairment. Obstructive or mixed physiology can be seen in bronchiolocentric forms of DPLD such as HP, RB-ILD, and sarcoidosis, or in patients with concomitant COPD. A reduction in the diffusing capacity for carbon monoxide (DLCO) is very commonly found but is not specific for a particular type of ILD. The decrease in DLCO is due, in part, to effacement of the alveolar capillary units but more importantly to the extent of mismatching of ventilation and perfusion of the alveoli. Lung regions with reduced compliance due to fibrosis may be poorly ventilated, but still be well perfused. The severity of the DLCO reduction does not correlate well with disease stage. In some ILDs, there can be considerable reduction in lung volumes and/or severe hypoxemia, but normal or only slightly reduced DLCO, especially in sarcoidosis. The presence of moderateto-severe reductions of DLCO in the presence of normal lung volumes should suggest ILD with associated emphysema, pulmonary vascular disease, LCH, or lymphangioleiomyomatosis. Normal or near-normal PFTs can be seen in early disease, with a mild decrease in DLCO often the only abnormality (this is most commonly seen in sarcoidosis and HP). Baseline PFTs also serve as an important comparison for future measurements. Serial PFTs should be performed on the same equipment by the same technician whenever possible. B.
Arterial Blood Gas
Resting arterial blood gas may be normal or reveal hypoxemia (secondary to a mismatching of ventilation to perfusion) and respiratory alkalosis. Carbon dioxide retention is rare and usually a manifestation of far-advanced end-stage disease. Importantly, a normal resting PaO2 (or O2 saturation by oximetry) does not rule out significant hypoxemia during exercise or sleep. Further, although hypoxemia with exercise and sleep is very common, secondary erythrocytosis is rarely observed in uncomplicated ILD. C.
Cardiopulmonary Exercise Testing
Because resting hypoxemia is not always evident and because severe exerciseinduced hypoxemia may go undetected, it is important to consider exercise testing with serial measurement of arterial blood gases (or measurement of oxygen saturation by pulse oximetry). Arterial oxygen desaturation, a failure to decrease dead space appropriately with exercise (i.e., a high VD/VT ratio), and an excessive increase in respiratory rate with a lower than expected recruitment
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of tidal volume provide useful information regarding physiologic abnormalities and extent of disease. D.
6-Minute Walk Test
The 6-minute walk test (6MWT), widely acknowledged as a valuable clinical tool in COPD, is currently under evaluation in ILD and may provide more accurate prognostic information than resting PFTs, especially in patients with IPF (7,8). E.
High-Resolution Computed Tomography
A recent chest X ray should be obtained, and it is important to review all old chest X rays to assess tempo of change in disease activity. However, the widespread availability of high-resolution computed tomography (HRCT) has revolutionized the diagnosis of DPLD. All patients suspected of having DPLD should undergo HRCT with supine, prone, and expiratory images. High-resolution images should be 2 mm or less in collimation and reconstructed using appropriate contrastenhancing algorithms. Prone imaging is essential, as it allows compression atelectasis to be distinguished from early DPLD. Expiratory images may demonstrate air-trapping that was underappreciated on standard inspiratory images. In the proper clinical setting, HRCT can be diagnostic of several common forms of DPLD and can obviate the need for surgical lung biopsy (9). V.
Ancillary Tests
A medical history, physical examination, PFTs, and HRCT should be performed on all patients with suspected DPLD. In many cases, this will provide sufficient data for a diagnosis. In others, the differential diagnosis will require additional ancillary testing. The most common of these procedures are bronchoscopy, serologies, and surgical lung biopsy. A.
Bronchoscopy
Bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy has a limited but important role in the evaluation of patients with DPLD. It remains the most accurate way to rule out infection or malignancy as the etiology of presumed DPLD. This is especially relevant when nontuberculous mycobacterial disease, fungal disease, and lymphangitic spread of malignancy are considerations. Bronchoscopy with transbronchial biopsy has a clear role in the diagnosis of sarcoidosis, with a diagnostic yield of close to 70% if adequate samples are obtained, and in the eosinophilic pneumonias (10–12). Several other findings on BAL can be suggestive of a diagnosis, e.g., lymphocytosis and low CD4/CD8 suggesting HP, a high CD4/CD8 suggesting sarcoidosis (13). While there remains controversy surrounding the role of transbronchial biopsy in other forms
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of DPLD such as IPF, it is generally accepted that a histopathologic diagnosis requires a surgical biopsy (3). B.
Serology
In patients with findings suggestive of CTD disease, autoimmune serologies should be obtained. There are no data to suggest that widespread serologic screening is beneficial. The choice of serological tests should be driven by the suspected underlying condition. In general, antinuclear antibody and rheumatoid factor should be checked, with additional testing for suspected rheumatoid arthritis (anti-cyclic citrillinated peptide antibodies and hand radiographs), scleroderma (scl-70 antibody), Sjogren’s syndrome (SS-A and SS-B antibodies), mixed CTD (RNP antibody), myositis (Jo-1 and PM-1 antibody and aldolase), and vasculitis (antineutrophil cytoplasmic antibodies, antibasement membrane antibody). In cases without a clear diagnosis but suspicion for CTD, the authors suggest sending the entire serological pattern as many of these patients will have undifferentiated CTD (14). C.
Surgical Lung Biopsy
Surgical lung biopsy refers to either a thoracoscopic or open surgical procedure in which a large (approximately 1–2 cm) biopsy is obtained, preferably from all lobes of the biopsied lung. Videoscopic-assisted thoracoscopic surgery is the preferred method in most patients as it has a lower morbidity and mortality. A full discussion of the role of surgical lung biopsy and histopathologic assessment in DPLD is beyond the scope of this chapter (15) (see chap. 4, ‘‘Pathology of Diffuse ILD’’). In general, patients who have undergone the evaluation discussed above without a diagnosis should be considered for surgical lung biopsy. VI. A.
Screening for Common Comorbidities Gastroesophageal Reflux Disease
Patients with DPLD (especially patients with IPF) have a high prevalence of GER (16–19). Several studies have suggested that chronic progressive lung fibrosis may be related to repeated microaspiration of gastric contents over long periods of time (20,21). Episodes of GER tended to occur at night and often extended into the proximal esophagus. Most patients with DPLD and GER did not have typical symptoms of heartburn or regurgitation. Typical radiological manifestations of insidious, chronic, progressive microaspiration-induced lung disease include mild basal pulmonary fibrosis and patchy opacities; bilateral pleural adhesions and pleural thickenings may also be seen. Chronic microaspiration can be proven by methods such as tracheal penetration on barium swallow, radioactivity in the lung on scintigraphy, BAL finding of large numbers of lipid-laden macrophages, or a foreign body reaction on lung biopsy (22,23).
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Pulmonary Hypertension
Pulmonary hypertension is common in patients with advanced fibrotic lung disease and contributes to substantial morbidity and mortality (24–26). A resting pulmonary mean arterial pressure greater than 30 mmHg has been associated with a poor prognosis in patients with IPF. In subjects whose vital capacity (VC) is less than 50% of predicted or whose diffusing capacity (DLCO) falls below 45% of predicted, pulmonary hypertension can be expected (27). Auscultatory finding of a loud pulmonic component of the second heart sound is consistent with the presence of pulmonary hypertension. Right heart catheterization is necessary to diagnose pulmonary hypertension because of the inaccuracy of echocardiography in identifying pulmonary hypertension in this setting. In one study, 48% of patients with pulmonary artery systolic pressure (PASP) 45 mmHg by echocardiography did not have pulmonary hypertension by right heart catheterization (24). In that study, the positive and negative predictive values of an echocardiographic PASP 45 mmHg for the presence of pulmonary hypertension on right heart catheterization in patients with ILD were 60% and 44%, respectively. C.
Obstructive Sleep Apnea
Sleep-disordered breathing is associated with chronic lung diseases. Patients with DPLD have been shown to have nocturnal desaturations and pulmonary hypertension. IPF patients have been shown to have disrupted fragmented sleep, less rapid eye movement (REM) sleep, and nocturnal desaturations during REM sleep (28). The Sleep Apnea Scale of Sleep Disorders Questionnaire and the Epworth Sleepiness Scale Questionnaire are validated screening tools for obstructive sleep apnea (29–31). Subjects identified to be at risk for sleep apnea by their scores on the Sleep Apnea Scale of Sleep Disorders Questionnaire or the Epworth Sleepiness Scale may be referred for nocturnal polysomnography. VII.
Importance of a Multidisciplinary Approach
The diagnosis of DPLD requires expertise across several disciplines: pulmonary medicine, radiology, and pathology. It is essential that clinicians enlist the help of experienced colleagues in other departments when faced with such a patient. When physicians participate in a multidisciplinary discussion of the clinical, radiographic, and pathologic data, the accuracy of the diagnosis improves substantially (5). Whenever possible, cases of suspected DPLD should be discussed by an experienced team in a conference setting where primary data can be reviewed. If this is not possible, clinicians should routinely send their HRCT and surgical lung biopsy slides to expert radiologists and pathologists for consultation. Although there are numerous causes of DPLD, five conditions make up the majority of cases seen by clinicians today: IPF (see chap. 12, ‘‘Idiopathic Pulmonary Fibrosis’’), nonspecific interstitial pneumonitis (NSIP) (see chap. 13,
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‘‘Nonspecific Interstitial Pneumonitis’’), CTD-related DPLD (see chap. 17, ‘‘Collagen Vascular Disease–Associated Pulmonary Fibrosis’’), exposure-related DPLD (see chap. 10–13), and sarcoidosis (see chap. 7, ‘‘Pulmonary Sarcoidosis’’). VIII.
Conclusions
Diffuse lung disease is often a diagnostic challenge for clinicians. An organized and detailed history and physical examination is essential to insure that clues to the etiology of disease are identified. HRCT and full PFTs should be obtained in all suspected cases. If the diagnosis remains unclear, consideration should be given to bronchoscopy, serological evaluation, and surgical lung biopsy. With a thoughtful multidisciplinary approach, almost all cases of DPLD can be accurately classified, providing important insight into prognosis and guidance on treatment. References 1. British Thoracic Society. The diagnosis, assessment and treatment of diffuse parenchymal lung disease in adults. Thorax 1999; 54(suppl 1):S1–S28. 2. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161:646–664. 3. American Thoracic Society/European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165:277–304. 4. Flaherty KR, Andrei A-C, King TE Jr., et al. Idiopathic interstitial pneumonia: do community and academic physicians agree on diagnosis? Am J Respir Crit Care Med 2007; 175:1054–1060. 5. Flaherty KR, King TE Jr., Raghu G, et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med 2004; 170:904–910. 6. Martinez FJ, Flaherty K. Pulmonary function testing in idiopathic interstitial pneumonias. Proc Am Thorac Soc 2006; 3:315–321. 7. Eaton T, Young P, Milne D, et al. Six-minute walk, maximal exercise tests: reproducibility in fibrotic interstitial pneumonia. Am J Respir Crit Care Med 2005; 171:1150–1157. 8. Flaherty KR, Andrei A-C, Murray S, et al. Idiopathic pulmonary fibrosis: prognostic value of changes in physiology and six-minute-walk test. Am J Respir Crit Care Med 2006; 174:803–809. 9. Gotway MB, Freemer MM, King TE Jr. Challenges in pulmonary fibrosis 1: use of high resolution CT scanning of the lung for the evaluation of patients with idiopathic interstitial pneumonias. Thorax 2007; 62:546–553. 10. Koerner SK, Sakowitz AJ, Appelman RI, et al. Transbronchial lung biopsy for the diagnosis of sarcoidosis. N Engl J Med 1975; 293:267–270.
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11. Pesci A, Bertorelli G, Manganelli P, et al. Bronchoalveolar lavage in chronic eosinophilic pneumonia. Analysis of six cases in comparison with other interstitial lung diseases. Respiration 1988; 54(suppl):16–22. 12. Gilman MJ, Wang KP. Transbronchial lung biopsy in sarcoidosis: an approach to determine the optimal number of biopsies. Am Rev Respir Dis 1980; 122:721. 13. American Thoracic Statement: Clinical role of bronchoalveolar lavage in adults with pulmonary disease. Am Rev Respir Dis 1990; 142:481–486. 14. Kinder BW, Collard HR, Koth L, et al. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med 2007; 176:691–697. 15. Collard HR, King TE Jr. The clinical significance of histopathologic subgroups in idiopathic interstitial pneumonia: is surgical lung biopsy essential? Semin Respir Crit Care Med 2001; 22:347–356. 16. Sweet MP, Hoopes C, Golden J, et al. Prevalence of delayed gastric emptying and gastroesophageal reflux in patients with end-stage lung disease. Ann Thorac Surg 2006; 82:1570. 17. Raghu G, Freudenberger TD, Yang S, High prevalence of abnormal acid gastrooesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006; 27:136–142. 18. Tobin RW, Pope CE II, Pellegrini CA, et al. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998; 158:1804–1808. 19. Sweet MP, Patti MG, Leard LE, et al. Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation. J Thorac Cardiovasc Surg 2007; 133:1078–1084. 20. Mays EE, Dubois JJ, Hamilton GB. Pulmonary fibrosis associated with tracheobronchial aspiration. Chest 1976; 69:512–515. 21. Bandla HP, Davis SH, Hopkins NE. Lipoid pneumonia: a silent complication of mineral oil aspiration. Pediatrics 1999; 103:E19. 22. Corwin RW, Irwin RS. The lipid-laden alveolar macrophage as a marker of aspiration in parenchymal lung disease. Am Rev Respir Dis 1985; 132:576–581. 23. Marom EM, McAdams HP, Erasmus JJ, et al. The many faces of pulmonary aspiration. Am J Roentgenol 1999; 172:121–128. 24. Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 2003; 167:735–740. 25. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002; 360:895–900. 26. Nadrous HF, Pellikka PA, Krowka MJ, Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest 2005; 128:2393–2399. 27. Campbell EJ, Harris B. Idiopathic pulmonary fibrosis (clinical conference). Arch Intern Med 1981; 141:771–774. 28. Bye PTP, Issa F, Berthon-Jones M, et al. Studies of oxygenation during sleep in patients with interstitial lung disease. Am Rev Respir Dis 1984; 129:27–32. 29. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991; 14:540–545. 30. Douglass AB, Bornstein R, Nino-Murcia G, The Sleep Disorders Questionnaire. I: Creation and multivariate structure of SDQ. Sleep 1994; 17:160–167. 31. Weaver TE, Laizner AM, Evans LK, et al. An instrument to measure functional status outcomes for disorders of excessive sleepiness. Sleep 1997; 20:835–843.
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2 Thoracic Imaging for Diffuse ILD and Bronchiolar Disorders
JOSEPH P. LYNCH, III Department of Medicine, Division of Pulmonary and Critical Care Medicine, Clinical Immunology and Allergy, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
S. SAMUEL WEIGT and ROBERT D. SUH David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
I.
Introduction
While the chest radiograph (CXR) remains the initial imaging tool for the lungs, high-resolution computed tomography (HRCT) is increasingly used to clarify CXR findings, to detect lung disease in a symptomatic patient with a normal CXR, and to monitor response to treatment and progression of many lung diseases (1,2). Compared with CXR and conventional CT, the primary advantage of HRCT is the high-spatial resolution enabling the detection of structures down to 0.2 to 0.3 mm (2,3). Regarded to be the most important subsegmental lung unit smaller than a lobe or segment, the secondary pulmonary lobule is the smallest anatomical unit regularly visualized at this resolution, and understanding of lobular anatomy is essential to the interpretation of HRCT (3) (Fig. 1). At the level of the secondary pulmonary lobule, the subtending lobular and intralobular acinar bronchioles, and arterioles and interlobular septal veins and lymphatics can all be readily seen in normal and, certainly, in abnormal situations (3). The interlobular septa are typically picked up when abnormally thickened (3,4). The superior ability to assess parenchymal details with HRCT provides a much more accurate assessment of pattern and distribution of diffuse lung disease 13
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Figure 1 In this HRCT of a patient with hydrostatic pulmonary edema, the interlobular septa are thickened by fluid (arrows), outlining the secondary pulmonary lobules. Abbreviation: HRCT, high-resolution computed tomography.
compared with CXR (5). In one study, the accuracy of HRCT was reviewed in 129 patients with a variety of interstitial pneumonias; the positive predictive value was 79% for HRCT diagnosis of cryptogenic organizing pneumonia (COP), 71% for usual interstitial pneumonia (UIP), 65% for acute interstitial pneumonia (AIP), 63% for desquamative interstitial pneumonia (DIP), but only 9% for nonspecific interstitial pneumonia (NSIP) (6). The relatively low diagnostic accuracy for NSIP may be due to the lack of established CT features for NSIP at the time of the study and a relatively higher number of atypical UIP patients in their studied population (7). More recently, HRCT has been used to substantiate a diagnosis of idiopathic pulmonary fibrosis (IPF) even in the absence of a surgical lung biopsy; in a prospective study, the positive predictive value of a confident CT diagnosis of UIP was 96% (8). The diagnostic approach for diffuse parenchymal lung diseases using HRCT is based on several patterns of abnormalities and the zonal distribution of the disease. The basic patterns of diffuse lung disease seen on HRCT include reticular patterns, nodular patterns, cystic patterns, and altered parenchymal attenuation. The reticular pattern describes thickened interlobular and intralobular septa. The nodular pattern describes airspace and interstitial nodules that are further classified based on their distribution. Perilymphatic nodules are typically patchy in distribution, found in the interlobular septa and interlobar fissures, as well as in the subpleural location. Perivascular nodules are typically diffuse in distribution and are the result of hematogenous dissemination. Centrilobular nodules can be patchy or diffuse, surround small vessels, and spare the subpleural region. The ‘‘tree-in-bud’’ pattern describes centrilobular nodules correlating with inflammatory infiltration of bronchiolar walls or the intrabronchiolar accumulation of mucus or pus. A cystic pattern describes focal regions of low attenuation with well-delineated walls. The distribution of cysts
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can be bronchiectatic (e.g., cystic fibrosis), subpleural (e.g., honeycomb cysts with IPF), or random (e.g., Langerhans cell histiocytosis, lymphangioleiomyomatosis). Altered attenuation typically describes ground glass opacification or mosaic attenuation patterns. Ground glass opacification can be focal or diffuse and describes a veil-like opacification that does not obscure vascular structures or cause air bronchograms. Mosaic attenuation describes variable regions of increased or decreased attenuation due to regional differences in perfusion or ventilation. Along with associated findings and the clinical history, these basic HRCT patterns and combinations of patterns can be useful in narrowing the differential diagnosis of diffuse lung diseases, some of which are described below.
II.
Idiopathic Interstitial Pneumonias
In 2002, The American Thoracic Society (ATS) and European Respiratory Society (ERS) published a classification schema recognizing seven idiopathic interstitial pneumonias (IIPs) (9) (Table 1). These IIPs have disparate clinical expression and prognosis and will be discussed individually. A.
Usual Interstitial Pneumonia
UIP is not only a distinct histological pattern observed in IPF (10,11), but can also be found in other etiologies [e.g., collagen vascular diseases (CVDs), asbestosis, and diverse occupational, environmental, or drug exposures] (10,12). The term IPF refers to a distinct clinical syndrome in patients with idiopathic UIP; IPF is the most common of the IIPs (accounting for 50–70% of IIPs) (10,12). The characteristic CT features of UIP are shown in Table 1 Classification of IIPs Histological pattern
Clinical-radiologic-pathologic diagnosis
Usual interstitial pneumonia
Idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis Nonspecific interstitial pneumonia (provisional) Cryptogenic organizing pneumonia Acute interstitial pneumonia Respiratory bronchiolitis–associated interstitial lung disease Desquamative interstitial pneumonia Lymphocytic interstitial pneumonia
Nonspecific interstitial pneumonia Organizing pneumonia Diffuse alveolar damage Respiratory bronchiolitis Desquamative interstitial pneumonia Lymphocytic interstitial pneumonia
Abbreviation: IIPs, idiopathic interstitial pneumonias. Source: Adapted from Ref. 9.
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Table 2 HRCT Features of UIP Patchy, heterogeneous involvement Predilection for peripheral (subpleural) and basilar regions Reticular abnormality (intralobular and interlobular septal lines) Honeycomb change Architectural distortion Bronchiectasis and bronchiolectasis Ground glass opacities may be present but are not prominent Abbreviations: HRCT, high-resolution computed tomography; UIP, usual interstitial pneumonia.
Figure 2 HRCT of a patient with IPF demonstrating classic features including heterogeneous involvement with reticulation, architectural distortion, and honeycomb changes with a paucity of ground glass opacities. The black arrows indicate traction bronchiectasis. Abbreviations: HRCT, high-resolution computed tomography; IPF, idiopathic pulmonary fibrosis.
Table 2 (2,13,14) (Figs. 2 and 3). Ground glass opacities (GGO) may be present in UIP, but are never the dominant feature (2,13). Extensive GGO suggest an alternative diagnosis [e.g., DIP, NSIP, or hypersensitivity pneumonitis (HP)] (13). Honeycomb change (HC) is often a prominent feature in UIP, but is uncommon in other IIPs (2,9,14). Zones of emphysema (typically in the upper lobes) may be present in smokers (15,16). Mediastinal lymphadenopathy occurs in 55% to 71% of patients with UIP, but is nonspecific (17–19). When CT features are ‘‘classical’’ for UIP, the accuracy of a confident diagnosis by CT by experienced observers is 90% to 100% (12,14,17,20,21). In this context, surgical biopsy is not warranted. However, less than two-thirds of patients with histological UIP display classical features of UIP on CT (2,12–14,22). In these patients, surgical lung biopsies should be performed to substantiate a specific histological diagnosis (2,12,14). B.
Nonspecific Interstitial Pneumonia
NSIP may occur in the context of underlying disease (e.g., CVD, drug-induced pneumonitis, HP) or in the idiopathic form (9,23,24). HRCT findings typically
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Figure 3 HRCT demonstrating classic UIP features including marked honeycomb changes with a subpleural and bibasilar predilection in a patient with systemic sclerosis. Abbreviations: HRCT, high-resolution computed tomography; UIP, usual interstitial pneumonia. Table 3 HRCT Features of NSIP Ground glass opacities prominent (76–100%) Predilection for peripheral (subpleural) and basilar regions Consolidation (16–80%) Reticular abnormality (46–93%) Nodules (0–18%) Honeycomb change (0–30%) Bronchiectasis and bronchiolectasis Abbreviations: HRCT, high-resolution computed tomography; NSIP, nonspecific interstitial pneumonia.
include both reticular and ground glass patterns, with a subpleural and basilar predominance (6,25,26). The salient CT features of NSIP are listed in Table 3 (6,24,26,27). The cardinal features discriminating NSIP from UIP are more GGO and minimal HC in NSIP (24,27) (Fig. 4). However, there is considerable overlap in radiographic features of UIP and NSIP (12,14,20,28), and distinguishing between
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Figure 4 HRCT of a patient with biopsy-proven NSIP demonstrating predominantly subpleural bilateral patchy ground glass opacities and reticulation with no significant honeycomb changes. Abbreviation: HRCT, high-resolution computed tomography. Table 4 HRCT Features of AIP Ground glass opacities prominent Consolidation (diffuse) Lung architecture preserved Honeycomb change absent (early stages) Reticulation, architectural distortion (late) Abbreviations: HRCT, high-resolution computed tomography; AIP, acute interstitial pneumonia.
the two requires a histopathologic diagnosis (21,27). Further, CT features of NSIP overlap with multiple inflammatory and infectious etiologies (13). C.
Desquamative Interstitial Pneumonia
DIP is a rare disease of smokers characterized by alveolar filling with pigmented (smoker’s) macrophages (29–32). The cardinal CT feature of DIP is GGO, reflecting macrophages filling the alveolar spaces (31–33) (Table 4, Fig. 5). Similar to UIP, DIP exhibits a proclivity for the subpleural and lower lung zones (6,33–35). Reticular abnormalities and subpleural nodules can occur, but are not the dominant HRCT patterns (6,33,34,36). Well-defined cysts within areas of GGO may be observed in DIP (33,35,36). With smoking cessation or corticosteroid therapy, GGO usually improve but progression to a reticular pattern can occur (31,32,36). D.
Respiratory Bronchiolitis–Associated Interstitial Lung Disease
Respiratory bronchiolitis–associated interstitial lung disease (RB-ILD), also observed primarily in smokers, is characterized by intraluminal collections of
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Figure 5 HRCT images demonstrating prominent ground glass opacities without architectural distortion in a patient with DIP. Abbreviations: HRCT, high-resolution computed tomography; DIP, desquamative interstitial pneumonia.
Figure 6 HRCT of a patient with RB-ILD showing a mosaic pattern, thickened bronchi, and centrilobular nodules best appreciated in the magnified view. Abbreviations: HRCT, highresolution computed tomography; RB-ILD, respiratory bronchiolitis–associated interstitial lung disease.
pigmented macrophages within the respiratory bronchioles and alveolar ducts; the distal lung parenchyma is spared (30–32,34,37–39). Cardinal CT features include 2- to 3-mm centrilobular nodules, thickening of the walls of central and peripheral airways, GGO, mosaic attenuation (reflecting air trapping), and centrilobular emphysema (31,34,37,39,40) (Table 4, Fig. 6). The extent of centrilobular nodules correlates with the degree of macrophage accumulation and inflammation in respiratory bronchioles (39–41). Patchy GGO is present in 50% to 75% of cases and reflects macrophage accumulation within alveolar
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Table 5 HRCT Features of DIP and RB-ILD DIP GGO prominent Subpleural distribution Lung architecture preserved Honeycomb change absent or minimal Cysts may develop in areas of GGO RB-ILD Thickened central and proximal bronchi Centrilobular nodules Focal GGO Mosaic pattern (air trapping) Centrilobular emphysema (upper lobes) Reticular or fibrotic change uncommon Abbreviations: DIP, desquamative interstitial pneumonia; RB-ILD, respiratory bronchiolitis–associated interstitial lung disease; GGO, ground glass opacities. Source: Adapted from Refs. 31, 34, and 39.
ducts and spaces (39,41,42). Intralobular lines, traction bronchiectasis, and peripheral reticular or HC are observed in a minority of patients, and reflect fibrosis involving the alveolar septa (31,39,40). Centrilobular nodules and GGO may improve or resolve with smoking cessation but reticular or emphysematous changes persist (37,39,40,43). E.
Acute Interstitial Pneumonia
AIP is the most fulminant of the IIPs, generally progressing to fatal respiratory failure within days to weeks (44–46). CXRs in AIP reveal bilateral airspace opacification with sparing of the costophrenic angles (44–46). Salient CT features include extensive GGO (75–100%), areas of consolidation (29–92%), patchy geographical distribution, and preserved lung architecture (44–46) (Table 5, Fig. 7). In later stages, architectural distortion, traction bronchiectasis, reticulation, and HC may develop (6,45). Patients who survive may heal with variable degrees of fibrosis (44,46). F.
Lymphocytic Interstitial Pneumonia
Lymphocytic interstitial pneumonia (LIP) is a benign disorder most commonly associated with CVD (particularly Sj€ ogren’s syndrome), Castleman’s disease, and diverse autoimmune and immunodeficiency states (including HIV infection) (47–49). Salient CT features of LIP include GGO (100%), centrilobular nodules (86%), interlobular septal thickening (93%), thickened bronchovascular bundles (93%), air cysts (71%), lymph node enlargement (71%), architectural
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Figure 7 HRCT images demonstrating diffuse patchy involvement of ground glass opacities, consolidation, and reticulation in a patient with AIP. Abbreviations: HRCT, high-resolution computed tomography; AIP, acute interstitial pneumonia. Table 6 HRCT Features of LIP (22 cases) Ground glass opacities (100%) Centrilobular nodules (100%) Thickening bronchovascular bundles (86%) Thickening interlobular septa (82%) Cystic airspaces (68%) Lymph node enlargement (68%) Airspace consolidation (41%) Architectural distortion (36%) Honeycomb change (5%) Abbreviations: HRCT, high-resolution computed tomography; LIP, lymphocytic interstitial pneumonitis. Source: Adapted from Ref. 51.
distortion (36%), and airspace consolidation (29%) (50–52) (Table 6, Fig. 8). LIP exhibits a predilection for bronchovascular bundles, interlobular septa, and pleura (50,53). Areas of GGO or centrilobular nodules reflect diffuse alveolar septal or peribronchiolar infiltrates with lymphocytes and plasma cells, respectively (50).
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Figure 8 HRCT of a patient with LIP demonstrating cystic airspaces (A), ground glass opacities, thickened bronchovascular bundles, and centrilobular nodules (B). Abbreviations: HRCT, high-resolution computed tomography; LIP, lymphocytic interstitial pneumonia. Table 7 Discriminating LIP from Malignant Lymphoma CT feature Cysts Airspace consolidation Nodules (>10-mm diameter) Masses (>30-mm diameter) Pleural effusion Mediastinal lymphadenopathy
LIP (n ¼ 17) (%) 82 18 6 6 0 71
Malignant lymphoma (n ¼ 44) (%) 2 66 41 11 25 59
p value <0.0001 <0.001 <0.005 NS <0.05 NS
Abbreviation: LIP, lymphocytic interstitial pneumonitis. Source: Adapted from Ref. 55.
Cysts likely reflect airway obstruction caused by peribronchiolar lymphocytic infiltration (50). Peribronchovascular and subpleural cystic airspaces may be observed in up to two-thirds of patients and may progress over time (49,51,54). Honeycomb cysts are uncommon (5–20%) (49–51) but may develop in areas of prior consolidation (50). In a study of 14 patients of LIP who had serial CT scans, 9 improved, 4 worsened, and 1 remained stable (50). Many parenchymal abnormalities were reversible (50). However, cysts or architectural distortion either worsened or did not change on follow-up (50). Additional cysts often developed in areas where centrilobular nodules had been present on initial CT scans. CT scans may help differentiate benign from malignant lymphoid proliferations (55). In a study of 17 patients with LIP and 44 with malignant lymphoma, marked differences in the prevalence of certain CT findings were noted (55). Cysts were found in 82% of patients with LIP (82%) but only 2% with lymphomas. Other differences are shown in Table 7 (55).
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Cryptogenic Organizing Pneumonia
COP typically reveals patchy alveolar infiltrates or consolidation on CXRs, often with air bronchograms, mimicking community-acquired pneumonia (56,57). A reticulonodular pattern has been noted in 15% to 30% (56–58). Cardinal CT findings include focal peripheral alveolar opacities with striking air bronchograms (56–60) (Fig. 9A,B). Salient CT features are shown in Table 8 (6,59–65). An unusual feature noted in COP is dense crescentic or ring-shaped opacities surrounding areas of GGO (64,66). This sign has been termed the ‘‘reversed halo sign’’ (64). Histologically, the GGO correspond to alveolar septal inflammation and cellular debris within airspaces, whereas the ring-shaped peripheral opacities correspond to organizing pneumonia within alveolar ducts (66). In a retrospective study, the ‘‘reversed halo sign’’ was present in 6 of 31 (19%) patients with COP, but was never observed in 30 patients with other diagnoses (64). CT features of COP overlap with chronic eosinophilic pneumonia (CEP), but the presence or absence of certain CT features can assist in differentiating these
Figure 9 HRCT images before and after corticosteroid treatment for COP. The pretreatment images (A,B) show a focal alveolar opacity with air bronchograms. A follow-up HRCT posttreatment (C,D) shows near complete resolution of the previous findings. Abbreviations: HRCT, high-resolution computed tomography; COP, cryptogenic organizing pneumonia.
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Table 8 HRCT Features of COP Dense consolidation with air bronchograms (70–91%) Ground glass opacities prominent (60–100%) Peripheral, basilar, and peribronchiolar predominance (>80%) Centrilobular nodules (30–63%) Bronchial dilatation (35–58%) Reticular opacities (15–50%) Reversed halo sign (19%) Honeycomb change (<10%) Abbreviations: HRCT, high-resolution computed tomography; COP, cryptogenic organizing pneumonia. Source: Adapted from Refs. 6, 59, and 61–64.
Table 9 HRCT Features of CEP (40 cases) Airspace consolidation (100%) Ground glass opacities (88%) Peripheral predominance (85%) Nodules (38%) Upper lobe predominance (38%) Bronchial wall thickening (23%) Interlobular septal thickening (18%) Abbreviations: HRCT, high-resolution computed tomography; CEP, chronic eosinophilic pneumonia. Source: Adapted from Ref. 73.
conditions (61) (Table 9). However, the distinction between COP and CEP can be made with confidence in a small percentage of cases. Overall, CT findings in COP are nonspecific and overlap with bronchioloalveolar cell carcinoma (BAC), lymphoma, CEP, and diverse infectious and inflammatory disorders (57). With corticosteroid therapy, HRCT improves in more than 75% of patients (Fig. 9C,D); a reticular pattern tends to be less responsive to treatment than pure consolidation (56,57,67). H.
Chronic Eosinophilic Pneumonia
CEP is a disorder characterized by an abnormal proliferation of eosinophils within the lung (68,69). CXRs reveal patchy subpleural alveolar infiltrates with a predilection for the upper lobes, described as the ‘‘photographic negative’’ of pulmonary edema (69–71). CT demonstrates airspace consolidation in nearly all patients with CEP, with a predilection for the middle and upper lobes and a peripheral distribution (61,71–73) (Fig. 10). GGO are present in >80% of cases
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Figure 10 HRCT demonstrating predominantly peripheral airspace consolidation in a patient with CEP. Abbreviations: HRCT, high-resolution computed tomography; CEP, chronic eosinophilic pneumonia. Table 10 Discriminating COP from CEP CT feature Airspace consolidation Peripheral predominance Peribronchial distribution Bronchial dilatation GGO predominant pattern Nodules predominant pattern Reticular predominant pattern Nodule or mass Nonseptal linear opacities Septal linear opacities
COP (n ¼ 38)
CEP (n ¼ 43)
p value
71% 66% 29% 58% 11% 11% 8% 32% 45% 40%
65% 56% 9% 28% 35% 0% 0% 5% 9% 72%
NS NS <0.05 <0.005 <0.01 <0.05 NS <0.005 <0.005 <0.005
Abbreviations: COP, cryptogenic organizing pneumonia; CEP, chronic eosinophilic pneumonia. Source: Adapted from Ref. 61.
and nodules or linear opacities in 18% to 38% (61,69,73,74) (Table 10). Bronchial dilatation was noted in 4% of CT scans from 40 patients with CEP (50). CEP is uniformly responsive to corticosteroid treatment with prompt resolution of radiographic abnormalities (69,73); however, relapses are common (69,71). III.
Sarcoidosis
Sarcoidosis is a systemic granulomatous disease of an unknown etiology that most commonly involves the lung or intrathoracic lymph nodes (75–77). Characteristic CT findings of sarcoidosis are listed in Table 11 (78–80). Cardinal features are micronodules and macronodules, irregularity and thickening of bronchovascular bundles, a proclivity for upper- and middle-lung zones, GGO, alveolar consolidation or mass-like lesions (76,80) (Figs. 11 and 12). Recently,
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Table 11 HRCT Features of Sarcoidosis Distribution along bronchovascular bundles and lymphatics Middle or upper lung zone predominance Mediastinal or hilar lymphadenopathy Irregularly thickened bronchovascular bundles Small nodules (<3-mm diameter), peribronchial and subpleural Confluent nodular opacities air bronchograms Crowding and retraction vessels near hilum Bronchiectasis and bronchiolectasis With advanced disease, architectural distortion, and cystic destruction Source: Adapted from Ref. 76.
Figure 11 HRCT of a patient with sarcoidosis demonstrating randomly distributed micronodules and macronodules most prominent along the bronchovascular bundles. Abbreviation: HRCT, high-resolution computed tomography.
Figure 12 HRCT demonstrating bilateral parenchymal nodularity with a predominate juxta bronchial distribution (A) and bulky hilar adenopathy (B) in this patient with pulmonary sarcoidosis. Abbreviation: HRCT, high-resolution computed tomography.
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Nakatsu et al. coined the term sarcoid galaxy to describe a large nodule encircled by a rim of numerous tiny satellite nodules (81). This sign was present in 16 of 59 (27%) sarcoid patients (81). Histologically, a sarcoid galaxy refers to conglomerate granulomas that are more concentrated in the center of the lesion. Areas of decreased attenuation (a mosaic pattern) may reflect air trapping due to granulomas in the small airways (80,82). In advanced sarcoidosis, architectural distortion, traction bronchiectasis, volume loss, bullae, honeycomb cysts, and mycetomas may be observed (78–80,83). The distribution of sarcoid in the upper- and middle-lung zones along bronchovascular bundles is in sharp contrast to UIP, which has a predilection for the basilar and subpleural regions (12). In addition, nodularity predominates in sarcoidosis (76), whereas UIP is predominantly reticular (12). Thickened bronchovascular bundles, thickened interlobular septa, and subpleural nodules are also found in lymphangitic carcinomatosis and lymphoma (84). The extent of pulmonary physiological impairment correlates with severity of disease on CXRs or CT scanning, but correlations are imprecise (83,85–89). The pattern of CT may reflect underlying pathology. Specific CT findings (e.g., thickening or irregularity of bronchovascular bundles, intraparenchymal nodules, septal and nonseptal lines, and focal pleural thickening) were correlated with pulmonary functional impairment, whereas other features (e.g., focal consolidations, GGO, or enlarged lymph nodes) were of minor importance (88). Hansell et al. confirmed inverse correlations between a reticular pattern on CT and several physiological parameters (89). Muers et al. noted that reticular and fibrotic abnormalities on CT scan correlated modestly with physiological aberrations, but mass lesions or confluence did not (90). Air trapping (a mosaic pattern) on expiratory CT suggests involvement of small airways (87,91,92). Bronchomalacia in sarcoidosis was recently described based on volumetric expiratory CT images (93). Lenique et al. evaluated 60 sarcoid patients with CT; increased bronchial wall thickness was noted in 65% and 23% had other luminal irregularities (94). These bronchial abnormalities correlated with the presence of mucosal granulomas. Notwithstanding these observations, correlations between CT and physiological parameters are imprecise and direct measurement of pulmonary function tests (PFTs) is necessary to assess the extent of impairment. Akira et al. examined initial and follow-up CT scans in 40 patients with pulmonary sarcoidosis (95). Predominantly nodular or multiple large nodules disappeared or decreased in size at follow-up. A conglomeration pattern shrank and evolved into bronchial distortion and decline in FEV1/FVC ratio. Interestingly, GGO and consolidation evolved into honeycombing in some patients. Because sarcoidosis has the potential to evolve over time, initial CT features have limited prognostic value (76). However, certain CT features have predictive value. Focal nodules, alveolar opacities, consolidation, or GGO suggest an active inflammatory component that may reverse with therapy (76,85,96). In contrast, distortion of lung parenchyma, coarse or linear bands, bronchiectasis, cystic radiolucencies, and bullae reflect irreversible fibrosis (78,79,85,96).
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Hypersensitivity Pneumonia
Radiographic features of HP are variable depending on the phase of the disease (i.e., acute, subacute, or chronic) (97–102) (Table 12). HRCT scans in acute HP reveal GGO and areas of airspace consolidation (99,100) (Fig. 13). The process is usually diffuse and symmetrical, but patchy or asymmetric involvement may occur (100). The cardinal CT feature of subacute HP is small (2–4 mm), poorly defined centrilobular micronodules (99,103). Additional features include GGO, Table 12 HRCT Features of HP Acute HP Diffuse ground glass opacities Airspace consolidation Subacute HP Centrilobular nodules (2–4 mm diameter) Ground glass opacities Predilection for middle or upper lung zone predominance Mosaic pattern (air trapping) Chronic HP Honeycomb change Architectural distortion Micronodules Ground glass opacities Emphysema Abbreviations: HRCT, high-resolution computed tomography; HP, hypersensitivity pneumonitis.
Figure 13 HRCT of a patient with acute HP demonstrating diffuse heterogeneous bilateral ground glass opacities throughout both lungs. Centrilobular nodules can be appreciated best in the magnified image. Abbreviations: HRCT, high-resolution computed tomography; HP, hypersensitivity pneumonitis.
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a predilection for middle and upper lung zones, areas of mosaic attenuation (air trapping) (98,99,103). Cysts were reported in 13% of patients with subacute HP (104). These cysts range in size from 3 to 25 mm in diameter, and presumably are due to partial bronchiolar obstruction by the peribronchiolar lymphocytic infiltrate in HP (104). The salient CT features of chronic HP include reticular pattern, traction bronchiectasis and bronchiolectasis, and architectural distortion (50%); HC (50%); GGO (57–71%); micronodules (32–42%); and emphysema (40–50%) (98–100,102,105,106). These CT features mimic UIP/IPF, but micronodules and extensive GGO are lacking in UIP (105). Further, honeycombing and lower lobe predominance, cardinal features of UIP, are found in a minority of patients with HP (96,105–107). V.
Pulmonary Alveolar Proteinosis
Pulmonary alveolar proteinosis (PAP), a rare autoimmune disorder caused by antibodies to granulocyte macrophage colony-stimulating factor (GM-CSF), results in excessive accumulation of surfactant-like material in the alveolar spaces, with resultant defects in gas exchange (108,109). The salient CT feature of PAP is patchy or geographic widespread airspace consolidation; air bronchograms are usually not found (109–113) (Table 13). With less severe cases, CT may reveal GGO without frank consolidation. Although airspace abnormality dominates, interstitial (reticular) patterns may be present (110,112). However, this is usually found only in areas with GGO or consolidation (112). Even with extensive disease, the lung architecture is preserved and fibrosis is uncommon (<10%) (110,114). A geographic pattern is most common, but diffuse or even localized GGO may be observed (110,114). Lower lobes are more often affected (114), but a zonal predominance is not typical of PAP (110,112). The degree of CT abnormalities correlates with impairment in pulmonary function (oxygenation and spirometry) (112). Intrathoracic lymphadenopathy is uncommon in PAP and suggests an alternative diagnosis (e.g., infection or malignancy) (114). Pleural effusions are not a feature of PAP (109,114). Table 13 HRCT Features of PAP Widespread airspace consolidation and ground glass opacities Variable distribution; may be patchy, geographic Crazy paving pattern Air bronchograms usually not present Interstitial (reticular) pattern may be found but not dominant Lung architecture preserved Fibrosis rare Pleural effusions not found Abbreviations: HRCT, high-resolution computed tomography; PAP, pulmonary alveolar proteinosis.
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Figure 14 HRCT image demonstrating thickened interlobular septa against a background of ground glass opacities or a crazy paving pattern in a patient with PAP. Abbreviations: HRCT, high-resolution computed tomography; PAP, pulmonary alveolar proteinosis.
Thickened interlobular septa against the background of GGO or airspace opacities may produce what has been termed ‘‘crazy paving’’ pattern (109,111,114) (Fig. 14). The linear network in the crazy paving pattern may represent thickening of interlobular septa (110,111), accumulation of surfactantlike material in the airspaces adjacent to the septa (115), or combination of intraalveolar and interstitial processes (116). This crazy paving pattern is found in virtually all cases of PAP (111,114), but is nonspecific (116,117). Disorders associated with the crazy paving pattern include BAC (118), acute exacerbation of UIP (116), AIP (116), acute respiratory distress syndrome (ARDS) (116,119), organizing pneumonia (116,120), lipoid pneumonia (121–123), drug-induced or radiation-induced pneumonitis (116), NSIP (124), sarcoidosis (120), leukemias or lymphomas (125), pulmonary alveolar microlithiasis (126), mycosis fungoides (127), pulmonary hemorrhage syndromes (120), infectious causes [particularly Pneumocystis carinii pneumonia (PCP)] (116,120), and others. However, the prevalence of the crazy paving pattern is much higher in PAP. In a review of >500 CT scans, prevalence rates for specific disorders included PAP (100%), DAD superimposed on UIP (67%), AIP (31%), cardiogenic edema (14%), druginduced pneumonitis (12%), pulmonary hemorrhage (9%), CEP (8%), COP (8%), PCP (7%), bacterial and mycoplasma pneumonia (6%), radiation pneumonitis (4%), and tuberculosis (1%) (116). Further, the number of segments involved in PAP is significantly greater than other processes (116). VI.
Pulmonary Langerhans Cell Histiocytosis
Pulmonary Langerhans cell histiocytosis (PLCH) is a rare disease of smokers often presenting as pneumothoraces or dyspnea (128–130). CT scans in PLCH shows numerous thin-walled cystic lesions, typically <10 mm in size; however, cysts may coalesce, sometimes exceeding 5 cm and assume bizarre shapes
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Table 14 HRCT Features of PLCH Numerous, thin-walled cysts; may coalesce Predilection for upper and middle lung zones Peribronchiolar nodules (67–78%) Sparing of costophrenic angles Pleural effusions rare Abbreviations: HRCT, high-resolution computed tomography; PLCH, pulmonary Langerhans cell histiocytosis.
Figure 15 HRCT demonstrating numerous thin-walled cysts in the middle and upper lung zones in a patient with PLCH. Abbreviations: HRCT, high-resolution computed tomography; PLCH, pulmonary Langerhans cell histiocytosis.
(131,132) (Table 14, Fig. 15). In PLCH, the cystic lesions have a proclivity for the upper lobes and spare the costophrenic angles; there is no central or peripheral predominance (128,129,131,133,134). Peribronchial nodules, ranging in size from 1 to 15 mm, are noted in two-thirds of patients with PLCH (131,132,134). The nodules represent peribronchiolar granulomas, whereas cysts represent dilated or destroyed bronchi and airways (130). These cysts or nodules are associated with areas of intervening normal lung parenchyma. Lesions may evolve from nodules to cavitary nodules, to thick-walled and thin-walled cysts (128,130–132). GGO were noted in 3% to 20% of patients with PLCH (129,131,133). GGO may reflect concomitant respiratory bronchiolitis (133). Mediastinal or paratracheal lymphadenopathy on CT is noted in up to one-third of patients (129,135). Pleural effusions are not a feature of PLCH (35,128,131,132).
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Lymphangioleiomyomatosis
Lymphangioleiomyomatosis (LAM) is a rare disorder in women characterized by abnormal proliferation of smooth muscle cells (136). During the course of the disease, pneumothoraces develop in 50% to 80%, chylous effusions in 7% to 39%, focal alveolar hemorrhage in 28% to 40% (137–143). CT features of LAM are highly distinctive and may be virtually pathognomonic (Table 15). Numerous thin-walled cysts, ranging in size from a few millimeter to >6 cm, are present throughout both lungs, with no specific anatomic distribution (138–143) (Fig. 16). The intervening lung parenchyma is normal. Cysts are usually round with well-defined thin walls, but coalescent cysts may result in bizarre shapes (136,139). Nodules, irregular lung-pleural interfaces, or reticular lines are not Table 15 HRCT Features of LAM Innumerable, small thin-walled cysts No specific anatomical distribution Intervening lung parenchyma is normal No nodules, linear lines, or irregular pleural-parenchymal interfaces Ground glass opacities (12–59%) but not dominant feature Pleural effusions (chylous) (21–39%) Pneumothoraces (29–81%) Cysts or angiomyolipomas in abdominal or pelvic organs or lymph nodes (30–80%) Abbreviations: HRCT, high-resolution computed tomography; LAM, lymphangioleiomyomatosis.
Figure 16 HRCT image demonstrating numerous randomly distributed thin-walled cysts in a female patient with LAM. A right-sided pleural effusion (black arrows) is also present and proved to be a chylothorax with thoracentesis. Abbreviations: HRCT, high-resolution computed tomography; LAM, lymphangioleiomyomatosis.
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found in LAM (35). The distribution and nature of these cystic lesions differ from cysts observed in other chronic pulmonary disorders (35). Honeycomb cysts, a prominent feature in UIP and CVD-associated pulmonary fibrosis, are distributed in the peripheral (subpleural) regions and are invariably accompanied by reticulation and distortion of lung parenchyma (20,35). By contrast, LAM is more homogeneous with a random distribution (35). Cysts may be present in DIP and RB-ILD (29–32,34,38), but the predominant findings in those disorders include GGO, with or without peribronchiolar nodules (35). Cystic lesions may be found in LIP (50), but LIP typically demonstrates thickening of interlobular septa and bronchovascular bundles; these features are lacking in LAM (35). In PLCH, the presence of nodules and upper lobe predominantly distinguish this disorder from LAM (35,130,144). Cystic lesions in emphysema lack welldefined walls, whereas cysts in LAM are more regular and have well-formed thin walls (35,142,145). GGO, not cited in early reports of HRCT in LAM (141,142), were noted in 12% (8 of 66) (143) and 59% (22 of 37) (140) patients in two more recent series. Foci of GGO may reflect alveolar hemorrhage, pulmonary hemosiderosis, or diffuse proliferation of smooth muscle cells (139,140). Pleural effusions may reflect chylothorax (137). Mediastinal or intrathoracic lymphadenopathy is unusual in LAM (35,140), but retrocrural adenopathy was noted in 26% of LAM patients in one series (145). Abdominal and pelvic CT scans reveal cysts or angiomyolipomas (AMLs) in kidney, spleen, pelvic organs, or retrocrural or para-aortic lymphadenopathy in 30% to 80% of patients with LAM (139,145–147). Ultrasonography or abdominal CT scans are important to diagnose and follow renal, intra-abdominal, or pelvic cystic or AML lesions (148–150). References 1. Raghu G. Interstitial lung disease: a diagnostic approach. Are CT scan and lung biopsy indicated in every patient? Am J Respir Crit Care Med 1995; 151(3 pt 1): 909–914. 2. Misumi S, Lynch DA. Idiopathic pulmonary fibrosis/usual interstitial pneumonia: imaging diagnosis, spectrum of abnormalities, and temporal progression. Proc Am Thorac Soc 2006; 3(4):307–314. 3. Webb WR. Thin-section CT of the secondary pulmonary lobule: anatomy and the image—the 2004 Fleischner lecture. Radiology 2006; 239(2):322–338. 4. Webb WR. High-resolution computed tomography of the lung: normal and abnormal anatomy. Semin Roentgenol 1991; 26(2):110–117. 5. Grenier P, Valeyre D, Cluzel P, et al. Chronic diffuse interstitial lung disease: diagnostic value of chest radiography and high-resolution CT. Radiology 1991; 179(1): 123–132. 6. Johkoh T, Muller NL, Cartier Y, et al. Idiopathic interstitial pneumonias: diagnostic accuracy of thin-section CT in 129 patients. Radiology 1999; 211(2):555–560. 7. Lynch DA, Godwin JD, Safrin S, et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med 2005; 172(4):488–493.
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64. Kim SJ, Lee KS, Ryu YH, et al. Reversed halo sign on high-resolution CT of cryptogenic organizing pneumonia: diagnostic implications. AJR Am J Roentgenol 2003; 180(5):1251–1254. 65. Bouchardy LM, Kuhlman JE, Ball WC Jr., et al. CT findings in bronchiolitis obliterans organizing pneumonia (BOOP) with radiographic, clinical, and histologic correlation. J Comput Assist Tomogr 1993; 17(3):352–357. 66. Voloudaki AE, Bouros DE, Froudarakis ME, et al. Crescentic and ring-shaped opacities. CT features in two cases of bronchiolitis obliterans organizing pneumonia (BOOP). Acta Radiol 1996; 37(6):889–892. 67. Lee JS, Lynch DA, Sharma S, et al. Organizing pneumonia: prognostic implication of high-resolution computed tomography features. J Comput Assist Tomogr 2003; 27(2):260–265. 68. Allen JN, Davis WB. Eosinophilic lung diseases. Am J Respir Crit Care Med 1994; 150(5 pt 1):1423–1438. 69. Marchand E, Cordier JF. Idiopathic chronic eosinophilic pneumonia. Semin Respir Crit Care Med 2006; 27(2):134–141. 70. Jederlinic PJ, Sicilian L, Gaensler EA. Chronic eosinophilic pneumonia. A report of 19 cases and a review of the literature. Medicine (Baltimore) 1988; 67(3):154–162. 71. Marchand E, Reynaud-Gaubert M, Lauque D, et al. Idiopathic chronic eosinophilic pneumonia. A clinical and follow-up study of 62 cases. The Groupe d’Etudes et de Recherche sur les Maladies ‘‘Orphelines’’ Pulmonaires (GERM‘‘O’’P). Medicine (Baltimore) 1998; 77(5):299–312. 72. Naughton M, Fahy J, FitzGerald MX. Chronic eosinophilic pneumonia. A longterm follow-up of 12 patients. Chest 1993; 103(1):162–165. 73. Johkoh T, Muller NL, Akira M, et al. Eosinophilic lung diseases: diagnostic accuracy of thin-section CT in 111 patients. Radiology 2000; 216(3):773–780. 74. Ebara H, Ikezoe J, Johkoh T, et al. Chronic eosinophilic pneumonia: evolution of chest radiograms and CT features. J Comput Assist Tomogr 1994; 18(5):737–744. 75. Lynch JP III, Kazerooni EA, Gay SE. Pulmonary sarcoidosis. Clin Chest Med 1997; 18(4):755–785. 76. Lynch JP III. Computed tomographic scanning in sarcoidosis. Semin Respir Crit Care Med 2003; 24(4):393–418. 77. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336(17): 1224–1234. 78. Brauner MW, Grenier P, Mompoint D, et al. Pulmonary sarcoidosis: evaluation with high-resolution CT. Radiology 1989; 172(2):467–471. 79. Nishimura K, Itoh H, Kitaichi M, et al. CT and pathological correlation of pulmonary sarcoidosis. Semin Ultrasound CT MR 1995; 16(5):361–370. 80. Nunes H, Brillet PY, Valeyre D, et al. Imaging in sarcoidosis. Semin Respir Crit Care Med 2007; 28(1):102–120. 81. Nakatsu M, Hatabu H, Morikawa K, et al. Large coalescent parenchymal nodules in pulmonary sarcoidosis: ‘‘sarcoid galaxy’’ sign. AJR Am J Roentgenol 2002; 178(6): 1389–1393. 82. Gleeson FV, Traill ZC, Hansell DM. Evidence of expiratory CT scans of smallairway obstruction in sarcoidosis. AJR Am J Roentgenol 1996; 166(5):1052–1054. 83. Abehsera M, Valeyre D, Grenier P, et al. Sarcoidosis with pulmonary fibrosis: CT patterns and correlation with pulmonary function. AJR Am J Roentgenol 2000; 174(6):1751–1757.
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84. Honda O, Johkoh T, Ichikado K, et al. Comparison of high resolution CT findings of sarcoidosis, lymphoma, and lymphangitic carcinoma: is there any difference of involved interstitium? J Comput Assist Tomogr 1999; 23(3):374–379. 85. Remy-Jardin M, Giraud F, Remy J, et al. Pulmonary sarcoidosis: role of CT in the evaluation of disease activity and functional impairment and in prognosis assessment. Radiology 1994; 191(3):675–680. 86. Muller NL, Mawson JB, Mathieson JR, et al. Sarcoidosis: correlation of extent of disease at CT with clinical, functional, and radiographic findings. Radiology 1989; 171(3):613–618. 87. Terasaki H, Fujimoto K, Muller NL, et al. Pulmonary sarcoidosis: comparison of findings of inspiratory and expiratory high-resolution CT and pulmonary function tests between smokers and nonsmokers. AJR Am J Roentgenol 2005; 185(2):333–338. 88. Drent M, De Vries J, Lenters M, et al. Sarcoidosis: assessment of disease severity using HRCT. Eur Radiol 2003; 13(11):2462–2471. 89. Hansell DM, Milne DG, Wilsher ML, et al. Pulmonary sarcoidosis: morphologic associations of airflow obstruction at thin-section CT. Radiology 1998; 209(3): 697–704. 90. Muers MF, Middleton WG, Gibson GJ, et al. A simple radiographic scoring method for monitoring pulmonary sarcoidosis: relations between radiographic scores, dyspnoea grade and respiratory function in the British Thoracic Society Study of Long-Term Corticosteroid Treatment. Sarcoidosis Vasc Diffuse Lung Dis 1997; 14(1):46–56. 91. Magkanas E, Voloudaki A, Bouros D, et al. Pulmonary sarcoidosis. Correlation of expiratory high-resolution CT findings with inspiratory patterns and pulmonary function tests. Acta Radiol 2001; 42(5):494–501. 92. Bartz RR, Stern EJ. Airways obstruction in patients with sarcoidosis: expiratory CT scan findings. J Thorac Imaging 2000; 15(4):285–289. 93. Nishino M, Kuroki M, Roberts DH, et al. Bronchomalacia in sarcoidosis: evaluation on volumetric expiratory high-resolution CT of the lung. Acad Radiol 2005; 12(5):596–601. 94. Lenique F, Brauner MW, Grenier P, et al. CT assessment of bronchi in sarcoidosis: endoscopic and pathologic correlations. Radiology 1995; 194(2):419–423. 95. Akira M, Kozuka T, Inoue Y, et al. Long-term follow-up CT scan evaluation in patients with pulmonary sarcoidosis. Chest 2005; 127(1):185–191. 96. Remy-Jardin M, Giraud F, Remy J, et al. Importance of ground-glass attenuation in chronic diffuse infiltrative lung disease: pathologic-CT correlation. Radiology 1993; 189(3):693–698. 97. Lalancette M, Carrier G, Laviolette M, et al. Farmer’s lung. Long-term outcome and lack of predictive value of bronchoalveolar lavage fibrosing factors. Am Rev Respir Dis 1993; 148(1):216–221. 98. Akira M, Kita N, Higashihara T, et al. Summer-type hypersensitivity pneumonitis: comparison of high-resolution CT and plain radiographic findings. AJR Am J Roentgenol 1992; 158(6):1223–1228. 99. Silva CI, Churg A, Muller NL. Hypersensitivity pneumonitis: spectrum of highresolution CT and pathologic findings. AJR Am J Roentgenol 2007; 188(2):334–344. 100. Cormier Y, Brown M, Worthy S, et al. High-resolution computed tomographic characteristics in acute farmer’s lung and in its follow-up. Eur Respir J 2000; 16(1): 56–60.
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101. Patel RA, Sellami D, Gotway MB, et al. Hypersensitivity pneumonitis: patterns on high-resolution CT. J Comput Assist Tomogr 2000; 24(6):965–970. 102. Ohtani Y, Saiki S, Kitaichi M, et al. Chronic bird fancier’s lung: histopathological and clinical correlation. An application of the 2002 ATS/ERS consensus classification of the idiopathic interstitial pneumonias. Thorax 2005; 60(8):665–671. 103. Lacasse Y, Selman M, Costabel U, et al. Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med 2003; 168(8):952–958. 104. Franquet T, Hansell DM, Senbanjo T, et al. Lung cysts in subacute hypersensitivity pneumonitis. J Comput Assist Tomogr 2003; 27(4):475–478. 105. Lynch DA, Newell JD, Logan PM, et al. Can CT distinguish hypersensitivity pneumonitis from idiopathic pulmonary fibrosis? AJR Am J Roentgenol 1995; 165(4):807–811. 106. Remy-Jardin M, Remy J, Wallaert B, et al. Subacute and chronic bird breeder hypersensitivity pneumonitis: sequential evaluation with CT and correlation with lung function tests and bronchoalveolar lavage. Radiology 1993; 189(1):111–118. 107. Adler BD, Padley SP, Muller NL, et al. Chronic hypersensitivity pneumonitis: high-resolution CT and radiographic features in 16 patients. Radiology 1992; 185(1): 91–95. 108. Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med 2003; 349(26):2527–2539. 109. Shah PL, Hansell D, Lawson PR, et al. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax 2000; 55(1):67–77. 110. Godwin JD, Muller NL, Takasugi JE. Pulmonary alveolar proteinosis: CT findings. Radiology 1988; 169(3):609–613. 111. Murch CR, Carr DH. Computed tomography appearances of pulmonary alveolar proteinosis. Clin Radiol 1989; 40(3):240–243. 112. Lee KN, Levin DL, Webb WR, et al. Pulmonary alveolar proteinosis: high-resolution CT, chest radiographic, and functional correlations. Chest 1997; 111(4):989–995. 113. Newell JD, Underwood GH Jr., Russo DJ, et al. Computed tomographic appearance of pulmonary alveolar proteinosis in adults. J Comput Tomogr 1984; 8(1):21–29. 114. Holbert JM, Costello P, Li W, et al. CT features of pulmonary alveolar proteinosis. AJR Am J Roentgenol 2001; 176(5):1287–1294. 115. Kang EY, Grenier P, Laurent F, et al. Interlobular septal thickening: patterns at high-resolution computed tomography. J Thorac Imaging 1996; 11(4):260–264. 116. Johkoh T, Itoh H, Muller NL, et al. Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings. Radiology 1999; 211(1):155–160. 117. Chung MJ, Lee KS, Franquet T, et al. Metabolic lung disease: imaging and histopathologic findings. Eur J Radiol 2005; 54(2):233–245. 118. Tan RT, Kuzo RS. High-resolution CT findings of mucinous bronchioloalveolar carcinoma: a case of pseudopulmonary alveolar proteinosis. AJR Am J Roentgenol 1997; 168(1):99–100. 119. Chan MS, Chan IY, Fung KH, et al. High-resolution CT findings in patients with severe acute respiratory syndrome: a pattern-based approach. AJR Am J Roentgenol 2004; 182(1):49–56. 120. Rossi SE, Erasmus JJ, Volpacchio M, et al. ‘‘Crazy-paving’’ pattern at thin-section CT of the lungs: radiologic-pathologic overview. Radiographics 2003; 23(6):1509–1519. 121. Franquet T, Gimenez A, Bordes R, et al. The crazy-paving pattern in exogenous lipoid pneumonia: CT-pathologic correlation. AJR Am J Roentgenol 1998; 170(2):315–317.
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122. Baron SE, Haramati LB, Rivera VT. Radiological and clinical findings in acute and chronic exogenous lipoid pneumonia. J Thorac Imaging 2003; 18(4):217–224. 123. Lee KH, Kim WS, Cheon JE, et al. Squalene aspiration pneumonia in children: radiographic and CT findings as the first clue to diagnosis. Pediatr Radiol 2005; 35(6):619–623. 124. Coche E, Weynand B, Noirhomme P, et al. Non-specific interstitial pneumonia showing a ‘‘crazy paving’’ pattern on high resolution CT. Br J Radiol 2001; 74(878):189–191. 125. Okada F, Ando Y, Kondo Y, et al. Thoracic CT findings of adult T-cell leukemia or lymphoma. AJR Am J Roentgenol 2004; 182(3):761–767. 126. Gasparetto EL, Tazoniero P, Escuissato DL, et al. Pulmonary alveolar microlithiasis presenting with crazy-paving pattern on high resolution CT. Br J Radiol 2004; 77(923):974–976. 127. Sverzellati N, Poletti V, Chilosi M, et al. The crazy-paving pattern in granulomatous mycosis fungoides: high-resolution computed tomography-pathological correlation. J Comput Assist Tomogr 2006; 30(5):843–845. 128. Tazi A, Soler P, Hance AJ. Adult pulmonary Langerhans’ cell histiocytosis. Thorax 2000; 55(5):405–416. 129. Vassallo R, Ryu JH, Colby TV, et al. Pulmonary Langerhans’-cell histiocytosis. N Engl J Med 2000; 342(26):1969–1978. 130. Tazi A. Adult pulmonary Langerhans’ cell histiocytosis. Eur Respir J 2006; 27(6): 1272–1285. 131. Moore AD, Godwin JD, Muller NL, et al. Pulmonary histiocytosis X: comparison of radiographic and CT findings. Radiology 1989; 172(1):249–254. 132. Brauner MW, Grenier P, Tijani K, et al. Pulmonary Langerhans cell histiocytosis: evolution of lesions on CT scans. Radiology 1997; 204(2):497–502. 133. Vassallo R, Jensen EA, Colby TV, et al. The overlap between respiratory bronchiolitis and desquamative interstitial pneumonia in pulmonary Langerhans cell histiocytosis: high-resolution CT, histologic, and functional correlations. Chest 2003; 124(4):1199–1205. 134. Stern EJ, Webb WR, Golden JA, et al. Cystic lung disease associated with eosinophilic granuloma and tuberous sclerosis: air trapping at dynamic ultrafast highresolution CT. Radiology 1992; 182(2):325–329. 135. Brambilla E, Fontaine E, Pison CM, et al. Pulmonary histiocytosis X with mediastinal lymph node involvement. Am Rev Respir Dis 1990; 142(5):1216–1218. 136. Johnson SR. Lymphangioleiomyomatosis. Eur Respir J 2006; 27(5):1056–1065. 137. Ryu JH, Doerr CH, Fisher SD, et al. Chylothorax in lymphangioleiomyomatosis. Chest 2003; 123(2):623–627. 138. Ryu JH, Moss J, Beck GJ, et al. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med 2006; 173(1):105–111. 139. Johnson S. Rare diseases. 1. Lymphangioleiomyomatosis: clinical features, management and basic mechanisms. Thorax 1999; 54(3):254–264. 140. Kitaichi M, Nishimura K, Itoh H, et al. Pulmonary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors. Am J Respir Crit Care Med 1995; 151(2 pt 1):527–533. 141. Aberle DR, Hansell DM, Brown K, et al. Lymphangiomyomatosis: CT, chest radiographic, and functional correlations. Radiology 1990; 176(2):381–387.
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142. Taylor JR, Ryu J, Colby TV, et al. Lymphangioleiomyomatosis. Clinical course in 32 patients. N Engl J Med 1990; 323(18):1254–1260. 143. Urban T, Lazor R, Lacronique J, et al. Pulmonary lymphangioleiomyomatosis. A study of 69 patients. Groupe d’Etudes et de Recherche sur les Maladies ‘‘Orphelines’’ Pulmonaires (GERM‘‘O’’P). Medicine (Baltimore) 1999; 78(5):321–337. 144. Bonelli FS, Hartman TE, Swensen SJ, et al. Accuracy of high-resolution CT in diagnosing lung diseases. AJR Am J Roentgenol 1998; 170(6):1507–1512. 145. Chu SC, Horiba K, Usuki J, et al. Comprehensive evaluation of 35 patients with lymphangioleiomyomatosis. Chest 1999; 115(4):1041–1052. 146. Bernstein SM, Newell JD Jr., Adamczyk D, et al. How common are renal angiomyolipomas in patients with pulmonary lymphangiomyomatosis? Am J Respir Crit Care Med 1995; 152(6 pt 1):2138–2143. 147. Matsui K, Tatsuguchi A, Valencia J, et al. Extrapulmonary lymphangioleiomyomatosis (LAM): clinicopathologic features in 22 cases. Hum Pathol 2000; 31(10): 1242–1248. 148. Woodring JH, Howard RS II, Johnson MV. Massive low-attenuation mediastinal, retroperitoneal, and pelvic lymphadenopathy on CT from lymphangioleiomyomatosis. Case report. Clin Imaging 1994; 18(1):7–11. 149. Avila NA, Kelly JA, Chu SC, et al. Lymphangioleiomyomatosis: abdominopelvic CT and US findings. Radiology 2000; 216(1):147–153. 150. Lemaitre L, Robert Y, Dubrulle F, et al. Renal angiomyolipoma: growth followed up with CT and/or US. Radiology 1995; 197(3):598–602.
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3 Genetics of ILD
FELIX A. WOODHEAD Royal Brompton Hospital and National Heart and Lung Institute, Imperial College, London, U.K.
R. M. DU BOIS National Jewish Medical and Research Center, Denver, Colorado, U.S.A.
I.
Introduction
It is well recognized that some human diseases such as cystic fibrosis run in families and that their inheritance follows a Mendelian pattern explained by the presence of a single aberrant gene. Other conditions occur in relatives of affected individuals at a higher rate than in the general population and this most likely reflects the interaction of one or more genes with one or more environmental factors. Such disorders are defined genetically as complex diseases. They include a number of common disorders such as hypertension, type II diabetes, and some of the diffuse lung diseases, especially systemic sclerosis and sarcoidosis. The strength of the genetic component of a particular disease can be assessed using genetic epidemiological techniques such as twin studies or family studies. The genetic component of disease susceptibility can be assessed by estimating the relative risk, defined as the risk of disease in the relative of an affected individual related to the risk in the general population. Such relative risk is defined as l with ls being the relative risk for a sibling and lr being the risk for a relative, usually first degree relatives. In general, the higher the relative risk, the more likely there will be a genetic component and thus the likelihood of identifying 43
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that component(s). Nonetheless, analysis of complex diseases raises particular difficulties and requires specific methodologies (1). Classical genetics relies on studying crosses between different strains of relatively simple but fast-reproducing organisms such as maize or the fruit fly Drosophila. These techniques allowed geneticists to see how different physical traits or phenotypes were inherited and to infer the chromosomal location of the responsible genes relative to one another. This was evidently not possible in humans but with the development of the polymerase chain reaction, it became possible to amplify DNA, sometimes coupled with restriction fragment length polymorphism (RFLP) analysis to further identify DNA variations, and to determine differences in individual genomes and across ethnic boundaries. Restriction enzymes cleave DNA at sites determined by base sequences every time they encounter a particular sequence of nucleotides (a so-called restriction site). Change in the sequence at this point by even one nucleotide will prevent the restriction enzyme recognizing this site. Individuals can also be distinguished genetically by the use of microsatellites. Throughout the genome, there are areas that consist of repeating series of short sequences of nucleotides. As the number of times the sequence is repeated varies between individuals, so does the overall length of this region. By amplifying the repeated area followed by separation on a gel, differing lengths can be resolved. By employing RFLP and microsatellites as genetic markers, geneticists were able, for the first time, to identify a gene by its position on a chromosome alone, so-called positional cloning (2). While initially developed in experimental organisms, these techniques were soon employed in human disease, leading to the localization of the genes responsible for a number of Mendelian disorders including cystic fibrosis (3). Identification of the affected gene provides information on the pathogenesis of the disease as well as allowing screening and genetic counseling. Interest in the genetics of human disease has continued to accelerate with the accumulation of genetic information and developments in bioinformatics since the turn of the millennium. The sequence of the human genome was published in 2001 (4,5). While a vast majority of the sequence is identical for all individuals, differences occur mainly because of ancestral mutations, duplications and deletions in DNA. Examples include areas of tandem repeats (variable number tandem repeats, VNTRs) and single nucleotides (single-nucleotide polymorphisms, SNPs, pronounced ‘‘Snips’’). When an alteration occurs in a sequence, it is inherited along with its neighboring sequence until broken up by chromosomal rearrangement, usually meiotic recombination (6). These so-called haplotype blocks vary in size across the genome with the most variation in length so far described in the HLA region (7). In general, the older a population is evolutionarily, the more time elapses to allow recombination, and the haplotype blocks are, therefore, shorter. This is shown by the international Human Haplotype Mapping Project (HapMap) (8), which is genotyping 4 distinct populations for commonly occurring variations. Haplotypes and their frequencies vary among populations. However, within a specific population, while the frequency of each haplotype may vary among individuals with specific trait and controls, the
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structures of the haplotype blocks are usually the same. Violation of this condition is often a sign that patient and control groups are not ethnically matched. The haplotype structure of the human genome can be both a help and a hindrance to genetic enquiry. While it may mean that fewer polymorphic loci are needed to show linkage to a haplotype, once linkage has been shown, it can be hard to know which of the possible SNPs or other alterations in the sequence within the block is responsible for the functional difference. A.
Complex Traits
Most genetic disorders have complex patterns of inheritance. Even a classic Mendelian disorder such as sickle-cell anemia caused by an abnormal b-globin gene can manifest different clinical forms depending on other genetic factors such as the ability to produce fetal hemoglobin. In general, a number of problems can frustrate the dissection of complex traits. Incomplete penetrance refers to the situation where individuals with a susceptibility allele do not develop a trait. Abnormalities in different genes or environmental factors may cause a similar or identical disease (phenocopy). This applies particularly when clinical phenotype is not defined precisely or where diseases are grouped broadly under a diagnostic ‘‘banner’’ such as ‘‘pulmonary fibrosis.’’ Even where phenotypes are precisely defined, locus heterogeneity, a situation whereby the same condition can be caused by mutation in a number of different genes (up to 14 in the case of Retinitis Pigmentosa), adds to the complexity of defining disease association. This situation must be distinguished from allelic heterogeneity where multiple variations in the same gene can cause disease. While this can be problematic in identifying all possible mutations, it will not cause problems mapping the responsible allele. Another confounder that is most obviously seen with experimental organisms such as mice is that of polygenic inheritance. A genetic alteration, for example, in a knock-out or knock-in mouse, can cause a noticeably different phenotype depending on the genetic background of the animal. In this regard, the introduction of a transgene leading to the overexpression of transforming growth factor beta 1 (TGF-b1) in C57BL/6 mice causes marked lung fibrosis, whereas the identical gene causes emphysema when introduced into a Balb/c mouse (9). Finally, the allelic frequency in the general population of a variation responsible for a condition can affect its chance of being positively associated. In general, the more common a disease-associated allele is in the general population, the lower will be the relative risk of carrying it. It was known for some time, for example, that there was a susceptibility locus for Alzheimer’s disease on chromosome 19. The allele for apolipoprotein E type 4 was subsequently found to be responsible, but as it is present at a frequency of *16% in most populations it had a low odds ratio. Conversely, as the three SNPs in NOD2/CARD15, which are associated with terminal ileal Crohn’s disease, are present at a frequency of only 1%, 2%, and 4% in the general population, the odds ratio was higher (10). In this regard, it is interesting to note that the
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HapMap project is only studying, by definition, alleles with a frequency of 5% or more, and these NOD2/CARD15 polymorphisms would have been missed using the HapMap approach. B.
Genetic Approaches
There are two main approaches to genetic association; linkage studies in families with a condition or case-control comparisons in sporadic disease. Linkage studies examine how chromosomal markers are transmitted through families. Techniques may either be parametric, where a mode of inheritance is assumed and compared with the observed pattern, or nonparametric such as the allele sharing approach. Here, the frequency of various chromosomal markers is compared among related individuals with a condition. If the marker is linked to the causative allele, it will be shared by affected individuals more commonly than other unassociated alleles. While this technique presumes no a priori knowledge of the causative gene, it requires larger numbers than parametric techniques. The most commonly utilized method for assessing the genetics of complex traits is the association study. Here, a gene that other data suggest may be involved in the condition is selected as a candidate. The allelic frequencies of polymorphisms in candidate genes and their immediate chromosomal regions are then determined in a cohort of affected individuals and compared with those in a cohort of unaffected people. If a different frequency is found, this can imply either that the allele is responsible for the condition or that it is in linkage disequilibrium with the true causative allele. Unfortunately, as it is known that allele frequencies differ in different populations, a ‘‘positive’’ association can also result from different ethnic mixes in the two cohorts (so-called genetic admixture or population stratification). It is, therefore, important to ensure population matching by checking in genes that are not relevant to disease pathogenesis for alleles whose frequencies for different ethnic groups are known. C.
Defining Disease
Of the interstitial pulmonary and bronchiolar disorders, some conditions are rare and share few features apart from their scarcity. Other conditions share the endpoint of progressive fibrosis of the lungs, although, in some cases (sarcoidosis and beryllium disease), the predominant form of inflammation is granulomatous. In some diseases, the fibrosis occurs together with other features of collagen vascular disease. In others, the fibrosing process is idiopathic. These idiopathic conditions can been subdivided using the criteria defined in the ATS/ERS statement on the idiopathic interstitial pneumonias (IIPs) (11). Even with this classification, there is acknowledged phenotypic heterogeneity, especially in nonspecific interstitial pneumonia (NSIP). Assuming that the different histopathological patterns reflect differences in pathogenesis rather
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than different manifestations of a single ‘‘fibrosis gene,’’ any attempt to group all or some of these conditions as ‘‘pulmonary fibrosis’’ will lead to a dramatic loss of genetic clarity. Other ways of increasing genetic power can be obtained by concentrating on severe disease, those cases with a positive family history and disease with early onset. While the lr of heart disease in twins is 7 for men and 15 for women before the age of 65, that for later onset disease is <2 (12). It should also be clear that it is important to study specific ethnic groups or, if this is not possible, ensuring that controls have the same ethnic mix as the disease cohort. II.
Diffuse Panbronchiolitis
Many of the techniques and problems of genetic studies are nicely illustrated by the example of diffuse panbronchiolitis (DPB), a disorder characterized by chronic sinusitis and inflammation of the airways of the lower respiratory tract. It occurs predominantly in East Asian populations (Japanese, Chinese, and Koreans), suggesting that there may be a founder effect. A.
Major Histocompatibility Complex Region
Using serological techniques, it was clear that there were HLA associations with the disease. In Japanese patients, these were with HLA-B54 (13), while in Koreans, the association was with HLA-A11. It seemed possible that a single allele was responsible for disease but was in LD with different class I genes in the two populations. The region between the class I and class II HLA genes on chromosome 6p contains the class III HLA genes responsible for a number of immunological functions. Tomita et al. examined the linkage in this area using RFLP but found the primary association with the disease to be with HLA-B (14). Other workers attributed the risk to the transporter associated with antigen-processing (TAP) genes, associations with which were made even in B54-negative patients (15). Subsequently, using fine mapping of the HLA region, Keicho et al. found that affected Japanese patients shared three consecutive linkage markers in the class I region (16). Seventeen of 20 Korean DPB patients also shared these markers (although the phase information for these patients—which chromosome carried each allele—was unavailable). The authors concluded that for both the populations, the susceptibility gene lies within a 200-kb stretch of chromosome 6p, 300-kb telomeric of the HLA-B genes. B.
Nonmajor Histocompatibility Complex Genes
Although the HLA genes have received the most attention, other genes have been associated with DPB. Emi et al. found an association of microsatellite markers with IL-8 (17), a gene found by other groups to be associated with
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infectious bronchiolitis (18). DPB is characterized by excessive mucin production. The MUC5AC protein is reported to be overproduced in the lungs of patients with DPB (19). Kamio et al. have reported an association between DPB and an insertion/deletion polymorphism in the promoter region of the MUC5B gene (20). Three major promoter haplotypes occur and the transcriptional activity of these corresponded to the strength of the disease association in which these haplotypes are involved. III.
Idiopathic Interstitial Pneumonias
The situation with IIPs is less clear than that with DPB. This group of disorders contains a number of distinct conditions, each of which may have a different genetic predisposition. It is recognized that cases of familial interstitial lung diseases (ILDs) occur (21–23). Some series report conditions not seen in adults such as pulmonary interstitial glycogenosis (22). Furthermore, older reports of lung fibrosis in children may not represent the same condition as the adult disease by the same name. In particular, idiopathic pulmonary fibrosis (IPF), as defined in the ATS/ERS consensus statement, does not appear to occur in children. One should, therefore be cautious about familial studies of IPF with children in the cohorts. In rare cases, germ-line mutations have been found, which lead to pulmonary fibrosis either alone or as part of a syndrome. In some cases, these alleles have also been implicated in sporadic disease. The genetics of IIP is summarized in Table 1. A.
Familial Disease
The true prevalence of familial ILD remains uncertain. Hodgson et al. surveyed all the 29 respiratory clinics in Finland (24). Diagnosis was made using the ATS/ ERS criteria with a biopsy rate of 31%. 1212 living patients with IPF were questioned about a family history. This led to the identification of 88 family pedigrees. The prevalence of sporadic disease was estimated to be 160 to 180 per million with that of familial disease being 5.9 per million. The rate was the highest in Eastern Finland, perhaps implying a founder effect. The same investigators embarked on a genomewide scan in six of these pedigrees using microsatellite linkage markers, which identified five loci of interest (25). Further, fine mapping in an extended set of 24 pedigrees identified a shared haplotype on chromosome 4q21. Two nonoverlapping genes are found within this haplotype LOC152586 and ELMOD2. Of these, the former is found only in the testis. By contrast, ELMOD2 is expressed throughout the body including alveolar macrophages and alveolar walls in healthy lungs. Messenger RNA levels were found to be significantly lower in IPF lungs than in controls, although there was no protein data presented. The researchers proposed ELMOD2 as a candidate gene for IPF. As yet, it is not clear if or how it might be (text continues on page 54)
ELMOD2
TERT
TERC (hTR)
Telomerase reverse transcriptase
Telomerase RNA component
Official symbol
ELMO/CED-12 domain containing 2
Official name
3q26
5p15.33
4q31.1
Position
Familial study (linkage and sequencing)
Association (sequencing)
Familial study (linkage and sequencing)
Association (sequencing)
Linkage
Study type
Table 1 Genetics of Idiopathic Interstitial Pneumonias
Tennessee, U.S.A. 73 probands of IIP families Controls of varied Ethnicities Probands from 44 IIP families, 44 patients with sporadic IIP Tennessee, U.S.A. 73 probands of IIP families Controls of varied Ethnicities Probands from 44 IIP families 44 patients with sporadic IIP
Finnish IPF families
Population
Heterozygous mutation in TERC found in one family
Region of 4q31.1 implicated. 2 genes present but only ELMOD-2 expressed in lungs. Levels reduced in IPF lung Heterozygous mutations in hTERT in 5 subjects (2 missense, 2 splice junction, 1 frameshift). None in 623 controls Six polymorphisms in families, 1 in sporadic disease hTR mutation in 1 proband. None in 194 controls
Notes
Genetics of ILD (Continued)
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28
29
28
25
References
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49
Surfactant, pulmonaryassociated protein C (surfactant protein C)
Official name
Position
8p21
Official symbol
SFTPC
14 members of family affected by IIP
Mexican. 84 pts. IPF 22 Japanese pts. with familial IIP 30 Japanese pts. with sporadic IIP U.K. and U.S. white, sporadic IIP 89 UIP, 46 NSIP, 104 controls
Family study
Association (RFLP) Association (sequencing)
SFTPC mutation in 13/135 (1% of cases) Only 1 nonsynonymous
G ? A 1st base intron 4 led to skipping of exon 4. Precursor protein lacked 38 amino acids. Complete absence of mature protein in lung. Mother had DIP, infant NSIP T ? A at exon 5 þ128 led to substitution of a glutamine for leucine at position 188 of the Pro-SPC molecule. Abnormal accumulation of protein in cytoplasm. 6 patients IPF, 3 NSIP No association with SFTPC polymorphisms found Exon 4 N138T, Exon 5 N186S Exon 5 N186S
Notes
37
38
38
36
35
33
References
50
Association (sequencing)
Mother and daughter
Population
Case report
Study type
Table 1 Genetics of Idiopathic Interstitial Pneumonias (Continued )
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2p13.2
SFTPB
2q14.2
6p21 HLAB, HLADRB1, HLADQB1
10q22.2q23.1
Position
SFTPA1
Official symbol
Interleukin 1 receptor IL-1RN antagonist
Surfactant, pulmonaryassociated protein A1 Surfactant, pulmonaryassociated protein B Major histocompatibility complex
Official name
Table 1 (Continued )
Association (SSP-PCR)
Association (RFLP)
Association (SSP-PCR)
Association (RFLP)
88 English fibrosing alveolitis patients and matched controls 61 Italian patients, 103 controls 54 white Czech IPF patients, 199 controls
75 Mexican IPF patients, 93 controls
Mexican. 84 pts. IPF
Mexican. 84 pts. IPF
German. Sporadic IIP. 25 IPF,10 NSIP
Association (sequencing) Association (RFLP)
Population
Study type
VNTR in complete LD with þ2018 SNP not associated with disease. No associations for polymorphisms of IL-1a or IL-1b
HLA-B*15-DRB1*0101DQB1*0501, HLA-B* 52-DRB1*1402DQB1*0301 and HLAB*35-DRB1*0407DQB1*0302 overrepresented in IPF Association of þ2018 SNP with disease in English and Italian patients
1580C allele of SFTPB and smoking IPF patients
2 non-synonymous variants in SFTPC found. No difference in frequencies between disease and controls Association of 6A4 haplotype of SFTPA1 and nonsmoking IPF patients
Notes
Genetics of ILD (Continued)
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41
40
36
36
39
References
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51
IL-10
IL-8
Interleukin 10
Interleukin 8 Association (SSP-PCR)
Association (SSP-PCR)
Association (SSCP)
Association (SSP-PCR)
Association (SSCP)
Association (RFLP)
Association (RFLP)
Study type
5q31.1-q33.1 Association (SSP-PCR)
2q35
2q35
4q13-q21
1q31-q32
6p21.3
Position
Notes
73 British Caucasoid IPF patients, 157 controls
No association found
88 English fibrosing Association of 308 A alveolitis patients polymorphism with and matched controls, disease in English and 61 Italian patients, Italian patients 103 controls 22 Caucasian Australian Association of 308 A IPF patients, polymorphism with IPF 140 controls 92 U.K. IPF patients, No association with 30 controls polymorphisms of TNF 30 UTR 74 white U.K. IPF No association found patients, 100 controls 96 British IPF patients, No association found 96 controls 71 British CFA patients, No association found 194 controls 71 British CFA patients, No association found 194 controls
Population
49
48
48
47
46
45
44
41
References
52
IL-8RA Interleukin 8 receptor, alpha (CXCR1) IL-8RB Interleukin 8 receptor, beta (CXCR2) Interleukin 12B IL-12B (IL-12, subunit p40)
TNF
Official symbol
Tumor necrosis factor
Official name
Table 1 Genetics of Idiopathic Interstitial Pneumonias (Continued )
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SERPINE1
7q21.3-q22 Association (RFLP)
Association (RFLP and sequencing)
Association (RFLP and sequencing)
Association (SSP-PCR)
Association (RFLP)
Association (SSP-PCR)
Study type No association found
Notes
No association with disease susceptibility þ869 (T ? C) polymorphism associated with a faster rate of lung decline as measured by gas transfer 30 Czech patients, SNPs at (590) and (33) 103 controls in IL-4 promoter associated with IPF 74 white Italian IPF Association between the patients, 166 controls C ? G polymorphism at nucleotide position þ5507 in exon 33 and disease. 96 Finnish IPF patients, þ5507 polymorphism not 96 Controls present in this population. No association found Michigan, U.S.A. No association found 88 IIP patients Data from 2120 controls
73 British Caucasoid IPF patients, 157 controls 128 white Spanish IPF patients, 140 controls
Population
58
56
55
52
51
49
References
Abbreviations: RFLP, restriction fragment length polymorphism; SSP-PCR, polymerase chain reaction using sequence-specific primers; SNP, single nucleotide polymorphism.
Serpin peptidase inhibitor, clade E, member 1 (plasminogen activator inhibitor-1)
CR1 Complement component (3b/4b) Receptor 1
1q32
5q31.1
IL-4
Interleukin 4
12q14
19q13.1
IFNG
Interferon, gamma
Position
Transforming growth TGFB1 factor, beta 1
Official symbol
Official name
Table 1 (Continued )
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involved in pathogenesis, although the protein shares conserved regions with apoptosis signaling proteins. Identifying familial ILD through a network of collaborators, Steele et al. studied the phenomenon in the United States (26). One hundred eleven families with two or more affected members were found. There were 309 affected and 330 unaffected individuals. While the commonest disease was IPF, 45% of the families were phenotypically heterogeneous and the number of affected members varied among pedigrees. Twenty families showed vertical transmission implying a dominant mode of inheritance with incomplete penetrance. Although there may have been some ascertainment bias due to incomplete information on unaffected family members, smoking appeared to increase the risk of familial ILD. 1.
Telomerase
Dyskeratosis congenita is a rare autosomal dominant disease leading to premature death from aplastic anemia and pulmonary fibrosis. It is caused by germ-line mutations in the genes encoding telomerase reverse transcriptase (hTERT) and telomerase RNA (hTR). A family has been reported with a heterozygous mutation in telomerase but which lacks the mucocutaneous features of dyskeratosis congenita and in which the predominant manifestation was pulmonary fibrosis (27). Armanios et al. (28) sequenced hTERT and hTR in probands from familial IIP cohorts in Tennessee. They found heterozygous mutations in hTERT in five subjects (four with usual interstitial pneumonia (UIP) and one with IIP, not otherwise defined) and heterozygous mutations in hTR in one subject (with UIP). No mutations were present in 623 healthy controls in the case of hTERT and 194 controls for hTR. The mutations were carried by some unaffected members of these families, suggesting that they might be susceptible to disease at a later date. On an average, the unaffected carriers were 11 years younger than their afflicted relatives. This may suggest variable penetrance or a later onset of familial IIP. Both affected individuals and healthy carriers had shorter telomeres than controls or noncarriers. When cells divide or age, telomeres shorten and unless bases are added to the telomeres, the cell eventually undergoes apoptosis signaling once the telomere reaches a critical length. The telomere connection was further explored by Tsakiri et al., who performed a SNP screen in two families with pulmonary fibrosis (29). The families comprised five individuals with IPF, five with pulmonary fibrosis, and six with unclassified pulmonary disease. Both the families showed linkage of affected individuals to markers on chromosome 5p15 where the telomerase TERT gene lies. Sequencing the gene identified distinct heterozygous mutations in the two families, a missense mutation in one family and a frameshift mutation in the other. Although some family members showed some of the aspects of dyskeratosis congenita, none had the mucocutaneous features. The authors found 4 additional mutations in 44 other families with inherited disease, and in one case
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Genetics of ILD
55
of 44 individuals, with sporadic disease. Heterozygous carriers of all the mutations had shorter telomeres than age-matched family members. 2.
Hermansky-Pudlak Syndrome
This rare autosomal-recessive condition is characterized by oculocutaneous albinism and platelet deficiency and, in some cases, lung fibrosis and bowel disease. Histopathologically, it is associated with the accumulation of ceroid (a chromolipid related to lipofuscin). Eight known mutated genes are responsible for the various subtypes (30), but only one, AP3B1, codes for a protein with a known function, the b3A subunit of the AP-3 coat protein. This is a heterotetrameric complex that mediates vesicle formation (31,32). How the abnormal gene leads to lung fibrosis or whether it is involved in sporadic disease is not yet known. 3.
Surfactant Proteins
Surfactant is important for the protection and adequate function of the lungs. Particular interest has focussed on surfactant protein (SFTP) C following a report by Nogee et al. of a mother and child with ILD (33). The mother had been diagnosed with DIP at the age of one. While the baby was normal at birth, it developed respiratory symptoms at the age of six weeks. Biopsy revealed NSIP. Both were found to possess an abnormal copy of the gene for SFTPC. A substitution of A for G in the first base of intron 4 abolished the normal donor splice site and led to the skipping of exon 4. This resulted in the precursor protein missing 37 amino acids, a change that could affect the protein tertiary structure and transport. Both mother and baby had a complete absence of mature SFTPC in BAL and lung tissue implying a dominant-negative effect. Further studies of an infant with a deletion in exon 3 of the SFTPC gene and progressive ILD showed that abnormal SFTPC accumulated in the cytoplasm of epithelial cells lending support to a dominant-negative effect (34). Thomas et al. reported a SNP in the SFTPC gene in 14 affected members of a family with ILD (35). A transversion of T to A at exon 5 þ 128 led to the substitution of a glutamine for leucine at position 188 of the Pro-SFTPC molecule. The mutation led to the accumulation of the protein in the cytoplasm with subsequent cell injury and death. Again there was phenotypic variation: 6 individuals had IPF while 3 (all children) had NSIP. Surfactant protein genes have also been examined by association studies in sporadic disease. Selman et al., stratifying patients by smoking, found an association between the 6A4 haplotype of SFTPA1 and nonsmoking IPF patients and the 1580C allele of SFTPB and smoking IPF patients (36). No associations were found with SFTPC. In a more recent study, the SFTPC gene was sequenced in 89 patients with sporadic IPF and different mutations found in 1% of the cases (37). Setoguchi et al. recently reported mutations in exons 4 and 5 of the SFTPC gene in patients with familial IIP as well as the exon 5 mutation in sporadic
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cases (38). Markart et al. examined SFTPC variants by the direct sequencing of the gene in 35 patients with IIP (25 IPF and 10 NSIP) and 50 healthy controls (39). They identified 2 nonsynonymous variants but frequencies were not different between patients and controls. To date, therefore, there have been no consistent surfactant protein polymorphism findings in sporadic IIPs. B.
Other Genes in Sporadic IIP
1.
MHC Region
While polymorphisms of the major histocompatibility complex (MHC) genes have been implicated in many diseases, only one study has been reported in IPF using genotyping rather than the older, serological techniques. Falfan-Valencia et al. investigated polymorphisms of HLA-B, -DRB1 and -DQB1 in 75 Mexican IPF patients and 93 controls (40). Three haplotypes were overrepresented among patients (HLA-B*15-DRB1*0101-DQB1*0501, HLA-B*52-DRB1*1402DQB1*0301, HLA-B*35-DRB1*0407-DQB1*0302). Bronchoalveolar lavage fluid from patients with the latter haplotype inhibited epithelial cell growth and induced apoptosis in vitro. Patients with this haplotype were also more likely to have had a rapid decline in their clinical disease. Some of the associated haplotypes are typical of Amerindian populations. The full significance of these findings or whether HLA associations will be found in different populations remains to be seen. 2.
Cytokine Genes
Tumor necrosis factor (TNF) and genes of the interleukin (IL) 1 cluster are both key cytokines that are expressed early in the inflammatory process and levels of the proteins are elevated in the lungs of patients with diffuse fibrosing lung disease. Whyte et al. examined variations in these genes in 81 English and 66 Italian patients (41). They found higher frequencies of a SNP at position þ2018 of the IL-1 receptor antagonist IL-1RN and at position 308 of TNF-A compared with controls from the same countries. Other workers failed to replicate the association for IL-1RN or other genes of the IL-1 cluster in 54 IPF patients of Western Slavonic ancestry (42). However, an association has been reported between the 889T allele in IL-1A and the severity of gas transfer deficits in IPF patients (43). A TNF-A association was confirmed in a study of 22 Australian IPF patients (44) but not in a group of 92 IPF patients from the west of England (45) or by Pantelidis et al. in 74 patients from the Southeast of England (46). The latter investigators who also investigated lymphotoxin-a, TNF receptor II, and IL-6 polymorphisms, however, reported an association between the G allele of an IL-6 intron 4A > G polymorphism and lower DLco levels. Co-carriage of the TNFRII 1690C allele and the IL-6 intron 4G allele was associated with presence of even more severe disease, defined by DLco, suggesting a combinatory effect of these two genes in IPF progression.
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The genes of other cytokines implicated in IPF have been examined by association studies. Neither IL-10 (47) nor IL-8 or its receptor (48) has been found to be associated with disease. Similarly Latsi et al. found no association in IPF either between a polymorphism known to affect IL-12 levels or the one which might potentially affect levels of IFN-g (49). While levels of TGF-b (a key mediator of fibrosis) are also under a degree of genetic control (50), Xaubet et al. found no association between two exon 1 polymorphisms in the gene and susceptibility to IPF (51). They did however report that the þ869 (T > C) polymorphism was associated with a faster rate of lung decline as measured by gas transfer, although levels of TBF-b were not measured. Recently, Vasakova et al. examined polymorphisms in a group of cytokines involved in Th1/Th2 differentiation in 30 Czech patients with IPF (52). They found a disease association with the CT genotypes at the positions (590) and (33) of the IL-4 gene. The same group also reported associations between some of the polymorphisms and alveolitis scores on high-resolution CT (53) and with clinical parameters (54). 3.
Complement and the Coagulation Cascade
Some studies have explored non-cytokine genes. Zorzetto et al. investigated variations in the complement receptor 1 gene (55). This receptor is thought to be important in the proper clearance of immune complexes. They reported a positive association in the C > G polymorphism at nucleotide position þ5507 in exon 33 in an Italian cohort of 74 IPF patients. This association could not be confirmed in a Finnish cohort (56) where the particular polymorphism appears to be absent in the population, although the Italian group has questioned the methodology of the Finnish investigators (57). Finally, although components of the coagulation cascade are altered in IPF with concentrations of tissue factor, plasminogen activator inhibitor (PAI)-1 and PAI-2 significantly elevated in bronchoalveolar lavage from patients, Kim et al. were unable to find an association with a polymorphism in the promoter region of the human PAI-1 gene and IIP in 88 American patients (58). IV.
Systemic Sclerosis
Diffuse ILD can complicate a number of connective tissue diseases but is particularly prevalent in systemic sclerosis. This condition is characterized by microvascular damage, immune activation, and the deposition of collagen in the skin and internal organs, including the lung. Moderate restrictive lung disease (FVC between 50% and 75% predicted) occurs in approximately a quarter of patients while severe disease (FVC less than 50% predicted) affects about one in eight (59). Immune activation is reflected by a high frequency of antinuclear antibody positivity. The nature of the extractable nuclear antigen correlates with the pattern of disease. While prevalences vary somewhat between populations, on average around 45% of scleroderma patients with ILD have antibodies against
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topoisomerase-1 while only about 12% have anti-centromere antibodies (60). The histopathological pattern associated with systemic scleroderma is most commonly NSIP (61,62). A.
Major Histocompatibility Complex Region
As with many immune-mediated conditions, genes of the MHC have been implicated in the predisposition to systemic sclerosis (63) (Table 2). The relatively weak association with HLA-DRB1*11 and disease overall is strengthened when looking at specific autoantibodies. In this regard, Feghali-Bostwick et al. found that although twins with scleroderma show only modest concordance for the pattern of disease, concordance was higher for autoantibodies (64). Furthermore, although ATA positivity is associated with HLA-DRB1*11 in Caucasians, Gilchrist et al. also found a strong association with HLADPB1*1301. While the DPB1 alleles are close to the DRB1 alleles there is a recombination hotspot between them so that linkage between the two loci is minimal compared with DRB1 and DQB1 (65). In an early study of Japanese patients with scleroderma, Kuwana et al. found an association of topoisomerase antibodies with -DQB1 alleles bearing a tyrosine residue at position 26 in the second hypervariable region of their b1 chain. There was also an association of anti-topoisomerase antibodies with -DRB1 alleles containing the amino acid sequence Phe, Leu, Glu, Asp, and Arg at positions 67–71 (67FLEDR71). The latter sequence aligned with a stretch of the topoisomerase 1 molecule previously determined to be a major epitope for B-cell activation (66). Anti-centromere antibodies also have an association with the MHC class II HLA-DR genes, -DRB1*01, *04, and *08. ACA positivity has also been associated with HLA-DQB1 alleles containing a polar amino acid (glycine or tyrosine) at position 26 (63). An even stronger association has been demonstrated with a polymorphism in the promoter of the gene for TNF (67), which also lies in the HLA region. However, because of the strength and complexity of linkage in this region, full four-digit HLA typing across this region is not yet reported in scleroderma in sufficient patients to confidently confirm that the primary association is with TNF as opposed to the biologically more likely HLA-DR. To our knowledge supertyping (grouping HLA alleles according to the amino acids of their peptide-binding grooves) has not yet been applied. This may well increase the class II association. B.
Nonmajor Histocompatibility Complex Genes
There is a large body of work on the genetics of systemic sclerosis (68). With the important caveat that autoantibody patterns appear to alter the chance of specific organ involvement, few studies have shown polymorphisms specific for pulmonary fibrosis in systemic sclerosis. Many studies have included too few (text continues on page 63)
Official symbol
Position
Study type
Population
Notes
Association U.S. patients: 850 white, (Taq man) 120 Hispanic, 130 African American Controls: 430 white, 146 Hispanic, 164 African American
PTPN22
1p13.3p13.1
Association 202 Caucasian patients, (SSP-PCR) 53 anti-topoisomerase positive
HLA-DPB1 6p21.3
Japanese patients: 28 antitopoisomerase positive, 34 anti-topoisomerase negative
Major histocompatibility complex, class II, DP beta 1 Protein tyrosine phosphatase, nonreceptor type 22
Association (RFLP)
HLA-DQB1 6p21.3
Japanese patients: 28 antitopoisomerase positive, 34 anti-topoisomerase negative
Major histocompatibility complex, class II, DQ beta 1
Association (RFLP)
HLA-DRB1 6p21.3
Major histocompatibility complex, class II, DR beta 1
Functional single nucleotide polymorphism (R620W) associated with anti-topoisomerase antibodies in whites but also with anti-centromere (relatively protective of lung fibrosis)
Association of anti-topoisomerase antibodies with -DRB1 alleles containing the amino acid sequence Phe, Leu, Glu, Asp, Arg at positions 67-71 (67FLEDR71) Association of anti-topoisomerase antibodies with -DQB1 alleles bearing a tyrosine residue at position 26 in the second hypervariable region of their b1 chain Association of anti-topoisomerase antibodies with HLA-DPB1*1301
A genetics of antitopoisomerase-1 antibodies (antibody most closely associated with lung fibrosis)
Official name
Table 2 Genetics of Systemic Sclerosis
Genetics of ILD (Continued)
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65
66
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Official symbol
Position
Study type
Population
FN1
GSTM1
GSTT1
MIF
Fibronectin 1
Glutathione S-transferase M1
Glutathione S-transferase theta 1
Macrophage migration inhibitory factor
Association (RFLP) 161 U.K. Caucasian patients, 253 controls
Association 152 U.S. patients: (SSP-PCR) 71 Caucasian, 50 Hispanic, 25 African American, 6 others 219 Controls: 78 Caucasian, 85 Hispanic, 56 African American 22q11.23 Association 152 U.S. patients: (SSP-PCR) 71 Caucasian, 50 Hispanic, 25 African American, 6 other 219 Controls: 78 Caucasian, 85 Hispanic, 56 African American 486 U.S. patients: 426 white, 22q11.23 Association (sequencing 60 ‘‘nonwhite’’ 254 controls: 229 white, and detection of 23 ‘‘nonwhite,’’ 2 not accounted for variable number repeats)
1p13.3
2q34
B genetics of systemic sclerosis (not concentrating on autoantibodies)
Official name
Table 2 Genetics of Systemic Sclerosis (Continued )
70
71 Significantly lower frequency of a haplotype defined by 173C and 794 with 7 CATT repeats (C7) with limited cutaneous disease. Pulmonary fibrosis less common in limited cutaneous disease than diffuse cutaneous disease.
70
69
References
Association in Caucasians of GSTT1 null alleles with systemic hypertension and with pulmonary involvement
Association of RFLP with restriction enzymes HaeIII and MspI with scleroderma-related fibrosing alveolitis Trend in Caucasians to association of GSTM1 null alleles with systemic hypertension. No association with pulmonary involvement
Notes
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Official symbol
FBN1
SPARC
Official name
Fibrillin 1
Secreted protein, acid, cysteine rich
Table 2 (Continued )
5q31.3q32
15q21.1
Position
Population
94 Caucasian patients, 70 controls 33 African American patients, 28 controls 51 Mexican American patients, 46 controls
Association 20 Choctaw patients, (sequencing 75 controls and SSCP)
18 Choctaw patients, Association (sequencing 49 controls 53 Japanese patients, and SSCP) 50 controls
Study type
77
76
References
Genetics of ILD (Continued)
Fibroblasts encoding this C7 haplotype produced more MIF on in-vitro stimulation than non-C7 haplotypes Five SNPs found by sequencing Choctaw patients. Association between disease and an intronic SNP in the gene (Intron C, þ49) among the Choctaw but not in the Japanese. Too few Choctaw with lcSSc to find any association with subtype Three new SNPs found by sequencing the gene in Choctaws. þ988 (C > G) in 30 UTR associated with disease in Choctaw and Caucasian patients. Same SNP associated with increased mRNA half-life. Associations between þ1551 C >G and Raynaud’s phenomenon and between the þ1922 T > G and pulmonary fibrosis across ethnic groups
Notes
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IL-1A
Official symbol
2q14
Position
Population
Association (RFLP)
18 Italian SSc patients
Association 121 Caucasian patients, (SSP-PCR) 200 controls
Study type
Six Haplotypes constructed from 8 SNPs. No associations between disease and subtypes found Among patients treated with cyclophosphamide those with T rather than C at position 889 of the IL-1a promoter showed a decrease in FVC despite treatment while those with the wild type had an improvement in vital capacity
Notes
81
78
References
62
Abbreviations: RFLP, restriction fragment length polymorphism; SSP-PCR, polymerase chain reaction using sequence-specific primers; SSCP, single-strand conformational polymorphism; SNP, single nucleotide polymorphism.
Interleukin 1, alpha
Official name
Table 2 Genetics of Systemic Sclerosis (Continued )
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Genetics of ILD
63
patients to be powered to distinguish ILD from other manifestations of systemic sclerosis. Nonetheless some of these studies invite comment. Avila et al. showed that two fibronectin RFLPs occurred at a different frequency in patients with scleroderma and ILD compared both with scleroderma patients without lung fibrosis and to controls (69). An American group has reported a number of positive associations in relatively large cohorts of patients. They found an association of a glutathione S-transferase theta (GSTT1) null allele with ‘‘pulmonary involvement’’ defined as ILD or pulmonary vascular disease (70). They also reported an association between the gene for the innate immunity mediator macrophage migration inhibitory factor (MIF) with diffuse cutaneous disease that is itself associated with a higher rate of pulmonary fibrosis (71). Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) is an intracellular protein referred to as a lymphoid tyrosine phosphatase. It is expressed only in hematopoietic cells and is involved in negative regulation of T-cell receptor (TCR) signaling. A functional single-nucleotide polymorphism in the gene (R620W) has been associated with a number of autoimmune diseases. Gourh et al., studying a cohort of 850 patients of various ethnicities, found an association between this SNP and white patients carrying the anti-topoisomerase antibody (which is itself associated with a higher incidence of ILD) (72). The same SNP was, however, also more common among patients carrying anti-centromere antibodies (relatively ‘‘protected’’ from lung fibrosis), therefore the polymorphism seems to be a risk factor for systemic sclerosis per se rather than ILD. The tight-skin mouse has been used as a model for scleroderma. It develops skin fibrosis and anti-topoisomerase antibodies although its lungs are affected by emphysema rather than pulmonary fibrosis. The genetic abnormality is a duplication of the gene for fibrillin1 (FBN1), a constituent of the extracellular matrix (73). The Choctaw are a tribe of native Americans with a high prevalence of systemic sclerosis (74). Using microsatellite markers, Tan et al. demonstrated a shared haplotype containing FBN1 was strongly associated with systemic sclerosis within the Choctaw (75). The same group later sequenced the FBN1 gene in Choctaw and Japanese patients with systemic sclerosis and found five SNPs (76). There was an association between disease and an intronic SNP in the gene (Intron C, þ49) among the Choctaw but not in the Japanese. There were too few Choctaw with limited disease (8 of 18) to assess any association with cutaneous extent of disease or the presence of pulmonary fibrosis. There was a trend toward an association of limited rather than diffuse cutaneous disease with a different, exonic SNP (Exon 15, þ1875) in the Japanese population but this did not hold after adjustment for multiple testing. Secreted protein, acidic and rich in cysteine (SPARC) is a multifunctional glycoprotein found within the extracellular matrix in a variety of tissues. It was found to be consistently upregulated in microarray analyses of tissue from scleroderma patients, and three new SNPs were found by sequencing the gene in
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Choctaws (77). The presence of the þ988 (C > G) polymorphism in the 30 untranslated region was associated with disease in 20 Choctaw and 94 Caucasian patients. The same SNP was associated with increased messenger RNA half-life. The authors also reported associations between the þ1551 C > G SNP and Raynaud’s phenomenon and between the þ1922 T > G polymorphism and pulmonary fibrosis. Lagan et al., however, analyzed these SNPs together with a further 5 in 121 Caucasian patients and failed to find any associations with disease (78). C.
Response to Treatment
Pulmonary fibrosis remains one of the more serious complications of systemic sclerosis and is often treated with cyclophosphamide (79,80). Beretta et al. looked retrospectively at polymorphisms in the IL-1 cluster in a group of 18 Italian patients who had been treated with oral cyclophosphamide (81). They found that patients with a T rather than C at position 889 of the IL-1a promoter showed a decrease in FVC despite treatment while those with the wild type had an improvement in vital capacity. Before this interesting finding can be used for therapeutic decision making, it will need to be confirmed prospectively in a larger cohort; a study of as few as 18 patients is problematic in terms of drawing any firm conclusion. V.
Sarcoidosis
The evidence for a genetic component to sarcoidosis is stronger than for many of the diffuse ILDs (Table 3). Familial clustering has been reported in Germany, Sweden, Japan, the United States, the United Kingdom, and Ireland with prevalences between 3.6% and 10%. A large collaborative American study (the ACCESS study) found 706 case control pairs from 10,862 first-degree and 17,047 second-degree relatives with sarcoidosis. The familial relative risk for siblings (OR 5.8) was higher than for parents (OR 3.8). There is a great deal of heterogeneity in the disease both with respect to outcome (spontaneous remission vs. progressive pulmonary fibrosis) and extent of involvement (pulmonary and extrapulmonary). These features also vary among ethnic groups with L€ ofgren’s syndrome being more common in northern Europeans, fibrotic lung disease in African Americans, and uveitis in Japanese patients. The earliest associations investigated were with HLA type, initially defined serologically. Later studies determined HLA alleles genetically, and linkage studies have been carried out both within the MHC and throughout the genome. Associations have also been found with genes outside of the MHC. The studies show the recurrent potential confounders of linkage and ethnic differences although common threads are emerging. (text continues on page 75)
6p21.3
HLA-DRB1
Major histocompatibility complex, class II, DR beta 1
Position 6p21.3
Official symbol
Major HLA-B histocompatibility complex, class I, B
Official name
Table 3 Genetics of Sarcoidosis
Association (PCR-SSO) Association (SSP-PCR)
Association (serological, PCR-SSO)
Association (SSP-PCR)
Association (RFLP)
Association (SSP-PCR)
Study type
189 U.K. patients, 288 controls 87 Polish patients, 133 controls 69 Czech patients, 158 controls
Germany 73 sarcoid, 162 controls 78 sarcoid, 50 controls Asian Indian
40 Japanese patients, 110 controls 75 patients, 130 controls 122 Scandinavian patients
166 Swedish patients, 210 controls
Population
HLA-DR14(DR6) and chronic disease Association between the amino acid at position 11 of HLA-DRB1 and risk of sarcoidosis
HLA-DR17 associated with acute disease HLA-DR14(DR6) and -DR15 with chronic disease HLA-DR3 associated with acute disease HLA-DR5 with chronic disease
Association of HLAB*07 and HLA-B*08 independently of class II genes HLA-DR5, -DR6 -DR8 and-DR9 associated with disease
Notes
Genetics of ILD (Continued)
98
97
95,96
94
92,93
91
References
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HLA-DPB1
HLA-DQB1
Major histocompatibility complex, class II, DQ beta 1
Official symbol
Major histocompatibility complex, class II, DP beta 1
Official name
268 white American patients 268 controls
Association (PCR-SSO)
Linkage study (microsatellites)
Association (analysis HLADPB1 exon 2) Association (PCR-SSO) 193 African American patients 193 controls 268 white American patients 268 controls 704 affected and unaffected African American subjects in 225 nuclear families with at least 2 members with sarcoidosis
38 white English patients, 47 Polish patients, 140 contols 68 African American patients, 108 controls
193 African American patients 193 controls
Association (PCR-SSO)
Association (ARMS-PCR)
Population
Study type
Examined linkage with 6 microsatellite markers across the MHC. Most tightly linked marker close to HLA-DQ locus. HLA-DQ associations stronger than those with -DR
HLA-DRB1*1101 associated with disease HLA-DRB1*1501 less common in disease HLA-DRB1*1101 and HLADRB1*1501 associated with disease No association with glutamic acid at position 69 of the -DP b chain No association with glutamic acid at position 69 of the -DP b chain Association with HLA -DPB1*0101
Notes
102
99
101
100
99
99
References
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6p21.3
6p21.3
Position
Table 3 Genetics of Sarcoidosis (Continued )
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Transporter 1, ATPbinding cassette, sub-family B
Official name
Table 3 (Continued ) Position
6p21.3
Official symbol
TAP1
149 Dutch patients 418 controls 67 Dutch sarcoidosis patients with SFN, 36 without 133 U.K. patients, 354 controls 102 Dutch patients, 214 controls 37 Dutch L€ ofgren’s syndrome patients
26 Japanese patients with cardiac sarcoidosis, 247 controls 117 U.K. patients, 290 controls 87 Slavonic Polish patients, 158 controls
Association (SSP-PCR) Association (SSP-PCR)
Association (RFLP) Association (ARMS)
Association (SSP-PCR)
No association with disease (but different frequencies between United Kingdom and Poland)
DQB1*0602 alleles inherited by affected offspring 20% more commonly than expected by chance DQB1*0201 transmitted to affected individuals only half as much as expected Association of DQB1*0602 with severe disease as part of a haplotype with DRB1*1501 DQB1*0602 associated with small fiber neuropathy (SFN) DQB1*0602 associated with serious disease DQB1*0201 associated with milder disease Extended MHC haplotype (TNF2-DRB1*03DQB1*0201) in 76% of L€ ofgren’s vs. 24% of controls DQB1*0601 associated with cardiac sarcoidosis
See above (78)
Transmission disequilibrium dtudy (SSP-PCR)
Association (SSP-PCR)
Notes
Population
Study type
Genetics of ILD (Continued)
110
109
107
106
105
104
103
References
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6p21.3
6p21.3
TAP2
TNF
BTNL2
Transporter 2, ATPbinding cassette, sub-family B
Tumor necrosis factor
Butyrophilin-like 2
85 Japanese patients, 91 controls 117 U.K. patients, 290 controls 87 Slavonic Polish patients, 158 controls 85 Japanese patients, 91 controls 96 U.K. patients, 354 controls 100 Dutch patients, 222 controls
Association (RFLP) Association (ARMS)
Extension sample 248 Replication 462 Total 1082
Association (SSP- 114 Czech patients, PCR and RFLP) 425 controls Linkage study Initial screen 372 German patients
Association (RFLP) Association (SSP-PCR)
Population
Study type
Increase in TNF-857T allele in disease Increase in TNF-307A (TNF-2) allele in patients with L€ ofgren’s syndrome TNF-307A associated with L€ ofgren’s Three-stage SNP screen of area identified in ref. (102). Stronger association with rs2076530 SNP in BTNL2 than with DR or DQ alleles Polymorphism leads to a stop codon and impaired membrane localization of protein
No association with disease
Thr-565, Ala-665 reduced in disease No linkage with HLA-DP
No association with disease
Notes
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113
112
111
110
111
References
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6p21.3
Position
Official name
Official symbol
Table 3 Genetics of Sarcoidosis (Continued )
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SLC11A1
TLR4
Toll-like receptor 4
Official symbol
Solute carrier family 11, member 1 (NRAMP)
Official name
Table 3 (Continued )
9q32-q33
2q35
Position
Association (RFLP)
Association (RFLP and microsatellite)
Association (SSP-PCR)
Sequencing of 490-bp region 219 African American spanning exon/intron 5. nuclear families with Association again with 686 individuals 736 African American and rs2076530. Stronger in white cases and 706 white than African matched controls American patients In the patient group as a whole 127 British patients, the HLA-DRB1*14, 243 controls DRB1*12 and BTNL2 161 Dutch patients rs2076530 A allele all (63 L€ ofgren’s associated with disease syndrome), 203 controls susceptibility. After exclusion of patients presenting with L€ ofgren’s syndrome and after adjusting for HLADRB1 alleles, the association between BTNL2 rs2076530 A and disease disappeared 157 African American (CA)n repeat in the immediate patients, 111 controls 50 region of gene associated with decreased risk of disease. Different from TB associated allele 141 German patients, Asp299Gly and Thr399Ile 141 controls mutant alleles in complete linkage disequilibrium. Borderline association with disease Association of alleles with chronic disease vs. controls
Family-based and case control association (sequencing)
Notes
Population
Study type
Genetics of ILD (Continued)
121
120
118
115
References
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Official symbol
CD14
NOD2
Official name
CD14 molecule
Nucleotide-binding Oligomerization domain containing 2
16q21
5q31.1
Position
Table 3 Genetics of Sarcoidosis (Continued )
53 Danish patients, 103 controls
Association (capillary electrophoresis SSCP) Family-based and case control
Overall no evidence of major contribution from this locus to susceptibility
G908R polymorphism associated with disease. No significant association with R702W or 3020insC No association found Variants compared with published SNP frequencies for controls No association found for R702W, G908R, or L1007fsinsC
125
124
123
122
122
122
References
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German study Complete families: 302 patients, 153 close relatives without sarcoidosis Trios: 127 patients, 254 parents without sarcoidosis
13 sarcoidosis patients with uveitis, 13 sarcoidosis without
Association (sequencing)
100 Greek patients, 150 controls
159 C ? T associated with disease
No association found with Asp299Gly and Thr399Ile
100 Greek patients, 150 controls
Association (RFLP and SSP-PCR) Association (RFLP and SSP-PCR) Association (RFLP and SSP-PCR) 100 Greek patients, 150 controls
Notes
Population
Study type
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Position
17q23.3
Xp22
ACE1
ACE2
Angiotensin I converting enzyme 1
Angiotensin I converting enzyme 2
Official name
Official symbol
Table 3 (Continued )
Association (SSP-PCR)
Association (PCR length polymorphism) Association (SSP-PCR)
Association (PCR length polymorphism) Association (PCR length polymorphism) Association (SSP-PCR)
265 healthy controls
Association and Linkage (TaqMan) Association
Gender-dependent increased risk of parenchymal lung disease
No association with susceptibility, severity, fibrosis or progression
184 U.K. patients, 386 controls 56 Czech patients, 179 controls 144 Dutch patients, 328 controls
61 Italian patients, 80 controls
Gender-dependent increased risk of parenchymal lung disease No association found
127
DD genotype conferred a threefold increased risk for sarcoidosis No association found
Genetics of ILD (Continued)
130
129
128
130
128
126
References
No association found
Notes
144 Dutch patients, 328 controls
60 white American patients, 48 controls
67 Italian patients, 76 IPF, 424 controls 183 African American patients, 111 controls
Population
Study type
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2q33
4p16.3
CTLA-4
Cytotoxic T-lymphocyteassociated protein 4
3q21
TNFAIP3 interacting TNIP2 protein 2 (inhibitor protein kB)
CD86
CD86 molecule
3q13.3q21
1q32
CD80
CD80 molecule
Position
Complement CR1 component (3b/4b) receptor 1
Official symbol
Official name
Table 3 Genetics of Sarcoidosis (Continued ) Population
115 U.K. patients, 99 controls 90 Dutch patients, 102 controls
156 Italian patients, 71 COPD, 94 controls
No association with disease susceptibility or BAL cell profiles No association with disease susceptibility or BAL cell profiles No association with susceptibility. Association of 318(C/T) CC genotype ( p ¼ 0.011) and AG or GG genotype at position þ49 (A/G) with ocular disease GG genotype of C5507G (Pro1827Arg) polymorphism associated with disease 881 (A/G), 826 (C/T), and 297 (C/T) studied Association GTT haplotype with disease susceptibility 826T decreased in frequency from X-ray stage II to IV possibly indicating a protective role against fibrosis
Notes
134
133
132
131
131
References
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Association (SSPPCR)
Association (RFLP)
Association (SSCP 146 Japanese patients, 157 controls and direct sequencing) Association (SSCP 146 Japanese patients, and direct 157 controls sequencing) Association 106 Japanese patients, (sequencing) 100 controls
Study type
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Official symbol
IL-1A
IL-18
CCR2
Official name
Interleukin 1, alpha
Interleukin 18
Chemokine (C-C motif) receptor 2
Table 3 (Continued )
3p21.31
11q22.2q22.3
2q14
Position
100 Japanese patients, 122 controls 66 Czech patients, 386 controls 137 Dutch patients, 167 controls
133 Dutch patients, 103 controls
Association (SSP-PCR) Association (RFLP) Association (SSP-PCR) Association (SSP-PCR)
161 Japanese patients, 176 controls
105 African American patients, 95 controls 95 Czech patients, 199 controls 147 U.K. patients, 101 controls 102 Dutch patients, 166 controls 119 Japanese patients, 136 controls
Population
Association (RFLP and SSP-PCR) Association (ARMS)
Association (SSP-PCR) Association
Linkage study
Study type
Trend to reduction not reaching significance No association with disease overall Association of haplotype 2 (A at 6752, A at 3,000, T at 3,547, and T at 4,385) with L€ ofgren’s syndrome
No association of 137 G/C, 607 C/A, or 656 G/T with disease susceptibility Four haplotypes deduced. No association with disease susceptibility V64I reduced in disease
Association with SNP at position 607
Strong linkage of marker with IL-1 Disease association with IL-1a889 SNP No association with disease susceptibility
Notes
Genetics of ILD (Continued)
143
142
141
139
138
137
136
42
135
References
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14q11.2
1q25.2q25.3
Chymase 1, mast cell CMA1
PTGS2
153 Dutch patients, 309 controls 122 Japanese patients, 111 controls 198 U.K. patients, 166 controls
Association with lower iVC in Dutch 765G > C SNP associated with susceptibility and outcome
CCR5D32 associated with disease and within disease associated with those patients requiring steroids Association of one haplotypes with parenchymal lung disease (CXR stage II vs. 0 or 1) and with persistent disease No association with disease overall Association with fibrotic vs. self-limiting disease No overall disease association
Notes
147
146
145
144
142
References
Abbreviations: ARMS, amplification refractory mutation system; PCR-SSO, polymerase chain reaction followed by probing with sequence-specific oligonucleotides; NRAMP, natural resistance-associated macrophage protein gene; RFLP, restriction fragment length polymorphism; SSP-PCR, polymerase chain reaction using sequence-specific primers; SSCP, single-strand conformational polymorphism; SNP, single nucleotide polymorphism.
Association (SSCP)
Association (SSP-PCR)
154 Dutch patients, 315 controls
106 U.K. patients, 142 controls 112 Dutch patients, 169 controls
Association (SSP-PCR)
Association (SSP-PCR)
66 Czech patients, 386 controls
Population
Association (SSP-PCR)
Study type
74
Prostaglandinendoperoxidase synthase 2
19q13.1
TGFB1
Transforming growth factor, beta 1
3p21.31
Position
CCR5
Official symbol
Chemokine (C-C motif) receptor 5
Official name
Table 3 Genetics of Sarcoidosis (Continued )
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Genetics of ILD A.
75
Major Histocompatibility Complex Region
There was much variability in early serological association studies with class I MHC (82–90). This is probably largely to do with methodology and to ethnic differences in the studies. The most consistent association to emerge has been of HLA-B8 with disease of acute onset and brief duration, although it has not been found in all studies and on some occasions the association has been weak. It seems likely that to a large extent the association may in fact be to class II genes in linkage disequilibrium with the class I alleles, a finding that fits more easily with the prominence of CD4þ T cells in the disease. Not withstanding this, Grunewald et al. reported associations of both HLA-B*07 and HLA-B*08 independently of class II genes (91). A variety of associations with class II genes have been found in different ethnic groups. They are complicated by the fact that the class II alleles have been reclassified over the years. The associations found were with HLA-DR5, -DR6, -DR8, and -DR9 in Japanese (92,93); between HLA-DR17(DR3) and acute disease, and between -DR14(DR6) and -DR15(DR2) and chronic disease in Scandinavia (94); in Germans between HLA-DR3 and acute disease and HLADR5 and chronic disease (95,96); in Asian Indians between HLA-DR14(DR6) and chronic disease (97). Despite these apparent differences, HLA-DR1 and -DR4 appear protective in Japanese, Scandinavians, and Italians. Foley et al., studying British, Czech, and Polish patients found an association between the amino acid at position 11 and risk of sarcoidosis (98). This residue is potentially at a crucial position in the HLA-DR molecule, lying between the a and b chains and showed the most variability. Susceptibility alleles contained small hydrophilic amino acids at this position while protective alleles coded for bulky, hydrophobic alleles. Genotyping 406 individuals from the ACCESS study for HLA-DRB1, -DRB3, -DQB1 and -DPB1 genes showed broadly similar associated alleles across ethnic boundaries (99). The HLA-DRB1*1101 allele was associated with sarcoidosis in both African Americans and whites. The population-attributable risk was 16% in African Americans and 9% in whites. The only divergent marker was HLA-DRB1*1501 that was associated with sarcoidosis in whites but was more common among controls than affected individuals within the African American population. Some forms of sarcoidosis can be virtually indistinguishable from chronic beryllium disease. The latter condition has been associated with HLA-DP alleles with a glutamic acid at position 69 of the -DP b1chain. This association has not been found in two association studies of sarcoidosis (100,101). Association with -DPB1 alleles were found in the ACCESS study but these were with HLADPB1*0101. HLA association studies have been bedeviled by the extensive but variable linkage disequilibrium within the region, which is the highest yet reported in the genome (7). Mindful of the importance of HLA in previous studies, Rybicki et al.
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examined linkage with six microsatellite markers across the MHC in 225 African American patients with family members as controls (102). The most tightly linked marker was close to the HLA-DQ locus. HLA-DQ associations were found to be stronger in this population than those with -DRB1 alleles. A subsequent study of this group examined transmission equilibrium of -DQ alleles. DQB1*0602 alleles were inherited by affected offspring 20% more commonly than expected whereas -DQB1*0201 was transmitted to affected individuals only half as much as expected by chance (103). Voorter et al. investigated 149 Dutch sarcoid patients. They too found an association of DQB1*0602, with severe disease, but this time as part of a haplotype with DRB1*1501 (104). Because of the tight linkage between these alleles in the Caucasian population, however, it was not possible to say with which was the primary association. More recently, an association with DQB1*0602 has also been made with a precise sarcoid phenotype, small fiber neuropathy (105). Sato et al. confirmed that in 235 British and Dutch sarcoid patients, individuals with DQB1*0602 tended to have more serious disease whereas DQB1*0201 was associated with milder disease (106). The latter group included patients with erythema nodosum and L€ ofgren’s syndrome. L€ ofgren’s syndrome has previously been associated with an A allele at position –307 of the TNF-a gene and with HLA-DRB1*0301. Genotyping 37 Dutch L€ ofgren’s patients (107) confirmed these associations and found 100% linkage disequilibrium between -DRB1*03 and -DQB1*0201 and 70% between them and the TNF allele establishing an extended MHC haplotype present in 76% of L€ ofgren’s patients (vs. 24% of controls). While L€ ofgren’s syndrome is most common in northern European populations, it is seldom seen in Japanese, among whom the HLA-DR3 allele does not occur. Cardiac sarcoid however does occur at a higher rate than in Caucasians. This complication was found to be associated with an uncommon polymorphism of TNF-A (TNF-A2) (108) and subsequently with DQB1*0601 (109). In this population, the two loci are not linked so the risk factors appear independent of one another. Other than the HLA genes, the MHC also contains other genes responsible for the initiation, targeting, enhancement, and control of the adaptive and to a lesser extent the innate immune response. They therefore arise as candidates whenever strong associations are found with HLA-DQ or -DR alleles. One example is the TAP genes (transporter associated with antigen processing). Foley et al. examined SNPs in the TAP1 and 2 genes in 117 U.K. caucasoids and 87 Slavonic Polish patients compared with ethnically matched controls (110). Different associations were found for the two groups compared with controls for TAP2. These associations were independent of HLA-DR genes. No association, however, was found between TAP1 or TAP2 and disease in a Japanese population (111). The TNF gene complex includes the TNF-a and TNF-b (lymphotoxin a) genes and is also within the MHC region. TNF is a key cytokine in granuloma
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77
formation and is likely key in the pathogenesis of sarcoidosis. Separate associations have been found with L€ ofgren’s syndrome and with severe disease (112). Mrazek et al. confirmed an association of a SNP at TNF-308 with L€ ofgren’s in a cohort of Czech patients (113). To what extent, however, these association are primary or to what extent related to extended MHC haplotypes (107) remains uncertain. Valentonyte et al. performed a SNP screen of 16.4 Mb of chromosome 6p21 and found an association with a 15-kb segment of the gene butyrophilinlike 2 (BTNL2), which was stronger than the association with DR or DQ alleles (114). BTNL2, a member of the B7 receptor family, is proposed to be involved in T cell costimulation. The authors found that the expression of a polymorphism that led to a stop codon impaired membrane localization of the protein. This association has also been reported in white Americans, although the association in African Americans was less strong (115). BNTL2 has recently been reported to inhibit T-cell activation (116) and to be overexpressed in an animal model of colitis (117). Its role in the respiratory tract is currently less clear. Spagnolo et al. have recently reported that the BTNL2 association may, in fact, be due to linkage disequilibrium with HLA-DRB1 (118). B.
Nonmajor Histocompatibility Complex Genes
The group that reported the linkage study of the MHC implicating BTNL2 had previously performed a genome-wide screen using 225 microsatellite markers tested in 63 families with affected siblings (119). The most significant association peak was found in the MHC but minor peaks were identified on chromosomes 1, 3, 7, and 9 and on the X chromosome. By the authors’ admission the markers were widely spaced and therefore of only modest sensitivity but the study does highlight the potential role of genes outside of the MHC. A number of candidate genes have been examined by association. The natural resistance-associated macrophage protein gene (NRAMP) has been associated with susceptibility to tuberculosis. Because of the histopathological similarities with tuberculosis, the association with sarcoidosis was studied (120). A (CA)(n) repeat in the immediate 50 region of the gene was overrepresented in 157 African American patients compared with ethnically matched controls, although the implicated polymorphism differed from both of the two SNPs associated with TB susceptibility. Toll-like receptors are involved in host responses to pathogen-derived molecules including lipopolysaccharide. An association was reported with acute sarcoidosis and two polymorphisms (Asp299Gly and Thr399Ile) in 141 German patients (121), although a Greek group could not repeat the finding (122). The latter group, however, did find associations with a G908R polymorphism in the CARD15/NOD2 gene as well as with a T at position –159 promoter of the CD14 gene. Both of these genes have been implicated in Crohn’s disease, another
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granulomatous condition. Four previous studies, however, have investigated and failed to find an association with the CARD15/NOD2 gene (123–126). 1.
Angiotensin-Converting Enzyme
Sarcoidosis can be associated with an elevated level of angiotensin-converting enzyme (ACE). Although this is raised only in about 60% of cases, an abnormal ACE level at presentation allows it to be used in monitoring disease. An insertion (I)/deletion (D) polymorphism affects circulating levels. While Maliarik et al. found an association of the DD variant with sarcoidosis in African American patients with sarcoidosis (127), they were unable to show this for their white Caucasian patients. Other groups have also failed to replicate the finding (128,129). More recently, however, a study of Dutch sarcoidosis patients found that a haplotype of seven SNPs in the gene of a homologue of ACE (ACE2) was associated with a gender-dependent increased risk of parenchymal lung disease (130). 2.
Lymphocyte Costimulatory Molecules
The reported association with BNTL2, a putative T-cell costimulatory molecule, has already been mentioned (114). Prior to its reporting other groups investigated similar molecules. Handa et al. studied polymorphisms of CD80 and CD86, also members of the B7 family, in 146 Japanese patients but found no associations with the disease (131). Hattori et al. explored polymorphisms in CTLA-4, a costimulatory molecule that engages members of the B7 family (132). Although no association was found with sarcoidosis overall, there was an association with the 318(C/T) CC genotype and AG or GG genotype at position þ49(A/G) with ocular disease in this Japanese population. As in IPF, complement receptor polymorphisms have been examined in sarcoidosis, testing the hypothesis that they may affect clearance of immune complexes. Associations of the GG genotype for the Pro1827Arg (C5507G) polymorphism of the CR1 gene were found (133) although these have yet to be replicated. The nuclear factor kappa B (NF-kB) transcription factor family is a critical regulator of immunologically mediated immediate transcriptional responses and is involved in cytokine gene expression. Activation of the NF-kB signaling pathway has been linked to the pathogenesis of sarcoidosis. The inhibitor protein kB (IkB) is crucial in terminating its action. Abdallah et al. studied three promoter SNPs at positions 881 (A/G), 826 (C/T), and 297 (C/T) in 205 United Kingdom and Dutch sarcoidosis patients and found an association with the GTT haplotype with disease susceptibility, while the 826T allele decreased in frequency from X-ray stage II to IV, possibly indicating a protective role against fibrosis (134). No association was found with lung function. The functional consequences of these variations remain unknown.
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Cytokines and Their Receptors
Variations in the cytokine genes have been suspected to affect sarcoidosis pathogenesis. An early linkage study examined anonymous polymorphic genetic markers tightly linked to chromosome regions containing TCR, IL, and interferon regulatory factor (IRF) genes in 105 African American patients. One of these two markers most strongly associated was within the IL-1 gene (135). An association was found with an IL-1a-889 CC genotype in 95 Czech patients (42), although this could not be replicated among 147 U.K. and 102 Dutch patients (136). IL-18 polymorphisms have also been studied, including those at positions 607 and 137 in the promoter. A haplotype consisting of an A at 607 and a C at 137 is known to have reduced promoter activity and so is predicted to lead to a lower level of the cytokine when stimulated. Takada et al. reported a disease-related association of an A > C allele at 607 among 119 Japanese patients (137), although this could neither be confirmed in another Japanese study (138) or in a study of 133 Dutch patients (139). The whole genome linkage study (119) identified a minor peak at chromosome 3. This corresponds to the location of the CCR2 and CCR5 chemokine receptors. These genes have come under a great deal of scrutiny following the finding that a polymorphism in CCR2 leading to a substitution of isoleucine for valine at position 64 (V64I) slows progression to AIDS in patients infected with HIV (140). The same polymorphism was found to be reduced in frequency in 100 Japanese sarcoidosis patients (141). A subsequent Czech study again showed a trend toward a reduction in frequency although this did not meet statistical significance (142). Spagnolo et al. investigated the CCR2 gene in more detail, analyzing eight SNPs across the gene. While there was no overall association with sarcoidosis, an association was found between L€ ofgren’s syndrome and a novel haplotype (haplotype 2), which includes four unique alleles (T at nucleotide position 4,385, T at 3,547, A at 3,000, and A at 6,752) (143). It was not possible to say if this association held for patients with L€ ofgren’s independent of the HLA DRB1*0301-DQB1*0201 haplotype previously associated with the disease and further ethically different cohorts will be needed to tease this out. The defined CCR2 haplotype was more common among HLA DRB1*0301-DQB1*0201 negative L€ ofgren’s patients but numbers were too small to reach significance. The CCR5 gene lies close to CCR2 on chromosome 3. CCR5 acts as a receptor for MIP-a and RANTES. A 32-base pair deletion in the gene that renders the receptor nonfunctional has been associated with sarcoidosis in a study of 66 Czech patients (142). Although no association was found in a cohort of British and Dutch patients between the polymorphism and risk of sarcoidosis, Spagnolo et al. found an association between parenchymal lung disease (radiological stage II or greater compared with stages 0 or I) and persistent parenchymal lung disease (144).
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As with CCR5, TGF polymorphisms appear to affect the likelihood of fibrotic disease rather than susceptibility to disease per se. Studying 154 Dutch sarcoidosis patients Kruit el al. found that the TGF-b3 4875 A and 17369 C alleles were more common in fibrotic disease than self-limiting disease, although there was no overall difference in allelic frequency between sarcoidosis patients overall and controls (145). 4.
Other Inflammatory Mediators
Workers from the same Dutch group also examined genetic polymorphisms in chymase, a mediator secreted by activated mast cells and implicated in tissue damage, in Dutch and Japanese patients (146). While no association was found with disease susceptibility, the 526 C/T SNP was associated with a lower inspiratory vital capacity in Dutch patients, suggesting it may be involved in functional outcome in sarcoidosis. Another mediator thought to be important in lung fibrosis is prostaglandin E2. It is found in decreased concentrations in the lungs of patients with sarcoidosis and may protect against fibrosis. A 765G > C polymorphism in the enzyme prostaglandin-endoperoxidase synthase has been shown to reduce its expression. Hill et al. found an association between the C allele and both disease susceptibility and outcome in 198 British patients (147). They replicated their findings in a second cohort of Austrian patients. VI.
Hypersensitivity Pneumonitis
As with many diseases a number of early studies of hypersensitivity pneumonitis (HP) were involved HLA associations determined serologically; results were variable (148–152). Camarena et al. studied class II alleles genetically in 44 Mexican patients with pigeon breeder’s disease (153). They found a significant increase in HLA-DRB1*1305 and HLA-DQB1*0501 compared with 50 exposed but asymptomatic subjects and 99 healthy controls. There was also an increased frequency in a TNF-a promoter G > A polymorphism at position 308. This mutation has been associated with higher levels of TNF-a production (154). The TNF polymorphism was confirmed to be associated with disease in 20 German patients with farmer’s lung although not statistically significantly with pigeon breeder’s lung (155). However, a study of 61 Japanese patients with HP (bird fancier’s lung and summer-type HP) failed to show any such association with disease (156). Tissue inhibitors of metalloproteinases (TIMPs) are involved in the turnover of extracellular matrix in the lung. They have been implicated in the pathogenesis of fibrosing lung diseases. Hill et al. examined two SNPs in TIMP-3 ( 915A > G and –1296T > C) and found that the *G*C haplotype appeared protective against pigeon breeder’s disease in a cohort from Mexico (157). A similar result was found in 41 Dutch patients (158).
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DNA Microarrays and High-Throughput Genotyping
Two related but separate technologies have aroused much interest recently. Microarrays have been developed to study simultaneously the levels of thousands of mRNAs in a cell or tissue of interest. By assessing which genes are upor downregulated and by grouping genes by function or ontology, investigators are able to draw conclusions about the underlying biology using a ‘‘systems biology’’ approach (159). Using this technique, Selman et al. were able to distinguish biopsies of HP from IPF (160). In HP, genes related to immune activation were upregulated, whereas in IPF it was genes involved in the cell cycle and in tissue remodeling. Microarrays from biopsies with NSIP seemed either to resemble those of IPF or of HP rather than having a distinct pattern of their own. These techniques have also been used to compare gene expression profiles in familial and sporadic interstitial pneumonia (161). The authors found that there were greater differences between familial and sporadic disease than were between IPF and NSIP. This is despite the apparent differences between familial and sporadic disease with respect to clinical course (162,163). The accompanying editorial however points out that the same classes of genes were involved in both familial and sporadic disease (164). Differences were in levels of up- or downregulation of particular genes which may in part be explained by the stage of disease at the time of sampling (e.g., surgical biopsy vs. transplant explant or autopsy). In particular samples taken from surgical biopsies may reflect more active disease and so have higher mRNA levels than samples from ‘‘burnt-out’’ disease taken at autopsy. Overall these studies provide a new insight into the pathology of ILDs and may suggest targets to explore by genotyping. More recently, it has become possible to assess variations in individual human genomes rapidly using high-throughput genotyping. A variety of technologies are employed including hybridization of genomic DNA to complementary oligonucleotides on an array (as in microarrays) or new techniques allowing rapid sequencing of genomic fragments. While many techniques claim to be able to assess thousands of SNPs quickly and relatively cheaply, some have been limited by the length of the fragments they can assess. This is crucial because of the phenomenon of phase. Two SNPs lying close to one another and each predicted to alter gene function will differ greatly in overall effect depending on whether they lie on the same haplotype or on different chromosome strands. It is possible that two ‘‘inactivating’’ SNPs on the same haplotype would lead to a single nonfunctional gene. The complementary functioning allele is likely to mask any effect. However, if they occur on separate strands, they would inactivate both alleles leading to no functioning protein. Furthermore, there are limitations to using this technology in the analysis of complex genes including the HLA and cytochrome p450 genes. The length of contiguous chromosome requiring analysis depends on the extent of linkage disequilibrium at a particular locus. In the case of the MHC region this is extensive. Given the importance of HLA associations in many diseases this remains a serious limitation.
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Conclusions
A great deal of genetic information has now accrued on individual interstitial lung and bronchiolar diseases. Much data from association studies has not been repeated by other groups. Problems are faced because of linkage and ethnic admixture. However, some patterns are emerging. While some genetic predispositions to IIPs are known, it is not clear to what extent they will be responsible for the majority of sporadic cases. It is intriguing how within families with a defined genetic abnormality phenotype can vary, for example, between NSIP and IPF. This may suggest that other factors, both genetic and environmental, affect the expressed phenotype. While DPB with its tendency to affect only Japanese and Korean patients, may be caused by one or only a few genes, HP may have various genetic associations depending on the exact eliciting antigen. For systemic sclerosis the strongest genetic associations are with autoantibody subset. These subsets further delineate the patterns of organ involvement with pulmonary fibrosis being common in the presence of anti-topoisomerase antibodies and uncommon with anti-centromere positivity. In sarcoidosis, different associations are seen in L€ ofgren’s syndrome, in lung manifestations, and more recently in ocular disease to suggest that they may actually comprise different, albeit closely related, diseases. Certainly precise phenotyping appears to be pivotal in establishing meaningful findings. This will be particularly important as new highthroughput techniques start to be applied to the genetics of interstitial pulmonary and bronchiolar disorders.
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62. Kim DS, Yoo B, Lee JS, et al. The major histopathologic pattern of pulmonary fibrosis in scleroderma is nonspecific interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19(2):121–127. 63. Mayes M, Reveille JD. Epidemiology, demographics, and genetics. In: Clements PJ, Furst DE, eds. Systemic Sclerosis. Philadelphia: Lippincott Williams & Wilkins, 2004:1–16. 64. Feghali-Bostwick C, Medsger TA Jr., Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum 2003; 48(7):1956–1963. 65. Gilchrist FC, Bunn C, Foley PJ, et al. Class II HLA associations with autoantibodies in scleroderma: a highly significant role for HLA-DP. Genes Immun 2001; 2(2):76. 66. Kuwana M, Kaburaki J, Okano Y, et al. The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma). J Clin Invest 1993; 92(3):1296–1301. 67. Sato H, Lagan AL, Alexopoulou C, et al. The TNF-863A allele strongly associates with anticentromere antibody positivity in scleroderma. Arthritis Rheum 2004; 50(2):558–564. 68. Assassi S, Tan FK. Genetics of scleroderma: update on single nucleotide polymorphism analysis and microarrays. Curr Opin Rheumatol 2005; 17(6):761–767. 69. Avila JJ, Lympany PA, Pantelidis P, et al. Fibronectin gene polymorphisms associated with fibrosing alveolitis in systemic sclerosis. Am J Respir Cell Mol Biol 1999; 20(1):106–112. 70. Tew MB, Reveille JD, Arnett FC, et al. Glutathione S-transferase genotypes in systemic sclerosis and their association with clinical manifestations in early disease. Genes Immun 2001; 2(4):236–238. 71. Wu SP, Leng L, Feng Z, et al. Macrophage migration inhibitory factor promoter polymorphisms and the clinical expression of scleroderma. Arthritis Rheum 2006; 54(11):3661–3669. 72. Gourh P, Tan FK, Assassi S, et al. Association of the PTPN22 R620W polymorphism with anti-topoisomerase I- and anticentromere antibody-positive systemic sclerosis. Arthritis Rheum 2006; 54(12):3945–3953. 73. Siracusa LD, McGrath R, Ma Q, et al. A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation. Genome Res 1996; 6(4): 300–313. 74. Arnett FC, Howard RF, Tan F, et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis Rheum 1996; 39(8):1362–1370. 75. Tan FK, Stivers DN, Foster MW, et al. Association of microsatellite markers near the fibrillin 1 gene on human chromosome 15q with scleroderma in a Native American population. Arthritis Rheum 1998; 41(10):1729–1737. 76. Tan FK, Wang N, Kuwana M, et al. Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations. Arthritis Rheum 2001; 44(4):893–901. 77. Zhou X, Tan FK, Reveille JD, et al. Association of novel polymorphisms with the expression of SPARC in normal fibroblasts and with susceptibility to scleroderma. Arthritis Rheum 2002; 46(11):2990–2999.
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4 Pathology of Diffuse Interstitial Lung Disease
W. DEAN WALLACE, CHI LAI, and MICHAEL C. FISHBEIN Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
I.
Interstitial Lung Disease
Pathologic evaluation of interstitial lung disease (ILD) should always follow appropriate clinical and radiologic workup. The pathologist should always be mindful of this as these data can be very helpful in interpretation. Very often, if the clinical disease picture is classic enough, the surgical lung biopsy is rendered unnecessary. Nevertheless, as both clinical and radiologic features can be nonspecific and many individual diseases have atypical features, the role of the pathologist is still important and essential in many cases (1). Both the clinician and pathologist should be aware of the limitations of the lung biopsy. Transbronchial biopsy has quite a limited role in evaluation of ILD with the most notable exceptions being for the diagnosis of sarcoidosis and infections and to exclude other disorders. In most other settings, the biopsy material is too small and nonspecific for a reliable interpretation (2). The optimum specimen for pathologic evaluation is multiple wedge biopsies from at least two lobes. Radiologic correlation should guide the surgeon to the best area for sampling. The specimens should not be sampled from the most severely affected area and should contain adjacent normal appearing tissue, 93
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if possible. The apices and most peripheral tips of the lobes should generally be avoided as they may only show nonspecific changes. If an infectious etiology is in the differential diagnosis, tissue should be taken for cultures directly from the operating room as this reduces the risk of specimen contamination (3–7). A.
Usual Interstitial Pneumonia
Usual interstitial pneumonia (UIP) is probably best regarded as a pattern of interstitial fibrosis. It may be idiopathic in about 50% of cases, or secondary to one of several known conditions such as collagen vascular diseases (CVD), chronic hypersensitivity pneumonitis, pneumoconioses, sarcoidosis, or druginduced disease to name but a few (8–10). It is the rare pathologist who always gets sufficient clinical and radiologic information to unequivocally rule out all secondary causes of UIP. Therefore, our group tends to use the terminology, ILD consistent with UIP pattern. If histologic features are present that suggest or confirm a specific etiologic entity, then those features should be highlighted. It is important to remember that clinical and radiologic data can trump microscopic findings by the pathologist and a good working relationship between clinicians, radiologists, and pathologists is essential (1,11). Likewise, the histologic diagnosis of UIP is only possible with an adequate wedge biopsy (or larger) that contains areas of normal lung. A biopsy that consists entirely of scarred lung tissue with honeycomb changes is neither specific nor sufficient for a histologic diagnosis of UIP. UIP is histologically characterized by progressive interstitial fibrosis with extensive architectural remodeling. The fibrosis is nearly always more severe in the lower lobes and the inferior portions of the upper lobes (3,6,8). If the fibrosis is equally distributed or more severe in the upper lobes then a diagnosis other than idiopathic UIP should be strongly considered. The UIP pattern of interstitial fibrosis has several classic features, not all of which are needed for a diagnosis of UIP pattern (Fig. 1). The fibrosis tends to be accentuated at the periphery of the lobules, especially in the subpleural area, with relative sparing around the bronchovascular bundle. As the fibrosis progresses there is often obliteration of entire lobules and the peripheral-lobular distribution may not be appreciated in areas of most severe scarring. One feature that is essential for the diagnosis of UIP is adjacent anatomically normal alveolar tissue (3,11). The abrupt transition between interstitial fibrosis with architectural remodeling and normal lung is characteristic and demonstrative of the ‘‘spatial heterogeneity’’ that is a key feature of the UIP pattern. The areas of fibrosis also tend to be at different stages of progression in different areas. In some locations the interstitial fibrosis appears ‘‘fresher’’ with edema and a scattered lymphocytic infiltrate; in other areas the scarring appears to be denser and older. This feature is termed ‘‘temporal heterogeneity’’ and is characteristic of UIP. At the edge of the encroaching fibrosis there are often fibroblastic foci present. Fibroblastic foci consist of crescent-shaped or oval outpouchings of
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Figure 1 (See color insert.) Usual interstitial pneumonia. (A) Gross photograph of explanted left lung with UIP. Note the greater involvement in the lower lobe and lower portion of the upper lobe. (B) Involvement of peripheral and subpleural area with fibrosis and architectural remodeling (original magnification, 40; H&E stain). (C) Sharp contrast between area of interstitial fibrosis (right) and normal lung (left) (original magnification, 40; H&E stain). (D) Crescent-shaped fibroblastic fibrosis with fresh fibrosis at edge of encroaching fibrosis (original magnification, 200; H&E stain). (E) Architectural remodeling with honeycomb change demonstrating cysts lined by bronchiolar epithelium and filled with mucin-containing inflammatory cells (original magnification, 40; H&E stain). Abbreviation: UIP, usual interstitial pneumonia.
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fresh, edematous fibrous tissue. The fibrosis has similar consistency to that seen in organizing pneumonia and may easily be mistaken for it. The connective tissue in organizing pneumonia is generally intra-alveolar, polypoid, and connected by a stalk to a nearby airway or alveolar wall. Organizing pneumonia is often associated with airways, while fibroblastic foci are typically at the edge of the lesions of interstitial fibrosis within alveolar septae rather than alveolar spaces. Some authors have suggested that the presence and number of fibroblastic foci may be an indication of the activity of the interstitial fibrosing process. It is important to remember that fibroblastic foci are characteristic of, but not specific for, UIP (7,10,12,13). A useful, but nonspecific, feature of UIP is honeycomb change in the areas of dense interstitial fibrosis. The scarring associated with UIP tends to destroy most airspaces and airways it encounters but invariably some airspaces remain. These airspaces develop lining of ciliated respiratory epithelium in a process termed bronchiolization. The airspaces fill with mucin that often contains inflammatory cells, especially neutrophils. The presence of neutrophils within the mucin does not in itself suggest an infectious process. Honeycomb changes are usually most severe at the lung peripheries and in the lower lobe. In some clinical settings, the presence of honeycomb changes recognized by radiologic images may supplant the need for a surgical biopsy (5). While UIP is typically a disease with slow progression, some patients experience more rapid deterioration in pulmonary function. This ‘‘exacerbation’’ of UIP is histologically characterized by acute lung injury superimposed on a background of UIP pattern of fibrosis. The acute lung injury manifests as type II pneumocyte metaplasia, organizing pneumonia, and interstitial and alveolar edema, with or without hyaline membranes characteristic of diffuse alveolar damage (DAD) (6,13). The presence of acute lung injury should initiate a search for potential causes such as infection or a hypersensitivity reaction. Immunoperoxidase stains for viral inclusions, including cytomegalovirus and adenovirus, may be useful, especially in immunocompromised patients. The presence of numerous eosinophils may indicate an acute eosinophilic pneumonia with acute lung injury. The presence of eosinophilia should be noted by the pathologist as it could indicate a separate treatable process from the UIP. Very prominent muscular pulmonary artery thickening may be seen in any disease with interstitial fibrosis including UIP. The arteries thicken in response to changing pressures associated with the restrictive infiltrating fibrosis through the lungs and the loss of the capillary bed in the areas of scarring. The presence of pulmonary artery thickening may be remarked upon but should not warrant an investigation for pulmonary hypertension unless specific vascular abnormalities such as plexiform or angiomatoid lesions are seen. In all patterns of interstitial fibrosis, fatty metaplasia may develop. This is usually seen in the immediate subpleural area but is not specific for UIP. For some reason, when fibrosis occurs in the lung, it is often accompanied by smooth muscle hypertrophy and hyperplasia that may be quite prominent.
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The lymphoplasmacytic interstitial infiltrates seen in UIP are generally sparse in comparison to other entities such as nonspecific interstitial pneumonia (NSIP) or hypersensitivity pneumonitis (HP). Extensive cellular infiltrates or follicular lymphoid hyperplasia should lead to consideration of other entities that may cause a UIP pattern of fibrosis such as CVD or HP. Pleural inflammation is not a feature of idiopathic UIP, and its presence indicates a second process or secondary form of UIP with pleuritis, most likely a CVD such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) (14). The UIP pattern of fibrosis may be seen concurrently in a patient with NSIP type fibrosis in other lobes. In this setting, it is important to emphasize the UIP pattern as this dominates the clinical course (11,15–17). An important consideration in evaluation of the pathology specimen with UIP is concurrent carcinoma. When present, carcinomas tend to be peripheral and in areas of fibrosis (12). Studies in the literature have reported rates of concurrent squamous and adenocarcinoma in UIP patients at as much as 31% (6). The prevalence of concurrent malignancy in our experience is not this high; nevertheless, the frequency is certainly higher than the normal population and demands careful review of the pathology material. Some studies have found only fair reproducibility for interpretation of ILD even among pulmonary pathologists, especially in distinguishing UIP from NSIP. However, radiologic studies and clinical assessment have similar suboptimal reproducibility results (1,18). Therefore, clinical criteria, imaging findings, and pathologic evaluation are all important for the definitive diagnosis of UIP (3). B.
Nonspecific Interstitial Pneumonia
The term nonspecific interstitial pneumonia (NSIP) was coined by Katzenstein and Fiorelli in 1994 to account for a pattern of interstitial fibrosis that appeared to have distinct features from UIP. Notably, it was observed that in some patients the interstitial process was more cellular than was typical for UIP and the characteristic features of spatial and temporal heterogeneity were not seen. Therefore, a new term, NSIP, was introduced (19). As with UIP, the NSIP pattern can be primary or secondary to numerous causes (6,12,20). Therefore, the pathologist should regard his/her role to be that of pattern recognizer and generally leave ultimate diagnosis to the managing clinician. Histologically, NSIP can be categorized into one of three patterns: cellular, fibrotic, or mixed. The hallmark of NSIP is homogeneity of the cellular of fibrosing process with gradual transition from normal lung anatomy to severe involvement (Fig. 2) (15). NSIP, cellular pattern, consists of interstitial lymphoplasmacytic infiltrates without specific accentuation in any portion of the lobules. If the infiltrate shows a preference for the centrilobular interstitium then another pattern, such as HP,
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Figure 2 (See color insert.) Nonspecific interstitial pneumonia. (A) NSIP fibrotic pattern: interstitial fibrosis in a temporally and spatially homogeneous pattern (original magnification, 20; Masson’s trichrome stain). (B) NSIP cellular pattern: interstitial lymphocytic infiltrates in a temporally and spatially homogeneous pattern (original magnification, 40; H&E stain). (C) NSIP fibrotic pattern: interstitial fibrosis in a temporally and spatially homogeneous pattern (original magnification, 200; H&E stain). Abbreviation: NSIP, nonspecific interstitial pneumonia.
should be considered. Very prominent infiltrates should warrant consideration for lymphoid interstitial pneumonia (LIP) or a low-grade lymphoma. Follicular lymphoid hyperplasia is not a feature of cellular NSIP and rather indicates CVD such as Sjo¨gren disease or immunoglobulin deficiency, especially in children. Likewise, granulomas and pleural inflammation are not features of idiopathic cellular NSIP and are more suggestive of sarcoidosis, HP, or CVD (21,22). NSIP, fibrosing pattern, is characterized by a temporally and spatially homogenous distribution of interstitial fibrosis that is distinct from UIP. Initially, there is preservation of the underlying architecture with distortion only seen later in the course. Fibroblastic foci may be seen but tend to be inconspicuous. There is no preferential area of involvement in the pulmonary lobule that is seen in UIP. Honeycomb changes may be seen in areas of severe fibrosis and are an important prognostic feature, indicating a course more similar to UIP. It is often difficult to distinguish NSIP with honeycomb changes from UIP but, as both entities have indistinguishable clinical features, it may be argued that this is unnecessary (7,16). NSIP, mixed cellular and fibrotic patterns, essentially is a histologic combination of the two and is presumably an intermediate step of progression from cellular to fibrotic NSIP.
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Hypersensitivity Pneumonitis
HP is an important cause of ILD and requires careful consideration by the pathologist. Features of HP range from subtle to severe and may have overlapping features with other entities such as NSIP, infection, and aspirationassociated lung disease. HP is an airway-centered ILD that may be acute or chronic. Acute HP is a type III hypersensitivity reaction, and chronic HP is a type IV hypersensitivity reaction. In both cases, the antigen is introduced to the lung through the airways and results in airway inflammation of some degree (23). Bronchioles may show features of constrictive bronchiolitis with subepithelial granulation tissue and fibrosis; however, complete luminal obliteration is not seen. As the disease progresses, peribronchiolar metaplasia develops via the canals of Lambert, also called Lambertosis (24). The classic histologic picture of HP is lymphoplasmacytic interstitial infiltrates with scattered poorly formed granulomas (Fig. 3). The interstitial infiltrates may show proclivity for the center of the lobules around the airways;
Figure 3 (See color insert.) Hypersensitivity pneumonitis. (A) Interstitial lymphoplasmacytic infiltrates in a temporally and spatially homogeneous pattern (original magnification, 20; H&E stain). (B) Peribronchiolar metaplasia (also called Lambertosis) in center of picture (original magnification, 20; H&E stain). (C) Poorly formed granuloma with giant cell and scattered macrophages (original magnification, 400; H&E stain).
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however, this feature may not always be evident. Occasional eosinophils and rare neutrophils may be present but should not be numerous (23,25). Scattered throughout the interstitium are poorly formed granulomas consisting of small clusters of epithelioid histiocytes and occasional giant cells. The granulomas tend to be near airways or arteries. If the granulomas are well formed or contain necrosis other diseases should be considered such as sarcoidosis or infection. The giant cells may contain small stellate-shaped asteroid bodies or calcified Schaumann bodies. Airspaces often contain scattered polyps of organizing pneumonia. Granulomas that appear to be ‘‘floating’’ in airspaces are more characteristic of an infectious process. If characteristic clinical and histologic features of both HP and an infectious process are present, it is important to recognize both entities. This is because some infections can lead to a hypersensitivity reaction, for example, Mycobacterium avium can result in ‘‘hot tub lung’’ in which an active mycobacterial infection and hypersensitivity reaction are occurring concurrently. Chronic HP may result in interstitial fibrosis in either a UIP or NSIP pattern. Honeycomb changes may be present in areas of severest scarring (25). Entities in the differential diagnosis for HP include, but are not limited to, NSIP, infection, and aspiration bronchiolitis. Granulomas are not a feature of NSIP and the granulomas in infections and aspiration tend to be well formed. However, granulomas may be poorly formed in patients treated with steroids. Recognition of organisms with special stains or food particles may be very helpful in arriving at the correct diagnosis. D.
Acute Interstitial Pneumonia
Acute interstitial pneumonia is simply idiopathic acute respiratory distress syndrome (ARDS) (26,27). As such, it should be regarded by the pathologist as a clinical diagnosis. The histologic features of acute interstitial pneumonitis (AIP) are the various phases of DAD. Initially, an increase of capillary leukocytes including neutrophils, macrophages, and lymphocytes are seen. Within a day, interstitial edema becomes more evident and type I pneumocytes undergo type II metaplasia and become swollen. As the alveolar wall becomes necrotic, fibrin and cellular residue forms a layer of eosinophilic material that lines the alveolar wall, the socalled hyaline membrane. Hyaline membranes are the defining feature of DAD. As the disease process progresses, polyps of organizing pneumonia develop and tend to replace the hyaline membranes (Fig. 4) (3,27,28). Interstitial fibrosis can develop very quickly and honeycomb changes may be present within three to four weeks. Therefore, it is important to recognize etiologic agents when possible as removal or treatment of the offending agent may alleviate the tissue damage and result in resolution before irreversible scarring develop. There are numerous potential causes of DAD, some of which have features that may be recognized histologically. Generally, the first consideration is
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Figure 4 (See color insert.) Acute interstitial pneumonitis. (A) Acute diffuse alveolar damage with alveolar walls lined by eosinophilic hyaline membranes and expanded by edema and leukocytes (original magnification, 200; H&E stain). (B) Chronic diffuse alveolar damage with interstitial fibrosis and architectural remodeling (original magnification, 100; H&E stain).
infection for which microbiologic cultures and appropriate laboratory studies are of paramount importance. The presence of viral inclusions, identified with or without the aid of immunohistochemistry stains, can confirm the diagnosis of viral disease. Bacterial and fungal infections usually present with a focal nodular lesion or lesions but should not be discounted in the immunocompromised patient where the process may be more diffuse and cause ARDS. Acute eosinophilic pneumonia can cause DAD. In this setting, eosinophils are usually numerous; however, they can quickly disappear following steroid treatment. Therefore, eosinophilic pneumonia is always in the differential diagnosis in the setting of DAD in a patient who has previously been treated with steroids. CVD, especially lupus, and drug toxicity can cause a picture of DAD identical to AIP. Histologic clues to the presence of CVD include pleural inflammation, follicular lymphoid hyperplasia, and the presence of capillaritis, which is engorgement of alveolar capillaries with numerous neutrophils (14). The presence of numerous foamy macrophages or foamy epithelial cells is sometimes seen in drug-associated acute lung injury (6). With either CVDs or drug toxicity, clinical correlation is required for the diagnosis. E.
Cryptogenic Organizing Pneumonia
The term cryptogenic organizing pneumonia (COP) refers to a distinct clinicopathologic entity of unknown etiology characterized by a histologic pattern of patchy organizing pneumonia (3,29,30). Organizing pneumonia is a relatively common, nonspecific manifestation of acute lung injury due to a wide variety of etiologies. These include reaction to a specific injury such as infections, drug reactions, toxic inhalants, CVD, radiation pneumonitis, and vasculitides; nonspecific reactive change at periphery of mass lesions such as neoplasms,
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Figure 5 (See color insert.) Cryptogenic organizing pneumonia. (A) Multiple patchy, temporally homogeneous, and polypoid fibroblastic plugs within distal airways, alveolar ducts, and peribronchiolar airspaces. Intervening areas of uninvolved lung are normal without significant architectural distortion (original magnification, 40; H&E stain). (B) Fibroblastic plug comprised of spindle-shaped cells within a relatively collagen poor, slightly basophilic acid mucopolysaccharide ground substance with scattered mononuclear inflammatory cells (400; H&E stain).
granulomas, and abscesses; or minor component of other pulmonary diseases such as NSIP, HP, and eosinophilic pneumonia (31–36). Microscopically, COP is characterized by patchy, temporally uniform, arborizing, and polypoid plugs of fibroblastic tissue that fill the bronchiolar lumens and peribronchiolar airspaces (Fig. 5) (37–39). The lung architecture is usually preserved without significant interstitial fibrosis. The intervening lung parenchyma between foci of organizing pneumonia is usually unremarkable or may exhibit changes of bronchiolar obstruction with intra-alveolar accumulation of foamy macrophages. The fibroblastic tissue consists of plump spindle-shaped cells embedded within a relatively collagen-poor, slightly basophilic acid mucopolysaccharide ground substance with variable numbers of mononuclear inflammatory cells. The fibrous plugs may eventually become lined by alveolar epithelial cells. Type II pneumocyte hyperplasia and a variable chronic inflammatory infiltrate of the alveolar septa may develop. Because of the large number of pathologic processes that can give rise to a histologic pattern of COP, a careful histopathologic examination should be performed to look for findings that might suggest an underlying condition. If no etiology can be determined pathologically, then the term ‘‘organizing pneumonia in a COP pattern’’ may be used. The differential diagnosis of the histologic pattern of COP includes the organizing phase of DAD and UIP, both of which may demonstrate fibroblastic proliferation. Organizing DAD shares some morphologic similarities with COP, but in contrast to the latter, DAD is typically a
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diffuse rather than a patchy, bronchiolocentric process. The fibroblastic foci of UIP can be confused with the fibroblastic plugs of COP. The former are usually smaller, nonbranching, nonbronchiolocentric, and located within the interstitium. To complicate matters, some cases of UIP in the accelerated phase may also exhibit organizing pneumonia. In these cases, however, the typical histologic changes of UIP are present. F.
Lymphoid Interstitial Pneumonia
LIP is a clinicopathologic entity characterized by a very prominent cellular lymphoplasmacytic interstitial infiltrate. Although it is classified as an idiopathic interstitial pneumonia (3), it is rarely idiopathic and more often due to one of a variety of conditions including infections (especially Epstein-Barr virus, human immunodeficiency virus, and Pneumocystis jiroveci), chronic active hepatitis, CVD such as Sjo¨gren syndrome and SLE, drug toxicity, immunodeficiency states, and after bone marrow transplantation (21,40–53). Primary B-cell lymphomas may develop in approximately 5% of patients with LIP associated with Sjo¨gren syndrome (54). Histologically, LIP exhibits a diffuse and densely cellular interstitial inflammatory infiltrate that markedly expands and distorts the alveolar septa (44,50,55). The inflammatory infiltrate consists mostly of small, mature lymphocytes, macrophages, and plasma cells (Fig. 6). LIP may also contain reactive lymphoid follicles along airways and lymphatic routes as well as occasional small, poorly formed, nonnecrotizing granulomas with or without multinucleated
Figure 6 (See color insert.) Lymphoid interstitial pneumonia. (A) Diffuse and densely cellular interstitial inflammatory infiltrate that markedly expands and distorts the alveolar septa with compression of the alveolar spaces (original magnification, 40; H&E stain). (B) Narrowed alveolar spaces due to significant expansion and distortion of the alveolar septa (original magnification, 200; H&E stain).
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giant cells. Immunohistochemically, the lymphoid population consists of a polyclonal mixture of B and T lymphocytes (44,54,56). The B lymphocytes are mostly confined to the germinal centers and the T lymphocytes are usually present within the interstitium. Despite the similarity to cellular NSIP, LIP is usually distinguished from it by the greater intensity of the lymphoid infiltrate. Other helpful features include more extensive fibrosis in NSIP and more prominent lymphoid follicles in LIP. The presence of occasional small, poorly formed, nonnecrotizing granulomas should raise the suspicion of HP, drug reaction, or infection, particularly due to atypical mycobacteria. Distinguishing HP from LIP requires recognition of the diffuse and heavier interstitial lymphoid infiltrate of LIP; the patchy, bronchiolocentric predominant interstitial infiltrate of HP; and the presence of peribronchiolar metaplasia in HP. The marked intensity of the lymphoid infiltrate raises the possibility of a low-grade lymphoma, particularly extranodal marginal zone lymphoma. This may be confirmed by demonstration of monoclonality via flow cytometry, gene rearrangement studies, or immunohistochemistry (44,54,57–61). Follicular bronchitis/bronchiolitis may have overlapping features with LIP. The former should be considered when the lymphoid infiltrate is primarily nodular and is predominantly centered on the airways. In such cases, the possibility of Sjo¨gren syndrome should be excluded clinically (62). Nodular lymphoid hyperplasia differs from LIP in that the former forms a solitary, discrete mass and is associated with more prominent fibrosis. In contrast, LIP is usually a diffuse process and typically does not exhibit significant fibrosis. G.
Respiratory Bronchiolitis
Respiratory bronchiolitis (RB) is a common incidental finding in lung specimens from asymptomatic cigarette smokers (63,64) and is histologically indistinguishable from respiratory bronchiolitis interstitial lung disease (RBILD). The latter term is used when there are clinical and radiographic features of ILD (65–67). The main histologic finding in RB is filling of bronchiolar lumens and peribronchiolar airspaces by pigmented macrophages, which contain intracytoplasmic finely granular, light golden brown substance that stains weakly with Prussian blue (iron) stain. In addition, there may be an associated mild lymphocytic bronchiolitis, mild interstitial fibrosis of the surrounding parenchyma, and peribronchiolar metaplasia (Fig. 7A) (68). H.
Desquamative Interstitial Pneumonia/Respiratory Bronchiolitis Interstitial Lung Disease
Desquamative interstitial pneumonia (DIP) and RBILD are clinicopathologic entities that occur mostly in current or former smokers (3,8,65,67,69–71). Because of their overlapping clinical features, pathogenesis, and histopathologic findings, most authorities regard these two entities as representing different ends of a spectrum of the same disease process (8,65,70,72,73).
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Figure 7 (See color insert.) RBILD/DIP. (A) Intraluminal macrophage accumulation within peribronchiolar airspaces. Mild peribronchiolar fibrosis and chronic inflammation is also present (original magnification, 200; H&E stain). (B) Unlike RBILD, the intraluminal pigmented macrophage accumulation in DIP tends to be more diffuse rather than being confined to peribronchiolar areas (original magnification, 100; H&E stain). Abbreviations: RBILD, respiratory bronchiolitis interstitial lung disease; DIP, desquamative interstitial pneumonia.
The histologic hallmark of DIP/RBILD is the prominent intra-alveolar accumulation of pigmented macrophages. DIP represents the more extensive and diffuse end of the spectrum (Fig. 7B). RBILD is usually confined to the peribronchiolar parenchyma. Moreover, mild, temporally uniform alveolar wall fibrosis, mild lymphocytic bronchiolitis, type II pneumocyte hyperplasia, and occasional eosinophils admixed with pigmented macrophages may be seen. Features of emphysema, including alveolar wall destruction with rounding of centrilobular airspaces and apparent floating fragments of alveolar walls, are invariably present. The differential diagnosis of DIP/RBILD includes focal DIP-like reactions in other ILDs, eosinophilic pneumonia, pulmonary alveolar hemorrhage syndromes, and postobstructive pneumonia. DIP-like reactions may be focally present in other ILDs such as UIP, NSIP, and pulmonary Langerhans cell histiocytosis (PLCH). In UIP, the interstitial fibrosis exhibits temporal and spatial heterogeneity and is typically more severe with marked architectural distortion characterized by honeycomb change. NSIP usually has more prominent interstitial fibrosis and chronic inflammation than that seen in DIP/RBILD. Although the distinction between the two may be difficult especially when the intraalveolar macrophage accumulation is prominent in NSIP, it may be unnecessary as both treatment and prognosis are similar. PLCH can be distinguished from DIP/RBILD by finding clusters or nodules of Langerhans cells, which, unlike the pigmented macrophages of DIP/RBILD, have eosinophilic cytoplasm and convoluted, bean-shaped nuclei. Additionally, bronchiolocentric, stellate-shaped
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scars are characteristic of PLCH. Eosinophilic pneumonia is a diagnostic consideration when intra-alveolar eosinophils admixed with pigmented macrophages are seen. However, the number of eosinophils in DIP/RBILD is generally not as numerous as that seen in eosinophilic pneumonia. Moreover, the latter is commonly associated with intra-alveolar fibrinous exudates as well as eosinophilic abscesses. The pigmented macrophages of DIP/RBILD may resemble the hemosiderin-laden macrophages seen in the pulmonary alveolar hemorrhage syndromes. In the latter, however, the macrophages usually contain coarser and refractile hemosiderin particles, which stain more intensely with the Prussian blue (iron) stain. Postobstructive pneumonia is characterized by intra-alveolar accumulation of macrophages, which, in contrast to DIP/RBILD, contain foamy cytoplasm and lack the finely granular, light golden brown pigment. I.
Pulmonary Langerhans Cell Histiocytosis
PLCH, also called eosinophilic granuloma or histiocytosis X, is a reactive proliferative disorder of Langerhans cells that is predominantly seen in current or former cigarette smokers (69,70,74–78). It is distinct from the systemic form of Langerhans cell histiocytosis (LCH), in which clonality has been demonstrated and is thus considered a true neoplasm (79). Histologically, PLCH is characterized by discrete, stellate-shaped nodules that are centered on small bronchioles with intervening areas of normal lung (Fig. 8A,B). The lung parenchyma peripheral to these nodules may exhibit
Figure 8 (See color insert.) PLCH. (A) Characteristic relatively well-circumscribed, bronchiolocentric, stellate-shaped nodule of PLCH (original magnification, 40; H&E stain). (B) Infiltration of an alveolar septum by Langerhans histiocytes, which have abundant eosinophilic cytoplasm and highly convoluted nuclei (original magnification, 400; H&E stain). (C) Electron microscopy demonstrates the characteristic rod and racquet-shaped pentalaminar Birbeck granules. Abbreviation: PLCH, pulmonary Langerhans cell histiocytosis.
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variable cystic dilatation due to traction emphysema. In active PLCH, the lesions tend to be quite cellular and consist of an interstitial infiltrate of Langerhans cells, eosinophils, plasma cells, and lymphocytes that infiltrate along the alveolar septa imparting the stellate shape of these lesions. Although eosinophils are often present in PLCH lesions, they are not necessary for the diagnosis as they may be absent in some cases. Cytomorphologically, Langerhans cells contain prominently convoluted nuclei, inconspicuous nucleoli, and variably abundant eosinophilic cytoplasm with indistinct cell borders. As PLCH lesions become older, they become progressively replaced by fibrous tissue and contain fewer Langerhans cells. In long-standing ‘‘burnt out’’ lesions, there may be no residual Langerhans cells and the only remnant of the PLCH lesion is the characteristic stellate scar, which may be the only clue to the diagnosis in the appropriate clinical context. Moreover, since most patients with PLCH are current or ex-smokers, RB or DIP-like areas and emphysematous changes are frequently encountered (72). A useful ancillary study in the diagnosis of PLCH is immunohistochemistry staining for S100 and CD1a, which are both helpful in highlighting the Langerhans cells (80–84). Electron microscopy demonstrates the characteristic intracytoplasmic, pentalaminar, rod- or racquet-shaped Birbeck granules in Langerhans cells (Fig. 8C) (82). However, immunohistochemistry has largely supplanted electron microscopy as a diagnostic tool in LCH. J.
Sarcoidosis
Sarcoidosis is unusual among ILD, as the diagnosis can usually be suggested by transbronchial biopsy, without the need for more tissue. Even in patients with normal chest X rays, transbronchial biopsies may show the characteristic, but nonspecific, nonnecrotizing granulomas. Grossly, the lung may have small and large nodules, regions of interstitial and/or confluent fibrosis, and cystic changes that may be mild or severe and diffuse. Enlarged hilar lymph nodes in combination with the above findings should suggest the diagnosis of sarcoidosis. Microscopically, the characteristic lesion is the nonnecrotizing granuloma as seen in other organs involved with sarcoidosis. The sarcoid granuloma tends to be well circumscribed and compact containing epithelioid macrophages and multinucleated giant cells. The giant cells may contain characteristic, but nonspecific, inclusions known as asteroid bodies, Schaumann bodies, and the rarely observed HamazakiWesenberg bodies (6,85). T lymphocytes are also present. The granulomas are common along the bronchial tree, which is why transbronchial biopsy is so effective in this disease. The granulomas also track with lymphatic channels and involve the interstitium as well. These well-circumscribed granulomas may become confluent resulting in dense regions of granulomatous inflammation with fibrosis in the lung. In late cases, granulomas may be difficult to find within the large fibrous scars. Necrosis may be observed; however, the diagnosis of ‘‘necrotizing sarcoid’’ should be made with trepidation, as often such cases prove
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to be infection rather than sarcoidosis. Granulomatous vasculitis affecting pulmonary arteries and veins may be seen, especially in severe cases. It is wise to remember that sarcoidosis is a diagnosis of exclusion, made by the managing clinician, and that none of the pathologic findings are diagnostic of this disease (Fig. 9).
II.
Pulmonary Fibrosis in Collagen Vascular Diseases
Lung disease is a common problem in CVD. Indeed 25% of deaths attributable to diffuse lung disease are in patients with CVD. The lung disease may be the primary cause of morbidity and mortality in CVD patients (14). All components of the respiratory system may be involved. The histologic patterns of disease are difficult to distinguish from idiopathic fibrotic diseases. In general, in CVD, the pathology in the lung involves tissues other than the interstitium, including the pleura, vessels, and/or airways. In CVD, the lung disease may present before or after other organ involvement. Lung disease has been found to precede systemic manifestations in 24% of CVD patients. In patients with new onset ILD it is important to determine whether the lung disease is a manifestation of CVD. There is considerable histopathologic overlap between the different CVDs as well as with the idiopathic ILDs (28). NSIP or UIP patterns of ILD occur in CVDs. There are, however, certain findings, that are quite characteristic of CVD. For example, pleural inflammation, interstitial lymphoplasmacytic infiltrates, follicular lymphoid hyperplasia, and vascular disease are features that may be present in all forms of CVD, but not usually in idiopathic ILD. Accordingly, when present with ILD these findings suggest the possibility of CVD. Patterns of fibrosis are generally NSIP, UIP, or a combination of the two types. Recent studies suggest that the fibrous NSIP pattern of fibrosis is more common than the UIP pattern of fibrosis (14). A.
Rheumatoid Arthritis
As many as 15% of patients with RA develop clinically significant ILD (86). The most common pulmonary complication of RA is pleuritis with or without effusions. Prominent follicular bronchiolitis containing well-formed germinal centers accompanying interstitial chronic inflammation is characteristic of RA. When interstitial fibrosis is present, the most common pattern tends to be NSIPlike; however, UIP-like fibrosis and intra-alveolar macrophage accumulation similar to DIP also occur. Pulmonary rheumatoid nodules are a specific but uncommon finding in RA patients, being detected on chest radiographs in 0.2% of patients (87). Rheumatoid nodules are usually subpleural or paraseptal and consist of a central core of necrotic tissue surrounded by palisading histiocytes (Fig. 10A–D).
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Figure 9 (See color insert.) Sarcoidosis. (A) Gross photograph of lung from a patient who underwent transplantation; note resemblance to UIP except that the disease is more severe in the upper lobe. (B) Transbronchial biopsy showing characteristic discrete granulomas within bronchial wall (original magnification, 40; H&E stain). (C) Granuloma protruding into a subpleural lymphatic channel (L) (original magnification, 100; H&E stain). (D) Granulomatous vasculitis in the wall of a pulmonary vein (original magnification, 100; H&E stain). (E) Asteroid body (original magnification, 400; H&E stain). (F) Schaumann body, inclusions often seen in giant cells within sarcoid granulomas (original magnification, 400; H&E stain). Abbreviation: UIP, usual interstitial pneumonia.
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Figure 10 (See color insert.) Collagen vascular diseases. (A–D) Lung from patient with rheumatoid arthritis: (A) chronic pleuritis with fibrosis (F) (original magnification, 40; H&E stain); (B) rheumatoid nodule (RN) (original magnification, 40; H&E stain); (C) constrictive bronchiolitis with subepithelial and peribronchiolar fibrosis (original magnification, 100; Masson’s trichrome stain); and (D) lymphoid hyperplasia with germinal centers (G) present (original magnification, 40; H&E stain). (E and F) Lung from patient with scleroderma: (E) gross photograph of lung with both honeycomb remodeling (asterisks) and fine collagenization (ring) of alveolar septae shown microscopically in panel F (original magnification, 40; Masson’s trichrome stain).
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Systemic Lupus Erythematosus
SLE may cause either acute or chronic lung disease. In SLE-associated lung disease, all tissues of the lung may be involved. Pleuritis with or without effusions is the most common pulmonary complication. Acute lupus pneumonitis (ALP) occurs in 1% to 4% of SLE patients and may be the first manifestation of the disease. The characteristic histologic lesion of ALP is DAD with hyaline membranes. Vasculitis, with or without fibrin thrombi, and diffuse alveolar hemorrhage with an associated capillaritis also occurs in some patients with clinical ALP. Immunofluorescence studies may demonstrate immunoglobulin and complement deposition in cases with capillaritis. Significant chronic ILD is not common in SLE; however, 30% of patients may demonstrate ILD by highresolution CT scans (88,89). Organizing pneumonia in a COP pattern is also seen as well as NSIP and UIP types of ILD with or without honeycomb change (90). C.
Progressive Systemic Sclerosis (Scleroderma)
Lung disease is a common manifestation of progressive systemic sclerosis (PSS). Unlike RA and SLE, pleural inflammation is not common. In some cases, PSS has a distinctive pattern of interstitial fibrosis. The fibrosis characteristically begins as a delicate expansion of alveolar walls due to collagen deposition with preservation of the underlying lung architecture and only sparse inflammation (‘‘collagenization of alveoli’’). If the fibrosis progresses it develops a more characteristic NSIP or UIP pattern. Honeycomb change may eventually occur. The other very ominous lesion of patients with PSS-associated lung disease is vascular obstruction with pulmonary hypertension. Histologically, the vascular lesions generally consist of concentric intimal proliferation with medial hypertrophy. Less commonly, plexiform lesions and pulmonary veno-occlusive disease may occur (Fig. 10E, F) (91,92). D.
Dermatomyositis/Polymyositis
In dermatomyositis (DM)/polymyositis (PM), ILD occurs in 20% to 30% of patients. Death is attributable to respiratory failure in 30% to 60% of patients with DM/PM (93,94). ILD in DM/PM has protean manifestations ranging from acute lung injury with DAD to chronic fibrosing ILD (Fig. 11A) (95). NSIP is reported to be the most common pattern of fibrosis, but UIP, LIP, and organizing pneumonia also occur (96). Skeletal muscle disease may contribute to the respiratory dysfunction in patients with DM/PM. E.
Sjo¨gren Syndrome
Sjo¨gren syndrome (SS) is characterized by infiltration of CD4-positive lymphocytes into different organs, most notably the lacrimal and salivary glands. In the lung, the disease manifests as a prominent lymphoreticular infiltration in the tracheobronchial tree with follicular bronchiolitis, atrophy of glands, and fibrosis
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Figure 11 (See color insert.) Collagen vascular diseases. (A) Organizing pneumonia with fibrous plug involving a bronchiole and adjacent alveolae. This lung is from a patient with polymyositis, but organizing pneumonia may be seen with a number of collagen vascular disorders (original magnification, 200; H&E stain). (B–D) Lung from a patient with Sjo¨gren syndrome: (B) lymphocytic interstitial pneumonia (original magnification, 40; H&E stain); (C) Congo red stain of amyloid deposit seen in the lung in Sjo¨gren syndrome (original magnification, 100; H&E stain); and (D) tissue in C under polarized light.
of small airways. Cysts may form secondary to airway obstruction from the follicular bronchiolitis. Other lesions include amyloid deposition and a variety of lymphoproliferative lesions. SS is commonly a component of mixed connective tissue disease and therefore can be associated with ILD. NSIP, both cellular and fibrosing types, may be the most common histologic pattern of disease (10), but other patterns that may be seen include organizing pneumonia, UIP, and LIP (Fig. 11B–D). Lymphoma may develop in 1% to 2% of patients with SS (43).
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20. Flieder DB, Koss MN. Nonspecific interstitial pneumonia: a provisional category of idiopathic interstitial pneumonia. Curr Opin Pulm Med 2004; 10:441–446. 21. Ito I, Nagai S, Kitaichi M, et al. Pulmonary manifestations of primary Sjo¨gren’s syndrome: a clinical, radiologic, and pathologic study. Am J Respir Crit Care Med 2005; 171:632–638. 22. Malamou-Mitsi V, Tsai MM, Gal AA, et al. Lymphoid interstitial pneumonia not associated with HIV infection: role of Epstein-Barr virus. Mod Pathol 1992; 5: 487–491. 23. Mohr LC. Hypersensitivity pneumonitis. Curr Opin Pulm Med 2004; 10:401–411. 24. Fukuoka J, Franks TJ, Colby TV, et al. Peribronchiolar metaplasia: a common histologic lesion in diffuse lung disease and a rare cause of interstitial lung disease: clinicopathologic features of 15 cases. Am J Surg Pathol 2005; 29:948–954. 25. Silva CI, Churg A, Muller NL. Hypersensitivity pneumonitis: spectrum of highresolution CT and pathologic findings. AJR Am J Roentgenol 2007; 188:334–344. 26. Vourlekis JS. Acute interstitial pneumonia. Clin Chest Med 2004; 25:739–747. 27. Bouros D, Nicholson AC, Polychronopoulos V, et al. Acute interstitial pneumonia. Eur Respir J 2000; 15:412–418. 28. Leslie KO. Historical perspective: a pathologic approach to the classification of idiopathic interstitial pneumonias. Chest 2005; 128(suppl 1):513S–519S. 29. Davison AG, Heard BE, McAllister WA, et al. Cryptogenic organizing pneumonitis. Q J Med 1983; 52:382–394. 30. Epler GR, Colby TV, McLoud TC, et al. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312:152–158. 31. Katzenstein ALA. Acute lung injury patterns: diffuse alveolar damage and bronchiolitis obliterans-organizing pneumonia. In: Katzenstein and Askin’s Surgical Pathology of Non-Neoplastic Lung Disease. 4th ed. Philadelphia: WB Saunders, 2006:17–49. 32. Yousem SA, Lohr RH, Colby TV. Idiopathic bronchiolitis obliterans organizing pneumonia/cryptogenic organizing pneumonia with unfavorable outcome: pathologic predictors. Mod Pathol 1997; 10:864–871. 33. Schlesinger C, Koss MN. The organizing pneumonias: an update and review. Curr Opin Pulm Med 2005; 11:422–430. 34. Kitaichi M. Differential diagnosis of bronchiolitis obliterans organizing pneumonia. Chest 1992; 102:44S–49S. 35. Lohr RH, Boland BJ, Douglas WW, et al. Organizing pneumonia. Features and prognosis of cryptogenic, secondary, and focal variants. Arch Intern Med 1997; 157:1323–1329. 36. Chang J, Han J, Kim DW, et al. Bronchiolitis obliterans organizing pneumonia: clinicopathologic review of a series of 45 Korean patients including rapidly progressive form. J Korean Med Sci 2002; 17:179–186. 37. Colby TV. Bronchiolitis. Pathologic considerations. Am J Clin Pathol 1998; 109:101–109. 38. Colby TV. Pathologic aspects of bronchiolitis obliterans organizing pneumonia. Chest 1992; 102:38S–43S. 39. Myers JL, Colby TV. Pathologic manifestations of bronchiolitis, constrictive bronchiolitis, cryptogenic organizing pneumonia, and diffuse panbronchiolitis. Clin Chest Med 1993; 14:611–622.
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40. Cha SI, Fessler MB, Cool CD, et al. Lymphoid interstitial pneumonia: clinical features, associations and prognosis. Eur Respir J 2006; 28:364–369. 41. Palmas A, Tefferi A, Myers JL, et al. Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. Br J Haematol 1998; 100:680–687. 42. Barbera JA, Hayashi S, Hegele RG, et al. Detection of Epstein-Barr virus in lymphocytic interstitial pneumonia by in situ hybridization. Am Rev Respir Dis 1992; 145:940–946. 43. Cain HC, Noble PW, Matthay RA. Pulmonary manifestations of Sjogren’s syndrome. Clin Chest Med 1998; 19:687–699. 44. Koss MN, Hochholzer L, Langloss JM, et al. Lymphoid interstitial pneumonia: clinicopathological and immunopathological findings in 18 cases. Pathology 1987; 19:178–185. 45. Church JA, Isaacs H, Saxon A, et al. Lymphoid interstitial pneumonitis and hypogammaglobulinemia in children. Am Rev Respir Dis 1981; 124:491–496. 46. Grieco MH, Chinoy-Acharya P. Lymphocytic interstitial pneumonia associated with the acquired immune deficiency syndrome. Am Rev Respir Dis 1985; 131:952–955. 47. Solal-Celigny P, Couderc LJ, Herman D, et al. Lymphoid interstitial pneumonitis in acquired immunodeficiency syndrome-related complex. Am Rev Respir Dis 1985; 131:956–960. 48. Morris JC, Rosen MJ, Marchevsky A, et al. Lymphocytic interstitial pneumonia in patients at risk for the acquired immune deficiency syndrome. Chest 1987; 91:63–67. 49. Strimlan CV, Rosenow EC, Divertie MB, et al. Pulmonary manifestations of Sjogren’s syndrome. Chest 1976; 70:354–361. 50. Strimlan CV, Rosenow EC, Weiland LH, et al. Lymphocytic interstitial pneumonitis. Review of 13 cases. Ann Intern Med 1978; 88:616–621. 51. Yood RA, Steigman DM, Gill LR. Lymphocytic interstitial pneumonitis in a patient with systemic lupus erythematosus. Lupus 1995; 4:161–163. 52. Helman CA, Keeton GR, Benatar SR. Lymphoid interstitial pneumonia with associated chronic active hepatitis and renal tubular acidosis. Am Rev Respir Dis 1977; 115:161–164. 53. Levinson AI, Hopewell PC, Stites DP, et al. Coexistent lymphoid interstitial pneumonia, pernicious anemia, and agammaglobulinemia. Arch Intern Med 1976; 136:213–216. 54. Banerjee D, Ahmad D. Malignant lymphoma complicating lymphocytic interstitial pneumonia: a monoclonal B-cell neoplasm arising in a polyclonal lymphoproliferative disorder. Hum Pathol 1982; 13:780–782. 55. Nicholson AG, Wotherspoon AC, Diss TC, et al. Reactive pulmonary lymphoid disorders. Histopathology 1995; 26:405–412. 56. Kradin RL, Mark EJ. Benign lymphoid disorders of the lung, with a theory regarding their development. Hum Pathol 1983; 14:857–867. 57. Tashiro K, Ohshima K, Suzumiya J, et al. Clonality of primary pulmonary lymphoproliferative disorders; using in situ hybridization and polymerase chain reaction for immunoglobulin. Leuk Lymphoma 1999; 36:157–167. 58. Herbert A, Walters MT, Cawley MI, et al. Lymphocytic interstitial pneumonia identified as lymphoma of mucosa associated lymphoid tissue. J Pathol 1985; 146:129–138.
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59. Julsrud PR, Brown LR, Li CY, et al. Pulmonary processes of mature-appearing lymphocytes: pseudolymphoma, well-differentiated lymphocytic lymphoma, and lymphocytic interstitial pneumonitis. Radiology 1978; 127:289–296. 60. Kurtin PJ, Myers JL, Adlakha H, et al. Pathologic and clinical features of primary pulmonary extranodal marginal zone B-cell lymphoma of MALT type. Am J Surg Pathol 2001; 25:997–1008. 61. Subramanian D, Albrecht S, Gonzalez JM, et al. Primary pulmonary lymphoma. Diagnosis by immunoglobulin gene rearrangement study using a novel polymerase chain reaction technique. Am Rev Respir Dis 1993; 148:222–226. 62. Yousem SA, Colby TV, Carrington CB. Follicular bronchitis/bronchiolitis. Hum Pathol 1985; 16:700–706. 63. Fraig M, Shreesha U, Savici D, et al. Respiratory bronchiolitis: a clinicopathologic study in current smokers, ex-smokers, and never-smokers. Am J Surg Pathol 2002; 26:647–653. 64. Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med 1974; 291:755–758. 65. Moon J, du Bois RM, Colby TV, et al. Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking related interstitial lung disease. Thorax 1999; 54:1009–1014. 66. Myers JL, Veal CF, Shin MS, et al. Respiratory bronchiolitis causing interstitial lung disease. A clinicopathologic study of six cases. Am Rev Respir Dis 1987; 135:880–884. 67. Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc 1989; 64:1373–1380. 68. Adesina AM, Vallyathan V, McQuillen EN, et al. Bronchiolar inflammation and fibrosis associated with smoking. A morphologic cross-sectional population analysis. Am Rev Respir Dis 1991; 143:144–149. 69. Aubry MC, Wright JL, Myers JL. The pathology of smoking-related lung diseases. Clin Chest Med 2000; 21:11–35. 70. Ryu JH, Colby TV, Hartman TE, et al. Smoking-related interstitial lung diseases: a concise review. Eur Respir J 2001; 17:122–132. 71. Ryu JH, Myers JL, Capizzi SA, et al. Desquamative interstitial pneumonia and respiratory bronchiolitis-associated interstitial lung disease. Chest 2005; 127:178–184. 72. Vassallo R, Jensen EA, Colby TV, et al. The overlap between respiratory bronchiolitis and desquamative interstitial pneumonia in pulmonary Langerhans cell histiocytosis: high-resolution CT, histologic, and functional correlations. Chest 2003; 124:1199–1205. 73. Heyneman LE, Ward S, Lynch DA, et al. Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process? AJR Am J Roentgenol 1999; 173:1617–1622. 74. Yousem SA, Colby TV, Chen YY, et al. Pulmonary Langerhans’ cell histiocytosis: molecular analysis of clonality. Am J Surg Pathol 2001; 25:630–636. 75. Brabencova E, Tazi A, Lorenzato M, et al. Langerhans cells in Langerhans cell granulomatosis are not actively proliferating cells. Am J Pathol 1998; 152:1143–1149. 76. Travis WD, Borok Z, Roum JH, et al. Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol 1993; 17:971–986.
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77. Friedman PJ, Liebow AA, Sokoloff J. Eosinophilic granuloma of lung. Clinical aspects of primary histiocytosis in the adult. Medicine (Baltimore) 1981; 60:385–396. 78. Schonfeld N, Frank W, Wenig S, et al. Clinical and radiologic features, lung function and therapeutic results in pulmonary histiocytosis X. Respiration 1993; 60:38–44. 79. Willman CL, Busque L, Griffith BB, et al. Langerhans’-cell histiocytosis (histiocytosis X)—a clonal proliferative disease. N Engl J Med 1994; 331:154–160. 80. Cagle PT, Mattioli CA, Truong LD, et al. Immunohistochemical diagnosis of pulmonary eosinophilic granuloma on lung biopsy. Chest 1988; 94:1133–1137. 81. Emile JF, Wechsler J, Brousse N, et al. Langerhans’ cell histiocytosis. Definitive diagnosis with the use of monoclonal antibody O10 on routinely paraffin-embedded samples. Am J Surg Pathol 1995; 19:636–641. 82. Mierau GW, Favara BE. S-100 protein immunohistochemistry and electron microscopy in the diagnosis of Langerhans cell proliferative disorders: a comparative assessment. Ultrastruct Pathol 1986; 10:303–309. 83. Soler P, Chollet S, Jacque C, et al. Immunocytochemical characterization of pulmonary histiocytosis X cells in lung biopsies. Am J Pathol 1985; 118:439–451. 84. Webber D, Tron V, Askin F, et al. S-100 staining in the diagnosis of eosinophilic granuloma of lung. Am J Clin Pathol 1985; 84:447–453. 85. Cheung OY, Muhm JR, Helmers RA, et al. Surgical pathology of granulomatous interstitial pneumonia. Ann Diagn Pathol 2003; 7:127–138. 86. Gabbay E, Tarala R, Will R, et al. Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med 1997; 156:528–535. 87. Shannon TM, Gale ME. Noncardiac manifestations of rheumatoid arthritis in the thorax. J Thorac Imaging 1992; 7:19–29. 88. Matthay RA, Schwarz MI, Petty TL, et al. Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine (Baltimore) 1975; 54:397–409. 89. Fenlon HM, Doran M, Sant SM, et al. High-resolution chest CT in systemic lupus erythematosus. Am J Roentgenol 1996; 166:301–307. 90. Weinrib L, Sharma OP, Quismorio FP Jr. A long-term study of interstitial lung disease in systemic lupus erythematosus. Semin Arthritis Rheum 1990; 20:48–56. 91. Cool CD, Kennedy D, Voelkel NF, et al. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol 1997; 28:434–442. 92. Yousem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol 1990; 21:467–474. 93. Douglas WW, Tazelaar HD, Hartman TE, et al. Polymyositis-dermatomyositisassociated interstitial lung disease. Am J Respir Crit Care Med 2001; 164:1182–1185. 94. Marie I, Hachulla E, Cherin P, et al. Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum 2002; 47:614–622. 95. Lee CS, Chen TL, Tzen CY, et al. Idiopathic inflammatory myopathy with diffuse alveolar damage. Clin Rheumatol 2002; 21:391–396. 96. Cottin V, Thivolet-Bejui F, Reynaud-Gaubert M, et al. Interstitial lung disease in amyopathic dermatomyositis, dermatomyositis and polymyositis. Eur Respir J 2003; 22:245–250.
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5 Immunosuppressive and Cytotoxic Drug Therapy for Diffuse ILD
ROBERT P. BAUGHMAN and ELYSE E. LOWER Department of Medicine, Interstitial Lung Disease and Sarcoidosis Clinic, University of Cincinnati, Cincinnati, Ohio, U.S.A.
I.
Introduction
Over the past 15 years there has been a palpable shift in the use of various agents in the treatment of diffuse interstitial lung diseases (ILDs). The original treatments focused on corticosteroids (CSs). This was because of the remarkable improvement seen in specific ILDs, such as sarcoidosis (1). For the idiopathic ILDs, a landmark paper by Carrington and colleagues suggested that an open lung biopsy could predict CS responsiveness [for the desquamative interstitial pneumonitis (DIP) pattern] versus poor CS response [for the usual interstitial pneumonitis (UIP) pattern] (2). Margaret Turner-Warwick was one of the first to study cyclophosphamide (CP) to treat idiopathic pulmonary fibrosis (IPF) (3). Her group report completed a double-blind randomized trial of CP for IPF, which identified several of the issues that still plague current trials in this area, including the high mortality of the disease and the apparent lack of response in patients with more severe disease at time of starting treatment (4). For sarcoidosis, early studies by Dr. Harold Israel demonstrated the steroidsparing properties of various cytotoxic agents such as methotrexate (MTX), 119
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azathioprine (AZA), and chlorambucil (5). Others demonstrated the utility of these drugs in sarcoidosis (6–8), with the largest studies using MTX (9,10). As the use of cytotoxic agents became more common in these diseases, biologic agents surfaced whose anti-inflammatory actions manipulate specific cytokines. These agents include cytokines such as interferon-g to modify the inflammatory response (11). Monoclonal antibodies that block specific cytokines offer another strategy. Infliximab, a monoclonal antibody directed against tumor necrosis factor (TNF), has been used successfully to treat pulmonary sarcoidosis (12,13). The success of this drug for sarcoidosis provides support for the concept that strategies against one cytokine can have profound influence on the inflammatory response seen in ILDs. This chapter will discuss the several agents that have been proposed for potential therapy for various diffuse lung diseases. Table 1 lists the agents to be discussed in general classes. Examples of the use of these drugs for specific ILDs are cited in the table. In most cases, the role of these drugs remains unclear. In fact, the value of any treatment for IPF is controversial (14,15). The focus of the chapter is not on the efficacy of individual treatments for the various ILDs but to provide a guideline behind the administration and monitoring. Whenever possible, the information will be derived from studies of pulmonary disease. II.
Corticosteroids
A.
Use in Interstitial Lung Diseases
CSs have been used extensively in every ILD. They were reported as effective in sarcoidosis shortly after the original reports of use in rheumatoid arthritis (RA) (1). Initial clinical trials questioned the benefit of CS in changing the longterm outcome of sarcoidosis (16,17), but recent randomized trials noted benefit (18,19). A meta-analysis supported the use of CS for some forms of sarcoidosis (20,21). CSs have been used in hypersensitivity pneumonitis with initial improvement in pulmonary function, but long-term benefit remains unclear (22). For pulmonary fibrosis, the role of CS is unclear (23,24). Early studies suggested a steroid-responsive group (25–27). However, with the new classification system that separates IPF from nonspecific interstitial pneumonia (NSIP), it is reasonable to assume that most ‘‘steroid responsive’’ cases of IPF were in fact cellular NSIP and that CSs have no impact on the chronic phase of IPF (14,23,28). However, CSs may have a role in treating acute exacerbations of IPF (29). B.
Mechanisms of Action
Glucocorticoids have multiple effects on the immune system through both transcriptional regulation of glucocorticoid receptor target genes (30) and nongenomic glucocorticoid receptor–dependent modulation of signal transduction pathways such as NF-kB (31,32).
Effective DBRPC (18) CT (19) MA (20)
Effective CS (8–10) DBRPC (35) Effective CS (97) Effective CS (7,8)
Effective CS (192,193)
Effective CR (337) CS (173) Effective CS (326) Effective CS (218,338) CT (339) Effective CS (328) Effective for skin CT (310,313) CS (311,312) Not as effective for pulmonary CT (318)
Corticosteroids
Methotrexate
Cyclophosphamide
Mycophenolate
Pentoxifylline Chloroquine/ hydroxychloroquine Minocycline Thalidomide
Leflunomide Azathioprine
Sarcoidosis
Drug
Effective CS (144) RT (145)
No evidence for chronic disease CT (23) MA (335) May help for acute decompensation CS (29)
IPF
Effective CS (336) DBRPC (147) Effective CS (183–185) DBRPC (147,187) Effective CS (170–172)
CVD-PF
Table 1 Cytotoxic and Immunosuppressive Therapy for Various Interstitial Lung Diseases
(Continued)
Effective DBRPC (22)
Hypersensitivity pneumonitis
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Effective for neurologic CS (302) Not effective pulmonary RT (303)
Effective CS (12,241–243) DBRPC (13,244) Effective CS (247) CR (248,249,344)
Cyclosporin A
Infliximab
Effective CS (254) CR (252,253)
Effective CR (343) CS (306)
CVD-PF
Hypersensitivity pneumonitis
Abbreviations: IPF, idiopathic pulmonary fibrosis; CVD-PF, collagen vascular disease associated pulmonary fibrosis; DBRPC, double-blind randomized, placebo controlled; CS, case series; CT, controlled trial; RT, randomized trial; MA, meta-analysis; CR. case report.
Effective for select patients DBRPCT (11,324) Effective CS (319) DBRPCT (320) Possibly effective for some patients DBRPCT (323)
Effective CS (340) CR (341) Not effective CS (307) Effective acute exacerbation CS (306,342)
IPF
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Bosentan
Pirfenidone
Interferon-g
Adalimumab
Sarcoidosis
Drug
Table 1 Cytotoxic and Immunosuppressive Therapy for Various Interstitial Lung Diseases (Continued )
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Immunosuppressive and Cytotoxic Drug Therapy for Diffuse ILD C.
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Dose and Route of Administration
The dose of glucocorticoids varies widely. Most studies have used initial doses of 20 to 40 mg/day of prednisone or its equivalent and then decrease the dose as tolerated. For pulmonary sarcoidosis, there is no clear-cut evidence for any particular initial dose of prednisone (21). In cardiac sarcoidosis, survival rates did not differ among patients treated with initial dose of >30-mg prednisone daily compared with lower doses (33). High-dose pulse methylprednisolone (1-g daily) has been used for some indications, but there are no randomized trials supporting its use. D.
Toxicity
The toxicity of glucocorticoids is well known. Weight gain, diabetes mellitus, and hypertension are frequently encountered. Most of these side effects are dose dependent. However, treatment with >20-mg prednisone for months is not uncommon for patients with ILD, especially sarcoidosis (19,34). In one study of acute pulmonary sarcoidosis, the average weight gain for patients treated with prednisone alone was over 40 lb (35). Prednisone therapy is also a risk factor for the development of sleep apnea, presumably on the basis of weight gain (36). In another study of sarcoidosis patients, individual complaints of easy bruising, increased appetite, moodiness, insomnia, and depression were present most of the time or always in over 30% of patients during treatment with more than 10 mg/day of prednisone. Fortunately, as the prednisone dose was reduced to 5 mg or less, these symptoms reduced but did not totally resolve (37). Osteoporosis is a major consequence of long-term steroid use. Doses as low as 5 mg/day for eight weeks can lead to changes in bone metabolism in healthy controls (38). Use of calcium alone did not prevent the risk for fractures associated with low-dose prednisone therapy (39). Several groups have noted osteoporosis as a consequence of CS therapy in sarcoidosis patients (40,41). Reversal of glucocorticoid-induced osteoporosis in sarcoidosis can be achieved with the use of bisphosphonates (42–44). Calcitonin has also been used (45). The use of calcium and vitamin D supplementation is recommended for RA patients and others at risk for osteoporosis (46,47). The use of calcium replacement in sarcoidosis is more complicated, since hypercalcemia and hypercalcuria occurs in up to 10% of sarcoidosis patients (48,49). The use of calcium and vitamin D replacement should be used with caution. Some recommend routine monitoring of urine for hypercalcuria (50). As a minimum, sarcoidosis patients on calcium supplement should have at least serum calcium checked regularly and should be warned about renal stones. Since the mechanism of hypercalcemia is often excessive vitamin D3-1,25 (51,52), one should monitor serum calcium during the sunnier times of the year when endogenous levels of vitamin D3-1,25 are higher. Opportunistic infections can be encountered with chronic steroid use. This risk includes routine bacterial infections (53) as well as T-cell-mediated infections such as tuberculosis (54). Deep-seated fungal infections, such as histoplasmosis
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Table 2 Risk of Developing Deep-seated Fungal Infections While Receiving Immunosuppressive Therapy for Sarcoidosis Number of patients treated
Drug
Number of clinic visits
Number of infections
Prednisone alone Methotrexate alone Prednisone plus methotrexate Hydroxychloroquine Azathioprine Leflunomide Cyclophosphamide Infliximab Thalidomide
235 86 214 187 117 48 23 29 21
1147 614 649 673 477 160 223 161 104
3 0 4 0 0 0 0 0 0
No therapy
108
210
0
Deep-seated fungal infections diagnosed over an 18-month period among 753 sarcoidosis patients treated at one clinic. Patients treated with prednisone or methotrexate alone or both drugs are noted. Patients may have been treated with one or more other drugs, including in combination with either prednisone or methotrexate. Only patients treated with prednisone, with or without methotrexate, developed infections. Source: Adapted from Ref. 60.
and cryptococcus, are mostly defended by T cells. In sarcoidosis, peripheral blood anergy would seem to make the patient more susceptible to these types of infections (55,56). However, a characteristic feature of sarcoidosis is an excess of CD4 T helper lymphocytes at the site of disease, such as the lung (57). This activity seems to sequester CD4 lymphocytes from the peripheral blood (58). CSs reduce CD4 activation and IL-2 production (59), which can leave the patient at risk for infections, particularly when additional immunosuppressive agents are used concomitantly. In a prospective study of 753 sarcoidosis patients seen during an 18-mo period at one clinic (60), there were 7 cases of fungal infection during this time (histoplasmosis in three, and cryptococcus and blastomycosis in two each). Table 2 summarizes the findings. No case of Mycobacterium tuberculosis was diagnosed during this time. In addition, the risk of infection is also influenced by the underlying disease of the patient (61). E.
Pharmacokinetics
The metabolism of CS involves the cytochrome P450 (CYP). Drugs inducing CYP can lead to changes in the level of CS, although the effect is usually clinically insignificant. For example, solid organ transplant patients have reduced P450 activity and have slower clearance of CS (62). The anticonvulsants phenobarbital and phenytoin are associated with increased clearance of CS (63); however, this effect is small and usually not clinically relevant (64). Similarly, rifampin exerts a similar effect, but this has only rarely led to CS nonresponsiveness (65).
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Ketoconazole can lead to reduced clearance of CS and a mild increase in levels (62,66,67). In addition, patients with significant liver or renal failure, age older than 65 years (68), or women receiving exogenous estrogen have increased unbound concentrations of prednisolone (69). Conversely, hyperthyroid patients have lower levels (70). There is one case report of an increased prothrombin time occurring in a patient on a stable dose of coumadin who subsequently received prednisone (71). This interaction seems rare and may be overshadowed by other drugs and events in the patient. Troleandomycin, a macrolide, has been shown to reduce clearance of methylprednisolone, but not prednisone (72). F.
Pregnancy
CS use appears safe during most portions of pregnancy (73,74). There is an increased rate of cleft palate when the drug is used during the first trimester (74). Because there is little evidence for exogenous steroids in breast milk, the drug can be used safely in breast-feeding mothers (75,76). G.
Monitoring Therapy
Patients on prednisone need to be monitored for hypertension and diabetes mellitus. Some physicians use prophylaxis regimens to prevent gastrointestinal (GI) bleeding, but the benefit of prophylaxis is unclear. Patients’ weights should be followed and symptoms of sleep apnea should be elicited. Given the potential for treatment of CS-induced osteoporosis, screening for osteoporosis should be done every one to two years for any patient on chronic CS therapy (77). Bisphosphonate and calcium supplementation should be considered in patients at risk for osteoporosis (47). III.
Cytotoxic Drugs
Several cytotoxic agents have been proposed to treat ILDs; Table 3 summarizes the risks and benefits of several of these drugs. A.
Methotrexate
1.
Use in Interstitial Lung Diseases
The use of MTX has been almost exclusively for sarcoidosis. It has been a useful steroid-sparing agent for chronic pulmonary disease (9,10) and exhibits steroidsparing effects in acute pulmonary sarcoidosis (35). While widely used to treat RA, there is no evidence to suggest that MTX prevents or treats RA-associated pulmonary fibrosis. 2.
Mechanism of Action
MTX is an antiproliferative agent that inhibits the synthesis of purines and pyrimidines; this effect suppresses various inflammatory cells (78). Further,
Milda Mild Moderate Rare Yes Possible Yes
Milda Mild Dose dependant, up to 10% Reported up to 5% Yes Possible Yes
Nausea Hematologic suppression Hepatotoxicity Drug-induced pneumonitis Teratogenic Carcinogenic Opportunistic infections
Mild moderate Mildc Minimal Rare Yesd Yes Yes
Azathioprine
b
Can be attenuated by coadministration with folic acid. May be attenuated by pretreatment with antiemetic, especially if drug is given intravenously. c Can be severe in patients with thiopurine methyltransferase deficiency. d Seems less teratogenic than other agents. e Increased risk for bladder cancer.
a
Leflunomide
Methotrexate
Drug
Table 3 Comparison of Cytotoxic Agents
Mild moderate Minimal None Rare Yes Yes Yes
Mycophenolate
Moderateb Moderate None Rare Yes Yese Yes
Cyclophosphamide
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MTX can lead to apoptosis activated T cells (79). Adenosine mediates many of the anti-inflammatory effects of MTX (80,81). Animal studies have shown that adenosine receptor antagonists such as caffeine and theophylline inhibit the antiinflammatory effect of MTX (82). 3.
Dose and Route of Administration
MTX has been administered at a wide range of doses, from 2.5 to 1000 mg. The higher doses have been reserved for treatment of malignancy. For sarcoidosis, the usual dose has been 10 to 15 mg orally once a week (9,10,83,84). Intramuscular administration leads to more predictable levels, and drug levels are more predictable and about 20% higher than the oral equivalent (85,86). However, there is little evidence that plasma levels correlate with the antiinflammatory activity of the drug (87). Therefore, routine monitoring of drug levels is not recommended. 4.
Toxicity
For many years, MTX has been the most widely used disease modifier in RA. It is the preferred agent compared with other immunomodulators, including cyctotoxic drugs (88,89). In RA patients, the use of MTX is associated with a lower risk of cardiovascular death (90). However, the antiproliferative effect of MTX is associated with its major toxicities. Suppression of the bone marrow is dose dependent, but can be influenced by other factors, including renal insufficiency. The underlying condition of the bone marrow is another important consideration. Sarcoidosis can directly affect the bone marrow (49,91,92). The dose can be adjusted for treating sarcoidosis patients. Doses as low as 2.5 mg/wk have been used successfully in patients with baseline leukopenia (93). Mucosal lesions (Fig. 1), nausea, and diarrhea are also consequences of MTX therapy. At doses of 15 to 25 mg used for arthritis, nausea has been reported by 40% to 60% of patients and diarrhea over 10% of the time (94,95). Stomatitis had also been reported in over 10% of cases from another series (96). This appears to be dose related, with no difference between placebos for any of these effects in a randomized trial of MTX for sarcoidosis (35). However, in a larger series of sarcoidosis, some sarcoidosis patients did discontinue MTX because of nausea (8,97). The hematologic and GI toxicity of MTX can be minimized by the use of low-dose folic acid supplement (1-mg folic acid per day) (98) without affecting the efficacy of MTX. MTX leads to decreased homocysteine levels that can be reversed with folic acid supplementation (99). Hepatic toxicity is a less common, but more worrisome, toxicity from the drug. One study of a large group of RA patients treated with MTX identified severe liver failure and cirrhosis in 24 patients with a five-year cumulative incidence of 1/1000 patients. Four of these 24 died of their initial liver failure (100). Roenigk et al. have developed a histologic classification (grade 0 to IV) commonly used to assess MTX hepatic toxicity (101). A meta-analysis of 636 total patients with RA or
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Figure 1 (See color insert.) Mucosal lesion on the tongue of a patient with sarcoidosis who had been taking methotrexate 10 mg once a week for two months. The lesion totally resolved on stopping methotrexate.
psoriasis in 15 studies concluded that 28% of patients progressed at least one grade while on therapy. Five percent of the patients had advanced liver disease (grade IIIB or IV). The major risk factors for developing liver damage included cumulative dose of MTX, heavy alcohol use, and underlying psoriasis (102). Patients had a 6.7% chance of progressive liver damage for each cumulative gram of MTX. These data led to the recommendation that liver biopsy be considered after each 1 to 1.5 g of MTX (101). However, the role of routine liver biopsies in patients with RA has been reevaluated. Current guidelines for RA patients suggest serial liver function tests (LFTs) are sufficient to monitor for MTX-induced hepatotoxicity (103). Liver biopsies are reserved for patients with rising LFTs if MTX is going to be continued. However, adherence to blood tests only can miss occasional patients with advance liver disease (104). The value of serial liver biopsies in psoriatic patients has been questioned (105,106). The role of liver biopsy in sarcoidosis remains unclear. One study evaluated the role of LFTs in predicting liver biopsy results in 100 serial liver biopsies of 56 patients with sarcoidosis treated for two or more years with MTX (107). Fourteen biopsies were interpreted as showing MTX toxicity. An additional 47 of the biopsies showed granulomas consistent with sarcoidosis. Among patients with MTX toxicity, transaminase levels were usually elevated. However, the level of the transaminases were significantly higher for those patients who had granulomas in the liver compared with those with MTX toxicity. No patient developed cirrhosis as a result of MTX. MTX can also cause a hypersensitivity pneumonitis (108–111). Risk factors include older age and hypoalbuminemia (112). The incidence has been estimated as high as 5% (108) but others reported a much lower incidence (113). The frequency reported in sarcoidosis patients receiving MTX is less than 2% (8), with cough the most common clinical presentation in that series. In all cases,
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the cough resolved after withdrawal of drug (8). Some of these patients were then treated with leflunomide (LEF) without any further pulmonary toxicity (97). In patients who have gone on to develop ILD from MTX, bronchoalveolar lavage findings were similar to those associated with sarcoidosis (114). In long-term studies, the rate of malignancy associated with low-dose MTX was similar to what would be expected for the general population (115–117). 5.
Pharmacokinetics
Because MTX is cleared by the kidney, the drug is not recommended for patients with moderate or more severe renal dysfunction (118). High-dose MTX can be directly nephrotoxic (119), but not at the low doses used for sarcoidosis. However, occasional toxicity is encountered during therapy because of other factors that precipitated renal failure and subsequent MTX toxicity (120). Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the clearance of MTX (121). However, the effect is relatively small and does not appear to have a clinically significant effect (118,122,123). Conversely, if NSAIDs induce acute renal failure, high levels of MTX and toxicity can be encountered. We have observed two patients who developed severe MTXinduced leukopenia associated with NSAID-induced renal failure. 6.
Pregnancy
Patients should be strongly advised not to become pregnant or father a child while taking MTX (124). MTX should not be used during pregnancy as even a single dose can induce a medical abortion (>90% probability) (88). However, the teratogenic effect is not clear, and successful normal pregnancies have occurred when MTX was discontinued during the first trimester (125). The drug is not recommended for breast-feeding women (76,126). The effect of MTX on the ovaries is short lived, and any effect is no longer apparent after six months. 7.
Monitoring
Complete blood counts and renal function should be monitored on a regular basis for patients receiving MTX (127). For leukopenic patients, the dose should be adjusted based on the white blood count (93). Liver function, especially transaminases, should be monitored (103,127). The routine use of liver biopsies after every 1 to 2 cumulative grams of MTX is controversial. However, it has been followed as a general guideline by our group (107,127). Although we have identified some patients with liver changes consistent with MTX toxicity, we have not yet encountered irreversible hepatotoxicity. Patients should be asked about nausea, diarrhea, and stomatitis. If present, these usually respond to dose reduction and the addition of 1-mg folic acid (98). This does not appear to affect the drug’s anti-inflammatory properties (118).
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R Leflunomide (Arava )
Use in Interstitial Lung Diseases
For ILDs, the reported use of leflunomide (Arava) has been limited to sarcoidosis (97,128). In most cases, LEF has been used as an alternative when MTX toxicity has been encountered or used in combination with MTX. 2.
Mechanism of Action
LEF inhibits the mitochondrial enzyme dihydro-orotic acid dehydrogenase, which plays a key role in pyrimidine synthesis (129,130). Because it is complimentary to the purine antagonism seen with MTX, these two drugs can be complimentary in action (131). LEF has no reported effect on adenosine. 3.
Dose and Route of Administration
LEF is given orally; the usual dose is 10 to 20 mg once a day. If nausea is encountered, the dose or frequency of administration can be reduced. Given the complimentary immunosuppression of LEF and MTX, the use of combination therapy has been studied (131). In a randomized trial of RA patients (132), the combination was superior to either agent alone. In one study of sarcoidosis patients with persistent symptoms despite MTX therapy, the addition of LEF to MTX was associated with improvement in >70% of patients (97). 4.
Toxicity
The toxicity of LEF is similar to MTX (133,134). The most commonly reported side effects are diarrhea, nausea, alopecia, rash, and headache (135). Anecdotally, alopecia seems more common with LEF than with MTX. However, diarrhea and nausea are more common with MTX. LEF has been successfully used in patients who have discontinued MTX due to GI toxicity (97). Although the rate of liver function abnormalities appears similar to that observed with MTX, the rate of severe liver toxicity is lower with LEF (135). Severe toxicity has been mostly reported when LEF is combined with other hepatotoxic agents such as MTX (136) or itraconazole (137). Pulmonary toxicity has been reported less frequently with LEF than with MTX (135). Although LEF has been successfully used to treat patients with MTX-associated pulmonary symptoms (97), LEF hypersensitivity has been reported (138,139). In one series of 14 cases culled from patients treated in Australia or New Zealand, 12 of the patients were receiving MTX. Most of these patients developed their pulmonary symptoms after LEF was introduced (139). 5.
Pharmacokinetics
LEF is administered orally. It is almost completely converted into its active metabolite, which has linear pharmacokinetics at the dosages employed in clinical practice. It has a long elimination half-life of greater than two weeks (140).
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Original studies included a loading dose of 100 mg orally for three days, followed by a daily dose of 10 to 20 mg/day (141). The loading dose was developed to shorten the time to reach steady state. Despite the loading dose, it requires approximately 20 weeks to reach steady state (140). Subsequently most clinicians no longer use the loading dose with no difference in clinical outcome (142). Nonspecific inducers of CYP and some drugs metabolized by CYP2C9 affect the metabolism of the active metabolite of LEF, so drug elimination may be enhanced (140). The use of LEF with MTX does not seem to alter the pharmacokinetics of either agent (143). 6.
Pregnancy
Like MTX, LEF is teratogenic and should not be given during pregnancy. Although there is little information about levels in breast milk, LEF is not recommended for breast-feeding mothers (76). 7.
Monitoring
The standard monitoring for patients receiving LEF includes complete blood counts and liver function studies every four to eight weeks. For leukopenia, the dose should be adjusted. Given the prolonged half-life of the drug, monitoring for any suspected drug toxicity should be maintained for two months after drug discontinuation. To date, there are no recommendations for screening liver biopsies for patients receiving LEF and no specific recommendations have been made to monitor for pulmonary toxicity. C. 1.
R Azathioprine (Imuran )
Use in Interstitial Lung Diseases
The use of AZA for IPF was first reported in an open-label trial by Winterbauer et al. (144). A subsequent double-blind, randomized trial demonstrated benefit versus placebo in approximately half of the patients treated (145). Demedts et al. demonstrated a higher response rate when AZA was given concomitantly with N-acetyl cysteine compared with AZA alone (146). AZA has also been used in the treatment of scleroderma-associated pulmonary fibrosis (147). Although not all investigators have reported benefit with the drug (148), the drug has also been useful in treating chronic pulmonary sarcoidosis (7). 2.
Mechanism of Action
Like MTX, AZA is a purine analog whose mechanism of action was originally simply cell synthesis disruption (149). While this mechanism may explain the benefit of high-dose AZA in treating acute leukemia, control of T-cell apoptosis may be a more important mechanism for its use as an antirejection and antiinflammatory drug (150).
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Dose and Route of Administration
For lung disease, AZA is administered orally with the usual dose 50 to 200 mg/day. An injectable form for intravenous (IV) use is available; intramuscular administration is not recommended. 4.
Toxicity
Overall, significant side effects occur in over 10% of patients (151,152). GI toxicity is frequently reported with AZA; in series, GI toxicity is more frequently reported than reported for MTX at levels of equal efficacy (153,154). With AZA, pancreatitis has been reported and liver toxicity is infrequent (152). Because liver toxicity is less than MTX, some clinicians prefer AZA in sarcoidosis patients with significant liver disease (155). Bone marrow suppression is a major toxicity. AZA can be associated with an increased risk for developing cancer. This risk has been mostly reported in transplant patients, where other drugs may be a factor (156,157). In nontransplant patients, some studies identified no increased risk (158), while others demonstrated a risk after treatment for 10 or more years (159). 5.
Pharmacokinetics
The parent compound AZA is metabolized to 6-mercatopurine (6-MP), which is subsequently metabolized by thiopurine methyltransferase (TPMT). Polymorphisms have been described for this enzyme. Negligible TPMT activity is reported in 0.3% of the population and low activity in 11% of the population (160). This leads to increased production of 6-thioguanine nucleotides (161). High levels of 6thioguanine nucleotides can lead to severe bone marrow suppression (162,163). Other AZA metabolites, 6-methylmercaptopurine ribonucleotides, are associated with hepatotoxicity. Although some groups advocate checking TPMT activity and monitoring metabolite levels (164,165), the role of monitoring levels remains unclear. Monitoring complete blood counts after the first few weeks of therapy will usually detect patients with negligible TPMT activity. Allopurinol blocks the metabolism of AZA, therefore leading to potentially toxic levels of the drug (165). However, in patients not responding to AZA, TPMT activity may be high. The addition of allopurinol can increase 6-thioguanine nucleotides and increase the effectiveness of the drug (166). 6.
Pregnancy
Although AZA is potentially teratogenic, its effect is less pronounced than most other cytotoxic drugs. It appears to be least teratogenic of all the cytotoxic immunosuppressive agents widely used (73). There is considerable anecdotal experience among solid organ transplant patients, where no increased rate of congenital malformations occurred in children born while mothers were receiving AZA (151,167). However, one study reported a higher spontaneous
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abortions and low birth weight children (167). The drug can be detected in breast milk and is not recommended while the patient is breast-feeding (168). 7.
Monitoring
Complete blood counts should be checked every 4 to 12 weeks in patients receiving the drug. For patients on stable dose and adequate blood counts, the blood may be checked less frequently than the patient at risk for low white count. LFTs need to be checked periodically. Some groups check TPMT levels prior to initiating therapy and monitor erythrocyte 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide levels during therapy. D. 1.
R Mycophenolate Mofetil (Cellcept )
Use in Interstitial Lung Diseases
Mycophenolate mofetil (MMF) is an immunosuppressant with less toxicity than AZA. Because it is associated with less leukopenia, MMF has replaced AZA in most protocols for the treatment of solid organ transplants (169). It has been reported as useful in treating ILD associated with collagen vascular disease (170–172) and sarcoidosis (173). 2.
Mechanism of Action
MMF seems to target the lymphocyte. It is a prodrug that is rapidly converted to mycophenolic acid (MPA), a potent and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). In the de novo purine synthesis pathway, IMPDH is the first of two enzymes responsible for the conversion of inosine monophosphate to guanosine monophosphate. On the other hand, IMPDH is not involved in the salvage pathway of purine biosynthesis. Mycophenolate causes a reduction of GTP and dGTP in lymphocytes but not neutrophils (174). This would explain its relatively selective effect on lymphocytes but not neutrophils. MPA also prevents the glycosylation of adhesion molecules that are involved in the attachment of lymphocytes to endothelium and potentially in leukocyte infiltration of allografts during immune responses. 3.
Dose and Route of Administration
Mycophenolate is usually administered orally, but an IV preparation is available. The initial dose is 500 mg twice a day and can be increased every one to four weeks as tolerated to a maximum dose of 1500 mg twice a day. 4.
Toxicity
The major toxicity of MMF is GI (175), which can be severe. GI bleeding has been reported in 3% of patients. Dose modification, including decreasing individual dose and increasing the frequency of administration from three to four times a day,
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can reduce toxicity (175). Drug fever can occur in up to 20% of patients. In addition, hematologic suppression can occur in patients receiving the drug. Mycophenolate has been reported to cause pulmonary fibrosis (176,177). As with all cytotoxic agents, opportunistic infections can occur with this drug (169,178). In one study comparing MMF to AZA for cardiac transplant, the rate of opportunistic infections was higher with MMF (169). Carcinogenicity, especially lymphoproliferative disorders, has also been reported, mostly in transplant patients (179). 5.
Pharmacokinetics
MMF is metabolized by the liver, and enterohepatic recirculation occurs. It is excreted in the urine, and dose reduction is required in moderate-to-severe renal disease. Tacrolimus increases MMF levels, while cyclosporine does not (180). Administration of metronidazole and some fluoroquinolones will reduce levels of mycophenolate by 10% to 20%. This reduction appears due to the effect of the antibiotics on GI flora and thus the elimination of the enterohepatic recirculation of the drug (181). 6.
Pregnancy
MMF is not recommended during pregnancy. It appears in breast milk and should not be used by breast-feeding mothers. 7.
Monitoring
Although MMF has less effect on the bone marrow than other cytotoxic agents, bone marrow suppression occurs. Therefore, complete blood counts should be performed on a regular basis. Since the disposition of MMF is by both the liver and kidney, renal and hepatic functions should be monitored. To reduce GI toxicity, drug level monitoring has been used in some patients (175). The peak level may not be as important as the area under the curve (182). E.
R Cyclophosphamide (Cytoxan )
1.
Use in Interstitial Lung Diseases
In case series, CP has been useful in the treatment of scleroderma-associated pulmonary fibrosis (183–186). This benefit was confirmed in two large randomized, placebo-controlled trials of either oral (187) or intermittent, IV CP (147). CP has also been used in IPF (4,188), nonspecific interstitial lung disease (189,190), and to treat refractory sarcoidosis (usually neurologic disease) (191–193). 2.
Mechanism of Action
CP is a classic alkylating agent, originally developed to treat malignancy. CP is inactive until it undergoes hepatic transformation to form 4-hydroxycyclophosphamide, which then breaks down to the alkylating agent, phosphoramide
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mustard (194). CP has a dose-dependent bimodal effect on the immune system. High doses induce an anti-inflammatory immune deviation (i.e., suppression of Th1 and enhancement of Th2), affect CD4CD25 (high) regulatory T cells, and establish a state of marked immunosuppression. 3.
Dose and Route of Administration
The drug can be given orally at doses from 50 to 200 mg/day or intermittent intravenously at doses from 500 to 2000 mg. The frequency of intermittent IV doses can be every two weeks (188), three weeks (195), or monthly (147,196). With IV administration, prophylactic antiemetics should be administered at the same time, such as the selective 5-hydroxytryptamine3 (5-HT3) receptor antagonists, for example, ondansetron or granisetron (188). The use of IV administration has been associated with a lower rate of response in Wegener’s granulomatosis in some (197,198), but not all studies (199). However, in scleroderma-associated pulmonary fibrosis, the reported response rate was higher for IV (147) than oral (187). This difference may reflect less frequent dose modification and compliance with IV versus the oral regimen. 4.
Toxicity
Of the cytotoxic agents used for ILD, CP is the most toxic. This toxicity is especially true for the oral dose regimen. Although some series noted half of the patients discontinued treatment because of toxicity (200), most series report lower rate of toxicity. The dose-limiting toxicity is leukopenia. Infection is directly related to the white blood cell count, and the risk for infection rises markedly if the white blood count goes below 3000 cells/mm3 (201). Leukopenia is better controlled with IV therapy. Anemia can be a problem with chronic therapy. Nausea and vomiting are also common side effects, but less frequent with intermittent IV therapy (197,202). Less GI toxicity may be the result of the common use of antiemetics with the IV regimen (188). CP is also associated with significant bladder toxicity. Hemorrhagic cystitis occurs more frequently with longer time of drug exposure (203). In a cohort of Wegener’s patients treated with oral CP, 75 of 145 (50%) developed nonglomerular hematuria. The median time to development was 37 months. Seven patients developed bladder cancer (204). The risk of both these genitourinary complications is much lower in patients receiving intermittent IV CP (199,205). Less bladder toxicity partly reflects the usage of lower total cumulative doses, since high-dose CP can lead to hemorrhagic cystitis (203). Mesna administration at the time of CP infusion can reduce the incidence of hemorrhagic cystitis. Mesna inactivates the alkylating metabolites, including acrolein, that have been implicated in the urotoxicity of CP (206). CP can lead to amenorrhea and early menopause (202,207). Pulmonary fibrosis is a rare complication of CP (208,209). Cardiotoxicity was noted in patients receiving very high-dose therapy in preparation for bone marrow transplantation (210).
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Pharmacokinetics
Hepatic or renal insufficiency does not significantly alter the pharmacokinetics of CP (194). Since immunosuppressive activity resides exclusively in the metabolites of CP (i.e., phosphoromide mustard and acrolein), pharmacokinetics are not predicted by the parent compound. Correlations between CP pharmacokinetics and pharmacodynamics are difficult to demonstrate. Measuring the metabolites is technically difficult (211). Drug interaction with other cytotoxic agents may increase neutropenia. One case report found the combination of CP plus infliximab was more likely to cause T-cell lymphopenia than either agent alone (212). 6.
Pregnancy
CP is teratogenic and should be avoided during pregnancy (213). In a mother receiving CP, the drug was found in the breast milk and the infant experienced neutropenia (214). 7.
Monitoring
Myelosuppression is dose dependent; monitoring white blood counts is usually sufficient for detecting bone marrow suppression. The nadir white blood cell count is usually encountered 9 days after an IV dose, but the range can be 6 to 21 days (215). Monocytosis is an early indicator of bone marrow recovery from chemotherapy, while low monocyte counts portend prolonged leukopenia (216). Anemia is a consequence of chronic CP use. Patients with hemoglobin levels of less than 11 gm% should be considered for erythropoietin therapy (217). A urine analysis should be performed every one to two months. Unexplained hematuria should be evaluated with cystoscopy and urine cytology, looking for hemorrhagic cystitis or bladder cancer. The risk for cystitis can be reduced by concurrent infusion of Mesna (206). IV.
Other Agents
A.
Antimalarial Agents
1.
Use in Interstitial Lung Diseases
Both chloroquine and hydroxychloroquine (Plaquenil1) have been reported as beneficial in treating sarcoidosis (218). In a randomized trial of chronic pulmonary disease, Baltzan et al. demonstrated that chloroquine slowed the progression of the disease (219). The antimalarials are associated with a higher rate of response for extrathoracic disease such as skin (218,220–223) and hypercalcemic manifestations. These drugs have not been studied in other ILDs. 2.
Mechanism of Action
The macrophage is the target for the antimalarial agents. Both drugs suppress release of proinflammatory cytokines (e.g., TNF) (224,225). In addition, antimalarial agents
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disrupt iron homeostasis in the liposome (226). The antimalarials can reduce TNF mRNA independently of the effect on liposomes (224). 3.
Dose and Route of Administration
Both antimalarial agents are administered orally with the usual dose for hydroxychloroquine 200 to 400 mg/day and chloroquine 250 to 750 mg/day. Parental administration is not recommended. Because of the higher toxicity reported with chloroquine, most physicians prefer hydroxychloroquine. A reduced dose of hydroxychloroquine is recommended for those with a low lean body mass. 4.
Toxicity
GI distress is the most commonly reported side effect. It is more commonly reported with chloroquine than hydroxychloroquine and often improves with dose reduction. Prolonged use of chloroquine can lead to retinal damage and eventual blindness if the drug is not discontinued (227). The incidence of ocular toxicity is lower with hydroxychloroquine, but routine examination screening for toxicity is still recommended for both drugs (228,229). Skin rashes can result from therapy, including bullous pemphigoid changes (230). Other rare complications include leukopenia (231,232), hepatitis (233), and myopathy (234). 5.
Pharmacokinetics
Both hydroxychloroquine and chloroquine are well absorbed when given orally (235). For hydroxychloroquine, the effectiveness and toxicity appear to be dose dependent (236). Both drugs have prolonged half-lives of over six weeks (237). Both drugs bind strongly to pigmented tissues but also bind to other cells such as mononuclear cells. Potentially important kinetic interactions have been documented for D-penicillamine and cimetidine (235). 6.
Pregnancy
Antimalarials are teratogenic in animals. However, there is limited evidence that the agents are harmful during pregnancy in humans (238). Given the animal data, antimalarial drugs should be used with caution during pregnancy. Hydroxychloroquine has not been associated with congenital malformations and seems preferable to chloroquine if usage is needed during pregnancy (239). Both drugs appear to be safe for breast-feeding mothers (76). 7.
Monitoring
Routine ophthalmic examination is recommended every 6 to 12 months for patients on these drugs (228,240). Complete blood counts and hepatic function should be checked every three to six months.
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R Infliximab (Remicade ) and Other Anti-TNF Biologic Agents
Use in Interstitial Lung Diseases
Currently, three anti-TNF-a agents are marketed for use (infliximab, etanercept, adlimumab). Although all agents have inhibitory effects on TNF-a, response rates for specific diseases vary among the three agents. Several case series noted that infliximab, a chimeric anti-TNF-a antibody, was effective in patients with refractory sarcoidosis (12,241–243). This led to two double-blind, randomized trials that demonstrated a significant improvement in the absolute vital capacity with infliximab therapy (13,244). In a subgroup analysis of 138 patients participating in a double-blind, randomized trial, patients with a vital capacity less than 70% had a greater response to therapy (13). Etanercept (Enbrel1), a TNF-a receptor antagonist, was associated with a higher failure rate in an open-label trial of pulmonary sarcoidosis (245). Etanercept was not different from placebo in the treatment of chronic sarcoidosis uveitis (246). Adalimumab (Humira1) was reported as effective in some cases of refractory sarcoidosis (247–249). TNF-a inhibitors have also been utilized to treat pulmonary fibrosis. In one study, IPF patients stabilized while receiving etanercept compared with progressive disease seen in the placebo-treated patients (250). In another report of symptomatic scleroderma patient with pulmonary fibrosis, quality of life improved while treated with infliximab, but the treatment did not affect the progression of pulmonary fibrosis or pulmonary hypertension (251). Case series suggest infliximab can improve RA-associated pulmonary fibrosis (252–254). However, other studies suggest that both infliximab (255,256) and etanercept (257) can be associated with development or progression of pulmonary fibrosis. Additionally, both drugs have been associated with the subsequent development of sarcoidosis (258–262).
2.
Mechanism of Action
As summarized in Table 4, this class of agents blocks TNF-a activity, although all three available drugs block the soluble form of TNF-a. However, there are differences in their effect on TNF-a-producing cells (263). Infliximab binds to the TNF-a on the surface of cells, inhibiting transmembrane TNF-a and inflammatory response (264,265). In bowel biopsies, infliximab caused apoptosis for inflammatory cells (266–268). In contrast, etanercept does not have this effect (266); this may in part explain the ineffectiveness of etanercept for Crohn’s disease (269). Adalimumab and infliximab induced apoptosis in peripheral blood monocytes whereas etanercept did not (270,271). Both etanercept and infliximab induce apoptosis of macrophages in the synovium of patients with RA (272). These differences in mechanism of action may explain the paradoxical responses reported with the anti-TNF-a agents (273–275). All three drugs work
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Table 4 Comparison of Biologic Agents to Inhibit TNF Characteristic
Infliximab
Adalimumab
Etanercept
Bind soluble TNF Bind TNF on cell surface Apoptosis of TNF releasing inflammatory cells Treat rheumatoid arthritis Treat Crohn’s disease Treat sarcoidosis Dose, route of administration, and frequency of treatment
Yes Yes
Yes Unknown
Yes Yes
Yes
Unknown
No
Yes
Yes
Yes
Yes Yes 3–5 mg/kg intravenously initially, 2 wk later, then every 4–6 wk Anaphylaxis
Yesa Yesb 40 mg subcutaneously every 1–2 wk
No No 25 mg subcutaneously two times a week
High
Local reaction, Less than infliximab Probable
Local reaction, Less than infliximab Probable
Yes
Unknown
Yes
Yes
Yes
Yes
Risk for allergic reaction Risk for reactivation of tuberculosis Risk for worsening severe left ventricular dysfunction Risk for malignancy a
Requires higher loading dose. May require higher loading dose.
b
equally well for rheumatoid and psoriatic arthritis. However, infliximab is superior to etanercept in the treatment of sarcoidosis, Crohn’s disease, and uveitis (269,276,277). Adalimumab was effective in treating Crohn’s disease using a higher dose than used for RA (278). 3.
Dose and Route of Administration
Infliximab is administered intravenously at a starting dose of 3 to 5 mg/kg. Two doses are given two weeks apart. The drug is then given at a maintenance schedule of every four to eight weeks. Higher doses (up to 10 mg/kg) are used in patients who stop responding to lower doses. In a randomized trial of sarcoidosis, response rate in the first six months of therapy were similar with doses of 3 mg/kg and 5 mg/kg (13). Etanercept is given subcutaneously at 25 mg twice a week. Adalimumab is given subcutaneously at a dose of 40 mg
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every one to two weeks. A recent study demonstrated benefit in treating Crohn’s disease with a loading dose of 160 mg, followed by 80 mg two weeks later, then 40 mg every two weeks (278). 4.
Toxicity
The overall safety of the anti-TNF-a agents is similar for all three agents (279). Infections are more frequent in patients receiving these drugs (280,281). Increased risk for pneumonia has been noted in some studies of patients with underlying lung disease (13,282). Interestingly, one study of RA on anti-TNF-a drugs found that patients on prednisone had an even higher risk for pneumonia (53). There is an increased risk for tuberculosis for all these agents (283–285). The risk was higher with infliximab (283,286). The risk for reactivation of tuberculosis seems to be within first three months in patients receiving infliximab (283), but is delayed to 6 to 12 months for those on etanercept (284,286). This may be a result of the difference the two drugs have on the granulomatous response of the disease. Allergic reactions to all three agents have been described. For etanercept, injection site reactions can occur in up to 20% of patients (287). Some patients develop recall reactions in areas of prior injections (288). More severe reactions, including anaphylactoid reactions, have been reported with infliximab. Up to 20% of patients with infliximab develop infusion reactions. The rate is lower for those patients receiving a concomitant cytotoxic drug such as MTX (289). Infliximab is a chimeric monoclonal antibody. Patients with infusion reactions to infliximab have been successfully treated with the humanized monoclonal antibody adalimumab (278,290). TNF-a antagonists are contraindicated in patients with advanced left ventricular disease. Both etanercept and infliximab were associated with increased mortality in patients with severe congestive heart failure (291,292). An increased risk for lymphoma has also been reported for patients receiving TNF-a antagonists (293,294). Patients treated for chronic obstructive pulmonary disease with infliximab experienced an increased rate of malignancy, but the difference compared with placebo was not significant (282). Use of etanercept in Wegener’s disease was associated with increased rate of solid organ tumors (295). Because most of the Wegener’s patients had been treated with CP, it is unclear whether this was the result of synergism with a known carcinogen (i.e., CP). Studies are ongoing to further define the risk of malignancy for this group of agents. 5.
Pharmacokinetics
All three drugs appear to have linear pharmacokinetics (296). A loading dose of two treatments two weeks apart seems important. In addition, a similar loading dose schedule was beneficial in using adalimumab for Crohn’s disease (278). Autoantibodies can develop against these agents, especially infliximab (280,297).
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In some cases, resistance can be overcome by increasing the dose and or frequency of the drug. 6.
Pregnancy
All three agents are teratogenic in animal studies, and these drugs are contraindicated during pregnancy. There is no information regarding safety with breast-feeding. 7.
Monitoring
Because of the risk of reactivation of latent tuberculosis (283), tuberculous screening with skin testing is required prior to initiating therapy. Screening and initiating therapy for latent tuberculosis reduces the risk of reactivation of tuberculosis by more than sevenfold (285). Sarcoidosis patients are often anergic (55) and other monitoring may be required. A rapid assay for interferong release after stimulation with M. tuberculosis specific antigens has proved helpful in studying immunosuppressed patients (298). In addition, sarcoidosis patients with a chest radiograph revealing upper lobe cavities should be treated with caution, since reactivation of tuberculosis with infliximab may be difficult to detect (13). Infliximab can induce autoantibodies that can be detected by looking for antinuclear antibodies (ANA). A positive double-stranded DNA testing is more specific. In some cases, this leads to a lupus-like condition (297). The presence of a positive ANA does not always correlate with symptoms. In most cases, the lupus-like symptoms resolve following discontinuation of infliximab (280). C.
Other Agents
Chlorambucil was used for refractory cases of sarcoidosis (6,299) with response rates similar to those reported with MTX. However, chlorambucil is carcinogenic and has been replaced by less toxic agents (300). Cyclosporine was associated with anecdotal responses in sarcoidosis in nonrandomized trials (301,302), but a randomized trial found that cyclosporine was no better than placebo as a steroid-sparing agent and was associated with a higher rate of relapses following withdrawal of CSs (303). Early reports evaluating the efficacy of cyclosporine in patients with pulmonary fibrosis who initially respond to steroids (304,305) suggested this drug may be more useful for NSIP. This was supported by a report looking at NSIP, using the new classification scheme (306). However, it is not clear that the drug is beneficial for IPF patients, with histology consistent with UIP (307). Cyclosporine is associated with hypertension, renal failure, and an increased risk for malignancy and opportunistic infections (308,309). Thalidomide can be effective for treating cutaneous sarcoidosis (310–312). Because the drug has many actions (313,314), including the suppression of TNF-a (313,315,316), it is a possible agent to treat pulmonary sarcoidosis (317).
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However, in a dose-escalation trial, thalidomide was ineffective in a cohort of 12 patients with pulmonary symptoms (310). In a trial of pulmonary sarcoidosis, thalidomide exhibited limited steroid-sparing benefit and no improvement in pulmonary lung function (318). Thalidomide is extremely teratogenic and use of the agent requires careful monitoring in both male and female patients. Thalidomide causes somnolence, constipation, and peripheral neuropathy in a significant number of patients (310). These side effects are dose dependent and may explain why thalidomide is not as useful for extracutaneous disease (318). Pirfenidone, a novel antifibrotic agent with multiple mechanisms of action, was evaluated as salvage therapy for patients with IPF, with equivocal results (319). A double-blind randomized phase II trial compared pirfenidone with placebo (2:1 ratio) in a cohort of 107 patients with IPF (320). The study was stopped prematurely because acute exacerbations were noted in five patients receiving pirfenidone (14%) compared with no cases in the placebo group. Although mortality was similar between the groups, pirfenidone had a favorable effect on the rate of decline of forced vital capacity (FVC) at nine months compared with placebo. However, the differences between groups were small. Further, the primary endpoint [change in lowest O2 saturation on 6-minute walk test (6MWT) over 6 or 9 months] was not met. Pirfenidone is administered orally and current trials are being performed to determine the appropriate dose. To date, the major toxicities have included nausea and sun sensitivity (320). Pirfenidone is not commercially available but a second randomized study evaluating pirfenidone versus placebo is in progress (InterMune, Inc., Brisbane, California, U.S.). Bosentan, a dual endothelin-1 (ET-1) receptor antagonist approved for treatment of pulmonary arterial hypertension (PAH) (321,322), has theoretical value in IPF-associated PAH, but data are limited. A double-blind randomized controlled trial (RCT) randomized 158 patients with IPF to bosentan or placebo (323). Patients with severe disease (FVC < 50% predicted) or diffusing capacity (DLCO) < 30% predicted, arterial oxygen tension (PaO2) < 55 mmHg) or PAH were excluded. At 12 months, bosentan was equivalent to placebo with regard to the primary endpoint (i.e., 6MWT); further, physiologic parameters did not differ between groups. However, a trend in favor of bosentan was noted in secondary endpoints, including time to death or disease progression (HR 0.61, p ¼ 0.12) and quality of life and dyspnea scores (323). Another RCT evaluating bosentan among IPF patients with severe disease or PAH is in progress. Interferon-g (IFN-g-1b) is an endogenous cytokine that downregulates expression of TGF-b. Initial studies employing recombinant IFN-g-1b were encouraging (11,324), but a large RCT showed no benefit and the study was ended because of ‘‘futility’’ in March 2007 (InterMune, Inc., Brisbane, California, U.S.). Pentoxifylline suppresses TNF-a release by alveolar macrophages (325) and was reported as useful in treating sarcoidosis (326,327). Pentoxifylline is administered orally (dose 200–400 mg three times a day). Side effects include
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nausea and diarrhea. Further studies are needed to establish the role (if any) of pentoxifylline as therapy for sarcoidosis. Minocycline has been used to treat sarcoidosis, but the mechanism of action is controversial. The original report showed benefit in treating cutaneous disease (328). The drug is an effective antimicrobial agent for Propionibacterium acnes, a putative agent for sarcoidosis (329). However, minocycline also displays anti-inflammatory effects (330). The drug can lead to nausea (331). Minocycline has also been associated with hepatitis, pneumonitis, and an autoimmune syndrome including polyarthritis (332–334). Like all tetracyclines, it should not be taken during pregnancy. V.
Conclusion
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13. Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006; 174:795–802. 14. Walter N, Collard HR, King TE Jr. Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc 2006; 3:330–338. 15. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med 2000; 161:646–664. 16. Young RL, Harkelroad LE, Lorden RE, et al. Pulmonary sarcoidosis: a prospective evaluation of glucocorticoid therapy. Ann Intern Med 1970; 73:207–212. 17. Israel HL, Fouts DW, Beggs RA. A controlled trial of prednisone treatment of sarcoidosis. Am Rev Respir Dis 1973; 107:609–614. 18. Pietinalho A, Lindholm A, Haahtela T, et al. Inhaled budesonide for treatment of pulmonary sarcoidosis. Results of a double-blind, placebo-controlled, multicentre study. Eur Respir J 1996; 9(suppl 23):406s. 19. Gibson GJ, Prescott RJ, Muers MF, et al. British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax 1996; 51:238–247. 20. Paramothayan S, Jones PW. Corticosteroid therapy in pulmonary sarcoidosis: a systematic review. JAMA 2002; 287:1301–1307. 21. Baughman RP, Selroos O. Evidence-based approach to the treatment of sarcoidosis. In: Gibson PG, Abramson M, Wood-Baker R, et al. eds. Evidence-based respiratory medicine. Malden: Blackwell Publishing Ltd, 2005:491–508. 22. Kokkarinen JI, Tukiainen HO, Terho EO. Effect of corticosteroid treatment on the recovery of pulmonary function in farmer’s lung. Am Rev Respir Dis 1992; 145:3–5. 23. Selman M, Carrillo G, Salas J, et al. Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial. Chest 1998; 114:507–512. 24. Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134:136–151. 25. Rudd RM, Haslam PL, Turner-Warwick M. Cryptogenic fibrosing alveolitis. Relationships of pulmonary physiology and bronchoalveolar lavage to response to treatment and prognosis. Am Rev Respir Dis 1981; 124:1–8. 26. Watters LC, King TE, Schwarz MI, et al. A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis. Am Rev Respir Dis 1986; 133:97–103. 27. Gay SE, Kazerooni EA, Toews GB, et al. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med 1998; 157:1063–1072. 28. Collard HR, Ryu JH, Douglas WW, et al. Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest 2004; 125:2169–2174. 29. Kim DS, Park JH, Park BK, et al. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J 2006; 27:143–150. 30. Oakley RH, Sar M, Cidlowski JA. The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J Biol Chem 1996; 271:9550–9559. 31. Lowenberg M, Verhaar AP, van den Brink GR, et al. Glucocorticoid signaling: a nongenomic mechanism for T-cell immunosuppression. Trends Mol Med 2007; 13:158–163.
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311. Carlesimo M, Giustini S, Rossi A, et al. Treatment of cutaneous and pulmonary sarcoidosis with thalidomide. J Am Acad Dermatol 1995; 32:866–869. 312. Nguyen YT, Dupuy A, Cordoliani F, et al. Treatment of cutaneous sarcoidosis with thalidomide. J Am Acad Dermatol 2004; 50:235–241. 313. Oliver SJ, Kikuchi T, Krueger JG, et al. Thalidomide induces granuloma differentiation in sarcoid skin lesions associated with disease improvement. Clin Immunol 2002; 102:225–236. 314. Moller DR, Wysocka M, Greenlee BM, et al. Inhibition of IL-12 production by thalidomide. J Immunol 1997; 159:5157–5161. 315. Tavares JL, Wangoo A, Dilworth P, et al. Thalidomide reduces tumour necrosis factor-alpha production by human alveolar macrophages. Respir Med 1997; 91:31–39. 316. Ye Q, Chen B, Tong Z, et al. Thalidomide reduces IL-18, IL-8 and TNF-alpha release from alveolar macrophages in interstitial lung disease. Eur Respir J 2006; 28:824–831. 317. Baughman RP, Iannuzzi M. Tumour necrosis factor in sarcoidosis and its potential for targeted therapy. BioDrugs 2003; 17:425–431. 318. Judson MA, Silvestri J, Hartung C, et al. The effect of thalidomide on corticosteroid-dependent pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2006; 23:51–57. 319. Raghu G, Johnson WC, Lockhart D, et al. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, openlabel phase II study. Am J Respir Crit Care Med 1999; 159:1061–1069. 320. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005; 171:1040–1047. 321. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelinreceptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358:1119–1123. 322. McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005; 25:244–249. 323. King TE Jr., Behr J, Brown KK, et al. Randomized, placebo controlled trial of bosentan for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008; 177; 75–81. 324. Ziesche R, Hofbauer E, Wittmann K, et al. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999; 341:1264–1269. 325. Tong Z, Dai H, Chen B, et al. Inhibition of cytokine release from alveolar macrophages in pulmonary sarcoidosis by pentoxifylline: comparison with dexamethasone. Chest 2003; 124:1526–1532. 326. Zabel P, Entzian P, Dalhoff K, et al. Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med 1997; 155:1665–1669. 327. Ulbricht KU, Stoll M, Bierwirth J, et al. Successful tumor necrosis factor alpha blockade treatment in therapy-resistant sarcoidosis. Arthritis Rheum 2003; 48:3542–3543. 328. Bachelez H, Senet P, Cadranel J, et al. The use of tetracyclines for the treatment of sarcoidosis. Arch Dermatol 2001; 137:69–73.
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329. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol 2002; 40:198–204. 330. Kloppenburg M, Verweij CL, Miltenburg AM, et al. The influence of tetracyclines on T cell activation. Clin Exp Immunol 1995; 102:635–641. 331. Shapiro LE, Knowles SR, Shear NH. Comparative safety of tetracycline, minocycline, and doxycycline. Arch Dermatol 1997; 133:1224–1230. 332. de Paz S, Perez A, Gomez M, et al. Severe hypersensitivity reaction to minocycline. J Investig Allergol Clin Immunol 1999; 9:403–404. 333. Elkayam O, Levartovsky D, Brautbar C, et al. Clinical and immunological study of 7 patients with minocycline-induced autoimmune phenomena. Am J Med 1998; 105:484–487. 334. Guillon JM, Joly P, Autran B, et al. Minocycline-induced cell-mediated hypersensitivity pneumonitis. Ann Intern Med 1992; 117:476–481. 335. Richeldi L, Davies HR, Ferrara G, et al. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2003; CD002880. 336. Dheda K, Lalloo UG, Cassim B, et al. Experience with azathioprine in systemic sclerosis associated with interstitial lung disease. Clin Rheumatol 2004; 23:306–309. 337. Moudgil A, Przygodzki RM, Kher KK. Successful steroid-sparing treatment of renal limited sarcoidosis with mycophenolate mofetil. Pediatr Nephrol 2006; 21:281–285. 338. Sharma OP. Effectiveness of chloroquine and hydroxychloroquine in treating selected patients with sarcoidosis with neurologic involvement. Arch Neurol 1998; 55:1248–1254. 339. Chloroquine in the treatment of sarcoidosis. A report from the Research Committee of the British Tuberculosis Association. Tubercle 1967; 48:257–272. 340. Alton EW, Johnson M, Turner-Warwick M. Advanced cryptogenic fibrosing alveolitis: preliminary report on treatment with cyclosporin A. Respir Med 1989; 83:277–279. 341. Lok SS, Smith E, Doran HM, et al. Idiopathic pulmonary fibrosis and cyclosporine: a lesson from single-lung transplantation. Chest 1998; 114:1478–1481. 342. Inase N, Sawada M, Ohtani Y, et al. Cyclosporin A followed by the treatment of acute exacerbation of idiopathic pulmonary fibrosis with corticosteroid. Intern Med 2003; 42:565–570. 343. Puttick MP, Klinkhoff AV, Chalmers A, et al. Treatment of progressive rheumatoid interstitial lung disease with cyclosporine. J Rheumatol 1995; 22:2163–2165. 344. Philips MA, Lynch J, Azmi FH. Ulcerative cutaneous sarcoidosis responding to adalimumab. J Am Acad Dermatol 2005; 53:917.
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6 Sarcoidosis: Pathogenesis and Epidemiology
¨ LLER-QUERNHEIM GERNOT ZISSEL, ANTJE PRASSE, and JOACHIM MU Department of Pneumology, University Medical Center, University Hospital Freiburg, Freiburg, Germany
I.
Introduction
Sarcoidosis is a chronic granulomatous disorder characterized by an accumulation of lymphocytes and macrophages in the alveoli. Ultimately, long-lasting, nontreated disease results in a distortion of the microarchitecture of the lower respiratory tract. Our present understanding of its pathogenesis is that several sequential immunological events are involved resulting eventually in granuloma formation: (i) exposure to one or several still elusive antigen(s), (ii) acquiring T-cell-immunity against the antigen(s) mediated by antigen processing and presentation by macrophages, (iii) generation of specific T-effector cells, (iv) activation of macrophages, and (v) induction of granuloma formation. These events, however, are dependent on a susceptible genetic background described by a variety of functional polymorphisms (1,2). Most cytokines and cell activations can only be found in the involved organs and not in the peripheral blood which means that cytokine networking and activation of a number of immune and epithelial cells are crucial in these compartmentalized processes. Nevertheless, all cell types recovered from the involved organs disclose features of activation and/or differentiation, i.e., they 163
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release cytokines or express surface markers indicating activation or differentiation. Up to now, the stimulus of this activation and differentiation is unknown. However, the fact that activation of T cells requires a T-cell antigen suggests that macrophages might be activated by the innate immune system and granuloma formation normally requires the uptake of nondegradable material by phagocytes. Hence, the immunopathogenesis of sarcoidosis is driven by a network of cells and cytokines which will be discussed in the following.
II.
Epidemiology of Sarcoidosis
Since many individuals with sarcoidosis are asymptomatic, estimates of the incidence rates and prevalence figures depend mainly on the way in which epidemiological data are generated. In Europe, sarcoidosis is the most frequently observed interstitial lung disease of unknown etiology. The prevalence rates range from 64 patients per 100,000 inhabitants in Sweden to 9 per 100,000 inhabitants in Italy with intermediate numbers (per 100,000) observed in Denmark (53), Germany (43), Ireland (40), Norway (27), The Netherlands (22), the UK (20), Switzerland (16) and France (10). The prevalence for the Caucasian population of North America is 11 and for African Americans 36 per 100,000 (3). Sarcoidosis is found in all races, affecting slightly more females than males. Most commonly, it manifests in adults in the third decade of age, although all ages can be affected. During the last four decades of the last century, a second peak in the fifties emerged (4). In childhood (below 15 years), sarcoidosis is extremely rare. Epidemiology in children is hampered by an additional differential diagnosis, i.e., Blau syndrome and related genetic granulomatous disorders subsumed under the term early-onset sarcoidosis (EOS). These disorders are characterized by mutations in the CARD 15 genes which are either inherited or sporadic (5–9). Interestingly, a mutation in chromosome 16 in this gene predisposes to Crohn’s disease, another granulomatous disorder (10). These mutations in the CARD 15 gene result in an exaggerated inflammatory response. However, in sarcoidosis, a CARD 15 mutation is not present (11). These genetic granulomatous disorders with manifestation in childhood (Blau syndrome and EOS) need to be differentiated from sarcoidosis in childhood (6). Analysis of familial clustering in sarcoidosis gained more and more of interest. In the literature, a wide range of prevalence of familial sarcoidosis is reported ranging from 1.7% to 18% (12,13). In a case-control etiological study of sarcoidosis (ACCESS), the relative risk of sarcoidosis was estimated investigating a large cohort of age, sex, and geographically matched cases and controls (13). Siblings had the highest relative risk (2.1–15.9), followed by avuncular relationship, grandparents, and then parents. When adjusted for age, sex, socioeconomic class, and shared environment, the familial relative risk was 4.7. White cases had a markedly higher familial relative risk compared with black cases (18.0 vs. 2.8).
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Differences in the pattern of organ involvement and the severity of the disease have been observed according to race and ethnic background. Erythema nodosum associated with acute disease and good prognosis is most frequently seen in young Caucasians, as originally described by Lo¨fgren (14). Lupus pernio and other cutaneous manifestations of sarcoidosis considered to be stigmata of chronic disease (15,16), appear more frequently in African Americans than in Caucasians (3). A recent study compared Arabic and Jewish patients in northern Israel and found similar incidence rates that interestingly increased from 0.2/100,000 in 1980 to 2/100,000 per year in 1996 in both the groups. Most interestingly, both groups differed in disease outcome (17). Only rough estimates of the mortality rates of untreated sarcoidosis are available. If untreated, it is associated with a mortality rate of *5%. In an epidemiological study from Denmark with a median follow-up of 27 years, an excess mortality from sarcoidosis and sarcoidosis-related diseases was perceived in the first 20 years in patients with advanced radiological findings and deteriorated lung function. Although the mortality of the sarcoid cohort was higher than that of the general population, the difference was not statistically significant (18,19). This number may differ in other ethnic groups (20–22) or cohorts with increased frequencies of certain manifestations, such as cutaneous sarcoidosis (23,24).
III. A.
Immunopathogenesis T-Cell Axis
T-cell activation is mandatory for the development of any granulomatous response. This notion is supported by the observation that T-cell-depleted mice are incapable of granuloma formation. The sarcoid T-cell response is characteristic of a T-cell-mediated response to antigen, highly suggestive of the presence of a persistent, poorly degradable antigen or antigens. A capping of the T-cell antigen receptor (TCR) of alveolar T cells in sarcoidosis and a normal transcription of the interleukin (IL)-2 gene suggest a recent activation of the cells via TCR followed by physiological activation. These two phenomena can only be observed in cells from bronchoalveolar lavage (BAL) fluid, indicating that the eliciting agent resides in the lung. A similar activation can be assumed for the T cells of the granuloma since they contain mRNA for IL-2, IL-6, and interferon (IFN)-g (25–27). The enumeration of IL-2 receptor (IL-2R)-positive T cells was one approach to estimate the number of activated alveolar T cells. Only a moderate increase in IL-2Rþ T cells with only a few cells going through the S phase of the cell cycle was observed (26,28), suggesting the presence of a small number of activated cells in the alveolar space or a dysregulation in the expression of the IL-2R. Results obtained by an in vitro study with sarcoid T cells excluded the latter possibility (28). Although relatively few T cells express IL-2R, serum levels of the soluble form of IL-2R (sIL-2R), which is released a few days after
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activation of T cells, can be used to gauge sarcoid T-cell activation. These serum levels are independent of radiographic types of sarcoidosis and can be used to guide therapy (29–31). Macrophages, epithelial cells, and endothelial cells are the main sources of chemoattractant mediators. Next to the clonal expansion of T cells in the lung, these mediators play a pivotal role in the accumulation of T cells in organs involved in sarcoidosis. Their concentration is related to the degree of alveolitis and the course of the disease (32,33). The antigen that attracts T cells to the lung followed by their activation remains elusive. A number of bacteria were scrutinized, however, formal proof employing Koch’s postulates has not been found. The diagnostic Kveim-Siltzbach reagent is a biological sample in which the antigen eliciting sarcoidosis might be contained. However, evidence for the presence of a bacterial antigen within this reagent was not found (34). An immunologic study revealed that its activity resides within the membrane fragments of alveolar macrophages (AMs), corroborating the hypothesis that a sarcoid-specific protein is presented by these cells (35). An observation of Klein et al. supports this notion. They described an increased percentage of TCR Vb2, Vb3, Vb6, and Vb8 families in intradermal lesions of Kveim skin-tests compared with peripheral blood; this increase was oligoclonal (36). These findings are consistent with an antigen-driven T-cell activation. The limited clonality of T cells was also demonstrated in sarcoid lung T cells by analyzing the nucleotide sequence of the TCR (37). This oligoclonality decreases after clinical improvement of the disease (either spontaneously or with corticosteroid therapy) (37). The TCR is composed of two variable chains, i.e., Va and Vb T-cell clones from the blood of sarcoid patients revealed normal Vb distribution whereas prominent changes in the usage of Vb genes of CD4 T cells were observed within lung tissue and BAL fluid, showing restriction of T-cell selection to the involved organ (38). Within the CD4 cells functional distinct subsets have been identified. In sarcoidosis, T-helper 1 (TH1) cells, which produce IFN-g and IL-2, are activated. In contrast, the marker cytokines of TH2 cells, IL-4, IL-5, IL-10, and IL-13, are not elevated in sarcoidosis. Both lineages derive from naive TH0 cells, which are able to release the whole panel of cytokines and differentiate in either TH1 or TH2 cells after antigen stimulation depending on antigen concentration, the affinity of the antigen to the major histocompatibility complex (MHC) class II molecules, and its nature. Ba¨umer et al. demonstrated that T-cell clones derived from peripheral blood, BAL cells, and lung parenchyma of sarcoid patients displayed the entire spectrum of cytokine patterns. TH2-like cells were demonstrated in all three body compartments including BAL fluid (39). From this one can assume that although TH2 cells are present, they are not activated or even suppressed resulting in a cytokine imbalance in the lung. These data on TCR Vbþ and TH1 cells suggest that T cells accumulate as a result of external selective pressure rather than in a random polyclonal fashion or by clonal expansion of one or a few T-cell clones.
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This observation has been extended to the TCR Va usage. A lung-restricted preferential use of the AV2S3-positive Va chain was identified in Swedish sarcoidosis patients expressing either the HLA-DRB3*0101 or DRB1*0301 MHC genes. These two MHC genes exhibited identical amino acid sequences in regions composing the antigen binding groove, which may enable antigen-presenting cells to present the same or similar antigenic peptides followed by expansion and activation of AV2S3-positive T cells within the lung (40). Comparing these cells with pulmonary T cells carrying other TCRs demonstrates their exaggerated expression of activation markers which suggests a strong immune response against the eliciting antigen (41) which might result in the good prognosis of patients with the expression of the named MHC genes in combination with the usage of these TCR Va chains (42). These data on MHC and selective use of TCR Va and b chains support the hypothesis that the immune response is elicited by a ‘‘nominal sarcoid antigen’’ eliciting a TH1 response. Employing immunoglobulin from sera of sarcoidosis patients in a proteomics approach, Song et al. detected an antigen that is poorly soluble in neutral detergent and resistant to protease digestion, consistent with the biochemical properties of granuloma-inducing sarcoidosis tissue extracts (Kveim-Siltzbach reagent). By matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF) and immunoblotting Mycobacterium tuberculosis catalase-peroxidase (mKatG) was identified as one of these antigens (43). Preliminary data shows that mKatG is able to elicit a granulomatous response in an animal model. However, it is only found in a subset of sarcoid tissue which suggests that other microbial antigens or endogenous proteins may promote local adaptive immune responses as part of the granulomatous inflammation. This leads to the concept that granulomas in sarcoidosis contain pathobiological relevant antigens and mKatG might be one of a number of yet undefined, poorly soluble, and protease-resistant sarcoid antigens. In most patients, sarcoidosis spontaneously resolves, consistent with elimination of the eliciting antigen. A successful immune response needs to be downregulated and regulatory T cells (Treg) control immune function. Treg are identified by their bright expression of IL-2R and FoxP3. In active disease, high numbers of Treg are observed in the lung and to a lower extent in lymph nodes and blood, whereas in controls and patients with inactive sarcoidosis, only low percentages of Treg are detected. Treg from patients with active sarcoidosis efficiently inhibit anti-CD3-induced proliferation of T cells and abolish IL-2 release. However, they only partially inhibit tumor necrosis factor (TNF)-a and IFNg release by CD25 cells (44). Another mechanism crucial for dampening the immune response is apoptosis. IL-15, a TH1-derived cytokine, is involved in the formation of sarcoid granuloma and may promote granuloma maintenance (45). IL-15 upregulates Bcl-2 expression of T cells, resulting in a blockade of T-cell clearance from sites of chronic inflammation. A number of apoptosis related gene products, including Bcl-2 and FasL (46,47), are upregulated in sarcoidosis which is consistent with a
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pro-survival profile for activated T cells. Overexpression of NFkB and upregulation of inhibitors of apoptosis were observed in sarcoid patients with progressive disease. BAL cells of sarcoidosis patients exhibit an exaggerated caspase-3 activity that renders them resistant to apoptosis (48). Whether programmed cell death is dysregulated in chronic sarcoidosis or is a consequence of antigen persistence with ongoing T-cell activation remains to be resolved. B.
Stimulatory Cell Axis
Extensive evidence affirms a fundamental role of pulmonary macrophages in the pathogenesis of sarcoidosis. First, multinucleated giant cells derived from macrophages form the center of sarcoid granuloma. Second, there is an increase in AMs in patients with sarcoidosis. Finally, these cells disclose several signs of recent activation. In addition, AMs from patients with sarcoidosis spontaneously produce TNF-a and other cytokines. Particularly TNF-a is thought to be the granuloma-promoting factor in sarcoidosis. A pivotal step in the generation of specific T-cell responses is the activation of T cells by their recognition of antigen, a process that depends on the antigenpresenting cell. The term ‘‘antigen-presenting’’ cell does not describe a certain cell type or lineage but it is merely a description of a cell function. In fact, cells from varying origin can function as antigen-presenting cells although there are large differences in their antigen-presenting capabilities. T cells recognize antigen by their T-cell receptor only when the antigen is presented within the antigen-binding groove of the MHC. Therefore, antigen must be taken up by the antigen-presenting cell, processed, inserted into the MHC molecule, and transported to the surface of the antigen-presenting cell ready to be detected by T cells. For full T-cell activation, however, antigen-presenting cells have to deliver costimulatory signals. Because both T cells and APC have to be in close cell-cell contact, the resulting complex is called ‘‘immunologic synapse’’ (analogous to nerve synapses) (49). In sarcoidosis, AMs display an altered phenotype that enables these cells to present antigen(s) with heightened efficiency. In contrast, in healthy volunteers the addition of AMs to proliferating T cells decreases their proliferation rate (50,51). Several groups (52–54) found that AMs from patients with sarcoidosis display an increased antigen-presenting capacity compared with controls. The phenomenon of increased accessory function of AMs is mainly restricted to AMs from patients with active sarcoidosis. In contrast AMs from patients with inactive disease did not reveal increased antigen-presenting capacity (55). Furthermore, Poulter and coworkers suggested that there are functionally different macrophage cell types and that macrophages which do not express RFD1 and RFD7 are highly efficient antigen-presenting cells (56). There is a strong link between the number of MHC II molecules on a distinct cell and their antigen-presenting capacity. AMs from patients with active sarcoidosis demonstrate a dramatic increase in MHC II molecules at their cell surface (57) that is within the range of monocyte-derived dendritic cells (DC) which are thought to be the best antigen-presenting cells. In addition, there are striking associations of HLA-DR subtypes with the clinical
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course of sarcoidosis (58–60) underscoring the importance of MHC-II expression in sarcoidosis. Furthermore, there is an increased expression of various costimulatory molecules on AMs from patients with sarcoidosis including CD154 (ligand for CD40), CD72 (ligand for CD5), CD80, CD86 (both ligands for CD28), and CD153 (CD30L) (61–66). Several molecules involved in cell adhesion [e.g., CD54 (ICAM), CD11a-c] are involved in antigen presentation and are increased in sarcoidosis (55). Blocking these molecules by neutralizing antibodies decreased accessory function of AMs (55,67). Further, in sarcoid patients the gene coding for butyrophilin-like (BTNL)-2, a molecule that inhibits T-cell activation (68), contains a single nucleotide polymorphism (SNP) that results in a truncated molecule. This truncated molecule is not able to insert itself in the cell membrane, leading to reduced control of T-cell activation. This SNP is associated with familial and sporadic sarcoidosis in Caucasians (69,70) and to a lesser extent in African Americans (71). In contrast to the extensive data supporting a role of AMs in the pathogenesis of sarcoidosis, few data are available regarding DC. Although the antigen of sarcoidosis is unknown, it is likely that antigen is gathered preferentially in the lung and transported into the draining lymph node. Only in the lymphoid tissue mature DC can activate naive T cells. The lymphadenopathy associated with sarcoidosis may reflect an ongoing accumulation of antigen-presenting cells. However, Munroe et al. showed that DC are primarily located in the paracortical zone (72). In lung lesions, however, DC were found only in one case with chronic disease; otherwise DC were sparse or absent. Lommatzsch and coworkers found no differences in plasmacytoid and mature DC populations between sarcoid patients and controls, but a certain CD1a-negative DC population was increased in sarcoidosis (73). These results were corroborated by Gibejova et al. who could not detect CCL20 mRNA (LARC, liver and activation related chemokine (MIP)-3a), a chemokine attracting immature DC, in BAL cells from patients with sarcoidosis (74). However, Facco and coworkers demonstrated increased release of CCL20 by AMs from patients with active sarcoidosis (75). In contrast to lung tissue, in sarcoid skin lesions, DC (interdigitating cells and Langerhans cells) were consistently associated with granuloma. In conclusion, DC are probably not important for the development and maintenance of lung pathology and pulmonary granuloma formation in sarcoidosis. However, in extrapulmonary sarcoidosis such as skin, DC appear to be of relevance for granuloma induction. One might speculate that AMs that acquired dendritic cell– like properties replace DC in the lung (62,76). This hypothesis is supported by the observation that processed AMs induce a granulomatous skin reaction in patients with sarcoidosis (analogous to the Kveim test) (35). This suggests that the unknown antigen persists within AMs and these cells are capable of presenting the antigen to T lymphocytes. However, activation of macrophages may be elicited by innate immune mechanisms. In particular, natural killer (NK) cells are increased and activated in the lungs of patients with sarcoidosis (77,78).
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Cytokines and the Cytokine Network
Cytokines are secreted regulatory proteins that control a variety of functions. While they are released by cells and target via binding to appropriate receptors expressed on other cells, they comprise a cell communication system to orchestrate cellular function at different levels. In contrast to hormones, cytokines act in close vicinity of the area of release and are rarely found in the circulation. A subgroup of cytokines is more likely to regulate cellular trafficking and therefore they are referred to as chemokines. One important effect of cytokines on cells is the induction of the release of other cytokines, thereby inducing a cascade of cytokine interaction. IL-2, for example, induces the release of IFNg by T cells that induces the release of CXCL10 (interferon-inducible protein-10; IP-10) and other mediators. Cytokine effects are not isolated events, but are part of a complex ‘‘cytokine network.’’ 1. TNF-a and the TNF-a Superfamily
TNF-a is the prototypic cytokine of a family of mediators either related biochemically or by interaction with the TNF-a-receptor family. The most important source for TNF-a in the lung are the AMs but T cells, NK cells, and neutrophils are also able to release TNF-a. Of all mediators, TNF-a is the most often investigated mediator in sarcoidosis. In summer 2007, a PubMed search with the keywords ‘‘sarcoidosis TNF-a’’ revealed 172 hits, including 31 reviews. In contrast, ‘‘sarcoidosis IL-2’’ revealed 141 hits including 17 reviews; ‘‘sarcoidosis IFNg’’ led to only 91 hits including four reviews. There are several clues linking TNF-a release to the pathogenesis of sarcoidosis. Several authors demonstrate that TNF-a release is upregulated in BAL cells from patients with active sarcoidosis (79–83). In sarcoidosis, TNF-a release is compartmentalized demonstrating increased TNF-a release by cultured BAL cells but virtually no release by peripheral blood cells (79). Release of high amounts of TNF-a by AMs segregates with the presence of aggregates of AMs in the tissue (84). Such aggregates may be considered as granuloma in status nascendi. Indeed, in a mouse model of mycobacterial infection, TNF-a cooperates with IFNg in the induction of granuloma formation; neutralization of one of these cytokines diminished the capacity of these mice to develop granuloma after infection (85,86). The finding of a significant shift toward the uncommon TNFA2 allele in patients with Lo¨fgren’s syndrome (87,88) raised the question of differences in genetic control of TNF-a release in sarcoidosis. However, we subsequently found that the TNF-a release in sarcoidosis is not determined by the TNFA polymorphism (89). Recently, Veltkamp and coworkers found a correlation of TNF-a release and the number of GT repeats in intron 1 of the toll-like receptor (TLR)2 gene after stimulation of peripheral blood monocytes with TLR2 ligands in a subgroup of sarcoid patients (90). TNF-a is recognized by cells expressing TNF-a receptors (TNFR). There are two TNFR known; TNF-R1 (CD120a, 55–60 kDa) and TNF-R2 (CD129b, 75–80 kDa). Both receptors mediate two different activities of TNF-a. CD120a
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is responsible for the apoptotic activities of TNF-a while CD120b activates NFkB resulting in cytokine activation and cell stimulation. Expression of CD120a is higher on AMs from sarcoid patients compared with controls (91). TNF-a was detected by enzyme-linked immunosorbent assay (ELISA) but TNF-a activity was lacking using bioassays. Both TNFRs are shed from cell surfaces by metalloproteinases and can be detected as soluble molecules binding TNF-a and inhibiting its biological activities. AMs from patients with sarcoidosis produce both receptors in higher amounts than AMs from controls (92,93). Interestingly, although both TNFRs are upregulated by lipopolysaccharide (LPS) stimulation and correlate with the concentration of TNF-a, the release of CD120b revealed the closest link to the TNF-a concentration (93). This is corroborated by Ziegenhagen et al. and Hino et al. demonstrating increased levels of CD120a and CD120b in serum and BAL fluids (94,95). Both groups reported increased levels of both receptors, but the highest values and best correlations were seen with CD129b indicating its important role in blocking TNF-a activities in sarcoid patients. Other cytokine members of the TNF-a superfamily are lymphotoxin-a (LTa), also known as (TNF-b), lymphotoxin-b (LTb), and nerve growth factor (NGF). LTa is found as a homotrimer and interacts with the same receptors as TNF-a. LTa is mainly produced by activated T cells. In mouse models LTa is essential in the defense against mycobacteria; its role in sarcoidosis needs to be elucidated. In contrast to LTa, LTb is only found bound to the membrane and forms heterotrimers with LTa in various ratios. In sarcoidosis, LTb expression was not only found mainly on CD4þ T cells but also on epithelioid cells and multinucleated giant cells in the lymph nodes (96) and within the granuloma (97). Receptor binding of LTb depends on the heterotrimer formation; LTa2b1 binds to TNFR1 whereas LTa1b2 binds to a specific receptor (LTbR) expressed on many cells. The lack of LTbR expression results in defective development of lymphoid organs (98) suggesting a role of LTb/LTbR in the control of lymph node and granuloma formation in sarcoidosis. NGF expression has been found to be upregulated in macrophages and T cells from patients with sarcoidosis (99). Besides its function in the neuronal system, NGF also stimulates chemotaxis of leukocytes and the proliferation of mast cells (100). Its role in sarcoidosis remains unclear. The molecule CD95 (Fas) is a member of the TNFR-super family; its ligand FasL belongs to the TNF-a superfamily. CD95 was expressed on lung T cells (66,91,101,102), and FasL was detected in AMs from sarcoid patients (101). However, the role of this ligand/receptor system in the immunopathogenesis of sarcoidosis remains unclear because no association with clinical features of sarcoidosis was detected (101). 2. TH1 Stimulatory Cytokines—the IL-12 Cytokine Family and IL-18
IL-12 is a heterodimer of two subunits p40 and p35 linked by disulfide bonds (IL-12p70). Interestingly, IL-12p40 shares some homologies with the extracellular
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domain of the IL-6R whereas p35 and IL-6 disclose homologies. It is assumed that IL-12 originates from an ancient receptor/ligand system of the IL-6 system. The p40 subunit is released in large amounts and forms a homodimer which is thought to act as an inhibitor of the TH1-inducing IL-12p70. The p40 subunit together with an additional subunit, p19, forms IL-23, another cytokine of the IL-12 family. IL-27, the latest member of this family, is formed by the subunits EBI3 (homolog to p40) and p28 (homolog to p35). IL-18 is produced as an inactive precursor molecule that has to be activated by IL-1-converting enzyme (caspase-1). Cytokines of the IL-12 family are mainly produced by lymphocytes, NK cells, and macrophages; IL-18 is mainly produced by macrophages and DC, and also by other cells (103). The cytokines of the IL-12-family and IL-18 are potent inducers of TH1 differentiation. Because sarcoidosis is a prototypic TH1 disease, IL-12 and IL-18 are likely to be involved in its pathogenesis. Indeed, in sarcoidosis, levels of IL-12, IL-27, and IL-18 were increased (104,105) whereas IL-23 was not. Steady state release of IL-12 in BAL cell cultures can be upregulated by LPS and Staphylococcus aureus (106). In patients with chronic skin sarcoidosis, treatment with thalidomide resulted in decreased granuloma size and reduction of epidermal thickness. Plasma IL-12 level increased and remained increased during treatment (107). In addition, numbers of DC and expression of HLA-DR on peripheral lymphocytes were increased. The authors concluded that thalidomide induces a focusing in the TH1 response with subsequent granuloma differentiation. In contrast, other authors found IL-12 were decreased by thalidomide or pentoxifylline (108,109). IL-12 is an important mediator involved in granuloma formation. Patients with genetic defects in the IL-12/IL-12R system exhibit defective granuloma formation and heightened susceptibility to infections from nontuberculous mycobacteria (110). A study using biopsy specimens from sarcoidosis, asthma patients and controls revealed an increased expression of IL-18 in airway epithelium of sarcoidosis patients but reduced expression in asthmatics (111). This study demonstrates that cells not only from the immune system but also nonimmune cells contribute to the immunoregulation in sarcoidosis. 3. TH1 Cytokines—IL-2, IL-15, IFN
IL-2, first mentioned in 1977, is one of the first cytokines described. By 1983, IL-2 was reported to be expressed in sarcoidosis (112). IL-15, a cytokine resembling IL-2 in many biological features, was first described in sarcoidosis in 1996 (113). IL-2 and IL-15 share the b- and g-chain of the receptor, whereas the a-chain is specific for the respective cytokine. The biological activity of IL-2 and IL-15 disclose a wide overlap; the cellular sources, however, are very distinct. IL-2 is produced almost exclusively by T cells, whereas IL-15 is released by epithelial cells, fibroblasts and monocytes but not T cells (100). IL-2 and IL-15
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are potent inducers of T-cell proliferation. Although IL-15 is a very potent cytokine, its expression is limited. IL-15-expressing cells were increased in sarcoidosis (114) but its overall release by BAL cells was relatively low (45). Because of its role in inducing proliferation and survival of T cells, IL-2 has been intensely studied in sarcoidosis. Our group noted that IL-2 served as a codeterminant of prognosis in sarcoidosis (115). In that study, patients presenting with high numbers of T cells in BAL and increased IL-2 release developed disease progression. This might be caused by the high potential of IL-2 to induce Treg. T-cell activation in an IL-2-rich milieu favors the development of Treg responsible for anergy and ineffective immune stimulation, whereas T-cell activation in an IL-2-deprived environment favors the development of effector T cells (116) causing a regular and adequate immune response. Therefore, IL-2 is a key factor in the immunopathogenesis of sarcoidosis. INFg is a product of TH1 cells and its release by BAL cells is increased in sarcoidosis (117). IFNg is a potent activator of macrophages, inducing reactive oxygen intermediates (ROI) and nitric oxide (NO). It is also an important regulator of granuloma induction. Recently, a functional IFNg-polymorphism was identified in patients suffering from Lo¨fgren’s syndrome. Association of the MHC-II molecule DRB1*03 with a functional polymorphism in the IFNg-gene, was associated with decreased IFNg levels (118). Likewise IL-12 deficiency or deficits in the IFNg/IFNgR system also cause disturbances of granuloma induction (110). In contrast, IFNg inhibits fibroblast proliferation and collagen synthesis and exerts antifibrotic activities. Most importantly, IFNg is a potent activator of macrophages. It induces the expression of chemokines like CXCL10, upregulates MHC-II expression, and induces ROI and NO release. IFNg primes macrophages to release higher levels of TNF-a or IL-1 after adequate stimulus, a phenomenon also seen in sarcoidosis (80). 4. Deactivating Cytokines––TGFb, IL-10
The high incidence of spontaneous remissions in sarcoidosis raised the question of participation of anti-inflammatory cytokines like IL-10 and TGFb in the immunoregulation of sarcoidosis. TGFb inhibits cytokine release by macrophages (119) and lymphocyte activation (120). In an early study, abundant TGFb staining in epitheloid cells of sarcoid granuloma was observed (121). However, the release of TGFb by BAL cells from sarcoid patients is controversial. In a study with sarcoidosis patients with clearly defined clinical outcomes, we demonstrated increased TGFb release by cultured BAL cells from patients undergoing spontaneous remission but not in other groups (122). Other authors employing non-characterized patient groups failed to demonstrate increased TGFb release by sarcoid BAL cells (123,124). Further, no association of sarcoidosis and functional polymorphisms in the TGFb1 gene was demonstrated (125,126). These studies are corroborated by Kruit et al.; however, the authors found an association with another polymorphism in the TGFb3 gene in patients
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developing fibrosis (127). This is of interest because TGFb3 has been shown to inhibit scar formation (128). IL-10 is a cytokine mostly released by lymphocytes, preferably of CD8 and TH2 phenotype, but also by B cells and macrophages. Like TGFb, IL-10 is a cytokine deactivating macrophage and lymphocytes (129–131). As for TGFb, conflicting results on IL-10 release by BAL cells exist. Some studies noted increased IL-10 in sarcoidosis patients with active disease (132,133) whereas others did not (106,122). No association was found with a functional polymorphism in the IL-10 gene (125). 5. Stimulators of Cell Differentiation—Colony-Stimulating Factors
M-CSF and GM-CSF are factors inducing proliferation, differentiation, and giant-cell formation of AMs (134), all these features frequently seen together in sarcoidosis. Both factors are released by activated T cells and are increased in BAL cell culture supernatants from sarcoidosis patients (133,135). 6. Regulators of Cellular Migration—Chemokines
Chemokines are small cytokines signaling via G-protein-coupled seven transmembrane receptors and attracting cells bearing the respective receptor type. In sarcoidosis a variety of chemokines responsible for attracting lymphocytes of the CD4þ TH1 type are increased [e.g., CCL5 (regulated upon activation, normal T cell expressed and secreted; RANTES), CXCL9 (monokine induced by gamma-Interferon; MIG) and CXCL10 (IP-10) are increased] (136–138). CXCL10 and CXCL9 are both produced by IFNg-stimulated macrophages whereas RANTES is released by TNF-a- or IL-1-stimulated T cells. Alveolar epithelial cells also release chemokines. TNF-a induces the release of CCL2 and CXCL8 (139,140) whereas IFNg induces the release of CXCL10 and CXCL9 (139). TNF-a, IL-1, and IFNg are increased in sarcoidosis which in turn induces these mediators. In addition, CXCR3-expressing cells accumulate in sarcoidosis and correlate with the increased release of its ligand CXCL10 (141–143). This may result in a positive feedback loop where the activation of T cells and macrophages results in an increase in IFNg release by these T cells, which in turn induces the release of chemokines attracting more T cells. Interestingly, BAL fluid from patients with active sarcoidosis revealed a CD4þ T-cell population bearing the chemokine receptors CXCR3, CCR6, and CXCR6 (75). This population was not seen in controls or patients with inactive disease. Migration of this population is induced by CXCL10 (ligand for CXCR3), CCL20 (ligand for CCCR6), and CXCL16 (ligand for CXCR6), mediators that are all expressed by macrophages from patients with active sarcoidosis. This CD4þ population releases IL-4 but not IFNg (75). IL-4 is a cytokine able to downregulate macrophage activation (129,144). In contrast, chemokines mostly released in a TH2 environment observed in fibrotic disorders (e.g., the chemokines signaling via CCR4 like CCL17 and
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CCL22) are not found in sarcoidosis (145). CCL18, a chemokine without known receptor, was either not detected (146) or was found only in patients with advanced chest X-ray types (147) suggesting that this chemokine is related to fibrosis. Although this chemokine is thought to be responsible for chemotaxis of lymphocytes, no association wither either T-cell subtype was observed. Chemokines inducing the accumulation of neutrophils like CCL3, CCL4, and CXCL8 are increased in sarcoidosis (33,148,149). Ziegenhagen et al. found increased levels of CXCL8 and CCL3 in patients disclosing progressive disease and demonstrated clinical relevance of this phenomenon (33). Cells of the monocyte/macrophage lineage play an important role in the pathogenesis of sarcoidosis. There are a variety of chemokines that induce chemotaxis of these cells (Table 1). Important chemokines in this respect are CCL2, CCL3, and CCL22. CCL2 is increased in patients with lower chest X-ray types (33,148,150) and who are at risk of relapses whereas relatively low values are seen in patients with advanced chest X-ray types (150). Other cytokines may serve as prognostic markers as suggested for CXCL8, CCL2, or CCL3 (33,150). A list of chemokines found in sarcoidosis is given in Table 1. Table 1 Chemokines in Sarcoidosis Systematic name
Aliases
Receptor(s)
Target cells
References
CCL2 CCL3
MCP-1 MIP-1a MIP-1b RANTES
Monocytes Neutrophils, monocytes Neutrophils T cells, eosinophils
148 33,148,156,157
CCL4 CCL5 CCL17 CCL18
T cells (TH2) Fibroblasts
141,145 147
CCR7 CCR6
DC T cells DC
74 75
CCL22
TARC PARC, AMAC1, DCCK1 MIP-3b, Exodus-3 LARC, MIP-3a, Exodus-1 MDC
CCR2 CCR1, CCR5 CCR5 CCR1, CCR3, CCR5 CCR4 Unknown
CCR4
145
CXCL8
IL-8
Monocytes, DC, NK cells Neutrophils
CXCL9 CXCL10 CXCL16
MIG IP10 SR-PSOX
T cells (TH1) T cells (TH1) T cells
136 136,143,161 162
CCL19 CCL20
CXCR1, CXCR2 CXCR3 CXCR3 CXCR6
149 148,157,158
159,160
Abbreviations: MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; DC, dendritic cells; RANTES, regulated upon activation normal T cell expressed and secreted; NK, natural killer.
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Model of Granuloma Formation in Sarcoidosis
Granulomas are highly organized structures created by macrophages, epitheloid cells, giant cells, and T cells. It is generally accepted that initiation of granuloma formation requires T-cell activation. There are many attempts to find a ‘‘sarcoid’’ antigen, either by analyzing the ‘‘Kveim-Siltzbach-Antigen’’ or granuloma tissue. Recently, mKatG as a tissue antigen was found in sera from sarcoid patients (43). Because the antibodies binding to mKatG are of the T-cell-dependent IgG type, mKatG may also serve as a T-cell antigen. These data support the view that mycobacteria may be a causative agent in sarcoidosis. Other authors detected DNA from Propionibacterium acnes in lymph nodes from sarcoid patients (151,152). In addition, P. acnes stimulates BAL lymphocytes from sarcoid patients (153). Granulomata induced in a mouse model of P. acnes display many features of sarcoid granuloma (154). In general, a nondegradable agent induces T-cell activation and activates AMs (Fig. 1). The activated T cells proliferate and release mediators attracting additional inflammatory cells and further activate macrophages. As a consequence, these mechanisms result in an accumulation of cells in the alveoli (alveolitis) and interstitium in sarcoidosis. Bacterial products also directly activate AMs via the receptors of the innate immune system (TOLL like receptors; TLR). This activation induces the expression of mediators (e.g., TNF-a and IL-12). Aggregates of macrophages are precursors of granuloma. Sarcoid patients with macrophage aggregates disclosed higher levels of TNF-a release compared with patients with differentiated granuloma (84). This is important because TNF-a is necessary for the development and integrity of granuloma (85,86). Under the influence of M-CSF and GM-CSF, the macrophages conflate to multinucleated giant cells. Epithelial cells enclose the inner circle of the granuloma to contain the possibly harmful and nondegradable agent. At least in the skin, sarcoid granuloma are surrounded by DC (155) that monitor the environment for escaping antigen and
> Figure 1 Model of granuloma formation in sarcoidosis. A yet unknown stimulus activates T cells (Tc) and macrophages (MF) leading in mediator release. IL-12 and IL-18 promote a TH1 response; IFNg activates macrophages and AEC-II to release CXCL10 and other chemokines. Additional inflammatory cells are recruited by increased chemokine release leading to the typical alveolitis in sarcoidosis. Under the influence of TNF-a and CSFs, the persistent presence of nondegradable material results in giant-cell differentiation and granuloma formation. The role of regulatory T cells and other T-cell populations is less defined. CXCL10, CCL20, and CXCL16 might induce the immigration of IL-4-releasing cells. TGFb-releasing cells might lead to spontaneous remission, whereas IL-10-releasing cells might lead to progressive disease. High and continuous TNF-a release indicated progressive disease, whereas high CCL18 release is associated with fibrosis in sarcoidosis. Abbreviations: IFN, interferon; AEC, alveolar epithelial cells; TNF-a, tumor necrosis factor; CSF, colony-stimulating factor; TGF, transforming growth factor.
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subsequently activate T cells. Activated T cells surrounding the outer border of the granuloma and activated cells within the granuloma release cytokines necessary for the maintenance of a functionally intact granuloma. Although the proof of a causative etiological agent in sarcoidosis is lacking, we can now clearly define its immunobiological characteristics. In chronic beryllium disease, an exact phenocopy of sarcoidosis, the antigen beryllium also starts a ‘‘sarcoid granuloma program.’’ Thus, it is feasible that not one single causative agent exists but several microorganisms, their products or even inorganic substances might induce pathogenetic mechanisms leading to a disease called sarcoidosis. References 1. Schurmann M. Genetics of sarcoidosis. Semin Respir Crit Care Med 2003; 24(2): 213–222. 2. Rybicki BA, Hirst K, Iyengar SK, et al. A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study. Sarcoidosis Vasc Diffuse Lung Dis 2005; 22(2):115–122. 3. Rybicki BA, Major M, Popovich J Jr., et al. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am J Epidemiol 1997; 145(3):234–241. 4. Hosoda Y, Sasagawa S, Yasuda N. Epidemiology of sarcoidosis: new frontiers to explore. Curr Opin Pulm Med 2002; 8(5):424–428. 5. Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr 1985; 107(5): 689–693. 6. Becker ML, Rose CD. Blau syndrome and related genetic disorders causing childhood arthritis. Curr Rheumatol Rep 2005; 7(6):427–433. 7. Kanazawa N, Okafuji I, Kambe N, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. Blood 2005; 105(3):1195–1197. 8. Jabs DA, Houk JL, Bias WB, et al. Familial granulomatous synovitis, uveitis, and cranial neuropathies. Am J Med 1985; 78(5):801–804. 9. Rotenstein D, Gibbas DL, Majmudar B, et al. Familial granulomatous arteritis with polyarthritis of juvenile onset. N Engl J Med 1982; 306(2):86–90. 10. Hampe J, Grebe J, Nikolaus S, et al. Association of NOD2 (CARD 15) genotype with clinical course of Crohn’s disease: a cohort study. Lancet 2002; 359(9318): 1661–1665. 11. Schurmann M, Valentonyte R, Hampe J, et al. CARD15 gene mutations in sarcoidosis. Eur Respir J 2003; 22(5):748–754. 12. Familial associations in sarcoidosis. A report to the Research Committee of the British Thoracic and Tuberculosis Association. Tubercle 1973; 54(2):87–98. 13. Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 2001; 164(11):2085–2091. 14. Lo¨fgren S. Primary pulmonary sarcoidosis. Acta Med Scand 1953; 145:424–465.
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7 Pulmonary Sarcoidosis
JOSEPH P. LYNCH, III Department of Medicine, Division of Pulmonary and Critical Care Medicine, Clinical Immunology and Allergy, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
MICHAEL C. FISHBEIN Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
ERIC S. WHITE Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, U.S.A.
I.
Introduction
The spectrum of sarcoidosis is protean, and virtually any organ can be involved (1–4). Multisystemic involvement is characteristic, but pulmonary involvement usually dominates (1–3,5–7). A recent study of 736 patients with sarcoidosis in the United States found that 95% had intrathoracic disease (8). In the next chapter, Dr. Judson discusses extrapulmonary sarcoidosis in depth. In this chapter, we limit our discussion to pulmonary manifestations of sarcoidosis (6). II.
Pulmonary Sarcoidosis
Abnormalities on chest radiographs are detected in 85% to 95% of patients with sarcoidosis (6,7,9–12). Cough, dyspnea, or bronchial hyperreactivity may be prominent in patients with significant endobronchial or pulmonary parenchymal involvement (6). However, 30% to 60% of patients with sarcoidosis are asymptomatic, with incidental findings on chest radiographs (6,11,13). The clinical course is heterogeneous. Spontaneous remissions (SRs) occur in nearly two-thirds of patients, but the course is chronic in 10% to 30% (9–12,14). 189
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Chronic, progressive pulmonary sarcoidosis may cause inexorable loss of lung function and destruction of the lung architecture (6,15). Fatality rates ascribed to sarcoidosis range from 1% to 5% (9–13,16,17). A recent epidemiological study in the United Kingdom identified 1019 cases of sarcoidosis between 1991 and 2003 (18). Mortality rates at three and five years for sarcoid patients were 5% and 7%, respectively, compared to 2% and 4% among age- and gender-matched controls without sarcoidosis. Causes of death were not reported. In the United States, mortality rates due to sarcoidosis were <1% in non-referral settings (12,13,19) but were higher in referral centers (likely reflecting a bias selecting for more severe cases) (5,20–22). In the United States and Europe, most deaths in patients with sarcoidosis were due to pulmonary complications; 13% to 50% of deaths were attributed to myocardial involvement (3,17,23). Conversely, in Japan, 77% of deaths ascribed to sarcoidosis were due to cardiac involvement (24). III.
Clinical Features of Pulmonary Sarcoidosis
Chest physical findings are usually minimal or absent in pulmonary sarcoidosis. Even when radiographic infiltrates are extensive, crackles are present in fewer than 20% of patients with sarcoidosis (6). Clubbing is uncommon in sarcoidosis (6). Fatigue and impaired quality of life (QOL) (25) are far more common among patients with sarcoidosis compared to healthy controls. IV.
Chest Radiographic Features in Sarcoidosis
Bilateral hilar lymphadenopathy (BHL) is present in nearly three-quarters of patients with sarcoidosis; concomitant involvement of right paratracheal lymph nodes is common (6,9–12) (Fig. 1). Computed tomographic (CT) scans often detect enlarged left paratracheal, para-aortic, and subcarinal lymph nodes, which are not evident on plain chest radiographs (6). Unilateral hilar lymphadenopathy on CT is uncommon (<10%) (26). Pulmonary parenchymal infiltrates (with or without BHL) are present in 20% to 50% of patients with sarcoidosis (6,7,11) (Figs. 2–4). Infiltrates preferentially involve the upper and mid lung zones, and may be patchy or diffuse (6,27). Reticulonodular infiltrates, macroscopic nodules, consolidation, or mass-like lesions may be evident (6). Pulmonary fibrosis may cause volume loss, hilar retraction, anatomic distortion, and coarse linear bands (Fig. 5). With advanced fibrocystic sarcoidosis, large bullae (28,29) (Fig. 6), cystic radiolucencies (30,31), mycetomas (28,32), or enlarged pulmonary arteries (attributable to secondary pulmonary hypertension) (28) may be observed. V.
Radiographic Classification Schema
The chest radiographic staging system developed more than four decades ago continues to have prognostic value (28). This classification schema defines the following stages: stage 0 (normal), stage I (BHL without pulmonary infiltrates),
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Figure 1 Stage I sarcoidosis. PA chest radiograph showing bilateral hilar and right paratracheal adenopathy. Abbreviation: PA, posterior-anterior.
Figure 2 Stage II sarcoidosis. PA chest radiograph demonstrates BHL and bilateral pulmonary infiltrates. Abbreviations: PA, posterior-anterior; BHL, bilateral hilar lymphadenopathy.
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Figure 3 Stage II sarcoidosis. PA chest radiograph demonstrating patchy alveolar and reticular opacities and BHL. Abbreviations: PA, posterior-anterior; BHL, bilateral hilar lymphadenopathy.
Figure 4 Stage III sarcoidosis. PA chest radiograph demonstrating diffuse reticulonodular infiltrates involving all lobes. Abbreviation: PA, posterior-anterior.
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Figure 5 Stage IV sarcoidosis. PA chest radiograph demonstrating distortion, upward retraction of hilae, and parenchymal infiltrates. Note prominent pleural thickening in both upper lobes. Abbreviation: PA, posterior-anterior.
stage II (BHL plus pulmonary infiltrates), stage III (parenchymal infiltrates without BHL), and stage IV (extensive fibrosis with distortion or bullae). Although exceptions exist, the prognosis is best with radiographic stage I, intermediate with stage II, and worst with stage III or IV (6,28). SRs occur in 60% to 90% of patients with stage I disease, 40% to 70% with stage II, 10% to 20% with stage III, and 0% with stage IV (6,9–11,28,33). Swedish investigators followed 505 patients with sarcoidosis (both treated and untreated) (11). At fiveyear follow-up (both treated and untreated patients), chest radiographs normalized in 82% of patients with stage I sarcoidosis, 68% with stage II, and 37% with stage III (11). Among 308 patients with initial stage I disease, 29 (9%) progressed to stage II and only 5 (1.6%) progressed to stage III or IV. Danish investigators followed 210 patients with sarcoidosis for 1 to 10 years (both treated and untreated) (10). Chest radiographs normalized in 57% of 116 patients with stage I disease; only 10 progressed to stage II; none developed stage III. Among patients with stage II, chest radiographs normalized in 48%; only 12% worsened. By contrast, chest radiographs normalized in only 1 of 10 (10%) with stage III sarcoidosis. The course of the disease was usually dictated within the first one to two years of presentation. Importantly, 85% of all SRs occurred within
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Figure 6 Stage IV sarcoidosis. PA chest radiograph demonstrating extensive bullous and cystic changes, with anatomic distortion from advanced fibrocystic sarcoidosis. Abbreviation: PA, posterior-anterior.
two years of presentation (10). Among patients who remained in stage II after two years of observation, chest radiographs eventually normalized in only 12% and worsened in 30%. Late relapses were rare in patients exhibiting stability for the first two years. Only 1 of 63 patients (1.6%) with stage I at presentation progressed after the second year (10). Several studies have noted that rates of late relapse are low (<10%) among patients who spontaneously remit (33–35). However, persistent infiltrates at two years predicted a chronic or persistent course (10,36). The ACCESS study in the United States prospectively followed 215 patients with sarcoidosis for two years (14). In most patients, pulmonary function, X-ray stage, and dyspnea scale did not change during the two-year period. Only 11 of 176 (6%) with stage 0, I, or II disease progressed to stage III or IV over the two-year followup period. Spirometry worsened in 12%. Involvement of additional organs occurred in 50 patients (23%) during that time frame (14). The incidence of radiographic stages differs according to geographic regions, ethnicity, and referral bias (Table 1). Most studies from Scandinavia cited a striking predominance of radiographic stage I and II disease (10,11), whereas some studies from the United States and British Isles cite a disproportionate representation of radiographic stage III and IV disease (22). Interestingly,
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Table 1 Distribution of Chest Radiographic Stages in Sarcoidosisa X-ray stage Country, year, (number of patients), (reference number) Sweden, 1984 (n ¼ 505) (11) Denmark, 1982 (n ¼ 243) (10) British Isles, 2000 (n ¼ 212) (40) British Isles, 1983 (n ¼ 818) (9) Finland, 2000 (n ¼ 437) (39)b Japan, 2000 (n ¼ 457) (39)b U.S.A. 1997 (n ¼ 337) (22) U.S.A. 1994 (n ¼ 98) (35) U.S.A. 1985 (n ¼ 86) (19) U.S.A. 2001 (n ¼ 736) (7)
0 (%)
I (%)
II (%)
III (%)
IVa (%)
3
61
25
10
1
0.4
55
40
9
51
20
15
5
14
56
18
11
ND
0
44
43
13
0
67
27
5
0
8
45
29
17
ND
20
18
27
10
25
10
49
21
20
ND
8
40
37
10
5
4.5
ND
0.4
a
Stage IV not universally adopted. Only included pulmonary sarcoidosis. Source: From Ref. 28.
b
cardiac sarcoidosis is much more common in Japan than in Europe or North America (3,4). VI.
Clinical Prognostic Factors
The presence of acute inflammatory manifestations (i.e., erythema nodosum, polyarthritis, and fever), termed Lofgren’s syndrome, portends an excellent prognosis, with high rates (>85%) of SRs (9,14,33,37,38). Conversely, the following factors were associated with a worse prognosis in sarcoidosis: age onset >40 years (9,36), hypercalcemia (9), extrathoracic disease (9,20), lupus pernio (9), splenomegaly (36), pulmonary infiltrates on chest radiograph (9,36), chronic uveitis, cystic bone lesions, nasal mucosal sarcoidosis (9), and lower annual family income (14). Ethnic, geographic, and genetic factors influence prognosis (36,39,40). Lofgren’s syndrome is three to six times more common in women (7,38). Black race is associated with a higher rate of chronic progressive disease, worse
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long-term prognosis, extrapulmonary involvement, and higher risk of relapses (5,9,14,21,22). The prognosis of pulmonary sarcoidosis was worse among Finnish compared to Japanese patients (39). Pietinalho et al. followed 437 Finnish and 457 Japanese patients for five years (39). At five-year follow-up, chest radiographs had normalized in 40% of Finnish and 73% of Japanese patients, respectively (p < 0.001). During the five-year period, initial stage I lesions progressed to higher stages in 20% of Finnish patients and 14% among Japanese patients. At five years, among patients with initial stage II disease, chest radiographs had normalized in 36% of Finnish and 73% of Japanese patients. Among patients with initial stage III disease, chest radiographs had normalized by five years in 24% of Finnish and 35% of Japanese patients, respectively (39). The influence of genetics on prevalence and clinical expression of sarcoidosis is discussed elsewhere in chapter 3 by Dr. Woodhead and duBois. VII.
Computed Tomographic Scans
Chest CT scans are superior to conventional chest radiographs in delineating parenchymal, mediastinal, and hilar structures, depicting parenchymal details, and discriminating inflammation from fibrosis (27,41,42). Characteristic features of sarcoidosis on CT include mediastinal and/or hilar lymphadenopathy, micronodules and nodules along bronchovascular bundles, predilection for mid and upper lung zones, an axial distribution, pleural or subpleural nodules, septal and nonseptal lines, confluent nodular opacities with air bronchograms (i.e., consolidation), and ground glass opacities (GGOs) (27,42,43) (Figs. 7–9). Hilar or mediastinal lymph adenopathy is present in 47% to 94% of patients with sarcoidosis (42). The most commonly involved nodal stations (in order of decreasing frequency) are right lower paratracheal, right hilar, subcarinal, and aortopulmonary window (42). Calcification of sarcoid lymph nodes may occur with long-standing disease (6). Nodules are present in >80% of patients with sarcoidosis, and represent aggregates of granulomas (27,42,43). Irregularity or thickening of bronchovascular bundles, occasionally with a ‘‘beaded’’ appearance, is a cardinal sign of pulmonary sarcoidosis (42). GGOs (hazy areas of increased attenuation) were noted in 16% to 83% of patients with sarcoidosis (42–44); both granulomatous and fibrotic lesions may give rise to this CT feature (42). Conglomerate masses (opacities >3 cm in diameter) may surround and encompass bronchi and vessels (42,45). Airway involvement may manifest as air trapping and a mosaic pattern on CT (42,46); these features are more readily exemplified by expiratory images (47). Emphysema may be observed in advancedstage sarcoidosis (typically stage IV), but is more extensive in smokers (48). Architectural distortion, hilar retraction, fibrous bands, bronchiectasis, honeycomb cysts, bullae, and enlarged pulmonary arteries may be observed with advanced disease (27,45,49). Distortion of the lung architecture may displace hilae, fissures, bronchi, or vessels (42,45). These diverse features preferentially involve the upper lobes (42,45). Multiple CT patterns or features may be present in individual patients, and may evolve over time (27).
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Figure 7 HRCT scan demonstrates cystic lesions, anatomic distortion, and traction bronchiectasis from advanced fibrocystic sarcoidosis. Abbreviation: HRCT, high-resolution thin-section CT.
Figure 8 HRCT scan at the level of the carina demonstrates extensive cystic lesions and bronchiectasis from advanced fibrocystic sarcoidosis. Abbreviation: HRCT, high-resolution thin-section CT.
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Figure 9 HRCT scan demonstrates dense alveolar consolidation, multiple nodules, ‘‘sarcoid galaxies,’’ and traction bronchiectasis. Note the cavitary lesion with a mycetoma. Abbreviation: HRCT, high-resolution thin-section CT.
Despite the enhanced accuracy of CT, routine CT is not necessary or costeffective in the management of sarcoidosis (50). Importantly, CT features do not correlate with bronchoalveolar lavage (BAL) or other parameters of disease activity, either at presentation or at follow-up (44). Further, findings on initial CT scan have limited prognostic value, since the disease has potential to evolve over time. Despite these limitations, high-resolution thin-section CT (HRCT) may be helpful in selected patients with stage II or III disease to discriminate active inflammation from fibrosis (27,42). Nodules, GGOs, consolidation, or alveolar opacities on CT suggest granulomatous inflammation, and may reverse with therapy (27,51), whereas honeycomb change, cysts, emphysema, coarse broad bands, distortion, or traction bronchiectasis indicate irreversible fibrosis (27,52). Additionally, chest CT scans may be helpful in the following circumstances: atypical clinical or chest radiographic findings; to detect specific complications of the lung disease (e.g., bronchiectasis, aspergillomas, fibrosis, superimposed infection, or malignancy); and normal chest radiographs but a clinical suspicion for sarcoidosis (3,27,42). The salient features and role of CT in the management of sarcoidosis are addressed in chapter 2. VIII.
Pulmonary Function Tests in Sarcoidosis
Abnormalities in pulmonary function tests (PFTs) are present in approximately 20% of patients with radiographic stage I sarcoidosis and in 40% to 80% of patients with stages II, III, or IV (6,9,10,28,53,54). Reduced lung volumes [e.g.,
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vital capacity (VC) and total lung capacity (TLC)] are characteristic (28). The diffusing capacity for carbon monoxide (DLCO) is the most sensitive of the PFT parameters (54), but the degree of impairment is less severe in sarcoidosis than in idiopathic pulmonary fibrosis (IPF) (6). Even when chest radiographs are normal, forced vital capacity (FVC) or DLCO are reduced in 15% to 25% and 25% to 50% of patients, respectively (6,53,55). Oxygenation is preserved until late in the course of sarcoidosis (6). Airflow obstruction [e.g., reduced forced expiratory volume in one second (FEV1) and expiratory flow rates] occurs in 30% to 50% of patients with pulmonary sarcoidosis (28,54,55). Patients with advanced pulmonary sarcoidosis (radiographic stage III or IV) may exhibit severe decrements in FEV1=FVC (28,56). A recent prospective study noted airflow limitation (defined as <70% FEV1=FVC ratio) in 20 of 228 (8.8%) consecutive Japanese patients with sarcoidosis (57). Airflow limitation was more common in males, smokers, and radiographic stage IV patients. Additionally, increased airway hyperreactivity in response to methacholine is common in patients with sarcoidosis (54,58,59). Airflow obstruction may be caused by multiple mechanisms including narrowing of bronchial walls (via granulomatous lesions or fibrotic scarring) (60,61), peribronchiolar fibrosis (62), airway distortion caused by pulmonary fibrosis (63), compression by enlarged lymph nodes (6), and small-airways disease (55). Impaired respiratory muscle function may contribute to dyspnea or exercise limitation in patients with sarcoidosis (54,64). Alterations in cardiopulmonary exercise tests (CPET) have been noted in 28% to 47% of patients with sarcoidosis (6,63,65,66). Typical findings include ventilatory limitation or increased dead space/tidal volume ratio (VD/VT) or widened alveolar-arterial O2 (A-a O2) gradient with exercise (63,65). CPET may be abnormal when static PFTs are normal (63,67). Exercise-induced desaturation correlated with reductions in DLCO (63,68–70), whereas lung volumes and expiratory flow rates did not (70). Although CPET is more sensitive than static PFTs in predicting work and exercise capacity, the practical value of CPET is limited. Spirometry and oximetry are usually adequate to follow the course of the disease (6). For patients with more severe disease, noninvasive six-minute walk tests (6MWT) provide additional quantitative data. The extent of pulmonary physiological impairment correlates with severity of disease by chest radiographs or CT scans (27,28,44), but correlations are imprecise. Specific CT findings (e.g., thickening or irregularity of bronchovascular bundles, intraparenchymal nodules, septal and nonseptal lines, and focal pleural thickening) correlate with functional impairment, whereas other features (e.g., focal consolidations, GGO, or enlarged lymph nodes) are less important (71). The pattern of CT may reflect underlying pathology. Hansell et al. noted that a reticular pattern on HRCT correlated inversely with FVC, FEV1, FEV1=FVC, and DLCO (72). Reticular and fibrotic abnormalities on HRCT correlate modestly with physiological aberrations, whereas mass lesions or confluence do not (73).
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Honeycomb change is most often associated with restriction and low DLCO, whereas bronchial distortion is often associated with reduced expiratory flow rates (45). Airflow obstruction may be suggested on CT when bronchial mural thickening, small-airway narrowing, or patchy air trapping is present (46,74,75). Reticular shadows and thickened bronchovascular bundles on HRCT were independently associated with lower FEV1=FVC ratio (57). CT patterns may evolve over time. Serial CT in 40 patients with pulmonary sarcoidosis showed several distinctive evolutionary patterns (76). Macroscopic nodules often disappeared or decreased in size at follow-up. Consolidation and GGO resolved in some patients, but evolved into honeycombing in other patients (associated with a decline in FVC). A conglomeration pattern shrank and evolved into bronchial distortion and a decline in FEV1=FVC ratio. Given the imprecise correlations between CT and physiological parameters, direct measurement of PFTs is critical to assess the extent and degree of pulmonary functional impairment. IX.
Influence of Pulmonary Function on Prognosis
Physiological parameters at the onset do not predict long-term outcome in patients with sarcoidosis, but mortality is higher among patients with severe physiological impairment (6,28,53). Sequential studies are invaluable to follow the course of the disease and assess response to therapy. VC improves more frequently than DLCO, TLC, or arterial oxygenation (6,28,53). Changes in VC and DLCO are concordant in >90 of patients (14,28). A prospective study in the United States of 193 sarcoid patients cited excellent concordance between changes in FVC and FEV1 (14). Given the variability of DLCO (53) and the expense of obtaining lung volumes, spirometry and flow-volume loops are the most useful and cost-effective parameters to follow the course of pulmonary sarcoidosis. Additional studies such as DLCO, TLC, or gas exchange have a role in selected patients. Criteria for assessing ‘‘response’’ or improvement have not been validated. Most investigators define a change in FVC > 10% to 15% or DLCO > 20% as significant (3). Responses to therapy are usually evident within 6 to 12 weeks of initiation of therapy (28,53). X.
Laboratory Features
Serum angiotensin–converting enzyme (SACE) is increased in 30% to 80% of patients with sarcoidosis, and may be a surrogate marker of total granuloma burden (6,28). False positives are noted in fewer than 20% of patients with other pulmonary disorders. Importantly, SACE may be normal in patients with active disease (28). SACE provides ancillary information when the activity of sarcoidosis is uncertain on clinical grounds, but SACE should not be used in isolation to dictate therapeutic interventions.
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Pathogenesis of Sarcoidosis
Sarcoidosis is characterized by accumulations of activated CD4 cells and macrophages at sites of disease activity (such as the lung) (77,78). Interactions between alveolar macrophages, T-helper (CD4þ) cells, and a Th1-cytokine network drive the granulomatous process (2,77,78). Factors that modulate or downregulate the granulomatous response have not been fully elucidated. The pathogenesis of sarcoidosis is discussed in detail in chapter 6 by Dr. Zissel and colleagues. XII.
Bronchoalveolar Lavage in Sarcoidosis
BAL has provided significant insights into the pathogenesis of sarcoidosis (79). BAL in sarcoidosis demonstrates increased numbers of activated lymphocytes (typically CD4þ T cells), alveolar macrophages, and myriad proinflammatory cytokines and mediators (78,79). BAL lymphocytosis is present in >85% of patients with pulmonary sarcoidosis; granulocytes are normal or low (28,79,80). The CD4/CD8 ratio is increased in 50% to 60% of patients with sarcoidosis (79). In late phases of sarcoidosis, neutrophils and/or mast cells may be increased (58,81). BAL cell profiles are not specific for sarcoidosis, but narrow the differential diagnosis (79,80,82). Importantly, BAL cell profiles fail to predict prognosis or responsiveness to corticosteroid (CS) therapy (2,79,83). Similarly, initial BAL CD4/CD8 ratios do not consistently predict outcome or responsiveness to therapy (79). In fact, marked CD4þ lymphocytic alveolitis is characteristic of Lofgren’s syndrome, which remits spontaneously in >85% of patients (28). BAL is expensive and invasive, and we see no clinical role for BAL in determining the need for therapy or following response. XIII.
Radionuclide Techniques
Radionuclide techniques [e.g., gallium67 citrate (84)], scintigraphy with somatostatic analogues [111indium-penetreotide- (85) or technetium99m-labelled depreotide] (86), or 18fluoro-2-deoxyglucose (18FDG) positron emission tomography (PET) scans (42,87) have been employed to diagnose or assess disease activity in sarcoidosis. These techniques are expensive, and clinical value has not been established. HRCT scans are superior to radionuclide techniques to assess inflammatory and intrathoracic involvement in sarcoidosis (27,42,44). Gallium67 scans are inconvenient (scanning is performed 48–72 hours after injection of the radioisotope) and lack prognostic value (88,89). However, Ga67 scans may have a role in selected patients in whom the diagnosis is difficult {e.g., cases with normal chest radiographs and features suggesting extrathoracic sarcoidosis [e.g., uveitis, involvement of the central nervous system (CNS), etc.]} (88). Uptake of Ga67 may identify appropriate sites to biopsy. PET scans may demonstrate increased metabolic activity in patients with pulmonary sarcoidosis (88), but the
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clinical value of PET is uncertain (42). PET has a potential role in identifying sarcoid activity at extrapulmonary sites [e.g., bone (90), cardiac (91), or neural (92) sites]. The value of radionuclide scans in assessing intrathoracic involvement remains to be established. XIV.
Pathology of Pulmonary Sarcoidosis
Non-necrotizing granulomas are the hallmark of sarcoidosis (2,93) (Fig. 10A–D). Histiocytes, epithelioid cells, and multinucleated giant cells comprise the center of the granuloma, surrounded by lymphocytes, plasma cells, and fibroblasts in the
Figure 10 (See color insert.) Pathology of pulmonary sarcoidosis. (A, B) Gross appearance of lungs. (A) Primarily dense fibrosis. (B) Primarily honeycomb change in upper lobe. (C) Typical non-necrotizing granulomas in bronchial wall. (D) ‘‘Pearls on a string’’ arrangement of parenchymal granulomas (C, D, H&E stain, 40).
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Figure 11 (See color insert.) Histopathology of pulmonary sarcoidosis. (A, B) Granulomas with Schaumann body (A) and asteroid body (B), characteristic but not specific for sarcoidosis H&E stain, 200) (C, D) Granulomatous arteritis (C) and venulitis (D) commonly seen in the lung with sarcoidosis (C, trichrome/elastic stain 100; D, H&E stain, 100).
periphery (2,93). The granulomata may be situated in the bronchial submucosa (Fig. 10C) or lung parenchyma; distribution along lymphatics may resemble a ‘‘string of pearls’’ (Fig. 10). Progressive fibrosis may result in end-stage ‘‘honeycomb lung’’ (93). Although this finding is nonspecific, the distribution of the fibrotic/cystic changes in the upper lobes is characteristic of sarcoidosis (Fig. 10A, B). Macroscopic necrosis is not a feature of sarcoidosis and suggests an alternative diagnosis (e.g., tuberculosis, fungal infection, vasculitis, etc) (3). Micronecrosis may be present, however, particularly in surgical lung biopsy specimens (93). Rarely, basophilic inclusions (Schaumann bodies) (Fig. 11A) or asteroid bodies (Fig. 11B) within giant cells may be identified (93). Progressive deposition of collagen may result in hyalinizing, relatively acellular granulomata. The
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granulomatous lesions in sarcoidosis are distributed preferentially along bronchovascular bundles and lymphatics (93). Incidental involvement of arteries or veins may be noted (93) (Fig. 11C,D). In a study of 128 open-lung biopsy specimens from patients with sarcoidosis, granulomatous vasculitis was found in 69% of biopsies (94). Venous involvement (92%) was more prevalent than arterial involvement (39%). The presence and extent of granulomatous vasculitis varies directly with the number of extravascular granulomas (93). An autopsy study of 40 patients with sarcoidosis detected granulomatous angiitis in 100% of cases (95). However, these changes are rarely observed in transbronchial biopsies or fine-needle aspiration biopsies (93). Destruction and distortion of bronchi and lung parenchyma may lead to bronchiectasis, cystic airspaces, bullae, emphysema, fibrosis, and secondary pulmonary hypertensive changes (93). Rarely, marked narrowing of pulmonary veins secondary to granulomatous angiitis [resembling pulmonary veno-occlusive disease (PVOD) may be the cause of pulmonary hypertension (93,96)].
XV.
Diagnosis of Pulmonary Sarcoidosis
Flexible fiberoptic bronchoscopy (FFB) with transbronchial lung biopsy (TBLB) is the initial diagnostic procedure of choice in patients with suspected pulmonary sarcoidosis (6). Sensitivity of TBLB ranges from 60% to 90%; yields are highest with radiographic stage II or III disease (28,93). Endobronchial biopsies (EBB) may reveal granulomas in up to 60% of patients with pulmonary sarcoidosis, and may enhance the yield of TBLBs (93,97). Transbronchial needle aspiration biopsies (TBNA) of mediastinal and/or hilar lymph nodes with Wang 18-, 19- or 22-gauge cytology needles are diagnostic in 63% to 90% of patients with pulmonary sarcoidosis (26,28,93,98,99). Characteristic cytological features of sarcoidosis include lymphocytes, clusters of epithelioid histiocytes, multinucleated giant cells with no or minimal necrosis, and negative stains for fungi and acidfast bacteria (AFB) (26,93,99). The combination of TBNA and TBLB has a higher yield than either procedure alone (93,100,101). TBNA is much less expensive than mediastinoscopic lymph node biopsy (102) but requires skill. Damage to the bronchoscope may complicate TBNA, particularly when performed by individuals with limited experience. Endoscopic ultrasound (EUS)– guided fine-needle aspiration (FNA) biopsies are associated with high yields in malignancy involving mediastinal lymph nodes (101,103), but experience in sarcoidosis is limited (26,101,104). EUS allows visualization of mediastinal structures including the paraesophageal space, aortopulmonary window, and subcarinal region (101,105) and is promising. CT-guided transthoracic FNA with or without core needle biopsy may be useful to diagnose malignant or benign lesions involving mediastinal or subcarinal lymph nodes (yields up to 78%) (106). In a recent series, TBNA with a 26-gauge needle revealed cytological features consistent with sarcoidosis in 88 of 116 patients (76%) with mediastinal or hilar adenopathy (107). Sensitivity of
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TBFNA cytology in this context was 79%, and specificity, 92% (107). Complications of transthoracic FNA include pneumothoraces (10–60%) or hemoptysis (5–10%) (106). The optimal approach to diagnosing mediastinal lymph nodes (i.e., TBNA or CT-guided FNA) depends on the expertise and preference of the local institution. Surgical lung biopsy is rarely required to diagnose sarcoidosis. However, when the above procedures are not definitive, biopsy of mediastinal lymph nodes and/or lung may be warranted. This can be done with cervical mediastinoscopy, the Chamberlain procedure (a parasternal mini-thoracotomy to biopsy aortopulmonary window or para-aortic nodes), or video-assisted thoracoscopic surgical biopsy (VATS) (28,108).
XVI. A.
Specific Complications of Intrathoracic Sarcoidosis
Pulmonary Vascular Involvement in Sarcoidosis
Clinically significant pulmonary vascular involvement is uncommon in sarcoidosis (28). However, sarcoid granulomatous lesions follow pulmonary vessels, and incidental histological involvement of vessels was noted in 42% to 89% of open-lung biopsies in patients with pulmonary sarcoidosis (62,94). Pulmonary arterial hypertension (PAH) was reported in 1% to 6% of patients with sarcoidosis (109–111); the incidence is much higher among patients with advanced fibrocystic sarcoidosis (112–115). One retrospective study noted PAH by Doppler echocardiography (DE) in 54 of 106 sarcoid patients (53%) (116). Predicted spirometric values and DLCO were lower, and FVC/DLCO ratio was significantly higher in patients with PAH. Not surprisingly, 60% of patients with PAH had stage IV sarcoidosis (compared to 23% without PAH). However, among patients with stage IV disease, FVC did not differ between patients with and without PAH (116). Review of the United Network for Organ Sharing (UNOS) database identified 363 patients with sarcoidosis listed for lung transplantation (LT) in the United States between January 1995 and December 2002 who had undergone right-heart catheterization (RHC) (115). PAH [defined as mean pulmonary arterial pressure (mPAP) > 25 mmHg] was present in 74%; 36% had severe PAH (defined as mPAP > 40 mmHg). Importantly, PFTs did not differ between those with or without PAH. However, patients with severe PAH were seven times more likely to require supplemental oxygen. Two previous studies found that PAH was an independent predictor of mortality among patients with sarcoidosis listed for LT (112,114). Mechanism(s) responsible for PAH in sarcoidosis include hypoxic vasoconstriction (117), infiltration or obliteration of pulmonary vessels by the granulomatous, fibrotic response (96,118), and extrinsic compression of major pulmonary arteries by enlarged lymph nodes (96). A retrospective study of 22 patients with sarcoidosis and PAH found that mPAP correlated inversely with
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carbon monoxide transfer factor (TCO) but not with spirometry (e.g., FVC, FEV1) (96). In that study, five lung explants from sarcoid patients with PAH undergoing LT were examined. Granulomas were predominantly located within the veins, associated with occlusive venopathy and chronic hemosiderosis; arterial lesions were minor (96). The diagnosis of PAH may be difficult. Noninvasive techniques include chest CT (119) and DE (112). CT features that suggest PAH include main pulmonary artery (PA) diameter >29 mm, segmental artery-to-bronchus ratio >1:1 in three of four lobes (119), and ratio of the diameter of the main PA and of the ascending aorta >1 (120). DE is superior to CT in estimating PAH, but is less accurate than RHC (112). In a cohort of 374 patients with end-stage lung disease (all types) who were being evaluated for LT, estimates of systolic pulmonary arterial pressure (sPAP) could be made by DE in 166 (44%) (112). However, DE misclassified 48% of patients as having PAH. Further, DE was less accurate in patients with interstitial lung disease (ILD) compared to patients with obstructive lung disease (OLD). Thus, a normal DE does not exclude PAH in patients with ILD. Further, an abnormal DE is not a reliable marker of PAH. When PAH is suspected in patients with sarcoidosis, a confirmatory RHC should be performed to assess the extent of pulmonary arterial pressure (PAP) and responsiveness to vasodilators. The presence of PAH in sarcoidosis markedly worsens survival. In one recent study of sarcoid patients with PAH, two- and five-year survival rates were 74% and 59%, respectively (96). In sharp contrast, five-year survival among sarcoid controls without PAH was 96.4%. Data regarding treatment of PAH complicating sarcoidosis are limited. Anecdotal successes were noted with CSs in some patients. In a retrospective review, three of five sarcoid patients with PAH and no evidence for pulmonary fibrosis responded favorably to high-dose CSs (96). In contrast, none of five with radiographic evidence for pulmonary fibrosis improved (96). The role of vasodilators (121) in sarcoid-associated PAH has not been elucidated, but short- and long-term responses were noted in case reports or small series (96,118,122). In the series of 22 patients with sarcoidosis and PAH reported by Nunes et al., 10 were treated with CSs, with reductions in sPAP in 3 (96). None received long-term vasodilator therapy. The authors urged caution in using vasodilator therapy, because of the potential for precipitating pulmonary edema in patients with veno-occlusive disease (96). Another retrospective study of seven patients with sarcoidosis-associated PAH noted favorable acute hemodynamic responses to intravenous (IV) epoprostenol in six of seven patients (122). Importantly, five patients receiving long-term IV epoprostenol were alive and had improved at least one NYHA/WHO class (122). Other rare vascular complications of sarcoidosis (limited to a few case reports) include pulmonary arterial stenoses from granulomatous involvement of the vessels, extrinsic compression of pulmonary arteries by enlarged hilar lymph nodes or fibrosing mediastinitis (6), pulmonary veno-occlusive disease (resulting from obstruction of interlobular septa veins by granulomata or perivascular
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fibrosis) (123), and narrowing or obstruction of innominate veins or superior vena cava (SVC) (6). Six cases of SVC syndrome have been published; extensive mediastinal lymphadenopathy compressing the SVC was a universal feature (28). XVII.
Necrotizing Sarcoid Angiitis and Granulomatosis
Necrotizing sarcoid angiitis and granulomatosis (NSG), initially described by Liebow in 1973 (124), is a variant of sarcoidosis characterized by pulmonary vasculitis, granulomas, and pulmonary nodules or infiltrates on chest radiographs (93,125–127). Since the original description, approximately 100 cases have been reported (28). Histological features in NSG demonstrate (i) a granulomatous vasculitis involving arteries and veins, (ii) confluent non-necrotizing granulomata involving bronchi, bronchioles, and lung, (iii) foci of parenchymal infarct-like necrosis, and (iv) variable degrees of fibrosis (93,128). Systemic vasculitis does not occur. Clinical and radiographic features of NSG are similar to ‘‘nodular sarcoid’’ (28,93) (Fig. 12). Nodular sarcoidosis (also termed nummular sarcoidosis) demonstrates focal nodules composed of masses of granulomas and hyalinized connective tissue (93). We agree with others (128) that NSC and nodular sarcoid are simply variants of sarcoidosis. Prognosis of these entities is usually
Figure 12 ‘‘Nodular’’ sarcoidosis. PA chest radiograph demonstrates BHL and right paratracheal lymphadenopathy and multiple focal alveolar opacities consistent with nodular sarcoidosis. Abbreviations: PA, posterior-anterior; BHL, bilateral hilar lymphadenopathy.
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good. NSG resolves (either spontaneously or in response to therapy) in most patients but relapses, and fatalities may occur (28,93,126–128). XVIII.
Bronchostenosis
Stenosis or compression of bronchi may result from granulomatous inflammation of the bronchial wall, extrinsic compression from enlarged hilar nodes, or distortion of major bronchi caused by parenchymal fibrosis (28,61). Atelectasis of involved lobes or segments may result (28,129). The right middle lobe is most often affected because of the small orifice, sharp angulation of the bronchus intermedius, and large number of local lymph nodes (28). French investigators retrospectively reviewed 2500 patients with sarcoidosis; 18 patients had >50% stenosis of proximal bronchi (61). Bronchoscopic patterns included single focal stenosis, multiple focal stenoses, and diffuse narrowing of the bronchial tree (61). Dyspnea, cough, wheezing, and high-pitched inspiratory ‘‘squeaks’’ or stridors may be evident (61). Helical CT scans are useful to determine the extent and nature of stenotic lesions in the lower respiratory tract (74). CS therapy may be efficacious, but delay in therapy may result in fixed stenoses and persistent ventilatory defects (61). Dilatation of endobronchial stenoses is reserved for symptomatic patients refractory to medical therapy (130). XIX.
Mycetomas
Mycetomas (typically due to Aspergillus species) may develop in cystic spaces (typically in the upper lobes) in patients with stage III or IV sarcoidosis (28,32). Ipsilateral pleural thickening usually precedes the fungus ball or air crescent sign (28). Mycetomas are often asymptomatic, but fatal hemorrhage can occur because of invasion of vessel walls (28). Surgical resection is advised for localized lesions in patients able to tolerate surgery (32), but the risk of surgery may be prohibitive in patients with severe parenchymal disease or extensive pleural adhesions (28). Systemic antifungal therapy is of unproven value. Bronchial embolization may control intractable bleeding (32). XX.
Pleural Involvement in Sarcoidosis
Clinically significant pleural manifestations (e.g., pneumothorax, pleural effusions, chylothorax) occur in 2% to 4% of patients with sarcoidosis (28,131,132). Pleural thickening may be observed on CT scans in 9% to 11% of patients with sarcoidosis, but is usually asymptomatic (28). The incidence is higher in patients with chronic fibrocystic sarcoidosis, particularly with stage IV disease (133). Sarcoid pleural effusions may be transudative or exudative; lymphocytosis occurs in two-thirds of cases (28,131,132), with predominance of CD4þ lymphocytes
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(28,132). Massive pleural effusions are exceptionally rare (134,135). Pneumothorax may reflect rupture of bullae or necrosis of subpleural granulomas (132). Chylothorax is a rare complication of sarcoidosis (only a few cases have been described) (28,136–138). XXI.
Lung Cancer Complicating Sarcoidosis
Lung cancer is more common in patients with IPF, but an association between sarcoid-related pulmonary fibrosis and lung cancer has not been found (139,140). XXII.
Sarcoidosis in HIV-Infected Patients
Sarcoid-like granulomatous response rarely complicates infection with human immunodeficiency virus (HIV) (141–144). Chest radiographic and histological findings are similar to sarcoidosis in non-HIV-infected patients (141–144). Most cases occur after beginning highly active antiretroviral therapy (HAART) (141,143–145), but sarcoidosis can precede institution of HAART (141,146). The sarcoid-like granulomas following HAART likely reflect immune reconstitution, with influx of naı¨ve and interleukin-2 (IL-2) receptor–positive CD4þ cells (147,148). Treatment is controversial, but favorable responses to CSs have been noted (142,148). XXIII.
Sarcoidosis Complicating Type 1 Interferon Therapy
Sarcoidosis is a rare complication of type 1 interferons (IFNs) (IFN-a or IFN-b) used to treat viral hepatitis and diverse autoimmune and malignant disorders (28,149–154). Type 1 IFNs evoke a Th1 lymphocyte bias and amplify granulomatous inflammation (151,152). Most cases resolve following withdrawal of rIFN-a or dose reduction (149,155), but CSs are required in some patients (152,156). XXIV. Treatment of Sarcoidosis Treatment of sarcoidosis remains controversial. CSs are the cornerstone of therapy for severe or progressive sarcoidosis (pulmonary or extrapulmonary), and often produce dramatic resolution of disease (28,157). The long-term benefit of CS therapy has not been established, as relapses may occur upon taper or cessation of therapy (5,22,28,157). Early prospective, randomized studies found no long-term benefit with CSs among patients with pulmonary sarcoidosis (158–161). However, these studies included patients with normal or near normal
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pulmonary function, and rates of SRs were high. Patients with severe or progressive disease were excluded. Interpretation of efficacy of therapy is confounded by heterogeneous patient populations, a high rate of SRs, differing doses and duration of therapy, inability to discriminate the effects of therapy from the natural history of the disease, and lack of validated standards for disease activity. A multicenter, prospective, randomized trial sponsored by the British Thoracic Society supports the use of CSs for patients with chronic persistent radiographic infiltrates (34). In that study, patients with stage II or III sarcoidosis and persistent radiographic infiltrates after six months of observation were randomized to prednisolone or no therapy. At long-term follow-up, PFTs improved in the CS-treated cohort. Thus, CSs may attenuate loss of pulmonary function, even in asymptomatic patients. Extensive clinical experience suggests that CSs are efficacious in patients with active, symptomatic disease involving lungs or extrapulmonary organs (1,5,28,157). The decision to treat requires a careful assessment of acuity and severity of disease, likelihood of SR, and risks associated with therapy. Treatment is rarely appropriate for stage I disease unless extrapulmonary symptoms are prominent. In symptomatic patients with stage II or III disease, a trial of CSs should be considered after an initial observation period (6 to 12 months). Immediate treatment is appropriate for patients with severe symptoms or pulmonary dysfunction and presumed active alveolitis. However, in patients with far advanced fibrosis, honeycombing, or bullae (radiographic stage IV), therapy is rarely efficacious. The appropriate dose and duration of CS therapy has not been evaluated in controlled, randomized trials. For most patients, an initial daily dose of prednisone 40 mg/day (or equivalent) for four weeks is sufficient; prednisone is then tapered (as tolerated) to 30 or 40 mg every other day within three months. Higher doses may be appropriate for patients with cardiac or CNS involvement or patients with severe pulmonary sarcoidosis. Responses to CSs are usually evident within four to eight weeks. Among CS responders, we continue prednisone, albeit in a tapering fashion, for a minimum of 12 months. The rate of taper is individualized according to response and adverse effects. In selected patients, long-term (often years) of low dose, alternate-day prednisone may be required to prevent relapses. Inhaled CSs suppress endobronchial or alveolar inflammation, but are expensive and have limited efficacy for pulmonary sarcoidosis (28,162–164). However, inhaled CSs may have an adjunctive role among patients manifesting bronchial hyperreactivity or cough.
XXV.
Alternatives to Corticosteroids
Immunosuppressive, cytotoxic, and immunomodulatory agents have been used to treat patients failing or experiencing adverse effects from CSs (165,166). The optimal agent(s) has not been determined as controlled studies comparing various agents are lacking. Favorable responses have been cited in pulmonary or
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extrapulmonary sarcoid with methotrexate (167), azathioprine (168,169), leflunomide (170–172), cyclophosphamide (CYC) (173,174), chlorambucil (175), cyclosporine A (176), antimalarials (chloroquine or hydroxychloroquine) (177,178), pentoxifylline (179,180), and thalidomide (181,182). Responses to mycophenolate mofetil were noted in anecdotal cases of extrapulmonary sarcoidosis (183–186), but data are lacking in pulmonary sarcoidosis. Topical tacrolimus was associated with anecdotal successes for cutaneous sarcoidosis (187,188); the role of this agent in pulmonary sarcoidosis has not been studied. Tumor necrosis factor-a (TNF-a) inhibitors (particularly infliximab) have been used, with anecdotal success, to treat refractory sarcoidosis (particularly lupus pernio) (166,189–192). Data in pulmonary sarcoidosis are limited (193–195). In a recent multicenter trial, 138 patients with chronic pulmonary sarcoidosis were randomized to placebo or infliximab (3 mg/kg) or infliximab (5 mg/kg) (194). At 24 weeks, the primary endpoint DFVC% predicted was slightly higher among infliximab-treated patients (2.5% above baseline) compared to placebo-treated patients (no change). This difference, although statistically significant, is of doubtful clinical significance. For patients with progressive pulmonary sarcoidosis refractory to CSs, we initiate treatment with azathioprine (dose 100 to 150 mg/day p.o.) or methotrexate (dose 15–25 mg once weekly orally). These agents can be used in lieu of or in addition to CSs. Because of potential serious toxicities (including oncogenesis) associated with CYC and chlorambucil (196), we do not use these agents to treat pulmonary sarcoidosis. However, CYC has a role for sarcoidosis involving the CNS (173,174), spinal cord (197), or extrapulmonary sarcoidosis (1) recalcitrant to CSs. Hydroxychloroquine (dose 200 mg twice daily) has minimal toxicity, and may have modest benefit as adjunctive therapy in selected patients with sarcoidosis (6,28). Infliximab is reserved for severe cases refractory to CSs and these alternative agents. Immunosuppressive, cytotoxic, and newer immunomodulatory agents are discussed in detail by Dr. Baughman in chapter 5.
XXVI. Lung Transplantation for Sarcoidosis LT (either single or bilateral) is a viable option for patients with end-stage pulmonary sarcoidosis refractory to medical therapy (113,198–200). From January 1995 to June 2006, 438 adults worldwide had received lung transplants for sarcoidosis (201). Long-term survival rates following LT for sarcoidosis are generally similar to other indications (198). However, in a retrospective review of U.S. data from 1995 to 2000, 30-day survival post-LT was 83% among 133 patients with sarcoidosis compared to 91% with other conditions ( p ¼ 0.002) (86). Mortality rates among sarcoidosis patients awaiting LT are high (27–53%) (112,114). These high mortality rates reflect delayed referral for LT (198). Factors associated with increased mortality among sarcoid patients awaiting LT
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include elevated mPAP (112,114), right atrial pressure (RAP) >15 mmHg (112), Black race, and need for supplemental oxygen (114). Pulmonary hypertension is an ominous sign and warrants prompt referral for LT (114,115). Typically, patients with sarcoidosis referred for LT have severe impairment in PFTs (113,114). A retrospective review of the UNOS database from 1995 to 2000 identified 405 patients with sarcoidosis listed for LT in the United States (114). Surprisingly, PFTs (FVC and FEV1) were similar among survivors and nonsurvivors but were severely reduced in both groups (mean FVC < 41–43% predicted, mean FEV1 < 37–37% predicted). Despite the limited discriminatory value of PFTs, referral for LT should be initiated when FVC falls below 50% predicted and/or FEV1 falls below 40% predicted (198). Interestingly, recurrent non-necrotizing granulomas have been noted in the transplant allografts in up to 35% of patients (202), but are not usually associated with symptoms (28). References 1. Lynch J III, Baughman R, Sharma O. Extrapulmonary sarcoidosis. Semin Respir Infect 1998; 13:229–254. 2. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336(17): 1224–1234. 3. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999; 160(2):736–755. 4. Judson MA. Extrapulmonary sarcoidosis. Semin Respir Crit Care Med 2007; 28(1):83–101. 5. Johns CJ, Michele TM. The clinical management of sarcoidosis. A 50-year experience at the Johns Hopkins Hospital. Medicine (Baltimore) 1999; 78(2):65–111. 6. Lynch JP III, Kazerooni EA, Gay SE. Pulmonary sarcoidosis. Clin Chest Med 1997; 18(4):755–785. 7. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001; 164(10 pt 1): 1885–1889. 8. Teirstein AS, Judson MA, Baughman RP, et al. The spectrum of biopsy sites for the diagnosis of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2005; 22(2):139–146. 9. Neville E, Walker A, James DG. Prognostic factors predicting the outcome of sarcoidosis: an analysis of 818 patients. Q J Med 1983; 208:525–533. 10. Romer FK. Presentation of sarcoidosis and outcome of pulmonary changes. Dan Med Bull 1982; 29(1):27–32. 11. Hillerdal G, Nou E, Osterman K, et al. Sarcoidosis: epidemiology and prognosis. A 15-year European study. Am Rev Respir Dis 1984; 130(1):29–32. 12. Henke CE, Henke G, Elveback LR, et al. The epidemiology of sarcoidosis in Rochester, Minnesota: a population-based study of incidence and survival. Am J Epidemiol 1986; 123(5):840–845.
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8 Extrapulmonary Sarcoidosis
MARC A. JUDSON Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, South Carolina, U.S.A.
I.
Introduction
Sarcoidosis is a multisystem granulomatous disease that most commonly affects the lung but may involve any organ. The manifestations of extrapulmonary sarcoidosis may vary from asymptomatic involvement to the presence of severe symptoms that may adversely impact the quality of life. The diagnosis of extrapulmonary sarcoidosis is often problematic. It is important to recognize when extrapulmonary symptoms should be considered to be manifestations of sarcoidosis. When extrapulmonary sarcoidosis is suspected, a diagnostic approach may be preferred that avoids the invasive biopsy of a visceral organ or biopsy confirmation altogether. The treatment of extrapulmonary sarcoidosis varies depending on the organs that are involved. This manuscript will outline the clinical aspects of extrapulmonary sarcoidosis in the most common and clinically important sites. Organ involvement will be discussed individually in terms of epidemiology, clinical manifestations, diagnosis, and treatment.
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Eye
A.
Epidemiology/Demographics
The frequency of ocular involvement in sarcoidosis ranges between 10% and 50% in American and European studies (1). In these reports, extraocular disorders such as lacrimal gland involvement and sicca syndrome were included (1). Ocular sarcoidosis seems to be more common in the Japanese where eye involvement has been reported in 64% to 89% of sarcoidosis patients (1). In the United States, ocular sarcoidosis is more common in African Americans than Caucasians (2,3). The low rates of eye involvement with sarcoidosis in some series may be because of the lack of thoroughness in examination of the eye (1). B.
Manifestations
Sarcoidosis may affect any part of the eye. Any ocular inflammation from sarcoidosis mandates treatment because it may lead to permanent vision impairment, and in 2% to 5% of cases, blindness (4,5). Uveitis is the most common ocular manifestation of sarcoidosis in most series (4,5). Anterior uveitis occurs in 20% to 70% of patients with ocular sarcoidosis (4–6) and typically presents as an iritis or iridocyclitis (1,7). Symptoms include blurred vision, red eyes, painful eyes, and photophobia. However in one-third of patients, the patient may present without ocular symptoms. Therefore, all sarcoidosis patients require a slit-lamp and fundoscopic examination regardless of the presence of ocular symptoms. The slit-lamp examination may reveal mutton-fat keratic precipitates (Fig. 1), which are aggregates of inflammatory cells in the corneal epithelium (1,7). Other lesions of anterior sarcoid uveitis that may be seen with a slit lamp include Busacca nodules on the iris (Fig. 2) and Koeppe nodules on the papillary margin (8). Both these nodules are almost exclusively found when anterior sarcoid uveitis is a chronic condition (8). Chronic anterior sarcoid uveitis may cause cataracts and glaucoma. Since corticosteroid use can also lead to cataract formation and
Figure 1 (See color insert.) Keratic precipitates seen as small white dots on slit-lamp examination of a patient with anterior uveitis from sarcoidosis.
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Figure 2 (See color insert.) Limbal granulomas on the margin of the iris in a patient with ocular sarcoidosis.
Figure 3 (See color insert.) Retinal vasculitis seen with posterior uveitis from sarcoidosis.
glaucoma, it is sometimes problematic to determine if these sequellae are from the disease or its treatment (1). Intermediate uveitis is a common manifestation of eye sarcoidosis. It is defined as inflammation of the vitreous, pars plana, and peripheral retina (1,3). Patients may be asymptomatic or complain of floaters or blurred vision (1,9). Posterior uveitis is found in up to 28% of patients with ocular sarcoidosis (Fig. 3) (4,7). This retinal involvement primarily affects the retinal veins. Perivenous infiltrates referred to as ‘‘candle-wax drippings’’ may be seen (10). Choroidal granulomas are observed in some cases and may result in epithelial atrophy or retinal scarring (8). Posterior uveitis may result in significant vision impairment. There are many infectious and noninfectious causes of uveitis other than sarcoidosis (Table 1) (1). In three series of unselected patients with uveitis, sarcoidosis was the cause in 2.5% to 12% of cases (11–13). Therefore, uveitis of unknown cause should not be assumed to be from sarcoidosis and appropriate diagnostic steps should be taken to determine the cause (1). Involvement of the lacrimal gland is clinically apparent in 15% to 28% of sarcoidosis patients (4,5) and may cause a ketatoconjunctivitis sicca syndrome (14).
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Table 1 Differential Diagnosis of Uveitis Noninfectious causes
Infectious
Sarcoidosis Idiopathic panuveitis Spondyloarthropathy Systemic lupus erythematosis Bechet’s disease Wegener’s granulomatosis Relapsing polychondritis
Toxoplasmosis HIV/CMV Lyme disease Tuberculosis Fungi Syphilis Herpes simplex virus
Abbreviations: HIV, human immunodeficiency virus; CMV, cytomegalovirus. Source: From Ref. 1.
Figure 4 (See color insert.) Episcleritis from sarcoidosis.
Optic neuritis from sarcoidosis is a rare but important manifestation because it may occur suddenly and be vision threatening (8). Any sarcoidosis patient who experiences sudden loss of vision or color vision requires immediate referral to an ophthalmologist and high-dose corticosteroid therapy. Sarcoidosis may also involve the conjunctiva, extraocular muscles, sclera (Fig. 4), and orbits (1). C.
Diagnosis
Because sarcoidosis is not the most common cause of uveitis, all patients with uveitis of unknown cause need to be carefully evaluated. If a patient has a previous history of extraocular sarcoidosis, sarcoid eye involvement may be assumed if the patient has uveitis, lacrimal gland abnormalities, or conjunctivits that cannot be explained by an alternate mechanism (1). Making the diagnosis of ocular sarcoidosis when the diagnosis of sarcoidosis has not been established in an extraocular site is problematic because an ocular biopsy is an invasive procedure. Such patients should undergo screening tests for sarcoidosis that should include a chest radiograph (1). A complete
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medical history and physical examination may direct the diagnostic workup further. For example, a skin lesion or enlarged peripheral lymph node may prompt a diagnostic biopsy. A study of transbronchial biopsy in a group of patients with uveitis suspected to be from sarcoidosis and with normal chest radiographs showed that the yield from this procedure was 62% (15). However this was a Japanese study where the prevalence of sarcoid uveitis is high, and it may be inappropriate to extrapolate these results to other populations. Another study of Japanese patients with suspected sarcoid uveitis who underwent transbronchial lung biopsy showed that the yield was 95% (19/20) when the chest computed tomography (CT) scan showed parenchymal disease and was 5% (1/19) when the lung parenchyma was normal (16). The chest radiograph and bronchoalveolar lavage lymphocyte counts were not useful in predicting the yield of transbronchial lung biopsy in these patients. Ocular biopsy is rarely performed because it is an invasive procedure. Conjunctival biopsy has a reasonable yield (up to 67%) if conjunctival nodules are present (17). It is controversial whether or not a blind biopsy of normalappearing conjunctival tissue is of value, with one study reporting a yield of 30% (17), while others have found such biopsies to be fruitless (18,19). A new technique of in vivo confocal microscopy may be useful in the diagnosis of sarcoidosis based on a typical appearance (20). This technique may also be useful to determine when a conjunctival biopsy will confirm the diagnosis of sarcoidosis (20). Lacrimal gland biopsies have a high diagnostic yield when the lacrimal gland is palpable or there is uptake in the gland of 67Ga on nuclear scanning (1). D.
Treatment
All ocular inflammation from sarcoidosis requires treatment because it has the potential to cause permanent vision loss. Corticosteroids are the mainstay of treatment for ocular sarcoidosis (1). Topical corticosteroids (i.e., eye drops) may be used for the treatment of anterior uveitis. Mydriatics are always instilled to suppress the inflammation and avoid synechiae (adhesion of the iris to the lens) (1). Intraocular pressure must be monitored regularly because glaucoma may be the result of sarcoid trabecular nodules or the result of corticosteroid therapy (1). Systemic corticosteroids are required for cases of anterior uveits that are refractory to eyedrops and for cases of intermediate and posterior uveitis because eyedrops cannot adequately penetrate deep into the eye. The initial corticosteroid dose is 40 mg/day of prednisone equivalent, which is adjusted according to the response to therapy. Corticosteroid-sparing alternatives are often considered for sarcoid uveitis because of the toxicity of systemic corticosteroids. Methotrexate (21), azathioprine (22), leflunomide (23), and infliximab (24) have been used for this purpose.
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Skin Epidemiology/Demographics
The frequency of chronic skin lesions in sarcoidosis ranges from 9% to 37% in various series (25–27). In A Case Control Etiology of Sarcoidosis study (ACCESS) sponsored by the National Institute of Health, chronic skin involvement was second in frequency [113/718 (15.7%)] only to lung involvement (28). Although cutaneous involvement may occur at any stage of the disease, it is most often present at the onset (25). In the United States, chronic skin sarcoidosis is more common in African Americans than Caucasians. In ACCESS, where patients were evaluated within six months of diagnosis, 19.7 % (64/325) of African Americans had specific (granulomatous) sarcoidosis skin lesions compared to 13.0% (51/393) of Caucasians (chi-square ¼ 5.5, p < 0.05) (25). Erythema nodosum, a nongranulomatous inflammatory skin lesion that occurs in approximately 10% of sarcoidosis patients (Fig. 5) (28). It is more common in women than men (28) and is also common in Europeans, Puerto Ricans, and Mexicans, particularly in women of childbearing age of these ethnicities (29).
Figure 5 (See color insert.) Erythema nodosum from sarcoidosis on the base of the foot that is an unusual location.
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Data from ACCESS suggest that granulomatous skin involvement develops more commonly than other new organ involvement within the first two years of the diagnosis of sarcoidosis [13/215 (6%)] (30). Although not subjected to statistical analysis, these ACCESS data suggested that new onset skin involvement was more common in African Americans than Caucasians [10/93 (10.7%) versus 3/117 (2.6%)]. B.
Manifestations
Cutaneous sarcoidosis lesions are divided into two categories: specific and nonspecific. Specific lesions reveal granulomatous inflammation on biopsy. Nonspecific skin findings are reactive inflammatory lesions that do not exhibit sarcoidal granulomas. 1.
Specific Lesions
Specific sarcoid lesions most often are found on the head and neck but may occur symmetrically or asymmetrically on any part of the skin and mucosa (31). Almost all morphologies have been reported including macules, papules, patches, plaques, and nodules (31). Despite the diversity in appearance, there are several clinical presentations that are typical for cutaneous sarcoidosis. The most common presentation is the papular form. These lesions are firm, 2 to 5 mm papules, and often have a translucent red-brown or yellow-brown appearance (31). The yellow-brown color has been likened to ‘‘apple jelly’’ (31). Papular lesions occur most commonly on the face and neck with a predilection for periorbital skin. Another distinctive specific sarcoidosis skin lesion is lupus pernio, relatively symmetric, violaceous, indurated plaque-like and nodular sarcoidal lesions occurring on the nose, ear lobes, cheeks, and digits (Figs. 6 and 7). Lupus pernio
Figure 6 (See color insert.) Lupus pernio lesions on the nose. The patient gave permission for publication of this photograph.
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Figure 7 (See color insert.) Lupus pernio lesions on the cheek, nose, as well as an ear lesion from sarcoidosis. The patient gave permission for publication of this photograph.
Figure 8 (See color insert.) Sarcoidosis skin lesions in a tattoo.
has been associated with systemic findings and a poor prognosis (29). These lesions are associated with a higher prevalence of upper respiratory tract disease (32). Lupus pernio lesions may directly extend into the nasal sinus leading to epistaxis, nasal crusting and direct sinus bone involvement. Cutaneous sarcoidosis may occur within scar tissue (33), tattoos (Fig. 8) (34), at traumatized skin sites, and around imbedded foreign material such as silica. Scar sarcoidosis may be the only cutaneous finding in a patient with systemic sarcoidosis; therefore, it is important to closely examine scar
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tissue in patients suspected of having the disease (31). The presence of sarcoidal granulomas surrounding foreign material is not specific for the diagnosis of sarcoidosis (35). Other signs of systemic or cutaneous involvement are required to confirm the diagnosis. Rarely, cutaneous sarcoidosis can present as persistent subcutaneous nodules. Alopecia may occur with involvement of the scalp that may be scarring or nonscarring (36,37). Biopsy shows noncaseating granulomas. Its reversibility is dependent upon the degree of destruction of hair follicles. Sarcoidosis may cause nail dystrophy and discoloration, but the incidence is very low (38). This manifestation may result from granulomas in the nail matrix or because of involvement of adjacent bone. Sarcoidal granulomas may form papules and plaques on the mucosal surfaces and tongue. Sarcoidosis is one cause of Mikulicz’s syndrome: the bilateral enlargement of the lacrimal, parotid, sublingual, and submandibular glands (31). 2.
Nonspecific Lesions
Erythema nodosum is the main nonspecific cutaneous manifestation of sarcoidosis. They present as violaceous to erythematous tender nodules on the extremities. In general, nonspecific sarcoidosis skin lesions are associated with an acute form of sarcoidosis that has a good prognosis where eventual resolution of the disease is common (39). C.
Diagnosis
The diagnosis of specific sarcoidosis skin lesions usually requires a confirmatory biopsy. On occasion, a clinical diagnosis of skin sarcoidosis may be made if the lesions are typical (e.g., lupus pernio or lesions present on scar tissue). Sarcoidosis is not the only cause of granulomatous inflammation of the skin, and other potential causes must be carefully excluded. Usually the diagnosis of skin sarcoidosis is not secure without evidence of extracutaneous granulomatous disease. The diagnosis of skin sarcoidosis tends to be made rapidly relative to other organ involvement with sarcoidosis because the skin lesions are evident and can be easily biopsied. In a cohort of ACCESS patients, the patients with skin sarcoidosis were diagnosed significantly faster than those with pulmonary sarcoidosis (30). Patents with nonspecific skin lesions such as erythema nodosum do not demonstrate granulomatous inflammation on biopsy. Therefore, skin biopsies should be avoided in these patients as the procedure has no value in their diagnosis. D.
Treatment
Because skin sarcoidosis is rarely associated with significant morbidity or mortality and may remit spontaneously, the decision to treat is based primarily on cosmetic concerns.
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Topical/Intralesional Therapy
Corticosteroid creams and injections may be useful for a few discrete skin lesions. Even lupus pernio may respond to corticosteroid creams, although intralesional corticosteroid injections are generally more effective. Topical tacrolimus cream has been reportedly effective lupus pernio in several cases as well (40). 2.
Systemic Corticosteroids
Corticosteroids are the drug of choice for the treatment of skin sarcoidosis. Usually a dose of 20 to 40 mg of prednisone equivalent/day is used initially and the dose is tapered depending on the treatment effect and the development of corticosteroid side effects. 3.
Antimaliarial Drugs
Hydroxychloroquine/chloroquine are often useful for patients with skin sarcoidosis (41). Their side-effect profile is much better than that of corticosteroids. However their maximum effect is often not achieved for several months. Therefore, they are often started simultaneously with corticosteroids, and the corticosteroids are tapered over several months while the antimalarials take effect. They cannot be used in patients with G6PD deficiency. Either drug, especially chloroquine, may cause retinal damage (41). Patients on antimalarial agents must therefore have regular ophthalmologic examinations. 4.
Methotrexate
Low-dose methotrexate, 10 to 25 mg a week, is used for the treatment of cutaneous sarcoidosis (42). Cutaneous improvement may be noted within one month, but maximal therapeutic benefit often does not occur until at least six months after the initiation of treatment. The drug requires careful monitoring of liver function tests and blood cell counts. Folic acid is recommended to be given in conjunction with methotrexate. Approximately 10% of sarcoidosis patients taking methotrexate develop hepatic fibrosis, even if their serum liver function tests are normal (43). Therefore liver biopsies should be considered after two grams of total therapy (usually after two years) (43). 5.
Tetracycline Derivatives
Minocycline and doxycycline have been reported to be effective for skin sarcoidosis in case series (44). Therapy with these drugs for more than two years may be required for them to be effective (44). Although these data suggest that sarcoidosis may be caused by an infectious agent, the tetracyclines also modify the immune response by suppressing activity of macrophages and T lymphocytes (45).
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Tumor Necrosis Factor Alpha Antagonists
Tumor necrosis factor alpha (TNF-a) is a cytokine that is secreted by macrophages associated with sarcoid granulomas (46). Antagonists of TNF-a including thalidomide (47), and infliximab (48) have been shown to be useful for the treatment of cutaneous sarcoidosis. Infliximab appears to be particularly useful for the treatment of lupus pernio (48). The use of infliximab is limited by its high cost and the need for intravenous administration. Fatal cases of tuberculosis have been associated with infliximab administration (49). Therefore, a tuberculin skin test is required prior to its use, and patients on the drug must be monitored closely for the development of tuberculosis. 7.
Other Agents
Allopurinol (50), isotretinion (51), fumaric acid esters (52), mycophenolate mofetil (53), and Tranilast (54) have been reported to be effective for sarcoidal skin disease. Resolution of sarcoidal skin lesions has occurred after radiation therapy (55), ultraviolet A1 therapy (56), phototherapy, and photodynamic therapy (57). IV. A.
Liver Epidemiology/Demographics
The reported frequency of hepatic sarcoidosis ranges widely depending on the method of detection. The frequency with which liver biopsy shows granulomas in sarcoidosis is usually 50% to 65% (58). Although the frequency of serum liver function test abnormalities in sarcoidosis is as high as 35% (59), it is lower than the frequency of histologic hepatic involvement. The frequency of signs or symptoms of hepatic involvement is lower still at approximately 5% to 15% (59–63). Therefore, although hepatic sarcoidosis is often present histologically, it usually does not cause liver blood test abnormalities or significant symptoms. Hepatic sarcoidosis is more than twice as common in African Americans compared to Caucasians (28,59,63). It is more likely that sibling pairs with sarcoidosis will both have liver involvement than two unrelated sarcoidosis patients (64), which suggests that there may be a genetic explanation for this phenotype. There is no increased prevalence based on gender or age (28,63). No geographic area of high prevalence has been identified. B.
Manifestations
Most patients with hepatic sarcoidosis are asymptomatic (59,65). The disease is often diagnosed by liver biopsy as part of a workup for abnormal serum liver function tests or abnormalities on an abdominal chest CT scan. Pruritus and abdominal pain are two of the more common symptoms, with the latter present in 15% (15/100) of cases (63). Jaundice, fever, and weight loss are present in less
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than 5% of cases (62,63). Hepatomegaly is found in 5% to 15% of sarcoidosis patients (61,66). The most common liver function test abnormality in hepatic sarcoidosis is an elevated serum alkaline phosphatase, which is present in more than 90% of patients with signs or symptoms of hepatic sarcoidosis (59,67,68) but is found in as few as 15% (32/217) of patients with histologic evidence of disease (62). Occasionally, this elevation may exceed 5 to 10 times the upper limits of normal (67,68). Fifty to 70% of patients with clinical evidence of hepatic sarcoidosis have elevations in serum transaminases that are usually less elevated than the serum alkaline phosphatase (63,67). Hypoalbuminemia, hyperbilirubinemia, and hepatic encephalopathy may rarely occur with chronic progressive disease (68,69). The exact frequency of hepatic abnormalities on abdominal CT is unknown because all series have involved a selection bias and/or have been retrospective. However, the radiographic features of hepatic sarcoidosis have been well described. Hepatomegaly is the most common liver abnormality detected on CT (70–73) and is frequently associated with splenomegaly (73). Hepatomegaly from sarcoidosis may occur in patients with normal chest radiographs (Scadding stage 0) (70). Hepatic nodules are found in less than 5% of patients in most series (70,73) although frequencies as high as 53% (17/32) have been reported (71). The nodules are typically discrete and of low attenuation, requiring intravenous contrast to be visualized (Fig. 9) (70,71,74,75). They are always multiple and usually innumerable with an average size of 0.6 to 0.75 cm in diameter but may be as large 2.0 cm and tend to become confluent as they enlarge (70,71). Hepatic nodules are seen much less frequently than splenic nodules (70,71,76). The
Figure 9 Hepatic and splenic nodules on abdominal CT scan from sarcoidosis.
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differential diagnosis of low-attenuation hepatic nodules includes metastatic malignancy, lymphoma, and various infections (71). On occasions, hepatic sarcoidosis will manifest as a chronic cholestasis syndrome featuring pruritus, jaundice, hepatomegaly, and marked elevations in serum alkaline phosphatase and cholesterol (69,77–79). This syndrome is more common in African Americans (78,80). The histology may mimic primary biliary cirrhosis (81). Granulomatous cholangitis leading to ductopenia seems to be the underlying mechanism causing chronic cholestasis (66). Rarely occlusion of intrahepatic portal vein branches by granulomatous inflammation may cause portal hypertension (69). An extremely rare cause of jaundice from sarcoidosis may occur from extrinsic compression of the biliary duct from lymphadenopathy around the porta hepaticus (82,83). In this situation, the jaundice often responds to corticosteroid therapy with shrinkage of the lymph nodes (82,83). Cirrhosis has been reported in 6% (6/100) of patients with hepatic sarcoidosis (63). Some of these patients have concomitant cholestatic features with loss of bile ducts indicating a pattern of primary biliary cirrhosis as previously described (63). However, cirrhosis in the absence of a cholestatic pattern may also be seen (63,67,84,85). Portal hypertension occurs in approximately three percent of patients with hepatic sarcoidosis (63). Although portal hypertension may occur by several mechanisms, the most common is from granulomas in the portal areas that restrict portal flow, causing a presinusoidal block (84–86). Portal hypertension can lead to gastric and esophageal variceal bleeding and death (87,88). Although all patients with sarcoidosis-related portal hypertension have significant hepatocellular disease, portal hypertension is the primary clinical abnormality (68). C.
Diagnosis
Because sarcoidosis is a multisystem granulomatous disease of unknown cause, the diagnosis of hepatic sarcoidosis requires clinico-radiologic findings supported by histologic evidence of noncaseating granulomas, exclusion of known causes of granulomas, and exclusion of isolated hepatic sarcoid reactions (29). The diagnostic approach differs depending on whether a liver biopsy has been done revealing noncaseating granulomatous inflammation or if a biopsy of an extrahepatic organ has demonstrated granulomatous inflammation and clinicoradiologic hepatic abnormalities have also been identified. These diagnostic situations will be discussed separately. 1.
Diagnostic Approach: Liver Biopsy Shows Granulomatous Inflammation
A patient with hepatic sarcoidosis virtually always demonstrates hepatic granulomas on liver biopsy (60). However, the presence of noncaseating hepatic granulomas does not establish the diagnosis of hepatic sarcoidosis, as there are
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many alternative causes, which must first be excluded. In fact, sarcoidosis was not the most common diagnosis in several large series of consecutive liver biopsies demonstrating hepatic granulomas (89–91). The likelihood of alternative diagnoses depends on patient demographics and the local prevalence of infectious diseases, such as histoplasmosis and tuberculosis histoplasmosis (58,62,89–91). Exclusion of alternative causes of hepatic granulomas requires a medical history to exclude causes related to systemic diseases and drugs. Biopsy specimens should be stained and cultured appropriately to exclude potential infectious causes of hepatic granulomas. This should include staining for fungi and mycobacteria at a minimum. Cultures or serologies for mycobacteria, fungi, Brucella, syphilis, Q fever, viral hepatitis, cytomegalovirus, Epstein-Barr virus, rheumatoid factor, antinuclear antibody, and antimitochondrial antibody may be required depending on the clinical setting (92). As previously mentioned, hepatic sarcoidosis may have a histologic appearance similar to primary biliary cirrhosis (68), which may make the diagnosis challenging. The diagnosis of hepatic sarcoidosis requires granulomatous inflammation in an additional organ. This is required to distinguish hepatic sarcoidosis from granulomatous hepatitis, an idiopathic granulomatous reaction confined to the liver that mimics sarcoidosis histologically (92,93). Histologic confirmation of sarcoidosis involvement in a second organ is not required if there is sufficient clinical evidence of second organ involvement and alternative causes are excluded. An instrument has been developed establishing clinical criteria of second organ involvement when noncaseating granulomas of unknown cause have been detected in a single organ (Table 2) (94). 2.
Diagnostic Approach for Hepatic Sarcoidosis When Biopsy of An Extrahepatic Organ Shows Granulomatous Inflammation
If a biopsy of an extrahepatic organ has demonstrated noncaseating granulomas of unknown cause, a diagnosis of hepatic sarcoidosis can often be cautiously made on clinical grounds without performing a liver biopsy. This can be done in situations where there is a hepatic abnormality that is typical of hepatic sarcoidosis and alternative causes of the hepatic abnormality are unlikely. It has been suggested (94) that if a biopsy of an extrahepatic organ shows noncaseating granulomas of unknown cause, the diagnosis of hepatic sarcoidosis can be made if the serum liver function tests are elevated more than three times the upper limit of normal, provided that there is no other clinical explanation for this abnormality. The diagnosis of hepatic sarcoidosis is probable if (i) an abdominal CT scan reveals abnormalities consistent with hepatic sarcoidosis (see above), or (ii) the serum alkaline phosphatase is elevated, provided that there is no other clinical explanation of these abnormalities (94).
Hypercalcemia/ hypercalciuria/ Nephrolithiasis
Liver
Eyes
Skin
Lungs
Organ
1.
1. 2. 3. 1. 2. 3. 1.
2.
1.
Increased serum calcium with no other cause
l
l
Bilateral hilar adenopathy Diffuse infiltrates l Upper lobe fibrosis Restriction on pulmonary functions tests Lupus pernio Annular lesion Erythema nodosum Lacrimal gland swelling Uveitis Optic neuritis Liver function tests > three times normal
Chest roentgenogram with one or more of the following
Definite
2. 1. 2.
1.
1. 2.
1. 2.
2. 3.
1.
Blindness Positive in vivo confocal microscopy Compatible computed tomography (CT) scan Elevated alkaline phosphate Increased urine calcium Nephrolithiasis analysis showing calcium
Macular/popular New nodules
Lymphocytic alveolitis by bronchoalveolar lavage (BAL) Any pulmonary infiltrates Isolated reduced diffusing capacity for carbon monoxide
Probable
2.
1.
1. 2.
1. 2.
1. 2.
(Continued)
Nephrolithiasis-no stone analysis Nephrolithiasis with negative family history for stones
Glaucoma Cataract
Keloids Hypopigmentation
Any other adenopathy Obstructive pulmonary function tests
Possible
Table 2 Clincial Criteria for Extrapulmonary Sarcoidosis Organ Involvement in Patients with Biopsy-Confirmed Sarcoidosis in Another Organa
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Cardiac
Renal
Treatment responsive cardiomyopathy Electrocardiogram showing intraventricular conduction defect or nodal block Positive gallium scan of heart Positive positron emission tomography (PET) scan of the heart
Steroid responsive renal failure in patient with diabetes and/or hypertension No other cardiac problem and: l
Ventricular arrhythmias l Cardiomyopathy 2. Positive thallium scan
1.
1.
2.
1.
1.
l
l
Cardiomyopathy Ventricular arrhythmias
In patient with diabetes and/or hypertension
Renal failure in absence of other disease
Unexplained headaches
1.
1.
Other abnormalities on magnetic resonance imaging (MRI) Unexplained neuropathy
Possible
Probable
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3. 4.
2.
1.
1.
4. 5. 6. 7. 8.
2. 3.
1.
Neurologic
Positive magnetic resonance imaging (MRI) with uptake in meninges or brainstem Peripheral nerve radiculopathy Cerebrospinal fluid with increased lymphocytes and/or protein Diabetes insipidus Bell’s palsy Cranial nerve dysfunction Peripheral nerve biopsy Positive positron emission tomography (PET) scan of CNS or spinal cord Treatment responsive renal failure
Definite
Organ
Table 2 Clincial Criteria for Extrapulmonary Sarcoidosis Organ Involvement in Patients with Biopsy-Confirmed Sarcoidosis in Another Organa (Continued )
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2. 1.
1.
1.
1. 2. 3.
Symmetrical parotitis with syndrome of mumps Positive gallium scan (Panda sign) Increased creatinine phosphokinase (CK)/aldolase, which decreases with treatment
Cystic changes on hand or feet Phalanges
Unexplained anemia Leukopenia Thrombocytopenia
Definite
Enlargement by:
New palpable node above waist Lymph node > 2 cm by computed tomography (CT scan)
1.
1.
Increased creatinine phosphokinase (CK)/aldolase
Unexplained hoarseness with exam consistent with granulomatous involvement
l
l
Exam Computed tomography (CT) scan l Radioisotope scan 1. Asymmetric, painful clubbing
1.
1. 2.
Probable
1.
1.
1. 2.
1.
1.
1.
Myalgias responding to treatment
Dry mouth
New onset sinusitis New onset dizziness
Arthritis with no other cause
Anemia with low mean corpuscular volume (MCV)
New palpable femoral lymph node
Possible
There can be no other explanation for the clinical finding in this table for these criteria to be valid. In addition, biopsy of each of these organs would constitute ‘‘definite’’ involvement. Source: From Ref. 137.
a
Other organs
Muscles
Parotid/salivary
Ear/nose/throat
Bone/joints
Spleen
Bone marrow
Non-thoracic
Organ
Table 2 (Continued )
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Treatment
Most patients with hepatic sarcoidosis do not require treatment (81). Although treatment with corticosteroids can improve liver function tests in approximately half of asymptomatic patients, three-fourths of such patients who are not treated eventually undergo spontaneous improvement in liver function tests and the rest remain stable (59). Furthermore, evidence suggests that corticosteroid treatment of hepatic sarcoidosis promotes relapse (87). On the basis of these data, therapy for hepatic sarcoidosis is not indicated in asymptomatic patients with liver function test elevations. Such patients should be followed with serial liver function tests, although it is rare for them to develop hepatic failure (59). Granulomatous hepatitis from sarcoidosis may require treatment if patients develop fever, nausea, vomiting, pruritus weight loss, or right upper-quadrant abdominal pain (67). Corticosteroids are usually effective in alleviating these symptoms (67,93). Many patients require a daily dose of prednisone in the 10 to 15 mg range. Therapy is often required for more than one year (67). Despite the potential risk of hepatic toxicity from methotrexate, it has been shown to be effective, reduce liver function test abnormalities, and to be corticosteroid sparing (67,95). As mentioned previously, patients with hepatic sarcoidosis may develop a chronic cholestatic syndrome with jaundice, fever, malaise, anorexia, weight loss, pruritus, and a cholestatic pattern of abnormal liver function tests (77–79). These symptoms are often severe and require treatment. Prednisone in doses of 30 to 60 mg/day may improve symptoms, lower serum alkaline phosphatase levels, and improve hepatomegaly (77,96). Ursodeoxycholic acid, which inhibits intestinal absorption and increases biliary secretion of cholic and chenodeoxycholic acids (97), is often effective for the cholestatic syndrome of hepatic sarcoidosis (98,99). A dose of 10 mg/kg/day has been recommended (98,99). Occasionally portal hypertension often develops with hepatic sarcoidosis as a consequence of biliary fibrosis or cirrhosis (84). Because these fibrotic changes are permanent, sarcoidosis-induced portal hypertension is usually unresponsive to corticosteroids or other therapy for sarcoid granulomas (84,86,100). Because on rare occasion portal hypertension is the result of granulomas in the portal areas that produce pressure that restricts portal flow, a therapeutic trial of corticosteroids is probably warranted. Otherwise, therapy for sarcoidosis-associated portal hypertension is managed in a similar fashion as portal hypertension from other causes: with intravenous vasopressin or octreotide and Sengstaken-Blakemore tube for acute esophageal or gastric variceal bleeding, sclerotherapy of varices, beta blockers, portocaval, splenorenal or transjugular intrahepatic portal-systemic shunt (TIPS), splenectomy, and liver transplantation as a last resort for refractory cases (84–86,88,101,102). Liver transplantation has been successfully performed for end-stage sarcoid liver disease (103). Survival is comparable to liver transplant recipients with
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other end-stage liver diseases (103). Sarcoidosis may recur in the allograft (104–106) similar to other solid organ transplants in sarcoidosis patients (107). V.
Heart
A.
Epidemiology/Demographics
Although 25% of patients show evidence of granulomatous inflammation affecting the heart on autopsy (108), only 5% of patients with sarcoidosis have signs or symptoms of cardiac involvement pre-mortem (109). Sarcoidosis also seems to be much more common in the Japanese. In the United States, 13% to 50% of sarcoidosis deaths have been attributed to cardiac involvement (110,111) compared to 85% in Japan (112,113). ACCESS (an American study with few individuals of Japanese descent) did not demonstrate a predilection for the presence or cardiac sarcoidosis at diagnosis or its development over time on the basis of race, age, or gender (28,114). B.
Manifestations
Sarcoidosis can affect any portion of the heart and produce a myriad of clinical problems that may simulate other more common cardiac disorders. Granulomas may massively infiltrate the myocardium causing congestive heart failure (115–117) or deposit in papillary muscles resulting in mitral regurgitation (118). Sarcoidosis may cause a granulomatous pericarditis with or without pericardial effusion (119,120). Long-term granulomatous inflammation may lead to myocardial scarring with the formation of ventricular aneurysms (121). Granulomatous inflammation may involve the myocardial conducting system resulting in serious consequences that include complete atrioventricular block, premature ventricular contractions, ventricular arrhythmias, and sudden death (115,116,119,120,122–124). The most feared complications of cardiac sarcoidosis are sudden death and progressive congestive heart failure and underscore why patients with cardiac sarcoidosis must be diagnosed early and followed with extreme vigilance (125). It is for these reasons that all patients diagnosed with sarcoidosis are recommended to have a baseline electrocardiogram (ECG), and all unexplained electrocardiographic abnormalities should be pursued (29,126). C.
Diagnosis
The diagnosis of cardiac sarcoidosis is problematic because although an endomyocardial biopsy that reveals noncaseating granulomas is the gold standard for the diagnosis, it is positive in less than one-quarter of cases because of the patchy distribution of the disease (127). Consequently noninvasive tests are usually relied upon to establish the diagnosis of cardiac involvement with sarcoidosis. Available tests include the ECG (120,121), echocardiogram (120), gallium-67 scan (128–130),
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thallium-201 perfusion scan (128,129), gadolinium enhanced magnetic resonance (MR) scan (131–133), and positron emission tomography (PET) (Fig. 10A,B) (134). The accuracy of thallium and gallium scans is enhanced by using a single photon– emission CT technique (119,120). Thallium defects from sarcoid heart disease can often be differentiated from ischemic heart disease in that the former may decrease in size with exercise (reverse distribution) (109). Each of these noninvasive tests have a different sensitivity and specificity. Unfortunately, an algorithm for the diagnosis of cardiac sarcoidosis has not been determined because of the diagnostic limitations of the ‘‘gold standard,’’ which is endomyocardial biopsy. Moreover, when noninvasive tests are compared with each other within the same clinical trials, there is a poor concordance of the tests such that a negative result on any one test does not ensure the possibility of another test being positive (120,133,135). Nevertheless, the Japanese Ministry of Health and Welfare (136) and the research group conducting ACCESS (137) have each developed guidelines for the application of noninvasive tests to the diagnosis of cardiac sarcoidosis. Both of these guidelines involve some combination of (i) the results of diagnostic noninvasive tests for cardiac sarcoidosis, (ii) histologic confirmation of noncaseating granulomatous inflammation in an extracardiac organ, and (iii) evidence of unexplained arrhythmias, conduction system abnormalities, or ventricular dysfunction. D.
Treatment
There is no consensus concerning the treatment of cardiac sarcoidosis because of the lack of controlled studies (125). Therapy often involves a combination of anti-sarcoidosis medications, antiarrythmic drugs, ionotropes, and pacemaker/ defibrillator implantation. Early and long-term corticosteroid therapy has been shown to improve the prognosis of cardiac sarcoidosis (116). In one large study of 95 Japanese patients with cardiac sarcoidosis (116), survival rates were 85% at 1 year, 72% at 3 years, 60% at 5 years, and 44% at 10 years. Twelve percent experienced sudden death and 30% died of congestive heart failure. A multivariate analysis identified left ventricular end-diastolic diameter (hazard ratio ¼ 2.6 per 10 mm increase, p ¼ 0.02), New York Heart Association (NYHA) function class (hazard ratio ¼ 7.7 per NYHA class, p ¼ 0.0008), and sustained ventricular tachycardia (hazard ratio ¼ 7.2, p ¼ 0.03) as independent predictors of mortality. Prognosis was excellent in patients treated with corticosteroids early before the development of left ventricular dysfunction. Although some have advocated that high-dose corticosteroids be used for cardiac sarcoidosis, this study failed to reveal a difference in outcome in those receiving 40 of prednisone/day compared to <30 mg/day. Some have suggested that life-long low dose (5–10 mg of prednisone equivalent/day) is beneficial for the long-term prognosis (119). These data suggest that symptomatic cardiac sarcoidosis should be treated aggressively and early. Subjects should be monitored closely for the development of
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Figure 10 (See color insert.) (A) A cardiac PET scan from a patient with mild cardiac sarcoidosis presenting with asymptomatic premature ventricular contractions. The PET scan reveals localized ventricular uptake. (B) A cardiac PET scan from a patient with severe cardiac sarcoidosis presenting with severe left ventricular dysfunction and ventricular arrhythmias. He developed a left ventricular thrombus from a wall motion abnormality and had an internal automatic defibrillator placed that fired several times before his disease was controlled.
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left ventricular dysfunction, which suggests that the corticosteroid dose be increased, an alternate agent be added, or cardiac transplantation be considered if the patient fails to respond. There is minimal data concerning alternative medications to corticosteroids for the treatment of cardiac sarcoidosis. These medications include methotrexate (120), cyclophosphamide (120), cyclosporine (120), and infliximab (138). The latter drug raises concerns as infliximab has a black box warning for use in patients with congestive heart failure. Some have proposed adding additional immunosuppressive such as azathioprine, hydroxychloroquine, and/or methotrexate to low-dose corticosteroids for cardiac sarcoidosis (139). Arrhythmias, especially ventricular arrhythmias should be treated aggressively. Antiarrhythmic drug therapy is empirical (140). Amiodorone is the preferred drug, but appears to be less effective than for other cardiomyopathies (140). In addition, amiodorone may cause pulmonary toxicity in patients with concomitant pulmonary sarcoidosis. The value of electrophysiologic examinations for estimating the probability of cardiac events, selecting antiarrhythmic therapy, and determining the need for placement of an automatic implantable cardioverter defibrillator is extremely limited (140,141). Indeed cardiac sarcoidosis patients found noninducible with electrophysiologic testing have experienced sudden death (141), probably because the granulomatous lesions are not static and can worsen over time (125). The management of asymptomatic cardiac sarcoidosis is controversial. One study demonstrated that sarcoidosis patients with asymptomatic cardiac involvement had an excellent prognosis without therapy (142). However only three3 such patients were found out of 82 patients screened, making this conclusion suspect. VI. A.
Neurologic Epidemiology/Demographics
Clinically apparent involvement of the nervous system occurs in 5% to 15% of sarcoidosis patients (143,144). However as with other forms of sarcoidosis, asymptomatic neurologic disease is much more frequent (145,146). Approximately 15% of sarcoidosis deaths in the United States are attributable to neurosarcoidosis (147). In ACCESS, sarcoidosis was more common in women than men [28/468 (6.0%) versus 6/268 (2.2%), chi-square 7.28, p < 0.01) (2). There was no predilection on the basis of age or race. B.
Manifestations
Neurosarcoidosis may present as an acute explosive illness or in a slow, chronic fashion (143). Any part of the nervous system may be affected including the cranial nerves, meninges (Fig. 11), pituitary gland, hypothalamus, parenchyma of the brain, brainstem (Fig. 12), spinal cord (Fig. 13), subependymal layer of the ventricular system, peripheral nerves, and blood vessels supplying the nervous structures (143).
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Figure 11 Diffuse meningeal enhancement on MRI scan from sarcoidosis.
Figure 12 Multiple high signal T1-weighted lesions in the brainstem from sarcoidosis.
Neurosarcoidosis most frequently involves the cranial nerves (143,146). A peripheral seventh nerve palsy (Bell’s Palsy) is the most common neurologic manifestation of sarcoidosis (29,146). It may be unilateral, bilateral, and frequently ‘‘predates’’ the diagnosis of sarcoidosis (146). Any other cranial nerve may be affected, and in many series the nerves supplying the extraocular muscles or optic nerves are not rarely involved (148–150).
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Figure 13 Sagittal T2-weighted fast spin echo image shows an intramedullary spinal cord mass from sarcoidosis at the C4 level that is of relatively low T2 signal with prominent surrounding cord edema.
Sarcoidosis may cause aseptic meningitis (146). Symptoms include fever, headache, and stiff neck. Cerebrospinal fluid (CSF) findings typically reveal a pleocytosis of lymphocytes (151), with a low CSF glucose in 20% of cases (152). The basal meninges may be affected resulting in cranial neuropathies (146). Sarcoid meningitis may be acute or chronic. Acute meningitis responds favorably to corticosteroids, whereas chronic meningitis is often recurrent and requires long-term therapy (146). Cerebral sarcoidosis lesions may develop in any portion of the brain. These lesions are more common in supratentorial locations than the cerebellum (153). These lesions may cause manifestations consistent with any space occupying lesions of the brain, and therefore may be life threatening. The lesions have a predilection for the hypothalamus and pituitary gland (143,149,150,153–155), which may result in hypogonadism (156), diabetes insipidus (156,157), or adenopituitary failure (158). There are many other manifestations of neurosarcoidosis. Probably one of the most underappreciated of these is spinal sarcoidosis. Patients may present with transverse myelopathy, autonomic dysfunction, paresis, radicular syndrome, and cauda equina syndrome (146,159,160). Sarcoidosis may cause a peripheral neuropathy (143,150), Guillain-Barre syndrome (146,150,161,162), and seizures (150,162); the presence of seizures portends a poor prognosis (146). Granulomatous infiltration of the CNS from
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sarcoidosis can result in cognitive decline or frank psychosis (149,150,163). Sarcoidosis may also cause a small fiber neuropathy that may be responsible for disabling neuropathic pain and paresthesias, and possibly cause restless leg syndrome and periodic limb movement disorder (164). It usually cannot be detected on routine nerve conduction testing (165). Special testing of cold and heat discrimination is often needed to secure this diagnosis (166). C.
Diagnosis
The diagnosis of neurosarcoidosis is often problematic because biopsy of neural tissue is an invasive procedure. Fortunately a tissue diagnosis of sarcoidosis can usually be made in another location as in one series of neurosarcoidosis other systemic manifestations were found in 97% and intrathoracic manifestations were found in 88% (143). Therefore, an assessment should always be made for sarcoidosis involvement in extraneural locations. This assessment should involve a physical examination, liver function tests, complete blood count, and a chest radiograph. An ophthalmic evaluation (searching for conjunctival or lacrimal gland involvement) should also be performed. If the above is unrevealing, a whole-body gallium-67 or PET scanning could be considered to identify a potential site for a diagnostic biopsy (146,167). If a biopsy of an extraneural tissue demonstrates granulomatous inflammation of unknown cause, certain neurologic presentations have been established to make the diagnosis of neurosarcoidosis ‘‘definite’’ or ‘‘probable’’ (137). These are listed in Table 2.
D.
Treatment
Corticosteroids are the cornerstone of treatment of neurosarcoidosis (168,169). However the response to corticosteroids is inconsistent and high doses are often required (150,151,168–170). Some have advocated a starting dose of 40 to 80 mg/day of prednisone equivalent (168). Relapses are common when the dose lowered to 20 to 25 mg/day of prednisone equivalent (149). If the corticosteroid dose cannot be tapered to the 10 mg/day of prednisone equivalent over the first several months, alternative medications should be considered. Most of these agents are not effective alone but may be corticosteroid sparing. Such agents have included methotrexate (170), hydroxychloroquine (168,171), chloroquine (168,171), azathioprine (172), cyclosporine (172,173), cyclophosphamide (170,174), and infliximab (175). Although studies of these agents have for the most part involved uncontrolled case series, methotrexate and cyclophosphamide appears to be the most efficacious. Radiation therapy has been used successfully in refractory cases (176).
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Calcium Metabolism Epidemiology/Demographics
Calcium metabolism is disregulated in active sarcoidosis. The primary disorder in calcium metabolism stems from an increase 1-a hydroxylase activity in sarcoid alveolar macrophages that converts 25-hydroxyvitamin D to 1, 25-dihydroxyvitamin D, the active form of the vitamin (177–179). This may manifest as hypercaluria, hypercalcemia, and nephrolithiasis with possible renal insufficiency (180). The reported incidence of hypercalcemia in sarcoidosis has varied from 2% to 63% in various series (180). These disparate findings may be attributable to differences in sunlight exposure, dietary calcium, skin color, and genetic factors of the populations studied. ACCESS found that a disorder in calcium metabolism from sarcoidosis was more common in men than women [17/268 (6.3%) versus 10/468 (2.1%), chi-square 7.38, p < 0.01], Caucasians compared to African Americans [20/393 (5.1%) versus 6/325 (1.8%), chi-square 23.3, p < 0.0001], and those diagnosed age 40 years compared to <40 years [22/401 (5.5%) versus 5/335 (1.5%), chi-square 7.15, p < 0.01] (2). B.
Manifestations
Hypercalcuria is three times more common than hypercalcemia in sarcoidosis (181). Undetected, persistent hypercalcuria and hypercalcemia can result in nephrocalcinosis, renal stones, and renal failure (182). Therefore, all patients diagnosed with sarcoidosis should have a serum calcium and creatinine measured and a urinalysis performed (29). It should be noted that these screening tests will not detect hypercalcuria, and therefore, renal complications may develop if these screening tests are normal. Therefore it may be appropriate to obtain a 24-hour urine for calcium and creatinine in subjects at high risk of hypercalcuria (e.g., Caucasian, male gender, diagnosis 40 years, high sunlight exposure). C.
Diagnosis
It is important to exclude alternative causes of hypercalcemia and hypercaluria before concluding that sarcoidosis is the cause. The three most common causes of hypercalcemia are primary hyperthyroidism, granulomatous disorders, and malignancies (183). It is important to exclude these disorders before initiating treatment for sarcoidosis-related disorders in calcium metabolism. At a minimum, a serum parathyroid hormone should be obtained and a medical history and physical examination should be performed. D.
Treatment
The treatment of sarcoidosis-related hypercalcemia includes (i) reduction of sunlight exposure, dietary calcium, oral calcium supplements, and vitamin D;
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(ii) maintenance of an expanded intravascular volume; (iii) reduction of the inappropriate production of 1, 25-dihydroxyvitamin D by sarcoid macrophages and granulomas; and (iv) reduction of 1, 25-dihydroxyvitamin D–induced intestinal calcium absorption and bone resorption (183). Mild hypercalcemia (serum calcium 11 mg/dL) can be treated initially with the first two approaches: restriction of dietary calcium and increased fluid intake. The patient should be advised to avoid sunlight, drink large amounts of fluids, and curtail intake of major sources of dietary calcium and vitamin D (183). If the serum calcium is greater than 11 mg/dL, the patient has nephrolithiasis, or the serum creatinine is elevated, drug therapy is usually required. The drug of choice is prednisone at an initial daily dose of 20 to 40 mg/day (183). Corticosteroids cause a rapid decline in serum calcium within 5 days and in urinary calcium excretion in 7 to 10 days (183). Failure of the serum calcium to normalize within two weeks on this corticosteroid regimen should alert the clinician to an alternate or coexisting disorder such as hyperparathyroidism, lymphoma, carcinoma, and myeloma (183). Once the calcium disorder is brought under control, the corticosteroid dose can be lowered over four to six weeks (183). The serum calcium and urinary calcium excretion rate should be closely monitored. If the patient develops intolerable corticosteroid side effects or fails to respond, chloroquine (184), hydroxychloroquine (185), and ketoconizole (186) have been used successfully.
VIII. A.
Other Organs
Spleen
The reported frequency of splenic involvement in sarcoidosis has varied, depending on whether it is detected on physical examination (5–14%), a radiographic test (33–53%), or a tissue biopsy (24–59%) (81,187–192). Patients with splenic sarcoidosis are usually asymptomatic (193). Left upperquadrant abdominal pain is occasionally present (187,193). Constitutional symptoms such as fever, night sweats, and malaise may occur (187). Massive splenomegaly is found in approximately 3% of patients with splenic involvement (81,194). Splenic sarcoidosis may cause hypersplenism resulting in leukopenia, thrombocytopenia, anemia, or any combination including pancytopenia (81,194,195). Abdominal CT may reveal splenomegaly (191,192,196). Splenic nodules are usually multiple and of low attenuation (Fig. 4) (191,192,196,197). Most patients with splenic sarcoidosis do not require treatment. Splenomegaly, including giant splenomegaly, may resolve spontaneously (187,198). Spontaneous resolution of splenomegaly may be more common when the spleen tip is less than 4 cm below the left costal margin (187). Treatment is indicated for (i) symptomatic abdominal pain from splenomegaly, (ii) functional asplenia, (iii) hypersplenism, or (iv) splenic
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rupture (81). Corticosteroids have also been effective for hypersplenism with normalization of leukopenia, thrombocytopenia, anemia, and pancytopenia (187,188), but the corticosteroid dose is not standardized (81). Splenectomy is rarely required (199). Indications for splenectomy include gross enlargement or discomfort, infarction, rupture, and hypersplenism with reduction in one or several blood cell lines (199,200). A corticosteroid trial is warranted prior to consideration of splenectomy.
B.
Sarcoidosis of the Upper Respiratory Tract
The incidence sarcoidosis of the upper respiratory tract (SURT) is unknown but probably under-recognized (201). The disease may affect any part of the upper airway including the sinuses, nose, larynx, tonsils, and tongue (201). SURT most commonly affects the nasal mucous membrane (201). Common symptoms of sarcoidosis nasal involvement include dryness, crusting, nasal discharge, stuffiness, obstruction, and epistaxis. A confirmatory nasal biopsy should be performed if this diagnosis is considered (201). Sarcoidosis patients with disfiguring lupus pernio skin lesions on the nose often have nasal sarcoidosis, and such patients should always be asked about nasal symptoms (202). Sinus involvement, the second most common form of SURT, is often associated with nasal disease (201). Symptoms include postnasal drip, periorbital pain, nasal obstruction, and headache (201). Laryngeal involvement usually occurs in patients with previously diagnosed sarcoidosis (201). The arytenoids, aryepiglottic folds, false cords, and subglottic areas are more commonly involved than the larynx (201,203). Common symptoms include stridor, dysphonia hoarseness, cough, dyspnea, and a sensation of a lump in the throat (204,205). Hoarseness may also occur from cranial nerve involvement or from mediastinal adenopathy compressing the recurrent laryngeal nerve (206). Tonsillar and tongue involvement with sarcoidosis are rare. Corticosteroids are the drug of choice for SURT (201). Often high doses are required. It is recommended to start at 20 to 40 mg/day of prednisone equivalent with or without a concomitant immunosuppressive agent (201). Intralesional injections may be effective if the lesions are localized. Nasal corticosteroid inhalation may diminish nasal obstruction and inflammation (207). Azathioprine (208), methotrexate (95), chloroquine, hydroxychloroquine (171), cyclophosphamide (209), and infliximab (210) have all been reported to be useful in case reports and series. Chemotherapy should be tried prior to consideration of surgical resection because lesions may recur and perforation of the nasal septum is a common complication after submucosal resection (211,212). Surgery is indicated in cases of expanding mass lesions, mass lesions causing airway obstruction acute respiratory distress, and mass lesions encroaching on the central nervous system that fail to respond to chemotherapy (201).
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Bone and Joint
Arthritis is present in 14% to 38% of sarcoidosis patients (213). Up to 70% of patients will complain of arthralgias (213,214). Sarcoid rheumatic involvement may be acute or chronic, and their characteristics are so disparate that it has been hypothesized that they are distinct entities (213,215). Acute sarcoid arthritis may be intermittent, migratory and can precede other manifestations of sarcoidosis by several months (213). Fever and other constitutional symptoms are often present (213). Acute sarcoid arthritis is very common with Lofgren’s syndrome where a periarthritis of large joints, especially the ankles and knees often occurs (216). In fact, the primary symptom of Lofgren’s syndrome is often difficulty walking related to joint pain. This arthritis is usually self-limiting averaging 11 weeks in duration (216). Chronic sarcoid arthritis is rare, affecting only 0.2% of sarcoidosis patients (217,218). It is usually found in African American patients (215,219). The arthropathy may be destructive (220). Synovial biopsy shows noncaseating granulomas (213). Sarcoid bone involvement occurs in 1% to 13% of patients (213). It is most common in patients between the ages of 30 and 50 and in African Americans (213). Bone lesions are most common in the bones of the hands and feet; however, the nasal bones, skull, and vertebrae may be affected (213). The lesions are often asymptomatic and routinely found on radiographic or MR studies. Radiologic findings usually show cystic or punched-out lesions (221). Sarcoidosis arthritis is usually treated with nonsteroidal anti-inflammatory agents (215), which are especially useful for acute sarcoid arthritis. Chronic destructive synovitis may require systemic corticosteroids or intra-articular injections (213). The addition of azathioprine or methotrexate may improve results and be corticosteroid sparing (213). D.
Miscellaneous
Hematologic abnormalities occur in approximately 30% of sarcoidosis patients (222). Four mechanisms exist by which sarcoidosis can affect the hematologic system: (i) direct involvement of the bone marrow by granulomas, (ii) sequestration of cells into areas of inflammation, (iii) immunologic destruction, and (iv) splenic sequestration (223). Sarcoidosis may cause peripheral lymphadenopathy (224,225). Isolated granulomatous inflammation in a peripheral lymph node is not diagnostic of sarcoidosis, as in approximately eight percent of cases this may represent a ‘‘sarcoid-like reaction’’ from malignancy or inflammatory disease (224). A sarcoid-like reaction may also occur in intrathoracic and intra-abdominal lymph nodes from visceral malignancies (226,227). Sarcoidosis muscle involvement is usually asymptomatic and resolves spontaneously (213). Skeletal muscle weakness occasionally develops (228).
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Rarely, palpable intramuscular nodules, an acute myopathy resembling polymyositis, and progressive myopathy may occur (229,230). Sarcoidosis of the breast may occur presenting as a lesion seen on mammography or a palpable breast mass (231,232). It is important that a breast mass detected in a sarcoidosis patient is not assumed to be related to the disease, as the patient may have concomitant breast carcinoma. This is particularly pertinent as patients with breast carcinoma may have related sarcoid-like reactions in extramammary sites (233). Sarcoidosis may rarely involve the female and male reproductive tracts (234). Sarcoidosis may affect any portion of the female genitourinary tract including the ovary (235), fallopian tube (236), uterus (237), and vulva (238). Cases of sarcoidosis of the male testis are particularly problematic because of the concern for possible testicular malignancy. Elevated beta-human chorionic gonadotrophic (b-HCG) and alpha-fetoprotein (AFP) levels are elevated in approximately half of the patients with nonseminomatous testicular carcinoma (239). However, normal levels of these proteins do not exclude the diagnosis of cancer. In an attempt to avoid unnecessary orchiectomy, young males with known sarcoidosis or a clinical situation compatible with sarcoidosis and normal AFP and b-HCG levels could be considered for close observation and repeated ultrasound, a brief empiric trial of corticosteroids, or possibly an excisional biopsy (234). Although 20% of patients with sarcoidosis may demonstrate granulomas in the kidneys, the clinical syndrome of granulomatous interstitial nephritis is rare (183). Glomerulonephritis of the membranous, mesangioproliferative, and cresentic types as well as IgA nephropathy have been reported sporadically (183). Peritoneal sarcoidosis is rare and can present with ascites (240). The CA125 serum level may be elevated; and therefore, this entity may be confused with ovarian carcinoma (241). Very rarely sarcoidosis may involve the gastrointestinal tract (242). Any portion of the gastrointestinal tract may be involved (242), and care must be taken to distinguish it from the granulomatous inflammation from Crohn’s disease (242,243). Rarely sarcoidosis can affect the thyroid gland, presenting as thyroiditis, a nodule, or mass (244,245).
IX.
Summary
Extrapulmonary sarcoidosis may affect any organ. A definitive diagnosis requires histologic confirmation in the appropriate clinical setting where alternative causes of granulomatous inflammation have been excluded (Table 3). There are certain clinical presentations of extrapulmonary sarcoidosis that are thought to be definite or probable for the diagnosis (Table 2). Although corticosteroids are usually the drug of choice for extrapulmonary sarcoidosis, there are some nuances depending on the specific organs involved (Table 4).
. Brucellosis . Toxoplasmosis
. Granulomatous histiocytic necrotizing (Kikuchi’s disease)
. Fungal disease
. Pneumocysis carinii
. Mycoplasma
. Rheumatoid nodules
. Reaction to foreign bodies: beryllium, zirconium, tattooing, paraffin, etc.
. Fungal infection
. Tuberculosis . Atypical mycobacteriosis
Skin
. Non-Hodgkin’s . Lymphoma
. Hodgkin’s disease
. .
. Schistosomiasis . Primary biliary cirrhosis . Crohn’s disease
.
.
.
. .
Drugs
Non-Hodgkin’s
Hodgkin’s disease
Mononucleosis Cytomegalovirus
Tuberculosis Histoplasmosis
Bone marrow
. Tuberculosis . Brucellosis
Liver
Extrapulmonary Sarcoidosis
Source: Adapted from Ref. 29.
. Drug reactions . Aspiration of foreign materials . Hodgkin’s disease . Wegener’s granulomatosis . Non-Hodgkin’s lymphoma . Chronic interstitial pneumonia, such as usual and lymphocytic interstitial pneumonia
. Sarcoid reaction in regional lymph nodes to carcinoma
. Cat-scratch disease
. Tuberculosis . Atypical mycobacteriosis
. Tuberculosis . Atypical mycobacteriosis
. Hypersensitivity pneumonitis . Pneumoconiosis: Beryllium, Titanium, Aluminum
Lymph node
Lung
Table 3 Major Pathologic Differential Diagnosis of Sarcoidosis at Biopsy and Surgical Pathology
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Table 4 Manifestations and Treatment of Extrapulmonary Sarcoidosis Treatment Organ
Manifestations
Drug of Choice
Alternativesa
Eye
Anterior uveitis: red eye, painful eye, photophobia Posterior uveitis: floaters, ; vision Optic neuritis: sudden loss of vision or color vision Erythema nodosumc: pain erythematous/violaceous lesions on extensor surface Localized lesion(s) Diffuse lesions
CED, CP
C, M, A, I
C
M, A, I
Cb
M, A, I
NSAIDd
C
CI, CC C
C, M, H, CQ M, H,CQ, I
Skin
Liver
Joints Heart Neurologic Hypercalcemia
Sinus
a
Asymptomatic LFT :
Do not treat
Fever, nausea, vomiting Pruritus, cholestasis Arthritis Joint destruction Symptomatic heart block Symptomatic arrhythmia Left ventricular dysfunction
C Ce NSAID C Cb,f Cb,g,h Cb,g,h Cb
Asymptomatic, serum CAþþ < 11 mg/dL Asymptomatic, serum CAþþ 11 mg/dL Nephrolithiasis, serum creatinine : Nasal obstruction Epistaxis, crusting Hoarseness Airway compromise
?, F
M, H, CQ, I M, H, CQ, I C, H, CQ, M, I H, CQ, M, I M, CYC M, CYC M, CYC M, CYC, H, CQ, A, I C, H, CQ
?, F, C
H, CQ
?, F, C
H, CQ
Ci Ci Ci Cj
M M M M
These drugs are usually corticosteroid sparing: low dose corticosteroids is usually required concomitantly. Consider high-dose corticosteroids: 40 to 80 mg prednisone daily equivalent/day. c Often presents as Lofgren’s syndrome: erythema nodosum, bilateral hilar adenopathy on chest radiograph, arthritis, fever. d For associated arthritis. e Addition of ursodeoxycholate often beneficial. f Consider pacemaker or internal defibrillator placement. g Consider internal defibrillator placement. h Consider heart transplantation. i Injection if localized. j Consider surgery. Abbreviations: :, increase; ;, decrease; ?, restrict dietary calcium; F, high fluid intake; CED, corticosteroid eye drops; CP, cycloplegics; C, corticosteroids—usually 20 to 40 mg prednisone equivalent/day; M, methotrexate; A, azathioprine; I, infliximab; CC, corticosteroid creams; CI, corticosteroid injections; H, hydroxychloroquine; CQ, chloroquine; NSAID, non-steroidal anti-inflammatory drugs; CYC, cyclophosphamide. Source: From Ref. 246. b
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132. Shimada T, Shimada K, Sakane T, et al. Diagnosis of cardiac sarcoidosis and evaluation of the effects of steroid therapy by gadolinium-DPTA-enhanced magnetic resonance imaging. Am J Med 2001; 110:520–527. 133. Vignaux O, Dhote R, Duboe D, et al. Clinical significance of myocardial magnetic resonance abnormalities in patients with sarcoidosis. Chest 2002; 122:1895–1901. 134. Barneveld PC, van Leeuwen C, van Isselt JW. Scintigraphic demonstration of myocardial sarcoidosis: the added value of single photon emission computed tomography. J Nucl Cardiol 1997; 4:256–257. 135. Bagg SA, Gordon LL, Judson MA. Diagnostic yield of non invasive tests for cardiac sarcoidosis. Proc Am Thorac Soc 2005; 2:A864(abstr). 136. Hiraga H, Yuwai K, Hiroe M, et al. Guideline for the Diagnosis of Cardiac Sarcoidosis: Study Report on Diffuse Pulmonary Diseases [Japanese]. Toyko, Japan: Ministry of Health and Welfare 1993:23–24. 137. Judson MA, Baughman RP, Teirstein AS, et al. ACCESS Research Group. Defining organ involvement in sarcoidosis: the ACCESS proposed instrument. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16:75–86. 138. Roberts SD, Wilkes DS, Burgett RA, et al. Refractory sarcoidosis responding to infliximab. Chest 2003; 124:2028–2031. 139. Deng JC, Baughman RP, Lynch JP. Cardiac involvement in sarcoidosis. Sem Respir Crit Care Med 2002; 23:513–527. 140. Schulte W, Kirstien D, Drent M, et al. Cardiac involvement in sarcoidosis. Eur Respir J Monogr 2005; 10:130–149. 141. Mezaki T, Chinushi M, Washizuka T, et al. Discrepancy between inducibility of ventricular tachycardia and activity of cardiac sarcoidosis: requirement of defibrillator implantation for the inactive stage of cardiac sarcoidosis. Intern Med 2001; 40:731–735. 142. Smedema JP, Snoep G, van Kroonenburgh MPG, et al. Cardiac involvement in patients with pulmonary sarcoidosis assessed at two university medical centers in the Netherlands. Chest 2005; 128:30–35. 143. Stern BJ, Krimholz A, Johns C, et al. Sarcoidosis and its neurologic manifestations. Arch Neurol 1985; 42:909–917. 144. James DG, Sharma OP. Neurosarcoidosis. Proc R Soc Med 1967; 60:1169–1170. 145. Sharma OP, Sharma AM. Sarcoidosis of the nervous sytem. A clinical approach. Arch Intern Med 1991; 151:1317–1321. 146. Hoitsma E, Sharma OP. Neurosarcoidosis. Eur Respir J Monogr 2005; 10:164–187. 147. Huang CT, Heurich AE, Sutton AL, et al. Mortality in sarcoidosis. A changing pattern of the causes of death. Eur J Respir Dis 1981; 62:231–238. 148. Kumar N, Frohmam EM. Spinal neurosarcoidosis mimicking an idiopathic inflammatory demyelinating syndrome. Arch Neurol 2004; 61:586–589. 149. Zajicek LP, Scolding NJ, Foster O, et al. Central nervous system sarcoidosis— diagnosis and management. Q J Med 1999; 92:103–117. 150. Oksanen V. Neurosarcoidosis: clinical presentations and course in 50 patients. Acta Neurol Scand 1896; 73:283–290. 151. Plotkin GR, Patel BR. Neurosarcoidosis presenting as chronic lymphocytic meningitis. Pa Med 1986; 89:36–37. 152. Powers WJ, Miller FM. Sarcoidosis mimicking glioma: case report and review of intercranial sarcoidosis like mass lesions. Neurology 1981; 31:907–910.
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153. Christoforidis GA, Spickler EM, Recio MV, et al. MR and CNS sarcoidosis: correlation of imaging features to clinical symptoms and response to treatment. Am J Neuroradiol 1999; 20:655–669. 154. Dumas JL, Valeyre D, Chapelon-Abric C, et al. Central nervous system sarcoidosis: follow-up at MR imaging during steroid therapy. Radiology 2000; 214:411–420. 155. Guoth MS, Kim J, de Lotbiniere ACJ, et al. Neurosarcoidosis presenting as hypopituitarism and a cystic pituitary mass. Am J Med Sci 1998; 315: 220–224. 156. Bullmann C, Faust M, Hoffmann A, et al. Five cases with central diabetes insipidus and hypogonadism as first presentation or neurosarcoidosis. Eur J Endocrinol 2000; 142:365–372. 157. Konrad D, Gartenmann M, Martin E, et al. Central diabetes insipidus as the first manifestation of neurosarcoidosis in a 10-year-old girl. Horm Res 2000; 54: 98–100. 158. Fery F, Plat L, van de Borne P, et al. Impaired counterregulation of glucose in a patient with hypothalamic sarcoidosis. N Engl J Med 1999; 340:852–856. 159. Sculley RE, Mark EJ, McNeely WF, et al. Case records of the Massachusetts General Hospital, Case 8-1998. N Engl J Med 1998; 338:747–754. 160. Hashmi M, Kyritsis AP. Diagnosis and treatment of intramedullary spinal cord sarcoidosis. J Neurol 1998; 245:178–185. 161. Nemni R, Galassi G, Cohen M, et al. Symmetric sarcoid polyneuropathy: analysis of sural nerve biopsy. Neurology 1981; 31:1217–1223. 162. Delaney P. Neurologic manifestations in sarcoidosis: review of the literature, with a report of 23 cases. Ann Intern Med 1977; 87:336–345. 163. Bona JR, Facker SM, Fendley MJ, et al. Neurosarcoidosis as a cause of refractory psychosis: a complicated case report. Am J Psychiatry 1998; 155:1106–1108. 164. Verbraecken J, Hoitsma E, van der Grinten CP, et al. Sleep disturbances associated with periodic leg movements in chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21:137–146. 165. Hoitsma E, Marziniak M, Faber CG, et al. Small fiber neuropathy in sarcoidosis. Lancet 2002; 359:2085–2086. 166. Hoitsma E, Drent M, Venstraete E, et al. Abnormal warm and cold sensation thresholds suggestive of small-fibre neuropathy in sarcoidosis. Clin Neurophysiol 2003; 114:2326–2333. 167. Israel HL, Albertine KH, Park CH, et al. Whole-body gallium 67 scans. Role in diagnosis of sarcoidosis. Am Rev Respir Dis 1991; 144:1182–1186. 168. Sharma OP. Neurosarcoidosis: A personal perspective based on the study of 37 patients. Chest 1997; 112:220–228. 169. Ferriby D, de Seze J, Stojkovic T, et al. Long-term follow-up of neurosarcoidosis. Neurology 2001; 57:927–929. 170. Lower EE, Broderick JP, Brott TG, et al. Diagnosis and management of neurological sarcoidosis. Arch Intern Med 1997; 157:1864–1868. 171. Sharma OP. Effectiveness of chloroquine and hydroxychloroquine in treating selected patients with sarcoidosis with neurological involvement. Arch Neurol 1998; 55:1248–1254. 172. Agbogu BN, Stern BJ, Sewell C, et al. Therapeutic considerations in patients with refractory neurosarcoidosis. Arch Neurol 1995; 52:875–879.
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173. Stern BJ, Schonfeld SA, Sewell C, et al. The treatment of neurosarcoidosis with cyclosporine. Arch Neurol 1992; 49:1065–1072. 174. Doty JD, Mazur JE, Judson MA. Treatment of corticosteroid-resistant neurosarcoidosis with a short-course cyclophosphamide regimen. Chest 2003; 124: 2023–2026. 175. Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with infliximab. Chest 2005; 127:1064–1071. 176. Kang S, Suh JH. Radiation therapy for neurosarcoidosis: report of three cases from a single institution. Radiat Oncol Investig 1999; 7:309–312. 177. Bell NH, Stern PH, Pantzer E, et al. Evidence that increased circulating 1-a, 25-dihydroxyvitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis. J Clin Invest 1979; 64:218–225. 178. Adams JS, Sharma OP, Gacad MA, et al. Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest 1983; 72:1856–1860. 179. Adams JS, Gacad MA. Characterization of 1a–hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J Exp Med 1985; 161:755–765. 180. Sharma OP. Vitamin D, calcium, and sarcoidosis. Chest 1996; 109:535–539. 181. Sharma OP, Trowell J, Cohen N, et al. Abnormal calcium metabolism in sarcoidosis. In: Turiaf J, Chabot J, eds. La sarcoidose: Rapp IV Conf Intern. Paris: Maison de Cie, 1967:627–632. 182. Rizzato G, Columbo P. Nephrocalcinosis as a presenting feature of chronic sarcoidosis: a prospective study. Sarcoidosis Vasc Diffuse Lung Dis 1996; 13:167–172. 183. Sharma OP. Renal sarcoidosis and hypercalcemia. Eur Respir J Monogr 2005; 10:220–232. 184. Adams J, Diz M, Sharma O. Effective reduction in the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis associated hypercalcemia with short course of chloroquine therapy. Ann Intern Med 1989; 111:437–438. 185. Barre P, Gascon-Barre M, Meekins J, et al. Hydroxychloroquine treatment of hypercalcemia in a patient with sarcoidosis undergoing hemodialysis. Am J Med 1987; 82:1259–1262. 186. Conron M, Beynon HLC. Ketoconazole fot the treatment of refractory hypercalcemic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2000; 17:277–280. 187. Kataria YP, Whitcomb ME. Splenomegaly in sarcoidosis. Arch Intern Med 1980; 140:35–37. 188. Salazar A, Mana J, Corbella X, et al. Splenomegaly in sarcoidosis: reporto f 16 cases. Sarcoidosis 1995; 12:131–134. 189. Serloos O, Koivunen E. Usefulness of fine-needle aspiration biopsy of the spleen in diagnosis of sarcoidosis. Chest 1983; 83:193–195. 190. Taavitsainen M, Koivuniemi A, Helmminen J, et al. Aspiration biopsy of the spleen in patients with sarcoidosis. Acta Radiol 1987; 28:723–725. 191. Warshauer DM, Dumbleton SA, Molina PL, et al. Abdominal CT findings in sarcoidosis: radiologic and clinical correlation. Radiology 1994; 192:93–98. 192. Folz SJ, Johnson D, Swenson SJ. Abdominal manifestations of sarcoidosis in CT studies. J Comput Assist Tomogr 1995; 19:573–579. 193. Selroos O. Sarcoidosis of the spleen. Acta Med Scand 1976; 200:337–340.
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194. Thadani U, Aber CP, Taylor JJ. Massive splenomegaly, pancytopenia and haemolytic anemia in sarcoidosis. Acta Haematol 1975; 53:230–240. 195. Haran MZ, Feldberg E, Miller G, et al. Sarcoidosis presenting as massive splenomegaly and bicytopenia. Am J Hematol 2000; 63:232–233. 196. Britt AR, Francis IR, Glazer GM, et al. Sarcoidosis: abdominal manifestations at CT. Radiology 1991; 178:91–94. 197. Warshauer DM, Molina PL, Hamman SM, et al. Nodular sarcoidosis of the liver and spleen: analysis of 32 cases. Radiology 1995; 195:757–762. 198. Ali Y, Popescu A, Woodlock TJ. Extrapulmonary sarcoidosis: rapid spontaneous remission of marked splenomegaly. J Natl Med Assoc 1996; 88:714–716. 199. Coon WW. Splenectomy for splenomegaly and secondary hypersplenism. World J Surg 1985; 9:437–443. 200. Webb AK, Mitchell DN, Bradstreet CMP, et al. Splenomegaly and splenectomy in sarcoidosis. J Clin Pathol 1979; 32:1050–1053. 201. Sharma OP. Sarcoidosis of the upper respiratory tract: selected cases emphasizing diagnostic and therapeutic difficulties. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19:227–233. 202. James DG, Barter S, Jash D, et al. Sarcoidosis of the upper respiratory tract (SURT). J Laryngol Otol 1982; 96:711–718. 203. Bower JS, Belen JE, Weg JG, et al. Manifestations and treatment of laryngeal sarcoidosis. Am Rev Respir Dis 1980; 12:325–332. 204. Krespi YP, Mitrani M, Hussain S, et al. Treatment of laryngeal sarcoidosis with intralesional steroid injection. Ann Otol Rhinol Laryngol 1987; 96:713–715. 205. Jaske R, Fleischman G. Diagnosis and therapy of laryngeal sarcoidosis. HNO 1985; 33:1118–1123. 206. Tobias JK, Santiago SM, Williams AJ. Sarcoidosis as a cause of left recurrent laryngeal nerve palsy. Arch Otolaryngol Head Neck Surg 1990; 116:971–972. 207. Sebastian B, Kleinsasser O. Sarcoidosis of the larynx. Laryngol Rhinol, Otol (Stuttg) 1985; 64:622–626. 208. Lewis S, Ainskie G, Bateman E. Efficacy of azathioprine as second-line treatment in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16:87–92. 209. Costabel U, Guzman J. Bronchoalveolar lavage in interstitial lung disease. Curr Opin Pulm Med 2001; 7:255–261. 210. Baughman RP, Lower EE. Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001; 18:70–74. 211. Hammond BL, Kataria YP. Nasal sarcoidosis with septal perforation. J Otolaryngol 1980; 9:31–34. 212. Pila Perez R, Sanchex Baez A, Madriano Lopez L. Nasal sarcoidosis. Report of the first case in Cuba. Acta Otorrinolaringol Esp 1990; 4:243–244. 213. Jansen TLTA, Geusens PPMM. Sarcoidosis: joint, muscle, and bone involvement. Eur Respir J Monogr 2005; 10:210–219. 214. West SG, Kotzin BL. Sarcoidosis. In:Hochberg MC, Silman AJ, Smolen JS, et al. eds. Rhjeumatology, 3rd ed. Edinburgh, Mosby: Elsevier, 2003:1735–1752. 215. Awada H, Abi-Karam G, Fayad F. Musculoskeltal and other extrapulmonary disorders in sarcoidosis. Best Pract Res Clin Rheumatol 2003; 17:971–987. 216. Glennas A, Kvein TK, Melby K, et al. Acute sarcoid arthritis: occurrence, seasonal onset, clinical features, and outcome. Br J Rheumatol 1995; 34:45–50.
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9 Hypersensitivity Pneumonitis
MOISE´S SELMAN and MAYRA MEJI´A Instituto Nacional de Enfermedades Respiratorias, Dr. Ismael Cosı´o Villegas, Me´xico DF, Me´xico
ANNIE PARDO Universidad Nacional Auto´noma de Me´xico, Me´xico DF, Me´xico
I.
Introduction
Hypersensitivity pneumonitis (HP), or extrinsic allergic alveolitis, represents a heterogeneous group of disorders resulting from repeated exposure to a variety of organic particles, which provokes, in a susceptible host, an immunologically mediated inflammation of the small airways and lung parenchyma (1). The causative antigens include a large spectrum of mammalian and avian proteins, fungi, bacteria, and some small-molecular-weight chemical compounds (Table 1). Furthermore, new HP-related antigens are continually being documented. For example, in the last 10 years most cases related to hot tub/spa exposure (hot tub lung), and likely, some cases of sauna taker’s lung, lifeguard lung, humidifier lung, and tap water–associated HP among others are associated to the exposure to aerosolized nontuberculous mycobacteria (NTM) (2). In these cases, Mycobacterium avium complex is the most frequently reported NTM, but Mycobacterium fortuitum, M. terrae, M. komossense, and M. immunogenum have also been reported as causative antigens (3). More recently, paecilomyces contamination on the surface of the dried processed wood was likely responsible for the HP in a small outbreak observed in a hardwood processing plant (4). 267
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Table 1 Sources and Antigens Involved in Hypersensitivity Pneumonitis Disease
Source
Antigen
Fungal and bacterial Farmer’s lung
Moldy hay, grain, silage
Ventilation/humidifier lung.
Contaminated forced-air systems; water reservoirs
Metal working fluidassociated HP Mushroom worker’s lung Malt worker’s lung
Metal working fluids
Saccharopolyspora rectivirgula, Thermoactinomyces vulgaris, Absidia corymbifera Thermoactinomyces vulgaris, Thermoactinomyces sacchari, Thermoactinomyces candidus Mycobacterium immunogenum
Moldy mushroom compost
Thermoactinomyces sacchari
Moldy barley
Aspergillus fumigatus, Aspergillus flavus Alternaria sp., wood dust
Woodworker’s lung Sauna taker’s lung Maple bark strippers’ lung Cheese washers’ lung Sequoiosis Stipatosis Suberosis Hot tub lung Summer-type pneumonitis HP in peat moss processing plant workers Hardwood lung Animal proteins Pigeon breeder’s disease
Oak, cedar, and mahogany dust, pine and spruce pulp Contaminated sauna water Aureobasidium sp., pullularia Moldy maple bark Cryptostroma corticale Moldy cheese Moldy sawdust Esparto fibers Cork dust
Penicillium casei Pullularia Aspergillus fumigatus Penicillium frequentans, Aspergillus fumigatus Hot tubs; swimming pools, Mycobacterium avium complex whirlpools Contaminated old houses Trichosporon cutaneum Peat moss processing plants
Monocillium sp. Penicillium citreonigrum
Hardwood processing plant
Paecilomyces
Parakeets, budgerigars, pigeons, chickens, turkeys Furrier’s lung Animal pelts Animal handler’s lung; Urine, serum, pelts Laboratory worker’s proteins lung Chemical compounds Pauli’s reagent Laboratory reagent alveolitis Chemical worker’s Polyurethane foams, spray lung paints, special glues. Epoxy resin lung heated epoxy resin Pyrethrum pneumonitis Insecticide
Avian droppings, feathers, serum Animal-fur dust Rats, gerbils
Sodium diazobenzene sulfate Isocyanates; trimellitic anhydride Phthalic anhydride Pyrethrum
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Importantly, it has been recently corroborated that indoor exposure to molds may also cause HP (5). Exposure to specific domestic indoor fungal spores is considered an unlikely cause of HP except in Japan where summer-type HP caused by home contamination of Trichosporon species is common (6). Therefore, in the presence of interstitial lung disease (ILD), clinicians should always consider HP in the spectrum of the differential diagnosis and should carefully search for any potential source of HP-related antigens. The wide variability in the clinical presentation, including the sometimes-subtle or -deceptive manifestations of the disease, and the absence of a single confident diagnostic test make diagnosis a difficult task. Furthermore, exposures may be difficult to determine, requiring in-depth environmental histories as well as meticulous home and workplace search of antigens. Clinicians caring for ILD patients need to be aware of this because incorrect or late diagnosis with the subsequent further exposure may inexorably result in the progression to fibrosis or emphysematous lesions. Given the wide variety and ubiquity of the potentially offending antigens, many individuals may be at risk for exposure in their occupational, domestic, or recreational environments. However, despite the large number of individuals exposed to potential HP-causing antigens, the prevalence and incidence of HP seems to be low. There are two putative reasons to explain this observation: (i) the disease is underrecognized and then underdiagnosed and (ii) the presence of other environmental or genetic cofactors (promoting factors) is necessary to trigger the development of the disease (1,7).
II.
The Promoting Factors
Since a large number of individuals are exposed to the etiological risk factors, but few develop the disease, independent risk factors should be implicated. HP ought to be considered as a multifactorial disease, resulting from the effect of the exposure to organic particles, and the complex interplay of other environmental factors and genetic susceptibility. However, an unambiguous promoting cofactor(s) has not been identified. HP likely develops under the control of multiple susceptibility genes; however, studies regarding this issue are scanty and have focused on the major histocompatibility complex (MHC) and few cytokines. Several alleles and haplotypes of MHC class II alleles have been implicated in conferring HP susceptibility (HLA-DRB1*1305/HLA-DQB1*0501) or resistance (HLA-DRB1*0802) in bird-related HP in Mexican patients (8). MHC class II sequences exhibit an extraordinary degree of variation that is concentrated on the amino acid residues that shape the peptide binding site and display highly allele-specific peptide binding capacity. This restricts antigen presentation to T helper cells and regulates the magnitude of the subsequent immune response. Additionally, specific peptide/ HLA class II complexes may determine the extent of the immune response
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through the activation of regulatory (suppressor) T cells. Therefore, some MHC class II alleles may contribute to HP disease susceptibility enhancing an exaggerated response to antigens. Polymorphisms of the tumor necrosis factor-a (TNF-a) gene promoter as well as intron 1 in the TNF-b gene have been examined in HP (9). The frequency for the TNFA2 allele, a genotype associated with increased TNF-a expression, was higher in farmer’s lung disease (FLD) patients than in controls or patients with pigeon breeder’s disease. However, a more recent study did not confirm this association nor were abnormalities found in the following cytokine genes: interleukin (IL)-10 (592C/A, 819C/T, 1082G/A), transforming growth factor (TGF)-b1 (509C/T, þ869T/C), and IL-6 (634C/G) in patients with summertype HP and pigeon breeder’s disease (10). At least two environmental factors may contribute to the development of HP as a promoting factor: viral infections and inhalation injury. Experimental models of HP have shown that animals challenged with respiratory syncytial virus or Sendai virus exhibit a more severe inflammatory response to subsequent Saccharopolyspora rectivirgula exposure, which may persist long after the viral infection has declined (11,12). Also, studies in humans have revealed that common respiratory viruses, primarily Influenza A, are often present in the lower airways of patients with HP (13). The reasons why viral infections may potentiate HP are unknown, but it may be related to virus-induced mucociliary dysfunction, increased expression of costimulatory molecules by alveolar macrophages, and increased secretion of chemokines, enhancing the recruitment of lymphocytes to the lungs (13,14). Exposure to a second injurious agent may play an important role as a promoting factor. In a study of two families with several members affected by HP, it was noticed that both families used a gamma isomer of hexachlorobenzene to eradicate mite infestations in their birds before developing the disease (15). More recently, it was suggested that exposure to pesticides, mainly organochlorine and carbamate pesticides, may be a potential risk factor for FLD (16). Some host processes may also contribute as a risk factor. The recognition of the long-term persistence of fetal cells in maternal blood and tissues (fetal microchimerism) decades after pregnancy has opened up a new field of research. Although its health implications are debated, it has been hypothesized that some autoimmune diseases that usually occur in middle-aged women and resemble graft-versus-host reaction disease are alloimmune diseases (17,18). Interestingly, a recent report provided evidence for increased frequency of circulating and lung fetal microchimerism in patients with HP (19). Microchimeric cells were macrophages and CD4þ or CD8þ T lymphocytes, corroborating the multilineage capacity of these cells and suggesting that they might be participating in the exaggerated immune response that characterizes this disease. However, the putative role of these microchimeric fetal cells in the HP lungs is unknown, although they seem to increase the severity of the disease.
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Clinical Presentation
Clinical manifestations of HP may occur in three forms: acute, subacute, and chronic (1). Several situations influence the clinical presentation including the nature of the organic particle and the intensity and frequency of antigen exposure. A.
Acute HP
Acute HP typically occurs four to eight hours after intermittent and intense antigen exposure. Symptoms and signs begin abruptly and include fever, chills, dyspnea, chest tightness, and dry or mildly productive cough. Symptoms gradually decrease over the next days but often recur after the next inhalation of the causative antigen. Between attacks the individual may be completely normal. Importantly, without a history of illness occurring within hours of exposure to an identifiable antigen, acute HP is indistinguishable from an acute respiratory infection such as an episode of influenza or atypical pneumonia caused by viral or mycoplasmal agents (20). In farmers, the differential diagnosis must include the organic dust toxic syndrome (ODTS) provoked by exposure to bacterial endotoxins and fungal toxins of moldy hay (21). Nevertheless, ODTS is self-limiting, with symptoms rarely exceeding 36 hours; also no specific antibodies against usual offending antigens are found, and chest radiograph is usually normal. B.
Subacute HP
Subacute HP is characterized by the gradual development of similar but less severe symptoms occurring during weeks or few months after continued exposure. Patients consult primarily because of progressive dyspnea and cough, often accompanied by fever. Patients also complain fatigue, anorexia, and weight loss. As with acute HP, removal of the patient from the offending environment improves the symptoms. C.
Chronic HP
Chronic HP may occur as either chronic insidious or chronic recurrent form (8). In the former, patients display continuous and low-level antigen exposure. This form is characterized by slowly progressive dyspnea on exertion with few, if any symptom during the early stages. Associated symptoms include cough, fatigue, malaise, and weight loss. The chronic recurrent form usually follows undiagnosed acute/subacute episodes (22). Patients with recurrent disease are generally exposed to higher concentrations of antigens compared with the chronic insidious form (22,23). Importantly, specific antibodies against the offending antigens are usually positive in the recurrent chronic HP but may be absent in more than 50% of chronic insidious HP patients (22). Subacute and chronic HP may mimic virtually any ILD. Differential diagnosis of the subacute form of the disease includes some granulomatous lung infections such as tuberculosis or histoplasmosis, noninfectious granulomatous lung disorders, i.e., sarcoidosis, and some other ILD like lymphoid interstitial
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pneumonia, cryptogenic organizing pneumonia (COP), and idiopathic nonspecific interstitial pneumonia. Chronic HP (primarily the insidious form) may be misdiagnosed as idiopathic pulmonary fibrosis (IPF) or other advanced fibrotic lung disorder if a careful history and specific studies are not carried out (22–24). Some patients, mainly those with FLD, may evolve to a chronic obstructive lung disease (25,26). The reason for these different outcomes (fibrosis vs. emphysema) is unknown, but it may be related with the characteristics in the inhaled antigen, the type of exposure, cigarette smoking status, and the genetic background. Interestingly, cigarette smoking plays a paradoxical effect on the development and clinical behavior of HP. On one hand, the disease is forestalled in smokers (27,28). Also, cigarette smokers with HP are less likely to develop crackles in the lungs, elevated erythrocyte sedimentation rates, and restrictive functional abnormalities than nonsmokers with HP (29). The putative protective mechanisms of tobacco smoke are unclear but seem to be related with its immunosuppressive and apoptotic effects primarily on the alveolar macrophages (30–33). Likewise, a potent inhibitory effect of nicotine on alveolar macrophage expression and/or release of cytokines have been observed in an experimental model of HP even after specific in vitro stimulation with S. rectivirgula (34). However, when the disease occurs in smokers (current or former), the clinical course seems to be more severe, and most patients develop chronic recurrent or the insidious form of the disease displaying a worse survival rate compared with nonsmokers (35). The reason is unknown, but it can be associated with changes in the lung T-cell subsets and with increased local induction of free radicals (36,37). On lung examination, tachypnea and bibasilar dry crackles can be found in any clinical presentation of HP. Wheezing, provoked by small airway obstruction, is uncommon but when present, may lead to an erroneous diagnosis, i.e., asthma. Patients with chronic HP may develop digital clubbing, pulmonary arterial hypertension, and even cor pulmonale (1,38). IV.
Laboratory Tests
The presence of serum IgG antibodies against the offending antigens is the only laboratory test that has a role in diagnosis. A slight/moderate neutrophilic leukocytosis with lymphopenia, increased levels of C-reactive protein, erythrocyte sedimentation rate, and immunoglobulin IgG and IgM has been described primarily in acute/subacute cases (1). Plasma lactate dehydrogenase (LDH) is elevated and decreases with improvement, suggesting that it may be useful in assessing the disease activity (39). With the exception of the chronic insidious fibrotic form of the disease, specific antibodies are usually detectable in HP patients. Specific antibodies may also be found in some exposed but asymptomatic individuals, but its presence is one of the major diagnostic criteria for the disease. Unfortunately, commercially available ELISA systems are usually incomplete, making it difficult to ascertain an etiological agent (and diagnosis).
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On the other hand, the advent of PCR-based assays may offer a more sensitive and rapid alternative for detecting and identifying microorganisms in contaminated fluids and patients. Real-time PCR of genetic targets unique to select microorganisms, microbial 16S ribosomal RNA gene DNA sequencing, amplified fragment length polymorphism-PCR, and repetitive element-PCR DNA fingerprinting can be useful (40). Regarding HP, PCR in combination with amplicon DNA, genome fingerprinting by pulsed-field gel electrophoresis, and quantitative competitive PCR have been successfully applied for identification and quantification of mycobacteria and Pseudomonas (41). V.
Chest Imaging
The chest radiograph remains the first imaging modality for the approach to ILD. In patients with mild, acute, or subacute HP, chest X rays may be normal. In acute HP, diffuse or patchy ground-glass attenuation and/or areas with air space consolidation may be observed. These changes disappear promptly with the cessation of exposure. In subacute HP, nodular or reticulonodular opacities with ground-glass attenuation may be found (Fig. 1A). The chronic stages are characterized by a predominantly reticular pattern that may evolve to honeycombing (Fig. 1B).
Figure 1 (A) Anteroposterior chest radiograph of a 33-year-old patient with subacute HP showing diffuse ground-glass attenuation. (B) Bird-related chronic HP. Chest radiograph shows shortening of the lung fields, diffuse reticulonodular opacities, and signs of pulmonary arterial hypertension. Abbreviation: HP, hypersensitivity pneumonitis.
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Figure 2 (A) A 36-year-old female with subacute HP. HRCT scan shows bilateral poorly defined centrilobular nodules and ground-glass opacities. (B) A 43-year-old female with subacute HP. HRCT illustrates ground-glass opacities and areas of decreased attenuation (mosaic pattern). Abbreviations: HP, hypersensitivity pneumonitis; HRCT, high-resolution computed tomography. A.
High-Resolution Computed Tomography
Ground-glass attenuation is the most frequent feature in acute HP (25). Subacute HP is characterized by ground-glass opacities, small, poorly defined centrilobular nodules, and mosaic attenuation on inspiratory images and air trapping on expiratory CT images (Fig. 2A, B) (42–44). Air trapping on expiratory imaging is likely explained by the bronchiolocentric inflammation. Findings of lung infiltration on inspiratory high-resolution computed tomography (HRCT) scans and air trapping on expiratory CT correlate with the functional measures of restrictive and obstructive lung disease, respectively (45). Nodules are usually diffuse with centrilobular distribution but are occasionally randomly distributed with upper lung predominance (46). Thin-walled cysts resembling those seen in lymphocytic interstitial pneumonia are occasionally noticed in patients with subacute HP (47). Chronic HP is characterized on HRCT by reticulation due to fibrosis superimposed on the findings of subacute HP. Fibrotic reticular opacities may evolve to honeycombing, mainly in chronic patients who show slowly progressive (insidious) disease, and may provoke traction bronchiectasis (Fig. 3) (22,48). In a recent report, patients with fibrotic HP had more extensive reticular pattern and were more likely to have traction bronchiectasis, honeycombing, and a usual interstitial pneumonia (UIP)-like pattern than those with nonfibrotic HP. Interestingly, while the presence of histological fibrosis was associated with decreased survival, the CT features were not (49). In these cases, the disease may mimic IPF. Occasionally, patients with chronic disease suffering recurrent subacute episodes show air space consolidation (48). In FLD, emphysematous changes are frequently seen and appear to be even more common than interstitial fibrosis.
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Figure 3 HRCT image of a patient with chronic fibrotic HP showing bilateral reticular opacities, traction bronchiectasis and bronchiolectasis, and subpleural cysts. Abbreviations: HP, hypersensitivity pneumonitis; HRCT, high-resolution computed tomography.
VI.
Pulmonary Function Testing
Lung functional abnormalities are neither specific nor diagnostic since similar changes are found in most ILDs. Independent of the clinical form, the mechanical dysfunction is characterized by restrictive ventilatory abnormalities with decreased forced vital capacity (FVC) and total lung capacity (1). The forced expiratory volume in 1 second (FEV1)/FVC ratio is usually over 75%. Reduced static lung compliance with increased elastic recoil pressure is also observed mainly in chronic patients. Correlations of CT changes and lung functional defects indicate that areas of mosaic pattern are associated with severity of air trapping (bronchiolitis) indicated by residual volume, whereas ground-glass opacification and reticular opacities correlate with restrictive lung function (45,50). However, a number of patients, primarily with FLD, display an obstructive pattern with decreased FEV1/FVC ratio and increased residual volume and evolve to a chronic obstructive pulmonary disease–like disorder (51). Emphysema is more common in smokers than in nonsmokers, but definite emphysema has been noted in nonsmokers. The mechanisms leading to emphysematous changes in FLD are unknown, but are probably multifactorial, and may include inflammation in the distal airways and proteolytic activity produced by fungi and thermophilic bacteria present in organic dust (51). Regarding gas exchange, patients exhibit resting hypoxemia, which usually worsens with exercise and increased alveolar-arterial oxygen gradient [P(A-a)O2]. In early and mild disease, patients may be normoxemic at rest, but exercise induces hypoxemia. Hypoxemia is provoked by ventilation-perfusion (VA/Q) disequilibrium and by decrease in the diffusing capacity of the lung for carbon monoxide (DLCO). Few hours after antigen exposure, HP patients show an increase in P(A-a)O2 and functional dead space ventilation during exercise, with a reduction of the breathing reserve (52).
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Studies measuring exhaled nitric oxide (NO) at several exhalation flow rates have revealed that the alveolar NO concentration correlates negatively with DLCO, vital capacity, and alveolar volume, suggesting that it may be a marker of disease severity (53). VII. A.
Bronchoalveolar Lavage Cell Profile
The most consistent finding in HP is a remarkable increase in the percentage of lymphocytes, often more than 50% (54). Smoking may reduce the percentage of bronchoalveolar lavage (BAL) lymphocytes. However, less than 30% of BAL lymphocytes make the diagnosis of HP uncertain. BAL lymphocytosis may also be found in a number of asymptomatic exposed individuals, suggesting that a moderate increase in the alveolar spaces is a normal reaction to facing the exposure or that a low-intensity subclinical alveolitis occurs in some cases (55). Most BAL lymphocytes are highly active T cells that exhibit an increase in cells bearing Vb2, Vb3, Vb5, Vb6, and Vb8 gene segments compared with the peripheral blood (56). B.
CD4+/CD8+ T-Cell Subsets
Analysis of CD4þ/CD8þ subpopulations has revealed conflicting results. Some studies support the notion that HP is characterized by an exaggerated accumulation of CD8þ T cells with a decrease in the CD4þ/CD8þ ratio (57,58), while others found that both the subsets are increased without changes in its ratio; others reported a predominance of CD4þ on the surface phenotypes of BAL T cells and increased CD4þ/CD8þ ratio (36) (Fig. 4). Several circumstances seem to explain this discrepancy. Regarding the type of HP, significant differences have been found between summer-type HP (low CD4þ/CD8þ ratio) and farmer’s lung (high CD4þ/ CD8þ ratio) with intermediate values in pigeon breeder’s disease and ventilation pneumonitis (59). Smoking also affects the T-cell subsets and smokers with HP usually have higher levels of CD4 with increased CD4þ/CD8þ ratio (59). Likewise, an increase in CD4þ T cells has been noticed in patients with chronic HP (36). Therefore, BAL CD4þ/CD8þ ratio in HP is variable and is probably dependent on the clinical form (acute, subacute, or chronic), smoking addiction (which also affects clinical behavior), type/dose of inhaled antigen, and the time elapsed since antigen exposure. A predominant increase in CD8þ occurs mostly in nonsmokers with acute/subacute HP, while a prevalent elevation of CD4þ is frequently found in smokers or those with chronic/fibrotic forms of the disease. On the other hand, the increase in CD4þ and CD8þ T cells in the lungs of individuals with HP display a predominantly Th1 cytokine profile (60). Thus, a predominance of IFN-g-producing T cells was found in the BAL but not from peripheral blood-derived T cells. This was associated with changes in IL-10 production and IL-12R expression by T cell recruited to the lung (60). More recently,
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Figure 4 Flow cytometry analyses of BAL T lymphocytes from two HP patients showing the percentage of CD4þ and CD8þ cells. (A) Subacute HP patient displaying a decrease CD4þ/CD8þ ratio. (B) Chronic former smoker HP patient demonstrating an increase in the CD4þ/CD8þ ratio. Normal values for BAL CD4þ/CD8þ ratio: 1.2 to 1.5. Abbreviation: HP, hypersensitivity pneumonitis.
we corroborated the Th1 feature of HP, and also that a switch to a Th2-type response may occur in chronic cases (61). Finally, increased natural killer cells, nonmajor histocompatibility complex (non-MHC)-restricted cytotoxic lymphocytes, and lymphokine-activated killer cells are usually detected in BAL from patients with HP. C.
B Lymphocytes and Plasma Cells
Lung tissue B cell expansion is suggested by the strong humoral reaction to inhaled antigens resulting in high titers of IgG antibody in blood and BAL (62). In this context, a modest but significant increase in plasma cells is also observed in this disease, mainly after recent exposure (63). This finding together with the increase in T lymphocytes may help to distinguish HP from others ILDs (64). D.
Macrophages
Lower percentages of alveolar macrophages are found in the BAL reflecting the increase in lymphocytes. Macrophages are in a high state of activation, overexpressing receptors of the MHC class II (i.e., HLA-DQ and HLA-DP) and intercellular adhesion molecule (ICAM)-1, (1,65). A relatively high percentage of them show cockade-like structures in their cytoplasm, although their significance is presently unclear (66). E.
Neutrophils
A moderate but significant increase in the percentage of neutrophils is observed in acute HP or after inhalation challenge (acute transient neutrophil alveolitis).
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In an important study, Drent et al. (67) evaluated the effect of the time elapsed between antigen exposure on the BAL cell profile. They demonstrated an increase in neutrophils in the first 24 hours after challenge with a subsequent drop, but levels remained higher than controls during 1 month. However, higher percentages of BAL neutrophils have been found in a number of chronic patients, particularly with pigeon breeder’s disease (68). Cigarette smoking may reduce the initial neutrophilic response after antigen challenge (69). F.
Mast Cells
Several studies show a small but significant increase in mast cells in HP (70,71). These cells resemble bronchial subepithelial tissue mast cells and display ultrastructural changes suggestive of activation and degranulation (72). A recent study including patients with a variety of ILDs showed that mast cells are increased in COP and HP (73). However, increased mast cells may also be found in ex-farmer’s lung patients who had quit farming and even in some normal farmers (70). G.
Effect of Time Elapsed Between Last Antigen Exposure and BAL Cell Profile
Drent and coworkers evaluated the behavior of BAL inflammatory cells from 59 nonsmoking HP patients at various time points after the termination of antigen inhalation (67). Early after exposure (less than 24 hr), BAL contained increased numbers of neutrophils, lymphocytes, eosinophils, and mast cells, with a concomitant reduction of alveolar macrophages. By two to seven days after antigen provocation, BAL revealed increases in lymphocytes, plasma cells and mast cells. Although higher than controls, a significant drop of neutrophils was noticed compared with the group of patients studied in the first 24 hours. In BAL obtained after 1 week, with the exception of the lymphocytes that remained high, the distribution of cell types tended to return to normal values. H.
BAL Proteins
A variety of molecules have been found increased in BAL fluid from HP patients probably reflecting the intense lung inflammatory environment. These include immunogloblulins (IgG, IgM, and IgA) immune complexes, leukotriene C4, and some cytokines such as macrophage inflammatory protein-1a IL-6 and IL-8 (1). Patients with acute intermittent FLD and with recent onset of pigeon breeder’s disease exhibit elevated levels of hyaluronic acid and procollagen 3 Nterminal peptide (74,75). Likewise, HP patients display high levels of fibronectin and vitronectin, two molecules involved in cellular adhesion, extracellular matrix organization, and tissue remodeling. In one study, the levels of both the proteins returned to normal levels if the BAL was performed five days after the last antigen exposure; this suggests a dynamic accumulation and clearance (76).
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Other authors found that some of these molecules such as hyaluronic acid, fibronectin, and fibroblast growth factor activity remain abnormal in patients with FLD, who remain asymptomatic despite daily contact with the farm environment (77). Additionally, the levels of SP-A in BAL fluid obtained from patients with acute FLD are significantly higher than that in asymptomatic dairy farmers, although this finding does not appear to correlate with either the clinical abnormalities or the prognosis of the disease (78). Likewise, BAL SP-A is also found highly increased in subacute/chronic HP patients with pigeon breeder’s disease (79). VIII.
Histological Features
The characteristic pathological feature of HP is the presence of poorly formed bronchiolocentric granulomas with an interstitial pneumonitis mostly composed of lymphocytes, plasma cells, and macrophages (80) (Fig. 5A, B). However, in HP provoked by NTM, exuberant non-necrotizing well-formed granulomas are usually found (81).
Figure 5 (See color insert.) (A) Lung biopsy specimen of subacute hypersensitivity pneumonitis showing bronchiolocentric interstitial inflammation and poorly formed granulomas around bronchiole. (B) Interstitial granulomatous lesion in another field of the same patient. (C) Chronic interstitial inflammatory infiltrate and fibrosis in an HP patient with two years of progressive symptoms before biopsy. Arrowhead shows a poorly formed granuloma. Abbreviation: HP, hypersensitivity pneumonitis.
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A number of bronchiolar alterations have been described including proliferative bronchiolitis obliterans in FLD (82), peribronchiolar inflammation/ fibrosis with smooth muscle hypertrophy, and extrinsic narrowing of the small airways in pigeon breeder’s disease (83), and less frequently, bronchiolitis obliterans organizing pneumonia (BOOP)-like lesions (84). Importantly, around 20% to 30% of patients with subacute or chronic HP exhibit a different histological pattern, including nonspecific interstitial pneumonitis (NSIP) (85), COP, or even UIP. In the original description of NSIP, a number of the examined samples showed histopathological lesions resembling HP (86). In these cases, the lungs show a temporally and geographically uniform inflammatory/fibrotic lesion without the characteristic bronchiolocentricity of HP. In patients with other histological patterns (i.e., NSIP, BOOP/COP, UIP, etc.), it is extremely important to corroborate an etiological cause. HP because of organic particle exposure may resolve after rectification of the environmental contamination (independent of the morphological manifestation) (87). The chronic stage is characterized by variable degrees of interstitial fibrosis (Fig. 5C) superimposed to subacute changes such as mild/moderate interstitial infiltration of lymphocytes, some giant cells, and occasionally, poorly formed granulomas (22,23,88). Recently, three patterns of fibrosis were described in chronic HP: (i) predominantly peripheral fibrosis in a patchy pattern with architectural distortion and fibroblast foci resembling, microscopically, UIP; (ii) relatively homogeneous linear fibrosis resembling fibrotic NSIP; and (iii) irregular predominantly peribronchiolar fibrosis (89). In some instances, mixtures of the UIP-like and peribronchiolar patterns were found. The presence of giant cells, poorly formed granulomas, Schaumann bodies, or inflammatory features of subacute HP may substantiate the diagnosis of HP. In another study dealing with patients with chronic pigeon breeder’s disease, it was found that half of them had morphological changes compatible with cellular or fibrotic NSIP, while many others displayed UIP-like lesions characterized by the temporal heterogeneous appearances of the fibrotic changes. In addition, two patients had histology suggestive of BOOP. Multinucleated giant cells were found in most patients, but granulomas were infrequent (84).
IX.
Diagnostic Criteria
Unfortunately, there is no single diagnostic test for this disease. The clinical behavior is similar to most ILDs; chest X rays and even HRCT may be normal in acute or mild subacute cases; specific serum precipitins may be negative, primarily in chronic cases, and commercial panels to search for antigens are usually incomplete and not easily available in many countries. Furthermore, important findings such as BAL lymphocytosis and HRCT images are typical but not specific for HP. Therefore, it is important for clinicians to have a high index of suspicion when dealing with ILD patients. Diagnostic criteria include:
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Acute HP: (1) Evidence of exposure (usually intense), documented by history and specific antibodies, (2) a flu-like syndrome, (3) increased BAL neutrophils and lymphocytes, and (4) significant improvement after removing the patient from the suspected environment and worsening after reexposure. Subacute HP: (1) Evidence of exposure with cause-effect relationship and precipitins against the offending antigen; (2) progressive dyspnea; (3) BAL lymphocytosis (usually over 50% in nonsmokers); (4) groundglass opacities, poorly defined centrilobular nodules, and mosaic attenuation on inspiratory images and of air trapping on expiratory CT images; (5) restrictive functional pattern plus hypoxemia and reduced DLCO. Chronic HP: (1) Evidence of exposure with cause-effect relationship and precipitins against the offending antigen; (2) clinical behavior of chronic ILD; (3) BAL lymphocytosis; (4) reticular opacities superimposed to subacute changes on HRCT; and (5) restrictive functional pattern plus hypoxemia and reduced DLCO. Additional Tools for Diagnosis
In subacute and mainly in chronic cases, a confident diagnosis may be difficult to achieve. In these cases, at least three additional tools can be used: (i) Environmental or laboratory-controlled inhalation challenge with the suspected antigen [should only be performed in experienced laboratories or research institutions (90,91)]; Fever and significant reduction of FVC or oxygen saturation few hours after the antigen provocation indicate a positive test; (ii) Antigen-induced lymphocyte proliferation; this test is positive in more than 90% of the recurrent and insidious chronic cases (22); and (iii) Lung biopsy. X.
Treatment and Outcome
The most important step in managing HP is to make an early diagnosis and to avoid the recurrent exposure to the offending antigen from work or domestic environment. A combination of interventions including fluid management, improved fresh air ventilation, and medical surveillance/restriction are important to decrease the incidence of occupational risk. Farmer’s lung can be reduced by adapting modern agricultural practices that reduce the moisture content of hay. Cleaning habitat is also important in home-related HP. Removal of T. cutaneum from colonizing places or birds prevent summer-type or bird-related HP relapses. A trial with oral prednisone (initial dose, 0.5 mg/kg/day) is recommended in subacute/chronic disease until objective improvement occurs, followed by a gradual reduction of the dose to a maintenance dose of 10 to 15 mg daily. However, prospective, randomized, placebo-controlled trials are scanty. A controlled study in
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FLD demonstrated that a relatively short course of corticosteroids accelerated the recovery from the acute stage (based on lung function), but did not influence the long-term prognosis (92). Inhaled corticosteroids have been occasionally found to reduce the side effects of long-term systemic steroid therapy. Improvement has been cited in subacute HP but studies are scanty (93,94). Patients with NTM-related HP have been treated with corticosteroids alone or with antimycobacterial therapy or even both, with significant improvement at the time of follow-up (95). Some in vitro studies suggest that thalidomide may be useful in HP (96). Among other effects, thalidomide reduces the secretion of TNF-a, IL-12p40, IL18, and IL-8 by alveolar macrophages. In this context, it can be speculated that specific immunomodulatory drugs (namely IMiDs), a family of structural and functional analogues of thalidomide (mostly explored in cancer), may have promise in HP (97). Likewise, TNF-a inhibitors (e.g., infliximab or etanercept) could be (with the exception of MAC-induced HP) tried, but clinical experience with these agents is lacking. In the fibrotic phase of HP, subsequent antigen avoidance and corticosteroid treatment may not reverse the disease. Some patients have progressive lung deterioration resulting in respiratory failure, cor pulmonale, and death (23,98). As in any other fibrotic lung disorder, there is no anti-fibrotic treatment for chronic advanced patients, and lung transplantation should be considered. A.
Prognosis and Survival
Patients with acute and subacute HP usually have a favorable outcome. By contrast, patients with the chronic form may evolve to diffuse lung fibrosis, and may succumb from the disease (22,23,98). In a general-population-based cohort study performed in a U.K. primary care database, the incidence of HP appeared to be stable over time, but HP patients had a markedly increased mortality rate compared with the general population (99). As mentioned, patients with FLD may develop emphysematous lesions but data regarding survival are sparse. Acknowledgment This work was partially supported by Universidad Nacional Auto´noma de Me´xico Grant SDI.PTID.05.6. References 1. Selman M. Hypersensitivity pneumonitis: a multifaceted deceiving disorder. Clin Chest Med 2004; 25(3):531–547. 2. Sood A, Sreedhar R, Kulkarni P, et al. Hypersensitivity pneumonitis-like granulomatous lung disease with nontuberculous mycobacteria from exposure to hot water aerosols. Environ Health Perspect 2007; 115(2):262–266.
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10 Berylliosis
LEE S. NEWMAN and HOLLY M. SACKETT Department of Preventive Medicine and Biometrics, School of Medicine, University of Colorado Denver, Denver, Colorado, U.S.A.
I.
Introduction
Beryllium is the fourth lightest element (atomic weight ¼ 9.02) and has chemical properties that make it an excellent material for high-technologic applications. Unfortunately, it continues to cause a significant burden of illness among those who work with the material. Lighter than aluminum and stronger than steel, beryllium has a low density (1.85 g/cm3), high melting point (23498F), high tensile strength and is corrosion resistant. Exposure to beryllium metal, oxide or alloy dust and fume occurs during the extraction of the mineral from its ores, beryl and bertrandite, and processing of beryllium into metal alloys and ceramic products. Perhaps most importantly, exposure occurs during secondary machining and processing of copper beryllium, aluminum-beryllium, and nickelberyllium alloys and ceramic products in other industries, including aerospace, automotive, biomedical, defense, energy and electrical, manufacturing, sporting goods, telecommunications, and the recycling and disposing of berylliumcontaining products, such as cell phones, computers, circuit boards, and assorted electronic parts (Table 1). The spreading use of beryllium in high-technology
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Table 1 Industries that Use Beryllium Industry
Products
Aerospace
Altimeters, braking systems, bushings and bearings for landing gear, electronic and electric connectors, engines, gyroscopes, mirrors (e.g., in space telescopes), precision tools, rockets, satellites, structural components Air-bag triggers, antilock brake system terminals, electronic and electric connectors, steering-wheel connecting springs, valve seats for drag-racing engines Dental crowns, bridges, partials, and other prostheses; medical laser and scanning electron microscope components; X-ray tube windows Heat shields, mast-mounted sights, missile guidance systems, nuclear-reactor components and nuclear triggers, submarine hatch springs, tank mirrors Heat-exchanger tubes, microelectronics, microwave devices, nuclear-reactor components, oil-field drilling and exploring devises, relays and switches Non-sparking tools, sprinkler-system springs Bellows, camera shutters, clock and watch gears and springs, commercial speaker domes, computer disk drives, musical-instrument valve springs, pen clips, commercial phonograph styluses Injection molds for plastics Golf clubs; fishing rods; naturally occurring beryl and chrysoberyl gemstones, such as aquamarine, emerald, and alexandrite; man-made gemstones, such as emeralds with distinctive colors Various beryllium-containing products Cellular-telephone components, electromagnetic shields, electronic and electric connectors, personal-computer components, rotary-telephone springs and connectors, undersea repeater housings
Automotive
Biomedical Defense Energy and electricity Fire prevention Instruments, equipment, and objects Manufacturing Sports goods and jewelry items
Scrap recovery and recycling Telecommunications
Source: From Ref. 186.
applications and various other industries has created a serious public health problem. (1) The problem is worldwide, with cases of chronic beryllium disease (CBD) or berylliosis being reported throughout North America, Europe, Asia, Russia, and Japan. (1) This chapter summarizes our present knowledge, based on epidemiologic workplace studies, research on the role of the immune response to beryllium, immunogenetics, and clinical research addressing the recent developments in CBD detection, diagnosis, and treatment.
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Historical Perspective
In the 1930s, reports of lung and skin disease in workers in beryllium industries were reported in Europe and Russia (2–4). In the early 1940s, Van Ordstrand et al. described beryllium workers in the United States with an acute pneumonitis or bronchiolitis (5). The link between beryllium and a form of chronic granulomatous lung disease was reported in 1946, when Hardy and Tabershaw described an outbreak of sarcoidosis-like illness in fluorescent lamp workers who worked with beryllium phosphors (6). Chronic disease was further identified in beryllium industry workers and their family members through household contact, and discovered in individuals living in areas surrounding beryllium industries (7–10). Early epidemiologic and exposure assessments led Sterner and Eisenbud (8) to hypothesize that beryllium-related health effects were immunologically mediated, resulting from a specific response to beryllium. A beryllium exposure standard was introduced in 1949 by the U.S. Atomic Energy Commission, setting occupational exposures at a permissible exposure limit (PEL) of 2 mg/m3 for an eight-hour time-weighted average and a peak short-term exposure limit (STEL) of 25 mg/m3. Although later research has established that this level of exposure is not sufficiently protective, it remains the current workplace exposure limit according to the U.S. Occupational Safety and Health Administration (OSHA). Based in part on studies of neighborhood cases surrounding a beryllium plant, the environmental standard for air around factories was set at 0.01 mg/m3 average over a 30-day period, which remains the present U.S. Environmental Protection Agency (EPA) regulation. Fortunately, the incidence of acute disease in the United States greatly declined after the implementation of the exposure standard and reduction of beryllium levels in the workplace (11,12). Unfortunately, numerous cases of CBD continue to occur (13–34). Adherence to the existing standard does not afford full protection from CBD (13,17,26–30,35–37). The American Conference on Governmental Industrial Hygienists has proposed a change of the threshold limit value for beryllium to 0.02 mg/m3 (38).
III.
Exposure and Toxicology
The number of workers with potential beryllium exposure is not known, although estimates in the United States have ranged from 134,000 workers currently exposed to 800,000 individuals currently and previously exposed (17,39,40). It is likely that these numbers underestimate the actual number of exposed individuals, as it is difficult to estimate the number of downstream users of beryllium and former workers, and it does not include estimates outside the United States (1). The prevalence of CBD, from 20 epidemiologic studies, has been estimated at 1% to 5% of exposed workers, depending on the group of workers studied
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(13,19,23,24,26–33,41–48). When groups of workers have been tested serially for evidence of CBD, disease rates are much higher, affecting as much as 15% of the workforce. Beryllium primarily targets the lung, lymph nodes, and skin, either by direct toxicity, by its impact on the immune system, or both. Skin lesions including subcutaneous granuloma formation and ulceration, occur following direct inoculation of beryllium into the skin. Cutaneous contact with beryllium salts can induce contact dermatitis. Skin contact may contribute to beryllium sensitization (49–51). However, it is unlikely that skin exposure in the absence of airborne exposure can result in CBD. The primary route of exposure in beryllium-related respiratory diseases is through inhalation of fumes and respirable dusts of beryllium salts, metal, oxides, or of beryllium-containing metal alloys. Once inhaled, beryllium particles obey the general principle of particle deposition in the lung (52–54). Most likely, the chemical properties of the inhaled beryllium particle also influence its toxicity. The solubility and the form of beryllium inhaled influence the development of an immune response and disease (54–57). Most of the beryllium inhaled is cleared by the lung’s mucociliary escalator and airway macrophages. Some of the remaining beryllium is moved to the regional lymph nodes and pulmonary interstitium, remaining in the lung for many years after the last exposure, retained within granulomas (58). Certain beryllium industrial processes and job tasks increase the risk of developing an immune response to beryllium and disease (Table 2) (13,23,24,26,27,29,31,32,48). Although the precise exposure-response relationship for CBD, continues to be the subject of study, it does not appear to be Table 2 Examples of Process-Related Risks by Industry Industry
Process-related risks
Ceramics
Dry pressing Firing Forming Lapping Machining Process development Ventilation maintenance Construction Heath physics Casting Machining Metallurgy Analytic laboratory Machining Point and chamfer Wire annealing Wire drawing Wire pickling
Nuclear weapons
Metal production Beryllium alloy finishing
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strictly linear. Both dose and duration of beryllium exposure have been associated with increased risk of sensitization and disease in some studies. In addition, individuals with measured higher beryllium exposures, some of who machined beryllium or worked in rod and wire production, have also been associated with increased risk of sensitization and disease (13,23,26,29,31). However, CBD has also been detected in workers with evidence of only very low levels of exposure, such as those working in decontamination and decommissioning of contaminated buildings, security guards, and administrative staff (23,24,32,33,59–61), and after as short an exposure duration as three months (42,48). Genetic susceptibility to beryllium likely contributes to disease, as discussed below.
IV.
Immunopathogenesis and Disease Susceptibility
Many questions raised by beryllium’s unconventional dose-response relationship promoted research on the immunologic effects of beryllium, beginning in the 1950s. Inhalation or tracheal instillation of various beryllium moieties damages the lungs mucosal barrier, increases lung permeability, induces an inflammatory response, and produces lung injury ranging from an acute chemical pneumonitis to a mononuclear cellular infiltration and formation of granulomas and/or fibrosis in a variety of species (62–72). Cumulatively, animal models support a beryllium-specific adaptive immune response with pathologic responses similar to those seen in humans that can be modified by both beryllium exposure and genetics. Numerous lines of evidence in humans suggest that beryllium induces an antigen-specific adaptive immune response. As early as 1951, Curtis showed that individuals with CBD developed a cutaneous delayed-type hypersensitivity when skin patch tested with beryllium salts. Some even developed a granulomatous response at the skin patch test site weeks later (73,74). When peripheral blood or bronchoalveolar lavage (BAL) cells are cultured in the presence of beryllium salts, those lymphocytes that possess memory for beryllium proliferate (14,15,18,19,21,22,75–78). These observations form the basis for the beryllium lymphocyte proliferation test (BeLPT), which is now widely used to detect beryllium sensitization and disease (15,18–24,78,79). This test has been found to discriminate CBD from other granulomatous diseases (80–82). BAL cells from CBD cases show a marked proliferative response to beryllium salts while those from other granulomatous diseases, such as sarcoidosis, do not (14,18,79). When the peripheral blood BeLPT was first evaluated as a potential screening tool in the 1980s, Kreiss et al. (19) and Newman et al. (20) showed that this immune biomarker enhances early detection of CBD. This observation has been confirmed in many other industries since that time. In these studies, some individuals were found to be sensitized to beryllium, as indicated by a positive response in the BeLPT and initiation of the adoptive immune response, without any
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evidence of pulmonary disease (22–24,26,78,83). Some of these individuals then developed granulomatous disease within a short follow-up period, indicating that sensitization precedes the inflammatory response in the lung and is a step in the progression from exposure to disease (23,59,61,84). In an initial study, Saltini et al. (21,85) showed that the adaptive immune response to beryllium requires class II major histocompatibility complex (MHC) for presentation of antigen to the T cells and for proliferation of memory T cells. Beryllium reactive T-cell clones recognize the antigen via their antigen receptor. This notion is supported by the findings of a limited subset of T-cell antigen receptors (TCARs) in the lungs compared with the blood of patients with CBD (60,86,87). These same TCARs are found preserved over time and across individuals with CBD but not in other granulomatous lung diseases, suggesting that these T cells are selected by exposure to beryllium (88). The exact form of the beryllium antigen is unclear at this time; beryllium may be acting in conjunction with a hapten (peptide) directly attaching to the MHC, forming a bridge between the T cell receptor (TCR) and the MHC or inducing a local conformational change in the MHC where the antigen presenting cell engages the TCR (82,89–91). Following antigen presentation and recognition, beryllium-specific immune effector cells are recruited to the site of disease and become activated (21,75,92,93). After T-cell recognition, key inflammatory cytokines are produced, including tumor necrosis factor-a (TNF-a), interleukin (IL)-6, IL-2, and interferon-g (INF-g) (93–96). These cytokines enhance the inflammatory and immune response and recruitment of the lymphocytes, macrophages, and other cells within the lung, while regulating the development of granulomas and the immune response in CBD, thus acting in a self-propagating manner that amplifies the inflammatory response in the target organ. Beryllium itself may enhance this immune response once initiated by at least two mechanisms. First, it is able to trigger apoptosis of macrophages, which may result in ongoing, cellular exposure to beryllium in the lung (97–99). Second, in vitro beryllium alters the production of reactive oxygen species, which can in turn augment the proliferative response to beryllium (99). This response may be limited by cells found at sites of granuloma formation and by the production of other cytokines. For example, mast cells found in the circumference of CBD granulomas produce fibrogenic growth factors such as basic fibroblast growth factor (BfGF), which may help promote the formation of a fibrotic capsule surrounding the granuloma (72). In vitro experiments suggest that IL-10 may be able to reduce the production of other cytokines important in the inflammatory response to beryllium, such as INF-g and TNF-a (100). A complicated network of cellular interactions and inflammatory mediators are likely important in enhancing and limiting the runaway immune response to beryllium. The progression from exposure to sensitization and disease in CBD hinges partly on an individuals genetic susceptibility. The seminal observation was made in a study by Richeldi et al. (101) demonstrating an increased frequency of MHC human leukocyte antigen (HLA) DPB1 with a glutamic acid residue at
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position 69 (E69) in patients with CBD compared with exposed individuals (102). More recent studies have confirmed this association, with the majority indicating that E69 is associated with sensitization, as it is present in 80% to 85% of subjects with both sensitization and disease but only 35% to 40% of nondiseased exposed subjects (103–109), and thus not specific for disease. Whether specific E69 variants pose greater risk of sensitization and/or disease has been proposed but is not clear at this time (103,106,107). It is unlikely that E69 will be a clinically useful marker to determine individuals at risk of sensitization and disease, as a large percentage of the general population has the same allelic substitution and this marker has a low-positive predictive value (PPV) for sensitization and disease (110). However, in vitro studies have demonstrated that E69 is functional and important in determining the cell’s ability to mount an immune response to beryllium, affecting beryllium-stimulated cell proliferation and cytokine production (89,98,111). Recent population-based and in vitro studies suggest that HLA-DRB1 may serve as an alternative pathway affecting antigen presentation to T cells in a minority of individuals analogous to E69 (103,108,112). It is likely that sensitization and CBD are multigenetic diseases, many of which have yet to be defined. Genes important in numerous stages of the immunopathogenesis of these processes may be implicated, and studies are ongoing investigating the importance of cytokine-associated functional gene polymorphisms (101,113–119). Regardless of an individual’s genetics, beryllium disease does not occur unless that person has been exposed to beryllium. V.
Clinical Disease
Depending on the amount, form, and route of exposure to beryllium, various diseases may result, ranging from acute or chronic lung disease, dermatologic disease, or cancer. As the respiratory disease and dermatologic disease are most common, they are the focus of this section. Beryllium-related pulmonary manifestations exist on a continuum from acute inhalational injury to acute pneumonitis, beryllium sensitization, and the chronic form, that has been called berylliosis, chronic berylliosis, and which is now known as chronic beryllium disease (CBD). A.
Acute Beryllium Disease
Exposure to elevated concentrations of beryllium, usually in the 25 mg/m3 range or greater, (120) can result in inflammation of the upper and lower respiratory tract and airways, tracheitis, bronchiolitis, pulmonary edema, and a lymphocytepredominant chemical pneumonitis (12,121–123). Although significantly less common than CBD, acute beryllium disease still occurs globally. In 2004, nine cases were reported from a South Korean liquid metal factory where measured beryllium exposures ranged from 3.13 to 112.3 mg/m3 (12). The manifestations
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of acute beryllium disease are not specific and may mimic many other inhalational injuries. The upper airway manifestations include beryllium nasal ulceration, nasopharyngitis, and tracheobronchitis. Tracheobronchitis may occur rapidly or gradually and often occurs concomitantly with chemical pneumonitis. Nonproductive cough, shortness of breath, substernal chest discomfort, and chest burning or tightness characterize the disorder. Examination reveals some similar features to the nasopharyngitis, including airway hyperemia as well as rales or rhonchi on auscultation of the chest. Radiographic evaluation may reveal increased bronchovascular markings. Therapy is mainly supportive for acute upper airway disease and should include removal from exposure. The symptoms of acute chemical pneumonitis include cough, occasionally productive of blood-tinged sputum, chest pain or a burning sensation, and dyspnea on exertion, which may progress to dyspnea at rest. Systemic symptoms are frequently present, including malaise, anorexia, and low-grade fever. In acute chemical pneumonitis, individuals usually appear quite ill, may be cyanotic, tachycardic, or tachypneic, and have rales noted on examination of the lungs. Hypoxemia may be present on arterial blood gas and low lung volumes on pulmonary function testing. The chest radiograph may be normal or may reveal diffuse bilateral alveolar infiltrates or severe bilateral pulmonary edema. Radiographic abnormalities usually develop within a few weeks of the onset of symptoms (121,123). There are no specific diagnostic criteria or laboratory evaluations available for the acute disease. A history of beryllium exposure with a compatible clinical picture is the principal means of establishing the diagnosis. Pathologically, a nongranulomatous pneumonitis is observed with inflammatory infiltrates composed of lymphocytes and neutrophils, bronchiolitis, and intraalveolar edema. The primary therapeutic intervention is removal from exposure. Corticosteroids, oxygen, rest, and even ventilatory support, if needed, are part of an appropriate treatment regimen. The signs and symptoms of acute chemical pneumonitis may resolve within several weeks to several months. In its most severe form, this acute disease may be fatal. Approximately 17% of the acute cases in the Beryllium Case Registry progressed to CBD (122). It is unclear whether return to work and further beryllium exposure is safe for individuals who have experienced the acute pneumonitis. B.
Beryllium Sensitization
The use of the blood BeLPT has defined a subset of exposed workers who develop an adaptive immune response to beryllium, but in whom there are no pathologic or clinical features of CBD. These individuals are asymptomatic and have normal pulmonary function, exercise tolerance, chest radiographs, and lung biopsies. Although their blood BeLPT is abnormal, they have not yet developed a clinically detectable inflammatory process in the lung. The rate of beryllium sensitization without disease in a few published studies has ranged from 1% to
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6% of all exposed workers. Of those individuals who underwent clinical evaluation due to an abnormal blood BeLPT, between 14% and 100% were found to have CBD at their initial visit (13,23,24,26,27,29,48,59,61). Newman et al. (84) longitudinally followed a cohort of 55 patients with beryllium sensitization who did not have detectable CBD at the time of their initial clinical assessment. They found that 31% developed CBD over a mean follow-up time of 3.8 years, resulting in a conversion rate from sensitization to CBD of 6% to 8% per year. Thus, sensitized individuals should remain under close medical supervision and be reexamined at intervals for signs of clinical progression. One risk factor for progression from sensitization to CBD is to work as a machinist, although other risk factors are unclear at this time and will require further long-term follow-up (84). In some individuals who have borderline or normal blood BeLPT, sensitization can be confirmed using beryllium sulfate patch testing, although this is not recommended as a routine clinical test, especially in current workers, due to the small, but possible, risk of inducing sensitization or of aggravating underlying CBD (74). As discussed below, beryllium-stimulated peripheral blood neopterin levels and/or the number of beryllium-specific blood cells producing INF-g by Enzyme-linked immunosorbent spot (ELISPOT) may help distinguish between sensitization and granulomatous inflammation (124,125).
C.
Chronic Beryllium Disease
Unlike acute beryllium disease, CBD can develop many years after exposure has ceased and typically has a gradual course and insidious onset of symptoms. On average, CBD develops 6 to 10 years after exposure, but has been reported to occur with a latency greater than 40 years and as early as 3 months after initial exposure. Nonspecific respiratory and systemic symptoms are characteristic of CBD. Most individuals with CBD present with some combination of fatigue, nonproductive cough, gradually progressive shortness of breath, and chest pain (121–123). Anorexia, weight loss, fevers, night sweats, and arthralgias are fairly common. Other organs besides the lungs can be involved, with signs and symptoms related to liver or myocardial involvement, hypercalcemia, or nephrolithiasis, although this is rarely seen in the United States today. Dry bibasilar rales, cyanosis, clubbing, lymphadenopathy, and skin changes may be present on examination, with other findings depending on the severity of the disease. Hepatomegaly and/or hepatic enzyme elevations are found in approximately 10% of cases (121,122). Depending on the severity of disease, symptoms of pulmonary hypertension, cor pulmonale, or respiratory failure may be present. In less severe disease, an abnormal chest radiograph may be the presenting feature. With increasing use of the blood BeLPT, screening of exposed workers in industry, asymptomatic cases of CBD are detected in which the individual has normal chest radiographs and pulmonary function, with or without abnormal gas exchange with exercise.
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Dermal
Beryllium can induce a number of dermatologic conditions, development of which may depend on the form of beryllium and magnitude of exposure. Contact dermatitis can occur on exposed areas of skin as a result of contact irritation or a sensitization to beryllium. It generally resolves with cessation of exposure. If the contact dermatitis involves the face, conjunctivitis, periorbital edema, and upper respiratory tract involvement may occur concomitantly (121,123). The use of beryllium-containing dental prostheses have been shown to cause the equivalent of oral contact dermatitis, and hand lesions in an individual making the oral prosthesis (126,127). Oral signs include chronic gingivitis and bleeding in the areas adjacent to beryllium-containing dental crowns and bridges. Ulceration or granulomatous nodular skin lesions may occur after accidental inoculation of the skin with splinters of beryllium metal, oxide, or crystal. The lesion will persist until the beryllium material is excised and the lesion debrided. The nodular granulomatous skin lesions may be confused with common warts and can occur without obvious skin inoculation in individuals who commonly handle beryllium and in patients with CBD. Because of the risk of sensitization, workers should wear personal protective equipment to limit dermal routes of exposure. E.
Carcinogenesis
Animal studies have shown that beryllium can induce cancer in many different species, with some species variability, depending on the mode of administration (68,70,71,128–132). A number of large epidemiologic studies have shown an increased risk of lung cancer among beryllium-exposed workers and among workers with acute beryllium disease, with standardized mortality ratios (SMRs) of 1.37 to 1.97 for production workers and 3.14 for those with acute beryllium disease (133–137). These studies have been criticized by some on methodological grounds, such as failing to account for confounding exposures, primarily tobacco smoke (138). Other studies have confirmed the association between beryllium and lung cancer in humans (139–141). In one study of Beryllium Case Registry cases, an increased risk of lung cancer was found in those individuals with acute and CBD (overall SMR ¼ 2.00) (139). Those with acute disease had a higher risk (SMR ¼ 2.32) compared to those with CBD (SMR ¼ 1.57) suggesting a possible doseresponse effect (139). An increased risk of lung cancer was observed in a separate study by Ward et al. (140) of beryllium-exposed workers, after adjusting for smoking. In that study, the risk to the beryllium-exposed population was less than for those with beryllium lung disease (SMR ¼ 1.26). Sanderson et al. (141) using the same cohort with four years of additional follow-up in a case-control study, found the updated lung cancer SMR to be 1.22. In this study, which controlled for tobacco use, average and maximum beryllium exposures were higher for cases than controls (141). A recent industry-funded reanalysis of this data set has suggested that when other statistical methods are employed, the size
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of this effect may appear smaller (142). Overall, the preponderance of data support the conclusion that beryllium is a human carcinogen, especially in those patients with beryllium-related lung disease. The International Agency for Research on Cancer reclassified beryllium as a class I human carcinogen in 1993 (128,129). Arguments to the contrary have been promoted by individuals employed by the beryllium industry using selective referencing of literature and data set reanalyses (138,142–146,). VI.
Diagnosis of CBD
The remainder of this chapter will focus on CBD, since this is, today, the most common beryllium-related condition encountered in medical practice. A.
Pulmonary Physiology
The pulmonary function abnormalities noted in CBD are typical of many interstitial lung diseases. A restrictive pattern of decreased lung volumes occurs in advanced disease, however, normal volumes with a mild obstructive pattern are more commonly found early in CBD (147,148). Mixed obstruction and restriction may also be observed (147,149). The diffusing capacity for carbon monoxide (DLCO) is abnormal in more advanced disease. Exercise tolerance testing is the most sensitive indicator of physiologic impairment in CBD, revealing defects in pulmonary physiology even when lung volumes, spirometry, and DLCO are normal (148). The most common abnormalities noted on exercise testing include reduced exercise tolerance, decreased oxygen consumption (VO2), an abnormal fall in oxygen levels, widening alveolar-arterial gradient, and ventilatory limitations to exercise. Some individuals with documented CBD may have normal exercise physiology, especially if diagnosed in workplace medical surveillance programs that employ the blood BeLPT as a screening tool. Because alterations in exercise physiology become apparent before PFT abnormalities do, it is a better tool to evaluate and follow gas exchange abnormalities early in the disease process. The use of an arterial line to monitor arterial oxygen levels results in fewer false positive results than oximetry in sensitization and CBD and thus is recommended if available, but in clinical practice can be replaced with pulse oximetry (150). Both PFTs and exercise testing are used to assess impairment, monitor the progression of sensitization and CBD and response to treatment. B.
Imaging Findings
Classical chest radiograph manifestations of CBD include bilateral middle to upper lobe predominant reticulonodular infiltrate, with or without mild hilar/ mediastinal lymphadenopathy. (Fig. 1). The interstitial opacities are typically characterized as small “p” or “q” in the International Labour Organization (ILO)
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Figure 1 Chest radiograph manifestations of CBD include bilateral middle to upper lobe predominant reticulonodular infiltrate, with or without mild hilar/mediastinal lymphadenopathy.
classification scheme (151). Chest X-ray abnormalities range in severity from normal to widespread bilateral interstitial fibrosis and honeycombing in any lung field. The large hilar nodes seen commonly in sarcoidosis are seen infrequently in CBD, although adenopathy is present on chest X ray in approximately one third of cases (16,152–155). Hilar adenopathy in the absence of interstitial opacities is rare in CBD although it has been described (33). Pleural abnormalities may be noted in a small number of patients, most often adjacent to areas of greatest parenchymal involvement (149). Over time, a reduction in lung volumes becomes apparent, and small nodules coalesce to form larger nodular opacities or even conglomerate masses. The chest radiograph is an insensitive screening tool (24). Disease is usually physiologically and symptomatically evident by the time the X ray appears abnormal (19,20). Thin-section computed tomography (CT) is more sensitive than the plain radiograph (155). The most common CT abnormalities are nodules, thickened septal lines, ground-glass opacification, hilar adenopathy, and bronchial wall thickening, even in nonsmokers (Figs. 2 and 3) (155–158). None of these findings are specific for CBD, but when taken in concert with specific tests like the blood BeLPT, they can confirm the diagnosis, especially in individuals who cannot medically undergo a bronchoscopy.
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Figure 2 The most common CT abnormalities are nodules, thickened septal lines, hilar adenopathy, and bronchial wall thickening, even in nonsmokers.
Figure 3 In early, active cases of CBD, the CT scan may show ground-glass opacification and subtle nodular densities. C.
Bronchoalveolar Lavage
In CBD, BAL cells include an increased number of total white cells with lymphocyte predominance (14,18,20,21). The lymphocytes are principally CD4þT cells,similar to those found in sarcoidosis and in some cases of hypersensitivity pneumonitis (159). Tobacco smoke affects BAL cell function and results in an increase in the macrophage percentage, complicating the interpretation of BAL
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cell count and differential and the BAL BeLPT. The extent of BAL cellularity, lymphocytosis, and BAL BeLPT response correlates with disease severity, suggesting that the magnitude of the inflammatory and antigenic response in the lung may help predict disease progression or response to therapy (25). The most important reasons to perform the BAL in suspected CBD is to obtain cells needed to perform the BeLPT, discussed below. D.
Laboratory Abnormalities
Besides the BeLPT and BAL findings, a number of less specific laboratory abnormalities are noted in some cases of CBD, including hyperuricemia (160), nonspecific evaluation of serum immunoglobulins (161), hypercalcemia, hypercalciuria, and abnormal hepatic enzymes (121,123). Polycythemia and ECG changes are uncommon despite progressive pulmonary disease noted is some patients (121,122). Elevated serum angiotensin converting enzyme (sACE) levels are found in some CBD patients but cannot discriminate this disorder from sarcoidosis (162,163). Alternative noninvasive tests are being researched to provide a diagnosis of CBD without the need for bronchoscopy. A study of beryllium salt-stimulated production of neopterin by blood cells in beryllium sensitization and CBD suggests that this surrogate marker of INF-g (and other cytokine) production may help distinguish between those individuals who are beryllium sensitized without disease and those with granulomatous involvement (CBD) with high sensitivity and specificity (125). Another test that holds promise for differentiating sensitization from CBD is the beryllium-stimulated ELISPOT, which detects the number of beryllium responsive cytokine producing cells present after 48 hours of beryllium salt stimulation in vitro (124). Other tests have been proposed as alternatives to the current BeLPT test, including two forms of flow cytometry– based LPT test (164,165). At this time, these tests are not available commercially but may be in the future, depending on the results of the next stages of research studies. E.
Pathology
The noncaseating granuloma is a hallmark of CBD and of some berylliumrelated skin disorders but is histologically indistinguishable from the granuloma found in sarcoidosis. Other pathologic abnormalities commonly found include a mononuclear cell interstitial infiltrate and varying degrees of fibrosis (121,122,166,167). The absence of granulomas on either transbronchial biopsy or thoracoscopic lung biopsy does not fully exclude CBD. The presence of multinucleated giant cells and mononuclear cell interstitial infiltrates are also consistent with CBD. The noncaseating granuloma usually contains epithelioid cells of monocyte lineage, multinucleated giant cells, and lymphocytes that are predominantly CD4þ T cells (Fig. 4). Using sensitive microprobe techniques, beryllium particles can be detected inside granulomas, even many years after a
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Figure 4 (See color insert.) Photomicrograph of lung biopsy from a patient with CBD. The noncaseating granuloma usually contains epithelioid cells of monocyte lineage, multinucleated giant cells, and lymphocytes that are predominantly CD4þ T cells.
worker’s exposures have ceased. It can discriminate between the granulomas found in CBD and those seen in sarcoidosis, Although this method has not been rigorously standardized for clinical use, it is used by pathologists as a diagnostic adjunct (58). F.
Diagnostic Evaluation
In the 1980s, the introduction of transbronchial biopsy, BAL, and the BAL BeLPT improved our ability to make a specific, accurate diagnosis of CBD. The diagnosis of CBD is now established by (i) demonstrating a beryllium-specific immune response, using the blood, or preferably, BAL BeLPT and (ii) pathologic changes consistent with CBD (20,74,78). In circumstances in which bronchoscopy is not being performed, the presence of a beryllium-specific immune response plus chest X ray or CT scan demonstration of changes consistent with CBD is sufficient evidence. By using an immunologic diagnostic criterion, patients who have little apparent history of beryllium exposure and who are at early stages of CBD can be detected. Early detection may improve disease prognosis. As with any diagnostic test, false-negative and false-positive results occur. For example, the results of the BAL and the BAL BeLPT may be affected by smoking tobacco, and the test is not 100% sensitive (22,83,168). In cases in which the blood and BAL BeLPT are equivocal or thought to be falsely negative, and in which there is strong need to confirm the diagnosis, beryllium patch testing can be used, although with some associated risk of inducing sensitization or aggravating CBD (74,126,127).
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Occasionally, an individual may be found to have abnormal blood BeLPTs, an abnormal BAL BeLPT, and BAL lymphocytosis but non-diagnostic lung biopsies. Diagnostic yield is improved by taking 6 to 10 transbronchial biopsies and requesting pathologists to cut extra sections through the tissue specimens. G.
Natural History
The clinical course of CBD is quite variable. While some individuals remain stable clinically for many years, most experience a gradual worsening of symptoms and physiologic dysfunction. Another subset of patients suffers a rapidly progressive debilitating course, ultimately developing respiratory failure within a few years of diagnosis. Historical mortality rates range from 5% to 38% and may be related to type of exposure (59,61,169). Individuals continue to die as a result of CBD today, although the current mortality rate is unknown. In general, CBD worsens if not treated. Occasionally, some cases may show spontaneously improved chest radiograph infiltrates or gas exchange after reduction or cessation of exposure (170,171). Removal from exposure and medical treatment are recommended, although the long-term impact of these interventions is unknown. The detection of CBD at an early stage may improve our ability to intervene early and change the natural history of disease. H.
Treatment and Follow-up
Unfortunately for current cases, there is no known cure for CBD. The goals of treatment are to reduce morbidity and mortality by inhibiting inflammation and slowing disease progression. Removal from exposure is recommended, although formal scientific evidence that removal from exposure changes the course of disease is limited. Corticosteroids are the first-line therapy for CBD, although they have never been tested conclusively in a randomized fashion or against a control population. Nonetheless, well-conducted clinical observational studies have shown the efficacy of corticosteroids in reducing symptoms of CBD and improving lung function, as well as relapse with steroid discontinuation (149,172–185). It is not known if corticosteroid treatment changes the course of early CBD. Before initiating corticosteroid therapy, a baseline evaluation should be performed, consisting of chest radiograph, thin-section CT, and complete PFTs including lung volumes, spirometry, DLCO, and exercise testing, with arterial blood gas measurements or pulse oximetry. Indications for treatment include (i) severe symptoms, such as debilitating cough or dyspnea; (ii) abnormal gas exchange, diminished exercise tolerance, or abnormal pulmonary physiology; (iii) progressive decline in these tests of impairment; or (iv) evidence of pulmonary hypertension or cor pulmonale. Initial corticosteroid therapy should be similar to that used in sarcoidosis: oral prednisone
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(or an equivalent) at a dose of approximately 40 mg either daily or on alternate days. After three to six months, the response to therapy should be reassessed objectively and the prednisone dose tapered gradually to the minimum dose required to sustain objective and symptomatic improvement. Therapy is usually continued lifelong, because disease relapses occur after steroid withdrawal (121–123). If corticosteroid therapy is not deemed necessary to treat disease, followup examination and objective testing should be performed on a yearly basis to monitor disease progression. Because of the need for lifelong treatment, patients should be informed of the long-term side effects of corticosteroids and be monitored and treated for consequences such as hypertension, hyperglycemia, osteoporosis, and cataracts. In addition to glucocorticoid therapy, more severe cases may require additional supportive measures. Supplemental oxygen should be prescribed as needed to improve hypoxemia and treat pulmonary hypertension of cor pulmonale. Diuretics may by necessary to treat significant right heart failure. Symptomatic obstructive physiology and cough may respond to inhaled bronchodilators and inhaled steroids, although their use has not been systematically studied. As in other chronic illnesses, regular immunizations should be administered to prevent influenza, pneumococcal, and herpes zoster infections. Antibiotics may be needed to treat episodes of infection. In those patients who fail to respond to corticosteroids or who experience severe side effects, other immunosuppressive agents may prove effective. For example, as in sarcoidosis, methotrexate (up to 20 mg orally per week) has a steroid-sparing effect in CBD. Because CBD is associated with high levels of beryllium-induced TNF-a cytokine production, it is possible that anti-TNF-a antibody treatment (e.g., infliximab) may prove beneficial for steroid-dependent patients. A proof of concept clinical trial of this medication is being conducted in CBD patients. Patients who are beryllium sensitized without granulomatous disease should be followed for evidence of CBD on average every two years, because of the risk of progression to disease. I.
Compensation
As for any occupational illness or injury, it is incumbent upon the diagnosing clinician to make patients aware that they have been diagnosed with a workrelated illness and that this may qualify them for workers’ compensation benefits. These benefits vary state to state and country to country. In the United States, patients with beryllium sensitization, CBD or lung cancer who have worked around beryllium at a U.S. Department of Energy site may qualify for a special compensation program under the Energy Employees Occupational Illness Compensation Act (EEOICPA) and should be encouraged to contact the U.S. Department of Labor.
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152. Wilson SA. Delayed chemical pneumonitis or diffuse granulomatosis of the lung due to beryllium. Radiology 1948; 50:770–779. 153. Robert AG. A consideration of the roentgen diagnosis of chronic pulmonary granulomatosis of beryllium workers. AJR 1950; 63:467–487. 154. Weber AL, Stoeckle JD, Hardy HL. Roentgenologic patterns in long-standing beryllium disease; report of 8 cases. Am J Roentgenol Radium Ther Nucl Med 1965; 93:879–890. 155. Newman LS, Buschman DL, Newwll JD Jr., et al. Beryllium disease: assessment with CT. Radiology 1994; 190(3):835–840. 156. Harris KM, McConnochie K, Adams H. The computed tomographic appearances in chronic berylliosis. Clin Radiol 1993; 47(1):26–31. 157. Akira M. High-resolution CT in the evaluation of occupational and environmental disease. Radiol Clin North Am 2002; 40(1):43–59. 158. Naccache JM, Marchand-Adam S, Kambouchner M, et al. Ground-glass computed tomography pattern in chronic beryllium disease: pathologic substratum and evolution. J Comput Assist Tomogr 2003; 27(4):496–500. 159. Newman LS. Beryllium disease and sarcoidosis: clinical and laboratory links. Sarcoidosis 1995; 12(1):7–19. 160. Kelley WN, Goldfinger SE, Hardy HL. Hyperuricemia in chronic beryllium disease. Ann Intern Med 1969; 70(5): 977–983. 161. Deodhar SD, Barna B, Van Ordstrand HS. A study of the immunologic aspects of chronic berylliosis. Chest 1973; 63(3):309–313. 162. Newman LS, Orton R, Kreiss K. Serum angiotensin converting enzyme activity in chronic beryllium disease. Am Rev Respir Dis 1992; 146(1):39–42. 163. Sprince NL, Kazemi H, Fanburg BL. Sarcoidosis and other granulomatous diseases. In: Jones-Williams W, Davies BH, eds. Serum Angiotensin 1-Converting Enzyme in Chronic Beryllium Disease. Cardiff: Alpha Omega Publishing, 1980: 287–300. 164. Farris GM, Newman LS, Frome EL, et al. Detection of beryllium sensitivity using a flow cytometric lymphocyte proliferation test: the Immuno-Be-LPT. Toxicology 2000; 143(2):125–140. 165. Milovanova TN, Pompa SH, Cherian S, et al. Flow cytometric test for beryllium sensitivity. Cytometry B Clin Cytom 2004; 60(1):23–30. 166. Freiman DG, Hardy HL. Beryllium disease: the relation of pulmonary pathology to clinical course and prognosis based on a study of 130 cases from the U.S. Beryllium Case Registry. Hum Pathol 1970; 1:25–44. 167. Dutra FR. The pneumonitis and granulomatosis peculiar to beryllium workers. Am J Pathol 1948; 24:1137–1165. 168. Stokes RF, Rossman MD. Blood cell proliferation response to beryllium: analysis by receiver-operating characteristics. J Occup Med 1991; 33(1):23–28. 169. Peyton MF, Worcester J. Exposure data and epidemiology of the beryllium case registry, 1958. AMA Arch Ind Health 1959; 19(2):94–99. 170. Sprince NL, Kanarek DJ, Weber AL, et al. Reversible respiratory disease in beryllium workers. Am Rev Respir Dis 1978; 117(6):1011–1017. 171. Nishikawa S, Hirata T, Kitaichi M, et al., Sarcoidosis and other granulomatous diseases. In: Jones-Williams W, Davies BH, eds. Three Years Prospective Study on Mantoux Reactions in Factory Workers Exposed to Beryllium Oxide. Cardiff: Alpha Omega, 1980:722–727.
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172. Kennedy BJ, Pare JA, Pump KK, et al. The effect of adrenocorticotropic hormone on beryllium granulomatosis; a preliminary report. Can Med Assoc J 1950; 62(5): 426–428. 173. Thorn GW, Forsham PH, Frawley TF, et al. The clinical usefulness of ACTH and cortisone. N Engl J Med 1950; 242(22):865–872. 174. DeNardi JM. Chronic pulmonary interstitial granulomatosis: preliminary report on two patients treated with ACTH. AMA Arch Ind Hyg Occup Med 1951; 3:543–546. 175. Hardy HL. General discussion on the treatment of chronic beryllium poisoning with ACTH and cortisone. Arch Ind Hyg Occup Med 1951; 3:629–630. 176. Kennedy BJ, Pare JA, Pump KK, et al. Effect of adrenocorticotropic hormone (ACTH) on beryllium granulomatosis and silicosis. Am J Med 1951; 10(2):134–155. 177. Wright GW. Interpretation of results of ACTH and cortisone therapy in chronic beryllium poisoning; data obtained by pretherapy and postherapy studies of pulmonary function. AMA Arch Ind Hyg Occup Med 1951; 3(6):617–621. 178. Hardy HL. Epidemiology, clinical character, and treatment of beryllium poisoning; progress report. AMA Arch Ind Health 1955; 11(4):273–279. 179. Denardi JM. Long-term experience with beryllium disease. AMA Arch Ind Health 1959; 19(2):110–116. 180. Gaensler EA, Verstraeten JM, Weil WB, et al. Respiratory pathophysiology in chronic beryllium disease; review of thirty cases with some observations after longterm steroid therapy. AMA Arch Ind Health 1959; 19(2):132–145. 181. Hall TC, Wood CH, Stoeckle JD, et al. Case data from the beryllium registry. AMA Arch Ind Health 1959; 19(2):100–103. 182. Kline EM, Moir TW. Long-term experience with beryllium disease; a report of twenty patients. AMA Arch Ind Health 1959; 19(2):104–109. 183. Sood A, Beckett WS, Cullen MR. Variable response to long-term corticosteroid therapy in chronic beryllium disease. Chest 2004; 126(6):2000–2007. 184. Seeler AO. Treatment of chronic beryllium poisoning. AMA Arch Ind Health 1959; 19(2):164–168. 185. Dattoli JA, Lieben J, Bisbing J. Chronic beryllium disease. a follow-up study. J Occup Med 1964; 6:189–194. 186. Kreiss K, Day GA, Schuler CR. Beryllium:a modern industrial hazard. Annu Rev Public Health 2007; 28:259–277.
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11 Silicosis and Asbestosis
ARNOLD R. BRODY North Carolina State University, Raleigh, North Carolina, U.S.A.
I.
Introduction
Asbestos and silica are naturally occurring minerals that are mined in various forms for numerous commercial purposes (1,2). Asbestos ore breaks down into fiber forms with a crystalline backbone, while silica can be in crystalline or amorphous (noncrystal) particle form. Asbestos is divided mineralogically into the serpentine form known as chrysotile and the amphibole forms that include crocidolite and amosite. Chrysotile constitutes about 95% of the world’s use, and the amphibole fibers, approximately the other 5% (1). All the asbestos varieties have been established as causative agents of all the asbestos-induced diseases (i.e., scarring, lung cancer, and mesothelioma), while it is only the crystalline form of silica that causes disease (1,2). The diseases asbestosis and silicosis are characterized by increased amounts of connective tissue in the lung from inhaling asbestos fibers and silica crystals, respectively (1,2). While there are relatively few new cases of either disease presenting to clinics in North America, there are numerous cases developing in countries where fewer controls and good industrial hygiene are practiced. There are excellent reasons to consider the fundamental cellular and 317
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molecular mechanisms that mediate the diseases. First, asbestosis and silicosis afflict millions of individuals worldwide, and second, the genes that drive these diseases are common to other fibrogenic processes. Thus, if investigators can know how these diseases are initiated and then progress to clinical presentation, it may be possible to develop effective therapeutic approaches for these and other similar lung diseases where none exists now. In the pages that follow are descriptions of (i) our current understanding of the deposition patterns of inhaled particles, (ii) the fate of inhaled fibers and crystals in the lung, (iii) induction of expression of genes that mediate the fibrogenic diseases, and (iv) how gene expression dictates the patterns of clinical presentation of disease. II.
Deposition of Inhaled Particles
When animals or humans are exposed to aerosolized fibers or particles, some proportion of the inhaled materials will be deposited in the nasal passages and upper airways. Other particles reach the conducting airways, including the terminal bronchioles, and part of the disease process is manifested there. Finally, a proportion of the asbestos fibers or silica crystals is deposited on the alveolar epithelium. With every breath that contains particles, more are deposited along the respiratory tract, thus triggering a series of pathobiological responses. All the diseases caused by asbestos and silica are dose responsive, i.e., the more particles inhaled, the more likely it is that the disease will develop and the more advanced the disease will finally appear (2). The deposition pattern of the inhaled fibers and particles proved to be quite interesting when first described. Through the 1960s and 1970s, investigators found that inhaled particles deposited preferentially at airway bifurcations (3). This is so because airflow in the conducting airways is so rapid that particle deposition is dictated by such mechanisms as inertial impaction and interception (3). However, the initial deposition pattern at the alveolar level was only suspected since no one had actually viewed individual particles and quantified their distribution. This was an important problem to solve because it is on the alveolar surfaces that inhaled toxic particles initially induce membrane injury and initiate the fibrogenic process. The question was answered when brief, high concentration inhalation exposures were carried out with rats and mice (4,5). Prior to the empirical findings reported in these papers, it was assumed that inhaled fibers and particles would be deposited evenly across the alveolar surfaces since bulk flow of inspired air was reported to be quite slow distal to the conducting airways (6). Conversely, it was learned that inhaled fibers and crystals are deposited preferentially on the epithelial surfaces of the bronchiolaralveolar duct (BAD) junctions and the alveolar duct bifurcations (ADBs) (4,5,7). These findings have been quantified and repeated by several different laboratories. This deposition pattern has been demonstrated for chrysotile (4,5), crocidolite (8), and amosite (9) asbestos fibers as well as for iron spheres (5) and
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silica crystals (7). These observations instigated a rethinking of the concept of inspired airflow at the alveolar level since a preferential deposition pattern of particles requires significant airflow. Airway biologists considered the particle deposition patterns and determined that there must be some flow past the terminal bronchioles and that the mechanism through which the fibers and crystals are deposited is one of ‘‘interception’’ (6). As will be discussed in more detail below, this deposition pattern explains the histopathological pattern of asbestosis and silicosis reported in animal models and afflicted humans. III.
Pathobiological Responses
Once fibers and particles land on the airway and alveolar surfaces, the epithelial lining cells quickly respond. In the conducting airways, the mucociliary escalator rapidly transports the inhaled materials to the mouth where they can be swallowed or expectorated. This ‘‘fast’’ clearance compartment clears the great majority of inhaled particles within the first 24 hours post exposure, while the ‘‘slow’’ clearance compartment at the alveolar level retains a smaller proportion of the asbestos and silica (2). Upon deposition on the Type I alveolar epithelial cells, it is likely that the first pathobiological response is lipid peroxidation of plasma membranes. This response has been shown for chrysotile and crocidolite asbestos in vitro (2,10). It is also clear that membrane damage proceeds quickly from exposure to silica crystals that are well known as inducers of membrane injury (11–13). An early sequela of Type I cell injury is an ‘‘alveolar leak’’ (14,15). Only selected components of serum circulating through the alveolar capillary bed are normally allowed to filter through the endothelium and interstitium to the gas exchange surfaces (14–16). Complement components, certain antibodies, and some peptide growth factors are among the proteins found as normal transudates from serum (14,16,17). When there is damage to the Type I epithelium, larger proteins such as albumin and fibronectin move to the airspaces, and this can clearly lead to lung fibrosis if the condition persists. If the alveolar epithelium is not repaired, intersititial fibroblasts proliferate into the alveolar spaces, using the abnormal levels of serum exudates as a growth medium, producing an extracellular matrix that accumulates in the airspaces and interstitium and is known as pulmonary fibrosis (2,18). This process typically takes decades before it is recognized clinically. Thus, to understand what has happened in these lungs, we must go back to the point where the particles have been deposited and there is alveolar injury. First, there are the multiple fibers or crystals that have deposited on an alveolar epithelial surface (Fig. 1). Lipid peroxidation could ensue (as discussed above) but may be blunted by the alveolar lining layer, which is known to have a strong buffering effect on particle toxicity (16,19). Within the first hour after a particle lands on the Type I epithelium, this cell type responds by actively surrounding and actually phagocytizing the fibers or crystals (Fig. 2) (4,7). These cells
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Figure 1 (A) SEM of a TB in a rat. The TB bifurcates at the BAD junction (arrow), a site where large numbers of fibers are intercepted and early lesions develop. ADs open from the BAD junction and lead to the ADBs (*), another site where high levels of cell proliferation ensue and prominent lesions develop. Significantly increased expression of genes that mediate fibrogenesis were demonstrated by LCM at these key anatomic sites. (B) SEM of numerous chrysotile asbestos fibers (arrow heads) that have deposited on the epithelial surface of an AD bifurcation in a rat during one hour of exposure. These fibers injure the alveolar epithelial cells, activate complement that generates C5a, thus attracting numerous macrophages that participate in the development of the fibrogenic lesions. About 20% of these fibers will be actively transported to the interstitial space by the epithelial cells. Abbreviations: SEM, scanning electron micrograph; TB, terminal bronchiole; BAD, bronchiolar-alveolar duct; AD, alveolar duct; ADB, alveolar duct bifurcation; LCM, laser capture microdissection. Source: From Ref. 51.
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Figure 2 (A) SEM of an ADB 48 hours after exposure to chrysotile asbestos fibers. Many of the deposited fibers have been covered by the alveolar epithelium (arrows) and others have been phagocytized by AM. (B) Transmission electron micrograph of chrysotile asbestos fibers (arrow heads) that have been transported from the alveolar space (*), through the AE, and are about to be deposited in the underlying alveolar interstitium. An interstitial MC and adjacent extracellular collagen (C) are observed. Abbreviations: SEM, scanning electron micrograph; ADB, alveolar duct bifurcations; AM, alveolar macrophages; AE, alveolar epithelium; MC, mesenchymal cell.
are not ‘‘professional phagocytes,’’ but they use an actin-mediated mechanism to translocate the inhaled particles from the alveolar surfaces to the underlying connective tissue compartment (20). It has been calculated that approximately 20% of the asbestos fibers that deposit on alveolar surfaces are transported to the interstitial space (8,21). This number has not been determined for silica, but it appears that relatively fewer crystals reach the interstitial compartment.
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This may be the best juncture for a description of the two diseases, asbestosis and silicosis, to diverge. While the end product of exposure (i.e., diffuse scarring of the lung at the alveolar level) is the same, the basic cellular and molecular mechanisms that mediate the diseases, apparently, are not. There are a number of details available as inhaled asbestos fibers are followed through the sequence that leads to interstitial fibrosis. Fewer such details are reported for silicosis, but it is clear that this disease is immune mediated and will be described accordingly. A.
Asbestos
The asbestos fibers that have been deposited on alveolar surfaces rapidly (within the first few hours post exposure) activate the third component of complement (C3) by the alternative pathway, thus generating C5a, a potent chemoattractant for macrophages and neutrophils (14,22). Since there are essentially no polymorphs on normal alveolar surfaces, complement activation initially attracts only macrophages to the sites of asbestos deposition in several animal models of asbestosis (4,14,23,24). When neutrophils are sequestered in the alveolar capillary bed or in the interstitium because of an underlying infection or inflammatory event, the polymorphs quickly respond to C5a and migrate to the sites of asbestos deposition as well (unpublished observations), thus confirming the concept of directed migration to the alveolar surfaces mediated by C5a. In humans, asbestos-induced fibrogenic lesions include a variety of inflammatory cell types (25), both acute and chronic, because the fibrogenic responses progress through multiple phases of fiber deposition, chemotaxis, and cell injury over decades (see further discussion below). Lung macrophages in animals and humans normally reside on the alveolar epithelium [one or two cells per alveolar space in nonsmokers and dozens per space in cigarette smokers (26)] and in the interstitial compartment (26). There is also a population of intravascular macrophages in the lung (27). The alveolar and interstitial macrophages migrate rapidly along a chemotactic gradient that ends at the duct bifurcations where asbestos fibers have deposited with every breath. Thus, the very first lesions caused by asbestos fibers are a combination of epithelial injury, macrophage accumulation, fibroblast activation, and accumulation of extracellular matrix (28). The epithelial injury and macrophage accumulation occur within the first few hours post exposure, and the matrix increases have been measured within 48 hours (28). A consequence of asbestos-induced cell injury is a prominent increase in the number of cells proliferating in several anatomic compartments. The alveolar epithelium was dramatically affected, with the percent of dividing cells increasing up to 40-fold after three consecutive days of exposure (29,30). Surprisingly, the airway epithelium in this model also exhibited significant increases in dividing cells (31). The increase was not expected because there was no apparent injury to this epithelial population. However, other excellent models of
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asbestos-induced injury show alterations in the airway epithelium (32). When the numbers of dividing cells were evaluated depending on their distance from the developing lesions, it was clear that the closer a cell population was to the fibrogenic lesions at the duct bifurcations, the higher the number of proliferating cells (31). Indeed, when ultrastructural morphometric studies were carried out on asbestos-exposed rats, the closer a lesion was to the end of an airway, the larger it was because of more fibers deposited (33). Lesion development requires cell proliferation as the interstitial mesenchymal cells increase and the injured epithelium is repaired. Interestingly, small vessels coursing through and adjacent to the developing lesions exhibited increases in dividing endothelial and smooth muscle cells in the vascular intima (34). The result was thickened vessel walls in the asbestos-exposed animals and was one of the earliest suggestions that there must be an array of asbestos-induced cytokines that were emanating from the sites of deposition and mediating lesion development. Cell division, increased cell numbers, and increased matrix production are all caused by asbestos exposure and postulated to be the result of specific cytokines that are generated by a variety of cell types (2,35). The first cytokine to be identified in the developing lesions in the asbestos model was the peptide growth factor transforming growth factor alpha (TGFa) (36). This made sense since TGFa is well known as a powerful inducer of epithelial cell proliferation, and perhaps this was the factor responsible for the dramatic increases in epithelial proliferation as discussed above. In humans with asbestosis, a few growth factors were identified, but it was difficult to know the source of these agents. One named alveolar macrophage–derived growth factor (AMDGF) was identified as a potent growth factor for mesenchymal cells and turned out in part to be insulin-like growth factor (37). Another early factor identified was plateletderived growth factor (PDGF), and this was found in the developing lesions of the rodent model (38). To find just where TGFa and the PDGF isoforms were expressed in the lesions, investigators turned to the rat and mouse inhalation model and the powerful techniques of in situ hybridization (ISH) and immunohistochemistry (IHC). ISH allows specific genes to be identified at sites of expression, and if nonradioactive techniques are used, the resolution is sufficient to identify expression in specific cell types. IHC, as the name implies, uses specific antibodies to identify proteins in tissues. If ISH and IHC are used concurrently, gene expression and its coded protein can be identified simultaneously (38). In the asbestos model, TGFa, the PDGF isoforms, TGFb, and tumor necrosis factor alpha (TNFa) have been identified in various cells of the developing fibrogenic lesions. The role of several of these has been determined. For example, if mice with both receptors for TNFa knocked out are exposed to asbestos, the animals fail to develop the fibroproliferative lesions (39). These knockout (KO) mice also are resistant to the fibrogenic effects of bleomycin and silica (40). TGFb is well known as a potent inducer of collagen matrix by fibroblasts and myofibroblasts (41); thus, a central question was raised as to whether or not TGFb would induce interstitial fibrosis in the lungs of the TNFa
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KO mice. TGFb was identified by ISH and IHC in the asbestos model (42,43), overexpression of TGFb had been shown to produce pulmonary fibrosis in animal models (44,45), and the factor has been identified in a number of cases of human IPF (41). Thus, the question as to whether TGFb would mediate fibrosis in the TNFa KO mice was reasonable, and the results of the experiments clearly showed that TGFb itself, when overexpressed by means of an adenovirus vector, rapidly caused interstitial fibrosis (46). These studies raise a number of central questions about the specific roles of cytokines and peptide growth factors in controlling cell proliferation and matrix production. It appears that TNFa is a major component since this factor can induce the expression of other factors such as TGFb and PDGF (47,48). But TGFb clearly is essential inasmuch as blocking its expression with an antibody prevents fibrogenesis in the commonly used bleomycin model (49). In the real world, expression of TNFa may be required to initiate a cascade of events that includes production of the other factors, while experimentally, the cascade can be initiated or interrupted at a number of points along the way. Further experiments are required before it becomes clear just which factors drive the disease asbestosis. A relatively new method is available to provide quantitation of gene expression at specific anatomic sites. The technique, known as laser capture microdissection (LCM), is superior to ISH because genes expressed can be quantified by real-time polymerase chain reaction (RTPCR) (50). LCM has been used to great advantage with the asbestos inhalation model. In one study, genes coding for cell cycle proteins were demonstrated in airway epithelial cells after asbestos exposure (32). Recently, genes that code for the peptides likely to mediate asbestosis were quantified (51). These were the growth factors discussed above, TNFa, TGFb, and PDGF, as well as the genes coding for matrix metalloproteinase (MMP) 9 and alpha 1 procollagen, which is required for extracellular matrix deposition. As expected, results showed that the highest levels of gene expression were at the sites of fiber deposition and lesion development (51). What could not be predicted was if LCM would reveal an in situ dose response of gene expression, i.e., would the BAD junctions, where the highest numbers of fibers are deposited and the most prominent lesions develop, exhibit the highest levels of expression followed by the first ADBs and then the second ADBs? The results at the BAD junctions and ADBs were compared with normal tissues from unexposed mice and with areas of the lung where fewer asbestos fibers are deposited initially, i.e., the airway walls and pleura. Results showed that expression at the BAD junctions was always higher for each of the genes than at any other anatomic site. The first ADBs were always higher than the second, and the bifurcations were higher than the airway walls and pleura, which, in turn, were generally significantly higher than normal, unexposed tissues. Finally, mice exposed to asbestos for three consecutive days exhibited significantly higher levels of gene expression at the BAD junctions and ADBs than animals exposed for two days. This appeared to be the first evidence in situ of a dose response to inhaled toxic fibers (51). Such findings could be instrumental in establishing
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potential therapeutic targets if it becomes clear that the gene products are indeed playing a role in disease development. Clinical asbestosis in humans can be diagnosed microscopically by radiographic findings and/or with a combination of exposure history along with signs and symptoms (52). The earliest functional change typically is shortness of breath from the interstitial scar tissue that causes a stiff lung and a restrictive pattern of dysfunction (2,52). The scarring also can occur within the alveolar capillary membranes, causing abnormalities in gas diffusion that commonly are exhibited in individuals with clinical asbestosis. The histopathological pattern seen in asbestosis appears just as one would predict on the basis of what has been demonstrated in the animal models, i.e., the earliest lesions develop closest to the ends of the terminal bronchioles, and over time, the lesions progress peripherally, finally coalescing decades later as severe asbestosis, which is seen on X-rays as linear opacities primarily in the lower lung zones (25,52). B.
Silica
There are similarities between the fibrogenic diseases caused by asbestos and silica, but there are clear differences as well. As discussed above, the initial deposition patterns of silica crystals are the same as asbestos fibers, producing fibrogenic lesions at the duct bifurcations. However, the development of these lesions clearly is mediated by immune mechanisms, separating the fundamental processes from those that drive asbestosis. Silicotic lesions are characterized by accumulations of macrophages and lymphocytes that are aggregated around the crystalline silica particles. The lymphocyte populations are largely T cells of several phenotypes, particularly those expressing CD4 and CD8 (2,53). These cells have been recovered from lavage fluids and are localized in bronchialassociated lymphoid tissue (BALT) and in draining lymph nodes (53). When the lymphocytes are separated from these sources in both humans and animal models, the cells are ‘‘activated,’’ expressing interleukin 2 receptors and undergoing spontaneous mitogenesis (54). The silicotic lesions that are chronic in afflicted individuals and animal models take on a nodular appearance, thus clearly separating the histopathological features of this disease from asbestosis (2). Because of the prominence of the lymphocyte populations and macrophages-containing particles, the nodules can have some features similar to the noncaseating granulomas of hypersensitivity pneumonitis. However, the nodules typically contain large numbers of birefringent crystals that can be readily seen with polarizing miscroscopy, thus aiding in the diagnosis (2,53). The lymphocytes associated with nodule formation exhibit largely a T-helper (Th)-1 phenotype, and several investigators have proposed that such cells would be likely to produce interferon gamma (IFNg) (53,55). This potent cytokine has a number of biological effects and is known to produce the activated state in T lymphocytes (53,54).
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A series of papers from the laboratory of G. Davis has elucidated several of the fundamental questions regarding the mechanisms of silicosis using mice that have inhaled crystalline silica (53,55,56). As expected, based on the deposition pattern of the particles described above (7), the disease is dose dependent, and the silicotic lesions develop along the walls of small airways and the alveolar ducts. The mice produce increased levels of IL-1 and TNFa, and these cytokines are localized within the developing silicotic lesions (53). IFNg (but not IL-4) was increased in the animals, and most interesting was the finding that IFNg KO mice exhibited reduced disease (53). The investigators asked if the source of IFNg was from a single cell population that had expanded or from multiple lymphocyte phenotypes that are present during the development of silicosis. The latter scenario was found to be true and strongly suggested that IFNg is the key cytokine in mediating silicosis. This is a reasonable postulate since lung macrophages are the initial responders to inhaled silica, and these cells are known to be stimulated by the crystals, consequently producing the Th-1 cytokines that mediate lymphocyte activation. These expanded lymphocytes then produce IFNg and the other inflammatory mediators that lead to the chronic fibrosis known as silicosis (53). It has been suggested that therapies directed at interrupting expression of IFNg will prevent the development of silicosis. The clinical presentation of silicosis usually begins with cough and perhaps shortness of breath (2). The X-ray findings from the dense scarring are primarily in the upper lung zones, but all regions of the lung can be involved. ‘‘Simple Silicosis’’ means that the pattern of disease is nodular, where the nodules described above have not coalesced and remain the discrete entities described above as seen microscopically (2). Another form of silicosis is ‘‘acute silicosis,’’ where very high concentrations of silica are inhaled over relatively brief periods, producing large amounts of pulmonary edema and rapidly progressing fibrosis (2). Complicated silicosis or ‘‘progressive massive fibrosis’’ ensues when large (greater than 1 cm) silicotic nodules have coalesced across lung zones, again when very high doses of dust are inhaled. Individuals with simple silicosis apparently can remain asymptomatic for many years, and pulmonary function tests show that typical findings are limitations in airflow, again separating silicosis from the restrictive defects caused by asbestosis (1,2). The microscopic nodular pattern of silicosis that results in these clinical features is more difficult to understand than the pattern of asbestosis. As described above, the lesions of asbestosis develop just as one would predict from the deposition pattern of the fibers. While it is clear that initial deposition of silica crystals is essentially the same as fibers, there is an airway component of the disease that is not understood on the basis of this deposition pattern. Thus, fibrosis of the alveolar walls could proceed through the rapid generation of oxygen radicals that are highly cytotoxic to epithelial cells and responding macrophages, and then there would be an influx of chronic inflammatory cells like the lymphocyte populations described above. However, silica crystals are found embedded along the airway walls. They must be taken up by epithelial
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cells and transported to the submucosa where they can be entrained in the BALT and induce the immune-mediated mechanisms described above. C.
Reactive Oxygen Species
Hopefully it was clear why a discussion of the processes leading to asbestosis and silicosis needs to be divided at some point. However, this is now a juncture where the disease mechanisms can come together again. There is very good evidence to suggest that reactive oxygen species (ROS) generated by asbestos fibers and silica crystals play fundamental roles in the generation of disease (2). All the asbestos varieties generate ROS because they contain iron (Fe II) in their basic mineral structure or accumulate iron from the environment (including biological fluids) (57). Crystalline silica is a well-known source of ROS, and the generation of radicals is enhanced on newly fractured crystal surfaces (11). Noncrystalline particles like titanium dioxide or carbonyl iron spheres fail to generate toxic levels of ROS. When asbestos fibers and silica crystals are inhaled and they deposit on the alveolar surfaces, the iron in the particles can reduce molecular oxygen to superoxide, which is dismutated to hydrogen peroxide (H2O2) (58). H2O2 in the presence of superoxide anions in turn can rapidly react in the presence of iron to form highly active hydroxyl radicals (OH–). This socalled ‘‘Fenton’’ reaction has been described by several groups and is known to be the source of ROS that injure cells and cause genetic damage (57,58), and both asbestos and silica are established human carcinogens (2). Interestingly, ROS also have been shown to activate TGFb from its latent form (LTGFb) to the bioactive molecule (59). Chrysotile and crocidolite asbestos were used in vitro to generate ROS through the Fenton reaction and ‘‘activate’’ TGFb (59). TGFb normally is produced by a variety of cell types bound to a latent-associated peptide (LAP) that prevents the TGFb from binding to its cell surface receptors (60). It was determined that ROS cause alterations in amino acid components of the LAP, thus preventing its annealing with the TGFb molecules and allowing the TGFb to be biologically active (59). This process of activation was also shown to be a mechanism through which TGFb is activated on alveolar surfaces consequent to asbestos exposure. In this model, mice were treated with an adenovirus vector that overexpresses LTGFb, which was strongly expressed in the lung and was spread along the alveolar surfaces. Since LTGFb was ‘‘latent,’’ it caused no fibrogenesis. When these animals were subsequently exposed to aerosolized chrysotile asbestos fibers, there was significant activation of the LTGFb, binding of the active TGFb to membrane receptors, and clearly enhanced development of asbestos-induced lesions from the abundant active TGFb (Pociask and Brody, unpublished observations). Receptor binding was shown by increases in STAT3 phosphorylation, and asbestos-induced lesions were compared with those in animals exposed to asbestos alone. We have proposed this as a fundamental mechanism through which particles that generate ROS can activate TGFb on alveolar surfaces, thus mediating pulmonary
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fibrogenesis (i.e., asbestosis and silicosis). It is clear in other models of asbestosis and silicosis that antioxidants are effective blockers of the fibrogenic process, thus demonstrating the central role of these mechanisms in the development of disease (2).
IV.
Summary
Much has been learned about the fundamental mechanisms of asbestosis and silicosis over the past few decades. We now have a paradigm that explains the development of these diseases starting with (i) a particle deposition pattern that explains the histopathological picture, (ii) cell injury through lipid peroxidation and/or generation of ROS by the particles, and (iii) upregulation of genes that code for a number of growth factors and cytokines that control proliferation and fibrogenesis. Here the processes of asbestosis and silicosis diverge because cytokines-elaborated consequent to silica exposure attract a significant population of Th-1 lymphocytes that invoke immune-mediated pathways. The disease mechanisms appear to merge again when factors such as TGFb, produced by epithelial cells, macrophages, and fibroblasts induce interstitial fibroblasts to produce an extracellular matrix. When chronic exposure to the particles produces clinical disease, there are no apparent effective treatments. The animal models suggest several points to target therapeutic approaches since antioxidants blunt both asbestosis and silicosis, and knocking out TNFa expression blocks both diseases as well. It seems most likely that effective treatments will require the use of silencing RNAs and vectors or small molecules that target expression of specific genes.
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8. Roggli VL, George MH, Brody AR. Clearance and dimensional changes of crocidolite asbestos fibers isolated from lungs of rats following short-term exposure. Environ Res 1987; 42(1):94–105. 9. Donaldson K, Brown DM, Miller BG, et al. Bromo-deoxyuridine (BRDU) uptake in the lungs of rats inhaling amosite asbestos or vitreous fibres at equal airborne fibre concentrations. Exp Toxicol Pathol 1995; 47(2–3):207–211. 10. Gendek EG, Brody AR. Changes in lipid ordering of model phospholipid membranes treated with chrysotile and crocidolite asbestos. Environ Res 1990; 53(2): 152–167. 11. Vallyathan V, Shi XL, Dalal NS, et al. Generation of free radicals from freshly fractured silica dust: potential role in acute silica-induced lung injury. Am Rev Respir Dis 1988; 138(5):1213–1219. 12. Wiessner JH, Henderson JD Jr., Sohnle PG, et al. The effect of crystal structure on mouse lung inflammation and fibrosis. Am Rev Respir Dis 1988; 138(2):445–450. 13. Driscoll KE. In vitro evaluation of mineral cytotoxicity and inflammatory activity. In: Guthrie GD Jr., Mossman BT, eds. Health Effects of Mineral Dusts. Washington: Mineralogical Society of America, 1993:489–512. 14. Warheit DB, Hill LH, George G, et al. Time course of chemotactic factor generation and the corresponding macrophage response to asbestos inhalation. Am Rev Respir Dis 1986; 134(1):128–133. 15. Merrill WW, Goodenberger D, Strober W, et al. Free secretory component and other proteins in human lung lavage. Am Rev Respir Dis 1980; 122(1):156–161. 16. Khan MF, Gallagher JE, Brody AR. Effect of proteins and lipids of the alveolar lining layer on particle binding and phagocytosis. Toxic in Vitro 1990; 4(2):93–101. 17. Kistler GS, Caldwell PR, Weibel ER. Development of fine structural damage to alveolar and capillary lining cells in oxygen-poisoned rat lungs. J Cell Biol 1967; 32(3):605–628. 18. Lasky JA, Brody AR. Interstitial fibrosis and growth factors. Environ Health Perspect 2000; 108(suppl 4):751–762. 19. Emerson RJ, Davis GS. Effect of alveolar lining material-coated silica on rat alveolar macrophages. Environ Health Perspect 1983; 51:81–84. 20. Brody AR, Hill LH, Hesterberg TW, et al. Intracellular translocation of inorganic particles. In: Clarkson TW, Sager PR, Syverson TLM, eds. The Cytoskeleton: Target for Toxic Agents. New York: Plenum (Springer), 1986:221–227. 21. Roggli VL, Brody AR. Changes in numbers and dimensions of chrysotile asbestos fibers in lungs of rats following short-term exposure. Exp Lung Res 1984; 7(2): 133–147. 22. Warheit DB, George G, Hill LH, et al. Inhaled asbestos activates a complementdependent chemoattractant for macrophages. Lab Invest 1985; 52(5):505–514. 23. Warheit DB, Chang LY, Hill LH, et al. Pulmonary macrophage accumulation and asbestos-induced lesions at sites of fiber deposition. Am Rev Respir Dis 1984; 129(2): 301–310. 24. McGavran PD, Butterick CJ, Brody AR. Tritiated thymidine incorporation and the development of an interstitial lesion in the bronchiolar-alveolar regions of the lungs of normal and complement deficient mice after inhalation of chrysotile asbestos. J Environ Pathol Toxicol Oncol 1989; 9(5–6):377–391. 25. Craighead JE, Abraham JL, Churg A, et al. The pathology of asbestos-associated diseases of the lungs and pleural cavities: diagnostic criteria and proposed grading
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41. Khalil N, Bereznay O, Sporn M, et al. Macrophage production of transforming growth factor beta and fibroblast collagen synthesis in chronic pulmonary inflammation. J Exp Med 1989; 170(3):727–737. 42. Perdue TD, Brody AR. Distribution of transforming growth factor-beta 1, fibronectin, and smooth muscle actin in asbestos-induced pulmonary fibrosis in rats. J Histochem Cytochem 1994; 42(8):1061–1070. 43. Brass DM, Hoyle GW, Poovey HG, et al. Reduced tumor necrosis factor-alpha and transforming growth factor-beta1 expression in the lungs of inbred mice that fail to develop fibroproliferative lesions consequent to asbestos exposure. Am J Pathol 1999; 154(3):853–862. 44. Sime PJ, Xing Z, Graham FL, et al. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest 1997; 100(4):768–776. 45. Warshamana GS, Pociask DA, Fisher KJ, et al. Titration of non-replicating adenovirus as a vector for transducing active TGF-beta1 gene expression causing inflammation and fibrogenesis in the lungs of C57BL/6 mice. Int J Exp Pathol 2002; 83(4):183–201. 46. Liu JY, Sime PJ, Wu T, et al. Transforming growth factor-beta(1) overexpression in tumor necrosis factor-alpha receptor knockout mice induces fibroproliferative lung disease. Am J Respir Cell Mol Biol 2001; 25(1):3–7. 47. Sullivan DE, Ferris M, Pociask D, et al. Tumor necrosis factor-alpha induces transforming growth factor-beta1 expression in lung fibroblasts through the extracellular signal-regulated kinase pathway. Am J Respir Cell Mol Biol 2005; 32(4):342–349. 48. Warshamana GS, Corti M, Brody AR. TNF-alpha, PDGF, and TGF-beta(1) expression by primary mouse bronchiolar-alveolar epithelial and mesenchymal cells: tnf-alpha induces TGF-beta(1). Exp Mol Pathol 2001; 71(1):13–33. 49. Giri SN, Hyde DM, Hollinger MA. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice. Thorax 1993; 48(10):959–966. 50. Betsuyaku T, Griffin GL, Watson MA, et al. Laser capture microdissection and realtime reverse transcriptase/ polymerase chain reaction of bronchiolar epithelium after bleomycin. Am J Respir Cell Mol Biol 2001; 25(3):278–284. 51. Yin Q, Brody AR, Sullivan DE. Laser capture microdissection reveals doseresponse of gene expression in situ consequent to asbestos exposure. Int J Exp Pathol 2007; 88(6):415–425. 52. American Thoracic Society. Diagnosis and initial management of nonmalignant diseases related to asbestos. Am J Respir Crit Care Med 2004; 170(6):691–715. 53. Davis GS, Pfeiffer LM, Hemenway DR. Interferon-gamma production by specific lung lymphocyte phenotypes in silicosis in mice. Am J Respir Cell Mol Biol 2000; 22(4):491–501. 54. Kumar RK, Li W, O’Grady R. Activation of lymphocytes in the pulmonary inflammatory response to silica. Immunol Invest 1990; 19(4):363–372. 55. Davis GS, Pfeiffer LM, Hemenway DR. Expansion of interferon-gammaproducing lung lymphocytes in mouse silicosis. Am J Respir Cell Mol Biol 1999; 20(4):813–824. 56. Davis GS, Leslie KO, Hemenway DR. Silicosis in mice: effects of dose, time, and genetic strain. J Environ Pathol Toxicol Oncol 1998; 17(2):81–97.
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57. Kamp DW, Weitzman SA. The molecular basis of asbestos induced lung injury. Thorax 1999; 54(7):638–652. 58. Aust AE, Lund LG, Chao C-C, et al. Role of iron in the cellular effects of asbestos. Inhalation Toxicology 2000; 12:75–80. 59. Pociask DA, Sime PJ, Brody AR. Asbestos-derived reactive oxygen species activate TGF-beta1. Lab Invest 2004; 84(8):1013–1023. 60. Massague J. TGFbeta signaling: receptors, transducers, and Mad proteins. Cell 1996; 85(7):947–950.
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12 Idiopathic Pulmonary Fibrosis
JOSEPH P. LYNCH, III Department of Medicine, Division of Pulmonary and Critical Care Medicine, Clinical Immunology and Allergy, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
RAJA S. MAHIDHARA David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
MICHAEL C. FISHBEIN Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
MICHAEL P. KEANE St. Vincent’s University Hospital and University College, Dublin, Ireland
DAVID A. ZISMAN and JOHN BELPERIO David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
I.
Introduction
Idiopathic pulmonary fibrosis (IPF) is a distinct clinical syndrome of unknown cause characterized by progressive dyspnea, dry cough, basilar crackles, a restrictive ventilatory defect on pulmonary function tests (PFTs), and the histological pattern usual interstitial pneumonitis (UIP) on surgical lung biopsy (1,2). Cryptogenic fibrosing alveolitis (CFA) and IPF are synonymous terms (2). The histological pattern UIP is found in IPF (1,2), but may be observed in other etiologies as well [e.g., collagen vascular disease (CVD), asbestosis, and diverse occupational, environmental, or drug exposures] (2–4). In 2002, the American Thoracic Society (ATS) and European Respiratory Society (ERS) published a classification schema recognizing seven idiopathic interstitial pneumonias (IIPs) (Table 1) (5). IPF/UIP is the most common of the IIPs, comprising 47% to 71% cases; nonspecific interstitial pneumonia (NSIP) accounts for 13 to 48% (6–12). In this chapter, we focus on IPF. The remaining IIPs are discussed elsewhere in this book. 333
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Table 1 Classification of Idiopathic Interstitial Pneumonias Histological pattern Usual interstitial pneumonia (UIP) Nonspecific interstitial pneumonia (NSIP) Organizing pneumonia (OP) Diffuse alveolar damage (DAD) Repiratory bronchiolitis (RB) Desquamative interstitial pneumonia (DIP) Lymphoid interstitial pneumonia (LIP)
Clinical-radiological-pathological diagnosis Idiopathic pulmonary fibrosis (IPF)/ cryptogenic fibrosing alveolitis (CFA) NSIP (provisional) Cryptogenic organizing pneumonia (COP) Acute interstitial pneumonia (AIP) Respiratory bronchiolitis interstitial lung disease (RB-ILD) DIP LIP
Source: Adapted from Ref. 5.
II.
Clinical Features of IPF
IPF primarily affects older adults (>age 55 years) (2,13). A dry, hacking cough may be the presenting symptom and is often paroxymal (2,14,15). Exertional dyspnea progresses inexorably over months to years (2,15). Physical examination reveals bibasilar end-inspiratory velcro rales in >80% of the cases; clubbing is noted in 20% to 50% (2,15). Cyanosis and cor pulmonale are late features (2,15). Extrapulmonary involvement does not occur (2,15). PFTs reveal reduced lung volumes (VA), reduced diffusing capacity for carbon monoxide (DLCO), and impaired oxygenation (16). High-resolution computed tomographic (HRCT) scans reveal reticulation and honeycomb change (HC), with minimal or no ground-glass opacities (GGO) (17,18) (CT features are discussed later). Laboratory aberrations are nonspecific (2). The erythrocyte sedimentation rate (ESR) is elevated in >60% of patients; circulating antinuclear antibodies (ANA) or rheumatoid factor are present in 10% to 26% (2,15). These serological parameters do not correlate with the extent or activity of the disease and have no prognostic value (2,15). Elevations of the glycoprotein KL-6 (19,20) and the lung surfactant proteins (SP) A and D (21) have been noted in serum and bronchoalveolar lavage fluid (BALF) in patients with IPF, and may have prognostic value. These assays are available in only a few research laboratories and additional studies are required to assess their specificity and clinical role. A.
Natural History and Clinical Course of IPF
The onset of IPF is usually indolent, but the disease progresses inexorably over months to years, with progressive fibrosis and destruction of lung parenchyma (2,15). In some patients, the disease may remain stable for months to years, whereas the course in others is accelerated, resulting in fatal respiratory failure within 6 to 18 months (15,22). Spontaneous remissions do not occur (2,15).
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Mortality rates exceed 50% by 4 years; mean survival ranges from 2.8 to 3.9 years (2,7,8,15,23–25).
III.
Histopathological Features of Usual Interstitial Pneumonitis
A cardinal feature of UIP is geographic and temporal heterogeneity (1,26,27). The disease has a striking predilection for basilar and subpleural (peripheral) regions of the lung with relative sparing of bronchovascular bundles (i.e., geographic heterogeneity) (1,26,27). The patchy, heterogeneous nature of UIP can be appreciated on low-power magnification (26) (see Chapter 4 for illustrative photomicrographs of UIP). In UIP, areas of normal lung, fibroblastic foci (FF) [aggregates of proliferating fibroblasts (FBs) and myofibroblasts], and HC (endstage fibrosis) are present concomitantly (i.e., temporal heterogeneity) (1,26,27). By contrast, other IIPs are temporally uniform (i.e., changes appear to have occurred over a single, relatively narrow time span) (1,8,26). FF are prominent in UIP and consist of spindle-shaped myofibroblasts within a pale-staining matrix that bulges into adjacent air spaces (1,26,27). FF are believed to represent areas of active, ongoing lung injury and are infrequent or absent in other IIPs (1,26,27). Patchy alveolar septal infiltrates of mononuclear cells and scattered lymphoid follicles may be present in UIP (1,2,5,26,27), but dense inflammation suggests an alternative diagnosis such as cellular NSIP, desquamative interstitial pneumonitis (DIP), hypersensitivity pneumonia (HP), etc. (8,26,27). HC is an essential feature for UIP (1,26). HC cysts are dilated bronchioles (often containing mucus and leukocytes) with thickened fibrous walls lined by bronchiolar epithelium (26). HC cysts may be observed in any end-stage lung disorder but are infrequent or absent in the other IIPs (1). Additional features of UIP include destroyed and disrupted alveolar architecture, traction bronchiectasis and bronchioloectasis, metaplasia and hyperplasia of type II pneumocytes, and pulmonary hypertensive changes (smooth muscle hyperplasia, vascular remodeling) (1,8,26). Additionally, ‘‘acute exacerbations’’ of IPF reveal diffuse alveolar damage (DAD), hyaline membranes, and foci of organizing pneumonia superimposed upon a background of UIP (28,29). The histological diagnosis of UIP requires a surgical lung biopsy, preferably with wedge biopsies from two or three sites (26,27). Care should be taken to avoid the worst areas (i.e., advanced HC). Optimally, a wedge biopsy with areas of normal lung and fibrosis is required to substantiate the diagnosis of UIP (26). The histological features of UIP overlap with NSIP (NSIP is discussed in detail elsewhere by Dr. Flaherty and colleagues in this book). However, in contrast to UIP, NSIP exhibits temporal homogeneity (8,30). Further, inflammation can be intense in some cases of NSIP (e.g., cellular NSIP) (8,27,30,31). Foci of organizing pneumonia or non-necrotizing granulomas are occasionally observed
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in NSIP (30) but are not found in UIP (1). However, discriminating UIP from fibrotic NSIP is difficult, even by expert pulmonary pathologists (6,9,11,32). In fact, both UIP and NSIP patterns may be present in individual patients (9,10,27,32).
IV.
Epidemiology
Idiopathic pulmonary fibrosis is rare, but precise data regarding incidence and prevalence are lacking (13,25,33). Most population-based epidemiological surveys were based on clinical diagnosis, death certificates, or diagnostic coding, and lacked histological confirmation; such studies included a mixture of interstitial lung diseases (ILDs), including disorders other than UIP (13,34–37). Studies from Europe (25,34,35,37) and Japan (36) cited prevalence rates of IPF ranging from 3 to 8 cases per 100,000. A retrospective study of IPF in New Zealand cited a lower incidence in those of Maori or Polynesian descent than in those of European descent (38). In the United States, prevalence rates range from 13 to 42 cases per 100,000 (13,33). The incidence of IPF may be increasing. The incidence of IPF increased progressively in the United Kingdom between 1991 and 2003 (25). Similarly, in the United States, deaths attributed to pulmonary fibrosis increased significantly from 1992 to 2003 (>28% increase) (39). The incidence of IPF is much higher in the elderly and males (13,33,36,39–41). Idiopathic UIP is rare in children or adults less than 40 years old (2,42,43). A.
Risk Factors for IPF
The cause of idiopathic UIP is unknown, but environmental and occupational exposures likely plan an etiological role in some cases (44–46). IPF is more common in current or former smokers (15,34,36,44,47,48). Risk factors in some studies include exposure to dusts or metals (34,36), organic solvents (36,49), and residence in agricultural or polluted urban areas (34,36,40,41). However, a study from the British Isles found no evidence for an increased risk of IPF among individuals exposed to wood or metal dusts (35). In that study, excess mortality due to IPF was noted in electricians, electrical engineers, firemen, and cleaners (occupations associated with exposure to potentially toxic fumes or chemicals) (35). A meta-analysis of six case-control studies found six exposures associated with IPF: ever smoking, agriculture farming, livestock, wood dust, metal dust, and stone/sand (44). Several studies cited increased levels of minerals in lung tissue from patients with ‘‘idiopathic’’ interstitial pneumonias (50,51), suggesting that at least some cases of ‘‘idiopathic’’ UIP likely represent pneumoconioses. The considerable variability that exists in the development of pulmonary fibrosis among workers exposed to similar concentrations of fibrogenic/ organic dusts implies that genetic factors are likely important in modulating the lung injury (44).
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Gastroesophageal Reflux as Cause of IPF
Chronic aspiration secondary to gastroesophageal reflux disease (GERD) is a possible cause (or contributory factor) in the pathogenesis of IPF (52–55), but this relationship is controversial. Pulmonary fibrosis is a common complication of systemic sclerosis (scleroderma), a disorder with an extremely high prevalence of esophageal dysmotility (56). A case-control study of >200,000 U.S. veterans noted an increased risk of IPF among patients with erosive esophagitis (odds ratio of 1.36) (57). Esophageal reflux has been noted in more than twothirds of patients with end-stage lung disease (including IPF) awaiting lung transplantation (LT) (53–55,58). Importantly, 30% to 50% of IPF patients with GERD have no symptoms of reflux (53,54,58). Further, severity of IPF does not correlate with GERD severity (53,54). Additional studies are required to assess the role of GERD or aspiration in the pathogenesis or progression of IPF.
V.
Pathogenesis of IPF
The pathogenesis of IPF is complex and likely involves myriad components (59–61) including repetitive lung injury [particularly to alveolar epithelial cells (AECs)] (62), destruction of subepithelial basement membranes (BMs), inflammation, cytokines and chemokines (63), exaggerated deposition of collagen and extracellular matrix (64), recruitment and proliferation of FBs (65,66), inappropriate wound-healing response (64), and excessive angiogenesis (67). A.
Genetic Factors in the Pathogenesis of IPF
Several lines of evidence suggest that genetic factors are important in the pathogenesis of IPF (42,68–72). Clusters of interstitial pneumonias/fibrosis in families [i.e., familial interstitial pneumonia (FIP)] have been noted in 0.5% to 3.7% of patients with IPF (68,71,72). FIP has an autosomal dominant pattern of inheritance with variable/reduced penetrance (68,69,71,73). Familial interstitial pneumonitis (IP) is indistinguishable from nonfamilial (sporadic) IPF, but patients tend to be younger with the familial variant (71). Interestingly, multiple types of interstitial pneumonias have been noted in familial IP [e.g., UIP, NSIP, DIP, and cryptogenic organizing pneumonia (COP)] (69,74). The largest study of FIP involved 111 families with 309 affected and 360 unaffected individuals (69). Consistent with previous studies of nonfamilial (sporadic) IPF, old age, male sex, and ever cigarette smoking were risk factors for FIP. Among 78 patients with histologically confirmed FIP, histological patterns included UIP (86%), NSIP (10%), COP (2.5%), and unclassified (1.3%) (69). Interestingly, 45% of pedigrees exhibited more than one histological pattern among affected family members (69). Gene expression profiles of lung tissues from patients with familial IP (either UIP or NSIP) exhibit striking similarities but differ from gene expression profiles in sporadic IPF (75–77). Overall, these genes generally
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encode proteins involved in chronic inflammation (i.e., chemokines, complement, and immunoglobulins), smooth muscle markers (i.e., smooth muscle cells and myofibroblast), and matrix mobilization and resolution (75–77). Mutations in the gene SFTPC for surfactant protein C (SP-C) are also associated with FIP (including UIP, NSIP, and DIP) (74,78–81). These studies suggest that SP-C deficiency or abnormal protein folding/function causes lung inflammation (i.e., NSIP and DIP) and lung fibrosis (i.e., UIP). Mechanistically, this may involve direct injury to the AECs and adjacent endothelium causing inflammation and fibrosis. Another mechanistic possibility is that the lack of surfactant or abnormal surfactant can produce alveolar collapse with shear stress/cell fracturing caused by abnormal opening and closing of alveoli (similar to ventilator-induced lung injury) (82). Recently, germline mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase, and telomerase RNA were implicated in dyskeratosis congenita, a rare hereditary disorder associated with premature death from aplastic anemia and pulmonary fibrosis (83). These mutations result in telomere shortening, which limits the replicative capacity of tissues and has been implicated in age-related disease (84). Interestingly, older age and smoking, two risk factors for IPF, also cause telomere shortening (83). This suggests that short telomeres may cause injury to lung cells (i.e., leukocytes, AECs, and FBs), thereby initiating an inflammatory response, which leads to lung fibrosis. Pulmonary fibrosis may also complicate diverse genetic disorders such as Hermansky-Pudlak syndrome (85), familial SP-C mutation (42,74,78,79), familial hypocalciuric hypercalcemia (86), neurofibromatosis (87), etc. Differences in susceptibility to fibrogenic agents may reflect genetic polymorphisms (68,70,88,89). Animal models involving different inbred strains of rodents demonstrate dramatic variability in their lung inflammatory/fibrotic response to injurious agents (88,90,91). The above studies suggest that IPF is a heterogeneous disorder caused by a number of environmental/occupational exposures in combination with genetic predispositions (Fig. 1). Multiple conclusions can be drawn from these studies. The first is that a genetic predisposition and the impact of smoking increase the risk of FIP (69) and suggest that the ‘‘multiple hits’’ hypothesis of redundant/recurrent injuries lead to persistent inflammation and eventual fibrosis (Fig. 1). Second, the finding of different pathological forms of IIP occurring in different members within the same family (i.e., with a mutation in a single dominant gene) (69,74,80) suggests that a common central mechanism is operative within each family and that the different phenotypes (i.e., inflammation–COP, DIP, NSIP vs. fibrosis–UIP) are influenced by the timing of diagnosis and clinical expression (i.e., early–inflammation ? NSIP and late–fibrosis ? UIP). Third, similar gene profiles from lung tissue of FIP patients with UIP and NSIP (75) suggest that NSIP may represent an early form of UIP. Additional studies are warranted, however, regarding the relationship of IPF and other IIPs. The importance of genetic factors in the incidence and clinical expression of IPF is discussed in detail by Drs. Woodhead and du Bois in chapter 3.
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Figure 1 Multiple environmental factors in combination with a genetic predisposition may cause pulmonary fibrosis. Multiple ‘‘hits’’ may be required to develop pulmonary fibrosis [(i) injury and (ii) a genetic predisposition]. The genetic predisposition allows lung injury to cause aberrant biochemical changes in which leucocytes and nonleukocytes release enormous amounts of profibrotic mediators in combination with an overzealous/ persistent immune response. Ultimately the lung remodeling mechanism ends in fibroplasia/fibrosis.
B.
Mechanisms of Lung Injury and Fibrosis in IPF
The pathogenesis of IPF is likely initiated by injury of AECs and destruction of subepithelial BMs (61,62). Recruitment and proliferation of FBs are critical events (66,92). Areas of rapidly proliferating myofibroblasts and FBs (i.e., fibroblastic foci) situated adjacent to sites of AECs and basal membrane damage are the primary sites of injury and repair (66,92). Soluble mediators secreted by cells in the surrounding milieu stimulate FB recruitment and proliferation. These include tumor necrosis factor a (TNF-a), transforming growth factor b (TGF-b), interleukin 8, and other cytokines and chemokines (63). AECs are an important source of these profibrotic cytokines (61). Leukocytic inflammation was initially considered to be the driving force leading to fibrosis in IPF, but more recent concepts suggest that inflammation plays a minor role in its pathogenesis (61,64). This concept is supported by
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the lack of response to corticosteroids (CS) or immunosuppressive agents in patients with IPF (2,15,23). This raises the question: Is the inflammation seen on lung biopsy in IPF simply an epiphenomenon associated with a more direct tissue/cellular injury? More specifically, certain lung injuries can cause a change in the phenotype of lung cells resulting in abnormal cellular communications, and hence, aberrant repair (64,67,92). Normally, when there is an injury to the lung alveolus (predominately epithelial and adjacent endothelial cells), the clotting cascade is upregulated, followed by epithelial/ endothelial cell release of proinflammatory mediators (cytokines, chemokines, and growth factors), which are maintained at the site of injury by binding to glycosaminoglycans (63). Leukocytes home to this site via selectins, integrins, chemokines, and cytokines, and secrete mediators that help repair injured tissue (61,63,67). During normal lung repair, this is followed by apoptosis of multiple cell types, changing the lung milieu to one that favors lung remodeling with matrix mobilization/resolution (i.e., matrix removal) and the eventual return of normal lung architecture/function (61,66,92). However, during the development of IPF, recurrent and persistent lung injury causes phenotypic changes of multiple cell types (nonleukocytes >> leukocytes). These phenotypic changes include resistance to normal apoptosis, augmented ability to proliferate, upregulation of proinflammatory/ fibrotic cytokines, and exaggerated matrix deposition, changing the lung milieu to one that favors lung remodeling with matrix deposition and scar formation (64,66,67,92). This concept of fibrosis with minimal inflammation has been corroborated by in vitro studies of mesenchymal cells from fibrotic tissue and in vivo studies using murine models of pulmonary fibrosis. Mesenchymal cells from fibrotic tissue demonstrate an augmented ability to proliferate and lay down matrix (61,66,92). Conversely, avb6 integrin gene– deficient mice [they cannot activate TGF-b from the latent form] develop inflammation without significant fibrosis following bleomycin challenge (93). Similarly, overexpression of TGF-b in murine AECs led to ongoing fibrosis without significant inflammation (94). The above studies suggest that IPF is due to an altered interaction between injured lung cells (i.e., epithelial/ endothelial cell and FB/myofibroblasts), which do not die (66), yet persistently release profibrotic cytokines, which leads to increased collagen production (61–63). C.
Is Inflammation Involved in the Pathogenesis of IPF?
Leukocytes are a major source of profibrotic mediators [i.e., TGF-b and plateletderived growth factor (PDGF)], which cause wound scarring (61,92). Recruited leukocytes communicate with other cells via release of cytokines, chemokines, and growth factors that are central to driving fibrosis during wound repair (63,67). The lung alveoli are lined with type I and II epithelial cells and capillary loops. The fusion of epithelial and endothelial cell BMs, with a supporting
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network of collagens, elastic fibers, resident FBs, and scattered leukocytes, create the BM of the alveolar-capillary unit (61,92). When alveolar inflammation occurs, it can take two pathways. One pathway is inflammation followed by lung remodeling, which results in resolution of the immune response and preservation of the lung architecture. The other pathway is inflammation followed by an augmented immune response, which drives fibrosis with architectural distortion and loss of lung function. Pneumonia is an example of how lung inflammation can be robust, yet can resolve or persist (the latter may result in fibrosis). Bacterial pneumonias cause an exuberant inflammatory process in the alveolar space (i.e., recruitment of neutrophils/mononuclear cells, proteinaceous/fibrous exudates, and mesenchymal cell proliferation). Following eradication of the infectious agent, the alveolar-capillary BM is preserved and the lung remodels with no significant fibrosis. However, if an overwhelming infectious inoculum causes damage to the alveolar-capillary BM or if the infectious agent persists producing chronic inflammation and injury, lung remodeling results in scar formation (95,96). While inflammation is necessary for fibrosis, there needs to be a breakdown of the BM to alter cellular communication (i.e., leukocyte to nonleukocyte) and drive fibrosis. IPF is associated with AEC and adjacent endothelial cell injury, persistent interstitial inflammation, and alveolar-capillary BM damage, committing lung remodeling to dense mature fibrosis, which has a patchy distribution (97). FF result from epithelial/endothelial cell necrosis, BM damage, and FB/myofibroblast proliferation and matrix deposition, causing alveolar collapse, which is partially absorbed into the interstitium (97). COP exhibits interstitial inflammation and intraluminal buds of organizing exudates comprised of FB/ myofibroblasts and immature matrix deposition (98). Morphologically, these buds have been compared to the FF of IPF. However, COP is exquisitely responsive to immunosuppressive therapy (98). A preserved BM may account for the lack of fibrosis in COP. Multiple studies have noted a link between inflammation and lung fibrosis. Studies involving multiple types of chronic pulmonary fibrotic disorders (i.e., CVD-associated ILD, asbestosis, sarcoidosis, drug toxicity, and chronic HP) demonstrate that a persistent alveolitis may be linked to lung fibrosis (61,67,99). This concept is supported by human studies demonstrating that lung biopsies from individual patients may exhibit histological features of both NSIP and UIP (9,10,32). Further, gene expression studies have shown that lung tissues from patients with NSIP and UIP display similar profiles (75,77). Molecular studies involving humans with IPF and animal models of lung fibrosis have found that multiple inflammatory/profibrotic cytokines are upregulated (67,100–103). Inhibiting these inflammatory/ profibrotic mediators attenuates inflammation and lung fibrosis (101–105). Collectively, these studies insinuate that chronic lung inflammation eventually leads to lung fibrosis.
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Mediastinal lymphadenopathy is frequently seen in patients with UIP, NSIP, and other IIPs (106–108). Presumably, this lymph enlargement is due to cytokines released by infiltrating parenchymal mononuclear cells, evoking the expansion and recruitment of dendritic cells (DC) and other antigen-presenting cells (APC) to local lymphoid tissue (i.e., hyperplastic reaction to a chronic inflammatory process) (107,109). The lymph node enlargement (LNE) noticed in both NSIP and UIP makes another case for persistent inflammation (e.g., NSIP) leading to fibrosis (e.g., UIP). In summary, IPF is a complex disorder that appears to occur in response to repetitive injury within the alveolar space that involves both inflammatory and noninflammatory components (Fig. 2). The AEC and adjacent endothelium are the major cells affected and initiate the release of cytokines followed by an intense immune response, which exacerbates alveolar-capillary BM damage. Without a normal BM, cellular communication (leukocyte to nonleukocyte) is altered, driving lung remodeling toward fibrosis.
Figure 2 Injury to the epithelium and adjacent endothelium leads to a lung remodeling, which causes fibrosis. (A) Noninflammatory mechanism—injury to the epithelium and endothelium causes ‘‘only these cells’’ to upregulate TGF-b, PDGF, and other mediators (cytokines, chemokines, and growth factors), which result in fibroplasia. (B) While injured epithelium and endothelium release some profibrotic mediators, it is the persistent inflammatory cells that are most important in driving (via cytokine release) fibrosis.
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Physiological Aberrations in IPF PFTs
Characteristic aberrations on PFTs in patients with IPF include: reductions in VA [e.g., vital capacity (VC) and total lung capacity (TLC)], normal or supranormal expiratory flow rates, reduced DLCO, hypoxemia or increased alveolar-arterial oxygen difference [PAO2–Pao2], which is accentuated by exercise (16,110,111). When emphysema and IPF are present concomitantly, there is lesser restriction and greater impairment in DLCO and oxygenation compared to lone IPF (112,113). Physiological derangements are similar with IPF and NSIP (6,7,110,114). B.
Cardiopulmonary Exercise Testing
Cardiopulmonary exercise testing (CPET) reveals hypoxemia or widened alveolar-arterial O2 gradient (AaDo2) in virtually all patients with IPF (110). Additional aberrations on CPET include reduced oxygen (O2) consumption (VO2), increased dead space (VD/VT), increased minute ventilation for the level of oxygen consumption, high frequency/low tidal volume breathing pattern, and low O2 pulse (110). CPET with arterial cannulation is invasive and logistically difficult (115,116). The six-minute walk test (6MWT) with oximetry is a noninvasive and relatively inexpensive way to ascertain the need for supplemental oxygen therapy and follows the course of IPF (115–118). C.
Relationship of PFTs to the Severity or Extent of Disease
Severe derangements in physiological tests (e.g., PFTs, DLCO, oxygenation) predict a worse survival in patients with IPF (47,114,119–122). Mortality rates were higher among patients with VC < 60% predicted or DLCO < 30% to 45% predicted (110,119,122–124). Changes in TLC are less predictive of prognosis (110). However, the prognostic value of any pulmonary functional parameter at one point in time is limited (120,125). Serial studies are helpful to follow the evolution of the disease (24,110,114,120). Not surprisingly, improvement or stability of forced vital capacity (FVC) or DLCO suggests an improved prognosis, whereas deterioration in VC (>10% decrease) or DLCO (>15% decrease) predicts a worse survival (24,110,114,120). Hypoxemia (at rest or exercise) is an independent predictor of mortality in IPF or fibrotic NSIP (115,116,118,120,126–128). Six-minute walk distance (6MWD) correlates with DLCO % predicted (115,122,128) and has prognostic value. In one study, IPF patients awaiting LT with 6MWD < 350 m had a shorter survival time than those with 6MWD > 350 m (127). A subsequent study by these investigators retrospectively analyzed the utility of 6MWD as a predictor of mortality in a cohort of 454 IPF patients awaiting LT (115). Lower 6MWD was associated with increased mortality (assessed at 6 months) and was superior to FVC% as a predictor of mortality. Patients with 6MWD < 207 meters had a more than fourfold greater mortality than those with 6MWD 207 m, even after adjustment for demographics,
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FVC percent predicted, pulmonary hypertension, and medical comorbidities (115). Flaherty et al. assessed the prognostic value of 6MWD and extent of desaturation on 6MWT in a cohort of 197 patients with IPF (125). By multivariate analysis, 6MWD was not a reliable predictor of mortality but the degree of desaturation during 6MWT had greater prognostic value. Patients with O2 saturation 88% during their initial 6MWT had a median survival of 3.2 years compared to 6.8 years for those with baseline SaO2 > 88% (p ¼ 0.006). The prognostic value of serial changes in FVC, DLCO, 6MWD, and desaturation area (DA) varied according to the extent of desaturation on 6MWT (125). Among patients with O2 saturation < 88% during 6MWT, a decrease in DLCO emerged as the only predictor of mortality; changes in FVC, DA, or walk distance were not predictive in this group. For patients with O2 saturation > 88% during 6MWT, decreases in FVC and increases in DA predicted subsequent mortality, whereas decreases in 6MWD and DLCO were less predictive. These data emphasize the importance of stratifying by baseline level of desaturation when assessing prognosis. D.
What Are the Best Physiological Tests to Assess Clinical Course or Response to Therapy?
Optimal parameters to follow the course of IPF have not been validated (2,110). We believe that serial measurements of FVC are optimal, as this parameter is more reproducible than TLC or DLCO (2,110). DLCO is more sensitive than FVC or TLC but has inherent variability, confounding interpretation of serial changes in DLCO (110). Normalizing the DLCO to VA, which yields the DLCO/VA ratio, has no advantage over DLCO (129). The ATS/ERS consensus statement on IPF defined a change from baseline as follows: 10% for FVC or TLC; 15% for the DLCO; 4% increase in O2 saturation or 4 mm increase in PaO2 during a formal CPET (2). CPET is less reproducible than static PFTs (128) and the value of CPET is marginal (130). We perform spirometry, DLCO, and 6MWT at threeto four-month intervals to gauge the evolution of the disease. We prefer 6MWT over CPET because of its simplicity and noninvasiveness (115,117,128). VII.
Radiographical Manifestations of IPF
Chest radiographs in UIP typically reveal diffuse, bilateral, interstitial (reticular) infiltrates, with a predilection for basilar and peripheral (subpleural) regions (2,18). Similar radiographic features may be noted in asbestosis (2) and CVDassociated pulmonary fibrosis (3,18). A.
The Role of High-Resolution CT Scans in the Diagnosis of IPF
High-resolution thin section (1–2 mm) CT scans are an integral component of the initial evaluation of suspected ILD. HRCT can be performed without contrast and has diagnostic and prognostic value (17,18,123). HRCT can demonstrate the
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pattern, extent, and distribution of the disease (17,18,123) (see chapter 2 for specific CT examples). Characteristic features of IPF/UIP on CT include coarse reticular or linear opacities (intralobular and interlobular septal lines), patchy involvement with a distinct predilection for the basilar and peripheral (subpleural) regions, and traction bronchiectasis or bronchioloectasis HC (17,18,123). GGO may be present in IPF but are never the dominant feature (17,18,123). Anatomic distortion and volume loss may be present (18,123). HC is often a prominent feature of UIP but is rare in other IIPs (17,18). Emphysematous changes may be present in smokers (113,131). Bronchovascular thickening, a cardinal feature of sarcoidosis, is minimal or absent in UIP (17). Mediastinal LNE occurs in 53% to 93% of patients with IPF (106–108,132–135) but is nonspecific (134,135). LNE in UIP usually involves only one or two nodal stations and the nodes usually measure <15 mm (132,135). The presence of LNE correlated with the extent of disease in some (132,134), but not all, studies (106,107). A recent study noted that increase in LNE over time was associated with progression of fibrosis in UIP or NSIP (132). B.
Can CT Features Obviate the Need for Lung Biopsy in IPF?
When CT features are ‘‘classical’’ for UIP (including presence of honeycombing), the accuracy of a ‘‘confident diagnosis’’ of IPF on HRCT by a trained observer is >90% (17,18,108,131,136). In this context, surgical lung biopsy is not necessary. However, a confident diagnosis of IPF can be made in fewer than two-thirds of patients even when UIP is documented on surgical lung biopsy (18,137). CT features of IPF/UIP overlap with NSIP (138,139) but NSIP is associated with predominantly GGO and minimal or no honeycombing (17,140). C.
Prognostic Significance of CT Pattern
The global extent of disease on HRCT correlates roughly with severity of functional impairment in IPF (18,131). The extent of disease of CT correlated best with FVC and DLCO (18,85,131). In a study of 54 patients with IPF without emphysema, extent of disease on CT correlated best with percent predicted DLCO (r ¼ 0.68), oxygen desaturation with exercise (r ¼ 0.64), and the physiological component of the clinical-radiographic-physiological (CRP) score (r ¼ 0.62); spirometry or VA were less helpful (141). In another study in IPF patients, the extent of GGO on CT correlated with FVC and Pao2 with exercise (131). Several studies assessed the evolution of CT over time (18,131,142). Pulmonary functional parameters improved only when GGO regressed on HRCT (18,131,142). Reticular or HC patterns reflect fibrosis and do not regress with treatment (18,131,142). Severe HC on CT is a strong predictor of mortality (>80% mortality within two years) (11,122,143). CT patterns ‘‘typical’’ of IPF/ UIP were associated with a higher mortality compared to ‘‘atypical’’ CT scans (114,144), suggesting that CT features ‘‘typical’’ of UIP likely reflect advanced disease.
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Composite Scoring Systems
Models that incorporate clinical, radiographic, and physiological criteria were developed to predict survival among patients with IPF (112,145). These models were derived from an earlier composite scoring system, which incorporated clinical (dyspnea), radiographic (chest X-rays), and physiological parameters (i.e., the CRP score) to more objectively monitor the course of IPF (146). A modification of the CRP scoring system incorporated age, smoking history, clubbing, changes on chest X-ray, percent predicted TLC, and PaO2 at the end of maximal exercise (112). This modified CRP score was highly efficacious in predicting five-year survival in a large retrospective cohort of IPF patients. However, this system is impractical in clinical practice settings. Wells and colleagues developed a composite physiological index (CPI), which incorporates CT and physiological parameters to assess outcomes in IPF (145). The CPI evaluates disease extent by CT and selected functional variables [i.e., % predicted FVC, forced expiratory volume in one second (FEV1), and DLCO]. In a cohort of IPF patients, higher (worse) CPI scores correlated with mortality better than individual variables (CT, PFTs, oxygenation). Further, CPI score was a better predictor of survival than the original (146) or modified (112) CRP scores. These various models are of interest but have not been validated in prospective studies.
VIII. A.
Ancillary Staging Techniques
Bronchoalveolar Lavage
Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) contributed significant insights into the pathogenesis of IPF and other ILDs but practical value is limited (2,147). Increases in polymorphonuclear leukocytes, mast cells, alveolar macrophages, and myriad cytokines are noted in BAL fluid from patients with IPF; lymphocyte numbers are usually normal (147). However, BAL cell profiles in IPF do not predict prognosis or therapeutic responsiveness (147). We do not believe BAL cell counts have a role to ‘‘stage’’ or follow IPF. B.
Radionuclide Scans
Historically, gallium citrate (Ga 67) scans were used to assess the extent of intrapulmonary inflammation (alveolitis) in diverse ILDs (15). However, Ga67 scans are nonspecific, expensive, inconvenient and do not predict prognosis or responsiveness to therapy (2). Thus, Ga67 scans have no role to stage or follow patients with IPF (15). Clearance of Tc diethylenetriamine pentaacetate (DTPA) aerosol is accelerated in IPF, and is a marker of increased lung permeability (15). Increased metabolic uptake may be noted by positron emission tomographic (PET) scans in patients with IPF (18). However, the sensitivity, specificity and clinical value of DTPA or PET scans to stage or follow IPF have not been elucidated.
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Complications of IPF Acute Exacerbations of IPF
Acute exacerbations of IPF are characterized by rapid development of cough, dyspnea, hypoxemia, and worsening pulmonary infiltrates in patients with known IPF (29,148–151). Presentation is similar to acute respiratory distress syndrome (ARDS) (29,148,149,151,152). The cardinal histological feature is DAD superimposed on a background of UIP (149,151). Idiopathic acute interstitial pneumonia (AIP) (28,152) exhibits similar clinical and histological features as acute exacerbations of IPF, but lacks the requisite features of UIP. Highdose intravenous (IV) pulse methylprednisolone has been used to treat acute exacerbations of IPF, but data on treatment are limited to anecdotal cases and small series (29,148,149,151). This entity is reviewed in chapter 15 and will not be further discussed here. B.
Lung Cancer Complicating UIP
Primary bronchogenic carcinoma complicates UIP in 5% to 13% of patients (153–157). The increased risk of lung cancer in IPF may occur in nonsmokers (154), but smoking increases the risk (153,155). Surgical resection is the treatment of choice for patients with localized non–small cell lung cancer (NSCLC) but morbidity and mortality rates are higher in patients with underlying IPF (156,157). C.
Pulmonary Hypertension Complicating IPF
Pulmonary arterial hypertension (PAH) and right ventricular (RV) dysfunction are common in IPF (158,159). The pathogenesis of PAH in IPF is complex, and does not correlate with VA or extent of pulmonary dysfunction (159–163). Pulmonary artery remodeling and proangiogenic cytokines are likely central to developing PAH in IPF (63,159,160,164), but ablation of pulmonary vessels (165) and vasoconstriction may play contributory roles (159). In patients with advanced IPF, PAH was noted in 20 to 84% of patients (113,158,159,162,166–171). However, one prospective study of IPF patients (all stages) noted PAH [mean pulmonary arterial pressure (mPAP) >25 mmHg] in only 8.1% (161). The presence of PAH is associated with markedly worse survival (113,161,162,166). In a cohort of 79 IPF patients, one-year mortality rates were 28% in those with PAH [defined as mPAP >25 mmHg by right heart catheterization (RHC)] compared to 5.5% in those without PAH (162). Another prospective study evaluated 61 patients with IPF who had RHC (161). Five-year survival was 83% among patients with normal pulmonary arterial pressure (PAP) and preserved DLCO (40% predicted) compared to only 16% among patients with high PAP, low DLCO, or both (p < 0.001) (161). Several investigators have found that the DLCO correlates with PAH, whereas FVC or VAs does not (159,162,163,170,171).
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Transthoracic echocardiography (TTE) is superior to chest CT as a predictor of PAH (172). Severe RV hypertrophy, reduced RV function, and abnormal bowing of the interventricular septum reflect RV dysfunction (169). TTE may allow estimation of systolic pulmonary arterial pressure (sPAP), which has prognostic value. In a study of 88 patients with IPF, median survival rates were related to sPAP (estimated by TTE) as follows: 0.7 years when sPAP > 50 mmHg; 4.1 years for sPAP of 36 to 50 mmHg; 4.8 years for sPAP < 36 mmHg (166). Multivariate analysis identified other parameters associated with a worse survival including male gender, lower DLCO, use of oxygen, history of coronary artery disease, and worse New York Heart Association (NYHA) class (166). Unfortunately echocardiograms are not consistently reliable in patients with ILDs (171,173). In one study of 106 patients with ILD, estimates of sPAP by TTE and RHC were discordant by >10 mmHg in 63% of patients (173). Accuracy improved when sPAP was <45 mmHg (173). We recently performed TTE and RHC in 61 IPF patients; estimation of right ventricular systolic pressure (RVSP) was possible in 33 patients (54%) (171). Using RVSP >40 mm by RHC as a cutoff, sensitivity and specificities for PAH were 76% and 38%, respectively. Exercise-induced desaturation, reduced DLCO (<40% predicted), or need for supplemental oxygen are surrogate markers for PAH in IPF (166,171). The FVC/DLCO ratio and SO2 may be markers for PAH (170,171). A model incorporating FVC/DLCO ratio and SO2 was superior to TTE (improved specificity and negative predictive value) in assessing PAH in a cohort of IPF patients (171). DLCO did not contribute to mPAP predictive above and beyond SO2, whereas FVC/DLCO ratio did. Elevated plasma brain natriuretic peptide (BNP) levels and reduced 6MWD may be surrogate markers of PAH in patients with IPF (163). In one study, 39 patients with pulmonary fibrosis and severe restriction (FVC < 55% predicted) had RHC, plasma BNP levels, and 6MWT (163). Among 28 patients with IPF, elevated levels of BNP correlated with increased PAP and pulmonary vascular resistance (PVR) and correlated inversely with 6MWD. Interestingly, PFTs did not correlate with either BNP or PAH (163). Given the prognostic importance of PAH in patients with IPF, treatment with sildenafil (a phosphodiesterase inhibitor) (167,174–176), prostacyclin (158), iloprost (168), or endothelin-1 receptor antagonists (ET-1 RA) (177,178) should be considered, but data are limited to small uncontrolled studies. Sildenafil was associated with improved pulmonary hemodynamics in a small series of ILD patients (167) and improved 6MWD in a small, retrospective study (175). A multicenter placebo-controlled trial sponsored by the IPFnet evaluating sildenafil for treating severe IPF is in progress. The use of endothelin-1 (ET-1) receptor blockers has theoretical value in IPF-associated PAH (158,159), but data are limited. A double-blind randomized controlled trial (RCT) randomized 158 patients with IPF to bosentan (an ET-1 RA) or placebo (178). Patients with severe disease (FVC < 50% predicted) or DLCO < 30% predicted, PaO2 < 55 mmHg) or PAH were excluded. At 12 months, bosentan was not superior to placebo with
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regard to the primary endpoint (i.e., 6MWD); further, physiological parameters (FVC, DLCO, SaO2) did not differ between groups. However, a trend in favor of bosentan was noted in secondary endpoints (including time to death or disease progression (hazard ratio 0.61, p ¼ 0.12) and quality of life and dyspnea scores (178). Another RCT evaluating bostentan among IPF patients with severe disease or PAH is in progress (BUILD-3) (179). Mediators such as TGF-b, TNF-a, PDGF and other profibrotic cytokines may be involved in the pathogenesis of IPF-associated PAH (63,159,180). Therapies targeting specific cytokines are worthy of study (59,60,181), but data are lacking.
X.
Therapy of IPF
A.
Immunosuppressive or Cytotoxic Agents
Therapeutic options for IPF are of unproven efficacy (15,23,179,182,183). Initial treatment strategies, based upon the concept that inflammation was a key factor in the pathogenesis of IPF, utilized high-dose CS and/or immunosuppressive or cytotoxic agents. CS have not been shown to be efficacious and have significant toxicities (particularly in elderly patients) (23,184,185). Similarly, immunosuppressive or cytotoxic agents have not been shown to influence mortality or clinical outcomes, but data are limited (15,23,179,186–190). Anecdotal responses to azathioprine (AZA) (188,189) or cyclophosphamide (CYC) (190) have been noted, but the preponderance of data suggest that these agents are ineffective as therapy for IPF (15,23,186,187). The ATS/ERS consensus statement concluded that ‘‘no data exist that adequately document any of the current treatment approaches improves survival or the quality of life for patients with IPF’’ (2). They further stated ‘‘The committee believes that therapy is not indicated in all patients.’’ However, given the poor prognosis of IPF, and the theoretical possibility that anti-inflammatory agents may have some impact in a subset of patients, the committee advocated an empirical trial or either AZA or CYC, alone or combined with low-dose CS, for symptomatic patients with progressive disease (2). These recommendations reflected expert opinion, but have not been validated. Further, toxicities associated with immunosuppressive or cytotoxic agents are appreciable (191). Management of patients with IPF is frustrating, since the disease progresses inexorably and treatment has not been shown to alter that natural history of the disease. Treatment may be offered to patients with severe symptoms and a declining course, provided that the pros and cons of therapy are discussed honestly. We emphasize to patients that no therapy has been proven to influence survival or clinically important outcomes. We rarely recommend therapy in elderly IPF patients with classical features of UIP on CT scan and a gradually deteriorating course. However, we consider treating patients with a subacute or deteriorating course, young age (<65 years), no specific contraindications, and/or surrogate markers of alveolitis (GGO on CT scan). In this context, we offer oral AZA (2–3 mg/kg/day) alone or combined with low-dose prednisone (20 mg every other day or equivalent). Unless there is unequivocal and
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objective improvement, we discontinue therapy after a three- to six-month trial. Further, treatment is discontinued among patients experiencing side effects or disease progression. CYC has potentially serious toxicities (191) and we rarely utilize CYC for IPF. Mycophenolate mofetil (MMF) and other immunosuppressive agents have been utilized by some clinicians, but these agents have not been evaluated in clinical trials. TNF-a antagonists (e.g., etanercept and infliximab) have been tried in some cases of pulmonary fibrosis (idiopathic and CVD-associated), but data are limited. In a prospective, placebo-controlled trial, etanercept was ineffective in achieving primary endpoints (physiological parameters), although trends favoring etanercept were observed in some secondary endpoints (192). Anecdotal responses to infliximab were noted in case reports of CVD-associated pulmonary fibrosis (193,194). However, TNF-a antagonists are expensive and have serious potential toxicities (194–196). Additional studies are required before endorsing these agents for IPF. B.
Other Agents
1. Gamma-Interferon-1b
Gamma-interferon (g-IFN)-1b is an endogenous cytokine, which downregulates the expression of TGF-b and may have antifibrotic effects. Initial studies employing recombinant g-IFN-1b were encouraging (124,197), but a large RCT showed no benefit and the study was ended because of ‘‘futility’’ in March 2007 (InterMune, Brisbane, CA). 2. N-Acetyl Cysteine
N-acetyl cysteine (NAC), an antioxidant that restores depleted glutathione levels in lung and BAL fluid (198), improved lung function in an early cohort of patients with IPF (199). A recent multicenter European trial randomized 182 patients with IPF to oral NAC (600 mg t.i.d.) or placebo (200). All patients received ‘‘conventional treatment’’ with AZA and low-dose CS. At 12-month follow-up, PFTs had deteriorated in both groups; however, the rate of decline in FVC and DLCO was lower in the NAC cohort. Although statistically significant, these changes in PFTs were small (absolute difference in FVC of 4.8% and in DLCO 5.1%) and of doubtful clinical significance. The benefit (if any) of NAC as therapy for IPF remains controversial. A multicenter RCT sponsored by the IPFnet is planned. Nonetheless, NAC is inexpensive and has few side effects, making it an attractive option for IPF (179,201). 3. Pirfenidone
Pirfenidone is a novel agent that inhibits TGF-b in vitro and inhibits bleomycininduced pulmonary fibrosis in animal models (202). Two uncontrolled, open-label
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studies in IPF suggested that oral pirfenidone may stabilize pulmonary function (203,204). Further, in a cohort of 11 patients with pulmonary fibrosis complicating Hermansky-Pudlak syndrome, pirfenidone was associated with a slower rate of decline compared to 10 patients receiving placebo (205). A recent randomized phase II trial compared pirfenidone to placebo (2:1 ratio) in a cohort of 107 patients with IPF (206). The study was stopped prematurely because acute exacerbations were noted in five patients receiving placebo (14%) compared to no cases in the pirfenidone group. The primary endpoint (change in lowest O2 saturation on 6MWT over 6 or 9 months) was not met. There were no significant differences between groups in mortality, TLC, DLCO, or resting PaO2. The rate of decline in VC at nine months was lower in the pirfenidone group (p ¼ 0.037), but differences between groups were small and of doubtful clinical significance. Pirfenidone is not commercially available, but a second RCT study evaluating pirfenidone versus placebo is in progress (InterMune, Brisbane, CA). 4. Anticoagulants
Inflammation and vascular injury in IPF may lead to a prothrombotic state, which could exacerbate lung injury (183). Japanese investigators randomized 56 IPF patients to anticoagulants (warfarin) or placebo (207). Three-year survival and freedom from acute exacerbations were improved in the anticoagulated group. However, the dropout rate was high, and it is possible that selection bias may have influenced the study. Given the risk associated with anticoagulation therapy, additional studies involving greater numbers of patients are required before endorsing this form of therapy. 5. Novel Agents
Novel agents with potential antifibrotic properties have theoretical value but have not yet been evaluated in IPF (discussed in detail elsewhere) (59,60,179). Agents that are currently being studied in IPF include imatinib mesylate, sirolimus, captopril, inhaled iloprost, and other inhibitors of fibrotic growth factors (179,182,183).
XI.
Lung Transplantation for IPF
LT is the best therapeutic option for patients with IPF with life-threatening disease (208–210). Since no medical therapies have been proven to influence survival in IPF, IPF patients should be referred to LT centers at the time of diagnosis (provided no contraindications exist). The decision to list for LT is best made by the local transplant team members, who are familiar with local waiting times. Either single (SLT) or bilateral sequential lung transplantation (BSLT) can be performed (208,209,211). Data from the International Society for Heart and Lung Transplantation (ISHLT) Registry reported that 19% of >17,000 LTs
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worldwide were performed for IPF; since 2000, IPF has accounted for an increasing proportion (26%) of LTs (211). A review of 824 IPF patients receiving lung transplants (SLT, n ¼ 636; BSLT, n ¼ 185) in the United States between 1994 and 2000 reported better early (one-month) and late (three-year) survival rates with SLT compared to BSLT (209). However, when posttransplant survival was reanalyzed contingent on survival to one month, survival rates were similar with SLT and BSLT. The increased mortality with BSLT likely reflects surgical problems or graft failure in the early transplant period. The most recent data from the ISHLT registry for recipients with IPF noted improved survival with BSLT versus SLT (p ¼ 0.03); survival rates were similar up to three years but diverged thereafter (211). Secondary PAH is not a contraindication to LT, but its presence may influence the operative and perioperative management. Whelan et al. reviewed 830 patients with IPF transplanted between 1995 and 2002 in the ISHLT registry; 77% had SLT; 23% had BSLT (212). By multivariate analysis, mPAP and BSLT were independent risk factors for mortality. Among SLT recipients, there was a linear relationship between PAP and 90-day mortality. However, only 8.3% of patients with SLT had mPAP > 40 mmHg. The decision as to which procedure (i.e., SLT or BSLT) should be followed depends upon the expertise of the local transplant program (210). However, given the improved survival with BSLT among patients with idiopathic PAH (211), most centers perform BSLT for IPF patients with secondary PAH. Acknowledgments This work was supported, in part, by grants from the National Institutes of Health (NIH) (HL080206-01 and HL086491-01 to JAB; HL087186 to MPK). References 1. Katzenstein A, Myers J. Idiopathic pulmonary fibrosis. Clinical relevance of pathological classification. Am J Respir Crit Care Med 1998; 157:1301–1315. 2. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161(2 Pt 1):646–664. 3. Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med 2007; 175(7):705–711. 4. Kocheril SV, Appleton BE, Somers EC, et al. Comparison of disease progression and mortality of connective tissue disease-related interstitial lung disease and idiopathic interstitial pneumonia. Arthritis Rheum 2005; 53(4):549–557. 5. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias.
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150. Suh GY, Kang EH, Chung MP, et al. Early intervention can improve clinical outcome of acute interstitial pneumonia. Chest 2006; 129(3):753–761. 151. Parambil JG, Myers JL, Ryu JH. Histopathologic features and outcome of patients with acute exacerbation of idiopathic pulmonary fibrosis undergoing surgical lung biopsy. Chest 2005; 128(5):3310–3315. 152. Vourlekis JS, Brown KK, Cool CD, et al. Acute interstitial pneumonitis. Case series and review of the literature. Medicine (Baltimore) 2000; 79(6):369–378. 153. Aubry MC, Myers JL, Douglas WW, et al. Primary pulmonary carcinoma in patients with idiopathic pulmonary fibrosis. Mayo Clin Proc 2002; 77(8):763–770. 154. Hubbard R, Venn A, Lewis S, et al. Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study. Am J Respir Crit Care Med 2000; 161(1):5–8. 155. Park J, Kim DS, Shim TS, et al. Lung cancer in patients with idiopathic pulmonary fibrosis. Eur Respir J 2001; 17(6):1216–1219. 156. Kumar P, Goldstraw P, Yamada K, et al. Pulmonary fibrosis and lung cancer: risk and benefit analysis of pulmonary resection. J Thorac Cardiovasc Surg 2003; 125(6):1321–1327. 157. Kawasaki H, Nagai K, Yoshida J, et al. Postoperative morbidity, mortality, and survival in lung cancer associated with idiopathic pulmonary fibrosis. J Surg Oncol 2002; 81(1):33–37. 158. Nathan SD, Noble PW, Tuder RM. Idiopathic pulmonary fibrosis and pulmonary hypertension: connecting the dots. Am J Respir Crit Care Med 2007; 175(9):875–880. 159. Patel NM, Lederer DJ, Borczuk AC, et al. Pulmonary hypertension in idiopathic pulmonary fibrosis. Chest 2007; 132(3):998–1006. 160. Colombat M, Mal H, Groussard O, et al. Pulmonary vascular lesions in end-stage idiopathic pulmonary fibrosis: histopathologic study on lung explant specimens and correlations with pulmonary hemodynamics. Hum Pathol 2007; 38(1):60–65. 161. Hamada K, Nagai S, Tanaka S, et al. Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis. Chest 2007; 131(3):650–656. 162. Lettieri CJ, Nathan SD, Barnett SD, et al. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 2006; 129(3): 746–752. 163. Leuchte HH, Neurohr C, Baumgartner R, et al. Brain natriuretic peptide and exercise capacity in lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 2004; 170(4):360–365. 164. Voelkel NF, Douglas IS, Nicolls M. Angiogenesis in chronic lung disease. Chest 2007; 131(3):874–879. 165. Renzoni EA, Walsh DA, Salmon M, et al. Interstitial vascularity in fibrosing alveolitis. Am J Respir Crit Care Med 2003; 167(3):438–443. 166. Nadrous HF, Pellikka PA, Krowka MJ, et al. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest 2005; 128(4):2393–2399. 167. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002; 360(9337): 895–900. 168. Olschewski H, Ghofrani HA, Walmrath D, et al. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med 1999; 160(2):600–607.
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189. Raghu G, Depaso WJ, Cain K, et al. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial. Am Rev Respir Dis 1991; 144(2):291–296. 190. Johnson MA, Kwan S, Snell NJ, et al. Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis. Thorax 1989; 44(4):280–288. 191. Lynch JP III, McCune WJ. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. Am J Respir Crit Care Med 1997; 155(2):395–420. 192. Raghu G, Lasley L, Costabel U, et al. A randomized placebo-controlled trial assessing the efficacy and safety of etanercept in patients with idiopathic pulmonary fibrosis (IPF) [abstract]. Chest 2005; 128(suppl):496S. 193. Bargagli E, Galeazzi M, Rottoli P. Infliximab treatment in a patient with rheumatoid arthritis and pulmonary fibrosis. Eur Respir J 2004; 24(4):708. 194. Antoniou KM, Mamoulaki M, Malagari K, et al. Infliximab therapy in pulmonary fibrosis associated with collagen vascular disease. Clin Exp Rheumatol 2007; 25(1):23–28. 195. Allanore Y, Devos-Francois G, Caramella C, et al. Fatal exacerbation of fibrosing alveolitis associated with systemic sclerosis in a patient treated with adalimumab. Ann Rheum Dis 2006; 65(6):834–835. 196. Ostor AJ, Crisp AJ, Somerville MF, et al. Fatal exacerbation of rheumatoid arthritis associated fibrosing alveolitis in patients given infliximab. BMJ 2004; 329(7477): 1266. 197. Ziesche R, Hofbauer E, Wittmann K, et al. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999; 341(17):1264–1269. 198. Meyer A, Buhl R, Magnussen H. The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosis. Eur Respir J 1994; 7(3):431–436. 199. Behr J, Maier K, Degenkolb B, et al. Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis. Adjunctive therapy to maintenance immunosuppression. Am J Respir Crit Care Med 1997; 156:1897–1901. 200. Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005; 353(21):2229–2242. 201. Hunninghake GW. Antioxidant therapy for idiopathic pulmonary fibrosis. N Engl J Med 2005; 353(21):2285–2287. 202. Iyer SN, Margolin SB, Hyde DM, et al. Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a three-dose bleomycin-hamster model. Exp Lung Res 1998; 24(1):119–132. 203. Raghu G, Johnson WC, Lockhart D, et al. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, openlabel Phase II study. Am J Respir Crit Care Med 1999; 159(4 Pt 1):1061–1069. 204. Nagai S, Hamada K, Shigematsu M, et al. Open-label compassionate use one yeartreatment with pirfenidone to patients with chronic pulmonary fibrosis. Intern Med 2002; 41(12):1118–1123. 205. Gahl WA, Brantly M, Troendle J, et al. Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome. Mol Genet Metab 2002; 76(3):234–242. 206. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005; 171(9):1040–1047.
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13 Nonspecific Interstitial Pneumonitis (NSIP)
KEVIN R. FLAHERTY Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, U.S.A.
I.
Introduction
Nonspecific interstitial pneumonia (NSIP) represents a distinct histopathologic category of interstitial lung disease (ILD), a disease associated with uniformappearing cellular histology characterized by temporal homogeneity. This represents a distinguishing histopathologic feature from usual interstitial pneumonia (UIP), a disease characterized by new and old lesions or temporal heterogeneity. Following UIP, the histopathologic pattern of idiopathic pulmonary fibrosis (IPF), NSIP represents the second most prevalent subtype of the idiopathic interstitial pneumonias (IIPs). Historically, the term NSIP was broadly applied to include cellular interstitial pneumonias associated with immunocompromised hosts, collagen vascular diseases (CVDs), toxin/environmental exposures, and acute lung injury/infections (1–7). Idiopathic cases of NSIP are also described. With their 1994 landmark series, Katzenstein and Fiorelli sought to establish NSIP as a distinct histopathologic entity with clinical features paralleling idiopathic UIP (IPF), expelling the notion of NSIP as a ‘‘wastebasket’’ category of ILD. The confusion
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surrounding a precise definition of NSIP was highlighted by the fact that it was considered as a provisional form of an IIP, as described in the American Thoracic Society/European Respiratory Society consensus classification of 2002 (8). This provisional diagnosis arose from uncertainty and a desire to further clarify the clinical condition it represents (8). The fact that a pattern of NSIP can be seen in varied clinical scenarios necessitates a comprehensive effort to identify a potential cause leaving the ‘‘idiopathic’’ category of NSIP as a diagnosis of exclusion. In this chapter, we explore the epidemiology, clinical features, physiology, pathobiology, natural history, and treatment of NSIP as a form of IIP. The clinical presentation of patients with NSIP is similar to that of other IIPs; cough and dyspnea on exertion are the predominant symptoms. The characteristic pulmonary physiology of NSIP includes a restrictive ventilatory defect associated with reduced gas transfer, a pattern similar to other IIPs. Ground-glass opacification (GGO) remains the hallmark characteristic of NSIP on highresolution computed tomography (HRCT) of the lung; however, radiographic studies are rarely diagnostic. Surgical lung biopsy (SLB) remains the gold standard for diagnostic confirmation. The varied pathobiology of NSIP is explored with possible contributors including an injured epithelium, altered matrix metalloproteinase expression, augmented chemokine activity, an altered coagulation pathway, and a persistently active mesenchyme. Despite a lack of prospective studies evaluating the natural history of NSIP, prognosis and response to therapeutic, immunosuppressive agents are reviewed. Specifically, the better prognosis of NSIP as compared with UIP is deconstructed.
II.
Epidemiology
The incidence and prevalence of NSIP remain undetermined. The lack of consensus regarding the definition of NSIP antecedent to 1994 limits the value of prevalence estimates prior to this time. Since Katzenstein and Fiorelli’s description of NSIP in 1994 (3), several groups have retrospectively evaluated cases of interstitial pneumonia previously classified as IPF/cryptogenic fibrosing alveolitis (IPF/CFA) to identify cases of NSIP (9–13). These series identified NSIP in 11% to 43% of cases. These retrospective estimates are further supported by the work of Visscher and Myers (14), which notes that NSIP makes up 14% to 35% of biopsy specimens obtained to evaluate interstitial pneumonia. The prevalence of IPF and the IIPs has been estimated at 3 to 20 per 100,000 (15–17). Extrapolating from these data, the prevalence of idiopathic NSIP likely ranges from 1 to 9 per 100,000. With a consensus definition of NSIP available, the need remains for a population-based, longitudinal database of ILD to allow accurate determination of the incidence and prevalence of this disease.
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Nonspecific Interstitial Pneumonitis III.
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Clinical Assessment and Diagnosis
The initial clinical evaluation of a patient with suspected NSIP should focus on confirming the presence of ILD. Concomitantly, a careful evaluation is required to separate idiopathic NSIP from clinical conditions associated with a NSIP histologic pattern such as connective tissue disorders (3,18–25), hypersensitivity pneumonitis (26), drugs (27,28), infection, and immunosuppression including HIV (1,2,4–7). Furthermore, recent literature suggests that a significant majority of patients diagnosed with idiopathic NSIP meet the recently defined criteria for undifferentiated connective tissue disease (29). Given the complex and overlapping nature of the IIPs, the diagnosis of NSIP requires a collaborative, integrative approach involving the clinician, radiologist, and pathologist (8,30). When a clinician works in concert with a radiologist and pathologist versus in isolation, more diagnostic agreement results in a more accurate diagnosis of NSIP (30). A diagnosis of NSIP is also more likely to be considered at centers with specialized expertise in ILD compared with community centers where a diagnosis of IPF appears more common (31). A.
Clinical Characteristics
Signs and symptoms of NSIP are typical of ILD, yet lack the specificity to allow differentiation from other forms of IIP. The most common symptoms of NSIP are cough and dyspnea. Fever remains a nonspecific symptom, present in up to one-third of cases. Interestingly, fevers may be more common in patients experiencing an acute exacerbation of NSIP, a recently characterized entity (32). In general, more patients with connective tissue related NSIP are females, while idiopathic NSIP is fairly balanced between males and females. In 2004, the American Thoracic Society/European Respiratory Society (ATS/ERS) task force evaluated 305 cases of ILD from multiple hospitals (33). In this case review, which utilized clinical-radiographicpathologic consensus, 67 cases of NSIP were identified. Of these cases, the age variation was from 26 to 73 years with females representing 67% of patients. The median age of patients with NSIP was 40 years or 10 years younger than the typical patient with UIP (34). Sixty-nine percent of patients had never smoked tobacco products (33), and unlike UIP, there is no association with cigarette smoking (35). In patients with NSIP, the most common physical examination findings are dry, basilar predominant, inspiratory crackles. These ‘‘velcro-like’’ crackles are heard in the vast majority of patients. Clubbing remains more common in UIP, yet can occur in NSIP. It should be kept in mind that none of the above features are specific to NSIP as the clinical characteristics of NSIP are insufficient to distinguish from other types of IIPs (3,9–13,18–20,22,24–26,36–42). Physical examination should include a systemic evaluation for signs of connective tissue disease given its common association with NSIP.
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Laboratory investigation of patients with suspected NSIP remains nonspecific yet experts recommend a complete blood count with differential, basic chemistries including assessment of renal function, liver function tests, antinuclear antibodies, rheumatoid factor, and a urinalysis (43). Physiologic assessment of patients with suspected NSIP should include full pulmonary function testing with gas-transfer assessment. Restrictive physiology characterized by a reduced total lung capacity (TLC) is typically present in NSIP; one series noted its presence in 69% of patients (33). A reduction in TLC to 59% to 72% of predicted norms has been reported (9,36,42). Impairment in gas transfer, characterized by reduced diffusion capacity of lung for carbon monoxide (DLCO), is often a more pronounced feature of NSIP. In the studies noted above, DLCO was noted to commonly range between 39% and 50% predicted in patients with NSIP. Despite the predicted physiologic abnormalities in patients with NSIP, neither pulmonary function testing, DLCO, nor exerciseinduced oxygen desaturation can be utilized to differentiate NSIP from other ILDs, including other IIPs. B.
Radiographic Evaluation
Evaluation of patients with suspected NSIP should include assessment of thoracic HRCT, a technique that utilizes 1 to 2 mm thick slices, allowing for maximal spatial resolution. Ideally, HRCT technique should include inspiratory supine and prone imaging as well as expiratory imaging to look for air trapping. The predominant feature of NSIP on HRCT is GGO, which is frequently associated with findings of fibrosis including a reticular pattern, lobar volume loss, and/or traction bronchiectasis (3,9,11,13,18,19,24,26,36,38,40,42,44–54) (Fig. 1). The distribution of GGO tends toward basilar predominance (54). A recent ATS/ ERS NSIP task force identified significant distributional heterogeneity of GGO with peribronchovascular, subpleural, and combined patterns noted (33). A reticular pattern of subpleural cysts, or ‘‘honeycombing,’’ is atypical of NSIP; rather, this pattern provides a distinguishing feature from NSIP with a high degree of accuracy in identifying cases of UIP (10,55,56) (Fig. 2). The identification of specific radiographic criteria of UIP/IPF can yield an accurate clinical diagnosis of IPF in up to two-thirds of cases, thus supplanting the need for a SLB (57). Unfortunately, the diagnostic accuracy of HRCT in cases of NSIP is more limited. Several series have evaluated the ability of HRCT to make a diagnosis of NSIP (as confirmed by SLB). Hartman et al. retrospectively evaluated radiographic interpretation in 50 patients with biopsyconfirmed NSIP. In this study, only a minority of patients (22%) had radiographic findings compatible with NSIP (50). Other series assessed the ability of HRCT to accurately differentiate among cases of histologically confirmed UIP or NSIP (51,55). One of these cohorts noted that of patients classified as having probable or definite NSIP on HRCT, only 18 of 44 patients had histopathologic findings of NSIP with the remaining 26 patients meeting criteria for UIP (55). In
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Figure 1 HRTC scan from a 52-year-old female with NSIP. (A) The upper and (B) lower lobes demonstrate mild GGO. Reticular thickening is also present in the right lower lobe. Abbreviations: HRCT, high-resolution computed tomography; NSIP, nonspecific interstitial pneumonia; GGO, ground-glass opacities.
Figure 2 HRTC from a 61-year-old male with UIP. (A) The upper and (B) lower lobes demonstrate peripheral honeycomb change consistent with a diagnosis of UIP. Abbreviations: HRCT, high-resolution computed tomography; UIP, usual interstitial pneumonia.
these series, the sensitivity of identifying NSIP ranged from 70% to 78% with a specificity of 63% to 64% (51,55). The interpretation of HRCT is further complicated by significant interrater variability (58). In a recent series, the interrater agreement (kappa) for a pattern of NSIP was moderate at 0.51; NSIP was involved in 55% of the cases with disagreement (58). It is important to remember that many patients with a radiographic appearance of NSIP will demonstrate a histopathologic pattern of UIP from a SLB (Fig. 3), highlighting
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Figure 3 HRTC scan from a 47-year-old female. (A) The upper lobes show peripheral reticular thickening. (B) The lower lobes show GGO. The HRCT picture was felt to be consistent with NSIP; however, the surgical lung biopsy showed UIP. Abbreviations: HRCT, high-resolution computed tomography; GGO, ground-glass opacities; NSIP, nonspecific interstitial pneumonia; UIP, usual interstitial pneumonia.
the importance of SLB for cases of suspected IIP that do not have a HRCT pattern of definite UIP (i.e., honeycomb change). Serial HRCT imaging demonstrates temporal variation in patients with NSIP; serial imaging has provided evidence of disease progression and regression (44,46,48,49,53). These data illustrate the limitations of HRCT in diagnosing NSIP. The role of HRCT in the evaluation of patients with suspected NSIP remains important; however, radiographic findings compatible with NSIP should be viewed as supportive rather than definitive. SLB should be obtained to confirm the diagnosis of NSIP. C.
Bronchoscopy/SLB
Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy (TBBx) has a limited role in the diagnostic evaluation of patients with suspected NSIP. Rather, BAL serves more of a role in its ability to exclude infection in patients undergoing evaluation for NSIP. BAL is more likely to demonstrate a predominant lymphocytosis in patients with NSIP as compared with UIP (13,18,19,42); however, other studies refute this finding (36,59). Although a recent study suggests a greater role for TBBx in adequately capturing the histopathology of UIP (60), there are no data supporting TBBx as an accurate means to diagnose NSIP. Tissue size is commonly inadequate to demonstrate the temporal homogeneity and uniform inflammation that are characteristic features of NSIP histopathology. The role of TBBx in the evaluation of suspected NSIP can provide a means to evaluate for other causes of ILD including sarcoidosis, hypersensitivity pneumonitis, atypical infection, and lymphangitic carcinomatosis.
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SLB is considered the gold standard for the evaluation of patients with suspected NSIP. Despite this fact, there are no prospective studies comparing the diagnostic yield of bronchoscopic-guided TBBX to SLB. With the evolution of video-assisted thoracoscopy (VATS), SLB can be performed with lesser morbidity and shorter hospitalizations than in the era of open lung biopsy (61). Studies evaluating patients with multiple-lobe biopsies have noted a pattern of UIP in one lobe with NSIP in another lobe in 13% to 26% of patients (62,63). Furthermore, patients who had a combination of histopathologic diagnoses including NSIP/UIP had a similar clinical course to patients with UIP/IPF identified in all lobes biopsied (62,63). On the basis of these data, it is recommended that multiple lobes of the lung be biopsied in patients undergoing SLB for evaluation of possible NSIP. Despite the relative safety of VATS-SLB, a decision to pursue SLB should take into account the patient’s age, comorbidities, and potential to alter disease course given biopsy result and subsequent therapeutic trial. Previous literature suggested that clinical deterioration associated with an acute exacerbation of IPF occurred in 2.1% of patients undergoing SLB for evaluation of UIP (64). Recently, SLB has been noted to exacerbate idiopathic NSIP with associated rapid deterioration in respiratory status (32). These findings warrant further investigation.
IV. A.
Histopathology and Pathogenesis Histopathology
Since 1994, the modern histopathologic definition of NSIP has evolved from a broad, inclusive definition based on exclusionary criteria to a specific classification of IIP (8). The fundamental histopathologic characteristics of NSIP include: (i) a uniform, cellular interstitial process associated with a lymphoplasmacytic infiltration of the alveolar septum and (ii) temporal homogeneity (8). This latter characteristic represents a marked distinction from the temporal heterogeneity that is the histologic hallmark of UIP (14). The absence to rare presence of fibroblastic foci and the absence to minimal presence of microscopic honeycomb change further distinguish NSIP from UIP/IPF. Importantly, the histopathologic features of NSIP must not fit the predominant pattern of other IIPs such as UIP, desquamative interstitial pneumonia, respiratory bronchiolitis, ILD, cryptogenic organizing pneumonia, acute interstitial pneumonia, or lymphocytic interstitial pneumonia (8). Although the features of NSIP can be sharply defined, the real-life separation of NSIP from other IIPs, particularly UIP/IPF, remains difficult. The histopathology of NSIP incorporates a broad spectrum of features with varied degrees of alveolar wall inflammation (cellular NSIP) versus paucicellular fibrosis (fibrotic NSIP) (Table 1) (8,12). Furthermore, it is not uncommon to identify small foci of honeycomb change, rare collection of fibroblastic foci, and
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Table 1 Histopathologic Features of Nonspecific Interstitial Pneumonia Pertinent positive findings: Cellular pattern: Mild-to-moderate interstitial chronic inflammation Type II pneumocyte hyperplasia in areas of inflammation Fibrosing pattern: Dense or loose interstitial fibrosis lacking temporal heterogeneity and/or patchy features of UIP Lung architecture appears lost on H&E stains but is relatively preserved on elastin stains Mild or moderate chronic inflammation Pertinent negative findings: Cellular pattern: Absence of dense interstitial fibrosis Organizing pneumonia is not the prominent feature Diffuse, severe alveolar septal inflammation is absent Fibrosing pattern: Temporal heterogeneity is absent Fibroblastic foci with dense fibrosis are not prominent Both cellular and fibrosing patterns: No acute lung injury pattern Inconspicuous or absent eosinophils Inconspicuous or absent granulomas Negative special stains for infectious organisms or viral inclusions Abbreviations: UIP, usual interstitial pneumonia; H&E, hematoxylin and eosin. Source: From Refs. 8 and 12.
even small foci of intraluminal fibrosis resembling bronchiolitis obliterans organizing pneumonia (BOOP) in specimens of NSIP (3). The overlap of histologic features within different subtypes of the IIPs can confound even the most expert pathologist. Nicholson et al. evaluated the level of agreement (kappa) among 10 expert thoracic pathologists in the United Kingdom (65). The diagnosis of NSIP was present in over 50% of divergent cases and the overall kappa for a diagnosis of NSIP was only 0.32 (fair). In a subsequent study, Lettieri et al. examined the agreement between general and specialty pathologists, finding discordance in more than 50% of cases and misclassification of NSIP by the general pathologist in 8 of 10 subjects (66). This misclassification represents an important problem as the prognosis of NSIP is predicted on the accuracy of pathologic classification, including the ability to differentiate fibrotic NSIP from UIP/IPF. Pathologists with expertise in ILD are also more likely to make a diagnosis of NSIP while community-based pathologists are more likely to make a diagnosis of IPF/UIP during an evaluation of the same specimens (31). The presence of fibrosis within NSIP tissue specimens also portends a worsening clinical prognosis and higher disease-specific mortality rates (3,10–13).
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Given these data and associated prognostic implications, expert pulmonary pathologists should serve as the primary interpreters of SLBs from patients with suspected NSIP. Furthermore, interpretation of tissue specimens should include a qualitative and quantitative assessment of fibrosis in individual cases of NSIP. B.
Pathogenesis
The pathogenesis of NSIP remains unknown and widely understudied as compared with its counterpart UIP/IPF. Many clinicians and scientists support the hypothesis that NSIP represents a variant of autoimmune disease given its known association with connective tissue disease, including dermatomyositis and scleroderma in particular. Data from UIP/IPF suggest a disease model involving epithelial cell injury, basement membrane degradation, possible epithelial to mesenchymal transition, and persistent fibroblast/myofibroblast activity. The fibroblast is a key effector cell in this paradigm of fibrotic lung disease (67) with the cytokine, transforming growth factor-beta (TGF-b), affecting a persistently active, differentiated myofibroblast phenotype. Interestingly, this model has not been substantiated in the pathogenesis of NSIP. Although there is an overlap in clinical, radiographic, and histopathologic features between NSIP and UIP/IPF, it remains unknown whether NSIP and UIP are separate entities or represent a continuum of the same pathophysiologic process. There are differences reported in the cytokine profiles/chemokine receptors (37,68–72) and matrix metalloproteinase profiles (73) of NSIP and UIP/IPF. These differences may explain the unique nature of the lymphoplasmocytic infiltrate associated with NSIP. The biochemical, cellular, and genetic studies to date are limited in their ability to form an explanatory paradigm for the pathogenesis of NSIP. Clearly, further studies are needed to better illucidate an understanding of the pathogenesis of NSIP. V.
Natural History and Prognosis
The natural history of NSIP is unknown as there are no prospective studies of untreated patients with NSIP. Most of the data regarding the outcome of patients with NSIP stem from retrospective analyses of patients previously classified as IPF/CFA; the vast majority of these patients were treated with immunosuppressive agents. Compared with IPF/CFA, the overall prognosis and response to therapy for NSIP are favorable (9–13). Latsi et al. illustrated this in a study comparing patients with UIP (n ¼ 61) and NSIP (n ¼ 43) (74). Patients with NSIP had a more favorable prognosis (median survival 56 vs. 33 months), however, survival differences did not appear until after two years of follow-up. Over time, an individual’s physiologic course may become as important or more important that the baseline histopathology (38,74,75). Histopathology (UIP vs. NSIP) predicted prognosis at baseline and when six-month changes in pulmonary physiology were examined. After 12 months of follow-up, physiology predicted subsequent mortality while histopathology was no longer predictive
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(74). At 12 months, change in DLCO was the strongest determinant of mortality (74). In a similar study, Jegal et al. found that at baseline a lower DLCO, older age, and diagnosis of UIP were risk factors for subsequent mortality while gender, forced vital capacity (FVC), and partial pressure of oxygen (PaO2) were not (38). Initial DLCO, change in FVC, and gender were predictors of mortality after six months of follow-up, while age, histopathology, baseline FVC, and PaO2 were not (38). Together these data suggest that histopathology is a good baseline predictor of subsequent mortality; however, changes in physiology over time become more important than histopathology. Patients with NSIP demonstrating signs of progression despite treatment should be considered for lung transplantation, similar to a patient with IPF/UIP. VI.
Management and Treatment
Patients with NSIP often have a favorable response to immunosuppressive therapy including but not limited to corticosteroids (3,9–13,18–20,22,26,36,40,41,76,77). Treatment response is variable, and progressive disease despite treatment is predictive of increased mortality (38,74). Multiple series suggest that most patients with NSIP warrant a trial of immunosuppressive therapy (3,9–13,18–20, 22,26,36,40,41,76,77). Furthermore, these series support that the majority of patients with NSIP will respond to treatment with immunosuppressive agents. In patients with CVD and concurrent NSIP, disease appropriate immunosuppressive treatment of the CVD will often suffice as treatment for the NSIP. Following an initial response, some patients will relapse following the cessation of immunosuppressive treatment, suggesting a need for long-term treatment (18). VII.
Conclusion
NSIP represents a distinct category of the IIPs with histopathologic features including uniform cellular histology associated with temporal homogeneity. Its association with varied clinical entities including CVD warrants a comprehensive evaluation to identify a potential cause. An accurate diagnosis of NSIP is furthered by a coordinated, integrative approach that includes the clinician, subspecialty pathologist, and subspecialty radiologist. This approach is further enhanced if undertaken in a center specializing in the diagnosis and treatment of ILD. References 1. Bojko T, Notterman DA, Greenwald BM, et al. Acute hypoxemic respiratory failure in children following bone marrow transplantation: an outcome and pathologic study. Crit Care Med 1995; 23:755–759. 2. Griffiths MH, Miller RF, Semple SJ. Interstitial pneumonitis in patients infected with the human immunodeficiency virus. Thorax 1995; 50:1141–1146.
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62. Flaherty K, Travis W, Colby T, et al. Histologic variability in usual and nonspecific interstitial pneumonias. Am J Resp Crit Care Med 2001; 164:1722–1727. 63. Monaghan H, Wells AU, Colby TV, et al. Prognostic implications of histologic patterns in multiple surgical lung biopsies from patients with idiopathic interstitial pneumonias. Chest 2004; 125:522–526. 64. Kondoh Y, Taniguchi H, Kitaichi M, et al. Acute exacerbation of interstitial pneumonia following surgical lung biopsy. Respir Med 2006; 100:1753–1759. 65. Nicholson AG, Addis BJ, Bharucha H, et al. Inter-observer variation between pathologists in diffuse parenchymal lung disease. Thorax 2004; 59:500–505. 66. Lettieri CJ, Veerappan GR, Parker JM, et al. Discordance between general and pulmonary pathologists in the diagnosis of interstitial lung disease. Respir Med 2005; 99:1425–1430. 67. Selman M, King Jr. T, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134:136–151. 68. Choi ES, Jakubzick C, Carpenter KJ, et al. Enhanced monocyte chemoattractant protein-3/CC chemokine ligand-7 in usual interstitial pneumonia. Am J Respir Crit Care Med 2004; 170:508–515. 69. Jakubzick C, Choi ES, Kunkel SL, et al. Augmented pulmonary IL-4 and IL-13 receptor subunit expression in idiopathic interstitial pneumonia. J Clin Pathol 2004; 57:477–486. 70. Keogh KA, Limper AH. Characterization of lymphocyte populations in nonspecific interstitial pneumonia. Respir Res 2005; 6:137. 71. Park C, Chung S, Ki S, et al. Increased levels of interleukin-6 are associated with lymphocytosis in bronchoalveolar lavage fluids of idiopathic nonspecific interstitial pneumonia. Am J Respir Crit Care Med 2000; 162:1162–1168. 72. Takehara H, Tada S, Kataoka M, et al. Intercellular adhesion molecule-1 in patients with idiopathic interstitial pneumonia. Acta Med Okayama 2001; 55:205–211. 73. Suga M, Iyonaga K, Okamoto T, et al. Characteristic elevation of matrix metalloprotinase activity in idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2000; 162:1949–1956. 74. Latsi PI, du Bois RM, Nicholson AG, et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med 2003; 168:531–537. 75. Flaherty K, Mumford J, Murray S, et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003; 168:543–548. 76. Shimizu S, Yoshinouchi T, Ohtsuki Y, et al. The appearance of S-100 proteinpositive dendritic cells and the distribution of lymphocyte subsets in idiopathic nonspecific interstitial pneumonia. Respir Med 2002; 96:770–776. 77. Kondoh Y, Taniguchi H, Yokoi T, et al. Cyclophosphamide and low-dose prednisolone in idiopathic pulmonary fibrosis and fibrosing nonspecific interstitial pneumonia. Eur Respir J 2005; 25:528–533.
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14 Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RB-ILD) and Desquamative Interstitial Pneumonia (DIP)
JAY H. RYU Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A.
I.
Introduction
Respiratory bronchiolitis–associated interstitial lung disease (RB-ILD) and desquamative interstitial pneumonia (DIP) are two of the seven entities currently classified under the rubric of idiopathic interstitial pneumonias (1). These two terms are used in referring to clinical-radiologic-pathologic diagnoses; underlying histopathologic patterns are RB and DIP, respectively (1). Accumulated evidence suggests that these disorders are related to cigarette smoking in most cases, i.e., smoking-related interstitial lung diseases (2,3). Cigarette smoke is a complex mixture of more than 6000 diverse chemicals and is the leading cause of preventable deaths in the United States (4,5). RB-ILD and DIP are highly related and with more extensive changes seen in DIP compared with RB-ILD.
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Respiratory Bronchiolitis–Associated Interstitial Lung Disease
Originally described by Niewoehner and colleagues in 1974 (6), RB is a histopathologic finding present in the vast majority of cigarette smokers and is characterized by the presence of pigmented intraluminal macrophages within first- and second-order respiratory bronchioles. In many smokers, RB simply represents a histologic marker of exposure to tobacco smoke and commonly occurs without clinical or radiologic evidence of lung disease. In a small minority of smokers, ILD occurs in association with this lesion, and this entity was named RB-ILD by Myers and colleagues in 1987 (7). All six patients described in their report were heavy smokers with chest radiographic evidence of parenchymal infiltrates; five patients presented with respiratory symptoms, while the remaining patient was asymptomatic. A.
Epidemiologic and Clinical Features
It is unknown why RB-ILD develops in some smokers. Although some patients are heavy smokers, a wide range of smoking exposure is seen in those affected with RB-ILD (8,9). Several case series have described clinical, radiologic, and histopathologic features of RB-ILD in the past 20 years (8–15). Most patients with RB-ILD are in their third through sixth decades of life, with roughly equal distribution between men and women (8–15). The majority of patients diagnosed to have RB-ILD are active smokers, and nearly all patients have a smoking history (8–15). Exceptional cases of RB-ILD in nonsmokers related to occupational exposures or secondhand smoke exposure have been described (11,13). Cough and dyspnea are common presenting complaints. Auscultation of the lungs reveals inspiratory crackles in about one-half of patients (8,9). Digital clubbing is occasionally seen (8,9,11). B.
Radiologic Features
Chest radiography generally reveals bilateral, fine reticular, or reticulonodular opacities in over two-thirds of patients but may appear normal in up to 20% of patients with RB-ILD (7,8). Bronchial wall thickening, described by some authors as a relatively common radiographic feature, can be difficult to appreciate (12). In some patients, ground-glass opacities may be the predominant abnormality on chest radiography (8). High-resolution computed tomographic (HRCT) findings in RB-ILD usually include areas of ground-glass attenuation (Fig. 1); fine centrilobular nodules and bronchial wall thickening are also common findings (8,9,12). Associated emphysematous changes are expected, but honeycombing is unusual (8,9,12).
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Figure 1 High-resolution chest CT of respiratory bronchiolitis–associated interstitial lung disease in a 50-year-old smoker. Patchy areas of ground-glass opacities are present bilaterally. C.
Pulmonary Function Findings
Pulmonary function results may sometimes be normal but more commonly show abnormalities in an obstructive, restrictive, or mixed pattern; reduced diffusing capacity is also common (8,9). The degree of physiologic abnormalities is typically mild to moderate rather than severe (8,9). Portnoy and colleagues (9) reported a significant response to inhaled bronchodilator in 12% of patients with RB-ILD. Resting hypoxemia is uncommon (8,9). D.
Diagnosis
The diagnosis of RB-ILD should be considered in adult patients with a smoking history and radiologic evidence of ILD. The suspicion for this diagnosis is heightened by the presence of ground-glass opacities and centrilobular nodules on HRCT. Definitive diagnosis generally requires a surgical lung biopsy (8,9). Bronchoscopic biopsy has a low yield in the diagnosis of RB-ILD, and bronchoalveolar (BAL) findings are nondiagnostic (8,9). Pigmented macrophages (smoker’s macrophages) can be seen in the BAL fluid and indicate exposure to tobacco smoke, but do not necessarily establish the diagnosis of RB-ILD. The histopathologic findings needed for the diagnosis of RB-ILD are those of RB itself, i.e., RB-ILD and RB cannot be separated on histopathologic basis alone (7,8,13). These features include the presence of yellow-brown pigmented macrophages in the lumens of respiratory bronchioles, alveolar ducts, and peribronchiolar alveolar spaces without significant associated interstitial pneumonia (2,8,9). At low magnification, these features are patchy and generally confined to peribronchiolar regions (bronchiolocentric). Mild peribronchiolar fibrosis can be seen.
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Management and Prognosis
Since most of the evidence suggests a causal role for tobacco smoking in the development of RB-ILD, smoking cessation needs to be an essential component of managing smokers diagnosed to have this disorder. This may be the only form of therapeutic maneuver needed for some patients with RB-ILD. Several reports have suggested improvement with the use of corticosteroids, whereas more recent data suggest that corticosteroid therapy has a relatively modest effect on the course of this disease (7–9). If corticosteroid therapy is employed, the dose and duration of corticosteroids need to be tailored to the severity of disease and individual circumstances. We typically use oral prednisone at the initial dose of 30 to 40 mg/day, with subsequent tapering over a course of several weeks or months. Other modes of pharmacologic therapy have included azathioprine, cyclophosphamide, inhaled corticosteroids, and inhaled bronchodilators; limited evidence suggests no substantial clinical benefit attributable to these therapies (9). For most patients with RB-ILD, the prognosis is generally good and progressive respiratory impairment is unusual (8,9). However, it should be noted that respiratory symptoms, pulmonary function abnormalities, and abnormal radiologic findings related to RB-ILD can persist for months to years despite smoking cessation (8,9). Portnoy and colleagues (9) have described clinical worsening in some patients with RB-ILD even after smoking cessation. In this regard, it is interesting to note that histologic changes of RB have been shown to persist for up to 30 years following smoking cessation (13). III.
Desquamative Interstitial Pneumonia
DIP was originally described in 1965 by Liebow (16), who coined the term DIP in the belief that desquamation of alveolar epithelial cells underlie the dominant histologic feature. In actuality, the cells filling the alveolar spaces are macrophages that contain finely granular dusty brown pigment. A.
Epidemiologic and Clinical Features
DIP usually affects adults; age at onset of symptoms is generally 30 to 50 years (8,10,17). Approximately 80% to 90% of patients with DIP are active smokers or have smoked in the past (8,10,17,18). There have been cases of DIP associated with connective tissue diseases, viral infections (e.g., hepatitis C), occupational/ environmental exposures, and drugs (e.g., nitrofurantoin) (17–21). In addition, a lesion resembling DIP has been described in infants with mutations in the surfactant protein C gene (22). The clinical presentation of patients with DIP is nonspecific and consists of chronic dyspnea and cough. Physical examination reveals inspiratory crackles in approximately 60% and digital clubbing in 25% to 50% of patients (8,10,17).
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Figure 2 High-resolution chest CT of desquamative interstitial pneumonia in a 58-year-old smoker. Extensive areas of ground-glass opacities are present bilaterally.
B.
Radiologic Features
Chest radiography will usually reveal parenchymal infiltrates, and lung volume appears reduced unless there is coexisting obstructive airway disease (8,10,17). The chest radiographic appearance is nonspecific and consists of patchy groundglass attenuation with a lower zone predominance or nonspecific reticular or reticulonodular pattern (8,10,17). The chest radiograph may look normal in up to 20% of DIP cases (8,10,17). HRCT usually reveals ground-glass opacities located predominantly in the lower lung zones and often with a peripheral distribution (Fig. 2). The HRCT findings in DIP can overlap with those of RB-ILD. Irregular linear opacities and reticular pattern can be present, but honeycombing is uncommon and limited in extent (12,23–25). Parenchymal cysts and emphysematous changes may also be seen in some patients (25). C.
Pulmonary Function Findings
Pulmonary function testing yields various patterns of abnormalities, with a restrictive defect being the most common (8,10,17). The degree of physiologic abnormalities tend to be more severe than those seen with RB-ILD, but pulmonary function results may be normal in up to 20% of patients at the time of diagnosis (8,10,17).
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Figure 3 Histopathology of desquamative interstitial pneumonia (DIP). Alveolar spaces are filled with pigmented macrophages. D.
Diagnosis
The diagnosis of DIP should be considered when ground-glass opacities are the predominant finding on HRCT, particularly in the presence of a smoking history. Definitive diagnosis of DIP usually requires a surgical lung biopsy. Bronchoscopic biopsy has a low yield in the diagnosis of DIP (8,10,17). As in RB-ILD, BAL findings are nonspecific and not diagnostic. Histopathologically, DIP is characterized by filling of alveolar spaces with pigmented alveolar macrophages (Fig. 3). Parenchymal involvement seen in DIP is more extensive and uniform compared with that of RB-ILD, but the histologic distinction between these two entities may at times be difficult (1,8,10). Alveolar septal fibrosis and mild interstitial inflammation may be present, but honeycomb change is unusual. Fibroblast foci are not seen. Compared with RB-ILD, DIP exhibits greater extent of interstitial fibrosis, lymphoid follicles, and eosinophilic infiltration (15). E.
Management and Prognosis
The development of DIP is likely related to smoking in the majority of adults with this disease, and smoking cessation is an essential component in the management of affected subjects. In nonsmokers with DIP, other potential causes that were previously discussed need to be considered and treated accordingly. Corticosteroid therapy provides a relatively modest benefit in the treatment of DIP and may not lead to complete resolution of disease even with long-term treatment (8,10,17,24,26). The dose and duration of corticosteroid therapy need to be tailored to the severity of disease and individual circumstances.
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We typically use oral prednisone at the initial dose of 30 to 60 mg/day, with gradual tapering over a course of several months. The role of cytotoxic and other immunosuppressive agents remains undefined, but successful use of these agents has been described in a few cases (27). Lung transplantation is a treatment option to consider for a minority of patients who have severe persistent disease. Recurrence of DIP can occur in the transplanted lung (28–30). The prognosis for patients with DIP is worse than that associated with RB-ILD and includes a mortality rate of 26% to 32% (8,10,17,18). DIP can gradually progress, particularly in those who continue to smoke (8). The most common causes of death are respiratory failure from progressive DIP and lung cancer (8). IV.
Conclusions
It appears likely that both RB-ILD and DIP are causally related to smoking in the majority of cases. Relatively little is known regarding the mechanisms by which tobacco smoke induces these interstitial lung diseases in a small minority of smokers. There are differences in the clinical course and prognosis associated with these two disorders, although clinical, radiologic, and histopathologic features do overlap. To date, there has been no documented progression from RB-ILD to DIP. References 1. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165:277–304. 2. Ryu JH, Colby TV, Hartman TE, et al. Smoking-related interstitial lung diseases: a concise review. Eur Respir J 2001; 17:122–132. 3. Caminati A, Harari S. Smoking-related interstitial pneumonias and pulmonary Langerhans cell histiocytosis. Proc Am Thor Soc 2006; 3:299–306. 4. Leistikow BN. The human and financial cost of smoking. Clin Chest Med 2000; 21: 189–197. 5. American Thoracic Society. Cigarette smoking and health. Am J Respir Crit Care Med 1996; 153:861–865. 6. Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med 1974; 291:755–758. 7. Myers JL, Veal CF Jr., Shin MS, et al. Respiratory bronchiolitis causing interstitial lung disease: a clinicopathologic study of six cases. Am Rev Respir Dis 1987; 135: 880–884. 8. Ryu JH, Myers JL, Capizzi SA, et al. Desquamative interstitial pneumonia and respiratory bronchiolitis-associated interstitial lung disease. Chest 2005; 127:178–184. 9. Portnoy J, Veraldi KL, Schwarz MI, et al. Respiratory bronchiolitis-interstitial lung disease: long-term outcome. Chest 2007; 131:664–671.
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10. Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc 1989; 64:1373–1380. 11. Moon J, du Bois RM, Colby TV, et al. Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking related interstitial lung disease. Thorax 1999; 54:1009–1014. 12. Heyneman LE, Ward S, Lynch DA, et al. Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process? AJR Am J Roentgenol 1999; 173:1617–1622. 13. Fraig M, Shreesha U, Savici D, et al. Respiratory bronchiolitis: a clinicopathologic study in current smokers, ex-smokers, and never-smokers. Am J Surg Pathol 2002; 26: 647–653. 14. Park JS, Brown KK, Tuder RM, et al. Respiratory bronchiolitis-associated interstitial lung disease: radiologic features with clinical and pathologic correlation. J Comput Assist Tomogr 2002; 26:13–20. 15. Craig PJ, Wells AU, Doffman S, et al. Desquamative interstitial pneumonia, respiratory bronchiolitis and their relationship to smoking. Histopathology 2004; 45: 275–282. 16. Liebow AA, Steer A, Billingsley JG. Desquamative interstitial pneumonia. Am J Med 1965; 39:369–404. 17. Carrington CB, Gaensler EA, Coutu RE, et al. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 1978; 298:801–809. 18. Travis WD, Matsui K, Moss J, et al. Idiopathic nonspecific interstitial pneumonia: prognostic significance of cellular and fibrosing patterns. Am J Surg Pathol 2000; 24:19–33. 19. Bone RC, Wolfe J, Sobonya RE, et al. Desquamative interstitial pneumonia following chronic nitrofurantoin therapy. Chest 1982; 81:321–325. 20. Lougheed MD, Roos JO, Waddell WR, et al. Desquamative interstitial pneumonitis and diffuse alveolar damage in textile workers: potential role of mycotoxins. Chest 1995; 108:1196–1200. 21. Kern DG, Kuhn C III, Ely W, et al. Flock worker’s lung: broadening the spectrum of clinicopathology, narrowing the spectrum of suspected etiologies. Chest 2000; 117: 251–259. 22. Nogee LM, Dunbar AE, Wert SE, et al. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 2001; 344:573–579. 23. Hartman TE, Primack SL, Swensen SJ, et al. Desquamative interstitial pneumonia: thin-section CT findings in 22 patients. Radiology 1993; 187:787–790. 24. Akira M, Yamamoto S, Hara H, et al. Serial computed tomographic evaluation in desquamative interstitial pneumonia. Thorax 1997; 52:333–337. 25. Sumikawa H, Johkoh T, Ichikado K, et al. Usual interstitial pneumonia and chronic idiopathic interstitial pneumonia: analysis of CT appearance in 92 patients. Radiology 2006; 241:258–266. 26. Hartman TE, Primack SL, Yang EY, et al. Disease progression in usual interstitial pneumonia compared with desquamative interstitial pneumonia: assessment with serial CT. Chest 1996; 110:378–382.
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27. Flusser G, Gurman G, Zirkin H, et al. Desquamative interstitial pneumonitis causing acute respiratory failure, responsive only to immunosuppressants. Respiration 1991; 58:324–326. 28. Barberis M, Mazari S, Tironi A, et al. Recurrence of primary disease in a single lung transplant recipient. Transplant Proc 1992; 24:2660–2662. 29. Verleden GM, Sels F, Van Raemdonck D, et al. Possible recurrence of desquamative interstitial pneumonitis in a single lung transplant recipient. Eur Respir J 1998; 11: 971–974. 30. King MB, Jessurun J, Hertz MI. Recurrence of desquamative interstitial pneumonia after lung transplantation. Am J Respir Crit Care Med 1997; 156:2003–2005.
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15 Acute Interstitial Pneumonia (AIP)
JASON VOURLEKIS Inova Fairfax Hospital, Falls Church, Virginia, U.S.A.
KEVIN K. BROWN National Jewish Medical and Research Center, Denver, Colorado, U.S.A.
I.
Introduction
The idiopathic interstitial pneumonias (IIP) are a heterogeneous group of pulmonary diseases that share a general though not universal propensity for the insidious development of chronic and progressive lung injury. Acute interstitial pneumonia (AIP) is unique among the IIP with its rapid onset, early respiratory failure, and high initial case fatality ratio. Survivors of the initial insult have a more favorable long-term prognosis than the most common of the IIP, idiopathic pulmonary fibrosis (IPF). A rare disease, our current knowledge of AIP is limited and is derived mostly from observational studies of small case series. II.
Historical Perspective and Current Case Definition
In 1935, Hamman and Rich reported four cases of a syndrome characterized by rapidly progressive fibrosing lung disease of unknown etiology that appeared to share a common histologic pattern on surgical lung biopsy (1,2). Based on the subsequent recognition that the clinical course of fibrosing interstitial pneumonia was not uniform and that the pathologic patterns seen on surgical lung biopsy 389
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Table 1 Case Definition of Acute Interstitial Pneumonitis Required criteria Acute lower respiratory tract illness of 60 days duration Diffuse bilateral radiographic infiltrates Organizing Diffuse Alveolar Damage on surgical lung biopsy Absence of any known inciting event or predisposing condition including infection, SIRS, environmental or toxic exposures, connective tissue disease, prior ILD Absence of a previously abnormal chest X-ray Abbreviations: SIRS, systemic inflammatory response syndrome; ILD, interstitial lung disease.
appeared to be separable, Averil Liebow proposed a comprehensive histopathologic classification scheme in 1975 that was widely adopted (3). He described five distinct pathologic patterns: usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), bronchiolitis obliterans with interstitial pneumonia (BIP), lymphoid interstitial pneumonia (LIP), and giant cell interstitial pneumonia (GIP). The clinically rapid forms of pulmonary fibrosis, including Hamman-Rich syndrome, were included under UIP (4). In 1986, Katzenstein and Myers reported eight patients who had acute respiratory failure and the lung pathologic pattern of organizing diffuse alveolar damage (DAD) (5). They likened the disease to the acute interstitial fibrosis first reported by Hamman and Rich and suggested the term ‘‘acute interstitial pneumonitis.’’ Subsequently, Olson et al. summarized the Mayo Clinic experience with AIP (6). As part of their study, they reviewed three of Hamman and Rich’s original cases and confirmed the organizing DAD pattern (7). These observations effectively established AIP and Hamman-Rich syndrome as the same clinicopathologic entity and clearly distinguished AIP from IPF. With the publication of two international consensus statements on the IIP, the American Thoracic Society and the European Respiratory Society formally recognized AIP as a distinct IIP with cardinal features of rapid symptom onset, unknown causation, and the presence of a DAD pattern on surgical lung biopsy (8,9). As these same clinical and pathologic features are present in patients with known causes of lower respiratory tract disease, in particular the acute respiratory distress syndrome (ARDS) and overwhelming lower respiratory tract infection, AIP is by necessity, a diagnosis of exclusion (Table 1). III.
Clinical Features
A rapid onset and progression of symptoms is characteristic. Medical attention is sought within days to not more than a few weeks of symptom onset. The majority of patients describe a flu-like prodrome that may include sore throat, headache, myalgia, and malaise (10). Cough is present in nearly all patients. Most patients complain of dyspnea at presentation, although occasionally it is a late symptom (11). Fever is variably present, ranging from 35–75% in selected
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case series. A small subset of patients experience the subacute onset of symptoms and initially present as outpatients (11,12). The physical examination findings are not specific. Patients appear acutely ill and most of them are tachycardic, tachypneic, and hypoxemic at baseline. Both crackles and wheezes may be heard. The presence of an exanthem, synovitis, or other signs of extrapulmonary disease is unusual and suggests an alternative diagnosis such as infection or a systemic autoimmune disorder. Initial radiographic findings may be minimal. Early in the disease course, plain chest films often show only patchy, air-space densities consistent with an atypical pneumonia (11). In most cases (Figs. 1 and 2) the infiltrates progress to
Figure 1 Anterior-posterior chest radiograph of a patient with acute interstitial pneumonitis. There is diffuse ground-glass abnormality present within all five lung lobes.
Figure 2 CT scan of a patient with biopsy-proven acute interstitial pneumonitis showing diffuse ground-glass infiltrate in both lungs. The pattern of abnormality is typical but not diagnostic of acute interstitial pneumonia.
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a diffuse alveolar pattern involving all five lobes (13). High-resolution computerized tomography (HRCT) shows primarily diffuse ground-glass opacities, though consolidative opacities with air bronchograms are also seen (13–15). With persistent or progressive disease, traction bronchiectasis indicative of fibrosis develops (14,15). IV.
Pathology
AIP is defined on surgical lung biopsy by the presence of the organizing, DAD pathologic pattern. Its histologic features include: a diffuse distribution of alveolar epithelial injury with a uniform temporal appearance, alveolar septal thickening due to organizing fibrosis, usually diffuse airspace organization (may be patchy or diffuse), and hyaline membranes (may be focal or diffuse). Granulomas, necrosis or abscesses, and positive evidence of infection, prominent eosinophils or neutrophils should all be absent (5,6,9) (Fig. 3). Proteinaceous fluid leaks into the alveolar space to form hyaline membranes. Complete effacement of air spaces can occur due to the apposition of adjacent alveolar septa denuded of their epithelium. The interstitial thickening results from a combination of edema, chronic inflammatory cell infiltrate, fibroblast proliferation and the deposition of immature collagen (5). In the proliferative phase the air space exudate is organized, there is type II cell hyperplasia, and scattered hyaline membrane remnants may be present. Spindle-shaped fibroblasts and immature collagen bundles can be seen both within the interstitium and the air spaces, and may resemble the fibroblast foci of UIP. A fibrotic phase can occur and here, microscopic honeycombing may be seen (6,11). This DAD pattern should be distinguished from cryptogenic organizing pneumonia (COP) and acute fibrinous and organizing pneumonia (AFOP). Rarely, DAD may be superimposed on a background pattern of UIP during an acute exacerbation of IPF (16). In COP, the fibroblastic proliferation occurs within intact bronchioles, alveolar ducts, and air spaces rather than the interstitium, with the production of immature collagen bundles, known as ‘‘Masson bodies’’ (17). AFOP is a recently described entity, characterized by the patchy presence of fibrin ‘‘balls’’ within the air spaces, the absence of hyaline membranes, and the presence of loose, fibrin-associated intraluminal connective tissue within the bronchioles and alveolar ducts (18). Septal fibrosis is minimal and a diffuse interstitial lymphoplasmocytic infiltrate is uniformly present.
V.
Pathogenesis
The underlying cause of AIP is by definition unknown, and while an understanding of the pathobiology would provide the template for treatment, only hypotheses are available. As with most of the interstitial lung diseases, these hypotheses are driven by the pathologic pattern seen on surgical lung biopsy.
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Figure 3 (See color insert.) Photomicrographs of multiple stages of hematoxylin-eosin stained diffuse alveolar damage. (A). Acute/exudative phase (200). Note the hyaline membrane (arrow); (B). Early organizing/proliferative phase (400). Note the airspace hyaline membrane being incorporated into organized fibroblastic tissue (arrow); (C). Late organizing phase (100). Note the expansion of the septae by fibroblastic tissue and cellular inflammation (arrow); (D). Fibrotic phase (40). This phase of acute interstitial pneumonia pattern histology is similar to fibrotic nonspecific interstitial pneumonia with homogenous interstitial thickening with collagen. Source: Courtesy of Steve Groshong, M.D., Ph.D.
The acute clinical onset of the disease and the temporal uniformity of the injury suggest a single initial insult. Pathologically, this begins with the exudative phase of DAD, with type I alveolar cell death, disruption of the alveolar-capillary membrane barrier, and exudation of proteinaceous fluid into the alveolar space with the formation of fibrin-rich hyaline membranes (19) (Fig. 3A). The hyaline membranes may provide scaffolding for the migration of inflammatory cells and fibroblasts into the alveolar space. Upregulation of adhesion molecules on the vascular endothelium and formation of intercellular gaps allows the migration of neutrophils into the alveolar septa and air spaces (20). These steps are associated with neutrophil and alveolar macrophage activation and the production of proinflammatory cytokines (21). The transition from exudative to proliferative DAD is marked by interstitial thickening, hyaline membrane remnants, organization of alveolar exudates, and early production of collagen (17,22) (Fig. 3B). Platelet-derived growth
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factor (PDGF) (23) and transforming growth factors alpha and beta (TGF-a, TGF-b) (24–27) all appear to play a role. The TGFs and PDGF are potent inducers of fibroblast proliferation (28,29), while TGF-b stimulates the conversion of fibroblasts to myofibroblasts (30) as well as the production of collagen and other extracellular matrix proteins. Myofibroblasts and alveolar epithelial cells both express matrix-metalloproteinases that disrupt the basement membrane and allow myofibroblasts to migrate into the airspace (31,32) where they produce collagen types III, IV, and VI, and fibronectin (32–35). The subsequent production of Type I collagen heralds a state of irreversible fibrosis due to its greater resistance to metalloproteinase digestion (35–37). This orderly progression from exudative through proliferative phases to lung fibrosis is not absolute. In an autopsy study of ARDS, only 37.5% of patients mechanically ventilated for two or more weeks before death, developed pulmonary fibrosis (38). Therefore, other factors are necessary to progress to endstage fibrotic lung (39). The factors that determine successful tissue repair versus progressive fibrosis in AIP are also unknown. In normal wound healing, tissue injury is followed by migration and proliferation of fibroblasts, production of extracellular matrix, angiogenesis, re-establishment of the epithelial border, and subsequent fibroblast cell death (apoptosis) with partial resorption of the matrix (40–42). The orderly resolution of the fibrin-rich hyaline membranes and re-epithelialization of the air space are likely essential to normal healing (40,43,44), however in DAD, myofibroblasts are protected from apoptosis while type II epithelial cells appear to be at increased risk of apoptosis (45–49). The consequences may be exuberant, uncontrolled fibroblastic proliferation, and failure to re-epithelialize the alveolus. VI.
Differential Diagnosis and Management
Any acute chest disease that produces early respiratory failure with diffuse radiographic infiltrates must be included in the differential diagnosis of AIP (Table 2). In the absence of an obvious cause, patients should initially be treated for severe community acquired pneumonia. As with any severe disease with a large and clinically diverse differential, the importance of a comprehensive medical history cannot be over emphasized. Review of prior diagnoses, all medications including illicit and recreational drug use, allergies, avocational, environmental, and occupational exposures is necessary. The finding of pathologic DAD on surgical lung biopsy is not unique to AIP (17). Hence, the biopsy findings are supportive but not diagnostic and must be interpreted carefully within the specific clinical context. For example, overwhelming pneumonia as well as several of the connective tissue diseases can be complicated by acute respiratory failure with DAD on biopsy (50–55). Most patients will require mechanical ventilation and, similar to ARDS, a low tidal volume, lung protective ventilatory strategy should be employed (56). Early bronchoalveolar lavage (BAL) helps exclude infection and diffuse alveolar
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Table 2 Differential Diagnosis of Acute Interstitial Pneumonitis Acute eosinophilic pneumonia Acute exacerbation of IPF or other chronic fibrosing ILDs Acute hypersensitivity pneumonitis ARDS Acute respiratory failure in collagen-vascular disease (e.g., dermatomyositis/ polymyositis, rheumatoid arthritis, systemic lupus erythematosus) COP (acute variant) Diffuse alveolar hemorrhage Drug-induced lung disease Infection Inhalational/toxic exposures Abbreviations: IPF, idiopathic pulmonary fibrosis; ILDs, interstitial lung diseases; ARDS, acute respiratory distress syndrome; COP, cryptogenic organizing pneumonia.
hemorrhage. The BAL cellular differential is also helpful. Neutrophilia is expected in AIP (10). Lymphocytosis or eosinophilia suggests alternative diagnoses such as hypersensitivity pneumonitis or acute eosinophilic pneumonia respectively (57). While transbronchial biopsy is helpful for diagnosis of infection or eosinophilic pneumonia, the amount of tissue obtained is generally insufficient to establish a confident pathologic pattern diagnosis of DAD or other diffuse interstitial lung diseases (ILDs). Should the results of BAL fail to provide a confident diagnosis, proceeding to surgical lung biopsy is recommended (58). The benefits of any pharmaceutical treatment for AIP are uncertain. Retrospective studies have shown conflicting results for corticosteroids (6,59). In the National Institutes of Health (NIH)-sponsored ARDS clinical research network (ARDSnet) study of corticosteroids versus placebo for late stage ARDS, the use of corticosteroids was associated with earlier liberation from mechanical ventilation but no difference in 60-day mortality (60). Furthermore, the observed mortality in both the treatment and placebo arms of 29.2% and 28.6% respectively, is consistent with the expected mortality using a lung protective ventilatory strategy (56,60). The compelling rationale for the use of corticosteroids has been their antiinflammatory and potentially antifibrotic effects (61). It is the authors’ practice to initiate treatment with intravenous corticosteroids, although this treatment decision primarily reflects the lack of other proven options and supportive care alone may yield comparable results. Given the rarity of AIP, it is likely that any treatment breakthroughs will be derived from studies of fibroproliferative ARDS (62). VII.
Survival
In-hospital mortality from AIP is common. Most studies have demonstrated case fatality ratios of 50% or greater (5,6,11–14,59,63–67). Two recent studies however, have both reported significantly lower, but still substantial, case
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Table 3 Summary of Published Case Series of Acute Interstitial Pneumonitis
First Reference author 5 6 13 63 12 14 11 69 65 66 59 67 Total
Katzenstein Olson Primack Ash Robinson Johkoh Vourlekis Ichikado Bonaccorsi Quefatieh Suh Parambil
Year published N (f/m) 1986 1990 1993 1995 1996 1999 2000 2002 2003 2003 2006 2007
8 (5/3) 29 (15/14) 7 (1/6) 1 (0/1) 1 (0/1) 36 (16/20) 13 (7/6) 31 (13/18) 4 (3/1) 8 (5/3) 10 (4/6) 12 159
Mean age (range)
Mean symptom duration (days)
Acute case fatality ratio (%)
28 (13–50) 50 (7–77) 65 (46–83) 70 49 61 (22–83) 54 (34–74) 60 (29–77) 57 (44–67) 48 (20–78) 62 (38–73) NA 55 (7–83)
3.5 (0–11) 62.5 18.3 (1–60) 59 NA 86 3 100 NA 0 NA 89 9.9 (0–60) 50 NA 68 36.8 (17–60) 75 16.8 (3–49) 12.5 13.5 (2–34) 20 NA 50 15.2 (0–60) 51
fatality ratios of 12.5% and 20% respectively (59,66). In both of these later studies, the diagnosis of AIP was established by surgical lung biopsy, raising the possibility of an ascertainment basis, whereby only patients ‘‘well enough’’ for biopsy were included. When all studies are pooled (Table 3), the mortality figure of 50% is greater than that seen in ARDS and suggests that AIP may have a different natural history. Several groups have tried to identify factors predictive of mortality in AIP. Olson et al. examined several histopathologic features including the degree of interstitial fibrosis and found no correlation with survival (6). Suh et al. attributed the low mortality in their study to an aggressive diagnostic approach coupled with early high dose, pulsed corticosteroids (59). However, both studies are observational, contain small numbers of patients, and are uncontrolled. Certain radiographic features on HRCT do appear to have predictive value. The greater the radiologic evidence of fibrosis based on the combined features of architectural distortion, traction bronchiectasis, bronchiolectasis, and honeycombing, the higher the likelihood of death (68). Similar data have been reported for ARDS (69). The natural history of AIP in survivors is variable and only limited longitudinal data is available (59,66). While ARDS survivors generally experience maximal recovery of lung function by six months and do not develop progressive lung disease (70,71), the outcome survivors of AIP varies. Many AIP survivors appear to ultimately gain complete recovery of lung function and resume their prior activity level without impairment. However, both stable persistently abnormal and progressive loss of lung function have been reported (11). Additionally though rare, survivors are at risk for recurrent AIP, subsequent respiratory events, and death.
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Conclusion
In contrast to the more insidious course of the other IIP, AIP is characterized by the rapid development of fulminant respiratory failure, few proven treatment options, and common early mortality. Clinically defined by the idiopathic presentation of pathologic DAD, its underlying cause(s) and pathobiology remains unknown. Substantial work remains to understand this rare disorder. Important initial steps toward this goal include the adoption of standard diagnostic criteria and sharing of valuable and limited clinical and biologic patient materials amongst research centers to allow the conduct of translational investigation. References 1. Hamman L, Rich AR. Fulminating diffuse interstitial fibrosis of the lungs. Trans Am Clin Climat Assoc 1935; 51(1):154–163. 2. Hamman L, Rich AR. Acute diffuse interstitial fibrosis of the lungs. Bull Johns Hopkins Hosp 1944; 74(1):177–212. 3. Liebow AA. Definition and classification of the interstitial pneumonias in human lung. Prog Respir Res 1975; 8(1):1–31. 4. Katzenstein ALA, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157(4):1301–1315. 5. Katzenstein ALA, Myers JL, Mazur MT. Acute interstitial pneumonia: a clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol 1986; 10(4): 256–267. 6. Olson J, Colby TV, Elliott CG. Hamman-rich syndrome revisited. Mayo Clin Proc 1990; 65(12):1538–1548. 7. Askin FB. Back to the future: the Hamman-Rich syndrome and acute interstitial pneumonia. Mayo Clin Proc 1990; 65(12):1624–1626. 8. King TTE Jr., Costabel U, Cordier JF, et al. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med 2000; 161(2):646–664. 9. Travis WD, King TE Jr., Bateman ED, et al. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165(2): 277–304. 10. Bouros D, Nicholson AC, Polychronopoulos V, et al. Acute interstitial pneumonia. Eur Respir J 2000; 15(2):412–418. 11. Vourlekis JS, Brown KK, Cool CD, et al. Acute interstitial pneumonitis: case series and review of the literature. Medicine 2000; 79(6):369–378. 12. Robinson DS, Geddes DM, Hansell DM, et al. Partial resolution of acute interstitial pneumonia in native lung after single lung transplantation. Thorax 1996; 51(11): 1158–1159. 13. Primack SL, Hartman TE, Ikezoe J, et al. Acute interstitial Pneumonia: radiographic and CT findings in nine patients. Radiology 1993; 188(3):817–820. 14. Johkoh T, Muller NL, Taniguchi H, et al. Acute interstitial pneumonia: thin-section CT findings in 36 Patients. Radiology 1999; 211(3):859–863.
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15. Akira M. Computed tomography and pathologic findings in fulminant forms of idiopathic interstitial pneumonia. J Thor Imaging 1999; 14(2):76–84. 16. Parambil JG, Myers JL, Ryu JH. Histopathologic features and outcome of patients with acute exacerbation of idiopathic pulmonary fibrosis undergoing surgical lung biopsy. Chest 2005; 128(5):3310–3315. 17. Katzenstein AA. Acute Lung Injury Patterns: Diffuse alveolar damage and bronchiolitis obliterans-organizing pneumonia. In: Katzenstein AA, Askin FB, eds. Surgical Pathology of Non-neoplastic Lung Disease. 3rd ed. Philadelphia: WB Saunders 1997:14–47. 18. Beasley MB, Franks TJ, Galvin JR, et al. Acute fibrinous and organizing pneumonia: a histologic pattern of lung injury and possible variant of diffuse alveolar damage. Arch Pathol Lab Med 2002; 126(9):1064–1070. 19. Pugin J, Verghese G, Widmer MC, et al. The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. Crit Care Med 1999; 27(2):304–312. 20. Doerschuk CM, Mizgerd JP, Kubo H, et al. Adhesion molecules and cellular biomechanical changes in acute lung injury. Chest 1999; 116(1):37S–43S. 21. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342(18):1334–1349. 22. Pache JC, Christakos PG, Gannon DE, et al. Myofibroblasts in diffuse alveolar damage of the lung. Mod Pathol 1998; 11(11):1064–1070. 23. Thornton SC, Por SB, Wlash BJ, et al. Interaction of immune and connective tissue cells: The effect of lymphokines and monokines on fibroblast growth. J Leukoc Biol 1990; 47(4):312–320. 24. Liu J, Brass DM, Hoyle GW, et al. TNF-a receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers. Am J Pathol 1998; 153(6): 1839–1847. 25. Brass DM, Hoyle GW, Poovey HG, et al. Reduced tumor necrosis factor-a and Transforming growth factor-b1 Expression in the lungs of inbred mice that fail to develop fibroproliferative lesions consequent to asbestos exposure. Am J Pathol 1999; 154(3):853–862. 26. Sime PJ, Marr RA, Gauldie D, et al. Transfer of tumor necrosis factor-a to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-b1 and myofibroblasts. Am J Pathol 1998; 153(3):825–832. 27. Fahy RJ, Lichtenberger F, McKeegan CB, et al. The acute respiratory distress syndrome: a role for transforming growth factor-b-1. Am J Respir Cell Mol Biol 2003; 28(4):499–503. 28. Desmouliere A, Geinoz A, Gabbiani F, et al. Transforming growth factor-b1 induces a-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 1993; 122(1):103–111. 29. Riches DWH, Worthen GS, Augustin A, et al. Inflammation in the pathogenesis of interstitial lung diseases. In: Schwarz MI, King TE Jr., eds. Interstitial Lung Disease. 4th ed. Hamilton-London: BC Decker Inc., 2003:187–220. 30. Keane MP, Belperio JA, Strieter RM. Cytokine biology and the pathogenesis of interstitial lung disease. In: Schwarz MI, King TE Jr., eds. Interstitial Lung Disease. 4th ed. Hamilton-London: BC Decker Inc., 2003:245–275.
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31. Matsubara O, Tamura A, Ohdama S, et al. Alveolar basement membrane breaks down in diffuse alveolar damage: an immunohistochemical study. Pathol Int 1995; 45(7): 473–482. 32. Hayashi T, Stetler-Stevenson WG, Fleming M, et al. Immunohistochemical study of metalloproteinases and their tissue inhibitors in the lungs of patients with diffuse alveolar damage and idiopathic pulmonary fibrosis. Am J Pathol 1996; 149(4): 1241–1256. 33. Raghu G, Striker LJ, Hudson LD, et al. Extracellular matrix in normal and fibrotic human lungs. Am Rev Respir Dis 1985; 131(2):281–289. 34. Kuhn C III, Boldt J, King TE Jr., et al. An Immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis. Am Rev Respir Dis 1989; 140(6):1693–1703. 35. Specks U, Nerlich A, Colby TV, et al. Increased expression of type VI collagen in lung fibrosis. Am J Respir Crit Care Med 1995; 151(6):1956–1964. 36. Zapol WM, Trelstad RL, Coffey JW, et al. Pulmonary fibrosis in severe acute respiratory failure. Am Rev Respir Dis 1979; 119(4):547–554. 37. Meduri GU, Eltorky M, Winer-Muram HT. The fibroproliferative phase of late adult respiratory distress syndrome. Semin Respir Infect 1995; 10(3):154–175. 38. Collins JF, Smith JD, Coalson JJ, et al. Variability in lung collagen amounts after prolonged support of acute respiratory failure. Chest 1984; 85(5):641–646. 39. McCormack FX. Genetic basis of interstitial lung disease. In: Schwarz MI, King TE Jr., eds. Interstitial Lung Disease. 4th ed. Hamilton: BC Decker Inc., 2003: 152–186. 40. Selman M, King TE Jr., Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134(2):136–151. 41. Herrick SE, Sloan P, McGurk M, et al. Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. Am J Pathol 1992; 141(5):1085–1095. 42. Desmouliere A, Redard M, Darby I, et al. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 1995; 146(1):56–66. 43. Toews GB. Cellular alterations in fibroproliferative lung disease. Chest 1999; 116 (S1):112S–116S. 44. Burkhardt A. Alveolitis and collapse in the pathogenesis of pulmonary fibrosis. Am Rev Respir Dis 1989; 140(2):513–524. 45. Guinee D Jr., Fleming M, Hayashi T, et al. Association of p53 and WAF1 expression with apoptosis in diffuse alveolar damage. Am J Pathol 1996; 149(2): 531–538. 46. Guinee D Jr., Brambilla E, Fleming M, et al. The potential role of BAX and BCL-2 expression in diffuse alveolar damage. Am J Pathol 1997; 151(4):999–1007. 47. Bardales RH, Xie SS, Schaefer RF, et al. Apoptosis is a major pathway responsible for the resolution of Type II pneumocytes in acute lung injury. Am J Pathol 1996; 149(3):845–852. 48. Adamson A, Perkins S, Brambilla E, et al. Proliferation, C-myc, and Cyclin D11 expression in diffuse alveolar damage: potential roles in pathogenesis and implications for prognosis. Hum Pathol 1999; 30(9):1050–1057.
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49. Martin TR, Hagimoto N, Nakamura M, et al. Apoptosis and epithelial injury in the lungs. Proc Am Thorac Soc 2005; 2(3):214–220. 50. Matthay RA, Schwarz MI, Petty TL, et al. Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine 1974; 54(5):397–409. 51. Pratt DS, Schwarz MI, May JJ, et al. Rapidly fatal pulmonary fibrosis: The accelerated variant of interstitial pneumonitis. Thorax 1979; 34(5):587–593. 52. Tazelaar HD, Viggiano RW, Pickersgill J, et al. Interstitial lung disease in polymyositis and dermatomyositis: clinical features and prognosis as correlated with histologic findings. Am Rev Respir Dis 1990; 141(3):727–733. 53. Kreidstein SH, Lytwyn A, Keystone EC. Takayasu arteritis with acute interstitial pneumonia and coronary vasculitis: expanding the spectrum. Arthritis Rheum 1993; 36(8):1175–1178. 54. Akikusa B, Kondo Y, Irabu N, et al. Six cases of microscopic polyarteritis exhibiting acute interstitial pneumonia. Pathol Int 1995; 45(8):580–588. 55. Muir TE, Tazelaar HD, Colby TV, et al. Organizing diffuse alveolar damage associated with progressive systemic sclerosis. Mayo Clin Proc 1997; 72(6):639–642. 56. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342(18):1301–1308. 57. Schwarz MI. The acute (noninfectious) interstitial lung diseases. Compr Ther 1996; 22(10):622–630. 58. Papazian L, Doddoli C, Chetaille B, et al. A contributive result of open-lung biopsy improves survival in acute respiratory distress patients. Crit Care Med 2007; 35(3): 755–762. 59. Suh GY, Kang EH, Chung MP, et al. Early intervention can improve clinical outcome of acute interstitial pneumonia. Chest 2006; 129(3):753–761. 60. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006; 354(16): 1671–1684. 61. Meduri GU, Tolley EA, Chrousos GP, et al. Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome. Am J Respir Crit Care Med 2002; 165(7):983–991. 62. Schultz MJ, Haitsma JJ, Zhang H, et al. Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia––a review. Crit Care Med 2006; 34(3):871–877. 63. Ash N, Liokumovich P, Cohen Y, et al. Acute interstitial pneumonia: a case of Hamman-Rich sydrome. Isr J Med Sci 1995; 31(6):367–370. 64. Ichikado K, Johkoh T, Ikezoe J, et al. Acute interstitial pneumonia: high-resolution CT findings correlated with pathology. AJR Am J Roentgenol 1997; 168(2):333–338. 65. Bonaccorsi A, Cancellieri A, Chilosi M, et al. Acute interstitial pneumonia: report of a series. Eur Respir J 2003; 21(1):187–191. 66. Quefatieh A, Stone CH, Digiovine B, et al. Low hospital mortality in patients with acute interstitial pneumonia. Chest 2003; 124(2):554–559. 67. Parambil JG, Myers JL, Aubry MC, et al. Causes and prognosis of diffuse alveolar damage diagnosed on surgical lung biopsy. Chest 2007; 132(1):50–57.
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68. Ichikado K, Suga M, Muller NL, et al. Acute interstitial pneumonia: comparison of high-resolution computer tomography findings between survivors and nonsurvivors. Am J Respir Crit Care Med 2002; 165(11):1551–1556. 69. Ichikdao K. Prediction of prognosis for acute respiratory distress syndrome with thin-section CT: validation in 44 cases. Radiology 2006; 238(1):321–329. 70. Davidson TA, Rubenfeld GD, Caldwell ES, et al. The effect of acute respiratory distress syndrome on long-term survival. Am J Respir Crit Care Med 1999; 160(6): 1838–1842. 71. McHugh LG, Milberg JA, Whitcomb ME, et al. Recovery of function in survivors of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1994; 150(1): 90–94.
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16 Lymphocytic Interstitial Pneumonia (LIP) and Other Pulmonary Lymphoproliferative Disorders
MICHAEL N. KOSS and HIDENOBU SHIGEMITSU Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A.
I.
Introduction
The reactive pulmonary lymphoid lesions are a group of inflammatory processes of diverse etiology characterized by the accumulation of numerous lymphocytes (as well as other chronic inflammatory cells such as plasma cells) within the lung. Often the lymphoid aggregates appear with germinal centers and proliferate along lymphatic routes or vessels. These lesions must be distinguished from lymphomas. Lymphoproliferative disorders involving the lung often arise from an underlying systemic disease (Table 1). When the lung is the principal or sole organ involved, the lymphoid infiltrates are considered to arise from a local source of lymphoid cells—the bronchus-associated lymphoid tissue or BALT. BALT refers to organized aggregates of lymphoid tissue that occur in the bronchial walls of many vertebrate species. BALT probably plays a role in immunologic response to airborne antigens that are inhaled onto the mucous surfaces of the airways. BALT is most prominent at branch points in the airways where, because of airflow turbulence, particulate antigens are most likely to deposit. Here, the bronchial epithelium and associated lymphoid cells appear 403
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Table 1 Diseases Associated with LIP Patterns in the Lunga Autoimmune diseases Sjogren syndrome (6,34,35) Primary biliary cirrhosis (1) Myasthenia gravis (41) Hashimoto’s thyroiditis (30) Systemic lupus erythematosus (37) Autoerythrocyte sensitization (39) Pernicious anemia (40) Immunodeficiency Acquired immune deficiency syndrome (30,82,120) Common variable immunodeficiency (121) Unexplained childhood immunodeficiency (122) Chronic active hepatitis (1,123) Virus-associated (excluding HIV infection) Epstein-Barr infection (14) Human herpesvirus-8 (24)/multicentric Castleman disease (25) Chronic active hepatitis (1) Drug induced Dilantin (124) Miscellaneous Crohn’s disease (125) Tuberculosis (126) Graft versus host disease (127) a
excluding animal hosts.
specialized for adherence, transport, and immunologic processing of these antigens. Most (about 60%) of the lymphoid cells of BALT are B cells, while the remaining lymphocytes are T cells. These B cells of the BALT consist predominantly of small lymphocytes that may be comparable to so-called marginal zone cells. They may be a form of memory cells that can circulate in the peripheral blood and then show preferential migration back to the organ of origin. BALT in normal man is sparse, but a striking reactive lymphoid proliferation can occur in disease. These hyperplastic changes can differ in extent and location within the lung. This is the case in reactive lesions such as follicular bronchiolitis, lymphocytic interstitial pneumonia (LIP), and nodular lymphoid hyperplasia (NLH). Usually it requires a wedge biopsy of the lung to identify the histologic features and perform the necessary special studies for diagnosis. Occasionally, a transbronchial biopsy is sufficient to confirm recurrent disease, particularly when supported by immunohistochemistry or flow cytometry on cells studied from the bronchoalveolar lavage. In these cases, small specimens (transbronchial biopsy,
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fine needle aspiration, and other cytologic preparations or closed pleural biopsy) may be sufficient. II.
LIP
A.
Definition
LIP is a clinicopathologic term used to describe several disorders that can be associated with dysproteinemia, autoimmunity (e.g., connective tissue diseases), or viral infections [e.g., human immunodeficiency virus (HIV)] (1). LIP is rarely an idiopathic disorder. LIP is characterized histologically by a diffuse, prominent interstitial lymphoid infiltrate (2). The infiltrate most often diffusely invades alveolar septa; it consists of lymphocytes and variable numbers of plasma cells (3). Other terms are lymphoid interstitial pneumonia, lymphoid interstitial pneumonitis, diffuse hyperplasia of BALT, lymphoplasmacytic pneumonia, and plasmacytic interstitial pneumonia. B.
Etiology/Pathogenesis
LIP is part of a spectrum of pulmonary lymphoid proliferations that includes follicular bronchitis/bronchiolitis, NLH, and MALT B-cell lymphoma (4,5). They can be difficult to differentiate from each other (5,6). Indeed, a substantial percentage of the cases that were initially classified by Averill Liebow (3) as LIP were subsequently found to be mucosa-associated lymphoid tissue (MALT) lymphomas. As a result, LIP was excluded from the classification of idiopathic interstitial pneumonias for several decades. Today, it is clear that the majority of patients with LIP have associated immunologic disorders, dysproteinemias or viral infections, so that LIP can be viewed as a morphologic pattern of lung injury that results from multiple causes with varying pathogenetic mechanisms rather than a distinct disease entity (1). However, a few cases of LIP do present as idiopathic disease. LIP therefore is still included in recent classifications of idiopathic interstitial pneumonias (7). LIP appears to be associated with several disorders of immunologic type: Cellular-induced autoimmunity and viral infection with secondary disordering of the immune response are proposed as the underlying mechanisms of disease (8–10). One study favored autoimmunity as a cause (11). This was based on the finding of minor clones of lymphoid cells with a high homology to autoreactive lymphocytes (rheumatoid factor, anti-DNA antibody, and G6-positive lymphocytes). This, in turn, suggests that immature B cells stimulated by autoantigens might play some role in the pathogenesis of LIP in adults (11). Still, there is a clear relation to viral infection in many cases of LIP, especially in children. In fact, there appears to be an association between LIP and several different viral infections. The culprits include Epstein-Barr virus (EBV), HIV-1, and human herpes virus-8 (HHV-8). Chronic EBV infection can produce a chronic interstitial pneumonitis with abundant lymphocytes. Of note, EBV DNA was found in lung tissues of 8 of
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10 children with LIP and acquired immune deficiency syndrome (AIDS) using southern blot hybridization (12). While it can be argued that HIV infection may be the triggering factor in children in this setting, EBV was reported to be present in a child with LIP who did not have evidence of HIV infection (13). EBV has also been found in lung tissue sections of adult cases of LIP in greater frequency than in control lung tissues (14–16). Of interest, EBV latent membrane protein-1 appears to be most prevalent in bronchiolar epithelial cells, not in lymphoid cells (16). The mechanism of EBV action to produce LIP is still unclear. Still, in no series of LIP cases is EBV present in all patients, suggesting that other viruses play a role (14,16). Further, EBV is not restricted to LIP—it can be found in a number of lymphoid processes in the lung and also in other types of pneumonitides. Specifically, a recent study showed EBV mRNA, proteins, and DNA not only in a single case of LIP, but also in other lymphoid proliferations in the lung, such as MALT lymphoma and two other non-Hodgkin lymphomas (17). Also, other interstitial lung diseases, such as adult idiopathic pulmonary fibrosis (IPF) and Langerhans cell histiocytosis, may show EBV (18). In one study, 70% of 20 patients with IPF were positive for both EBV viral capsid antigen and gp 340/ 220 by immunohistochemistry compared with 9% of the 21 controls (19). The relation between infection with HIV and the development of LIP in children is a well-known one and naturally focuses attention on HIV as the causative agent for LIP. Since disorders in T-cell regulation induced by retroviruses such as HIV can produce polyclonal B-cell activation and hyperplasia, the relation of viral infection to LIP is of great interest. Indeed, HIV has been found in bronchoalveolar lavage fluids and lung tissues of some patients with AIDS (20–22). Children who are infected with HIV may have CD8-lymphocytosis in lung tissue, bronchoalveolar lavage fluid, peripheral blood, and salivary gland. These children often show the human leukocyte antigen (HLA)-DR5 haplotype. In one case, epithelial cells lining the air spaces expressed HLA-DR, while lymphocytes and macrophages in the alveolar spaces expressed transforming growth factor-b (TGF-b) strongly, suggesting that abnormal expression of HLA-DR in nonimmune cells and exaggerated production of TGF-b played important roles in the pathogenesis of LIP in this patient (23). Finally, a case of LIP not associated with Kaposi’s sarcoma or with HIV infection had HHV-8 (24). Multicentric Castleman disease can be associated with a plasma-cell-rich type of LIP (25,26). Of interest, HHV-8 has been detected in the lymph nodes of some patients with this variant of Castleman disease (27). C.
Clinical Features
In children, LIP is most often seen with AIDS (28,29). One autopsy series suggested an incidence of 6% (30), but the frequency of hospitalization for LIP has decreased among children since the widespread use of highly active
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antiretroviral therapy (HAART) (31). Indeed, the presence of LIP in a child younger than 13 years (assuming that the test for HIV is positive) is now part of the case definition of AIDS, even when no opportunistic infection is present. In children without HIV, LIP is usually associated with congenital immune deficiencies, particularly hypogammaglobulinemia. Familial forms of LIP have also been reported (32,33). LIP in adults is associated with a large variety of extrapulmonary disorders (Table 1). These include Sjogren syndrome (17–25% cases of LIP) (34–36), systemic lupus erythematosus (37,38), autoerythrocyte sensitization (39), Hashimoto’s thyroiditis (3), pernicious anemia (40), myasthenia gravis (41), chronic active hepatitis, and primary biliary cirrhosis (1). The disease is usually seen in women during the fifth through seventh decades (1,3,8) and is most commonly associated with Sjogren syndrome. Up to 25% of cases of LIP are due to Sjogren syndrome and 0.9% of cases of Sjogren syndrome have LIP (42,43). In one study of 20 patients with Sjogren syndrome, nine had radiographic evidence of interstitial infiltrates, and LIP was one of a number of findings, ranging from follicular bronchiolitis to fibrosis with honeycombing (44). Most adult patients with LIP do not have AIDS. Adults who are infected with HIV have either minimal or mild interstitial lymphoid infiltrates (so-called nonspecific interstitial pneumonitis), not LIP (21,28,45). Still, occasional adults with AIDS develop LIP (46). Symptoms of LIP in children are usually insidious and nonspecific with tachypnea and cough. Physical examinations reveal bibasilar crackles on chest auscultation, and digital clubbing may be seen in advanced cases. Lymphadenopathy and hepatosplenomegaly may be seen in HIV-related cases; however, these findings are thought to occur rarely in non-HIV-related LIP (47). Furthermore, hypergammaglobulinemia is usually present in HIV-related LIP as opposed to hypogammaglobulinemia that may be seen with non-HIV-related cases (48). In adults, LIP commonly develops over months to even years. Symptoms are the usual ones seen in diffuse interstitial lung disease. Thus, 50% to 80% of patients have cough and/or dyspnea (9). Constitutional symptoms, including weight loss, pleuritic chest pain, arthralgias, and fever, may also be seen. Bibasilar crackles may be heard on chest auscultation and clubbing is rarely seen. There can also be signs and symptoms related to associated immunologic diseases such as Sjogren syndrome or myasthenia gravis (34). The most remarkable laboratory abnormality is the presence of dysproteinemia, occurring in at least 60% of adult patients. Most frequently, there is hypergammaglobulinemia (49). In about 10% of cases, there is hypogammaglobulinemia (1,34). Pulmonary function tests in both children and adults classically show a restrictive ventilatory defect with reduced lung volumes and diffusing capacities. These abnormalities have been shown to be consistent and sensitive indicators of disease in LIP (43). Gas exchange abnormalities leading to hypoxemia may also
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occur (50). Analysis of bronchoalveolar lavage typically shows an increase in both the number and percentage of lymphocytes.
D.
Radiologic Features
The chest X-ray features of patients with LIP are nonspecific and variable. There are bibasilar reticular infiltrates with small (<1 cm) or large (1–3 cm) poorly defined bilateral nodules or patchy consolidations (1,3,10,34) (Fig. 1). These changes are typically seen in the lower lung zones. Pleural effusions and hilar lymphadenopathy are uncommon (3); if they are present, one must consider alternate diagnoses such as malignant lymphoma. In HIV-related cases, the abnormalities can be more diffuse with nodular patterns, and hilar or mediastinal adenopathy can also be seen (51,52). The usual high-resolution CT findings are diffuse bilateral ground-glass infiltrates, ill-defined nodules, interlobular septal thickening, and a few thin-walled cysts, typically less than 3 cm in diameter (53) (chap. 2, Fig. 8).
Figure 1 Radiologic appearance of lymphocytic interstitial pneumonia showing a coarse reticular pattern in the lower lobe.
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Surgically obtained lung biopsy is required to confirm the diagnosis. Transbronchial lung biopsy has a limited role as a confirmatory procedure and is mainly used to exclude infectious processes. LIP in adults is usually treated with corticosteroids, but response is variable. The improvement in symptoms related by some patients after treatment is difficult to assess, since spontaneous remission has been reported (9). Due to the lack of controlled trials, data supporting the dosing and duration of treatment are unclear. Liebow and Carrington (3) reported resolution with corticosteroids in five patients in their study. Strimlan et al. (8) also reported response with corticosteroids, although some of their patients received other immunosuppressive treatments. Other immunosuppressive treatments, such as azathioprine, were shown to be effective in one study of primary Sjogren syndrome with LIP (44). Antiviral therapy has not been shown to be effective in adults with HIV-related LIP (54,55). In our experience, equal numbers of patients died, improved, and remained stable (1). In general, about one-third to one-half of adults with LIP die within five years (29). Death is most frequently due to infectious complications of treatment with immunosuppressive drugs, but occasionally patients die from respiratory insufficiency or malignant lymphoma. B-cell lymphomas can develop in patients with LIP, particularly when they have associated Sjogren syndrome. About 5% of patients with LIP develop disseminated malignant lymphoma (1,56), in particular B-immunoblastic sarcoma (57). Well-differentiated lymphomas associated with prolonged survival can also occur in patients with LIP (35), but here the concern is that the disease may have been lymphoma all along. As noted above, a minor population of monoclonal lymphoid cells can be present in LIP-like lesions, supporting the idea that evolution of LIP to lymphoma can occur. LIP in children with AIDS has a variable prognosis. It may respond to corticosteroid treatment with significant clinical improvement (29); still, it may evolve into lymphoma on occasion. Antiviral agents alone have been reported to be possibly useful (58). Treatment of hypogammaglobulinemia with intravenous gammaglobulin has been reported with success in children with HIV (59). E.
Pathologic Features
As noted above, LIP is part of a spectrum of pulmonary lymphoid proliferations, ranging from follicular bronchitis-bronchiolitis to low-grade malignant lymphoma, patterns which may be difficult to distinguish from each other (5). When reactive lymphoid nodules are centered in a lymphatic distribution about airways, vessels, and interlobular septa, the disease is termed follicular bronchitis/ bronchiolitis [or pulmonary lymphoid hyperplasia (PLH)] in the pediatric AIDS literature) (60). As the disease becomes more florid and the reactive lymphoid infiltrate extends into the lung interstitium, then the process is termed LIP (3). This diffuse interstitial infiltrate consists of small lymphocytes with variable numbers of admixed plasma cells (Fig. 2). HIV-infected patients may show
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Figure 2 (See color insert.) Lymphocytic interstitial pneumonia. The low magnification view, left panel, shows the diffuse distribution of the interstitial infiltrate, while the high magnification view, right panel, shows abundant interstitial lymphocytes.
few plasma cells, while occasional cases of LIP are so rich in plasma cells that they have been termed lymphoplasmacytic pneumonia (61) or plasma cell interstitial pneumonitis (9,62). Germinal centers can be seen in up to 50% of cases of LIP (1,3,8). The lymphocytes within the interstitium are mostly T cells. A few cases of LIP associated with hypogammaglobulinemia have been studied using frozen tissues and appear to consist largely of T cells (63) and more particularly of T-helper cells (64). B cells can occur, but they are present in cuffs around lymphoid follicles. These B cells show polyclonal staining for immunoglobulin light chains (1,10,56). The predominant phenotype of the lymphocytes in patients with LIP and AIDS is either T cells (29) or B cells (65). Occasional multinucleated giant cells or ill-formed granulomas are embedded in the lymphoid infiltrate in up to 50% of cases (1). The giant cells may contain cholesterol clefts. Why giant cells occur is unclear, but they are also seen in MALT lymphomas of the lung (66). Possibly, they are a reaction to lipid released by cellular breakdown. F.
Differential Diagnosis
The differential diagnosis of LIP is low-grade marginal zone B-cell lymphoma of MALT (MALToma) and interstitial pneumonitides in the lung, including nonspecific interstitial pneumonitis and hypersensitivity pneumonitis (Table 2).
þ/– þ/– – – –
– þ – Polymorphous
þ – – Polymorphous þ þ – – –
– þ
LIP
þ –
NLH
þ, present; –, absent; þ/–, may be present or absent.
Germinal centers Plasma cells Dutcher bodies Monoclonality Monocytoid B cells
Chest radiograph Mass Diffuse Histologic Localized Diffuse interstitial Peribronchial only Infiltrate
Feature
þ/– þ/– – – –
– – þ Polymorphous
– þ
FB
þ þ (lymphangitic) – Monomorphic with fibrosis/polymorphous þ/– þ/– þ þ þ
þ þ
Maltoma
Table 2 Differential Diagnosis of Nodular Lymphoid Hyperplasia (NLH), Lymphocytic Interstitial Pneumonia (LIP), Follicular Bronchiolitis (FB), and Extranodal Marginal Zone Lymphoma (Maltoma)
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MALToma can produce a widespread interstitial pattern in radiographic studies and in histologic sections. Further, reactive lymphoid follicles or their remnants can be present in MALTomas. Finally, nodules of low-grade lymphoma can be surrounded by reactive lymphoid cells in an interstitial pattern (67). In fact, it is probable that some cases classified as LIP on purely morphologic grounds are malignant lymphomas (68). For that reason, it is ‘‘inadvisable’’ for the pathologist to make a diagnosis of LIP based solely on the hematoxylin and eosin (H&E) stain; immunostains for clonality or molecular studies are ‘‘advised’’ to support the diagnosis. Hilar lymphadenopathy or pleural effusion accompanying the lung infiltrate is more suggestive of malignant lymphoma than of lymphoid interstitial pneumonitis. Microscopically, malignant lymphoma is strongly favored if the lymphoid infiltrate shows a distinctly lymphangitic pattern, monomorphism, and/or invasion of parietal pleura or regional lymph nodes (69). Invasion of bronchial cartilage or of visceral pleura by the cellular infiltrate also favors malignant lymphoma, but it does not exclude a reactive process. As noted above, immunohistochemical stains and in doubtful cases polymerase chain reaction for immunoglobulin gene rearrangement should be performed to determine whether the lymphoid infiltrate is monoclonal, as would be expected in lymphoma, or polyclonal, as would be expected in LIP (11,67). However, of five cases morphologically believed to be LIP, some of them showed a minor monoclonal population, which was interpreted as neoplastic clones hidden in normally reactive lymphocyte clones (11). Still, whether these minor clonal proliferations are truly emerging lymphomas is still debatable, as shown by experience in other extranodal sites such as gastrointestinal tract. NLH shows abundant reactive lymphoid nodules and intervening reactive lymphoid cells, so it is microscopically similar to some cases of LIP. The difference is that this disease occurs in chest imagining studies as one or several localized lesions, rather than as a diffuse bilateral interstitial infiltrate. Angioimmunoblastic lymphadenopathy (AIBL) can involve the lung in the form of diffuse interstitial infiltrates. Typically, there is little difficulty in distinguishing AIBL from LIP since AIBL has a distinctive set of clinical features, including generalized lymphadenopathy, hepatosplenomegaly, Coombs-positive hemolytic anemia, and skin rash. Microscopically, AIBL is polymorphous but includes numerous atypical immunoblasts as well as lymphocytes and plasma cells. The cellular infiltrate also predominantly involves lymphatic routes (around airways and vessels), rather than the interstitial compartment, as in the case of LIP (69). LIP and hypersensitivity pneumonitis (extrinsic allergic alveolitis) may be difficult to distinguish. Radiographically, both show bilateral infiltrates. Microscopically, hypersensitivity pneumonitis may resemble LIP in showing interstitial lymphocytic infiltrates containing ill-formed granulomas. Hypersensitivity pneumonitis has a patchier (airway-centered) and milder interstitial pneumonitis, and it can show bronchiolitis obliterans, a feature not seen in LIP.
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Finally, prominent peribronchial lymphoid aggregates can be present in both nonspecific and usual interstitial pneumonia patterns of injury associated with connective tissue diseases such as systemic lupus erythematosus and rheumatoid arthritis. The lymphoid infiltrate is typically denser and more diffuse in LIP. III. A.
NLH of the Lung Definition
NLH was the name given by Kradin and Mark (10) to one or more nodules consisting of reactive lymphoid cells. The idea of masses of reactive lymphoid tissue in the lung is controversial because most pulmonary masses produced by microscopically low-grade lymphoid proliferations, even those with abundant germinal centers, are extranodal marginal zone B-cell lymphomas of MALT type (MALTomas) (4,70,71). This has led to the suggestion that localized reactive lymphoid nodules in the lung (formerly termed pseudolymphomas) do not exist (6,70,72). The largest immunohistochemical and molecular pathologic study of NLH suggested that NLH of the lung can occur, but that it is rare (73). B.
Etiology/Pathogenesis
The etiology of NLH is not clear. Unlike LIP, there is no known association with HIV infection, connective tissue diseases, or Sjogren syndrome. Of interest, we found two cases that showed a small microscopic focus of acute inflammation or a small foreign body aspiration granuloma, suggesting that inflammatory stimuli may give rise to the prominent follicular lymphoid masses (73). C.
Clinical Features
NLH is rare. In a review of the files of the Department of Pulmonary and Mediastinal Pathology of the Armed Forces Institute of Pathology (AFIP), only 14 putative cases were found (73). Men slightly outnumber women (ratio, 1.3:1). The patients ranged in age from 19 to 80 years (mean, 60 years; median 65 years). Seventy percent of patients had incidental lesions found on routine chest X-ray (74). Symptoms, when present, included shortness of breath, cough, hemoptysis, and/or pleuritic chest pain (75). Serological studies have not been systematically performed. Surgical excision of the nodule(s) was adequate therapy. In the one large series, there was no recurrence in any case and all patients were alive without evidence of disease or died of other diseases in one to six years (73). D.
Radiologic Features
A majority (65%) of cases are radiographically solitary lesions measuring from 2 to 5 cm; the remainder cases have two or occasionally several lesions. Chest
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CT scan reveals solid lesions that are usually located in the subpleural areas (75,76). Concomitant hilar, mediastinal, or paraesophageal lymphadenopathy can occur, and its presence does not exclude the diagnosis of a benign process. Pleural effusions and lymphadenopathy are rare, and if detected, should raise the possibility of lymphoma. E.
Pathologic Features
NLH is always grossly and histologically localized. The most striking features are numerous reactive germinal centers with well-preserved mantle zones and sheets of interfollicular mature plasma cells (Figs. 3 and 4). There is usually interfollicular fibrosis of a varying degree that at least focally obliterates the underlying lung architecture (Fig. 4). The plasma cells do not contain Dutcher bodies, the intranuclear inclusion seen in lymphoplasmacytic lymphomas. Giant cells can be present in the lymphoid infiltrate, but this is a nonspecific feature, since they can be seen in low-grade B-cell lymphomas and LIP. Lymphoepithelial lesions of the type frequently seen in MALTomas are not seen. Hilar, mediastinal, or paraesophageal lymph nodes show benign reactive follicular hyperplasia. Immunohistochemical stains show a reactive pattern of B- and T cells. In particular, the germinal centers show cuffs of CD20-positive B cells, while the interfollicular lymphocytes are CD3-positive T cells, a pattern that mimics that of reactive lymph nodes (73). The CD20-positive lymphocytes do not coexpress
Figure 3 (See color insert.) Nodular lymphoid hyperplasia. The low magnification view shows a lymphoid mass with many follicle centers obliterating the underlying lung parenchyma.
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Figure 4 (See color insert.) Nodular lymphoid hyperplasia. Follicle centers with interfollicular fibrosis obliterate the underlying lung architecture.
either CD43 or CD5, as might be seen in lymphomas, and the immunoglobulin light chain reactivity is polyclonal. Molecular genetic analysis shows no rearrangement of immunoglobulin heavy chain genes (73). F.
Differential Diagnosis
The principal differential diagnosis is MALT lymphoma, lymphoid interstitial pneumonitis, and follicular hyperplasia of BALT. Pertinent features of the differential diagnosis are shown in Table 2. Certainly, the most important disease in differential diagnosis is MALT lymphoma (4,66,71). This low-grade B-cell lymphoma of the lung is far more frequent than NLH; hence, any solitary lymphoid mass in the lung is much more likely to be MALT lymphoma than NLH. The age distribution, symptoms, and chest radiographic appearance of patients with MALT lymphomas and NLH are similar (4,66,71). Histologically, most MALT lymphomas contain sheets of small lymphocytes, admixed plasma cells, and reactive germinal centers (4,66,77). At times, the follicular proliferation can be exuberant and follicles can show large mantle zones; further, these follicles are often polytypic (about 75% of cases) (71). Lymphomas differ in showing a sheet-like pattern of growth of small lymphocytes. They are also more invasive of surrounding the lung, with penetration of bronchial cartilage plates (occurring in up to 66% of cases), plaque-like involvement of pleura over a low-power field
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(over 50% of cases), and more extensive lymphangitic spread (66,69). MALT lymphomas also invade bronchiolar epithelium to produce lymphoepithelial lesions. The lymphocytes in these lesions coexpress CD20 (B-cell marker) and CD43, that is, they have the immunophenotype of MALT lymphomas. These lesions are not typically found in NLH (4,66,73,78), but if they occur, their lymphocytes express CD3 (T cell marker). Finally, lymphomas usually (about 75% of cases) show a monoclonal pattern for immunoglobulin light-chain staining in paraffin sections. Still, it has been suggested that lymphomas may arise as a focal process, even in a lesion dominated by a seemingly reactive mass (70,79). Both immunohistochemical and molecular analysis should be used in tandem to evaluate for clonality in these cases. The typical histologic appearance described above together with the absence of clonality by these studies are the essential criteria for the diagnosis of NLH, but the reader will note that these are negative findings, so the problem of excluding an incipient lymphoma will always remain. For sure, we do not recommend that the diagnosis of NLH be made on needle or transbronchial biopsies. Although germinal centers are less frequent in LIP than in NLH, they certainly occur, and so there can be great similarity at the microscopic level. The essential difference is that LIP is grossly, histologically, and radiographically more diffuse, that is, there are diffuse reticulonodular or small nodular infiltrates. One problem area is that there may be reactive lymphoid lesions characterized by several bilateral nodules in the lung; it can be difficult to decide in this situation whether the patient has LIP or multifocal NLH. We think that if there is evidence of interstitial disease radiographically, LIP is the better term in these cases. Castleman disease (giant lymph node hyperplasia) can show structures that resemble follicles and intervening sheets of plasma cells, but the disease is usually restricted to lymph nodes, including the peribronchial nodes, while NLH is extranodal. Of interest, there have been cases of multinodular and diffuse LIPlike lesions (25,80) in the lung in the setting of the plasma cell variant of Castleman disease. Finally, follicular bronchitis/bronchiolitis shows peribronchial/peribronchiolar nodular aggregates of lymphoid cells that contain reactive germinal centers. The essential difference is that the lesion is confined largely to the airway, and there is no evidence of a mass by chest imaging studies (81).
IV. A.
Follicular Bronchitis/Bronchiolitis Definition
This name, also termed follicular hyperplasia of BALT, refers to the presence of lymphoid aggregates, usually with reactive follicles, next to and confined to the walls of the airways and septal areas (81). This pattern of inflammation can be seen in a variety of diseases, including HIV infection/AIDS, where it is called
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PLH and where lymphoid aggregates without follicles may predominate (82), congenital immune deficiency syndromes such as Wiskott-Aldrich syndrome, collagen vascular diseases (particularly rheumatoid arthritis), prolonged exposure to certain environmental agents such as polyethylene flock, and infectious and obstructive pneumonias including localized infections (10,81,83–89). It can also occur as an idiopathic finding (88). B.
Clinical Features
Follicular bronchiolitis is usually seen in adults, although it may also be seen in children (6,81). Patients typically have progressive dyspnea, cough and fever; some may even present with recurrent pneumonia or weight loss (81). In cases where rheumatoid arthritis is the underlying cause, rheumatoid factor is often seen at very high titers (1:640 to 1:2560). Pulmonary function tests commonly reveal a restrictive physiology; however, an obstructive physiology may be seen due to the inflammation surrounding the bronchioles. Abnormalities in gas exchange are reflected by arterial hypoxemia, widened AaDO2 gradient, and hypocapnia. Peripheral blood eosinophilia may be observed in patients with hypersensitivity syndrome. Patients can have a history of repeated respiratory infection or progressive dyspnea; some respond to steroid treatment (88,90). Wedge biopsy is the best method of making a definitive diagnosis. C.
Radiologic Features
Chest radiograph findings are similar to those of LIP. They include bilateral small nodules and reticular opacities. HRCT demonstrates nodules of varying sizes (up to 12 mm) in a centrilobular and peribronchial distribution (91). Bronchial wall thickening, bronchiectasis, bronchiolectasis, and ground-glass opacities have also been described (92,93). D.
Pathologic Features
Grossly, there are numerous minute nodules located adjacent to airways (10). Microscopically, there are peribronchiolar and/or peribronchial nodular aggregates of lymphoid cells, often containing reactive germinal centers (Figure 5) (81). Clonality studies on limited numbers of cases using immunohistochemistry and polymerase chain reaction analysis for immunoglobulin heavy chain gene rearrangement shows a polyclonal or oligoclonal pattern and not a monoclonal one (94). E.
Differential Diagnosis
The absence of a mass by chest X-ray helps distinguish follicular hyperplasia from NLH (Table 2). The separation between follicular bronchitis/bronchiolitis,
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Figure 5 (See color insert.) Follicular bronchitis/bronchiolitis. The low magnification view, left panel, shows the peribronchiolar location of lymphoid aggregates in this condition. The right panel shows a reactive follicle center in one of the lymphoid aggregates.
in which the lymphoid cells are largely confined to peribronchial and lobular septal areas, and lymphoid interstitial pneumonitis, in which the lymphoid infiltrate penetrates more diffusely into the alveolar septae, is arbitrary because cases with overlapping appearance can occur (5,6). V.
Giant Lymph Node Hyperplasia (Castleman Disease)
A.
Definition
Giant lymph node hyperplasia or Castleman disease is a lymphoproliferative disorder associated with prominent lymphadenopathy. Castleman disease can be localized or multicentric (95). Microscopically, there are hyaline vascular or plasma cell subtypes. B.
Clinical Features
The clinical features for this disorder vary depending on the type of Castleman disease. In general, patients with unicentric hyaline vascular disease, the most common type, usually present in their second and fifth decade. This type is seen in about 90% of all cases and affects both genders equally (96,97). Symptoms are mild and typically related to local effects from the enlarged lymph nodes.
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Constitutional symptoms are rare and affected individuals not infrequently are totally asymptomatic. In contrast, the plasma cell variant is typically multicentric and is associated with systemic features, including fever, night sweats, fatigue, weight loss, splenomegaly, hepatomegaly, and massive lymphadenopathy. These symptoms may be dramatic and even life threatening (98). Polyclonal hypergammaglobulinemia is found on laboratory testing (25). Other findings such as anemia, thrombocytopenia, elevated erythrocyte sedimentation rate, and abnormal liver and kidney function tests are frequently present (98,99). There is elevation of serum interleukin-6 (26). HIV-seropositive individuals appear at increased risk for the development of multicentric Castleman disease and may rarely develop the bilateral interstitial infiltrates of interstitial pneumonia (namely, LIP—see below) on radiographic studies (100). Castleman disease can occur together with Kaposi sarcoma (101). The outcome in multicentric Castleman disease is guarded, and progression to lymphoma, usually non-Hodgkin’s lymphoma, can occur in it (101). A plasmablastic lymphoma can develop in patients with a plasma cell variant of multicentric Castleman disease; HHV-8 antigen has been detected in plasmablasts from patients with both of these entities (101). Recently, an antiinterleukin-6 receptor antibody, tocilizumab, has been used to treat successfully a small number of patients (102). C.
Radiologic Features
Unicentric hyaline vascular type is typically associated with solitary hilar or mediastinal adenopathy but sometimes it appears as a nodule in the interlobar fissure (103–106). The usual clinical concern with this appearance is malignancy (107). The adenopathy on CT scan is homogeneous and is enhanced by contrast, which also demonstrates its vascularity. Calcifications may be noted in 5% to 10% of the cases (25,108). Multicentric Castleman disease usually demonstrates extensive lymph node involvement, in contrast to the solitary involvment with unicentric Castleman disease. In addition, pulmonary parenchymal abnormalities such as thin-walled cysts, thickening of the bronchovascular bundles, and interlobular septal thickening, subpleural nodules, ground-glass attenuation, air-space consolidation, and bronchiectasis can be seen (25). D.
Pathologic Features
The hyaline vascular type of Castleman disease is well circumscribed and typically involves mediastinal lymph nodes, but it can affect hilar and peribronchial lymph nodes. The lesion often has a thick fibrous capsule, and fibrous septa can traverse it (109). There is a marked proliferation of hyalinized vessels within the centers of the abnormal germinal centers, and the germinal centers are surrounded by concentric arrays of lymphocytes, producing an onionskin
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appearance. The interfollicular zone shows proliferated small vessels. Plasma cells stain in a polyclonal pattern; suppressor T cells are present in the interfollicular zone. The multicentric variant is characterized by numerous germinal centers, with an interfollicular stroma rich in plasma cells and small vessels. In this variant, the pulmonary parenchyma can also rarely show an associated lymphocytic interstitial pneumonia that is rich in CD138 (syndecan-1)-positive plasma cells (26,110). HHV-8 DNA is often detected in biopsies of lymph nodes from patients with multicentric Castleman disease (27,101,111). There is an interesting report of two patients who had both ‘‘primary’’ pulmonary hypertension and Castleman disease; of these, one had HHV-8 demonstrated in lung tissue (and specifically in the plexiform lesions) (112). VI. A.
Posttransplant Lymphoproliferative Disorders Definition
The posttransplant lymphoproliferative disorders (PTLD) are abnormal proliferations of lymphoid cells typically containing EBV that occurs in the setting of chronic immunosuppression needed for organ transplantation. The lymphoid proliferations have a variety of histologic, immunophenotypic, genotypic, and clinical features. Most are B-cell lesions, but rarely there may be T-cell proliferations. B.
Clinical Features
The incidence of PTLD depends on the organ transplanted and generally increases with increasing immunosuppression (113). Patients who undergo lung and heart-lung transplants have an incidence of 4% to 10% of PTLD (114,115), but the lung can be involved no matter what organ is transplanted. The disease usually occurs in the first year after transplantation. The major risk factor is primary infection with EBV; other potential risks are nonrenal transplantation, history of cytomegalovirus sero-mismatch (positive donor, negative recipient), and type and intensity of immunosuppression (in particular, the use of cyclosporine and antilymphocyte antibodies) (116). Open lung biopsy is often necessary for diagnosis. The main radiologic manifestations of PTLD consist of single or multiple nodules. The clinical course depends on a complex of findings, including histologic subtype, (see below) clonality, and oncogene expression. In general, plasmacytic hyperplasia regresses after reduction of immunosuppression and therapy with antiviral agents. Polymorphic lymphoproliferative disorder has a variable clinical course. One cannot predict progression to lymphoma in a given case. Treatment is usually a short period of reduced immunosuppression, which, if there is no clinical improvement, is followed by chemotherapy. Patients who have malignant lymphomas typically show widespread (stage III or IV) disease and have a poor outcome (117).
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Pathologic Features
PTLD in the lung usually presents as infiltrates of lymphoid cells distributed in a lymphangitic pattern around bronchi and vessels and beneath pleura, or as solid nodules. There are a variety of cell types that can be encountered. The WHO classification attempts to combine molecular and phenotypic features to arrive at a prognostically valuable classification (118). Reactive plasmacytic hyperplasia and infectious mononuclear-like PTLD are benign reactive processes consisting of a mixture of small lymphocytes, numerous plasma cells, and scattered immunoblasts. It spares the underlying lung architecture. In general, the lymphocytes are polyclonal and consist of a mixture of both B cells and T cells (114). EBV nucleic acid is present in most cases. There is no evidence of clonality in either immunoglobulin light or heavy chain genes or T-cell receptor genes, nor are there oncogenes present. Plasmacytic hyperplasia is seen most often in children and young adults after transplantation. Polymorphic PTLD consists of a spectrum of lesions, with varying proportions of plasmacytoid cells, lymphocytes, immunoblasts, and atypical lymphoblasts. The atypical immunoblasts may even resemble Reed-Sternberg cells. Almost all cases consist of solid nodules and show foci of necrosis (117,119). The lymphoid cells are usually B cell in type, but there can be admixed T cells. The B cells may be monoclonal or polyclonal in terms of light chain expression, but they always show clonal rearrangement of the immunoglobulin light chain gene and EBV virus; no oncogenes are expressed. Monomorphic PTLD refers to a family of lymphoid proliferations that histologically are malignant lymphomas or multiple myelomas (117). The cells are monotonous in appearance and they show plasmacytoid or immunoblastic differentiation. Most fall into the category of diffuse large B-cell lymphomas; there are also occasional small noncleaved lymphomas. Immunophenotypically, the tumors are either B cell or null cell, but they always show clonal immunoglobulin and EBV viral gene rearrangements. Of interest and of potential diagnostic importance, they can show p53 overexpression and c-myc and ras expression. References 1. Koss MN, Hochholzer L, Langloss JM, et al. Lymphoid interstitial pneumonia: clinicopathological and immunopathological findings in 18 cases. Pathology 1987; 19(2):178–185. 2. Travis WD, Colby TV, Koss MN, et al. Non-Neoplastic Disorders of the Lower Respiratory Tract. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology, 2002:266–290. 3. Liebow AA, Carrington CB. Diffuse pulmonary lymphoreticular infiltrations associated with dysproteinemia. Med Clin North Am 1973; 57(3):809–843.
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116. Alam S, Chan KM. Noninfectious pulmonary complications after organ transplantation. Curr Opinion Pulmon Med 1996; 2:412–418. 117. Chadburn A, Cesarman E, Knowles DM. Molecular pathology of posttransplantation lymphoproliferative disorders. Semin Diagn Pathol 1997; 14:15–26. 118. Harris NL, Swerdlow SH, Frizzera G, et al. Post-transplant lymphoproliferative disorders. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology & Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2001:264–271. 119. Knowles DM, Cesarman E, Chadburn A, et al. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood 1995; 85(2):552–565. 120. Saldana M, Mones J. Lymphoid interstitial pneumonia in HIV infected individuals. Prog Surg Pathol 1992; 12:181–215. 121. Popa V. Lymphocytic interstitial pneumonia of common variable immunodeficiency. Ann Allergy 1988; 60(3):203–206. 122. Waters KA, Bale P, Isaacs D, et al. Successful chloroquine therapy in a child with lymphoid interstitial pneumonitis. J Pediatr 1991; 119(6):989–991. 123. Helman CA, Keeton GR, Benatar SR. Lymphoid interstitial pneumonia with associated chronic active hepatitis and renal tubular acidosis. Am Rev Respir Dis 1977; 115(1):161–164. 124. Chamberlain DW, Hyland RH, Ross DJ. Diphenylhydantoin-induced lymphocytic interstitial pneumonia. Chest 1986; 90(3):458–460. 125. Dawson A, Gibbs AR, Anderson G. An unusual perilocular pattern of pulmonary interstitial fibrosis associated with Crohn’s disease. Histopathology 1993; 23: 553–556. 126. Maurer J, Ho-Soon H. Lymphocytic interstitial pneumonitis manifesting concurrently with active tuberculosis. Arch Intern Med 1984; 144:1855–1857. 127. Perreault C, Cousineau S, D’Angelo G, et al. Lymphoid interstitial pneumonia after allogeneic bone marrow transplantation: a possible manifestation of chronic graftversus-host disease. Cancer 1985; 55(1):1–9.
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17 Connective-Tissue Disease-Associated Interstitial Lung Disease
H. NUNES, Y. UZUNHAN, and D. VALEYRE UPRES EA 2363, Service de Pneumologie, Hoˆpital Avicenne, Assistance Publique-Hoˆpitaux de Paris, Universite´ Paris 13, Bobigny, France
P. Y. BRILLET UPRES EA 2363, Service de Radiologie, Hoˆpital Avicenne, Assistance Publique-Hoˆpitaux de Paris, Universite´ Paris 13, Bobigny, France
M. KAMBOUCHNER Service d’Anatomie Pathologique, Hoˆpital Avicenne, Assistance Publique-Hoˆpitaux de Paris, Universite´ Paris 13, Bobigny, France
A. U. WELLS Interstitial Lung Disease Unit, Royal Brompton Hospital, London, U.K.
I.
Introduction
The connective tissue diseases (CTDs) are a heterogeneous group of immunologically mediated inflammatory conditions of unknown etiology, accompanied by diverse autoantibodies and affecting multiple organ systems. In adults, the more frequent CTDs comprise rheumatoid arthritis (RA), systemic sclerosis (SSc), Sjo¨gren’s syndrome (SjS), systemic lupus erythematosus (SLE), polymyositis/ dermatomyositis (PM/DM), and mixed CTD (MCTD). Lung involvement in CTDs is a common problem and a major cause of morbidity and mortality (1,2). The wide spectrum of respiratory manifestations varies with individual CTDs (Table 1). Nonspecific respiratory complications include drug toxicity, opportunistic infections, aspiration pneumonia due to gastro-esophageal reflux or pharyngolaryngeal involvement, pulmonary embolism, and lung malignancy (1,2). All anatomical compartments of the lung can be involved: airways from trachea to bronchioles, vessels, interstitium, pleura, and diaphragm (Table 1). Together with pulmonary hypertension (PH), interstitial lung disease (ILD) is the most frequent manifestation. 429
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Table 1 Involved Thoracic Anatomical Structures in Connective Tissue Diseases
Pleura Interstitium Airways Vessels (vasculitis and/or PH) Muscles
RA
SLE
þþþ þþ þþ þ þ
þþþ þ þþ þ
SSc
DM/PM
SjS
MCTD
þþþ þ þþ þ
þþþ þ
þ þþ þþ þ
þ þþþ þ þþ þ
þþþ
Abbreviations: RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; DM/PM, dermatomyositis/polymyositis; SjS, Sjogre¨n’s syndrome; MCTD, mixed connective tissue disease; PH, pulmonary hypertension.
This chapter focuses on ILD associated with CTDs (CTDs-ILD). We summarize recent concepts and areas of controversy in CTDs-ILD and review each CTD separately. II.
General Concepts in CTDS-ILD
A.
Lessons from the New Classification of Idiopathic Interstitial Pneumonias
The CTDs-ILD largely consist of the seven histological patterns defined in the international consensus classification of the idiopathic interstitial pneumonias (IIPs): usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), diffuse alveolar damage (DAD), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), and lymphoid interstitial pneumonia (LIP) (3). In the CTDsILD and the IIPs, similar relationships exist between histological patterns and many clinical and radiological features, but there are also important differences. 1.
CTDs-ILD Vs. IIPs: Pathology and Pathogenesis
First, the prevalence of histological patterns differs strikingly between the CTDsILD and the IIPs. UIP is the most common pattern of the IIPs, whereas NSIP predominates in most CTDs (1,2,4), with the exception of RA (4). Furthermore, histological evaluation is complicated in the CTDs-ILD by the fact that interstitial processes are often admixed in the same patient. NSIP or UIP often coexist with OP in DM/PM or RA, and both patterns may be associated with involvement of other anatomical sites, such as vascular disease in SSc or SLE and bronchiolitis in RA or SjS (5,6). Involvement of several lung compartments can be viewed as a hallmark of CTDs-ILD (5). There are also qualitative differences in histological patterns between CTDs-ILD and IIPs (5). Compared with the IIPs, CTDs-ILD tend to be characterized by more intense interstitial chronic inflammation with prominent germinal centers (5), but a lower profusion of fibroblastic foci in the CTDs-UIP (7). Lastly, pathogenetic distinctions are described
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between IIPs and CTDs-ILD in relation to myofibroblast phenotypes (8) and cytokine profiles (9,10). 2.
CTDs-ILD Vs. IIPs: Evolution and Prognosis
The natural history of the CTDs-ILD differs from that of the IIPs. In idiopathic disease, UIP is unresponsive to therapy and has a much worse outcome than NSIP. By contrast, outcomes appear to be similar for UIP and NSIP in patients with CTDs (4,11,12), with the possible exception of RA (13). Whether the prognosis of CTDs-ILD and IIPs truly differ has long been debated (4,11,12,14–20). Historical observations suggesting a better outcome in patients with CTDs-ILD (14,17–20) were drawn from uncontrolled studies that, in most cases, predate the reclassification of the IIPs. The better prognosis of CTDs-ILD may, in part, reflect earlier diagnosis in CTD, as a result of intense evaluation, or a higher frequency of NSIP rather than essential differences in natural history as suggested by a case-control study in which CTDs-ILD had a worse survival IIPs, when adjusted for age (16). However, in a large recent study in which 269 patients with IIPs were compared with 93 patients with CTDs-ILD, verified by surgical lung biopsy (SLB), survival was significantly longer in the CTDs-ILD population (131 vs. 80.5 months, p < 0.0001) (4). Patients with CTDs-UIP lived longer than those with idiopathic pulmonary fibrosis (IPF), and a better survival in UIP was independently associated with the presence of CTD, younger age and lesser impairment of pulmonary function. By contrast, survival was uniform in NSIP, irrespective of whether it occurred in the setting of CTD, corroborating an earlier smaller study (12). Of note, RA-UIP may be an exception among CTDs (4). Episodes of rapid deterioration have been described in idiopathic NSIP and more recently in CTDs-ILD, resembling acute exacerbations of IPF and featuring DAD superimposed UIP or fibrotic NSIP (21). In a recent study, acute exacerbations occurred in 4 of 93 patients with histologically proven CTDs-ILD including 3 with RA-UIP and 1 with SSc-NSIP (21). The estimated one-year frequency was 5.6% among all patients with CTDs-UIP, but was higher in those with RA-UIP. As in IIPs, the outcome was poor. B.
Detection of Unsuspected CTD in Patients with ILD
A detailed history, review of systems, and physical examination are critical in the recognition of occult CTD (1). The measurement of muscle enzymes should be part of routine investigation. Appropriate immunological laboratory tests include rheumatoid factor (RF), antinuclear antibodies (ANA), and extractable nuclear antigens, a panel that measures the most common antigens that are responsible for a positive ANA (1). It should be recognized that the borders between IIPs and CTDs-ILD are often blurred. ILD may precede the systemic manifestations of CTD by several months or years, especially in RA or DM/DM (1). Even in the absence of a
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well-defined CTD, 10% to 20% of patients with IIPs have systemic symptoms and serological abnormalities suggestive of an autoimmune disorder. The entity of undifferentiated connective tissue disease (UCTD) has been proposed to categorize patients with features of a systemic autoimmune disorder, not meeting diagnostic criteria for CTD. Diagnostic criteria, applying to up to 25% of patients presenting with systemic autoimmune disease, comprise signs and symptoms evocative of a CTD, positive serological results, and disease duration of at least one year. Kinder et al. demonstrated that 37% of all patients with IIPs admitted to their institution met criteria for UCTD, including 88% of those with a pattern of NSIP on SLB (22). There has been a resurgence of interest in ILD associated with formes frustes of CTDs, namely ‘‘amyopathic’’ DM or DM ‘‘sine myositis’’(23–26) and SSc ‘‘sine scleroderma’’ (27). Fisher et al. found that 2.5% of patients of a large cohort of ILD fit the diagnostic criteria for ‘‘SSc sine scleroderma’’ (27). In other studies of IIPs, positive anti-synthetase (28) and anti-Th/To antibodies (29) considered highly specific of inflammatory myopathies and SSc have been detected. On the basis of these findings, it has been suggested that ‘‘idiopathic’’ NSIP might be an ‘‘autoimmune interstitial pneumonia’’ confined to the lungs or with a predominant pulmonary expression (22,30). C.
Detection and Management of ILD in Patients with Known CTD
The detection and management of the CTDs-ILD is usefully conceptualized as a series of key questions. 1.
Is ILD Present?
No uniformly accepted protocol exists for the detection of ILD in patients with known CTD (1). Clinical symptoms are nonspecific, and exertional dyspnea is an unreliable marker of CTDs-ILD. Coexistent arthritis or myositis may limit exercise tolerance, thereby masking lung disease in some patients, but in other patients, dyspnea may result solely from the work of locomotion. Furthermore, ILD may be subclinical in CTD and may escape diagnosis (1). Among pulmonary function tests (PFTs), diffusing capacity for carbon monoxide (DLCO) is the most sensitive parameter but does not discriminate between interstitial and vascular disease. High-resolution computed tomography (HRCT) is more sensitive and specific than chest radiography, but, when used as a ‘‘Screening’’ modality has created its own problems with the disclosure of subtle abnormalities of uncertain significance. 2.
What is the Nature of ILD?
HRCT is pivotal for the characterization of specific ILD. In our view, SLB adds little and does not justify the morbidity of the procedure, given the likelihood of
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NSIP (1,2,4) and the prognostic irrelevance of histological subtypes in most CTDs (4). However, SLB remains appropriate in a minority of cases with HRCT appearances atypical of the known profile of an individual CTD, especially in RA and primary SjS, and other disorders, such as amyloidosis, superimposed malignancy, opportunistic infections, or drug toxicity, are suspected. The CTDs-ILD should not be ‘‘lumped’’ as a single entity because disease may involve different compartments of the lung in multiple combinations, as judged by histological examination, clinical presentation, PFT profile and/or HRCT picture. The presence of disease in multiple anatomical sites may be useful in discriminating CTDs-ILD from IIPs and in recognizing specific CTD. Characteristic combinations include PH and ILD in SSc, muscle involvement and ILD in PM/DM, bronchiolitis and ILD in RA and SjS, or pleural involvement and ILD in RA and SLE. 3.
What is the Clinical Significance of ILD?
Because of the very high prevalence of silent disease, it is often difficult to assign clinical significance to ILD. The problem is compounded by the variation between CTDs. The prevalence of clinically significant ILD is relatively low in RA, SjS, and SLE, compared with SSc and PM/DM. Furthermore, most patients with limited CTDs-ILD do not develop major progressive disease (31–34). Prognostic evaluation of CTDs-ILD should include the careful staging of severity at presentation, using PFTs and HRCT, and serial PFT evaluation is central to the detection of progression. 4.
In Whom and When Should ILD be Treated?
Decisions on treatment should be based on the nature of the underlying CTD, the duration of systemic disease, and prognostic evaluation of the lung disease. In irreversible fibrotic disease, progression may be slowed or prevented by treatment but there is also a risk of causing side effects with overly vigorous treatment, without a therapeutic gain. Treatment should be considered when disease is severe at presentation or when there is recent symptomatic or functional deterioration. When other lung compartments are involved in conjunction with ILD, the challenge lies in determining which process predominates, especially when disease reversibility is questionable. In this regard, the association of ILD with PH is a difficult problem in patients with CTDs, especially in SSc (35). PH may be secondary to chronic lung disease but may also result from an intrinsic vascular process, particularly when PH is out of proportion with the severity of interstitial disease. The recognition and treatment of disproportionate PH may provide symptomatic improvement (35). Patients with CTDs have often been excluded from consideration for lung transplantation because of concerns about multiple organ involvement, gastroesophageal reflux, or Raynaud’s disease. However, in highly selected patients
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with CTDs complicated with ILD or PH, long-term successful transplantation outcomes can be achieved (36). III.
Systemic Sclerosis
SSc is a systemic disorder of the connective tissue characterized by deposition of excessive extracellular matrix, microvascular obliteration, and abnormalities of humoral and cellular immunity. The prevalence of SSc is approximately 30 to 120 per million, with a 3 to 8/1 female preponderance and a peak incidence in the fourth to sixth decades (37). Diagnostic criteria for SSc were developed by the American College of Rheumatology (38). Limited and diffuse skin disease differs in clinical presentation, autoimmune signature, and evolution. Limited disease (about 60% of all patients with SSc) is defined by distal cutaneous sclerosis that can involve the face but not the trunk or limbs proximal to the elbows and knees. Diffuse disease (about 40% of all patients with SSc) is defined by proximal cutaneous sclerosis, extending to the trunk. In SSc sine scleroderma most features of SSc are present, except for skin thickening (37). ANA is positive in 90% to 100% of all patients. Anti-centromere antibodies, present in up to 60% of patients with limited SSc, and anti-topoisomerase I antibodies (anti-SCl-70 antibodies), found in 20% to 40% of patients with diffuse SSc (37) are mutually exclusive. PH and ILD are the most frequent respiratory manifestations in SSc (Table 1) (1,2,37,39) and the two leading causes of mortality (40–42). Despite an improvement in survival of patients with SSc over the last 30 years, the frequency of death from pulmonary fibrosis has increased from 6% to 33% (41). This may reflect better outcomes in renal disease. A.
Epidemiology and Risk Factors of SSc-ILD
Estimates of prevalence of ILD are especially problematic in SSc, as pulmonary fibrosis is one of three minor diagnostic criteria (38). Patients with ILD are often asymptomatic and the prevalence of ILD depends on the mode of diagnosis. Pulmonary fibrosis is found at autopsy in 75% to 100% of patients (43,44). An isolated reduction in DLCO is present in most patients with SSc but a restrictive defect occurs in only 23% to 40% (45–48). Abnormalities are evident on chest radiography in 25% to 65% (46–50), the highest prevalence among CTDs, and HRCT identifies limited ILD in a further subgroup (48,51–53). In one study, 91% of patients had evidence of ILD at HRCT, whereas only 39% had interstitial abnormalities on chest radiography (52). In the largest prospective study, with complete evaluation of 73 consecutive patients with diffuse SSc, evidence of ILD was present on chest radiography in 53% and on HRCT in 70%, decreases in DLCO, forced vital capacity (FVC), and total lung capacity (TLC) were noted in 64%, 52%, and 21%, respectively, and bronchoalveolar lavage (BAL) abnormalities were found in 48% (48).
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Factors predisposing to ILD in SSc are not well understood. ILD occurs in SSc subgroups but is more frequent in diffuse SSc, whereas PH is more common in limited SSc (1,2,37,39). A recent analysis by the EUSTAR (Eular Scleroderma Trials and Research) group core set data from 3656 patients with SSc revealed that ILD was present in 53% and 35% in diffuse and limited SSc, respectively (54). In other studies, ILD is strongly associated with anti-topoisomerase I antibody positivity but is rare in patients with anti-centromere seropositivity, suggesting a protective role for this antibody (46,47,55–58). Patients with the anti-Th/To antibody may develop concurrent ILD and vascular disease (58,59). Lung involvement may be more prevalent and severe in African Americans, maybe because of a tight association with anti-topoisomerase I antibody positivity (60). In a prospective U.S. study of patients with early SSc, the frequency of radiographically evident pulmonary fibrosis at presentation was significantly higher in African Americans (46%) than in Hispanics (25%) or Whites (19%) (46). B.
Pathogenesis of SSc-ILD
It is generally accepted that lung involvement is autoimmune, with innate susceptibility and environmental trigger factors amplifying injury and the immune response (61). SSc-ILD is linked to the carriage of human leukocyte antigen (HLA) DR3/DR52a or the anti-topoisomerase antibody (62). Other candidate genes have been incriminated. SPARC is a matricellular protein that modulates cell-cell and cell-extracellular matrix interactions. A relationship between polymorphic loci of the SPARC gene and ILD has been suggested (63) but not confirmed (64). Fibronectin is a glycoprotein that binds to integrins and extracellular matrix components. An association between fibronectin gene polymorphisms and ILD has been found (65). Ultrastructural studies suggest that endothelial and/or epithelial injury precedes inflammation and fibrosis in early SSc-ILD (51). Thereafter, both proliferation of myofibroblasts and the overdevelopment of capillary microvessels seem to be involved in progressive lung fibrosis (66). T lymphocytes may play a fundamental role. T-cell responses to epitopes of DNA topoisomerase I are restricted, both in healthy subjects and in those with SSc (67–69). Thus, the anti-topoisomerase antibody may provoke a pathogenetic immune response in individuals with responsive T-cell clones. Lung tissue of patients with SSc-ILD displays lymphoid follicles with germinal centers and CD4 T cells of both TH1 and TH2 subsets that express the hallmark profile of cytokines [interleukin-4 (IL-4), IL-5, and g-interferon (INF-g)] in balanced numbers at the mRNA level (10), as well as accumulation of ‘‘memory type’’ lymphocytes (70). In BAL, patients with SSc-ILD show a predominance of CD8 T cells that produce Th2 cytokines, most notably IL-4, in contrast to those with no ILD (71). Multiple cytokines, chemokines, and other mediators are present in lung tissue in SSc-ILD, contributing to a cascade of lung inflammation. These include a predominant Th2 cytokine milieu, IL-8, monocyte chemoattractant protein-1 (MCP-1), and RANTES (9,72–74).
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Table 2 Frequency of ILD Patterns of Involvement in Connective Tissue Diseases
NSIP UIP OP DAD DIP LIP
RA
SLE
SSc
DM/PM
SjS
MCTD
þþ þþþ þþ þ þ þ
þ (?) þ (?) þ þþ
þþþ þþ þ þ
þþþ þþ þ þ
þþþ þ þ
þþþ þ (?) (?) (?)
þ
þþ
Note: þ signs indicate the relative frequency of each manifestation. An empty cell indicates no or exceptional description of the manifestation. Abbreviations: ILA, interstitial lung disease; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; DM, dermatomyositis; PM, polymyositis; SjS, Sjo¨gren’s syndrome; MCTD, mixed connective tissue disease; NSIP, non-specific interstitial pneumonia; UIP, usual interstitial pneumonia; OP, organizing pneumonia; DAD, diffuse alveolar damage; DIP, desquamative interstitial pneumonia; LIP, lymphocytic interstitial pneumonia.
The other major event in SSc-ILD is mesenchymal cell proliferation and connective tissue matrix deposition. Many growth factors involved in several pathways of fibrosis have been incriminated, including fibronectin (50), transforming growth factor-b (TGF-b) (75,76), connective tissue growth factor (CTGF) (77), endothelin-1 (ET-1) (78,79), and coagulation cascade proteins (80). Fibroblasts from patients with lung disease exhibit dysregulated type I collagen biosynthesis and impaired mRNA downregulation (81). C.
Pathology of SSc-ILD
Publications postdating the reclassification of IIPs have established that NSIP is the most frequent pattern (4,11,27,82,83) (Table 2). NSIP (Fig. 1) is found in 56% to 79% of all SLB samples, while UIP is present in 8% to 44% (4,11,27,83). OP is very rare (84,85), and DAD is exceptional (21,82,86) usually occurring in established NSIP (21,82). Pulmonary vascular changes may be present in association with interstitial lesions, even in the absence of overt PH (5,87). D.
Clinical Features of SSc-ILD
Although reported up to 40 years after the onset of SSc (88), ILD generally occurs within the first 3 years (46,89) and may precede disease. Subtle SSc may be missed until the physician is prompted by the presence of lung disease. However, the presence of ILD in SSc sine scleroderma is well documented and almost certainly under-recognized (27). Patients with SSc-ILD are asymptomatic until lung disease is advanced. Symptoms usually consist of chronic progressive dyspnea, non-productive cough, and fine bibasilar crackles. Digital clubbing is exceptional. Limited and diffuse SSc are virtually identical with respect to dyspnea, PFT, and BAL
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Figure 1 Typical pattern of mixed nonspecific interstitial pneumonia in a patient with systemic sclerosis. The interstitium is infiltrated by lymphocytes. Fibrosis is present but mild with temporal homogeneity. Fibroblastic foci are absent. Note the presence of lymphoid follicles (arrow). HES 20.
findings (90). The St. George’s Respiratory Questionnaire (91) and SF-36 (92) are helpful instruments to evaluate the quality of life in SSc-ILD. Secondary PH with the clinical features of right ventricular strain is common in end-stage disease, but PH also occurs as a primary pulmonary vascular process. Moderate to severe PH is frequently associated with SSc-ILD (54,93,94). In one study, PH presence in SSc-ILD was 17.9% and was strongly associated with a low PaO2, regardless of the extent of fibrosis: mean pulmonary artery pressure (PAP) was disproportionate to PFT impairment in 33% of patients (94). SSc-ILD is characterized by a restrictive defect and a decreased DLCO. PFTs, and especially DLCO levels, correlate well with the extent of disease on HRCT (45,95,96). Rarely, scleroderma of the chest wall may cause extrathoracic restriction. Cardiorespiratory exercise testing may detect occult lung involvement by showing increased functional dead space ventilation and widened an alveolararterial oxygen gradient (96,97). The six-minute walk test, a simple, inexpensive and reproducible test that gives a good indication of patient’s exercise capacity, has yet to be validated in SSc-ILD as an outcome measure (98,99). E.
Imaging of SSc-ILD
HRCT features, reported in numerous studies (53,95,96,100–104), appear to be homogeneous, reflecting the high prevalence of a pure NSIP pattern (Fig. 2A,B) (100), compared with other CTDs. HRCT abnormalities include ground-glass attenuation (74–100%) and linear opacities (74–90%), alone or with traction bronchiectasis or bronchiolectasis (68–76%), consolidation (33%), and honeycombing (30–40%). Early disease is predominantly peripheral and posterior at
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Figure 2 (A) and (B) HRCT appearances in a patient with systemic sclerosis, showing a pattern suggestive of nonspecific interstitial pneumonia in association with esophageal dilatation and pericardial thickening.
the lung bases, evolving superiorly, centrally, and anteriorly (101,102). Mediastinal lymphs nodes are often enlarged on HRCT (53,101), but not on chest radiography. An increased pulmonary artery diameter, indicative of PH, pericardial effusion, and esophageal dilatation provide supportive evidence for a diagnosis of SSc sine scleroderma (27). Recently, it has been suggested that densitometric data are more closely related to the severity of lung disease than visual assessment (105,106). HRCT is not accurate in distinguishing between active inflammatory and irreversible fibrotic disease (53,105,107–109) as ground glass usually persists, with evolution to reticulation and traction bronchiectasis on serial HRCT (101,102,104). F.
BAL in SSc-ILD
BAL has been extensively investigated in SSc but appears to add little extra useful information and is no longer routinely performed in SSc-ILD. ‘‘Alveolitis,’’ defined as an increase in neutrophils count >3% or eosinophils >2% (50), does not correlate with histological findings (11,83) and varies greatly according to the lobe in which BAL is undertaken (107,109). In several studies, a neutrophilia or granulocytosis on BAL has been associated with progression of lung disease (48,50,110). However, BAL findings appear to reflect disease extent and are not independently linked to progression of disease (111). Thus, treatment decisions should not be influenced by BAL findings. G.
Diagnosis of SSc-ILD
No validated diagnostic algorithm exists for the detection of progressive SScILD. In patients with antitopoisomerase I antibody positivity, PFT every three months and HRCT every six months for the first three years, and until abnormalities are stable, have been advocated (112). However, serial HRCT carries a significant radiation burden and an alternative strategy is to base repetition of HRCT on serial PFT change. Patients not at increased risk, including those with
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anti-centromere antibody and those with longstanding disease, require less extensive monitoring (112). SLB is seldom warranted in SSc-ILD as it provides no useful prognostic information. H.
Evolution and Prognosis of SSc-ILD
Studies of the rate of change of PFT in SSc indicate that, on average, FVC levels diminish three times as rapidly, and DLCO twice as rapidly, as in normal individuals (33,34,47,50,113). More severe reduction in FVC and/or DLCO predict PFT decline in SSc (33,34). However, only 5% to 13% of patients suffer from severe restrictive lung disease (FVC < 75%) (34,47). Steen et al. reported that in patients ultimately developing a severe restrictive defect, FVC levels fell by 32% per year during the first two years of SSc, 12% in the next two years, and 3% thereafter (47). In a study of 80 patients with SSc-ILD, there was little average decline in PFT, with a median loss of FVC of only 2.5% at three years, but change was highly variable in individual patients (11). Clinical and laboratory data, including the presence of anti-topoisomerase antibody and skin extent, are not predictive of PFT deterioration and/or the severity of lung disease (33,34,47). In a longitudinal HRCT study, normal HRCT appearances at baseline were consistently unchanged at follow-up, but SSc-ILD on HRCT progressed in 50% of cases (102). The clearance of radio-labeled diethylene triamine pentacetate (99mTc-DTPA) is used in some centers to evaluate prognosis. Persistently rapid clearance, indicating a loss of epithelial cell integrity, confers an increased risk of PFT decline (51,114). Serum concentrations of KL-6 and surfactant protein A or D, biomarkers secreted by alveolar type II epithelial cells, are increased in active and severe ILD in Japanese SSc patients (115–117). In one study, outcome did not differ significantly between NSIP (5-year survival 90%, 10-year survival 69%) and UIP/end-stage lung (11). About 40% of patients with SSc-ILD die from causes directly attributable to restrictive lung disease and in another 27%, lung involvement is a major contributing factor (47). Mortality in SSc-ILD increases with more severe reduction in FVC and DLCO at baseline, decline in DLCO at three years (11) and more extensive disease on HRCT at presentation (95), but varies little with the histological pattern of ILD (4,11). In a recent nested case-control study, lung cancer was not associated with pulmonary fibrosis, scleroderma subtype, or anti-topoisomerase antibody status (118). I.
Treatment of SSc-ILD
1.
Immunosuppressive Treatment
Various immunosuppressive drugs have been employed in SSc-ILD including cyclophosphamide, azathioprine, and mycophenolate mofetil (MMF). The most frequent treatment regimen involves low-dose prednisolone (<10 mg/day or 20 mg on alternate days). Higher-dose corticosteroid therapy has been implicated in the precipitation of renal crises.
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Cyclophosphamide
Until recently, the use of cyclophosphamide to preserve lung function and improve survival in SSc-ILD was based on uncontrolled data (119–122). However, two randomized placebo-controlled trials have now been reported. The multicenter North-American Scleroderma Lung Study included 158 patients with active and symptomatic SSc-ILD who were assigned to placebo or oral cyclophosphamide for 12 months, followed by 12 months of follow-up (123). Findings at 12 months favored active treatment with regard to FVC (relative difference 2.53%, p < 0.003), TLC, dyspnea, and scores of quality of life, although there was no DLCO effect (123). Cyclophosphamide was similarly efficacious in limited and diffuse SSc (90). The maximal benefit was seen at 18 months, but the treatment effect disappeared at 24 months for both FVC and TLC (124). The multicenter British FAST (Fibrosing Alveolitis in Scleroderma) Trial included 45 patients with SSc-ILD who received either placebo or monthly intravenous cyclophosphamide for six months followed by azathioprine for six months (125). There was a marginal trend in favor of active treatment for FVC (relative difference 4.19%, p ¼ 0.08), but no effect on DLCO or HRCT (125). Taken together these studies are strongly indicative of a significant but modest treatment effect from cyclophosphamide in SSc-ILD. Strikingly, in both studies, disease progression was entirely abolished by active treatment. It is likely that patients with overtly progressive disease, with the most to gain from cyclophosphamide, were under-represented due to the ready availability of open treatment and, thus, the low magnitude of the treatment effect should not be extrapolated to clinical practice. Furthermore, the use of BAL as an inclusion criterion in the Scleroderma Lung Study can be questioned. Importantly, the benefit of cyclophosphamide was transient after the cessation of treatment, underlining the need for an equally effective but less toxic long-term therapy. The use of intravenous cyclophosphamide appears to be associated with a lower risk of hematuria, and marrow toxicity. Azathioprine
In a randomized unblinded prospective trial, azathioprine was less efficacious than oral cyclophosphamide in stabilizing lung function (126) but in a small retrospective series, FVC rose or stabilized in most cases 12 months of treatment (127). On the basis of these limited data, azathioprine may have a useful role in selected cases. MMF
MMF, a novel well-tolerated immunosuppressive agent, has been used in SScILD (128,129). In a retrospective series of 28 patients with CTDs-ILD (mostly SSc-ILD), PFT remained stable when MMF was used as first-line treatment or after other agents (129). However, no firm recommendation can be made in the absence of controlled data.
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Other Specific Treatments
There is no evidence that penicillamine has a useful treatment effect (130). Similarly, although presented only in abstract form at the time of writing, a large randomized placebo-controlled trial of SSc-ILD found that anti-endothelin-1 therapy with bosentan had no effect on the six-minute walk distance or PFTs. A multicenter U.S. study evaluated autologous hemopoietic stem cell transplantation in patients with diffuse SSc for less than four years and significant visceral organ involvement, or progressive lung disease in the previous six months with diffuse or limited SSc (131). The protocol included high-dose immunosuppressive therapy and total body irradiation. Thirty-four patients were enrolled, all with lung disease. After four years, skin softening was striking and sustained, despite the conventional wisdom that fibrotic skin abnormalities are irreversible, and visceral organ involvement was largely stable. FVC levels had risen (1.66%/yr, p ¼ 0.01) and decreases in DLCO were not statistically significant. Significant regression of lung disease was seen in 8 of 27 evaluable patients. Two patients experienced fatal pulmonary toxicity with the initial treatment protocol, but no further events occurred after lung shielding was adopted for total body irradiation. The five-year survival was 64% and mortality related to treatment was 23% (131). In a recent pilot Dutch-French study, in which total body irradiation was not used, survival was better than in the earlier study and PFTs remained stable after a median follow-up of 5.3 years (132). 3.
Treatment of Associated Conditions
Until recently, no specific treatment has been used in PH associated with SScILD. However, novel oral agents including bosentan and the phosphodiesterase inhibitor, sildenafil, should be considered in PH (35). Treatment of gastroesophageal reflux and supervening heart failure and infection is also important. Supplementary oxygen therapy is sometimes required and pulmonary rehabilitation may improve quality of life. Patients with end-stage lung disease are candidates for single lung transplantation, provided there is no evidence of major disease activity in other organs (36). IV.
Rheumatoid Arthritis
RA is characterized by a chronic symmetrical inflammatory arthritis and is diagnosed using American Rheumatism Association criteria (133). In recent years, the diagnostic accuracy of keratin antibodies (AKA) and, especially, cyclic citrullinated peptide antibodies (anti-CCP), has been increasingly accepted. The presence of antiCCP antibodies may become the diagnostic marker of choice in early RA, with a specificity of 96% and a comparable sensitivity to the widely used but less specific RF (134). RA is the most common CTD, affecting 1% to 2% of the general population, with a predilection for women (sex ratio 2.5:1) and a peak incidence between the fourth and seventh decades (133).
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A wide variety of specific and nonspecific pulmonary manifestations are observed in RA but ILD, with or without airway involvement, is probably the predominant and most serious manifestation (Table 1) (1,2,135). Pulmonary fibrosis is the second or third most frequent cause of death (3.9–17.5%), after infection or cardiovascular accidents (136–138). A.
Epidemiology and Risk Factors of RA-ILD
The prevalence of ILD in RA varies with the mode of detection. ILD is evident on chest radiography in 1% to 6% (139–143). A restrictive defect is infrequent (5–12%), but TLCO is reduced in 33% to 57% of unselected patients (31,139,140,144). BAL abnormalities are present in 0% to 33% of patients with no clinical evidence of ILD (140,145–147). In an early SLB study in volunteers with RA, interstitial lesions were disclosed in 60%, without respiratory symptoms in nearly 50% (148). A wide variation in the prevalence of HRCT abnormalities, of 4.2% to 68% (139,140,149–152), probably reflects selection bias. In a study of recent-onset RA, ILD was present on HRCT in 33% (140). However, as HRCT findings correlate poorly with symptoms, chest radiography, and PFT, their clinical relevance is unclear (139,140,149,151,152). In the largest study, ILD was seen on HRCT in 19% of 150 consecutive patients and was associated with bilateral basal crackles in 54%, TLCO <75% in 82%, restrictive PFT in 14%, bilateral infiltration on chest radiography in 14%, but dyspnea in only 18% (139). Lung involvement is generally accepted to be more prevalent in smokers, males, with positive ANA and high titres of RF and with nodular disease, extraarticular involvement, or severe disease (141–143,152–154). Smoking, which predisposes to RA, may be the strongest independent risk factor for ILD, with an odds ratio of 3.76 for a cumulative cigarette exposure exceeding 25 pack-years (153). However, these predisposing factors are not found consistently (139,140). Moreover, while the predilection for UIP is real in males and smokers, women and nonsmokers may be more likely to develop NSIP (13,155). HLA-B8 and Dw3 positivity may confer susceptibility for ILD in RA (156). An association of a1-protease inhibitor phenotypes with ILD has been reported (157,158), but not confirmed (159). B.
Pathogenesis of RA-ILD
The pathogenesis of RA-ILD is uncertain. A marked increase of CD4 T cells (160) and follicular CD20 B-cell hyperplasia (161) are reported, and there is a diffuse infiltration of mast cells (161,162). The prevalence of well-organized inducible bronchus-associated lymphoid tissue (BALT) is increased in RA-ILD and SjS-ILD, compared with other ILDs (163). BALT consists of numerous B-cell follicles containing germinal centers and follicular dendritic cells, surrounded by loosely defined T-cell infiltration. BALT is associated with increased expression of lymphoid-organizing chemokines, such as CXCL13 and CCL21,
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as well as cytokines, co-stimulatory molecules, and enzymes that are involved in the immunopathology of RA. Lastly, the presence of BALT correlates with tissue damage in the lungs of RA patients (163). Given the high specificity of anti-CCP antibodies, it has been suggested that citrullination of proteins plays a key role in articular and extra-articular pathogenesis. Citrullinated proteins are present in lung samples from patients with RA-ILD (164). Patients with BALT exhibit higher levels of anti-CCP antibodies in BAL fluid (163). Moreover, lung citrullination is spatially associated with inflammatory aggregates (164) and BALT (163) in keeping with a pathogenetic role. Interestingly, there is a striking association between smoking and the presence of RF and anti-CCP antibodies in RA. It has been suggested that tobacco may trigger RA-specific immune reactions to (auto)antigens, modified by citrullination in carriers of HLA-DR-shared epitope alleles (165). It appears that lung citrullination may be induced by smoking, judging from the presence of citrullinated proteins in BAL in smokers but not in nonsmokers (165). Taken together, these data support the existence of a model of geneenvironment interaction in patients with anti-CCP positive RA and ILD. C.
Pathology of RA-ILD
Published results are sparse (4,6,13,155,166–169) and need to be interpreted with caution as some studies antedate the reclassification of the IIPs, and there is likely to be major bias in the selection of patients for SLB. However, an NSIP pattern appears to be less prevalent than in other CTDs (Table 2). Recent data indicate that UIP (Fig. 3A,B) may be more frequent than NSIP (4,13,166,168). In the largest series of 28 biopsy-proven cases, UIP and NSIP were the primary pattern in 62.1% and 37.9%, respectively (4). To examine selection bias, clinical and HRCT features were compared between biopsied and non-biopsied patients with RA-ILD. No significant difference was found and more than 80% of the non-biopsied group had typical HRCT features of UIP (4) in keeping with an earlier report (13). The histological picture can be complex. UIP and NSIP can overlap and may coexist with other patterns. Follicular or constrictive bronchiolitis is the major or a secondary pattern in up to 35% of cases (6,155,167). OP is present in 10% to 22% (13,155,166,167,169). DAD is rare and may occur in isolation (155,168,170) or superimposed on UIP (21), NSIP (168), or OP (170). DIP may be related to smoking rather than CTD (6,155,167,169), and LIP is rare (171). D.
Clinical Features of RA-ILD
In most patients, ILD postdates the onset of RA (13,139,172), sometimes by less than two years (140). ILD can also present simultaneously or several years before systemic disease (30,133,173), the latter sequence occurring most often in patients with NSIP (13,30,173). In one series, ILD preceded RA in 16.7% of cases and developed concurrently in 16.7% (13).
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Figure 3 (A) and (B) Patient with rheumatoid arthritis. Patchy fibrosis with remodeling of the lung architecture showing a prominent subpleural distribution consistent with usual interstitial pneumonia. There is a temporal heterogeneity with preserved areas of normal lung. Interstitial inflammation is mild. A, HES 20. Inset: The bronchial lumen is partially obliterated by a focus of loosely organized connective tissue. B, HES 100.
Clinical symptoms are nonspecific and include progressive dyspnea, nonproductive cough, and fine bibasal crackles. Unlike other CTDs, digital clubbing is not uncommon in RA-ILD (16–27.8%) (13,139,172,174), although less frequent than in IPF (172). In RA, apical fibrosis may mimic the lung disease of ankylosing spondylitis (175). In a handful of cases, extensive apical cavitation occurs without nodules or other causes of fibrocavitary disease, including mycobacterium infection, and the course is sometimes fulminant (176). Decreased DLCO and a restrictive defect are typical in RA-ILD, with mixed defects also seen (13,155,177). As many patients are smokers, an obstructive defect may denote emphysema or RA-related constrictive bronchiolitis.
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Imaging of RA-ILD
The most frequent signs on HRCT are reticular opacities (15–98%), ground-glass attenuation (2–90%), honeycombing (6–71%), and consolidation (3–35%) (13,139,140,149,151,152,155,166,168,174,177). A pure reticular pattern, with or without honeycombing, is present in 41% to 78.6% (13,139,155,166,177). Ground-glass attenuation is the most common lesion in early RA and early ILD (140,177). The HRCT pattern is usually accurate against SLB findings (13,155,166,168). In one series, the four observed HRCT patterns suggested UIP (41%) (Fig. 4A,B), NSIP (30%), bronchiolitis (17%) or OP (8%), with frequent UIP/NSIP overlap (155), and concorded with findings in most of the
Figure 4 (A) and (B) HRCT appearances in a patient with rheumatoid arthritis and a history of heavy smoking. The destructive fibrotic abnormalities are typical of usual interstitial pneumonia, admixed with emphysema in upper lobes.
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17 patients undergoing SLB (155). Exceptions included UIP at HRCT but NSIP at SLB (n ¼ 2), NSIP at HRCT but DIP at SLB (n ¼ 1), and LIP at HRCT but NSIP at SLB (n ¼ 1). HRCT often discloses a complex admixture of lesions, termed ‘‘rheumatoid lung.’’ Bronchiectasis is present in 8% to 75% of patients, but the distinction between primary bronchiectasis and traction bronchiectasis due to pulmonary fibrosis is often difficult (139,140,149,151,152,155,166,177). Bronchiolitis is also frequent, manifesting as centrilobular nodules, tree-in-bud sign, mosaic perfusion, or air trapping (139,149,151,152,155,166,177). Emphysema is present in 5% to 43% of patients (13,139,140,149,151,152,155,166,174,177) and is widely viewed as a trait of RA-ILD, unlike findings in other CTDs. Emphysema is more frequent with an HRCT pattern of UIP, as opposed to NSIP (155). Other features include pulmonary rheumatoid nodules and pleural effusion or thickening can be observed. Pulmonary artery enlargement has been observed in nearly half of patients with RA-ILD, in spite of the fact that overt PH is rare in RA (155). F.
BAL in RA-ILD
Alveolitis is present in 0% to 33% of patients with normal radiography and PFTs (140,145–147), but does not denote progressive disease. BAL is usually abnormal in patients with clinically overt ILD, with a neutrophilic alveolitis typical, either alone or in association with a lymphocytosis and/or eosinophilia (13,140,145,177). BAL profiles do not differ between UIP and NSIP (13). G.
Diagnosis of RA-ILD
The most vexing diagnostic problem is to distinguish between RA-ILD and infection or drug-induced lung disease. The risk of serious pulmonary infection is twofold higher in patients with RA than in controls and is likely to rise with the widespread use of tumor necrosis factor-a (TNF-a) antagonists. Most disease-modifying agents used in RA can cause ILD, including methotrexate, gold, penicillamine, sulphasalazine, leflunomide, and TNF-a blockade (178,179). The reported incidence of methotrexate pneumonitis varies from 0.86% to 6.9%, equating to a frequency of 1/100 patient years. The risk is maximal in the first year of treatment and is higher in smokers and with underlying lung disease (178,179). Life-threatening lung toxicity from leflunomide, presenting as acute interstitial pneumonia or acute aggravation of progressive preexisting ILD has been recently reported, especially in Asian patients (180–182). Leflunomide-related acute interstitial pneumonia had a prevalence of 0.5% in a national Japanese survey (180,183). By contrast, the risk of major pulmonary toxicity from leflunomide was not increased in patients with no previous methotrexate use and no history of ILD in a casecontrol Canadian study, suggesting that published reports may reflect the selective use of leflunomide in high-risk patients (184). There are widespread
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anecdotal reports that all three licensed TNF-a antagonists, but mainly infliximab, can cause fatal acceleration of preexisting RA-ILD (185). Etanercept may also potentiate granulomatous pneumonia without evidence of mycobacterium infection (186,187). HRCT and BAL are invaluable in distinguishing between RA-ILD and infection or drug-induced lung disease and often obviate SLB in the delineation of ILD subtypes. SLB is sometimes helpful when HRCT does not discriminate clearly between UIP and NSIP, although it can be argued that the utility of SLB is limited, as the histological subtype does not materially influence treatment decisions, and the prognostic implications are still uncertain. SLB is strongly indicated in clinically significant RA-ILD when HRCT appearances are difficult to classify, and especially when concurrent pulmonary vasculitis is suspected. H.
Evolution and Prognosis of RA-ILD
In asymptomatic patients with RA, a longitudinal study showed no significant increase in the prevalence of a restrictive or mixed defect over 10 years (9.7 vs. 14.6%) (31). By contrast, in established RA-ILD, the outcome is often poor, although varying from slow progression over a decade or longer to a fulminant decline. In a retrospective report of patients admitted to hospital with severe RA-ILD, the median survival was 3.5 years and 5-year survival was 39% (188). In a small prospective evaluation of 18 consecutive patients with RA-ILD: the median survival was 5 years and five-year survival was 44%; notably, only 11% of deaths were due to respiratory failure (18). In a shorter prospective study of 29 patients with RA-ILD, two-year survival was 86%, and 34% of cases had progressive disease: an initial DLCO <54% strongly predicted disease progression (174). Digital clubbing may also be an adverse marker (18). UIP may carry a poorer prognosis than NSIP (13), in contrast with other CTDs-ILD. In a recent study, the mortality of RA-UIP was similar to that of IPF and higher than in other CTDs-UIP on univariate but not multivariate analysis (4). RA-ILD can be complicated by acute exacerbations with a fatal outcome in all cases (21,166,170). The one-year frequency of acute exacerbation has been estimated at 11.1% in patients with RA-UIP, which is higher than in other CTDs-ILD (21). I.
Treatment of RA-ILD
Many agents have been tried in RA-ILD including steroids, azathioprine, cyclophosphamide, cyclosporin, and anti-TNF-a antagonists, but there are no well-designed trials (135). Methotrexate should be avoided in patients with established ILD because of the risk of lung toxicity in a setting of poor lung reserve. Leflunomide should be used with caution, especially if combined with methotrexate. Although TNF-a blockade has stabilized lung disease in several anecdotal reports (189–191), this treatment cannot be recommended, as there are many anecdotal reports of major lung toxicity.
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Sjo¨gren’s Syndrome
SjS is a chronic autoimmune disease characterized by a lymphocytic infiltration of the exocrine glands (192). The hallmark of SjS is dryness of the mouth and eyes (sicca syndrome), resulting from involvement of the salivary and lacrymal glands. The disease spectrum extends from organ-specific exocrinopathy to a systemic disorder with diverse extraglandular manifestations. The exocrinopathy can be encountered alone (primary SjS) or in association with another autoimmune disease (secondary SjS) (192). On the basis of a recent international consensus, diagnosis requires either a positive minor-salivary-gland biopsy sample or anti-Ro/SS-A or anti-La/SS-B antibodies (192). With an estimated population prevalence of about 0.5%, primary SjS is one of the three most common CTDs. There is a female preponderance (male-female ratio, 1:9) and age peaks after menarche (ages 20–30) and after menopause (mid-50s) (192). Glandular and extra-glandular lymphocytic infiltration of the lung finds expression in a continuum from benign to malignant disease (from follicular bronchiolitis to LIP to lymphoma) (1,2). Airway involvement and ILD are the most frequent respiratory manifestations (Table 1). Lung involvement tends to be more frequent and severe in secondary than in primary SjS (193,194), with many of the lung abnormalities in secondary SjS ascribable to the associated CTD. A.
Epidemiology and Risk Factors of SjS-ILD
The prevalence of ILD in SjS depends on the methods used for detection. In historical series primary and secondary SjS were pooled (193–199). Lung involvement is usually subclinical. In the largest prospective study, containing 100 patients with primary SjS, about 5% had abnormal radiography, and a reduction in FVC and DLCO was found at presentation in 12% and 10%, respectively (197). BAL yields an alveolitis in about half of cases without clinical manifestations (147,200). HRCT reveals abnormalities in a third of unselected patients with primary SjS (201) and in up to 89% of patients with respiratory symptoms (202), but significant pulmonary fibrosis in only approximately 20% (201,202). Over two-thirds of dyspneic patients with primary SjS have interstitial abnormalities on transbronchial biopsy (203). ILD may be more common in primary than in secondary SjS (19) and is not linked to gender or smoking habits. Serological abnormalities do not differ from those in patients with other extra-glandular systemic manifestation, with ANA, anti-Ro/SS-A, and anti-La/SS-B present in 69% to 100%, 67% to 94%, and 27% to 50%, respectively (181,204,205). B.
Pathogenesis of SjS-ILD
Little has been written about pathogenetic mechanisms in ILD in SjS, which are likely to be common to lung disease and systemic disease (192). Well-developed inducible BALT is present in SjS-ILD and plays a similar role to that in RA-ILD
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(163). Environmental triggers such as viral infection may be important (192) and reactivation of Epstein Barr virus (EBV) latent infection has been incriminated in patients with pulmonary involvement (206). C.
Pathology of SjS-ILD
Case series are infrequent and contain small numbers of patients (6,181,204,205,207) (Table 2). LIP was considered historically to be the cardinal form of ILD in primary SjS (1,2). However, in two more recent studies, NSIP was the most common pattern of involvement (181,205). Ito et al. evaluated 33 patients with primary SjS and histologically confirmed ILD (31 cases with SLB and 2 autopsies) (181). The histological patterns were NSIP (n ¼ 21, 63%, including 20 cases with fibrosing disease), bronchiolitis (n ¼ 4), primary pulmonary lymphoma (n ¼ 4), amyloidosis (n ¼ 2), and unclassifiable fibrosis (n ¼ 3) (181). Remarkably, LIP was never seen, in accordance with another Asian study (207), and was present in only 16.7% in a series in the United States (205). It is likely that in earlier series, NSIP was classified as LIP and it is also possible that in some cases, lymphoma, now diagnosed from immunohistochemistry and molecular analyses, may have been viewed as LIP. With this proviso, SjS is still the major cause of LIP (Fig. 5A,B), accounting for half of cases (171). Other histological patterns of ILD reported in primary SjS include UIP (205,207), OP (6,205,208) and, rarely DAD (208). Follicular bronchiolitis (Fig. 6) is frequently associated with NSIP as a major or minor lesion (6,181). Amyloid can be associated with LIP or lymphoma. Well-formed granulomas are also described (6,204). D.
Clinical Features of SjS-ILD
ILD is usually diagnosed at presentation or soon after the first sicca symptoms (204,205,207). In the large cohort of Skopouli et al., 4% of patients with primary
Figure 5 (A) and (B) Lymphocytic interstitial pneumonia pattern in a patient with primary Sjo¨gren’s syndrome. Alveolar septae are enlarged by a dense mature lymphocytic infiltrate, including a follicle with germinal center. A, HES 40. The alveolar lining is entirely preserved. B, HES 100.
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Figure 6 Follicular bronchiolitis observed as an associated lesion in a patient with primary Sjo¨gren’s syndrome and a pattern of nonspecific interstitial pneumonia. The lumen is narrowed by an extensive peribronchiolar lymphocytic infiltrate. HES 100.
SjS had ILD at presentation and only 6% developed ILD during a median followup of 3.6 years (209). Davidson et al. followed 30 patients for 10 years and showed that ILD always appears within four years of the diagnosis of SjS (32). Symptoms are chronic and include progressive shortness of breath, nonproductive cough, and fine bibasal crackles. Expiratory wheeze also occurs (205), but digital clubbing is seen in only 0% to 6% of patients (205,207). Decreased DLCO and a restrictive defect are typical, the latter being seen in 58% to 67% of cases (181,205). Obstructive changes compatible with bronchiolitis are present in 9% to 15% (181,204). E.
Imaging of SjS-ILD
In primary SjS, the most frequent signs on HRCT are ground-glass opacity (11–92%) with occasional mosaic attenuation, small centrilobular nodules (6–44%), bronchiectasis (6–46%), cysts (3–46%), consolidation (2–25%), and honeycombing (8–25%) (201,202,205,210–212). These lesions predominate in basal and peripheral zones. The accuracy of HRCT-histological correlations depends on the pattern of involvement (181,205,207). Ito et al. identified HRCT patterns of NSIP (Fig. 7) (55%), UIP (13%), bronchiolitis (13%), isolated cysts (10%), LIP (3%) and OP (0%) (181). An HRCT pattern of NSIP was highly predictive, with positive and negative predictive values of 94% and 77%, respectively. However, other HRCT patterns had a diagnostic accuracy of only 15%, with an HRCT pattern of UIP sometimes seen with a histological pattern of NSIP (181). Honeycombing is seldom present in LIP (205). LIP is indistinguishable from lymphoma at HRCT. Cysts (Fig. 8), long thought to be a highly specific marker of LIP, may also occur with a histological pattern of lymphoma
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Figure 7 HRCT appearances in a patient with Sjo¨gren’s syndrome. The fibrotic abnormalities are compatible with NSIP, and there are areas of air-trapping strongly suggestive of bronchiolitis.
Figure 8 HRCT showing areas of cystic lung destruction in a patient with primary Sjo¨gren’s syndrome. Lymphocytic interstitial pneumonia was evident histologically, with no evidence of MALT lymphoma or amyloidosis at pathology. Abbreviation: MALT, mucosa-associated lymphoid tissue.
and/or amyloidosis (181,205,213,214). The mechanisms of cyst formation are uncertain, a ‘‘check-valve’’ effect from partial bronchiolar obstruction, due to lymphocytic infiltration or amyloid deposits, is often invoked. F.
BAL in SjS-ILD
An abnormal differential cell count is present in 44% to 55% of asymptomatic patients, mainly as a pure lymphocytic alveolitis (147,200). Most lymphocytes
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are T cells (65%), with a CD4/CD8 ratio of about 2.0, although B cells (2%) and NK cells (12%) also occur (215). Alveolitis can regress spontaneously over time (147,215). Strangely, BAL lymphocytosis >15% was associated with a very poor outcome in one study, with no convincing explanation offered (216). G.
Diagnosis of SjS-ILD
An NSIP appearance on HRCT is highly predictive of histological findings. However, SLB is warranted in suspected pulmonary lymphoma, especially when HRCT shows a LIP or cystic patterns. BAL may disclose aberrant B lymphocytes that exhibit cytological abnormalities, and/or the presence of a strong B-cell clonal population on molecular analysis (217). In this context, the histological confirmation of lymphoma is mandatory. H.
Evolution and Prognosis of SjS-ILD
A longitudinal study of lung function in unselected patients with primary SjS was reassuring. Davidson et al. showed a significant fall in DLCO at 4 years compared with baseline values, but at 10 years, there was no further decline (32). The prognosis of patients with overt ILD is also good. In the series of Ito et al., the probability of survival was 84% at five years for all patients and 83% for those with NSIP at SLB; 90% of deaths were related to lung disease (181). Adverse indicators were lower PaO2 and the presence of microscopic honeycombing (181). In a series of 18 patients with primary SjS-ILD, PFTs improved or remained stable except in three patients with UIP, one with NSIP and one with amyloidosis; 39% of patients died during follow-up after a median interval of 67 months (205). Rarely, episodes of fatal acute exacerbation occur in patients with primary SjS-ILD (205). The natural history of LIP remains obscure. A fibrosing evolution (218), eventually resulting in respiratory insufficiency has been reported, but is rare (171). Whether or not LIP is a pre-malignant disorder is still a matter of debate, but transformation to lymphoma appears to be very uncommon (171). Lymphoproliferative malignancies occur in approximately 7% of patients with primary SjS, a prevalence that is 40 times higher than in the general population (192). MALT-type lymphomas of the lung (Fig. 9), also called BALT lymphomas, are extranodal marginal-zone B-cell neoplasms, not usually associated with viruses (192). BALT lymphoma is usually detected in routine or incidental examination. HRCT features are similar to those of patients without SjS (214). The course of the disease is quite indolent, even in cases with extensive or prominent HRCT abnormalities (214). I.
Treatment of SjS-ILD
Steroids have been widely used in primary SjS-ILD (181,204,205) but may cause major morbidity due to acceleration of periodontal disease. Other drugs often used
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Figure 9 HRCT appearances in a patient with primary Sjo¨gren’s syndrome and a MALT lymphoma. Abbreviation: MALT, mucosa-associated lymphoid tissue.
in primary SjS-ILD are hydroxycloroquine (205), azathioprine (181,204,205), cyclophosphamide (181,205,219), and cyclosporin (181,220). However, their efficacy is uncertain and the risk of lymphoma necessitates caution in their use. B-cell depletion by monoclonal antibody to CD20 (rituximab) has demonstrated encouraging results for systemic disease in primary SjS and may also have an effect on lung involvement (221,222). VI.
Polymyositis/Dermatomyositis
Idiopathic inflammatory myopathies include PM, DM, and sporadic inclusionbody myositis (223). These acquired systemic disorders of unknown etiology affect skeletal muscles and other organs. The diagnostic criteria of Bohan and Peters are used in most studies. More rigorous diagnostic criteria require clinical features, muscle enzyme elevation, electromyographic abnormalities, and typical changes on muscle biopsy (223) and, recently, the integration of serological features (224). PM is characterized by symmetric proximal muscle weakness. DM is similar to PM, but with the addition of skin lesions, consisting of an edematous heliotrope (blue-purplish) rash around the upper eyelids, an erythematosus rash on the face, neck and anterior chest (V sign), Gottron’s rash (a raised violaceous eruption or papules at the knuckles, prominent in metacarpophalangeal and interphalangeal joints), mechanic’s hands (thick cracked skin and dirty horizontal lines in the lateral and palmar areas of the fingers), and subcutaneous calcinosis (223). When present with little or no muscle involvement (223), these skin manifestations are termed ‘‘hypoamyopathic’’ DM and ‘‘amyopathic’’ DM respectively, known collectively as ‘‘clinically amyopathic’’ DM (CADM). Inflammatory myopathies are well-recognized paraneoplastic phenomena.
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The idiopathic inflammatory myopathies are rare with a frequency of 6 to 10 per million population (223). DM is the most common at all ages, affecting both children and adults and women more than men. PM is usually encountered after the second decade (223). The clinical and serological expression of these myopathies varies considerably according to ethnicity. Pulmonary complications result from both direct and indirect injury, with respiratory muscle dysfunction and ILD, the most frequent specific manifestations (Table 1) (1,2,223,225). Lung involvement is frequent in PM/DM and is increasingly recognized as a frequent source of morbidity and the major cause of mortality (26,226–230). A.
Epidemiology and Risk Factors of PM/DM-ILD
ILD occurs in approximately 40% of cases with a wide reported range of 5% to 65% (26,227–229,231–235). In a recent prospective study, of newly diagnosed PM/DM, pulmonary symptoms were present in 71% of patients and objective evidence of ILD (as judged by chest radiography, HRCT, or a restrictive ventilatory defect) was found in 65%, with 18% clinically silent (231). Adult patients with PM and DM are equally predisposed to develop ILD, but ILD is very frequent in Asian patients with CADM (26). ILD is extremely rare in inclusion-body myositis. B.
Auto-Antibodies in PM/DM
Many myositis-specific antibodies are reported in PM/DM, with anti-aminoacyltRNA synthetases, the most frequent (Table 3) (223,236). ILD and the presence of anti-synthetase antibodies are strongly associated. Anti-Jo1 antibodies, which occur most commonly, are found in 30% to 100% of cases with ILD, but in 0% to 37% of other PM/DM patients (28,224,233–235,237–241). The anti-synthetase syndrome (1,2,223,225,236) consists of an association between anti-synthetase antibodies and, in a variable proportion of cases, myositis, fever, arthritis, Raynaud’s phenomenon, mechanic’s hands, and ILD, which is present in 75% to 89% of cases (28,224,233–235,237–241). The anti-Mi2 antibody, usually found in DM, is also associated with ILD, whereas the anti-SRP antibody is generally not (236). Anti-Jo1 antibodies are more frequent in PM, whereas non-anti-Jo1 antibodies are more common in DM, and especially in patients with ILD and CADM (236,242–246). Anti-synthetase antibodies are also reported in IPF (28). Myositis-associated antibodies occur also in other CTDs or overlap syndromes (discussed later), which raises nosological issues (Table 3). The antiRo/SS-A antibody has been associated with the anti-synthetase syndrome. C.
Pathogenesis of PM/DM-ILD
ILD in PM/DM is generally thought to be mediated by an immunological response to a viral infection in a genetically susceptible individual. HLA class II governs both the clinical phenotypic expression of PM/DM and the presence of
Ribonucleoprotein complex associated with ribosomes (translocation regulation factor) Nuclear helicase
Anti-Mi-2
Aminoacyl-tRNA-synthetase Histidyl-tRNA-synthetase Threonyl-tRNA-synthetase Alanyl-tRNA-synthetase Glycyl-tRNA-synthetase Glutaminyl-tRNA-synthetase Asparaginyl-tRNA-synthetase Isoleucyl-tRNA-synthetase
Anti-signal recognition particle (SRP)
Myositis-specific autoantibodies Anti–tRNA synthetases Anti-Jo-1 (PL-1) Anti-PL-7 Anti-PL-12 Anti-EJ Anti-JS Anti-KS Anti-OJ
Antigen target
10–15%
<5%
&20% <5% <5% <1% <1% <1% <1%
Prevalence in PM/DM
Table 3 Main Antibodies Associated with Idiopathic Inflammatory Myopathies
Connective-Tissue Disease-Associated Interstitial Lung Disease (Continued)
*Non anti-Jo-1 antisynthetase antibodies seem to target patients with mild or no overt myositis Anti-SRP syndrome: - Severe myositis - Myocardial involvement - Resistance to steroids ILD very rare In DM (>90%) Sometimes associated with ILD
Antisynthetase syndrome: - Myositis* - ILD (75–89%) - Polyarthritis (50–90%) - Raynaud’s phenomenon (20–50%) - Mechanic’s hands (70%) - Fever (50–80%)
Distinctive clinical feature
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Small ribonucleoprotein Ribonucleoprotein
Anti-U1-RNP
Anti-Ro/SSA
4–26%
5–10%
1–5%
5–10%
Prevalence in PM/DM
In scleroderma, myositis, and scleroderma/ PM-DM overlap syndromes (Caucasians). Sometimes associated with ILD In scleroderma/PM-DM overlap syndromes (Asians) Sometimes associated with ILD Marker for Sharp’s syndrome, also seen in other CTDs and myositis Sometimes associated with ILD Usually associated with anti–tRNA synthetase antibodies
Distinctive clinical feature
Abbreviations: PM, polymyositis; DM, dermatomyositis; ILD, interstitial lung disease; CTDs, connective tissue diseases.
DNA-binding protein
Peptide complex forming an exosome (exoribonuclease activities)
Anti-Ku
Myositis-associated autoantibodies Anti-PM-Scl
Antigen target
Table 3 Main Antibodies Associated with Idiopathic Inflammatory Myopathies (Continued )
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anti-synthetase antibodies (236). Associations between DRB1*0405 and ILD, and between DRB1*0405 and anti-synthetase antibodies, are reported in Asian patients (247). DRB1*03-DQA1*05-DQB1*02 haplotypes are strongly associated with both anti-synthetase antibodies and ILD in Asian patients, irrespective of myositis subtypes (248). No direct association was found between EBV or cytomegalovirus (CMV) and PM/DM-ILD, using polymerase chain reaction and in situ hybridization in lung tissue from patients dying of lung disease (249). However, it remains possible that viruses play an indirect role: several cases with PM/DM, ILD, and hepatitis C have been reported (250). Both cellular and humoral autoimmune factors may contribute to the pathogenesis of PM/DM-ILD. In patients with NSIP, most B cells are localized inside and/or around lymphoid follicles, CD4 T cells are distributed diffusely in fibrotic areas and unrelated to lymphoid follicles, and most CD8 T cells are distributed diffusely, especially in relatively normal alveoli (251). Shared T-cell receptor V-gene expression in CD4 and CD8 T lymphocytes in BAL fluid and muscle tissue of patients with PM/DM, carrying HLA-DRB1*03 allele and the anti-Jo1 antibody, suggests common target (auto)antigens (252). Interestingly, the pathogenesis of PM/ DM-ILD may vary with the clinical presentation and/or underlying histological pattern. Patients with rapidly progressive ILD have a higher CD4/CD8 T-lymphocyte ratio in the peripheral blood than those with a gradual onset (253). Endothelial damage produce pro-fibrotic factors such as TGF-b or ET-1 (254). Circulating antiendothelial cell antibodies have been linked to ILD independently of the presence of anti-synthetase antibodies (255). D.
Pathology of PM/DM-ILD
In PM, DM, or CADM alike, NSIP is the most frequent common pattern, seen in 36% to 82% of biopsy-proven cases (4,6,23,25,237,256) (Table 2). UIP is found in 4.5% to 45% (6,23,25,228,234,237,256,257) and OP (Fig. 10) in 0% to 38% (6,23,234,237,257). DAD (Fig. 11A,B) is present as a predominant or minor superimposed lesion in 0% to 28.6% (6,25,228,229,237,256,257), but may be under-reported as SLB is often impracticable when the onset of disease is severe and acute. In many biopsies, there is more than one pattern of disease, with coexistent NSIP and OP (Fig. 12) especially frequent (6). Active or healed vasculitis is occasionally seen in addition to DAD (229,258). LIP is rare (23). A histological transformation from NSIP to DAD is reported (259). E.
Clinical Features of PM/DM-ILD
ILD usually presents immediately before or after the onset of systemic symptoms (260) but may precede the systemic symptoms by months or years (260). ILD presents before the diagnosis of PM/DM in 5% to 30% of patients, concurrently with PM/DM in 21.4% to 95.6%, and after the onset of systemic disease, usually within one to two years, in 38.9% to 60% (23,25,28,228,234,237,239,256). As
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Figure 10 Organizing pneumonia pattern in a patient with polymyositis. There are polypoid plugs of organizing connective tissue within both alveolar ducts and adjacent alveolar spaces. The architecture of the lung is preserved and the connective tissue is all the same age. There is a moderate associated interstitial inflammatory infiltrate. HES 100.
Figure 11 (A) and (B) Acute phase of diffuse alveolar damage pattern in a patient with dermatomyositis. The lung shows interstitial and intra-alveolar edema associated with fibrinous exsudate and hyaline membranes (arrow). A, HES 40. Inset: Alveolar duct is filled with loose fibro-inflammatory plug extending within adjacent airspaces. B, HES 40.
myositis is often subclinical, the presence of a subtle skin rash or increased muscle enzymes may be diagnostically crucial in apparently idiopathic ILD. The measurement of anti-Jo1 and non-anti-Jo1 anti-synthetase antibodies may be revealing, with the latter more frequently associated with little or no overt muscle involvement. Electromyographic examination and muscle MRI may identify potential sites for biopsy. Arthralgia/arthritis and Raynaud’s phenomenon are often associated with lung involvement, independently of anti-synthetase antibodies (228,229,233,234,239,253). Malignancy is much less prevalent in patients with ILD than in those without ILD
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Figure 12 Combined pattern of cellular nonspecific interstitial pneumonia and organizing pneumonia in a patient with polymyositis. The interstitium is intensely infiltrated by lymphocytes. Fibrosis is minimal. Note the intraluminal plugs of connective tissue (arrow). HES 40.
(234,261). Based on the presentation of ILD, patients with PM, DM, and CADM can be categorized into three subsets, with uncertain relative frequency, due to variable diagnostic criteria, ethnicity, and nature of patient referral. In 15.6% to 63.3% of patients, there is an acute/subacute onset with severe, rapidly progressive dyspnea often evolving to respiratory failure (24,25,228,234,239,241,253). This presentation may be difficult to distinguish from antibiotic-resistant infectious pneumonia as sputum production, fever (25), and increased C-reactive protein (CRP) levels (24) are frequent. Pneumomediastinum and subcutaneous emphysema are occasional features (26,228,241). DAD is usually present at SLB (25,228,253,256), although NSIP is also described (25,234). Rapidly progressive ILD occurs more often in DM than in PM, at least in Asian populations, and is most frequent in patients with less prominent myositis (25,26,228,253,256). A novel antibody in CADM, antiCADM-140 may be associated with rapidly progressive ILD (262). In 35.7% to 84.4% of cases, ILD is chronic, with insidious dyspnea and cough (24,25,228,234,239,241,253). NSIP or UIP (25,234) are more common at SLB than OP (234,253). In Europeans, unlike Asians, ILD has a chronic benign course in CADM (23). In 25% to 31% of patients, aysmptomatic ILD is disclosed incidentally by chest radiography or PFTs (228,234). F.
Imaging of PM/DM-ILD
In HRCT studies of PM/DM-ILD, ground-glass attenuation is the most frequent sign (48–100%), alone, or admixed with reticular opacities (50–83%). Other features include subpleural or peri-bronchovascular consolidation (40–100%), traction bronchiectasis or bronchiolectasis (14.8–67%), and honeycombing
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Figure 13 HRCT appearances in a patient with polymyositis, showing findings compatible with nonspecific interstitial pneumonia.
(3.6–22%) (23–25,234,237,239,256,263,264). Subpleural curvilinear abnormalities are also described (24,263,265), probably representing evolution of OP (263,265). In chronic and asymptomatic cases, the disease (Fig. 13) tends to be concentrated peripherally in the lower lobes, with a higher frequency of traction bronchiectasis and honeycombing than in acute/subacute disease (Fig. 14A–D), which is patchier, more diffuse, and characterized by consolidation and groundglass attenuation (25,239). HRCT and histological findings generally correlate well (263), although the HRCT distinction between DAD and OP, and between OP and NSIP may be difficult (228). Pleural effusions and pneumomediastinum are occasional findings.
Figure 14 (A) and (B) HRCT appearances in a patient with dermatomyositis, with an acute/subacute presentation. The HRCT abnormalities are indicative of organizing pneumonia with probable underlying diffuse alveolar damage.
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Figure 14 (C) and (D) Regression of HRCT abnormalities is evident following three months of corticosteroid therapy. Incidental note is made of a pneumomediastinum. G.
BAL of PM/DM-ILD
BAL shows a lymphocytic, neutrophilic, or mixed alveolitis. The profile is neutrophil dominant in rapidly progressive ILD (24,25,234,239,241) and a high CD4/CD8-lymphocyte ratio is frequent in slowly progressive ILD (25,253). H.
Evolution and Prognosis of PM/DM-ILD
Symptomatic ILD significantly shortens survival in patients with inflammatory myopathies, whereas asymptomatic ILD does not (26). In a case series of 70 patients with PM/DM-ILD, survival was 85.8%, 74.4%, and 60.4% at one, three, and five years, respectively (237), with similar findings subsequently reported (234). Deaths are mainly lung related (234,237). However, mortality ranges from 50% to 100% in patients with acute ILD despite intensive immunosuppression (24–26,228,234,241,253). Mortality is higher with an acute presentation, neutrophilic alveolitis, an initial FVC 60%, or DLCO <45%, but does not vary with anti-Jo1 antibody status (228,234,241,253). In Asian studies, ILD is more refractory to therapy and outcome is worse in DM than in PM, and most importantly, in CADM (26,256). Complete resolution of ILD may occur with underlying OP or NSIP (23,234) and, surprisingly, in a patient with UIP (234). Resolution is observed in 19%, improvement in 56%, and deterioration in 25% (234). Relapses may occur when treatment is tapered (23,234,239). I.
Treatment of PM/DM-ILD
Optimal treatment is not established. Corticosteroids are usually instituted initially, but a subset of patients is steroid-refractory, and myopathy may complicate long-term high-dose treatment. Second-line strategies have included pulse steroids, oral or intravenous cyclophosphamide, azathioprine, methotrexate, cyclosporin A, hydroxychloroquine, tacrolimus, MMF, g-globulins, and plasma exchange (1,2,223,225), but all data are uncontrolled and
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retrospective. Schnabel et al. have provided some realistic guidance on therapeutic goals (239). In patients with nonprogressive ILD, effective treatment to control extrarespiratory systemic disease is usually associated with stability of ILD, but lung disease tends to be slower to respond (239). In rapidly progressive ILD, immediate aggressive treatment is warranted. The authors recommend an initial pulse of intravenous corticosteroid therapy followed by six to nine infusions of cyclophosphamide at three to four weekly intervals. In survivors, maintenance treatment with azathioprine or methotrexate in combination with low-dose corticosteroid is appropriate (239). An intensive initial approach results in a better survival than a step-up strategy in patients with progressive PM/DM-ILD (266). Cyclophosphamide is generally effective in improving PFT or preventing further progression of lung disease (23,234,239,241,267), except in the setting of a Hamman-Rich-like syndrome. T-cell-targeted therapies, including cyclosporin A and tacrolimus, have been proposed for PM/DM-ILD (268–272). The early use of cyclosporin A, alone or with cyclophosphamide, has provided encouraging data in acute/subacute disease (269,270). In a retrospective study of 15 patients with PM/DM-ILD, tacrolimus led to a sustained rise in PFT (271,272). The efficacy of g-globulins is uncertain. VII.
Systemic Lupus Erythematosus
SLE is a heterogeneous autoimmune disease that may affect virtually any organ, but predominant manifestations include non-deforming arthritis, serositis, photosensitivity, renal, hematological, and central nervous system involvement. Diagnosis is based on American Rheumatism Association criteria (273,274). The prevalence of SLE is estimated as 23.8/100,000 and there is a ninefold female excess (275), mostly occurring in the third to fifth decades. SLE has the widest variety of pulmonary manifestations among CTD (Table 1), but infection is most commonly implicated. ILD is much less common in SLE than in other systemic rheumatic diseases. Diffuse alveolar hemorrhage due to capillaritis presents with diffuse infiltrates on chest radiography and is life threatening, but affects less than 2% of patients (276). Acute lupus pneumonitis occurs in 1.4% to 12% of patients and is not usually viewed as an ILD, even though the main histological feature is DAD (277–279). Although sepsis, renal disease and thrombosis are the main causes of death in SLE, lung disease appears to be an indicator of overall prognosis (280,281). A.
Epidemiology and Risk Factors of SLE-ILD
The association of ILD with SLE has long been recognized, but the prevalence of significant ILD is no higher than 3% to 8% (282,283). Interstitial fibrosis has been reported on SLB or at autopsy in 4%, 33%, and 70% (284–286), with these striking inconsistencies likely to represent variability in definition. PFT are
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abnormal in up to two-thirds of asymptomatic patients (281,287). Abnormalities are seen on chest radiography in 6% to 24% (287,288) and on HRCT in 30% to 38% (289). In a recent longitudinal study, cumulative rates of ‘‘pulmonary damage,’’ defined using the Systemic Lupus International Collaborating Clinics Damage Index, were 7.6% and 11.6% at 5 and 10 years, respectively (290). Forty-six (7.3%) patients had pulmonary damage after a mean disease duration of 5.3 years, including 25 with ‘‘pulmonary fibrosis.’’ Age, a history of pneumonitis, and antiRNP antibody were independently associated with a shorter time, and photosensitivity and oral ulcers with a longer time to pulmonary damage (290). ILD is more frequent in older patients, males, and late onset SLE (275,282,291–293). Relationships between ILD and anti-Ro/SS-A antibody, and between reduced DLCO and anti-U1 RNP antibody, were observed in one series (294,295). However, in a large observational study of clinical associations with autoantibody clusters in SLE, no serological associations were observed with ILD (296). Five to 10% of SLE patients are believed to have drug-induced disease, characterized by the presence of the antihistone antibody. Whereas dermatological, renal, and neuropsychiatric abnormalities are rare, the pleuropulmonary manifestations are particularly common in these cases (297). A similar spectrum of lung manifestations is reported (297,298). B.
Pathogenesis of SLE-ILD
Immunofluorescence studies demonstrate granular deposits of IgG and C3 (the third protein of the classical complement pathway) along the alveolar walls, the interstitium, and endothelial cells, supporting the hypothesis that alveolar damage is mediated by immune complex deposition in acute lupus pneumonitis. Both DNA and anti-DNA antibodies have been identified in the immune complexes (299). The view that acute pulmonary hemorrhage results from immune complexmediated inflammation is very plausible. Indeed, immune-based microvascular injury may be an inciting trigger in the constitution of parenchymal fibrosis in CTDs, particularly in SLE (300). Lupus patients with pulmonary involvement have a stronger pro-inflammatory cytokine profile (277,301,302). C.
Pathology of SLE-ILD
Pathological findings postdating the ATS/ERS classification of IIPs are meager, explaining the difficulties in determining histological patterns of ILD involvement in SLE (Table 2). The most common pattern is DAD, usually in relation to acute lupus pneumonitis (278,285). In prior autopsy records, interstitial fibrosis and lymphocytic infiltrates with peribronchial lymphoid hyperplasia were noticed (285,293). Although mild vascular hypertrophy of the pulmonary blood vessels was described in some cases in addition to ILD, there was no obvious evidence of true vasculitis (285,293). In a recent study, SLB of two patients with
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SLE showed a major pattern of UIP for one and follicular bronchiolitis with minor NSIP areas for the other (6). In contrast to the other CTDs, the place of NSIP in SLE has not been yet definitely settled (4,6). LIP has been documented in SLE, but whether or not it was simply due to associated SjS is unknown (303–305). Isolated observations of OP have also been published (306–308). D.
Clinical Features of SLE-ILD
ILD in SLE may occur as a residual feature of acute lupus pneumonitis (278,288) or may present insidiously, often with mild flares of pulmonary activity (277,293,309). The symptoms are nonspecific with persistent dyspnea on exertion, occasional pleuritic chest pain, and non-productive cough. Physical examination may reveal fever, cyanosis, or bibasilar crackles. Clubbing is less common in SLE-ILD than in IPF (310). The pattern and severity of PFT impairment do not correlate with systemic disease activity, as judged by antiDNA antibodies and serum complement levels (293,311,312). ILD can occur in the absence of active disease in other organs (282,312). Interestingly, the presence of scleroderma-like traits in SLE is associated with a higher prevalence of restrictive defects or reduced DLCO (313). Progressive severe ILD rarely complicates SLE but is seen in some patients with SLE features as part of an overlap syndrome (314). BAL to rule out infection and alveolar hemorrhage is crucial in patients presenting with major infiltrates. As in other CTDs, subclinical alveolitis (lymphocytic, neutrophilic, or mixed) is often present in SLE (147). E.
Imaging of SLE-ILD
HRCT abnormalities occur typically in the basal lung zones and consist of irregular linear opacities, ground-glass opacities, honeycombing, and traction bronchectasis, as in UIP or fibrotic NSIP. Mild enlargement of mediastinal lymph nodes is frequent. Discrete nodules and interlobular septal thickening are occasionally present (315). Consolidation with ground-glass attenuation may be indicative of acute lupus pneumonitis, hemorrhage, or, occasionally, OP (315,316). Disease is more extensive on HRCT with a longer duration and greater impairment of PFT (289). F.
Prognosis and Treatment of SLE-ILD
The clinical course of chronic ILD is almost always slowly progressive, with stabilization over years (293,315). There is a paucity of data on the efficacy of corticosteroids, and immunosuppressive or cytotoxic agents. In one series, 9 of 14 patients responded to four weeks or more of corticosteroid therapy, but follow-up was short (293). The choice of immunosuppressive agent is uncertain, with cyclophosphamide often used in severe or progressive disease.
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Mixed Connective Tissue Disease and Overlap Syndromes
Mixed Connective Tissue Disease
The entity of MCTD was first formulated in patients with the combined features of SLE, SSc, and PM/DM, and the presence of high titers of antibody against small nuclear U1RNP (317). Although controversial, the validity of MCTD is now largely accepted (318,319). Among several diagnostic systems, Sharp’s criteria, which exclude patients with anti-Sm antibody, are increasingly preferred. The prevalence of MCTD is unknown and it tends to affect women in the fourth decade. Lung involvement is increasingly recognized as an important feature of MCTD (317,320–322) and a major cause of mortality (Table 1). Sometimes secondary to ILD, but more commonly a primary event, PH is the most frequent disease-associated cause of death (318,323). In longitudinal studies, the lung has been involved in 20% to 85% of patients (320,321). Approximately two thirds of asymptomatic patients have reduced DLCO, chest radiographic abnormalities, or both (322), and nearly half have a restrictive ventilatory defect (321,322). In a retrospective study of 144 consecutive patients with MCTD, ILD was seen on HRCT in 66.6% of cases (324), with more severe fibrosis occurring when SSc was the predominant clinical feature (321). There is a paucity of histological data, based on the ATS/ERS classification of IIPs, with NSIP reported in a handful of cases (4). Early signs on HRCT in early include areas of ground-glass attenuation, alone (78%) or in association with mild reticular abnormalities (22%) (Fig. 15) (324,325). In later disease, honeycombing is exceedingly rare, even when fibrosis is extensive (324–326). The distribution on HRCT is predominantly basal, peripheral, and posterior.
Figure 15 HRCT appearances in a patient with mixed connective tissue disease, suggestive of nonspecific interstitial pneumonia.
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Figure 16 HRCT appearances in a patient with scleromyositis, showing prominent organizing pneumonia, associated with ground-glass attenuation (indicative of underlying nonspecific interstitial pneumonia).
In the retrospective study of Bodolay et al. (324), patients with MCTD-ILD received high-dose steroid therapy for four to six weeks (324). HRCT abnormalities regressed in approximately 50%, with little change in PFTs. In the remaining patients, a combination of corticosteroids and cyclophosphamide was highly efficacious, with HRCT appearances reverting to normal in 70% of cases and mild residual pulmonary fibrosis in 30% (324). B.
Sclero(dermato)myositis
Among overlap syndromes, ILD seems to be particularly frequent in patients with sclero(dermato)myositis. Sclero(dermato)myositis differs from MCTD by the absence of features of SLE (327). The anti-PM/Scl antibody is characteristic, although also found in PM, DM, or SSc without features of overlap syndromes (328). The reported prevalence of ILD in patients with this antibody is variable, reaching 85% in one series (Fig. 16) (329). Despite the high frequency of ILD, patients with the anti-PM/Scl antibody have a favorable outcome (329). References 1. Strange C, Highland KB. Interstitial lung disease in the patient who has connective tissue disease. Clin Chest Med 2004; 2549–559, vii. 2. Crestani B. The respiratory system in connective tissue disorders. Allergy 2005; 60:715–734. 3. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161:646–664.
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289. Bankier AA, Kiener HP, Wiesmayr MN, et al. Discrete lung involvement in systemic lupus erythematosus: CT assessment. Radiology 1995; 196:835–840. 290. Bertoli AM, Vila LM, Apte M, et al. Systemic lupus erythematosus in a multiethnic US Cohort LUMINA XLVIII: factors predictive of pulmonary damage. Lupus 2007; 16:410–417. 291. Boddaert J, Huong DL, Amoura Z, et al. Late-onset systemic lupus erythematosus: a personal series of 47 patients and pooled analysis of 714 cases in the literature. Medicine (Baltimore) 2004; 83:348–359. 292. Cheema GS, Quismorio FP Jr. Interstitial lung disease in systemic lupus erythematosus. Curr Opin Pulm Med 2000; 6:424–429. 293. Weinrib L, Sharma OP, Quismorio FP Jr. A long-term study of interstitial lung disease in systemic lupus erythematosus. Semin Arthritis Rheum 1990; 20:48–56. 294. Boulware DW, Hedgpeth MT. Lupus pneumonitis and anti-SSA(Ro) antibodies. J Rheumatol 1989; 16:479–481. 295. Hedgpeth MT, Boulware DW. Interstitial pneumonitis in antinuclear antibodynegative systemic lupus erythematosus: a new clinical manifestation and possible association with anti-Ro (SS-A) antibodies. Arthritis Rheum 1988; 31:545–548. 296. To CH, Petri M. Is antibody clustering predictive of clinical subsets and damage in systemic lupus erythematosus? Arthritis Rheum 2005; 52:4003–4010. 297. Murin S, Wiedemann HP, Matthay RA. Pulmonary manifestations of systemic lupus erythematosus. Clin Chest Med 1998; 19:641–665, viii. 298. Yung RL, Richardson BC. Drug-induced lupus. Rheum Dis Clin North Am 1994; 20:61–86. 299. Inoue T, Kanayama Y, Ohe A, et al. Immunopathologic studies of pneumonitis in systemic lupus erythematosus. Ann Intern Med 1979; 91:30–34. 300. Magro CM, Ross P, Marsh CB, et al. The role of anti-endothelial cell antibodymediated microvascular injury in the evolution of pulmonary fibrosis in the setting of collagen vascular disease. Am J Clin Pathol 2007; 127:237–247. 301. Al-Mutairi S, Al-Awadhi A, Raghupathy R, et al. Lupus patients with pulmonary involvement have a pro-inflammatory cytokines profile. Rheumatol Int 2007; 27:621–630. 302. Thornton SC, Robbins JM, Penny R, et al. Fibroblast growth factors in connective tissue disease associated interstitial lung disease. Clin Exp Immunol 1992; 90:447–452. 303. Filipek MS, Thompson ME, Wang PL, et al. Lymphocytic interstitial pneumonitis in a patient with systemic lupus erythematosus: radiographic and high-resolution CT findings. J Thorac Imaging 2004; 19:200–203. 304. Pines A, Kaplinsky N, Olchovsky D, et al. Pleuro-pulmonary manifestations of systemic lupus erythematosus: clinical features of its subgroups. Prognostic and therapeutic implications. Chest 1985; 88:129–135. 305. Yood RA, Steigman DM, Gill LR. Lymphocytic interstitial pneumonitis in a patient with systemic lupus erythematosus. Lupus 1995; 4:161–163. 306. Gammon RB, Bridges TA, al-Nezir H, et al. Bronchiolitis obliterans organizing pneumonia associated with systemic lupus erythematosus. Chest 1992; 102:1171–1174. 307. Min JK, Hong YS, Park SH, et al. Bronchiolitis obliterans organizing pneumonia as an initial manifestation in patients with systemic lupus erythematosus. J Rheumatol 1997; 24:2254–2257.
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308. Otsuka F, Amano T, Hashimoto N, et al. Bronchiolitis obliterans organizing pneumonia associated with systemic lupus erythematosus with antiphospholipid antibody. Intern Med 1996; 35:341–344. 309. Schattner A, Liang MH. The cardiovascular burden of lupus: a complex challenge. Arch Intern Med 2003; 163:1507–1510. 310. Renzoni E, Rottoli P, Coviello G, et al. Clinical, laboratory and radiological findings in pulmonary fibrosis with and without connective tissue disease. Clin Rheumatol 1997; 16:570–577. 311. Evans SA, Hopkinson ND, Kinnear WJ, et al. Respiratory disease in systemic lupus erythematosus: correlation with results of laboratory tests and histological appearance of muscle biopsy specimens. Thorax 1992; 47:957–960. 312. Sant SM, Doran M, Fenelon HM, et al. Pleuropulmonary abnormalities in patients with systemic lupus erythematosus: assessment with high resolution computed tomography, chest radiography and pulmonary function tests. Clin Exp Rheumatol 1997; 15:507–513. 313. Groen H, ter Borg EJ, Postma DS, et al. Pulmonary function in systemic lupus erythematosus is related to distinct clinical, serologic, and nailfold capillary patterns. Am J Med 1992; 93:619–627. 314. Keane MP, Lynch JP III. Pleuropulmonary manifestations of systemic lupus erythematosus. Thorax 2000; 55:159–166. 315. Kim JS, Lee KS, Koh EM, et al. Thoracic involvement of systemic lupus erythematosus: clinical, pathologic, and radiologic findings. J Comput Assist Tomogr 2000; 24:9–18. 316. Kim HJ, Park JY, Kim SM, et al. Systemic lupus erythematosus with obstructive uropathy. Case report and review. J Korean Med Sci 1995; 10:462–469. 317. Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease—an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972; 52:148–159. 318. Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum 1999; 42:899–909. 319. Smolen JS, Steiner G. Mixed connective tissue disease: to be or not to be? Arthritis Rheum 1998; 41:768–777. 320. Derderian SS, Tellis CJ, Abbrecht PH, et al. Pulmonary involvement in mixed connective tissue disease. Chest 1985; 88:45–48. 321. Prakash UB. Respiratory complications in mixed connective tissue disease. Clin Chest Med 1998; 19:733–746, ix. 322. Sullivan WD, Hurst DJ, Harmon CE, et al. A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine (Baltimore) 1984; 63:92–107. 323. Maddison PJ. Mixed connective tissue disease: overlap syndromes. Baillieres Best Pract Res Clin Rheumatol 2000; 14:111–124. 324. Bodolay E, Szekanecz Z, Devenyi K, et al. Evaluation of interstitial lung disease in mixed connective tissue disease (MCTD). Rheumatology (Oxford) 2005; 44:656–661. 325. Kozuka T, Johkoh T, Honda O, et al. Pulmonary involvement in mixed connective tissue disease: high-resolution CT findings in 41 patients. J Thorac Imaging 2001; 16:94–98.
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326. Saito Y, Terada M, Takada T, et al. Pulmonary involvement in mixed connective tissue disease: comparison with other collagen vascular diseases using high resolution CT. J Comput Assist Tomogr 2002; 26:349–357. 327. Jablonska S, Blaszczyk M. Scleroderma overlap syndromes. Adv Exp Med Biol 1999; 455:85–92. 328. Marguerie C, Bunn CC, Copier J, et al. The clinical and immunogenetic features of patients with autoantibodies to the nucleolar antigen PM-Scl. Medicine (Baltimore) 1992; 71:327–336. 329. Vandergheynst F, Ocmant A, Sordet C, et al. Anti-pm/scl antibodies in connective tissue disease: clinical and biological assessment of 14 patients. Clin Exp Rheumatol 2006; 24:129–133.
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Figure 4.1 Usual interstitial pneumonia (see page 95).
Figure 4.2 Nonspecific interstitial pneumonia (see page 98).
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Figure 4.3 Hypersensitivity pneumonitis (see page 99).
Figure 4.4 Acute interstitial pneumonitis (see page 101).
Figure 4.5 Cryptogenic organizing pneumonia (see page 102).
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Figure 4.6 Lymphoid interstitial pneumonia (see page 103).
Figure 4.7 RBILD/DIP (see page 105).
Figure 4.8 PLCH (see page 106).
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Figure 4.9 Sarcoidosis (see page 109).
Figure 4.10 Collagen vascular diseases (see page 110).
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Figure 4.11 Collagen vascular diseases (see page 112).
Figure 5.1 Mucosal lesion on the tongue of a patient with sarcoidosis who had been taking methotrexate 10 mg once a week for two months. The lesion totally resolved on stopping methotrexate (see page 128).
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Figure 7.10 Pathology of pulmonary sarcoidosis (see page 202).
Figure 7.11 Histopathology of pulmonary sarcoidosis (see page 203).
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Figure 8.1 Keratic precipitates seen as small white dots on slit-lamp examination of a patient with anterior uveitis from sarcoidosis (see page 224).
Figure 8.2 Limbal granulomas on the margin of the iris in a patient with ocular sarcoidosis (see page 225).
Figure 8.3 Retinal vasculitis seen with posterior uveitis from sarcoidosis (see page 225).
Figure 8.4 Episcleritis from sarcoidosis (see page 226).
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Figure 8.5 Erythema nodosum from sarcoidosis on the base of the foot that is an unusual location (see page 228).
Figure 8.6 Lupus pernio lesions on the nose. The patient gave permission for publication of this photograph (see page 229).
Figure 8.7 Lupus pernio lesions on the cheek, nose, as well as an ear lesion from sarcoidosis. The patient gave permission for publication of this photograph (see page 230).
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Figure 8.8 Sarcoidosis skin lesions in a tattoo (see page 230).
Figure 8.10 (A) A cardiac PET scan from a patient with mild cardiac sarcoidosis presenting with asymptomatic premature ventricular contractions. The PET scan reveals localized ventricular uptake. (B) A cardiac PET scan from a patient with severe cardiac sarcoidosis presenting with severe left ventricular dysfunction and ventricular arrhythmias. He developed a left ventricular thrombus from a wall motion abnormality and had an internal automatic defibrillator placed that fired several times before his disease was controlled (see page 243).
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Figure 9.5 (A) Lung biopsy specimen of subacute hypersensitivity pneumonitis showing bronchiolocentric interstitial inflammation and poorly formed granulomas around bronchiole. (B) Interstitial granulomatous lesion in another field of the same patient. (C) Chronic interstitial inflammatory infiltrate and fibrosis in an HP patient with two years of progressive symptoms before biopsy. Arrowhead shows a poorly formed granuloma. Abbreviation: HP, hypersensitivity pneumonitis (see page 279).
Figure 10.4 Photomicrograph of lung biopsy from a patient with CBD. The noncaseating granuloma usually contains epithelioid cells of monocyte lineage, multinucleated giant cells, and lymphocytes that are predominantly CD4þ T cells (see page 303).
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Figure 15.3 Photomicrographs of multiple stages of hematoxylin-eosin stained diffuse alveolar damage (see page 393).
Figure 16.2 Lymphocytic interstitial pneumonia (see page 410).
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Figure 16.3 Nodular lymphoid hyperplasia (see page 414).
Figure 16.4 Nodular lymphoid hyperplasia (see page 415).
Figure 16.5 Follicular bronchitis/bronchiolitis (see page 418).
Figure 20.1 Constrictive bronchiolitis (see page 529).
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Figure 21.3 Typical lesion of OB in an open lung biopsy of a lung transplant patient with a progressive decline of the FEV1 (see page 547).
Figure 22.4 Lung pathology in BO showing bronchiolar inflammation and luminal obliteration associated with excess fibrous connective tissue (see page 563).
Figure 22.6 Lung pathology in BOOP showing the presence of intraluminal granulation tissue in bronchioli, alveolar ducts, and alveoli (see page 567).
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Figure 25.1 Patterns of pathology of WG (see page 608).
Figure 26.2 ENT manifestations: bilateral maxillary sinusitis. Source: Courtesy of the French Vasculitis Study Group (see page 646).
Figure 27.2 Renal biopsy from a patient with MPA demonstrating crescentic glomerulonephritis with focal and segmental change and an area of fibrinoid necrosis, shown by arrow. (Haematoxylin and Eosin 200) (see page 662).
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Figure 28.4 Medium-power photomicrograph of lung showing diffuse intra-alveolar hemorrhage [hematoxylin and eosin (H&E) stain] (see page 681).
Figure 28.5 High-power photomicrograph of lung showing intra-alveolar hemorrhage and hemosiderin-laden macrophages [hematoxylin and eosin (H&E) stain] (see page 682).
Figure 28.6 High-power photomicrograph of lung showing capillaritis with neutrophils within widened alveolar septum [hematoxylin and eosin (H&E stain)] (see page 682).
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Figure 32.2 Expanded alveolar septa due to smooth muscle infiltration in a patient with LAM (see page 754).
Figure 33.1 Histologic findings in PAP (see page 772).
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18 Other Pleuropulmonary Complications of Connective Tissue Diseases
CHARLIE STRANGE Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, South Carolina, U.S.A.
I.
Introduction
The connective tissue diseases (CTDs) by definition involve multiple organs of the body. Similarly, these CTD may involve multiple anatomic areas of the lungs and extrapulmonary thorax, which can influence the course of disease. Although interstitial lung disease (ILD) is the most common manifestation of most of the CTD, a separate chapter is focused on the pathology, treatment, and clinical outcome of the many ILD presentations. Dr. Nunes and colleagues reviewed the pleural and non-ILD pulmonary manifestations of the CTD in chapter 19.
II.
Rheumatoid Arthritis
The most common CTD throughout the world is rheumatoid arthritis (RA). Thoracic manifestations of RA are numerous (Table 1) including forms of ILD. The thoracic disease manifestations independent of ILD include pleural effusions, bronchiolitis obliterans (BO) without an organizing pneumonia, rheumatoid nodules, upper airway obstruction, and acute rheumatoid pneumonitis. 487
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Strange
Table 1 Pleuropulmonary Manifestations of Rheumatoid Arthritis Parenchymal pulmonary disease Interstitial lung disease Usual interstitial pneumonia Nonspecific interstitial pneumonia Diffuse alveolar damage (Acute respiratory distress syndrome) Organizing pneumonia Lymphocytic interstitial pneumonia Chronic eosinophilic pneumonia Apical fibrobullous disease Nodules Rheumatoid (necrobiotic) nodules Pneumoconiotic nodules (Caplan’s syndrome) Drug-induced lung disease Penicillamine Methotrexate Gold Celecoxib Mycophenalate Respiratory infections Amyloid Pulmonary vascular lesions and pulmonary hypertension Airway disease Upper airway obstruction Cricoarytenoid arthritis Airway nodules Vasculitis of recurrent laryngeal nerve Bronchiectasis Bronchiolitis obliterans Follicular bronchiolitis Diffuse panbronchiolitis Pleural disease Pleuritis with or without effusion Sterile or septic empyema Necrobiotic rheumatoid nodules associated with bronchopleural fistula Pyopneumothorax Thoracic cage immobility
Although some of these are rare manifestations, a working knowledge of the pathogenesis, clinical expression, and treatment will be covered. A.
Rheumatoid Pleural Effusion
Pleural effusions are one of the most common thoracic presentations of RA and the causes are shown in Table 2. Although approximately 20% of patients will
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report a history of pleurisy, pleural involvement with chronic inflammation and fibrosis has been found in 38% to 73% of patients at autopsy (1). Approximately 5% of patients will have an effusion. Pleural effusions are more common in men and those with rheumatoid nodules. Effusions often arise during periods of active articular disease. RA pleural effusions have a characteristic biochemical profile. Glucose is less than 30 mg/dL in 70% to 80% of effusions (2). Pleural fluid pH is often near 7.00, and effusions are usually neutrophilic exudates. Cytology typically shows giant multinucleated macrophages in a background of granular debris. Since pleural space infection is in the differential diagnosis and may be increased in frequency in RA (3,4), cultures should be obtained. The pleural fluid rheumatoid factor is increased usually greater than 1:320 and higher than serum values. RA pleural effusions may be chronic and recurrent (5). Lung entrapment may be a consequence of chronic pleural inflammation and some transition to a trapped lung that may have transudative characteristics. Rarely, cholesterol-rich pleural effusions may develop (6). Therapy is directed against the systemic disease with effusions usually resolving at a mean of 14 months (7). Occasionally, repeated thoracentesis or intrapleural corticosteroids have been shown effective in large or recurrent symptomatic cases. B.
Airways Obstruction
Airway obstruction is more frequent among RA patients than in other CTD. Some series have suggested that the incidence of obstructive spirometry may be as high as 36% (8,9), although the majority of obstructive airways disease patients are asymptomatic. The mechanism of airways obstruction is multifactorial. Since cigarette smoking appears to be involved in the pathogenesis of RA, some of the obstruction is undoubtedly smoking related. However, some studies would suggest that there is a synergy in which the association of smoking and RA produces more frequent obstruction than would occur with either disease alone (10,11). Other theories include the influence of the more frequent carrier status for a-1 antitrypsin deficiency (PiMZ) (12), which is also a risk for airways obstruction or the more frequent respiratory infections that occur due to immune suppression. C.
Cricoarytenoid Arthritis
A unique presentation of airway obstruction in RA is due to cricoarytenoid arthritis. The cricoarytenoid joint is the only true joint in the larynx that can be involved with RA. When the vocal cords are unable to adduct because of arthritis, severe inspiratory stridor develops with a flow volume loop typical of variable extrathoracic upper airway obstruction. Cricoarytenoid arthritis is also seen in gout, systemic lupus erythematosus (SLE), and Reiter’s syndrome but is more common in RA. The symptoms of cricoarytenoid arthritis may be subtle
Pleural inflammation
Pathogenesis
Breakdown of inflammatory cells Sterile empyema Rupture of necrobiotic nodule into pleural space Trapped lung Pleural fibrosis from previous rheumatoid effusion
Cholesterol-rich effusion
Rheumatoid arthritis Rheumatoid effusion
Effusion
Surgical decortication if impairment is significant
Transudative effusion
Some effusions may be exudative if ongoing pleural inflammation. These are called lung entrapment
Rare
Rare
Corticosteroids improve resolution Corticosteroids can prevent progression of nodules
Mean resolution in 14 months Glucose < 30 mg/dL and pH 7 in 80%
Comments
Corticosteroids with or without additional immunosuppressives
Treatment
Thick pus that fails to grow on bacteriology
Low pH < 7.00 Low glucose < 30 mg/dL High LD > 1000 IU/L Neutrophil predominant exudate Milky, PF cholesterol > S cholesterol
Characteristics
Table 2 Pleural Disease in the Connective Tissue Diseases
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SSc effusion
Local pleural inflammation
Local pleural inflammation
Complement mediated local pleural inflammation
Pathogenesis
Lymphocytic usually small
Neutrophilic exudate Usually small
Neutrophilic exudate PF ANA > serum and > 1:160 PF C3 and C4 > serum
Characteristics
Abbreviations: PF, pleural fluid; ANA, antinuclear antibody; S, serum, LD, lactate dehydrogenase.
Sjogren’s Syndrome Sjogren’s effusion
Systemic sclerosis
Systemic lupus erythematosus Lupus serositis
Effusion
Table 2 (Continued )
Unknown
May be steroid responsive
Corticosteroids and other immunosuppressants
Treatment
Rare
Rare, <10% lifetime incidence Pleural adhesions common (2/3 of patients) at autopsy
Pleuritic pain can be disabling
Comments
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including a foreign body sensation in the pharynx, hoarseness, ear pain, dysphagia, or odynophagia. Therefore, some series have suggested this manifestation is present in up to one-fourth of RA patients (13). Other causes of upper airway obstruction in RA include rheumatoid nodules that may involve the vocal cords or upper trachea and vasculitis of the recurrent laryngeal nerves. Most of these symptoms resolve with increased immunosuppression. D.
Apical Fibrobullous Disease
Another uncommon presentation of RA in the lung is the presence of apical fibrobullous lung disease similar to ankylosing spondylitis. These presentations may occasionally precede arthritis onset. E.
BO, Follicular Bronchiolitis, and Diffuse Panbronchiolitis
One of the most unresponsive complications of RA is BO. The pathology of this disorder involves circumferential narrowing and obliteration of small airways with loss of airway patency that is usually permanent. Symptomatic progression can be indolent; however, most of the airways that are lost cannot be recovered with anti-inflammatory therapy. Other forms of airways disorders have also been described. Follicular bronchiolitis is a form of airways inflammation in which airways are obstructed by external compression of the bronchioles, rather than by direct luminal occlusion. A lymphocytic and plasma cell infiltrate surround the airway with germinal centers present within lymphoid follicles. Follicular bronchiolitis also has been described in Sjogren’s syndrome, immunodeficiency syndromes, hypersensitivity-type reactions, and some chronic infections (14,15). The other pathologically similar disease, diffuse panbronchiolitis, has also been seen in RA (16). The pathology is different in that smaller airways are involved at the level of the respiratory bronchiole. F.
Bronchiectasis
Bronchiectasis is common in chest computed tomography (CT) case series in RA, seen in up to 30% of patients without ILD (17). However, the underlying pathology and clinical consequences of disease remain poorly characterized. The underlying etiology can be airways traction from ILD or nodular disease (18). However, the degree of rheumatoid airways inflammation can be very difficult to determine since infectious inflammation produces similar symptoms of cough, mucus production, and occasional hemoptysis. Treatment of all forms of airways disease in RA with corticosteroids has yielded variable results, although chronic macrolide therapy has shown some promise (19).
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Figure 1 Chest computed tomography demonstrating multiple pulmonary nodules from rheumatoid arthritis. Note that nodules are of different sizes and may be scattered randomly throughout the lung parenchyma. Cavitation can occur as seen in the largest nodule on this cut from chest computed tomography.
G.
Rheumatoid Nodules
Rheumatoid nodules may be the most common presentation of RA in the lung (20). The typical nodules are localized to the lung interlobular septa, usually in a subpleural distribution. The nodules may be single or multiple and can cavitate (Fig. 1). The patient is usually asymptomatic, although hemoptysis and pneumothorax have been described associated with cavitation (21). Because of the association of RA and smoking and the increased risk of cancers associated with RA, the appearance of lung nodules gives no assurance that the nodules are benign (22). Caplan, in 1953, described the association of cavitary lung nodules that were as large as 5.0 cm in diameter in Welsh coal miners with RA (23). Subsequently, other occupational dust exposures have been associated with this rare syndrome. H.
Acute Rheumatoid Pneumonitis
A rare form of rheumatoid involvement of the lung is an acute pneumonitis characterized by diffuse alveolar damage (24). Some cases of this disorder have occurred within a week of stopping corticosteroids with a presentation akin to the acute respiratory distress syndrome (ARDS). I.
Therapy
Therapy for all the presentations of RA-associated lung disease is not based on high-level evidence-based medicine in part because of the heterogeneity of
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presentations. This disease also remains difficult to study because of the increased use of anti-inflammatory medications in RA. There is no evidence that the incidence of pulmonary disease is less than in years past. This raises the issue of whether lung disease in any of its presentations mandates more aggressive immunosuppressive therapy than would otherwise be used to suppress the arthritic manifestations of disease. The current wisdom is that therapy should be instituted on the basis of progressive radiographic and physiologic deterioration. Whether lung biopsy aids in the treatment response remains unknown. III.
Systemic Lupus Erythematosus
SLE is a common CTD with frequent chest manifestations (Table 3). The most common chest manifestation is pleurisy that can occur with or without a pleural effusion. Although ILD has been described in SLE, more common is a presentation of lung parenchymal injury called lupus pneumonitis. SLE may also cause alveolar hemorrhage, a particularly serious form of lung involvement. This review will discuss what is known about these disease states. Table 3 Thoracic Manifestations of SLE Infection Serositis Pleurisy with effusions Exudative pleural effusion Pericarditis with or without effusion Parenchymal lung disease Interstitial lung disease Acute lupus pneumonitis Organizing pneumonia Lymphocytic interstitial pneumonia Diffuse alveolar hemorrhage Airway disease Upper airway obstruction Epiglottitis and laryngitis Cricoarytenoid arthritis Bronchiectasis Bronchiolitis obliterans Shrinking lung syndrome Diaphragmatic dysfunction Pulmonary vascular disease Thromboembolic disease Pulmonary arterial hypertension Mediastinal and axillary lymphadenopathy Abbreviation: SLE, systemic lupus erythematosis.
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SLE Pleurisy
Pleural involvement in SLE is very common with at least 50% of patients having chest pain with a pleuritic component. An autopsy series has shown adhesions, thickening, or effusions in 93% of cases (25). Pleural effusion without concomitant pleurisy is uncommon. The effusions are usually bilateral neutrophilic exudates. Antinuclear antibody and antibodies to DNA are present in pleural fluid and are usually higher than serum values (26) suggesting the presence of local pleural immunologic inflammation. Spontaneous hemothorax and pneumothorax have been described (27) but are rare. B.
Lupus Pneumonitis
Acute lupus pneumonitis is a syndrome characterized pathologically by diffuse alveolar damage in which complement activation creates an acute lung injury resulting in dyspnea, cough, and fever. Radiographically, the most common feature is consolidation that mainly involves the lower lung zones. However, in an SLE cohort, the most common cause of lung consolidation is bacterial pneumonia. Therefore, other diagnostic studies are mandatory. Less acute presentations can occur. A case report of lupus pneumonitis with normal computed tomography scans has been described (28). Migratory infiltrates can also occur. The diagnostic evaluation requires samples from the lower respiratory tract. While some individuals have advocated a surgical lung biopsy, most practitioners will perform bronchoscopy with bronchoalveolar lavage (BAL). The BAL is sent for cultures for bacteria, mycobacteria, and fungi. A cell count in acute lupus pneumonitis is typically neutrophil predominant. Exclusion of pulmonary emboli is usually performed, particularly if the patient has circulating antiphospholipid antibodies. The resolution of acute lupus pneumonitis often occurs quickly once immunosuppressives have been initiated. Corticosteroids in high dose are indicated, although cases of relapse on corticosteroid monotherapy have been seen (29). Therefore, the usual patient will be started on adjunctive immunosuppressives dictated by the extent of multiorgan involvement and the confidence that infection has been excluded or adequately treated. Experience with azathioprine, methotrexate, cyclophosphamide, cyclosporine, and mycophenalate mofetil has been reported. Following episodes of lupus pneumonitis, spirometry is useful to define the resolution and to taper immunosuppressive therapy. Death appears to be rare; however, gas exchange abnormalities persist in the majority of patients (30), and a rare patient will have persistent interstitial infiltrates. C.
Alveolar Hemorrhage
Pulmonary hemorrhage occurs infrequently in patients with SLE. While bloodstreaked sputum may occur with almost any lung process, diffuse alveolar
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hemorrhage (DAH) is a unique disease process in SLE. Pathologically, the blood is usually arising from a pulmonary capillaritis (31), although the majority of patients are managed without lung biopsy. Clinical manifestations include an abrupt increase in cough and dyspnea. The incidence of hemoptysis has varied from 42% to 66% at presentation (31) and can be the initial presentation of SLE. Fever is occasionally present. Lupus nephritis is usually seen at the time of presentation (32). Chest radiographs and computed tomography show alveolar opacities that may begin as a patchy distribution before becoming more confluent. Since infection is often present in SLE, a BAL is an important diagnostic tool when SLE-associated DAH is suspected. The typical BAL becomes progressively red on serial aliquots. Hemosiderin is usually seen even in clinically abrupt cases suggesting that small vessel injury has been subclinical for some time. A hemosiderin scoring system has been developed to assist pathologists in identifying the intensity of the hemosiderin content (33,34). Empiric antimicrobial therapy is given until cultures return negative. Although no randomized studies have been performed, recommendations for therapy have been extrapolated from SLE nephritis in which pulse corticosteroids appear beneficial. A case series in which greater than 4 g methylprednisolone were given within 48 hours of symptom onset produced good survival (35). An experience with plasmapheresis has been developed that is now often reserved for cases refractory to pulse corticosteroids (36). D.
Shrinking Lung Syndrome
The shrinking or vanishing lung syndrome is defined by low lung volumes and reduction in maximal inspiratory pressure (MIP) and maximal expiratory pressures (MEP), in the absence of other thoracic manifestations of SLE. The clinical syndrome usually presents after other manifestations of SLE have been present for some time. A review of 49 cases showed that only one-third of cases had a proven myopathy (37). A high incidence of Sjo¨gren’s Syndrome A (SSA) antibodies has been noted. Clinically, the most common symptoms include dyspnea and pleuritic chest pain (38). Chest radiography reveals elevated hemidiaphragms. Some improvement has been noted using inhaled b agonists and theophyllline. A more global evaluation of SLE disease activity usually leads to an increase in immunosuppressive therapy using corticosteroids, methotrexate, cyclosporine, mycophenalate, cyclophosphamide, or azathioprine, with subsequent improvement in symptoms (38). IV.
Polymyositis/Dermatomyositis
The many systemic manifestations of polymyositis and dermatomyositis (PM/DM) include a variety of clinical presentations in which muscle weakness is problematic. Upper airway and proximal esophageal muscular integrity is important to prevent
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aspiration and associated bacterial pneumonia. Leg muscular weakness and associated deconditioning produces exercise intolerance greater than the degree of pulmonary physiologic impairment. Diaphragm weakness from myositis can cause small lung volumes. ILD and a more severe form of diffuse alveolar damage (39) that clinically fits within the definition of ARDS is the subject of the adjacent chapter. This review will focus on these nonparenchymal clinical disease states. A.
The Myositis Syndromes
PM/DM is an idiopathic inflammatory myopathy; however, a number of autoantibody subclassifications correlate with features of clinical disease. When clinical muscle weakness is encountered in the pulmonary clinic, one recent addition to the laboratory armamentarium is the myositis antibody panel. These panels of autoantibody tests can define antibodies to many of the aminoacyltRNA synthetases and sometimes help define a CTD when previously not suspected. The most common syndrome is now termed the ‘‘antisynthetase syndrome’’ when autoantibodies are present in the setting of variable components of fever, myositis, Reynaud’s phenomenon, arthritis, mechanic’s hands, and ILD (40). Alternative PM/DM diagnostic strategies include targeting muscle weakness with magnetic resonance imaging (MRI) or electromyography (EMG) in preparation for muscle biopsy. It should be noted that some forms of idiopathic myopathy, such as inclusion body myositis, have not been associated with ILD but can present with respiratory impairment due to muscle weakness (41). B.
Upper Airway and Esophageal Muscular Weakness
Aspiration pneumonia is the most important pulmonary disease in PM/DM because it markedly increases the risk of death or disease deterioration (42,43). The prevalence of pneumonia is increased because of difficulties in pharyngeal solid and liquid fluid transport, a poor cough reflex, and immunosuppression. Dysphagia incidence is high (up to 67% in one series) at presentation (44). Myositis involves all striated muscle in this disease including muscles of the soft palate, pharynx, and upper two-third of the esophagus. The esophageal involvement can be severe causing cricopharyngeal achalasia. Careful evaluation by speech pathologists, gastroenterologists using esophageal manometry, radiologists using barium studies, and surgeons skilled at esophageal myotomy is required for optimal outcome. Pleural effusion has been described in PM/DM; however careful consideration should evaluate whether such cases are associated with aspiration pneumonia or an overlap syndrome (45). V.
Systemic Sclerosis (Scleroderma)
Systemic sclerosis (SSc, scleroderma) is a complicated systemic disease with many pulmonary manifestations. Although ILD and pulmonary arterial hypertension are the best-studied causes of dyspnea in SSc, these topics are covered in
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other chapters. Therefore, this review will discuss the other causes of chest restriction, including skin disease and pleural effusions, cardiac dysfunction, pericardial effusions, and aspiration pneumonia. An obstructive disease has been described that may result from bronchiolar tortuosity. Lastly, the coexistence of an organizing pneumonia should be recognized since prednisone is sometimes beneficial. A.
Serositis
Exudative pleural effusions are uncommon in SSc, but their presence because of SSc alone has been described (45). Since SSc also can produce diastolic cardiac dysfunction, a thoracentesis is recommended to exclude a transudative effusion that would focus therapy on congestive heart failure. Pericardial effusions have been seen that are occasionally large enough to benefit from drainage with resolution of symptoms. Since effusions are prone to recur, most patients receive a pericardial window at the time of drainage. B.
Esophageal Disease
The smooth muscle of the lower two-third of the esophagus is impaired in SSc and gastroesophageal reflux and aspiration events are common in all forms of SSc. The degree of esophageal dismotility, whether measured by air esophagram size on CT scan (46), impedance plethysmography, or dual probe pH sampling (47), is severe when studied in the majority of patients, regardless of symptoms. Therefore, a proton pump inhibitor (PPI) is standard therapy in most SScaffected individuals. Alkaline reflux may still remain and cause symptoms. Controversy will remain about whether and to what extent esophageal reflux contributes to lung disease. Most cross-sectional studies have found a poor correlation between reflux severity and ILD severity (47), although no long-term prospective evaluations are available. Nevertheless, when dense-dependent consolidation is seen on a CT scan, the possibility of aspiration pneumonia should be considered. C.
Obstructive Lung Disease
Obstructive lung disease has been seen in SSc (48). One of the complicating factors in defining this disorder is the frequency of cigarette smoking in most case series. Other diseases that have prominent interstitial components, such as asbestosis, also have described a mild obstructive lung disease that is presumably from narrowing or tortuosity of some airways early in the fibrotic process (49). Treatment with bronchodilators or corticosteroids rarely produces clinical improvement. D.
Organizing Pneumonia
Bronchiolitis obliterans with organizing pneumonia (BOOP) is now called cryptogenic organizing pneumonia (COP) when the cause is idiopathic (50). When secondary to a CTD, such as RA or SSc, variable terminology is used.
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SSc-associated COP is a treatable form of airways and parenchymal disease in which loose connective tissue elements fill the terminal airways. Since corticosteroid therapy has no effect on the nonspecific interstitial pneumonia (NSIP) that usually characterizes SSc ILD, identification of COP becomes important. Although still controversial, corticosteroids are usually avoided in SSc for fear of precipitating SSc renal crisis (51). Whether corticosteroids will precipitate an SSc renal crisis now that patients with diffuse SSc are treated prophylactically with an angiotensin converting enzyme (ACE) inhibitor remains unknown. The typical findings of COP on chest CT are different from NSIP or usual interstitial pneumonia (UIP). Therefore, chest CT is the most common test that prompts a clinical trial of corticosteroids for presumed SSc-associated COP. A thoracoscopic lung biopsy is recommended for definitive diagnosis. Corticosteroids alone often prove problematic for CTD-associated COP because of the frequency of relapse after corticosteroids are withdrawn. Therefore, other immunosuppressive drugs are often used with corticosteroids as sparing agents. E.
Lung Cancer
Bronchogenic carcinoma is increased in frequency in SSc independent of cigarette smoking. Carcinoma may be of any cell type, although the majority are adenocarcinomas (52). Both lung cancer and non-Hodgkin’s lymphomas were found increased in a Swedish population-based epidemiologic study (53). Since nodules are not part of SSc ILD, any nodular appearance should prompt biopsy. Therapy is unchanged from standard of care, although radiation therapy in SSc may have accelerated radiation fibrosis (54). VI.
Sjo¨gren’s Syndrome
SS presents in two forms within the CTD. Secondary SS complicates other CTD. Since screening for SS usually occurs during the initial evaluation of other CTD, this disease is rarely missed. On the contrary, primary SS often encounters diagnostic delay because of the many presenting symptoms. In addition to variable degrees of dry eyes and dry mouth, dryness of other mucus membranes occurs. Cough is a manifestation of xerotrachea, and maintenance of airway moisture often helps symptoms. A lymphocytic bronchiolitis is often present (55) and can progress to involve the lung parenchyma with lymphocytic interstitial pneumonia (LIP). The lymphocytic bronchiolitis with or without intermittent bacterial pneumonias can also progress to bronchiectasis. Rarely, lymphoma of the lung will develop, occasionally of the mucosa-associated lymphoid tissue (MALT) type (56). Rarely, other manifestations of SS will present in the lung. Lung cysts are occasionally large (up to 10 cm3) and multiple (Fig. 2) with cysts occasionally becoming secondarily infected (57,58). The pathogenesis of lung cysts in SS
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Figure 2 The cysts associated with Sjogren’s syndrome may appear to have no wall when small. However, when cyst size increases, a thin wall is evident. These cysts can be quite large as demonstrated in the cut from chest computed tomography.
remains unknown. One theory suggests that thick mucus or lymphocytic airways disease acts as a one-way valve resulting in airway obstruction. There is no known treatment, and they are usually asymptomatic. Pulmonary amyloidosis also has been described in SS (59). Although corticosteroid and immunosuppressive therapy can limit the lymphocytic inflammation, it does little to help airway dryness or inspisated mucus in bronchiectatic airways that can be occasionally helped with nebulized saline or N-acetyl cysteine. VII.
Lung Vasculitis
Other chapters deal with necrotizing granulomatous vasculitis (previously called Wegener’s granulomatosis). This and other antineutrophil cytoplasmic antibodies (ANCA)–associated vasculitides, such are microscopic polyangiitis and pulmonary capillaritis, are covered in other chapters. However, other CTD can present with pulmonary vascular disease. Behcet’s syndrome can present with pulmonary artery aneurysms. The Hughes-Stovin Syndrome, another cause of pulmonary vasculitis, has been variably listed as a separate lung vascular disease. A vascular injury has been defined as part of Crohn’s disease–associated lung disease. VIII.
Relapsing Polychondritis
Relapsing polychondritis is a systemic inflammatory disease of cartilage. At the time of first presentation, a red painful area of chondritis is often misdiagnosed as a cellulitis. Common areas of involvement include the outer ear and nose.
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However, the trachea is also made of cartilage and can be involved with repetitive cycles of inflammation, ulceration, and scarring that may ultimately present with tracheal stenosis. The two CTDs most often associated with tracheal stenosis include relapsing polychondritis and necrotizing granulomatous vasculitis. Stenosis in both diseases is most common in the subglottic space. IX.
Summary
In summary, the connective tissue disorders frequently involve the lung with a variety of disorders that impact clinical symptoms and outcome. Knowledge of these disorders will assist in optimal clinical outcomes. The impact of the pulmonary specialist is more appreciated when clinical care is provided in a comprehensive approach. Therefore, successful centers that deal with the CTDs foster collaborative care for these complicated disorders. References 1. Sahn SA. The pathophysiology of pleural effusions. Annu Rev Med 1990; 41:7–13. 2. Lillington GA, Carr DT, Mayne JG. Rheumatoid pleurisy with effusion. Arch Intern Med 1971; 128(5):764–768. 3. Jones F, Blodgett R. Empyema in rheumatoid pleuropulmonary disease. Ann Intern Med 1971; 74:665–671. 4. Dieppe PA. Empyema in rheumatoid arthritis. Ann Rheum Dis 1975; 34(2):181–185. 5. Joseph J, Sahn SA. Connective tissue diseases and the pleura. Chest 1993; 104(1): 262–270. 6. Ferguson G. Cholesterol pleural effusion in rheumatoid lung disease. Thorax 1966; 21(6):577–582. 7. Faurschou P, Francis D, Faarup P. Thoracoscopic, histological, and clinical findings in nine case of rheumatoid pleural effusion. Thorax 1985; 40(5):371–375. 8. Geddes D, Webley M, Emerson P. Airways obstruction in rheumatoid arthritis. Ann Rheum Dis 1979; 38(3):222–225. 9. Doyle JJ, Eliasson AH, Argyros GJ, et al. Prevalence of pulmonary disorders in patients with newly diagnosed rheumatoid arthritis. Clin Rheumatol 2000; 19(3): 217–221. 10. Kroot EJ, van Gestel AM, Swinkels HL, et al. Chronic comorbidity in patients with early rheumatoid arthritis: a descriptive study. J Rheumatol 2001; 28(7):1511–1517. 11. Collins RL, Turner RA, Johnson AM, et al. Obstructive pulmonary disease in rheumatoid arthritis. Arthritis Rheum 1976; 19(3):623–628. 12. Beckman G, Beckman L, Bjelle A, et al. Alpha-1-antitrypsin types and rheumatoid arthritis. Clin Genet 1984; 25(6):496–499. 13. Lofgren R, Montgomery W. Incidence of laryngeal involvement in rheumatoid arthritis. N Engl J Med 1962; 267:193–195. 14. Howling SJ, Hansell DM, Wells AU, et al. Follicular bronchiolitis: thin-section CT and histologic findings. Radiology 1999; 212(3):637–642. 15. Yousem SA, Colby TV, Carrington CB. Follicular bronchitis/bronchiolitis. Hum Pathol 1985; 16(7):700–706.
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16. Sugiyama Y, Saitoh K, Kano S, et al. An autopsy case of diffuse panbronchiolitis accompanying rheumatoid arthritis. Respir Med 1996; 90(3):175–177. 17. Hassan WU, Keaney NP, Holland CD, et al. High resolution computed tomography of the lung in lifelong non-smoking patients with rheumatoid arthritis. Ann Rheum Dis 1995; 54(4):308–310. 18. Shadick NA, Fanta CH, Weinblatt ME, et al. Bronchiectasis. A late feature of severe rheumatoid arthritis. Medicine (Baltimore) 1994; 73(3):161–170. 19. Hayakawa H, Sato A, Imokawa S, et al. Bronchiolar disease in rheumatoid arthritis. Am J Respir Crit Care Med 1996; 154(5):1531–1536. 20. Yousem SA, Colby TV, Carrington CB. Lung biopsy in rheumatoid arthritis. Am Rev Respir Dis 1985; 131(5):770–777. 21. Gordon D, Broder I, Hyland R. Rheumatoid arthritis. In: Cannon GW, Zimmerman GA, eds. The Lung in Rheumatic Diseases. New York, NY: Marcel Dekker, Inc., 1990:229. 22. Jolles H, Moseley PL, Peterson MW. Nodular pulmonary opacities in patients with rheumatoid arthritis. A diagnostic dilemma. Chest 1989; 96(5):1022–1025. 23. Caplan A. Certain unusual radiological appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax 1953; 8(1):29–37. 24. Park IN, Kim DS, Shim TS, et al. Acute exacerbation of interstitial pneumonia other than idiopathic pulmonary fibrosis. Chest 2007; 132(1):214–220. 25. Ropes M. Systemic lupus erythematosus. Cambridge: Harvard University Press, 1976. 26. Riska H, Fyhrquist F, Selander RK, et al. Systemic lupus erythematosus and DNA antibodies in pleural effusions. Scand J Rheumatol 1978; 7(3):159–160. 27. Passero F, Myers A. Hemopneumothorax in systemic lupus erythematosus. J Rheumatol 1980; 7(2):183–186. 28. Susanto I, Peters JI. Acute lupus pneumonitis with normal chest radiograph. Chest 1997; 111(6):1781–1783. 29. Holgate ST, Glass DN, Haslam P, et al. Respiratory involvement in systemic lupus erythematosus. A clinical and immunological study. Clin Exp Immunol 1976; 24(3): 385–395. 30. Matthay RA, Hudson LD, Petty TL. Acute lupus pneumonitis: response to azathioprine therapy. Chest 1973; 63(1):117–120. 31. Zamora MR, Warner ML, Tuder R, et al. Diffuse alveolar hemorrhage and systemic lupus erythematosus. Clinical presentation, histology, survival, and outcome. Medicine (Baltimore) 1997; 76(3):192–202. 32. Liu MF, Lee JH, Weng TH, et al. Clinical experience of 13 cases with severe pulmonary hemorrhage in systemic lupus erythematosus with active nephritis. Scand J Rheumatol 1998; 27(4):291–295. 33. Kahn FW, Jones JM, England DM. Diagnosis of pulmonary hemorrhage in the immunocompromised host. Am Rev Respir Dis 1987; 136(1):155–160. 34. Drew L, Finley T, Golde D. Diagnostic lavage and occult pulmonary hemorrhage in thrombocytopenic immunocompromised patients. Am Rev Respir Dis 1977; 116(2): 215–221. 35. Barile LA, Jara LJ, Medina-Rodriguez F, et al. Pulmonary hemorrhage in systemic lupus erythematosus. Lupus 1997; 6(5):445–448. 36. Erickson RW, Franklin WA, Emlen W. Treatment of hemorrhagic lupus pneumonitis with plasmapheresis. Semin Arthritis Rheum 1994; 24(2):114–123.
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37. Warrington KJ, Moder KG, Brutinel WM. The shrinking lungs syndrome in systemic lupus erythematosus. Mayo Clin Proc 2000; 75(5):467–472. 38. Karim MY, Miranda LC, Tench CM, et al. Presentation and prognosis of the shrinking lung syndrome in systemic lupus erythematosus. Semin Arthritis Rheum 2002; 31(5):289–298. 39. Lee CS, Chen TL, Tzen CY, et al. Idiopathic inflammatory myopathy with diffuse alveolar damage. Clin Rheumatol 2002; 21(5):391–396. 40. Plastiras SC, Soliotis FC, Vlachoyiannopoulos P, et al. Interstitial lung disease in a patient with antisynthetase syndrome and no myositis. Clin Rheumatol 2007; 26(1):108–111. 41. Teixeira A, Cherin P, Demoule A, et al. Diaphragmatic dysfunction in patients with idiopathic inflammatory myopathies. Neuromuscul Disord 2005; 15(1):32–39. 42. Marie I, Hachulla E, Hatron PY, et al. Polymyositis and dermatomyositis: short term and long term outcome, and predictive factors of prognosis. J Rheumatol 2001; 28(10):2230–2237. 43. Marie I, Hachulla E, Cherin P, et al. Opportunistic infections in polymyositis and dermatomyositis. Arthritis Rheum 2005; 53(2):155–165. 44. Freemer M, King TE Jr. Connective tissue diseases. In: Schwarz MI, King TE Jr., eds. Interstitial Lung Disease. 4th ed. Hamilton, Ontario, Canada: BC Decker, Inc., 2003:535–598. 45. Highland KB, Heffner JE. Pleural effusion in interstitial lung disease. Curr Opin Pulm Med 2004; 10(5):390–396. 46. Bhalla M, Silver RM, Shepard JA, et al. Chest CT in patients with scleroderma: prevalence of asymptomatic esophageal dilatation and mediastinal lymphadenopathy. AJR Am J Roentgenol 1993; 161(2):269–272. 47. Troshinsky MB, Kane GC, Varga J, et al. Pulmonary function and gastroesophageal reflux in systemic sclerosis. Ann Intern Med 1994; 121(1):6–10. 48. Guttadauria M, Ellman H, Emmanuel G, et al. Pulmonary function in scleroderma. Arthritis Rheum 1977; 20(5):1071–1079. 49. Miller A, Lilis R, Godbold J, et al. Spirometric impairments in long-term insulators. Relationships to duration of exposure, smoking, and radiographic abnormalities. Chest 1994; 105(1):175–182. 50. Demedts M, Costabel U. ATS/ERS international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Eur Respir J 2002; 19(5): 794–796. 51. Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 1998; 41(9):1613–1619. 52. Talbott JH, Barrocas M. Carcinoma of the lung in progressive systemic sclerosis: a tabular review of the literature and a detailed report of the roentgenographic changes in two cases. Semin Arthritis Rheum 1980; 9(3):191–217. 53. Rosenthal AK, McLaughlin JK, Gridley G, et al. Incidence of cancer among patients with systemic sclerosis. Cancer 1995; 76(5):910–914. 54. Abu-Shakra M, Lee P. Exaggerated fibrosis in patients with systemic sclerosis (scleroderma) following radiation therapy. J Rheumatol 1993; 20(9):1601–1603. 55. Wells AU, du Bois RM. Bronchiolitis in association with connective tissue disorders. Clin Chest Med 1993; 14(4):655–666.
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56. Tonami H, Matoba M, Kuginuki Y, et al. Clinical and imaging findings of lymphoma in patients with Sjogren syndrome. J Comput Assist Tomogr 2003; 27(4): 517–524. 57. Ryu JH, Swensen SJ. Cystic and cavitary lung diseases: focal and diffuse. Mayo Clin Proc 2003; 78(6):744–752. 58. Perez-Castrillon JL, Gonzalez-Castaneda C, Del Campo F, et al. Cavitary lung lesion in a patient with Sjogren’s syndrome. Postgrad Med J 1999; 75(890): 765–766. 59. Sakai K, Ohtsuki Y, Hirasawa Y, et al. [Sjogren’s syndrome with solitary nodular pulmonary amyloidosis]. Nihon Kokyuki Gakkai Zasshi 2004; 42(4):330–335.
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19 Cryptogenic Organizing Pneumonia and Other Causes of Organizing Pneumonia
ROMAIN LAZOR Department of Respiratory Medicine, University Hospital, Bern, Switzerland, and Department of Respiratory Medicine, Reference Center for Orphan Pulmonary Diseases, Louis Pradel University Hospital, Lyon, France
VINCENT COTTIN and JEAN-FRANC ¸ OIS CORDIER Department of Respiratory Medicine, Reference Center for Orphan Pulmonary Diseases, Hospices Civils de Lyon, Louis Pradel University Hospital, University of Lyon, Lyon, France
I.
Introduction
Organizing pneumonia (OP) is an uncommon type of inflammatory and fibroproliferative disorder of the lung. Although its histological features were known since the beginning of the 20th century, OP has been described only in the early 1980s by Davison et al. (1). Epler et al. used the term ‘‘bronchiolitis obliterans with organizing pneumonia’’ (BOOP) to underline its frequent association with bronchiolitis obliterans (2). Data accumulated over the next two decades to further define and characterize this new syndrome (3–27) and culminated in its recent classification among the idiopathic interstitial pneumonias (23). II.
Terminology
The wording used by Epler gave rise to semantic confusion between bronchiolitis obliterans (usually associated with airflow obstruction) and bronchiolitis obliterans with organizing pneumonia (BOOP), which are clinically and histologically distinct entities. The term BOOP has thus been replaced by the more accurate term of organizing pneumonia (23), since bronchiolitis obliterans 505
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is an accessory finding and is not always present. Another misunderstanding came from the fact that the concept of ‘‘organizing pneumonia’’ was used by pathologists to describe a particular but otherwise not specific histological lesion and by chest physicians to designate a clinicopathological syndrome. The term organizing pneumonia pattern now refers to the histological lesion and organizing pneumonia (OP) to the clinicopathological syndrome (23). OP occurring in association with a variety of causes and clinical contexts is called secondary OP. If no cause can be identified, OP is termed cryptogenic organizing pneumonia (COP). III.
Epidemiology
The first valuable epidemiological data on OP have been provided only recently by a retrospective analysis of biopsy-proven cases diagnosed in Iceland between 1984 and 2003 (28). This study took advantage from the fact that all pathology specimens in Iceland are evaluated at only two departments, thus allowing a comprehensive nationwide search for available cases. The mean annual incidence of OP was 1.97/100,000, with 1.10/100,000 for COP and 0.87/100,000 for secondary OP (28). Men and women were equally affected, at a mean age of 67 years. No relationship between OP occurrence and smoking has been demonstrated so far. IV.
Pathogenesis
The intra-alveolar fibrosis of OP is a model of inflammatory lung disease sharing many similarities with cutaneous wound healing (29–32). OP is initiated by an injury to the alveolar epithelium leading to epithelial cell necrosis and shedding, denudation but overall preservation of the epithelial basal membranes despite the formation of gaps, increased alveolar permeability, and exudation of plasma proteins, including coagulation factors, into the alveolar space (29,31). The endothelium is only mildly damaged. In contrast with diffuse alveolar damage (DAD), no hyaline membranes are found. The first stage of intra-alveolar organization is characterized by activation of the coagulation cascade and accumulation of fibrin clots containing lymphocytes, some polymorphonuclear cells, and occasional plasma cells and mast cells (14,31,33). In the second stage, fibroblasts migrate from the alveolar interstitium through gaps in the injured basal membrane, colonize the fibrin residues, proliferate, transform into myofibroblasts, and produce an extracellular myxoid matrix. Inflammatory cells (lymphocytes, neutrophils, some eosinophils) infiltrate the alveolar interstitium. Alveolar type II cells proliferate to provide re-epithelialization of the basal membranes. During the third stage, the intra-alveolar granulation tissue undergoes progressive organization into mature fibrotic ‘‘buds’’ rich in collagen I and III filling the alveoli, alveolar ducts,
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and distal bronchioles, without disruption of the parenchymal architecture (2,3,6,14,33).
V.
Mechanisms of Intra-Alveolar Organization and Fibrosis, and its Resolution
The initial epithelial alveolar damage with leakage of plasma proteins and fibrin formation within the alveolar lumen has been especially studied in acute respiratory distress syndrome, and in pulmonary fibrosis (29,30,34–38). The intraalveolar formation of fibrin results from an imbalance between the coagulation and fibrinolytic cascades, with a net result of clotting (39). Recently, increased levels of thrombin activable fibrinolysis inhibitor (a potent inhibitor of fibrinolysis) and of protein C inhibitor have been found in bronchoalveolar lavage (BAL) from patients with interstitial lung disease, especially OP (40). In addition to providing a provisional fibrin matrix for the migration of cells (including fibroblasts), the coagulation and fibrinolysis factors and inhibitors (especially plasminogen activator inhibitor-1) play a complex role in fibrogenesis (38). Intra-alveolar fibrosis resulting from organization of inflammatory exudates characterized by dramatic reversibility with corticosteroids, contrasts with fibrosis in the other fibrosing idiopathic interstitial pneumonias, especially usual interstitial pneumonia (UIP), which is irreversible. The connective matrix of the intra-alveolar buds initially consists of fibronectin, type III collagen, proteoglycans, and a minority of collagen type I fibers, leaving empty large areas of the extracellular space. The cellular rings of fibroblasts-myofibroblasts are intercalated with connective matrix sheets consisting of loose bundles of thin collagen type I fibers mixed with fibronectin, collagen and procollagen type III, and proteoglycans. In the mature fibrotic buds, the connective network consists of thin collagen I fibers maintained together by thinner fibrils of collagen and procollagen type III, and fibrin to form bundles resulting in a loose connective network where fibronectin and type III procollagen and collagen are codistributed at a higher rate than type I collagen. Such a loose connective matrix with an abundant type III collagen is more susceptible to degradation and reversal of fibrosis (31,41,42). This contrasts with the predominant deposition of type I collagen in UIP. Collagen VI coexpressed with collagen III rather than collagen I may also participate in the regulation of matrix deposition in OP (43). Glycoproteins such as tenascin likely play a role in loosening the adhesive interactions between cells and the pericellular matrix components in OP (44). The matrix metalloproteinases (MMPs) that cleave protein components of the extracellular matrix play a central role in tissue remodeling (45). The two collagenolytic MMPs especially involved in the destruction of subepithelial basement membranes are MMP-2 (preferentially secreted by fibroblasts and epithelial cells) and MMP-9 (preferentially produced by inflammatory cells). MMP-2 is expressed in BAL fluid and regenerated type II cells in OP, whereas
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MMP-9 is preferentially expressed in UIP (46). The concentrations of MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) are more increased in BAL fluid of patients with OP than in those with UIP (47). These data suggest that an imbalance between MMPs and TIMPs may play a role in the connective tissue remodeling of OP. Laminin-5, a glycoprotein involved in cell attachment, migration, proliferation, differentiation, and apoptosis expressed in epithelial cells of wound healing, is also expressed in regenerating epithelial cells in OP and UIP (48). The role of the myofibroblast in wound healing and fibrosis is critical (49,50). Several recent studies have demonstrated that myofibroblasts involved in bleomycin- and radiation-induced experimental pulmonary fibrosis originate as circulating progenitors from the bone marrow and not only from resident fibroblasts of the pulmonary interstitium (51–53). Whether this also occurs in OP is currently unknown. In OP resolution, the disappearance of myofibroblasts and fibroblasts may occur by apoptosis, possibly through loss of transforming growth factor (TGF)-b signaling (54,55). Hence, apoptotic activity is increased in the newly formed connective tissue in OP (56). Intra-alveolar buds in OP are further characterized by prominent capillarization, which resembles granulation tissue in cutaneous wound healing (57). Vascular endothelial growth factor and basic fibroblast growth factor are widely expressed in intra-alveolar buds (58). Angiogenesis mediated by these growth factors could contribute to the reversal of buds in OP. A murine model of intraluminal fibrosis has been developed with intranasal inoculation of reovirus serotype 1/L into CBA/J mice (59). In this model, severe pneumonia initially characterized by prominent peribronchiolar lymphocytic inflammation secondarily evolves to intraluminal fibroblastic lesions indistinguishable from OP. Interestingly, these lesions develop in CBA/J mice but not in other strains, suggesting that genetic host factors are critical in the development of intra-alveolar fibrosis. With a higher titer of inoculated reovirus 1/L, CBA/J mice develop DAD with typical hyaline membranes and high mortality, suggesting that the severity of the initial injury may determine the progression toward either OP or DAD (60,61). T lymphocytes likely play a role in OP. The BAL cytokine profile is characterized by increased monocyte chemotactic protein (MCP)-1, interleukin (IL)-12, IL-10, and IL-18 in OP as compared with controls and UIP, consistent with macrophage and lymphocyte activation and expansion of T helper-1 response (62). In the reovirus 1/L-induced lung injury model, neonatally thymectomized CBA/J mice still develop DAD but no longer develop OP, suggesting that T cells are required for the development of OP but not for DAD (63). In patients receiving allogeneic hematopoetic stem cell transplantation, T-cell depletion with alemtuzumab prior to allograft prevented the subsequent occurrence of bronchiolitis obliterans and OP in all of 84 cases, whereas these complications occurred in 16 out of 197 patients receiving the conventional allograft regimen (p < 0.04) (64).
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Clinical and Imaging Characteristics
The clinical and imaging presentations of OP are usually characteristic, but may mimic other pulmonary diseases. Three broad categories have been individualized (6), but other less common and/or atypical imaging patterns have been reported. A.
Classical Multifocal Form
The classical form accounts for 40% to 70% of cases of OP (18,19,65). The disease onset is usually subacute with flu-like symptoms, dry cough and mild dyspnea, often associated with fatigue, fever, and weight loss (2,6,9,13). Productive cough, chest pain, myalgias, arthralgias, and night sweats are less common. Hemoptysis is rare (66). There is no finger clubbing. Pulmonary auscultation discloses sparse inspiratory crackles over affected areas (18). Wheezing is usually absent. As classical OP often mimics pulmonary infection, many patients initially receive empirical antibiotic therapy. The lack of improvement under this treatment usually prompts further procedures. The diagnosis may therefore be delayed for weeks to months (2,4–6,9,10,19,20). Rarely, OP is an incidental finding at chest X ray (19,20). At imaging, classical OP is characterized by multiple patchy bilateral opacities predominating in the lower lung fields and the subpleural areas, often associated with an air bronchogram (Fig. 1) (4–6,12,17,65). The chest computed
Figure 1 Chest CT scan in the classical multifocal form of organizing pneumonia: multiple bilateral alveolar opacities with an air bronchogram, mainly located in the subpleural areas.
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Table 1 Differential Diagnosis of Migratory Pulmonary Infiltrates Organizing pneumonia (cryptogenic or secondary) Chronic idiopathic eosinophilic pneumonia Secondary eosinophilic pneumonias due to parasitic infections, drug toxicity, etc. Churg-Strauss syndrome Allergic bronchopulmonary aspergillosis Wegener’s granulomatosis Lupus pneumonitis Hypersensitivity pneumonitis Others (psittacosis, thromboembolic pulmonary manifestations) Source: From Refs. 11, 67–70, 132, and 133.
tomography (CT) scan usually shows more opacities than the standard chest X ray, thus showing the multifocal nature of the disease. Spontaneous disappearance of some opacities and appearance of new infiltrates in other sites occur in 25% to 50% of cases (16,20). Such ‘‘migrating opacities’’ provide a diagnostic clue for OP, since the differential diagnosis is relatively narrow (Table 1) (67–70). Pleural effusion is uncommon (5,20). Positron emission tomography (PET) has shown a significant increase of fluorodeoxyglucose uptake in parenchymal lesions of OP (71). Pulmonary function testing usually discloses a mild-to-moderate restrictive ventilatory defect, moderately reduced carbon monoxide diffusion capacity, and mild-to-moderate hypoxemia (2–6,9,16). Severe hypoxemia may occasionally occur due to a right-to-left blood shunt through densely consolidated lung parenchyma (72). Airflow obstruction is found in a minority of cases, usually smokers (2), and probably reflects preexisting chronic obstructive pulmonary disease. BAL shows a mixed pattern alveolitis (6,9,13,16,20,73,74), with predominance of lymphocytes (20–40%) and a slight increase of neutrophils (*10%) and eosinophils (*5%). Mast cells (1–2%) and plasma cells (*1%) are often present (20). The lymphocytes CD4/CD8 ratio is usually decreased (6,13,16,20,73,74). Predominance of eosinophils over lymphocytes is uncommon (16) and suggests the diagnosis of eosinophilic pneumonia (a condition that may sometimes overlap with OP). Blood differential count usually reveals moderate leucocytosis with increased neutrophils (18,19). Increased C-reactive protein and erythrocyte sedimentation rate are common features (6,11,18). B.
Localized Form
This particular form, which has been termed ‘‘localized,’’ ‘‘focal,’’ ‘‘nodular,’’ or ‘‘solitary’’ OP, represents 5% to 20% of cases (6,18,19). It appears as a solitary nodule (<3 cm) or mass (>3 cm) (Fig. 2) with smooth, lobulated, or spiculated margins (6,75–77), often localized in the upper lobes (6). Bilateral lesions may occur in a minority of cases (78). Up to 62% of patients are asymptomatic, and the lesion is found incidentally at chest imaging (77–80). Underlying COPD has been reported in up to 67% of cases, and recurrent respiratory infections in 57%
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Figure 2 Chest CT scan in the localized form of organizing pneumonia: dense rounded mass with irregular margins located in the left lower lobe, resembling malignancy.
(78,80), suggesting that focal OP may result from nonresolving infection in this particular context (78,80). In support of this hypothesis, one study reported the frequent occurrence of small neutrophil aggregates in the vicinity of localized OP with otherwise typical OP pattern at histology (80). However, in another study, most cases were idiopathic (79). At imaging, localized OP cannot be distinguished from primary or metastatic malignancy, and presents with contrast enhancement on CT (79) and positive tracer uptake on PET scans (78,79). These features usually lead to surgical resection, and the diagnosis of OP is made at pathological examination. The surgical procedure consists in a wedge resection and is curative in most cases, without the need for subsequent corticosteroid therapy (78,79). One challenge is to avoid unnecessary lobectomy in this benign disorder simulating lung cancer. C.
Diffuse Infiltrative Form
This form has been reported in 10% to 40% of cases (2,6,12,18,19,81), but probably constitutes a heterogeneous group. Some early cases would probably be now better classified as nonspecific interstitial pneumonia (NSIP), where intraalveolar buds of granulation tissue are a common accessory histopathological feature. Other cases truly overlap with NSIP and other types of idiopathic interstitial pneumonias. Occasionally, OP may present as a severe, rapidly progressive disease with respiratory failure resembling acute respiratory distress syndrome (20,82–88). Some of the reported cases were cryptogenic (20,83,84,89), and others were associated with connective tissue diseases, drugs, or toxic exposure (87–89). It is likely that some cases diagnosed as severe OP had in fact acute interstitial pneumonia or acute respiratory distress syndrome, with OP being only an ancillary feature or overlapping with DAD at the organizing stage. Acute exacerbations of
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fibrotic interstitial lung diseases, especially UIP and NSIP have also been associated with histological patterns of OP or DAD at lung biopsy, the former being associated with a better short-term prognosis (90). Other cases of severe OP may correspond to ‘‘acute fibrinous and organizing pneumonia,’’ which combines pathological and clinical features of OP and DAD (91). D.
Atypical Forms
Rarely, OP may present as multiple nodules (92), sometimes cavitary (93–95), or with an air bronchogram, or as striking ring-like opacities (96). A micronodular pattern may occur, with either well-defined nodules of *8-mm diameter or small diffuse poorly defined nodules (96). A bronchocentric pattern has been described (97), as well as a perilobular pattern resembling thickened interlobular septa (96). Radial and circumferential subpleural linear opacities have also been reported (65,92,98,99). VII.
Histopathological Diagnosis
Buds of granulation tissue filling the distal airspaces (alveoli, alveolar ducts, respiratory bronchioles, bronchioles) constitute the histological hallmark of OP, with associated features including mild interstitial inflammatory infiltrate, type II cell hyperplasia, and intra-alveolar foamy macrophages (Fig. 3) (2,3,14,33). However, this elementary lesion is in no way specific and may be seen as a minor feature in other disorders such as infections, NSIP, hypersensitivity pneumonitis,
Figure 3 Histopathological pattern of organizing pneumonia: buds of granulation tissue containing myofibroblasts, inflammatory cells, and a connective matrix, filling the alveolar spaces. Mild inflammatory infiltrate of the alveolar interstitium.
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Table 2 Disorders in Which Organizing Pneumonia Pattern May Be Found at Histopathology as an Ancillary Component Neoplasms Pulmonary infections Organization distal to airway obstruction Aspiration pneumonia Nonspecific interstitial pneumonia Hypersensitivity pneumonitis Desquamative interstitial pneumonia Chronic idiopathic eosinophilic pneumonia Secondary eosinophilic pneumonias Churg-Strauss syndrome Wegener’s granulomatosis Primary pulmonary lymphoma Diffuse alveolar damage Drug reactions and toxic exposures Others Source: From Refs. 23 and 33.
chronic idiopathic eosinophilic pneumonia, Wegener’s granulomatosis (WG), pneumonia distal to airway obstruction, etc. (14,33) (Table 2). In resected lung cancers, OP pattern can be found in the vicinity of tumoral tissue in up to 40% of cases (100). Thus, the histological diagnosis of OP requires not only the buds of granulation tissue within distal airspaces to be the main histopathological lesion but also the absence of features suggesting another diagnosis. The latter include granulomas, acute bronchiolitis, necrosis, hyaline membranes, and prominent infiltration by eosinophils or neutrophils (14,23). The main differential diagnosis of OP pattern at histopathology includes NSIP and the organizing stage of DAD (23). VIII.
Clinicopathological Diagnosis
The definite diagnosis of OP requires the combination of compatible clinical and imaging features with a histopathological OP pattern (22). If the imaging and clinical picture are typical, a transbronchial lung biopsy showing typical intraalveolar buds is considered sufficient to diagnose OP. However, follow-up is necessary to reconsider the diagnosis if the clinical course or response to treatment is unusual. If the initial clinical and imaging features are atypical, a video-assisted thoracoscopic surgical lung biopsy is necessary to verify that OP pattern is the main histopathological lesion and not just an ancillary feature in the frame of another pathological process. Disorders mimicking the clinical and imaging features of OP, which may initially respond to corticosteroid treatment, include primary pulmonary lymphoma, WG, NSIP, or hypersensitivity pneumonitis. Diagnosis of OP without histopathological proof should be restricted to
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cases with typical clinicoradiological and BAL features, with a clearly identified causal agent of OP such as radiation therapy for breast cancer. In a frail or old patient, an unfavorable risk-benefit ratio may legitimate the absence of lung biopsy, but such a decision should be carefully weighed against the morbidity of prolonged empirical corticosteroid therapy in the same case. IX. A.
Differential Diagnosis Distinction Between OP and Other Disorders
The differential diagnosis of OP depends in part on the clinical and radiological presentation. In cases of areas of consolidation at imaging, one should consider infection, bronchioloalveolar carcinoma, primary pulmonary lymphoma, eosinophilic pneumonias (either idiopathic or secondary to a known cause), and pulmonary vasculitis, especially WG and Churg-Strauss syndrome. In WG, not only clinical and imaging characteristics may resemble OP, but histological features of OP pattern may also occur (14). These usually consist of small foci of OP at the periphery of otherwise typical granulomatous lesions, but in some cases the OP pattern may constitute the main histological finding, although the clinical picture does not differ clinically from classical WG (14,101). The distinction between OP and WG may thus be difficult in some cases. If OP presents as a diffuse infiltrative disorder at imaging, the differential diagnosis includes NSIP, hypersensitivity pneumonitis, desquamative interstitial pneumonia, and other idiopathic interstitial pneumonias. In patients presenting with a solitary nodule, lung cancer is the main working diagnosis until proven otherwise. When multiple nodules or masses are present, the differential diagnosis includes metastatic lung tumor, lymphoma, and pulmonary infection including septic emboli. B.
Etiological Diagnosis of OP
OP has been associated with numerous stimuli and clinical contexts (Table 3) (22,24,25,96,102–104). A comprehensive list can be found elsewhere (27). OP Table 3 Causes of Secondary Organizing Pneumonia with Relative Frequencies Infections (bacterias, viruses, fungi, parasites) Drugs (see http://www.pneumotox.com) Solid tumors and hematological malignancies Connective tissue diseases Radiation therapy for breast carcinoma Allografts (lung, bone marrow, kidney, liver) Inflammatory bowel diseases Toxic exposures Postobstructive pneumonia and aspiration pneumonia Source: From Refs. 27 and 127.
*45% *20% *15% *10% *8%
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frequently occurs in association with various infections mostly caused by bacteria, but occasionally also by viral, fungal, and parasitic agents. Another frequent cause of OP is a drug reaction (27). A comprehensive and updated list of incriminated drugs is available on http://www.pneumotox.com. OP can also arise in the context of connective tissue diseases, such as rheumatoid arthritis or the idiopathic inflammatory myopathies, and in various types of solid cancers and hematological malignancies, where it should not be mistaken for neoplasm progression or recurrence (105). Of note, bleomycin can occasionally induce OP manifesting as pulmonary nodules mimicking metastatic tumor (106–110). OP can also occur during myelo- or lymphoproliferative syndromes and after lung or bone marrow transplantation. In the latter, a clear association has been recently demonstrated between OP and both acute and chronic forms of graftversus-host disease, suggesting that a causal relationship may exist between the two disorders (102). OP may occur in women receiving radiation therapy for breast cancer (20,111–119), with a reported incidence of 1.8% among 2056 patients (120). In contrast to classical radiation pneumonitis, which is limited to the radiation field, radiation-induced OP affects the lung also outside the radiation field and frequently involves the contralateral lung. The outcome is favorable with corticosteroid treatment (114). In the majority of cases, OP has no recognizable cause (20) and is thus termed COP. COP has been integrated in the recent classification of idiopathic interstitial pneumonias (23). Since there is no clinical, radiological, or histological characteristic allowing to confidently distinguish COP from secondary OP, the diagnosis of COP is made by exclusion, when the search for a cause remains negative. It is likely that an unrecognized infectious process is the underlying trigger in some or even most cases of COP.
X.
Treatment
Corticosteroids are the current standard treatment of OP (2,6,9,11,16–19), although spontaneous improvement has occasionally been reported (2). Clinical improvement is usually observed within two days after treatment onset. At imaging, pulmonary infiltrates usually markedly improve within a few days and disappear completely within a few weeks. The speed of response to corticosteroids in OP is slower than in chronic idiopathic eosinophilic pneumonia, but faster than in NSIP and roughly comparable to hypersensitivity pneumonitis. The spectacular and reproducible response to corticosteroids can further be considered as an additional diagnostic feature of the clinical syndrome of OP, and if this response is poor, the initial diagnosis should be reconsidered. Removal of the causing agent should be done in secondary OP, whenever possible. After resolution has been obtained, corticosteroids are usually tapered over 6 to 12 months, but there is no consensus regarding the optimal doses of prednisone and treatment duration. In patients with typical COP, we start at a dose
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of prednisone of 0.75 mg/kg/day during two to four weeks. Corticosteroids are then usually tapered over six months and stopped. However, this duration can extend up to 12 months or even longer due to relapses in a significant proportion of patients (see below). Side effects of prolonged corticosteroid treatment occur in up to 25% of patients (19). In an attempt to better define the requirements of corticosteroid treatment in COP, a pilot standardized therapeutic regimen has been used by our group (19). A retrospective comparison of patients having received this treatment with a group treated with other prednisone regimens did not reveal any differences in terms of efficacy, delay to remission, occurrence of relapses, morbidity, or final outcome. In contrast, cumulated doses of prednisone after one year were reduced twofold in the group having received the standardized treatment (19). The therapeutic regimen used by our group may thus provide a framework to guide management and limit the burden of corticosteroid therapy, while maintaining the same efficacy on disease control as higher dose regimens. In severe cases of classical OP, we initially use IV boluses of prednisolone during three consecutive days. Cyclophosphamide is added only exceptionally in acutely ill patients who do not improve within a few days of corticosteroid treatment. Some macrolides have been found to have anti-inflammatory properties and are being used in airway diseases such as panbronchiolitis, cystic fibrosis, bronchiectasis, and asthma. The treatment of OP with erythromycin or clarithromycin has been reported in small series (121–124). After three months of therapy, full or partial remission was achieved in most patients, whereas others required addition of prednisone for disease control. Although their effect appears slower and less constant than with corticosteroids, macrolides might become a therapeutic option in OP, either alone or associated with corticosteroids. This issue requires further studies. In severe cases of diffuse infiltrative OP, boluses of corticosteroids (84–86) or immunosuppressive treatment with cyclophosphamide, azathioprine, or cyclosporin A have been used (25,82,87,125,126), although the efficacy of these strategies is not clearly established. In the 38 cases reported in 4 series of 5 cases (83,84,87,88), all patients received high-dose corticosteroids (0.1–3 g equivalent prednisone/day), 12 received immunosuppressive drugs (mostly cyclophosphamide), and 13 required mechanical ventilation.
XI.
Clinical Course and Outcome
In classical multifocal COP, the outcome is usually excellent with a normalization of symptoms and imaging in more than 80% of cases (19). In a minority of cases, some minor fibrous sequelae persist at imaging. Overall mortality in COP is reported to be <5% (19,20). It has been suggested that the prognosis could be less favorable in secondary OP than in COP (2,18,87), but a recent formal comparison did not find any significant difference in clinical features, response to therapy, relapses, and outcome (127). Factors that have been
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associated with a poorer outcome in COP include a diffuse infiltrative pattern at imaging (6,128), lack of lymphocytosis at BAL (6,73,87), associated connective tissue disease (87), and interstitial fibrosis with architecture remodeling of lung parenchyma (83). In the 38 cases reported in 4 series of 5 cases with available data (83,84,87,88), 38 patients received high-dose corticosteroids (0.1–3 g equivalent prednisone/day), 12 received immunosuppressive drugs (mostly cyclophosphamide), and 13 required mechanical ventilation. Regarding final outcome, 12 patients recovered, 3 evolved to chronic respiratory insufficiency, 1 required lung transplantation, and 22 died. Whether immunosuppressive agents had a beneficial effect is unclear. Classical COP is characterized by frequent relapses when corticosteroid treatment is tapered or stopped (1,2,6,19). The initial episode and the subsequent relapses may be viewed as a single process, which progressively attenuates over time. In a series of 48 cases, one or more relapses occurred in 58% of cases (19). At the time of first relapse, most patients were still under corticosteroid treatment for the initial episode. Most relapses occurred within one year and under <10 mg/day of prednisone. A relapse occurring under high doses (>20 mg/day) or >18 months after the initial episode is unusual and should be carefully reevaluated. Relapses were not due to insufficient treatment of the initial episode (19). Delayed treatment onset (19), mild elevation of serum gammaglutamyltransferase and alkaline phosphatase (19), more severe hypoxemia at first examination (129), and multifocal opacities (130) have been associated with the occurrence of relapses. Importantly, relapses did not affect morbidity and mortality (19). Therefore, the prevention of relapses by prolonged and aggressive treatment appears unnecessary in most cases, and the strategy should rather aim at minimizing the adverse effects of corticosteroids. Aggressive treatment of relapses was initially recommended (131), but they now appear as a relatively benign phenomenon, which can usually be controlled with a moderate increase of corticosteroid treatment. Accordingly, we use a low-dose regimen of six-month duration to treat relapses of COP (19), starting at 20 mg/day of prednisone. To avoid unnecessary concerns, the possible occurrence of relapses, and even multiple relapses, should be explained to the patient. Relapses are uncommon in localized OP (78,79), but if they occur, corticosteroids are also effective. References 1. Davison AG, Heard BE, McAllister WA, et al. Cryptogenic organizing pneumonitis. Q J Med 1983; 52:382–394. 2. Epler GR, Colby TV, McLoud TC, et al. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312:152–158. 3. Katzenstein AL, Myers JL, Prophet WD, et al. Bronchiolitis obliterans and usual interstitial pneumonia. A comparative clinicopathologic study. Am J Surg Pathol 1986; 10:373–381.
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20 Obliterative Bronchiolitis: Classification, Causes and Overview
VENERINO POLETTI GB Morgagni Hospital, Forlı`, Italy and University of Parma, Parma, Italy
GIANLUCA CASONI GB Morgagni Hospital, Forlı`, Italy
MAURIZIO ZOMPATORI University Hospital of Parma, Parma, Italy
ANGELO CARLONI Azienda Ospedaliera S. Maria, Terni, Italy
MARCO CHILOSI University of Verona, Verona, Italy
I.
Introduction
Bronchiolitis is an inflammatory and fibrosing disorder that primarily affects the small conducting airways, often sparing a considerable portion of the lung parenchyma and usually with a mild involvement of the larger airways. Damage to the bronchiolar epithelium is usually considered the first step of the process. Repair leads to influx of immune and inflammatory cells, proliferation of granulation tissue in the airway walls, the lumen, or both. Epithelium atrophy or hyperplasia may be part of the tissue reaction to damage. Recovery or, vice versa, scarring with collagen deposition and architectural derangement are the two extremes of the repairing processes. As bronchioles are in between bronchi at one side and alveoli to the other side, involvement of these structures may be also evident with bronchiectasis or centrilobular inflammation and fibrosis as accompanying findings. Most cases of bronchiolitis are infectious in nature or related to inhalation of toxins, dusts, or gases. Other causes of bronchiolitis include drugs, collagen vascular disease, graft versus host disease, lung transplantation, 525
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chronic occult aspiration, and inflammatory bowel disease (IBD). Idiopathic forms are increasingly recognized and, finally, peculiar forms such as diffuse panbronchiolitis (DPB) or cicatricial bronchiolitis associated with diffuse neuroendocrine peribronchiolar cell hyperplasia are part of the clinicoradiologic and anatomic spectrum of these disorders. II.
Anatomy and Definition
Bronchioles are small airways (internal diameter of 3 mm or less) that do not contain cartilage, and usually mucus-secreting glands, in their walls (1). These airways consist of membranous bronchioles (extending from approximately generation 8–14) that are purely air conducting and respiratory bronchioles containing alveoli in their walls (2,3). Respiratory bronchioles communicate directly with alveolar ducts and are in the range of 0.5 mm or less in diameter. Both types of bronchioles have ciliated cell lining epithelium that becomes progressively more flattened in the distal airways. Although the respiratory bronchioles have variable numbers of Clara cells, goblet cells are not a normal feature in either membranous or respiratory bronchioles. Bronchioles are, along with the pulmonary artery branches and lymphatic vessels, wrapped by a connective tissue sheath and located in the centrilobular zone (2). Bronchiolitis may be defined as a process centered in and around membranous and/or respiratory bronchioles with sparing of a considerable portion of the other parenchymal structures in which inflammatory cells and mesenchymal tissue are both present (1,4). The distribution and amounts of the cellular and mesenchymal components vary from case to case and, along with varying involvement of the neighboring structures (bronchi and centrilobular alveolar spaces), are at the basis of the variety of histopathologic, radiographic, and clinical aspects of bronchiolitis. The course is usually chronic, but it may be acute or subacute. Pulmonary function tests usually document an obstructive impairment; however, in early stages these tests may be normal. Specific laboratory markers for bronchiolitis are not yet identified. The high-resolution computed tomography (HRCT) scan allows identification of more specific patterns that correlate with the involvement of small airways and it is clinically useful for confirming a suspected bronchiolar lesion. III.
Classification
A number of attempts to classify these conditions have been made. Two schemes are however used more frequently in defining cases of bronchiolitis. A clinical classification divides cases into several groups according primarily to proved or presumed etiology or the pulmonary or systemic diseases with which they are often associated (Table 1).
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Table 1 Clinical Classification of Bronchiolitis . Inhalation bronchiolitis Toxic fume inhalation Irritant gases and mineral dusts Organic dusts . Infectious and postinfectious bronchiolitis . Drug-induced bronchiolitis . Collagen-vascular disease-associated bronchiolitis . Inflammatory bowel disease–associated bronchiolitis . Post-transplant bronchiolitis . Paraneoplastic pemphigus–associated bronchiolitis . Neuroendocrine cell hyperplasia with bronchiolar fibrosis . Diffuse panbronchiolitis . Cryptogenic bronchiolitis . Miscellaneous Familial forms of follicular bronchiolitis Immunodeficiency Lysinuric protein intolerance Ataxia-Telangiectasia IgA nephropathy
Although an etiologic classification is useful for reminding the physician when to suspect the presence of bronchiolitis, the more convenient classification scheme is based on histologic characteristics as the histologic patterns generally show a better correlation with the radiologic manifestations, the natural history of disease, and the response to therapy. The broad spectrum of inflammatory and fibrotic lesions found in bronchiolitis may be stratified in four main histologic patterns (Table 2). A.
Cellular Bronchiolitis
The bronchiole’s structures show an increased number of inflammatory cells. Depending on the cell type present, the lesion is termed acute (neutrophils) or Table 2 Histopathologic Classification of Bronchiolitis . Cellular bronchiolitis Follicular bronchiolitis Diffuse panbronchiolitis Respiratory bronchiolitis . Bronchiolitis with inflammatory polyps or bronchiolitis with intraluminal polyps . Constrictive (cicatricial) bronchiolitis Neuroendocrine hyperplasia and bronchiolar fibrosis . Peribronchiolar fibrosis and bronchiolar metaplasia
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chronic (lymphocytes, plasma cells, macrophages). The presence of giant cells containing intracytoplasmic foreign material may suggest an association with chronic aspiration. Necrosis of epithelial and inflammatory cells (bronchiolar mucosal necrosis), submucosal edema or necrosis, neutrophilic microabscesses, and germinal center hyperplasia are part of the wide spectrum of pathologic changes observed in cellular bronchiolitis. Follicular bronchiolitis is a descriptive term for a subset of cellular bronchiolitis in which lymphoid hyperplasia and reactive germinal centers along the small airways and bronchioles are the prominent features. DPB (5) is another peculiar morphologic form of cellular bronchiolitis involving mainly and predominantly respiratory bronchioles. It is characterized by chronic inflammation of bronchioles with interstitial accumulation of foam cells in the walls of respiratory bronchioles, adjacent alveolar ducts, and alveoli. Severe chronic inflammation is centered first on respiratory bronchioles and only in the advanced stage also on distal membranous bronchioles. There is a mural infiltrate of lymphocytes, plasma cells and histiocytes, and intraluminal aggregates of neutrophils. Most significant characteristic is the accumulation of foamy macrophages in the interalveolar walls. B.
Bronchiolitis with Inflammatory Polyps or Bronchiolitis with Intraluminal Polyps
Bronchiolitis obliterans (BO) with intraluminal polyps is characterized by the presence of buds or polyps of granulation tissue projecting or completely filling the lumens of membranous and/or respiratory bronchioles. These polyps can have a myxoid or pale staining matrix (rich in acid mucopolysaccharides) in which elongated myofibroblasts and inflammatory cells are embedded or they can be richer in collagen fibers. C.
Constrictive or Cicatricial Bronchiolitis
Constrictive bronchiolitis is characterized by subepithelial acellular fibrosis in the walls of membranous and respiratory bronchioles causing concentric narrowing or complete obliteration of the airway lumen (Fig. 1); smooth muscle hyperplasia may also be present. Progressive concentric narrowing is associated with distortion of the lumen, mucostasis, and patchy chronic inflammation. Cicatritial bronchiolitis may be a very subtle lesion, the only clue present in the biopsy specimen being the reduction of the number of bronchioles compared with that of centrilobular arterial branches. A peculiar form of constrictive bronchiolitis, neuroendocrine cell hyperplasia with bronchiolar fibrosis has been reported by Aguayo et al. in 1992 (6). The mildest lesion consists of linear zones of neuroendocrine cell hyperplasia in the bronchiolar mucosa with focal subepithelial fibrosis. In more obvious lesions, plaque of eccentric fibrous tissue partially occludes the lumen. In most severe stage there is a total occlusion of the lumen by fibrous tissue with few visible neuroendocrine cells.
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Figure 1 (See color insert.) Constrictive/cicatritial bronchiolitis: adventitial and submucosal subtle scarring with partial lumen obliteration. The lumen of the bronchiole is smaller than that of the adjacent pulmonary artery (H&E, mid power). D.
Peribronchial Fibrosis and Bronchiolar Metaplasia
Bronchiolar and peribronchiolar scarring is associated with metaplastic bronchiolar epithelium that extends onto the adjacent fibrotic alveolar walls. Inflammatory cells are scanty and usually in the bronchiolar lumen. In some cases the pattern consists of respiratory bronchioles that end in multiple fibrouswalled channels covered by cuboidal epithelium rather than opening into thinwalled alveolar ducts. IV.
Radiographic Findings
Radiographic manifestations of diseases affecting the small airways are polymorphous. The chest radiograph can be often normal in patients with documented bronchiolitis, and its sensitivity to detect small airways disease is exceedingly low. HRCT scan is currently the best imaging technique for the evaluation of patients suspected of having bronchiolitis. Radiologic and pathologic correlations are schematically reported in Table 3 (2,7,8). Features of bronchiolar disease on HRCT scan can be broadly categorized into direct and indirect signs (7). Direct CT findings of bronchiolar disease include centrilobular nodules, V- and Y-shaped branching linear opacities that represent the ‘‘tree in bud’’ pattern (Fig. 2) and have as morphologic counterpart bronchiolar wall thickening, bronchiolar dilatation (bronchiolectasis), and luminal filling with mucus
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Table 3 Classification of HRCT Findings in Bronchiolar Diseases CT features
Type of bronchiolitis
Structures mainly involved
Centrilobular nodules and branching lines (tree in bud) Centrilobular nodules (with ground-glass attenuation)
Cellular bronchiolitis
Membranous and respiratory bronchioles
Cellular bronchiolitis Bronchiolitis with inflammatory polyps Cicatritial bronchiolitis Bronchiolitis with inflammatory polyps
Respiratory bronchioles Centrilobular airways
Low attenuation (mosaic perfusion) and expiratory air trapping Mixed pattern
Cellular bronchiolitis Bronchiolitis with inflammatory polyps, cicatricial bronchiolitis
Respiratory and membranous bronchioles Membranous bronchioles Respiratory and membranous bronchioles
and/or inflammatory cells. In cases with an infectious origin, the linear branching and nodules are often accompanied by scattered areas of ground-glass attenuation or consolidation (which reflect the involvement of the adjacent alveolar structures and therefore progression to pneumonia). Ground-glass attenuation (i.e., hazy increase in opacity without obscuring normal vessels) or consolidation
Figure 2 HRCT. Bilateral small centrilobular nodules (‘‘tree in bud’’ pattern) in patient with Haemophilus Influenzae bronchiolitis.
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(i.e., more marked density obscuring vessels) is mainly due to alveolar filling that occur in respiratory bronchiolitis-interstitial lung disease or in hypersensitivity pneumonitis. Indirect signs of bronchiolar disease on CT include subsegmental atelectasis and air trapping. Air trapping due to small airway disease often results in a ‘‘mosaic pattern’’ of lung attenuation (multilobular, geographic density differences of the lung parenchyma), which however is not specific for bronchiolar diseases. In bronchiolar diseases, the mosaic pattern is caused by hypoventilation of alveoli distal to bronchiolar obstruction (cicatricial scarring of many bronchioles), which leads to secondary vasoconstriction (consequently, underperfused lung) and is seen on CT scans as areas of decreased attenuation. Uninvolved segments of lung show normal or increased perfusion with resulting normal or increased attenuation, respectively. Paired CT scans performed in inspiration and expiration (dynamic HRCT) are useful for distinguishing bronchiolar disease from pulmonary vascular disease and some diffuse infiltrative diseases that may also cause a mosaic pattern. In bronchiolar disease, the lucent regions of lung seen at inspiration remain lucent at expiration because of air trapping and show little increase in lung attenuation or decrease in volume as seen for primary vascular lung disease. A mixed pattern (e.g., association of tree in bud with mosaic perfusion and expiratory air trapping) can be seen in different entities such as bronchiectasis and acute bronchopulmonary infections (in particular Mycoplasma pneumoniae pneumonia and chronic aspiration). Abnormalities of bronchi are a variable feature on HRCT scan in patients with documented bronchiolitis, but are not unexpected given the anatomic continuity of bronchi with the small airways; it seems that bronchial dilatation and bronchial wall thickening are relatively late features of constrictive bronchiolitis, and are more frequent in immunologically mediated disease such as rheumatoid arthritis or post transplantation. In conclusion the CT findings of the bronchiolar disorders can be classified into four major patterns. The first pattern consists of centrilobular nodules and branching lines, which usually represents an active, cellular bronchiolitis. The second pattern consists of ground-glass attenuation and consolidation; respiratory bronchiolitis and hypersensitivity pneumonitis are typical examples of this pattern. The third pattern is characterized by areas of low attenuation and mosaic perfusion and, in expiratory phase, by air trapping. The form of bronchiolitis characteristically associated with these alterations is constrictive bronchiolitis, although cases in which inflammatory polyps involve only the membranous bronchioles may give origin to the same radiologic alterations. Mixed features (so called ‘‘head cheese pattern’’ with coexistence of centrilobular nodules, ground-glass opacification, and mosaic oligemia) are observed mainly in infectious bronchiolitis and hypersensitivity pneumonitis. Episodes of spontaneous pneumothorax, pneumomediastinum, and interstitial emphysema may be a clinicoradiologic manifestation of obliterative bronchiolitis mainly in subjects following hematopoietic stem cell transplantation (9).
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Ventilation-perfusion scans may be helpful since a markedly abnormal pattern of patchy, matched ventilation and perfusion defects is often seen. Magnetic resonance imaging with hyperpolarized 3He, 99mTc-Technegas, and 133Xe dynamic SPECT have made possible the noninvasive reproducible measurement of structure-function relationship in small airways (10).
V.
Pulmonary Function Impairment
Because the cross-sectional area of small airways is much more greater than that of the central airways, it was believed that bronchioles contributed little to total airflow resistance, although more recent data indicate their contribution is possibly half again greater than that originally suggested, amounting to 30% to 40% of total resistance (11). Physiological measurements of small airways function include vital capacity (VC) and flow rates at low lung volumes (MMEF 25%) (4,12). VC may be reduced in spite of a normal forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF). VC is not specific and maximum expiratory flow rates at low lung volumes probably better reflect small airway function. These last tests are however technically harder to perform and show considerable variability as they are dependent on absolute lung volume, making results difficult to interpret. A reduction in gas transfer coefficient (TLCO) as well as hypoxemia may be recognized late in the disease or in forms involving the adjacent alveolar structures (4). Recently exhaled nitric oxide (eNO) measurements were shown to provide useful information for discriminating patients with unstable bronchiolitis obliterans syndrome (BOS) from those with stable BOS. The findings suggested that, in patients with BOS, a raised eNO fraction may predict the development of functional impairment during long-term follow-up. Therefore, measurements of eNO appear to be an accurate test for the early diagnosis of BOS (13).
VI.
A.
Specific Clinicopathologic Forms of Diseases Involving the Small Conducting and/or Transitional Airways BO Secondary to Irritants inhalation
Inhaled gases and fumes can produce severe bronchiolitis with acute ulceration and inflammation followed by occlusion of the airways by loose connective tissue and finally by complete stenosis and occlusion. Functionally significant bronchiolitis has been reported after exposure to ammonia, oxides of nitrogen, fire smoke, hydrogen selenide, phosgene, hydrogen bromide, manganese sulfate, sulfur dioxide, chlorine gas, thionyl chloride, grain dust, flavoring agents in popcorn production workers, free base cocaine, and exposure to incinerator
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fly ash. A peculiar form of lymphocytic bronchiolitis and peribronchiolitis with lymphoid hyperplasia was reported in workers at nylon flock facilities (4). Symptoms of obstructive lung function and bronchiolitis are experienced by workers in the poultry and swine confinement industries. It is likely that many more agents can produce this condition. The distribution and extent of the lung injury depends on the concentration of the agent, duration of exposure, route and pattern of breathing, solubility and biologic reactivity of the agent, and biologic individual susceptibility. The typical clinical course following toxic fume exposure consists of three phases: an acute onset, with upper respiratory symptoms, and sometimes, pulmonary edema, a latent period, and finally an irreversible obstructive, mixed, or restrictive physiological picture with dyspnea and cough. Physical examination reveals dry crackles over the lower lobes, particularly in inspiration, and a midexpiratory squeak. Chest radiographs are normal or show hyperinflation and air trapping. Bronchiectasis may coexist. In a series of Iranian wartime mustard gas–exposed victims along with expiratory air trapping, HRCT scan also documented tracheobronchomalacia (14). Histologically there is a pure constrictive bronchiolitis. A 1992 study of 20 patients with silo filler’s disease in New York (15) confirmed that the irreversible constrictive bronchiolitis lesion is rare; however, the mortality from the acute process remains high, 20% died within the first 24 hours from acute alveolar injury and massive pulmonary edema. The prognosis is poor, as steroids seem to have no beneficial effects (16). Bronchodilators are occasionally helpful and methylene blue should be administered in case of presence of methemoglonemia. B.
Infectious and Postinfectious Bronchiolitis in Adults
BO or constrictive bronchiolitis is a rare form of chronic obstructive lung disease in adults that follows an insult to the lower respiratory tract. It is a lesion of the membranous and respiratory bronchioles that begins with bronchiolar epithelial injury, followed by an inflammatory reaction resulting in progressive concentric narrowing with distortion and obliteration of the small airways. Bronchiolitis following a severe lower tract infection is the most common form of BO reported. Several pathogenetic agents have been associated with the development of postinfectious BO (PBO), in particular, as a manifestation of an acute infection in adults may be due to viruses, more frequently in immunocompromised hosts or in elder people. Cases due to Adenovirus, Herpes simplex, Respiratory syncitial virus, Cytomegalovirus, Mycoplasma pneumoniae, acid fast Mycobacteria, Bordetella pertussis, influenzavirus have been described. Uncommon causes of infectious bronchiolitis are Legionella pneumophila, Haemophilus influenzae, Klebsiella pneumoniae, Serratia marcescens, Aspergillus or Mucor, Nocardia asteroides, Rubella, Measles, Enteroviruses, HIV, Malaria, Cryptosporidium species, and Microsporidia (Encephalitozoon hellem). Typical inclusions or
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identification of the offending microorganism with more sophisticated techniques in serum, throat swabs, tracheal aspirates, bronchoalveolar lavage fluid, or lung biopsies can help address a definitive diagnosis. Histologically nonspecific, acute or chronic, or granulomatous cellular bronchiolitis, is observed in the majority of cases. Follicular bronchiolitis is reported especially in HIV patients. Clinically, patients may have fever, cough, sore throat, sinusitis and rhinitis, dyspnea, cough, hypoxemia, and wheezing. The term ‘‘hot tub lung’’ has been used to describe cases of hypersensitivity pneumonitis-like syndrome in patients exposed primarily to aerosolized Mycobacterium avium complex (17). The majority of patients have dyspnea, cough, and fever. HRCT scan shows ground-glass opacities and nodules. Pulmonary function tests document mainly an obstructive impairment. Bronchoalveolar lavage (BAL) profile is characterized by a lymphocytosis with elevated CD4/CD8 ratio. Histology is characterized by exuberant, nonnecrotizing bronchiolocentric granulomatous inflammation (usually with well formed granulomas) and the presence of patchy chronic interstitial pneumonia and organization. The development of pulmonary hypersensitivity syndrome in response to other mycobacterial species, including BCG in intravesical therapy for bladder carcinoma and Mycobacterium immunogenum in contaminated metal working fluid workers, have been reported. Therapy includes steroids and antimycobacterial drugs. However, recently it has been shown that antimycobacterial therapy does not appear to be required in the management of this disease. Although corticosteroids may be helpful in the treatment of severely affected patients, others can be managed by avoidance of additional exposure alone (17). Only sporadic cases of fixed airflow obstruction with mosaic oligoemia and expiratory air trapping secondary to infections have been reported in the adult population. The agents that have been associated with bronchiolitis include viruses (Adenovirus type 3, 7, and 21, Rubella, Measles, Influenza, Parainfluenza, Cytomegalovirus, and Mycoplasma pneumoniae). Constrictive bronchiolitis is the most common histopathologic pattern found following infection; bronchiolitis with inflammatory polyps has been more rarely reported. ‘‘Swyer-James syndrome’’ (also termed MacLeod’s syndrome, unilateral or lobar emphysema, and unilateral hyperlucent lung) is a peculiar variant of PBO. It usually develops as a sequel of viral pulmonary infection in infancy or early childhood and leads to alveolar destruction and obliterative bronchiolitis. Nonviral cases include infections such as Mycoplasma pneumonia, tuberculosis, pertussis, and noninfectious causes such as aspirated foreign bodies, irradiation, and hydrocarbon ingestion. Radiologically, chest X-ray findings are nonspecific, whereas HRCT scan provided a better definition of the extent and distribution of the disease. BAL analysis may document an inflammation (with a predominance of neutrophils and CD8þ cells) also in clinically stable patients, suggesting that there is an ongoing active process (4). It has been suggested that the accumulation of neutrophils and the expansion of CD8þ cells may have a role in the
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development of pulmonary impairment after the initial lung infection and in the clinical course of the disease. C.
Drug-Induced BO
Gold compounds (18), penicillamine (19), lomustine (20), and tiopronin (21) have been associated with pure BO. In the cases in which an open lung biopsy was performed a concentric constrictive bronchiolitis was identified. Most of the patients reported were women. Dyspnea, cough and wheezing, and a highpitched inspiratory sqeak were the symptoms and signs more frequently described. Pulmonary function tests showed a fixed obstruction on expiration. Chest X-ray films were normal or showed a mild hyperinflation. These patients were also affected by rheumatoid arthritis so that a conclusive proof of an association between these drugs and constrictive bronchiolitis is lacking. This form of bronchiolitis may be characterized by a rapidly deteriorating course and pulmonary insufficiency. An outbreak of rapidly progressive respiratory distress associated with consumption of uncooked Sauropus androgynus, a vegetable, has been recently reported in Taiwan. Sauropus Androgynus is claimed to be effective in weight control (22). Most of the patients were young or middle aged women. Respiratory symptoms (cough and dyspnea) occurred about ten weeks after ingesting the vegetable juice. Other symptoms included dizziness, insomnia, and palpitations. Laboratory tests were normal. Although chest radiographs were essentially normal, HRCT scan of lung revealed bilateral bronchiolar wall thickening and dilatation and low attenuation areas with air trapping. Pulmonary function tests disclosed severe obstructive impairment with no response to bronchodilators. A moderate to severe reduction in diffusion capacity was also observed. Histopathologic changes ranged from light bronchiolar inflammation and fibrosis to severe constrictive bronchiolitis. Areas of BO-organizing pneumonia or of bronchiolitis with inflammatory polyps were also reported. Segmental ischemic necrosis of the small bronchi has also been reported. Neutrophils and, to a lesser extent, eosinophils were increased in the lavage fluid. Lung transplantation is the only effective treatment reported. D.
Connective Vascular Diseases and Bronchiolitis
Connective tissue BO occurs most commonly in women with rheumatoid arthritis and has a particularly poor prognosis, often a fatal outcome within three years (23,24). This airflow lesion has also been reported in other connective tissue disorders (but less frequently) including lupus erythematosus, ankylosing spondylitis, Sjogren’s syndrome, and scleroderma. This topic is deeply discussed elsewhere in this book by Dr. Strange.
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IBD-Associated BO
Pulmonary complications occur in an estimated 0.21% of patients with IBD (25,26), ulcerative colitis being most often associated with lung problems. The most common presentation is large airway disease, such as tracheobronchitis, chronic bronchitis, or bronchiectasis. Bronchiolitis is extremely rare. Cellular bronchiolitis with intraluminal accumulation of neutrophils and chronic inflammation in the wall, cicatricial bronchiolitis, and epithelial ulceration, aspects similar to that described in diffuse panbronchiolitis, have been reported in patients with ulcerative colitis. In Crohn’s diseases the histopathologic spectrum is wider, having features of granulomatous bronchiolitis associated with necrobiotic pulmonary nodules have been reported (27). Chronologically, small airway involvement can develop at any time during the course of IBD. In about 80% of cases, however, the onset of pulmonary symptoms follows the diagnosis of IBD by months to years. Patients may have cough, dyspnea, or systemic symptoms such as fever or asthenia. The spectrum of HRCT scan changes is broad; bronchiectasis, thickening of the bronchioles walls, mosaic perfusion and air trapping findings, centrilobular nodules, and branching linear opacities (tree in bud appearance) have been reported. In patients with IBD, there is a dysfunction of the small airways despite their normal PFTs (28). This observation, along with the observed impairment of the lung transfer factor for carbon monoxide shown to be present in the active phase of the disease, supports the hypothesis that a subclinical inflammation in both the airways and the lungs accompanies the main inflammation in the bowel. Inhaled or oral steroids are the recommended treatments. F.
Paraneoplastic Pemphigus and Constrictive Bronchiolitis
Paraneoplastic pemphigus is an autoimmune disease that accompanies more frequently an overt or occult malignant non-Hodgkin’s lymphoma and causes blisters (29). It has also been reported in patients with other neoplasms (chronic lymphocytic leukemia, Castleman’s disease, thymoma, retroperitoneal sarcoma, Waldenstro¨m macroglobulinemia). It is characterized by the presence of IgG autoantibodies that react against desmosomal and hemidesmosomal plakin proteins, desmosomal transmembrane proteins, and an unidentified 170-kd antigen. A recently recognized complication in about 30% of patients is respiratory failure with clinical features of BO (30). A study suggests that constrictive BO associated with paraneoplastic pemphigus may be one of the facets of autoimmune responses associated with malignant lymphomas (31). The large airways appear to be involved early in the course of the disease with subglottic stenosis and diffuse mucosal thickening and blisters. Acantholysis of differentiated ciliary epithelium from the underlying basilar cells is evident in endobronchial biopsy specimens. Later involvement of small airways leads to respiratory failure and death. Evidence to date indicates that autoantibodies directed against plakin proteins may be responsible of acantholytic changes in
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the bronchial/bronchiolar epithelium observed in these cases. A case of mucous membrane pemphygoid with fatal bronchial/bronchiolar involvement has been reported recently (32). G.
Neuroendocrine Cell Hyperplasia with Bronchiolar Fibrosis
In 1992, Aguayo et al. (6,33) reported six patients, all nonsmokers, with moderate chronic airflow obstruction, three of whom had peripheral carcinoid tumors and three had progressive dyspnea. All the patients were nonsmoker women and had foci of neuroendocrine hyperplasia around bronchioles along with partial or total occlusion of their lumen by fibrous tissue. Recently, Davies et al. (34) reviewed 19 patients diagnosed with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia between 1992 and 2006. Most patients were women (n ¼ 15) and nonsmokers (n ¼ 16). Clinical presentation was either with symptomatic pulmonary disease (group 1; n ¼ 9) or as an incidental finding during investigation for another disorder, most frequently malignant disease (group 2; n ¼ 10). In group 1, cough and dyspnea were the most frequent symptoms, with an average duration of 8.6 years before diagnosis. Both groups showed mainly stable disease without treatment, although one patient progressed to severe airflow obstruction and one was diagnosed at single lung transplantation. Mosaic oligoemia with nodule(s) was the typical pattern of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia on high-resolution computed tomography, but one case had normal imaging despite airflow obstruction. Lung function tests showed obstructive (n ¼ 8), mixed (n ¼ 3) or normal (n ¼ 5, all in group 2) physiology. Two patients underwent a BAL and showed a lymphocytosis (30%) with mild chronic bronchiolitis being seen in all biopsies. Tumorlets and associated typical carcinoids (n ¼ 9) showed weak positivity for thyroid transcription factor-1. Three patients had atypical carcinoids, one with multiple endocrine neoplasia type 1 syndrome. In patients with carcinoid tumors, neuroendocrine cell hyperplasia has been considered to represent a preneoplastic lesion (4,34). Fibrous obliteration of the airways is postulated to be associated with the actions of certain peptide secretory products, such as bombesin, of the proliferating neuroendocrine cells (35). H.
Diffuse Panbronchiolitis
DPB is an idiopathic inflammatory disease (5), well recognized in Japan and principally affecting the respiratory bronchioles, causing a progressive, suppurative, and severe obstructive respiratory disorder. If left untreated, DPB progresses to bronchiectasis, respiratory failure, and death. It was first described in the early 1960s. Subsequently, in 1969, the disease was named DPB to distinguish it from chronic bronchitis. ‘‘Diffuse’’ refers to the distribution of the lesions throughout both lungs, and ‘‘pan-’’ refers to the involvement of inflammation in all layers of the respiratory bronchioles. HRCT findings are peculiar;
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nodular shadows are distributed in a centrilobular fashion, often extending to small, branching linear areas of attenuation (tree in bud pattern). Peripheral air trapping is usually confirmed in expiratory films. In addition, dilatation of airways and bronchial wall thickening are present. Histologically, DPB is characterized by chronic inflammation, localized mainly in the respiratory bronchioles and adjacent centrilobular regions, with characteristic interstitial accumulation of foamy histiocytes, neutrophils, and lymphocyte infiltration. The distinctive imaging and histologic features, the coexisting sinusitis, and the isolation of Haemophilus influenzae and Pseudomonas aeruginosa in the sputum enhance disease recognition. Neutrophils and T-lymphocytes, particularly CD8þ cells, together with the cytokines interleukin-8 and macrophage inflammatory protein-1, are believed to play key roles in the development of DPB. A significant improvement in the prognosis of this potentially fatal disease has been recently reported thanks to the use of long-term therapy with macrolide antibiotics, the effect of which is attributed to an anti-inflammatory and immunoregulatory action (5). 1.
Crytpogenic Bronchiolitis
When constrictive bronchiolitis occurs with no identifiable cause, it is referred to as cryptogenic constrictive bronchiolitis (36). It is rare and occurs mostly in women. Patients present with persistent cough and worsening dyspnea. Basilar inspiratory crackles may be heard on auscultation of the lungs in some patients. Progressive airway obstruction, often associated with air trapping, is seen by pulmonary function testing in the majority of affected patients. I.
Mimickers of BO
The small airways can be more or less involved in the context of specific wellknown disorders. Furthermore, the clinical and roentgenologic findings of vascular diseases can overlap with those of obstructive bronchiolitis. Asthma and chronic obstructive pulmonary disease are well-recognized diseases of both large and small airways and the most frequent mimickers of specific forms of bronchiolitis. Centrilobular ground-glass nodules and airflow obstruction may radiographically characterize subacute hypersensitivity pneumonitis. These cases are characterized histologically by cellular bronchiolitis, patchy interstitial alveolar inflammation, foamy intra-alveolar macrophages, intra-alveolar loose fibrotic buds, and poorly formed, scattered, nonnecrotizing granulomas. The definitive diagnosis is usually based on the clinical history, results of laboratory tests for serum precipitins, and BAL fluid findings of marked lymphocytosis. In a few cases, lung biopsy is required. Sarcoidosis can involve primarily the bronchi and bronchioles, causing obstruction, impairment, and wheezing. The incidence of bronchial hyperreactivity is also increased in patients with sarcoidosis.
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Carcinomatous lymphangitis has a distinctive HRCT pattern (nodular thickening of the peribronchiolar-vascular spaces and of the peripheral lobular septa) (37). However, neoplastic infiltrates associated with a desmoplastic reaction can be prominent in the peribronchiolar-vascular lymphatics and also in the lumen of the centrilobular arteries; wheezing and dyspnea are the symptoms at onset and a tree in bud pattern may be evident in the HRCT scan slides. Bronchiolocentric chronic lymphocytic leukemia and small lymphocytic lymphomas, primary in the lungs, have been reported (38,39). Thromboembolism, cellulose lung granulomatosis resulting from intravenous injection of cellulose or other filler material, and intravascular neoplastic emboli (tumor thrombotic lung microangiopathy) can all mimic obstructive bronchiolitis either for the clinical profile and for the CT scan features. J.
Practical Clinical Approach to Patients with Bronchiolitis
The clinical spectrum of bronchiolar inflammatory disorders in adults is wide. Clinical diagnosis usually is an attempt to fit a given problem into one of a series of syndromes. Specific settings are known to be associated to the onset of a bronchiolar injury and in these settings investigations are recommended also in asymptomatic patients. The presence of wheezing on auscultation, expiratory squeaks or crackles, and pulmonary function tests indicating an air flow obstruction address to consider the bronchioles as the anatomic site involved. Laboratory markers suggesting a bronchiolar lesion are an increased serum Ca 19-9, an increased ESR, or the presence of autoantibodies. The essential diagnostic step is then HRCT study with dynamic (inspiratory and expiratory) scans. The pattern of mosaic oligoemia and expiratory air trapping can be considered per se sufficient for a definitive diagnosis in specific clinical settings (post-transplanted patients, bronchiolitis due to toxic gases and fumes, and metabolic disorders). BAL is part of the armamentarium to exclude infections and to confirm a neutrophilic or mixed (neutrophils and lymphocytes) profile. Histologic documentation is however deemed useful in the other cases. Surgical lung biopsy is clinically warranted in cases of mosaic oligoemia and expiratory air trapping, as the small samples obtained by transbronchial lung biopsy (TBB) do not allow to correctly classify the pathologic pattern. In cases of tree in bud pattern, alveolar/ground-glass attenuation, or mixed pattern, transbronchial lung biopsy, and BAL are the first choice as infections (tuberculosis, mycoses, viruses, and lobular bacterial pneumonia), neoplasms (bronchioloalveolar cell carcinoma, lymphomyeloproliferative disorders, and carcinomatous lymphangitis), or cryptogenic inflammatory lung disorders (organizing pneumonia, eosinophilic pneumonias, hypersensitivity pneumonitis, Langerhans cell granulomatosis, and sarcoidosis) that may mimick bronchiolitis can have a definitive diagnosis in this way. As ANCA-associated vasculitides can have clinical, roentgenologic, and
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Figure 3 Practical approach to bronchiolitis.
histologic overlaps with bronchiolitis, serum ANCA titers should always be part of the laboratory tests performed in patients with supposed bronchiolitis. A practical diagnostic algorithm is shown in Figure 3. References 1. Colby TV. Bronchiolitis. Pathologic considerations. Am J Clin Pathol 1998; 109:101. 2. Muller NL, Miller RR. Diseases of the bronchioles: CT and histopathologic findings. Radiology 1995; 196:3–12. 3. Ryu JH, Myers JL, Swensen SJ. Bronchiolar disorders. Am J Respir Crit Care Med 2003; 168:1277–1292. 4. Poletti V, Chilosi M, Zompatori M. Bronchiolitis. In: Gibson GJ, Geddes DM, Costabel U, et al., eds. Respiratory Medicine. Saunders 2003; 2:1526–1539. 5. Poletti V, Casoni G, Chilosi M, et al. Diffuse panbronchiolitis. Eur Respir J 2006; 28:862–871. 6. Aguayo SM, Miller YE, Waldron JA, et al. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med 1992; 327:1285.
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7. Pipavath SJ, Lynch DA, Cool C, et al. Radiologic and pathologic features of bronchiolitis. AJR Am J Roentgenol 2005; 185:354–363. 8. Hansell DM, Rubens MB, Padley SP, et al. Obliterative bronchiolitis: individual CT signs of small airways disease and functional correlation. Radiology 1997; 203: 721–726. 9. Sverzellati N, Zompatori M, Poletti V, et al. Small chronic pneumothoraces and pulmonary parenchymal abnormalities after bone marrow transplantation. J Thorac Imaging 2007; 22:230–234. 10. Yokoe K, Satoh K, Yamamoto Y, et al. Usefulness of 99mTc-Technegas and 133Xe dynamic SPECT in ventilatory impairment. Nucl Med Commun 2006; 27:887–892. 11. Macklem PT, Mead J. Resistence of central and peripheral airways measured by a retrograde catheter. J Appl Physiol 1967; 22:395–401. 12. Evans DJ, Grenn M. Small airways: a time to revisit? Thorax 1998; 53:629. 13. Brugiere O, Thabut G, Mal H, et al. Exhaled NO may predict the decline in lung function in bronchiolitis obliterans syndrome. Eur Respir J 2005; 25:813–819. 14. Ghanei M, Moqadam FA, Mohammad MM, et al. Tracheobronchomalacia and air trapping following mustard gas exposure. Am J Respir Crit Care Med 2006; 173:304. 15. Zwemer FL, Pratt DS, May JJ. Silo filler’s disease in New York State. Am Rev Respir Dis 1992; 146:650–653. 16. Mann JM, Sha KK, Kline G, et al. World Trade Center dyspnea: bronchiolitis obliterans with functional improvement: a case report. Am J Ind Med 2005; 48:225–229. 17. Hanak V, Kalra S, Aksamit TR, et al. Hot tub lung: presenting features and clinical course of 21 patients. Respir Med 2006; 100:610–615. 18. Tomioka R, King TE Jr. Gold-induced pulmonary disease: clinical features, outcome, and differentiation from rheumatoid lung disease. Am J Respir Crit Care Med 1997; 155:1011–1020. 19. Boehler A, Vogt P, Speich R, et al. Bronchiolitis obliterans in a patient with localized scleroderma treated with D-penicillamine. Eur Respir J 1996; 9:1317–1319. 20. Camus P, Costabel U. Drug-induced respiratory disease in patients with hematological diseases. Semin Respir Crit Care Med 2005; 26:458–481. 21. Demaziere A, Maugars Y, Chollet S, et al. Non-fatal bronchiolitis obliterans possibly associated with tiopronin. A case report with long-term follow-up. Br J Rheumatol 1993; 32:172–174. 22. Wang JS, Tseng HH, Lai RS, et al. Sauropus androgynus-constrictive obliterative bronchitis/bronchiolitis: histopathological study of penumonectomy and biopsy specimens with emphasis on the inflammatory process and disease progression. Histopathology 2000; 37:402–410. 23. Herzog C, Miller R, Hoidal J. Bronchiolitis and rheumatoid arthritis. Am Rev Respir Dis 1981; 124:636–639. 24. Perez T, Remy-Jardin M, Cortet B. Airways involvement in rheumatoid arthritis. Am J Respir Crit Care Med 1998; 157:1658–1665. 25. Mahadeva R, Walsh G, Flower CD, et al. Clinical and radiological characteristics of lung disease in inflammatory bowel disease. Eur Respir J 2000; 15:41. 26. Camus P, Piard F, Ashcroft T, et al. The lung in inflammatory bowel disease. Medicine (Baltimore) 1993; 72:151. 27. Freeman HJ, Davis JE, Prest ME, et al. Granulomatous bronchiolitis with necrobiotic pulmonary nodules in Crohn’s disease. Can J Gastroenterol 2004; 18:687–690.
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28. Tzanakis N, Samiou M, Bouros D, et al. Small airways function in patients with inflammatory bowel disease. Am J Respir Crit Care Med 1998; 157:382–386. 29. Nguyen VT, Ndoye A, Bassler KD, et al. Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus. Arch Dermatol 2001; 137:193–206. 30. Nousari HC, Deterding R, Wojtczack H, et al. The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med 1999; 340:1406–1410. 31. Hasegawa Y, Shimokata K, Ichiyama S, et al. Constrictive bronchiolitis obliterans and paraneoplastic pemphigus. Eur Respir J 1999; 13:934–937. 32. Gamm DG, Harris A, Mehram RJ, et al. Mucous membrane pemphigoid with fatal bronchial involvement in a seventeen-year-old girl. Cornea 2006; 25:474–478. 33. Miller RR, Muller NL. Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumors. Am J Surg Pathol 1995; 19:653. 34. Davies SJ, Gosney JR, Hansell DM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax. 2007; 62:248–252. 35. Cohen AJ, King TE, Gilman LB, et al. High expression of neutral endopeptidase in idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells. Am J Respir Crit Care Med 1998; 158:1593–1599. 36. Kraft M, Mortenson RL, Colby TV, et al. Cryptogenic constrictive bronchiolitis: a clinicopathologic study. Am Rev Respir Dis 1993; 148:1093–1101. 37. Zompatori M, Bna C, Poletti V, et al. Diagnostic imaging of diffuse infiltrative disease of the lung. Respiration. 2004; 71:4–19. 38. Trisolini R, Lazzari Agli L, Poletti V. Bronchiolocentric pulmonary involvement due to chronic lymphocytic leukemia. Haematologica 2000; 85:1097. 39. Palosaari DE, Colby TV. Bronchiolocentric chronic lymphocytic leukemia. Cancer 1986; 58:1695–1698.
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21 Obliterative Bronchiolitis Following Lung or Heart-Lung Transplantation
GEERT M. VERLEDEN, LIEVEN J. DUPONT, BART M. VANAUDENAERDE, ROBIN VOS, and E. M. VAN RAEMDONCK University Hospital Gasthuisberg, Leuven, Belgium
I.
Introduction
Lung (L) and heart-lung (HL) transplantation (Tx) is the ultimate therapeutic option for carefully selected patients with end-stage heart-lung or lung disease, such as Eisenmenger’s complex, emphysema, cystic fibrosis, and interstitial lung diseases. Although the procedure is mainly performed to alleviate symptoms and to improve quality of life, most patients experience an improved survival compared to non-transplanted patients, with a mean actuarial five-year survival of 50% for lung and 44% for heart-lung transplants according to the International Society for Heart and lung Transplantation (ISHLT) database (1). In the author’s lung transplant program, the five-year survival increased from 50% in the initial experience to about 75% in more recent years (p < 0.0001, Fig. 1). This improved survival is mainly due to better operative and perioperative outcomes, thanks to improved surgical techniques, perioperative anaesthetic and intensive care management and better understanding, and availability of immunosuppressive drugs. Obliterative bronchiolitis (OB) or bronchiolitis obliterans syndrome (BOS), the clinical correlate of OB, remains the leading cause of morbidity and late mortality after HL or LTx, accounting for about 30% of late mortality (1). The 543
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Figure 1 Actuarial survival of lung transplantation only (excluding heart-lung transplantation) in the University hospital Leuven, Belgium according to two different time periods. The first period (from 1991 until December 2000, n ¼ 150) has a significantly inferior survival compared to the second period from January 2001 until June 2007 (n ¼ 191).
prevalence of OB/BOS after LTx has not changed significantly, remaining at 40% to 50% five years after transplantation (1). However, some patients with BOS may survive for prolonged periods, which in part may reflect introduction of azithromycin therapy (discussed in detail later). In this chapter, we review the incidence, risk factors, clinical features, diagnosis and treatment of OB/BOS, with emphasis on the potential role of newer macrolide antibiotics.
II.
Prevalence and Clinical Presentation of OB/BOS
In the recent ISHLT registry report, the one-, three-, and five-year prevalence rates of OB in adult lung transplant recipients (LTRs) followed-up between April 1994 and June 2005 were 10%, 30%, and 44%, respectively (1), whereas the one-, three- and five-year mortality rates from BOS were 5%, 26%, and 29%, respectively (1). OB/BOS is the single most important factor responsible for late mortality after lung transplantation, and affects 33% of LTRs who survive more than five years (1). OB was initially described in 1987 in a patient who developed a progressive decline in forced expiratory volume in one second (FEV1) after a HLTx (2). OB/BOS is characterized by a reduction in pulmonary function parameters,
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most specifically in FEV1, and forced expiratory flow FEF25–75, attributed to irreversible airways obstruction. Inhaled short-acting b2-agonists produce no significant reversibility. The onset of symptoms is usually insidious, with progressive exertional dyspnea, often accompanied by cough. Sometimes respiratory tract infections [cytomegalovirus (CMV) or non-CMV viral infections] or an acute immunological event (e.g., acute rejection) seem to have triggered the onset of OB (3), with acute dyspnea and wheezing. After antirejection treatment there may be some recovery of FEV1, but after a short time period (sometimes only a couple of weeks), progressive airflow obstruction ensues, which may plateau at very low volumes (Fig. 2, patient A). This clinical presentation of OB may have a poor prognosis leading to death of the patient in a few months, and is recalcitrant to medical treatment. In other patients, progression of BOS is slow
Figure 2 (A). Typical FEV1 evolution in a patient with late acute BOS. After a very stable period of several years, there is a documented acute rejection episode (arrow), with some improvement of the FEV1 after classical treatment, however, quickly followed by a very rapid decline in the FEV1, indicative of fBOS. (B). Natural evolution of FEV1 in a patient with slowly progressing BOS and biopsy-proven OB. During the last months of evolution, there appears to be a spontaneous arrest in the FEV1 decline. This is compatible with the NRAD phenotype, left untreated and leading to pure OB at the end. (C). Another patient with BOS, who has a spontaneous arrest of the FEV1 decline, with a plateau, reached after several months of evolution. Abbreviations: FEV1, forced expiratory volume in one second; BOS, bronchiolitis obliterans syndrome; fBOS, fibrotic BOS; OB, obliterative bronchiolitis; NRAD, neutrophilic reversible allograft dysfunction.
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and superinfections are frequent; colonization of the airways with Pseudomonas aeruginosa and Aspergillus fumigatus is common (Fig. 2, patient B). Highresolution computed tomographic (HRCT) scans of the thorax may reveal hyperinflation (air trapping), especially in the rapidly progressive patients and/or bronchiectasis and other signs of chronic infection (4). Auscultation of the lungs is often normal, but occasional rales and in later stages, squeaks may be heard, possibly pointing to a more inflammatory form of BOS. Once established, OB is usually progressive and may lead to severe airways obstruction with respiratory insufficiency and death, resulting from infectious exacerbations. In other patients, the progression may be arrested, either spontaneously or in response to treatment (Fig. 2, patient C) (5,6). Long-term survival after lung transplantation depends on the development and the severity of BOS (7). Further, OB/BOS also causes significant morbidity, loss of health-related quality of life (8,9), and constitutes a tremendous cost due to an increase in used health-care resources, in particular hospitalization and medication (10), further emphasizing the need to focus efforts on prevention of BOS to enhance the cost-effectiveness of LTx.
III.
Pathology of Chronic Rejection
OB is the accepted pathologic manifestation of chronic allograft rejection, and the current consensus is that chronic rejection causes or at least significantly contributes to the deterioration of the pulmonary function in OB/BOS (11,12). OB is essentially a scarring process affecting the small noncartilage containing airways of the lung graft, which may evolve from a chronic neutrophilic inflammation of the airways over several years or from a direct and severe injury to the epithelium of the airways, over several months directly leading to fibrosis (13). Since OB is difficult to diagnose pathologically by transbronchial biopsies, the 2001 BOS recommendations are that the pathological term ‘‘obliterative bronchiolitis’’ (bronchiolitis obliterans) should be used only when histology demonstrates dense fibrous scar tissue affecting the small airways (14). The presence of a lymphocytic submucosal infiltrate or intraluminal granulation tissue is insufficient for a diagnosis of OB. Furthermore the obliterative lesion can be defined as active when it is associated with a mononuclear cell infiltrate and inactive when inflammatory cells are absent (13). The initial pathological process appears to be a lymphocytic infiltration of the submucosa of the airways and epithelium that is known as lymphocytic bronchiolitis (15). Epithelial damage is common in both lymphocytic bronchiolitis and OB with epithelial cell necrosis leading to denudation and frank ulceration of the mucosa. The resulting inflammatory reaction involving fibroblasts and myofibroblast migration into the lumen leads to the formation of intraluminal granulation tissue often polypoid that can result in subtotal or total obliteration of the small airway (Fig. 3).
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Figure 3 (See color insert.) Typical lesion of OB in an open lung biopsy of a lung transplant patient with a progressive decline of the FEV1. The airway is entirely obliterated by a fibrous plug (arrow). Abbreviations: OB, obliterative bronchiolitis; FEV1, forced expiratory volume in one second. Source: Courtesy of Prof. E.K. Verbeken, Leuven, Belgium.
IV.
Risk Factors for Chronic Rejection
Several risk factors for the development of OB/BOS have been identified, that can be subdivided into immunological and nonimmunological risk factors. Late or recurrent/refractory acute rejection and lymphocytic bronchitis/bronchiolitis were the most convincing (16), which together with repeated A1 acute rejection, noncompliance, human leucocyte antigen (HLA) mismatches at the A locus and total HLA mismatches, constitute the immunological risk factors (17). Several nonimmunological risk factors have been proposed, although not yet widely accepted. These include CMV pneumonitis; ischemia-reperfusion injury; early nonspecific bronchial hyperresponsiveness; donor and recipient age; graft ischemic time; transplantation for primary pulmonary hypertension; GER; and bacterial/fungal/non-CMV viral infections (17). It was recently shown that transient colonization of the airways with Pseudomonads is associated with a neutrophilic inflammation of the airways (18), and that persistent colonization may predispose to the development of OB/BOS (19), suggesting that earlier and aggressive treatment to prevent airway colonization may be warranted. GER is also regarded as a nonimmunological risk factor for the development of BOS and is a reversible cause of allograft dysfunction after lung transplantation (20). Fundoplication in patients after lung transplantation, led to a significant survival difference, together with an improvement of the pulmonary function (21). These
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studies are, however, limited by their retrospective design and nonrandom patient selection, which might induce a selection bias. Additional, prospective studies are needed to corroborate these results. How GER might induce BOS is not clear, although GER (as evaluated by the presence of pepsin in bronchoalveolar lavage (BAL) fluid may be associated with acute rejection (22) and recently a correlation was found between bile acids in BAL fluid, neutrophils, interleukin-8 (IL-8), and the development of BOS (23). As a consequence, GER may exert its deleterious effect through immunological as well as nonimmunological mechanisms. V.
Pathophysiology of BOS
OB/BOS probably results from a primary insult (ischemia-reperfusion injury, acute rejection, infection, aspiration, etc.) to the airway epithelium, which may be unique and severe or rather repetitive and less severe, and immunological (HLA-antibody driven) or nonimmunological (innate and adaptive immune response). This insult upregulates dendritic cells in the epithelium, attracting more inflammatory cells (at first, lymphocytes) leading to epithelial damage and inflammation, with resultant production of chemokines and cytokines from the epithelium itself, smooth muscle cells, macrophages, and neutrophils (IL-1, -2, -4, -6, -8, -10, -12, -13, etc.). Activated neutrophils may further increase epithelial damage via the production of reactive oxygen species and metalloproteinases (24). After an initial inflammatory phase, a fibroproliferative phase occurs, driven by myriad growth factors [platelet-derived growth factor (PDGF), insulin growth factor (IGF), fibroblast growth factor (FGF), transforming growth factor-b (TGF-b), endothelin-1 (ET-1), etc.] leading to proliferation of smooth muscle cells and fibroblasts (myofibroblasts) and eventually resulting in deposition of collagen and the typical fibrous, obliterative lesions of the airways (17,25). Although initially thought that OB/BOS is characterized by a predominantly neutrophilic airways inflammation with upregulation of airway IL-8, it is becoming clear that at least two different BOS phenotypes can be distinguished, based on the results achieved with azithromycin as additive treatment for patients with BOS (13). Chronic allograft dysfunction may present as a neutrophilic airways inflammation, starting rather early after lung transplantation and characterized by an increase in the FEV1 while being treated with azithromycin, whereas the other phenotype lacks neutrophilic airway inflammation, starts rather late after transplantation and does not respond to azithromycin (26). As a consequence, the first phenotype can no longer be considered as BOS, since BOS is defined as a largely irreversible airways obstruction (14). We have therefore proposed renaming this phenotype as neutrophilic reversible allograft dysfunction (NRAD), whereas the second phenotype truly represents BOS/OB [or fibrotic BOS (fBOS)] (13). The characteristics of the two proposed phenotypes of BOS are summarized in Table 1.
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Table 1 Characteristics of the Two Phenotypes of BOS NRAD BAL Clinic Time of onset Progression Histology Radiology Effect of azithromycin
Excess neutrophils (>15%) Coarse crackles, increased sputum production Early after transplantation (<1 yr) Slow (several years) Inflammatory, ends up in fibrosis Airway wall thickening, mucus plugging, bronchiectasis Improvement of FEV1 (reversible)
Fibroproliferative BOS (fBOS) Neutrophils <15% No crackles, no sputum Later (>1 yr) Rapid (<6–12 mo) Pure fibrosis (?) Air trapping, consolidation No effect on FEV1 (irreversible)
Abbreviations: NRAD, neutrophilic reversible allograft dysfunction; fBOS, fibrotic bronchiolitis obliterans syndrome; BAL, bronchoalveolar lavage; FEV1, forced expiratory volume in one second. Source: From Ref. 13.
A schematic view of the interplay between innate and adaptive immunity and the evolution from the inflammatory to the fibroproliferative phase of OB/BOS is presented in Figure 4. VI.
Diagnosis
OB is the histological manifestation of chronic graft failure following lung transplantation, however, it is difficult to prove pathologically with transbronchial biopsies (TBB), because of their low sensitivity (28%), and specificity (75%) (17,27). As a consequence, in 1993, a committee sponsored by the ISHLT proposed a clinical definition, called BOS (28) to standardize nomenclature, to facilitate the description of the natural history of graft failure, to enhance accurate recording of outcome following transplantation, and to measure the impact of therapeutic interventions. A recent revision of the criteria divided BOS into five stages, based on pulmonary function criteria (14) (Table 2). Within each BOS category, there is a subtype a and b, based on whether there is no pathologic evidence of OB or no pathologic material for evaluation (a) or there is pathologic evidence of OB (b). Several clinical conditions that adversely affect lung function have to be excluded before diagnosing BOS (e.g., infection, acute rejection, bronchial anastomotic problems, disease recurrence, aging, native lung hyperinflation, disease progression, and factors that induce a restrictive defect such as pleural disease, steroid myopathy, pain, etc.) (14). In the 2001 revision of the BOS criteria (14), the FEF25–75 was also included in the staging parameters, since this parameter declines earlier than the FEV1 (29). This led to the introduction of a new sub-category referred to as ‘‘potential’’ BOS
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Figure 4 Possible pathophysiologic events involving innate and adaptive immunity, leading to BOS/OB. Repeat milder stimuli to the respiratory epithelium (such as for instance GER, colonization, etc.) may lead to stimulation of innate immunity ending up in neutrophilic airway inflammation, which may be reversible upon treatment with azithromycin. However, if left untreated, chronic neutrophilic inflammation and increased oxidative stress may further stimulate fibroblast activation, epithelial to mesenchymal transition, with migration of (myo)fibroblasts, leading to fibrosis of the airway wall and fibrotic plugs in the airways, typically for OB. A more severe epithelial injury (as for instance in acute rejection and CMV infection) may directly lead to fibroblast activation and OB in a short time period, without any neutrophils being present in the airways. Abbreviations: BOS, bronchiolitis obliterans syndrome; OB, obliterative bronchiolitis; GER, gastroesophageal reflux; CMV, cytomegalovirus. Table 2 The BOS classification, as percentage of the best postoperative value (14) BOS stage
FEV1/FEF25–75a (% of baseline)
0 Potential BOS 1 2 3
FEV1 FEV1 FEV1 FEV1 FEV1
> 90% and FEF25–75 > 75% 81–90% and/or FEF25–75 < 76% 66–80% 51–65% < 50%
a Best postoperative FEV1 and FEF25–75 is defined as the average of two postoperative best measurements, three to six weeks apart. Abbreviations: BOS, bronchiolitis obliterans syndrome; FEV1, forced expiratory volume in one second; FEF, forced expiratory flow.
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stage (BOS 0-p). This new classification increased the sensitivity of the physiological change for the diagnosis of BOS but this has been of dubious value. The FEV1 criteria for BOS 0-p was a reasonable predictor of BOS stage 1 since 57% of bilateral lung transplant (BLT) recipients with BOS 0-p (defined by the FEV1 stage) progressed to stage 1. By contrast, only 37% of BLT recipients with BOS stage 0-p (based upon the FEF25–75 criteria) progressed to stage 1 (30). Therefore, reaching BOS stage 0-p should heighten vigilance for possible evolution to higher stages, but does not reliably predict the further decline of pulmonary function. As a consequence, surrogate markers have been evaluated to diagnose OB. These include HRCT scanning (to assess the presence of air trapping and/or bronchiectasis) and indices of ventilation (helium slope), and exhaled nitric oxide (FENO). These surrogate markers are promising, but are not sufficiently sensitive or specific to allow an adequate and earlier diagnosis of OB/BOS. Recently, a prospective study by Van Muylem et al. evaluated FENO, exhaled carbon monoxide (CO) and helium slope (31). The helium slope had better sensitivity than exhaled NO and CO for detecting BOS stages 0-p and 1. Exhaled biomarkers have high negative predictive values, but low specificity and low positive predictive values (31). These markers are not available in most centers, but may play an adjunctive role in selected patients.
VII.
Treatment
Unfortunately, there is a paucity of double-blind, randomized studies investigating the impact of interventions to prevent or treat BOS (32). Therefore, it is difficult to define whether any intervention reflects a true effect on the FEV1 evolution or rather constitutes the natural history of OB/BOS. Treatment may therefore consist in a combination of preventing the disease and pharmacological intervention once OB/BOS is diagnosed. Acute rejection during the first months after transplantation, refractory and recurrent acute rejection are among the major risk factors for OB/BOS. Several studies have examined the effect of treating refractory acute rejection and recurrent acute rejection episodes, hoping to reduce the prevalence of OB/BOS. There is some evidence that initial therapy with either mycophenolate mofetil (MMF) (33–35) or tacrolimus (36–38) instead of azathioprine and cyclosporine, respectively, or induction therapy with cytolytic agents (rATG or OKT3) (39) and IL-2 receptor blockers (40) might reduce the incidence of acute rejections but the impact on the development of chronic allograft dysfunction is not clear. Other strategies that have been used to treat (recurrent) acute rejection and BOS are total lymphoid irradiation (TLI), nebulized budesonide, extracorporeal photochemotherapy (ECP), ganciclovir prophylaxis and methotrexate, with variable results (6,41). Most of the recent studies have investigated the role of changing the maintenance immunosuppressive regimen to treat BOS, once the diagnosis is confirmed. A sentinel publication in 1987 noted that the addition of azathioprine
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improved the rate of decline in FEF25–75 in HLTx patients with OB (2). Since then, several drugs and experimental therapies have been investigated. Several open, nonrandomized studies showed that switching from cyclosporine to tacrolimus arrested the decline of the FEV1 in 50% to 90% of patients with progressive OB/BO; results were even better when the switch is performed earlier in the disease evolution (6). Similar results were cited with switching from azathioprine to MMF (6). Anecdotal responses have been cited with methotrexate (41), cyclophosphamide (42) and cytolytic therapy (43) but data are limited. The only double-blind placebo-controlled study with addition of inhaled steroids demonstrated no effect (44). By contrast, aerosolized cyclosporine has a promise for preventing OB/BOS, although the results only come from one group (45) and have been much criticized (46). Sirolimus and everolimus are new antiproliferative drugs that have successfully been used after liver and kidney transplantation. However, little data are available regarding the treatment of BOS with these therapies in lung transplantation. The available data suggests that addition of rapamycin may arrest the decline of FEV1 and may, at least in some patients, improve the FEV1 (47,48). In one recent study, everolimus seemed to prevent the decline in FEV1, at least one year after the introduction, but this effect was lost in the next year later (49). TLI and ECP may also reduce the speed of FEV1 decline, without producing major side effects (50,51). Recent experience with neomacrolide antibiotics (e.g., azithromycin) suggests benefit in a subset of lung transplant recipients (LTRs) with OB/BOS. Three open (nonrandomized) studies found that azithromycin improved the FEV1 in about 40% of LTRs in different stages of BOS, whereas another study demonstrated no effect on the FEV1 (52). In the first study, Gerhardt et al. added azithromycin (250 mg, three times a week) in six LTRs with BOS and showed a significant improvement of the FEV1 (þ17.1% or an absolute increase of 0.5 L) after a mean follow-up of 13.7 weeks (53). This study was corroborated by Verleden et al. (54) and Yates et al. (55), who also reported an increase in FEV1 of about 15% to 18% in half of the treated patients. These studies are the first to show a significant improvement of the FEV1 in BOS patients with medical treatment. In one LTR with long-standing BOS, azithromycin resulted not only in improved pulmonary function, but also significant amelioration of bronchiectasis on CT scan (56). The possible mechanisms of action of azithromycin in BOS patients are unknown, but several hypotheses have been put forward (57) including inhibition of the transcription of quorum sensing genes, which may prevent production of tissue-damaging proteins and which have indeed been detected in clinically stable LTRs without any signs of infection (58). Macrolides may also have a positive effect on GER since they are motilin agonists; and an anti-inflammatory effect involving neutrophils which are found in increased amounts in the BAL fluid of some but not all patients with BOS (28). In favor of this latter mechanism, we recently demonstrated that azithromycin reduced airway neutrophilia and IL-8 in
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patients with OB/BOS (28). More importantly, the improvement in FEV1 three months after adding azithromycin to the existing immunosuppressive treatment correlated with the initial BAL neutrophilia (28). This decrease in BAL neutrophilia with azithromycin may be realized via IL-17, which has been implicated in the pathophysiology of acute and chronic rejection (59). IL-17 stimulates IL-8 production from epithelial and airway smooth muscle cells (60,61), resulting in neutrophil recruitment. We showed that azithromycin inhibited the IL-17induced production of IL-8 in human airway smooth muscle cells in vitro in a concentration-dependent fashion. The mechanisms included inhibition of different mitogen-activated protein (MAP) kinases as well as antioxidative effects (62). Therefore, we believe that azithromycin exerts its effect by interfering with the chronic, IL-8 driven neutrophilic inflammation in the airways of patients with BOS, which explains why only patients with neutrophilic airway inflammation have a favorable response (28). These results showing the additive value of azithromycin in the treatment of some patients with BOS, lead to a new concept of phenotyping BOS as previously explained (57). Selected patients with BOS failing medical therapy and with progressive deterioration in FEV1 may be candidates for retransplantation. In the recent ISHLT registry, only 1.1% of all lung transplantations are retransplants for BOS (1). However, in single centers this number may be higher. In our own program there were nine retransplantations for end-stage BOS out of 393 lung transplant procedures (2.3%). In the Hannover experience, 8.5% of lung transplants were retransplantations (for end-stage OB/BOS, acute graft failure, or airway complications) (63). In the largest cohort reported (230 retransplantations from 47 lung transplant programs), 146 were performed for chronic rejection. The overall actuarial survival of retransplantation was 47% at one year (64), which is substantially worse than first transplants (1). However, in the more recent series from Hannover, survival rates for retransplantation for BOS were 78% and 62% after one and five years, respectively (63). The prevalence of chronic rejection after retransplantation for BOS was comparable to first transplants. In general, the best intermediate-term functional results of retransplantation occurred in more experienced centres, in nonventilated patients and in patients undergoing retransplantation more than 2 years after the first transplantation (64). VIII.
Conclusion
Lung transplantation has come of age but the development of chronic allograft dysfunction (BOS) remains the leading cause of late mortality. Recent new insights in pathophysiology and treatment with azithromycin have raised new hopes for patients suffering from this condition. It is our belief that these new concepts may have an impact on the prevalence of OB/BOS and may improve long-term survival, but scientific proof is still lacking.
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19. Vos R, Vanaudenaerde BM, Geudens N, et al. Pseudomonal airway colonization: a risk factor for BOS after lung transplantation? Eur Respir J 2008; Feb 6; [Epub ahead of print]. 20. Palmer SM, Miralles AP, Howell DN, et al. Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation. Chest 2000; 118:1214–1217. 21. Cantu E III, Appel JZ III, Hartwig MG, et al. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease. Ann Thorac Surg 2004; 78:1142–1151. 22. Stovold R, Forrest IA, Corris PA, et al. Pepsin, a biomarker of gastric aspiration in lung allografts: a putative association with rejection. Am J Respir Crit Care Med 2007; 175:1298–1303. 23. D’Ovidio F, Mura M, Tsang M, et al. Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation. J Thorac Cardiovasc Surg 2005; 129:1144–1152. 24. Smith GN, Mickler EA, Payne KK, et al. Lung transplant metalloproteinase levels are elevated prior to bronchiolitis obliterans syndrome. Am J Transplant 2007; 7:1856–1861. 25. Boehler A, Estenne M. Post-transplant bronchiolitis obliterans. Eur Respir J 2003; 22:1007–1018. 26. Verleden GM, Vanaudenaerde BM, Dupont LJ, et al. Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2006; 174:566–570. 27. Kramer MR, Stoehr C, Wang JL, et al. The diagnosis of obliterative bronchiolitis after heart-lung and lung transplantation: low yield of transbronchial biopsies. J Heart Lung Transplant 1993; 12:675–681. 28. Cooper JD, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature for clinical staging of chronic dysfunction in lung allografts. J Heart Lung Transplant 1993; 12:713–716. 29. Patterson GM, Wilson S, Whang JL, et al. Physiologic definitions of obliterative bronchiolitis in heart-lung and double lung transplantation: a comparison of the forced expiratory flow between 25% and 75% of the forced vital capacity and forced expiratory volume in one second. J Heart Lung Transplant 1996; 15:175–181. 30. Hachem RR, Chakinala MM, Yusen RD, et al. The predictive value of bronchiolitis obliterans syndrome stage 0-p. Am J Respir Crit Care Med 2004; 169:468–472. 31. Van Muylem A, Knoop C, Estenne M. Early detection of chronic pulmonary allograft dysfunction by exhaled biomarkers. Am J Respir Crit Care Med 2007; 175: 731–736. 32. Williams TJ, Verleden GM. Azithromycin: a plea for multicenter randomized studies in lung transplantation. Am J Respir Crit Care Med 2005; 172:657–659. 33. Palmer SM, Baz MA, Sanders L, et al. Results of a randomised, prospective, multicenter trial of mycophenolate mofetil and azathioprine in the prevention of acute rejection. Transplantation 2001; 71:1772–1776. 34. Gerbase MW, Spiliopoulos A, Fathi M, et al. Low doses of mycophenolate mofetil with low doses of tacrolimus prevent acute rejection and long-term function loss after lung transplantation. Transplant Proc 2001; 33:2146–2147. 35. McNeil K, Glanville AR, Wahlers T, et al. Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients. Transplantation 2006; 81:998–1003.
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22 Pulmonary Complications of Bone Marrow Transplantation
BEKELE AFESSA and STEVE G. PETERS Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A.
I.
Introduction
Tens of thousands of patients undergo blood and marrow transplantation (BMT) annually, primarily for hematologic malignancies. Since both their innate and acquired immune systems are impaired, infectious and noninfectious complications occur frequently in BMT recipients. The recovery of the immune system following BMT depends on the underlying disorder, stem cell source, and complications such as graft versus host disease (GVHD). Pulmonary complications develop in 25% to 60% of BMT recipients and are the immediate cause of death in approximately 61% (1). The main pulmonary complications are listed in Table 1. The posttransplant period is divided into three phases: preengraftment (0 to 30 days), early postengraftment (30–100 days) and late posttransplant (>100 days). The pulmonary complications follow characteristic time patterns (2). Although infections may present as diffuse pulmonary or bronchiolar disorders, this chapter will focus on noninfectious complications. Among the noninfectious pulmonary complications, pulmonary edema, diffuse alveolar hemorrhage (DAH) and periengraftment respiratory distress syndrome (PERDS) usually occur during 559
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Table 1 Pulmonary Complications in Blood and Marrow Transplant Recipients Infectious Viral Bacterial Mycobacterial Fungal Protozoan Noninfectious Acute pulmonary edema Diffuse alveolar hemorrhage Periengraftment respiratory distress syndrome Bronchiolitis obliterans syndrome Bronchiolitis obliterans organizing pneumonia Idiopathic pulmonary syndrome Delayed pulmonary toxicity syndrome Pulmonary cytolytic thrombi Pulmonary veno-occlusive disease Progressive pulmonary fibrosis Pulmonary hypertension Hepatopulmonary syndrome Pulmonary alveolar proteinosis Eosinophilic pneumonia
the first 30 days following transplant (Fig. 1). Idiopathic pneumonia syndrome (IPS) can occur at any time following transplant. The diagnostic evaluation of BMT recipients with pulmonary infiltrates and/or respiratory symptoms is outlined in Figure. 2. II.
Noninfectious Pulmonary Complications
A.
Pulmonary Function and Upper Airway Abnormalities
Pulmonary function test (PFT) abnormalities occur frequently following allogeneic BMT. A decreased carbon monoxide diffusion (DLco) develops in up to 83% and restrictive and obstructive ventilatory defects in up to 35% and 23%, respectively, of allogeneic BMT recipients (3). Significant mucosal injury occurs in about 75% of BMT recipients. Upper airway inflammation due to mucositis may lead to laryngeal edema, dysphagia, and aspiration pneumonia. Life-threatening upper airway complications are more common in children. B.
Bronchiolitis Obliterans
About 45% of long-term survivors of allogeneic BMT develop chronic GVHD. Histologic pulmonary manifestations of GVHD include diffuse alveolar damage,
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Figure 1 Timing of the major noninfectious pulmonary complications following blood and marrow transplantation. Abbreviations: BO, bronchiolitis obliterans; DAH, diffuse alveolar hemorrhage; GVHD, graft versus host disease; IPS, idiopathic pneumonia syndrome; P edema, pulmonary edema; PERDS, periengraftment respiratory distress syndrome; phase I, preengraftment period; phase II, early postengraftment period; phase III, late postengraftment period.
Figure 2 Diagnostic approach to blood and marrow transplant recipients with pulmonary complications. Abbreviations: FOB, fiberoptic bronchoscopy; HRCT, high-resolution computed tomography of the chest; PFT, pulmonary function test; VATS, video-assisted thoracoscopic surgery.
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Figure 3 CT of the chest in a patient with BO showing diffuse areas of parenchymal hypoattenuation, proximal bronchiectasis, and subsegmental bronchial dilatation Abbreviation: BO, bronchiolitis obliterans; CT, computed tomography. Source: Adapted from Ref. 5.
lymphocytic bronchitis/bronchiolitis with interstitial pneumonitis, bronchiolitis obliterans organizing pneumonia (BOOP), and bronchiolitis obliterans (BO). Although BO almost exclusively affects allogeneic BMT recipients with GVHD, there are two fatal case reports in autologous recipients (4). The overall frequency of BO in allogeneic BMT recipients is about 3.9% (1). In long-term survivors with GVHD, the incidence may reach 35%. GVHD, advanced donor and recipient age, myeloablative conditioning, methotrexate use, antecedent respiratory infection, and serum immunoglobulin deficiency are risk factors for BO (1,5). The pathogenesis of BO is not well understood, but the association with chronic GVHD has led to the hypothesis that host bronchiolar epithelial cells are a target for donor cytotoxic T-lymphocytes (1,5). BO is rare in the first two months and may occur up to nine years after transplant. Twenty percent of the patients with BO had no respiratory symptoms at the time of the abnormal PFT. The clinical presentation includes dry cough and dyspnea in most patients. Wheezing is present in 40% and antecedent cold symptoms in 20% of the patients. Airflow obstruction is the hallmark of BO. Chest radiograph is usually normal or may show hyperinflation (1,5). High-resolution computed tomography (HRCT) of the chest may show decreased lung attenuation, bronchial dilatation, centrilobular nodules, and nonhomogeneous air trapping (Fig. 3). Bronchoalveolar lavage (BAL) may show neutrophilic and/or lymphocytic inflammation. Transbronchial lung biopsy is usually nondiagnostic, and surgical lung biopsy is required to make a definitive diagnosis of BO. The histologic hallmark of BO is fibrinous obliteration of the small airway lumen (Fig. 4). However, surgical
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Figure 4 (See color insert.) Lung pathology in BO showing bronchiolar inflammation and luminal obliteration associated with excess fibrous connective tissue. Alveoli and their ducts are spared. (hematoxylin and eosin and Verhoeff-Van Gieson elastic tissue stain). Abbreviation: OB, bronchiolitis obliterans. Source: Adapted from Ref. 5.
biopsies are rarely indicated since a clinical diagnosis usually can be made by the presence of irreversible airflow obstruction, and the exclusion of other causes, in allogeneic BMT recipients with chronic GVHD. The treatment of BO consists of corticosteroids and augmented immunosuppression, targeting chronic GVHD. However, a minority of patients shows clinical improvement (5). There is a report of eight BMT recipients with BO whose pulmonary function improved after treatment with azithromycin (6) and one BMT recipient treated with infliximab (7). In addition to immunosuppression and anti-inflammatory therapy, prophylaxis against Pneumocystis jirovecii pneumonia and Streptococcus pneumoniae should be provided to patients with BO. In selected patients with respiratory failure secondary to BO, lung transplantation may be an option (1). The rate of decline in the forced expiratory volume in one second (FEV1) of BMT recipients is widely variable. Despite treatment with bronchodilators, corticosteroids, and immunosuppression, improvement in lung function is noted in only 8% to 20%. The reported case fatality rates of BO in BMT recipients range from 10% to 100%, with overall mean case fatality rate of 61% (1,5,8). C.
Acute Pulmonary Edema
Acute pulmonary edema in BMT recipients may result from a combination of both hydrostatic and nonhydrostatic (capillary leak) factors. Hydrostatic pulmonary
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edema may result from high volumes of fluid for medications, total parenteral nutrition, and multiple transfusions. Clinical features include weight gain, dyspnea, and bibasilar crackles. The radiographic findings may include vascular redistribution, increased interstitial markings, Kerley B lines, and ground-glass opacities. Cardiomegaly is generally absent unless there is associated cardiac dysfunction. Acute pulmonary edema can be prevented and treated with fluid restriction and diuretics. D.
IPS
The National Heart, Lung, and Blood Institute (NHLBI) defined IPS by the presence of widespread alveolar injury, with associated symptoms of cough and dyspnea, hypoxemia, and restrictive physiology, in the absence of infection or heart failure (9). Although DAH and PERDS meet the diagnostic criteria of IPS, their response to treatment and clinical courses are different (10,11). The overall incidence of IPS is 10%, ranging between 2% and 17% (5,12). Advanced age, transplant for malignancy other than leukemia, pretransplant chemotherapy, total body irradiation, GVHD, and positive donor cytomegalovirus serology are risk factors for the development of IPS. Although the pathogenesis of IPS is not well defined, lung-tissue injury, inflammation, and cytokine release are implicated. The clinical presentation of IPS includes dyspnea, dry cough, hypoxemia, and nonlobar radiographic infiltrates (9). The spectrum is broad, ranging from acute respiratory failure to incidental radiographic abnormalities. Because IPS mimics infectious pneumonia, the majority of patients are on antibiotics at the time of diagnosis. The median time of IPS onset is 21 to 65 days and the range from 0 to 1653 days after transplant. Despite the variable onset, the majority of patients with IPS present within the first 120 days following BMT. The clinical and radiographic findings cannot be used to differentiate between patients with infectious and idiopathic pneumonia. PFT and computed tomography (CT) of the chest are nonspecific. The NHLBI workshop requires BAL or lung biopsy to exclude infectious etiology before diagnosing IPS. Videoassisted thoracoscopic lung biopsy may be needed to confirm the diagnosis if transbronchial lung biopsy is contraindicated or inadequate. Lung biopsies of patients with IPS may show diffuse alveolar damage, organizing or acute pneumonia, and interstitial lymphocytic inflammation. Despite case reports of response to treatment with corticosteroids, larger studies have not shown any outcome benefit. Currently, accepted treatment options are limited to supportive care and prevention and treatment of infection. There is a report of three BMT recipients with IPS whose lung function improved following etanercept administration (13). Lung transplant may offer a therapeutic option for selected patients. Although the pneumonitis resolves in about 31%, the clinical course of IPS is often complicated by viral and fungal infections, pneumothorax, pneumomediastinum, subcutaneous emphysema, pulmonary fibrosis, and autoimmune polyserositis (5). The case fatality of IPS is
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about 74%, ranging between 60% and 86% (5,14). The one-year survival rate is less than 15%. For those who require mechanical ventilation, the hospital mortality exceeds 95% (15). E.
DAH
DAH occurs in approximately 5% of BMT recipients, with a range of approximately 2–21% (10). It occurs with equal frequency in autologous and allogeneic recipients. Advanced age, intensive chemotherapy, and total body irradiation are risk factors for DAH. Despite the presence of thrombocytopenia, DAH is not corrected with platelet transfusion. Airway inflammation has been associated with subsequent DAH. The etiology and pathogenesis of DAH in the BMT recipient have not been clearly established (10). Alveolar hemorrhage associated with increased level of tumor necrosis factor-a has been described in an animal model of BMT (16). Symptoms of DAH typically include dyspnea, fever, and cough. Hemoptysis is reported in less than 20% (10,17). The onset of DAH is usually within the first 30 days of BMT. Chest radiographs show alveolar and interstitial infiltrates involving middle and lower lung zones (Fig. 5). Although HRCT of the chest may detect abnormalities not identified by plain chest radiograph, it has a limited role in DAH. The most common CT findings are bilateral areas of ground-glass attenuation or consolidation. The visual description of progressively bloodier return or the presence of 20% or higher hemosiderin-laden macrophages in BAL fluid is used for the diagnosis of DAH (17). Diffuse alveolar damage is the main histologic finding in DAH.
Figure 5 A portable chest radiograph of a bone marrow transplant recipient with DAH showing bilateral diffuse pulmonary infiltrates. Abbreviation: DAH, diffuse alveolar hemorrhage.
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Despite a lack of strong supporting evidence, BMT recipients with DAH are treated with systemic corticosteroids with good response (10,17). There are case reports of allogeneic BMT recipients with DAH successfully treated with recombinant factor VIIa. The majority of BMT recipients with DAH require mechanical ventilation for respiratory failure. The reported mortality rate of DAH ranges between 48% and 100%. F.
PERDS
PERDS refers to the pulmonary component of the engraftment syndrome. It occurs in about 5% of autologous BMT recipients and responds favorably to treatment (11). The pathogenesis of PERDS is not known. It is believed to be due to a complex interaction between conditioning-related endothelial damage and cytokine release associated with the neutrophil and lymphocyte recovery. The median time to onset of PERDS is 11 days (range 8–25) after transplant. Dyspnea is the initial symptom in patients with PERDS and fever is present at the onset of symptoms in 63% of such patients. Bilateral pulmonary infiltrates may not be present on plain chest radiograph at the onset of symptoms. The diagnostic criteria of PERDS include fever (>38.38C) and pulmonary injury, in the absence of cardiac dysfunction or infection, within five days of neutrophil engraftment. BAL shows neutrophilic inflammation. Transbronchial lung biopsy cannot be performed safely in most BMT recipients during the periengraftment period because of thrombocytopenia. Surgical lung biopsy may show diffuse alveolar damage but is rarely necessary (11). High-dose corticosteroids usually lead to rapid clinical improvement in PERDS (11). A short course of corticosteroid therapy has been used effectively to prevent engraftment syndrome in autologous BMT recipients (18). Unlike DAH and IPS, only about one-third of BMT recipients with PERDS require ICU admission and mechanical ventilation. The reported case fatality rate of PERDS is approximately 21% (11). G.
BOOP
The medical literature on BOOP in BMT recipients is limited to case reports. The onset of BOOP is within the first two years after transplant (5,19). Cough, dyspnea, and fever are the presenting symptoms. Chest radiographs and CT show patchy air space consolidation, ground-glass attenuation, and nodular opacities. Exhaled nitric oxide concentration may be elevated initially and then decline as response to treatment (20). The definitive diagnosis of BOOP in BMT recipients requires transbronchial, or, more commonly, surgical lung biopsy that shows patchy intraluminal fibrosis, with polypoid plugs of immature fibroblasts resembling granulation tissue obliterating the distal airways, alveolar ducts, and peribronchial alveolar space (Fig. 6). Most BMT recipients with BOOP respond favorably to treatment with corticosteroids (1,5). Radiographic abnormalities usually clear within one to three months of initiating therapy. Erythromycin has been used
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Figure 6 (See color insert.) Lung pathology in BOOP showing the presence of intraluminal granulation tissue in bronchioli, alveolar ducts, and alveoli. There is also interstitial infiltration with mononuclear cells and foamy macrophages (hematoxylin and eosin stain). Abbreviation: BOOP, bronchiolitis obliterans organizing pneumonia. Source: Adapted from Ref. 5.
in conjunction with corticosteroid in one patient with favorable outcome. The case fatality rate of BOOP in BMT recipients is about 19% (1,5). H.
Delayed Pulmonary Toxicity Syndrome
Delayed pulmonary toxicity syndrome (DPTS) develops in up to 72% of autologous BMT recipients who have received high-dose chemotherapy for breast cancer. The relatively high frequency, low mortality, and good response to corticosteroid treatment distinguish DPTS from IPS. The pathogenesis of DPTS is not known. The depletion of reduced glutathione and impaired antioxidant defenses caused by cyclophosphamide and BCNU has been implicated. Patients with DPTS present with cough, dyspnea, and fever (1). The onset of symptoms ranges from two weeks to four months following transplantation. In the context of prior breast cancer treated with high-dose chemotherapy and autologous BMT, DPTS is diagnosed by demonstration of a decline in DLco and exclusion of infectious causes. CT of the chest commonly shows ground-glass opacities (21). Because of the typical clinical presentation and response to therapy, invasive procedures such as bronchoscopy can sometimes be avoided. Corticosteroid therapy for DPTS usually results in resolution of symptoms and improvement in DLco without long-term pulmonary sequelae (1). No deaths attributable to DPTS have been reported. I.
Pulmonary Cytolytic Thrombi
Pulmonary cytolytic thrombi (PCT) is a noninfectious pulmonary complication of unknown etiology. It occurs exclusively after allogeneic procedures, typically
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in the setting of GVHD. All but one of the 17 BMT recipients with PCT reported in the medical literature are from a single institution (22–24). Sixteen of the 17 patients were under 18 years at the time of diagnosis. Although the hemorrhagic infarcts in PCT are similar to those seen in angioinvasive fungal infections, none of the lung biopsies in the reported PCT cases had evidence of infection. The development of PCT exclusively in allogeneic BMT recipients, chiefly in those with GVHD, suggests that it may be a manifestation of GVHD (22). Most BMT recipients with PCT have active GVHD at the time of presentation. The onset of PCT is at a median of 72 days after transplantation. All patients are febrile and some have cough at presentation, but dyspnea has not been noted. Chest radiographs may be normal in 25% of the patients with PCT. Abnormal chest radiographic findings include nodules, interstitial prominence, and atelectasis. Chest CT shows multiple peripheral pulmonary nodules, ranging from a few millimeter to four centimeter in size. BAL is used to exclude infection. Because of the peripheral and intravascular location of the nodules, transbronchial lung biopsy is unlikely to yield a diagnosis. Histologic demonstration of PCT requires surgical lung biopsy or necropsy. Histologic findings include occlusive vascular lesions and hemorrhagic infarcts due to thrombi that consist of intensely basophilic, amorphous material that may extend into the adjacent tissue through the vascular wall (22). Most of the patients with PCT described in the literature improved clinically within 1 to 2 weeks and radiographically over weeks to months (25). There has been no reported death attributed to PCT. Of the 15 BMT recipients with PCT reported from the University of Minnesota, 10 were still alive at an average of 13 months after diagnosis and five died, one from GVHD and four from infectious complications (1). J.
Pulmonary Veno-occlusive Disease
Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension that has been associated with various conditions including BMT. The incidence of PVOD in BMT recipients is not known. In one autopsy study, PVOD was reported in 19 of 154 of allogeneic BMT recipients (12%) (26). However, no case of PVOD was identified in a recent autopsy review of 71 adult BMT recipients, including 39 allogeneic (27). Approximately 28 BMT recipients with PVOD have been reported in the literature (1). Most underwent transplant for hematologic malignancy, and only two of the 28 patients with PVOD had autologous grafts. The triad of pulmonary arterial hypertension, radiographic evidence of pulmonary edema, and normal pulmonary artery occlusion pressure suggests PVOD. The definitive diagnosis of PVOD requires surgical lung biopsy or necropsy. There is no proven therapy for PVOD. There are case reports of steroid therapy in BMT recipients with PVOD, with conflicting results (1).
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Other Pulmonary Complications
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Pulmonary Alveolar Proteinosis
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Pulmonary alveolar proteinosis is characterized by excessive accumulation of surfactant lipoprotein in the alveoli, leading to abnormal gas exchange, and diagnosed by the presence of periodic acid Schiff proteineceaous material in BAL fluid. It has been reported in few BMT recipients (27,28). Chest radiographs show diffuse infiltrates. The roles of BAL and aerosolized granulocytemacrophage colony-stimulating factor in BMT recipients with pulmonary alveolar proteinosis are unknown. 2.
Chronic Eosinophilic Pneumonia
Three cases of chronic eosinophilic pneumonia have been reported in BMT recipients, one autologous and two allogeneic. Despite initial response to steroid therapy, one patient had a fatal course (29). 3.
Transfusion-Related Acute Lung Injury
Transfusion-related acute lung injury (TRALI) is a clinical syndrome characterized by bilateral pulmonary edema in association with transfusions of blood products. It has been reported following the infusion of allogeneic hematopoietic stem cells during BMT (30,31). 4.
Sarcoidosis
Sarcoidosis is uncommon in BMT recipients. The first reported BMT recipients with sarcoidosis received stem cells from donors with sarcoidosis (32). More recently, sarcoidosis has been reported in autologous BMT recipients as well as in allogeneic recipients who received stem cells from donors without sarcoidosis (33). References 1. Afessa B, Peters SG. Chronic lung disease after hematopoietic stem cell transplantation. Clin Chest Med 2005; 26(4):571–86, vi. 2. Afessa B, Peters SG. Major Complications following Hematopoietic Stem Cell Transplantation. Semin Respir Crit Care Med 2006; 27(3):297–309. 3. Marras TK, Szalai JP, Chan CK, et al. Pulmonary function abnormalities after allogeneic marrow transplantation: a systematic review and assessment of an existing predictive instrument. Bone Marrow Transplant 2002; 30(9):599–607. 4. Paz HL, Crilley P, Patchefsky A, et al. Bronchiolitis obliterans after autologous bone marrow transplantation. Chest 1992; 101(3):775–778. 5. Afessa B, Litzow MR, Tefferi A. Bronchiolitis obliterans and other late onset noninfectious pulmonary complications in hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 28(5):425–434.
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6. Khalid M, Al Saghir A, Saleemi S, et al. Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study. Eur Respir J 2005; 25(3):490–493. 7. Fullmer JJ, Fan LL, Dishop MK, et al. Successful treatment of bronchiolitis obliterans in a bone marrow transplant patient with tumor necrosis factor-alpha blockade. Pediatrics 2005; 116(3):767–770. 8. Dudek AZ, Mahaseth H, DeFor TE, et al. Bronchiolitis obliterans in chronic graftversus-host disease: analysis of risk factors and treatment outcomes. Biol Blood Marrow Transplant 2003; 9(10):657–666. 9. Clark JG, Hansen JA, Hertz MI, et al. NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis 1993; 147(6 Pt 1):1601–1606. 10. Afessa B, Tefferi A, Litzow MR, et al. Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002; 166(5): 641–645. 11. Capizzi SA, Kumar S, Huneke NE, et al. Peri-engraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 27(12):1299–1303. 12. Chen CS, Boeckh M, Seidel K, et al. Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation. Bone Marrow Transplant 2003; 32(5):515–522. 13. Yanik G, Hellerstedt B, Custer J, et al. Etanercept (Enbrel) administration for idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2002; 8(7):395–400. 14. Keates-Baleeiro J, Moore P, Koyama T, et al. Incidence and outcome of idiopathic pneumonia syndrome in pediatric stem cell transplant recipients. Bone Marrow Transplant 2006; 38(4):285–289. 15. Kantrow SP, Hackman RC, Boeckh M, et al. Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation. Transplantation 1997; 63(8):1079–1086. 16. Piguet PF, Grau GE, Collart MA, et al. Pneumopathies of the graft-versus-host reaction. Alveolitis associated with an increased level of tumor necrosis factor mRNA and chronic interstitial pneumonitis. Lab Invest 1989; 61(1):37–45. 17. Afessa B, Tefferi A, Litzow MR, et al. Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002; 166(10):1364–1368. 18. Mossad S, Kalaycio M, Sobecks R, et al. Steroids prevent engraftment syndrome after autologous hematopoietic stem cell transplantation without increasing the risk of infection. Bone Marrow Transplant 2005; 35(4):375–381. 19. Yotsumoto S, Okada F, Yotsumoto S, et al. Bronchiolitis obliterans organizing pneumonia after bone marrow transplantation: association with human leukocyte antigens. J Comput Assist Tomogr 2007; 31(1):132–137. 20. Kanamori H, Fujisawa S, Tsuburai T, et al. Increased exhaled nitric oxide in bronchiolitis obliterans organizing pneumonia after allogeneic bone marrow transplantation. Transplantation 2002; 74(9):1356–1358. 21. Wilczynski SW, Erasmus JJ, Petros WP, et al. Delayed pulmonary toxicity syndrome following high-dose chemotherapy and bone marrow transplantation for breast cancer. Am J Respir Crit Care Med 1998; 157(2):565–573.
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22. Gulbahce HE, Pambuccian SE, Jessurun J, et al. Pulmonary nodular lesions in bone marrow transplant recipients: impact of histologic diagnosis on patient management and prognosis. Am J Clin Pathol 2004; 121(2):205–210. 23. Morales IJ, Anderson PM, Tazelaar HD, et al. Pulmonary cytolytic thrombi: unusual complication of hematopoietic stem cell transplantation. J Pediatr Hematol Oncol 2003; 25(1):89–92. 24. Peters A, Manivel JC, Dolan M, et al. Pulmonary cytolytic thrombi after allogeneic hematopoietic cell transplantation: a further histologic description. Biol Blood Marrow Transplant 2005; 11(6):484–485. 25. Woodard JP, Gulbahce E, Shreve M, et al. Pulmonary cytolytic thrombi: a newly recognized complication of stem cell transplantation. Bone Marrow Transplant 2000; 25(3):293–300. 26. Wingard JR, Mellits ED, Jones RJ, et al. Association of hepatic veno-occlusive disease with interstitial pneumonitis in bone marrow transplant recipients. Bone Marrow Transplant 1989; 4(6):685–689. 27. Sharma S, Nadrous HF, Peters SG, et al. Pulmonary complications in adult blood and marrow transplant recipients: autopsy findings. Chest 2005; 128(3):1385–1392. 28. Cordonnier C, Fleury-Feith J, Escudier E, et al. Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med 1994; 149(3 Pt 1):788–794. 29. Gross TG, Hoge FJ, Jackson JD, et al. Fatal eosinophilic disease following autologous bone marrow transplantation. Bone Marrow Transplant 1994; 14(2):333–337. 30. Noji H, Shichishima T, Ogawa K, et al. Transfusion-related acute lung injury following allogeneic bone marrow transplantation in a patient with acute lymphoblastic leukemia. Intern Med 2004; 43(11):1068–1072. 31. Urahama N, Tanosaki R, Masahiro K, et al. TRALI after the infusion of marrow cells in a patient with acute lymphoblastic leukemia. Transfusion 2003; 43(11):1553–1557. 32. Padilla ML, Schilero GJ, Teirstein AS. Donor-acquired sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19(1):18–24. 33. Bhagat R, Rizzieri DA, Vredenburgh JJ, et al. Pulmonary sarcoidosis following stem cell transplantation: is it more than a chance occurrence? Chest 2004; 126(2):642–644.
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23 Pulmonary and Airway Complications Related to September 11th
DAVID J. PREZANT Fire Department of the City of New York (FDNY); Albert Einstein College of Medicine and Montefiore Medical Center, New York, New York, U.S.A.
STEPHEN LEVIN Mount Sinai School of Medicine, New York, New York, U.S.A.
THOMAS K. ALDRICH Albert Einstein College of Medicine and Montefiore Medical Center, New York, New York, U.S.A.
I.
Introduction
On September 11, 2001, aerial terrorist attacks on the World Trade Center (WTC) led to its collapse, producing a plume of dust and ash that spread throughout lower Manhattan and beyond (1). Concurrent with this physical destruction, combustion of approximately 91,000 liters of aircraft fuel ignited numerous structural fires, many of which smoldered until mid-December of 2001. An estimated 525,000 people, including over 90,000 workers were potentially exposed to the resulting pollutants during the collapse, rescue, recovery, and cleanup efforts (2,3). Pulverized building materials predominated in the initial period post collapse, while combustion-derived pollutants increased as rescue, recovery, and cleanup progressed (4). The fires at the site created toxic combustion products such as polycyclic aromatic hydrocarbons (PAHs), dioxins, volatile organic compounds, and various other known carcinogenic compounds (1,4–6). Contaminants such as asbestos, hydrochloric acid, polychlorinated biphenyls (PCBs), silica, and heavy metals were found in the dust and ash resulting from the WTC collapse (1,4,5).
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This chapter expands upon two prior reviews by these authors (2,7) and focuses on the respiratory health, diagnostics, and treatment algorithms. The evidence is clear that the upper and lower respiratory symptoms, experienced by many who were exposed, were primarily due to respired WTC dust (particles coated with combustion by-products). There was an exposure-response gradient with the highest symptom prevalence found in those directly exposed to the dust cloud arriving during the morning of 9/11/01 (8–10). Ninety-five percent of the respirable WTC dust was composed of large particulate (10 microns in diameter) matter (1). Particles of this size have conventionally been thought to be filtered by the upper respiratory tract, rarely entering the lower respiratory structures (4). However, there are a number of reasons to expect lower airways to be at risk from the dust cloud. First, it has been shown that alkaline dust impairs nasal clearance mechanisms and most WTC dust samples had a pH greater than 10 (11). Second, the nasal filtration system is optimally functional during restful breathing. However, WTC rescue/recovery workers, as a consequence of their work activities (moderate- to high-level physical exertion), were breathing at high minute ventilations where mouth breathing predominates. Finally, although only a small percentage of particles larger than 10 microns tend to impact the lower airways, the huge magnitude of the WTC dust cloud meant that a small percentage of particles that penetrated deep into the lung may have added up to a significant exposure (12). In fact, in a study of 39 firefighters from the Fire Department of the City of New York (FDNY) 10 months after exposure (12), it was shown that the WTC dust did penetrate into the lower airways as particulate matter (>10 microns) consistent with WTC dust, with associated increases in inflammatory cells and cytokines in induced sputum.
II.
World Trade Center Cough Syndrome
WTC cough syndrome is a chronic cough syndrome, thought to be the consequence of upper and lower respiratory diseases. Upper respiratory tract disease, usually but not always, manifested as cough, has been due to reactive upper airways dysfunction syndrome (RUDS), chronic rhinosinusitis, and/or gastroesophageal reflux disease (GERD). Lower respiratory tract disease, also most commonly manifested as cough, but often with associated chest tightness, shortness of breath, and exercise intolerance occurs due to reactive (lower) airways dysfunction syndrome (RADS) or irritant-induced asthma, types of asthmatic bronchitis that often lead to chronic obstructive airways diseases and in a few cases, interstitial lung diseases such as sarcoidosis, pulmonary fibrosis, and bronchiolitis obliterans. During the first five years post 9/11/01, high rates of upper and lower respiratory irritant symptoms, e.g., primarily cough, were described in at least seven WTC rescue/recovery worker groups (Table 1) (1). In 13,854 previously healthy, exposure-stratified FDNY rescue workers, self-reported daily cough was
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present in 99% on day one (9/11/01), 53% during the first month post collapse, 46% during the first year post collapse, and 31% during the next two to four years (9). In the New York/New Jersey (NY/NJ) WTC consortium’s non-FDNY cohort, consisting of police, sanitation, transportation, construction, and other workers, 69% of the first 9442 responders reported new or worsened upper (62.5% of 9442) or lower (46.5% of 9442) respiratory symptoms during their WTC-related efforts with symptoms persisting to the time of examination in 59% (on an average, eight months after they stopped their rescue/recovery/cleanup activities) (13), and in another study, they found that in the previously asymptomatic group, 44% developed lower respiratory symptoms during their work at the WTC site. Analysis again demonstrated that the incidence of lower respiratory symptoms was directly related to arrival time (3,10); 77% of 240 previously healthy NYC emergency service unit (ESU) police officers had upper and/or lower respiratory symptoms during the first five months post collapse (14). In 471 NYC police officers, (426 with no pre-9/11 chronic respiratory disease), 44% reported having a cough at both 1 and 19 months post collapse but over the same time interval, reported increasing prevalence of shortness of breath (18.9% to 43.6%) and wheeze (13.1% to 25.9%) (15); 77% of 96 ironworkers had upper and/or lower respiratory symptoms six months post collapse (16). In a study of 269 transit workers, those caught in the dust cloud had significantly higher risk of persistent lower respiratory and mucous membrane symptoms (17), and in 183 cleanup workers, the prevalence of upper and lower respiratory symptoms increased as the cumulative number of days spent at WTC increased (18). Respiratory consequences have also been noted in WTC studies on community residents, children, and office workers in lower Manhattan (19–21). A WTC Health Registry study confirmed that out of 8418 adults who were caught in the collapse on 9/11, 57% experienced new or worsening respiratory symptoms after the attacks (3). The ‘‘WTC cough syndrome’’ was first reported by the FDNY WTC Medical Monitoring and Treatment Program (8). During the first six months following the WTC attack, FDNY Bureau of Health Services described a syndrome of clinical, physiologic, and radiographic abnormalities due to significant unrelenting airway inflammation in an initial cohort of 332 FDNY rescue workers. Because so many were affected, the case definition specified a persistent cough severe enough to require at least four weeks of continuous leave (medical, light duty, or retirement) with onset during six months, following the WTC collapse. More recently, FDNY reported that between 9/11/01 and 6/30/07, 1847 (*13%) FDNY rescue workers have met this strict case definition, and over 728 have qualified for permanent respiratory disability benefits (9). Clinical symptoms were consistent with aerodigestive mucosal inflammation (rhinosinusitis, bronchitis, acid reflux), with a surprisingly high rate of gastroesophageal reflux complaints (87%) (8). Physiologic evidence of asthmatic airway inflammation in those with the syndrome included response
FDNY rescue workers; iron workers; ESU police officers; technical, law enforcement, construction workers; transit workers and cleanup workers
FDNY rescue workers; iron workers; ESU police officers; technical, law enforcement, construction workers; transit workers and cleanup workers FDNY rescue workers; technical, law enforcement, construction workers, and survivors
FDNY rescue workers; ESU police officers; iron workers
WTC cough syndrome
Chronic rhinosinusitis or RUDS
Pulmonary function abnormalities
GERD
Study cohort
Clinical syndrome
Table 1 WTC-related Upper and Lower Respiratory Diseases
Persistent upper gastrointestinal complaints including persistent heartburn With or without respiratory symptoms
Accelerated FEV1 and FVC decline FEV1 < LLN and/or FVC < LLN and/ or FEV1/FVC < LLN and/or bronchodilator response Large airway dysfunction on forced oscillation Persistent bronchial hyperreactivity (methacholine PC20 8 mg/mL)
Pathophysiologic testing not available
Bronchial hyperreactivity (methacholine PC20 8 mg/mL): 23% (high exposure), 8% (moderate exposure) Decrease in FEV1, FVC and MFEF25–75%, FEV1/FVC ratio. Reversible abnormality on spirometry. Pathophysiologic testing not available
Productive cough, wheeze, shortness of breath, chest-tightness
Nasal congestion/drip, sore throat, sinusitis.
Pulmonary function abnormalities
Clinical symptoms
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Spectrum of asymptomatic to symptoms of asthma, constitutional symptoms and/or arthralgias
FDNY rescue workers and a case report of an engineer
NYC police officer (case report)
SLGPD or Granulomatous pneumonitis
Bronchiolitis obliterans
Adult respiratory distress syndrome requiring mechanical ventilation. After corticosteroid treatment and discharge from ICU, hypoxia resolved and pulmonary functions gradually returned to lower limits of normal. Biopsy evidence of sterile nonnecrotizing granulomatous disease. Pulmonary functions ranging from normal to documented hyperreactivity. Rare cases of decreased diffusion. Decreasing lung volumes with biopsy evidence for bronchiolitis obliterans and rare nonnecrotizing granuloma.
Pulmonary function abnormalities
Abbreviations: WTC, world trade center; FDNY, Fire Department of the city of New York; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; MFEF, maximum forced expiratory flow; RUDS, reactive upper airway dysfunction syndrome; ESU, emergency service unit; GERD, gastroesophageal reflux dysfunction; LLN, lower limits of normal; SLGPD, sarcoid-like granulomatous pulmonary disease; NYC, New York City.
Cough, wheeze, shortness of breath
Cough with blackish sputum, fatigue, malaise, fever, dry cough, pleuritic chest pain.
FDNY firefighter (case report)
Eosinophilic pneumonitis
Clinical symptoms
Study cohort
Clinical syndrome
Table 1 (Continued )
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to bronchodilators (63% of those diagnosed) and nonspecific bronchial hyperreactivity determined by methacholine challenge testing (24% of those diagnosed), indicating that these rescue workers had a high rate of asthmatic physiology (8). Radiologic confirmation of airway inflammation in these firefighters included CT scan evidence of air trapping (abnormal retention of air in the lungs after expiration) in 51%, and bronchial wall thickening in 24% (8). The incidence of this syndrome was correlated with WTC dust exposure intensity (estimated by initial arrival time at the WTC site). Nearly all of the firefighters and EMTs who developed WTC cough syndrome had been exposed during the first 48 hours post collapse and most had been exposed during the morning of 9/11 (8,9).
III.
Chronic Rhinosinusitis and Reactive Upper Airways Dysfunction Syndrome
RUDS is defined as chronic rhinosinusitis (nasal and/or sinus inflammation) initiated by high-level exposure to inhaled irritants, with recurrence of symptoms after re-exposure to irritants. Diagnosis depends largely on symptoms without quantifiable diagnostic tests. High rates of upper airways symptoms have been described in various groups involved in rescue, recovery, and cleanup at the WTC site (Table 1), with higher prevalence in those who were more highly exposed. In 13,854 previously healthy FDNY rescue workers, stratified for severity of exposure by arrival time at the WTC site, self-reported that sinus congestion and/or drip was present in 80% on day one (9/11/01), 40% during the first month post collapse, 25% during the first year post collapse, and 32% during the next two to four years (9). In the same group, sore or hoarse throat was reported in 63% on day one (9/11/01), 54% during the first month post collapse, 46% during the first year post collapse, and 22% during the next two to four years (9). An exposure intensity gradient was evident for those with initial and persistent symptoms. In the NY/NJ Consortium of non-FDNY rescue workers/ volunteers, 66% of those directly exposed to the dust cloud reported upper respiratory symptoms such as congestion, runny nose, headache, sinus pain, sore throat, ear pain or blockage, hoarse voice, etc (10). In 96 ironworkers, who were on the pile from the afternoon of 9/11, usually on long shifts without respiratory protection, 52% had persistent sinus complaints, with corresponding physical signs such as rhinosinusitis in at least 30% of the cohort (16). In 240 NYPD ESU officers between one to five months after the collapse, 41% had persistent nasal and/or throat symptoms (14). The main diagnoses associated with these symptoms are chronic rhinosinusitis, but there is considerable overlap with asthmatic and GERD symptoms and the literature pre- and post-WTC clearly shows that successful treatment requires a coordinated approach to treat all of these related conditions.
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Gastroesophageal Reflux Disease
In the general population, gastroesophageal reflux disease (GERD) has been well described as a causal or exacerbating factor for inflammatory airway diseases such as asthma. Among FDNY rescue workers, several studies have now described high rates of reflux disease. Eighty-seven percent of 332 FDNY rescue workers diagnosed with WTC cough reported GERD requiring treatment (8) and in a study of 179 exposure-stratified FDNY rescue workers, 45% of those who were found to be hyperreactive by methacholine challenge testing (1–6 months post collapse) reported GERD (22). Reports of GERD were not limited to FDNY rescue workers (Table 1), as the NY/NJ consortium of non-FDNY workers/volunteers has also reported that in their first year of operation, 54% of their patients had GERD (10). The WTC Health Registry reported that out of a cohort of 8418 adult survivors caught in the collapse, 23.9% reported heartburn or acid reflux (3). Clinical experience at all three WTC Clinical Centers of Excellence (FDNY, Mt. Sinai Consortium and Bellevue Hospital) suggests that many responders have persistent symptoms that have required prolonged or even chronic use of medications to control acid production (personal communications from Drs K. Kelly, S. Levin, and J. Reibman). Though no clear mechanism for the development of GERD has been described in this setting, ingestion of airborne particulate WTC material or particulates cleared from the airways, along with stress, dietary triggers, and medication use (GERD is increased with certain medications used for WTC-related conditions) are the presumed causes, often acting in combination. Consensus literature pre- and post-WTC clearly shows that without successful GERD treatment there can be no or only minimally effective treatment for upper and lower respiratory conditions such as sinusitis and asthma (23,24).
V.
Asthma and Reactive (Lower) Airways Dysfunction Syndrome
Occupational reactive airways dysfunction syndrome (RADS) is defined as persistent respiratory symptoms and nonspecific airway hyperreactivity in patients with a history of acute exposure to an inhaled agent (gas or aerosol) and no prior history of allergies, smoking, or asthma (25). The definition of RADS can usefully be extended in the WTC context (Table 1) to include those with repeated irritant exposure who have developed irritant-induced asthma. RADS can progress to irreversible lower airways obstructive disease. In a sample of FDNY rescue workers whose bronchial hyperreactivity was measured six months after 9/11/01, those who arrived at the WTC site on 9/11 were 7.8 times more likely to experience bronchial hyperreactivity than those firefighters who arrived to the site at a later date and/or had lower exposure
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levels (22). In this FDNY study, RADS emerged in 20% of highly exposed (present during the morning of collapse) and 8% of moderately exposed rescue workers (present after the morning of 9/11 but within the first 48 hours) (22). Consistent with human observational studies, mice acutely exposed to high levels of WTC particulate matter developed pulmonary inflammation and airway hyperreactivity (26). Findings in FDNY rescue workers over the first two years are consistent with the evolving non-WTC scientific literature indicating that RADS with documented continuing bronchial hyperreactivity can persist in individuals even after exposure had ceased and with appropriate therapy (4,27,28). In the first year of the NY/NJ Consortium Program for non-FDNY workers/volunteers, it was found that 45% reported symptoms consistent with lower airway disorders, including asthma and asthma variants (13). The WTC Registry has published its findings on self-reported ‘‘newly diagnosed asthma (post 9/11/01) by a doctor or other health professional’’ in WTC rescue and recovery workers (29). Of the 25,748 WTC workers without a prior history of asthma, newly diagnosed asthma was reported by 926 workers, for a three-year incidence rate of 3.6%, or 12 times higher than the expected rate of 0.3% in the general adult population (30). Increased incidence of newly diagnosed asthma was associated with (a) being caught in the dust cloud on 9/11/01, (b) earlier arrival time relative to the collapse, (c) work on the pile, and (d) cumulative exposure (especially greater than 90 days) (29). When all of the above factors were adjusted for in a multivariate analysis, occupation and work tasks were not significant predictors of risk (29). Pulmonary function declines or abnormalities were significantly related to WTC exposure intensity (based on arrival time) in FDNY and non-FDNY workers (Table 1). This remained true even after accounting for pre-existent disease and/or cigarette smoking (8,10,22,27,28,31,32). For 12,079 FDNY rescue workers in the first year post-WTC, a significantly greater average annual decline in forced expiratory volume in 1-second (FEV1) of 372 mL was noted in the first year post 9/11/01 when compared to the normal annual decline of 31 mL found in the five years of pre-WTC testing—a substantial accelerated decline in pulmonary function (32). Similar findings were found for the forced vital capacity (FVC). In the NY/NJ consortium report on 8384 non-FDNY workers/volunteers, 28% had abnormal pulmonary function test results (10). They also found that a low (FVC, a measure of lung capacity) was five times more likely among the nonsmoking portion of their cohort than expected in the general U.S. population (which includes smokers and nonsmokers) (10). Overall, WTC dust exposure intensity was related to lower FVC and a higher rate of pulmonary function test abnormalities (10), demonstrating that WTC exposure had a substantial impact on lung function. Studies in both the cohorts (FDNY and non-FDNY) are currently underway to determine the course of pulmonary function over the next five years post-WTC, specifically, whether it has improved, stabilized, or declined, if there are differences in clinical course within or between the cohorts, and which factors might be predictive of favorable or unfavorable outcome.
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For NYC residents, in a telephone survey performed five to nine weeks after 9/11, 27% of known adult asthmatics questioned said that they experienced more severe asthma symptoms in the weeks following the attacks (19). In a post9/11/01 study of Battery Park residents (located adjacent to WTC), who did not report a prior history of asthma, increased respiratory symptoms were reported and airway hyperreactivity was demonstrated by methacholine challenge testing (20). A study of Chinese children showed increased asthma medication use in a clinic located near WTC, as compared to a clinic located in Queens with similar patients and physician staffing (21). A survey of Medicaid patients during the first three months post collapse (9/11/01 to 12/31/01) showed a significant increase in self-reports of worsening asthma in both lower Manhattan and western Brooklyn and those reporting worsening of their asthma did increase their utilization of asthma healthcare services (33). VI.
Interstitial Lung Diseases
Reports have shown a higher-than-expected rate of sarcoidosis or sarcoid-like granulomatous lung disease in FDNY rescue workers (34). Environmental causes of sarcoidosis or sarcoidosis-like granulomatous disease are well established (35). In the first five years post-WTC (9/11/01 to 9/10/06), pathologic evidence consistent with new-onset sarcoidosis was found in 26 FDNY rescue workers—all with intrathoracic adenopathy (enlarged lymph nodes) and 6 (23%) with additional disease outside the chest (34). Figure 1 shows that 13 FDNY patients were identified during the first year post-WTC (yielding an incidence rate of 86 per 100,000) and 13 during the next four years (yielding an average annual
Figure 1 The number of cases of biopsy proven World Trade Center sarcoid-like granulomatous pulmonary disease (WTC-SLGPD) in the five years since 9/11/01 as compared to pre-WTC cases of sarcoidosis or SLGPD starting from 1985 in rescue workers from the Fire Department of the City of New York (FDNY).
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incidence rate of 22 per 100,000, as compared to 15 per 100,000 for the FDNY personnel during the 15 years pre-WTC and 5–7 per 100,000 for non-FDNY male Caucasian populations) (36). Early arrival time was not a predictor of disease and cumulative exposure time was not reported, but the number of patients with disease was too small to reliably demonstrate an effect. This abnormally high incidence raises the possibility that unknown causative environmental agents were generated or aerosolized during the WTC collapse/ combustion (35). Thus far, studies of WTC patients with sarcoidosis have not identified definitively which environmental agent(s) may be responsible for this disease, and the role of individual susceptibility to such exposures remains to be studied. To date, with the exception of sarcoidosis, interstitial lung diseases have not been reported in any case series or population study of WTC workers, but single-case reports of eosinophilic pneumonia (37), bronchiolitis obliterans (38), and granulomatous pneumonitis (39) have been described (Table 1). The lay press has reported at least four case fatalities in non-FDNY WTC-exposed subjects due to interstitial pulmonary fibrosis, sarcoidosis (with cardiopulmonary involvement), and granulomatous pneumonitis (40). In addition, the FDNY WTC Medical Monitoring and Treatment Program has identified two cases of eosinophilic pneumonitis (37) (both resolved on systemic corticosteroids without recurrence) and five cases of bilateral pulmonary fibrosis (including one fatality; personal communication D. Prezant). These six cases showed no pathologic evidence of granulomatous disease or sarcoidosis, and specialized pathologic analyses have not yet been performed to determine if any specific contaminant (silica, heavy metal, etc) was present.
VII.
Diagnostic Evaluation
The goal of this section is not to review respiratory diagnosis, treatment, and patient management treatment strategies in general but rather to concentrate on those aspects that might be unique or specific to WTC disease or for that matter nearly any disaster with significant exposure to respirable particulates and combustion by-products. The patient history should include questions to document prior and current exposures (environmental and occupational), the intensity and duration of exposure(s), the temporal relationship of symptoms to exposure and whether these symptoms were new in onset or, for those with preexisting disease, whether they represent acute or chronic exacerbations. Strategies for evaluating the intensity of exposure include completing a timetable recounting exposure, the time of first exposure, the time of last exposure, the number of hours, and days exposed; the individual’s location during exposure; a description of specific activities during exposure; and for respiratory protection the type and extent of use. Physical examination should focus on all areas of potential
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exposure including skin, eyes, mucous membranes, upper and lower airway, lung, and any other exposure-specific sites. An important consideration when obtaining the medical history is accounting for the ‘‘healthy-worker effect.’’ Because rescue workers are generally healthy and physically active prior to exposure, the severity of their symptoms and findings may be different than the general population. Post-exposure, they may remain asymptomatic at rest or even with mild exercise. Changes from baseline and provocability (exercise, irritant exposures, and changes in temperature and humidity) may be more important. Attention should be paid to the emotional impact, not only of the exposure itself, but also of the development of respiratory and physical impairments that may have resulted from the exposure to the mentally and physically stressful environment. Because post-traumatic stress is a common complication, some assessment of prior mental health history, current stress, support system, and resilience is important. Mental health issues and concerns may complicate ‘‘WTC cough’’ treatment and adherence with medication use. Initial pulmonary function evaluation includes spirometry. As these records may be used for diagnosis, treatment, and litigation, careful attention to quality control should be maintained. Post-bronchodilator spirometry can be part of this initial evaluation or can be reserved for those patients with (a) symptoms, (b) spirometry that is abnormal (<80% predicted) or even at the lower limits of normal (healthy-worker effect), or (c) who show a significant decrease from prior spirometry (if available). Abnormalities in pulmonary function should be further investigated as clinically indicated with determination of lung volumes, diffusion, bronchodilator response, nonspecific bronchial reactivity, and/or chest CT imaging as resources allow. A restrictive impairment (normal to supranormal FEVI/FVC ratio) with significant improvement after bronchodilator administration (8,10,14), hyperreactivity after methacholine challenge testing (8,22,32), normal lung volumes (8), and normal diffusion (8) has been described after inhalation exposures. For these reasons, we believe it is more accurate to classify this finding as ‘‘pseudo-restriction’’ until further diagnostic testing is performed. This may be the result of mucous impaction, air trapping, or other yet undetermined pathophysiology. Predisaster exposure, many may have had above normal pulmonary function when expressed as percent predicted and, therefore, use of cut-off points to judge for ‘‘normality’’ in this population should be carefully and individually evaluated. This fact is highlighted by the NYC firefighter WTC study (8,32). Spirometry results obtained after WTC exposure were for most firefighters above the lower limits of predicted normal for the general population but when compared to their own individual spirometry results obtained pre-exposure, significant losses in pulmonary function were noted and the decrease demonstrated a dose-intensity effect with the greatest decrease observed in those present on 9/11/01 during the morning of the collapse (32). Given the unfortunate likelihood that the first responders may suffer future
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exposures, we recommend that all receive annual ‘‘baseline’’ spirometry as part of their general health monitoring. In symptomatic patients with normal or near-normal spirometry results and symptoms following the disaster consistent with hyperreactivity or asthma, the methacholine challenge test should be considered if a formal diagnostic test is required. If formal diagnostic proof is not required for legal, disability, or research purposes, most physicians reserve this test for symptomatic patients who do not report classic symptoms or who fail to report or demonstrate a response to bronchodilators. Under any circumstance, challenge testing is contraindicated due to safety considerations when spirometry shows anything less than minimal abnormalities (41). In patients who do not report symptoms consistent with hyperreactivity or asthma or who have significant abnormalities on spirometry or chest imaging, pulmonary function tests including full lung volumes and diffusing capacity are recommended as the next diagnostic test after spirometry and instead of methacholine challenge testing, especially if hypoxic or restrictive disease is suspected. In asymptomatic individuals, chest radiographs generally find no acute abnormalities. However, there may be widespread interest amongst those exposed to chest radiographs as new ‘‘baselines.’’ In symptomatic patients, chest radiographs and CT scans have been reported to show bronchiectasis, bronchiolitis obliterans, atelectasis, lobar consolidation, and interstitial pneumonitis (hypersensitivity, eosinophilic pneumonitis, granulomatous disease, and fibrosis) (4). Inspiratory and expiratory CT scanning have been utilized to show air trapping, bronchial wall thickening, and mosaic attenuation (8). Because the clinical utility of these findings in a nonresearch setting remains unclear, we recommend that inspiratory and expiratory CT scan of the chest be reserved for individuals with significant unexplained symptoms, hypoxia, or reduced total lung capacity (TLC) or carbon monoxide lung diffusion capacity (DLCO). Another area of intense research is the use of CT scans of the chest for lung cancer screening (42). Their future use in high-risk patients (high exposure; tobacco smokers) might be a consideration depending on the results of soon to be completed lung cancer screening studies in tobacco smokers from the general population. Invasive diagnostic testing such as induced sputum, bronchoalveolar lavage, and/or biopsy following exposure in asymptomatic and symptomatic rescue workers have been used to demonstrate increased markers of inflammation and particle deposition exposure (12,37). While these measures may have value in a research setting, they have limited diagnostic or prognostic value. In a clinical setting, bronchoscopy should be performed on those with significant abnormalities on chest imaging or perhaps, when there is failure to respond to therapy. Sinus CT scan and direct laryngoscopy are recommended in those with chronic rhinosinusitis unresponsive to medical treatment for at least three months (43). Gastroesophageal endoscopy is recommended for those with GERD either unresponsive to medical treatment or with reoccurrence after two to three months of therapy (44).
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Treatment
Not many references describing the treatment of WTC or disaster-related chronic cough or dyspnea have been published. Recently, consensus treatment guidelines have been published as a joint collaborative effort of the three WTC centers of excellence (FDNY, NY/NJ consortium coordinated by Mt. Sinai Medical Center, and the Environmental Health Center at Bellevue Hospital) and the WTC Registry (24). The recommended approach includes a comprehensive plan of synergistic care treating the upper and lower airways with (a) nasal/sinuses with nasal steroids and decongestants (Fig. 2), (b) gastroesophageal reflux with proton pump inhibitors and dietary modification (Fig. 2), and (c) the lower airway with bronchodilators, corticosteroid inhalers, and leukotriene modifiers (Fig. 3). For the minority that uses tobacco products, a multimodality tobacco cessation program should be instituted (45) to improve treatment success rates and reduce the incidence of late-emerging diseases such as malignancy and cardiac and
Figure 2 Treatment algorithm for ‘‘WTC cough’’ when presentation suggests that the primary causes are upper airway–related diseases––chronic rhinosinusitis and/or gastroesophageal reflux disorder.
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Figure 3 Treatment algorithm for WTC cough when presentation suggests that the primary causes are lower airway–related diseases—obstructive (e.g., asthma, bronchitis) or restrictive (interstitial diseases).
cerebral vascular diseases. Most patients have reported symptoms and required treatment for involvement of at least two of the above organ systems. Our experience has proven the multicausality of respiratory symptoms in a disasterexposed population, with contribution of any combination of upper and lower respiratory processes. When the clinical presentation is atypical (e.g., interstitial lung disease) or there is failure to respond after approximately three months of treatment, we recommend additional invasive diagnostic testing such as chest CT, bronchoscopy, sinus CT, laryngoscopy, and/or endoscopy (23,24,43,44,46–49). As the WTC dust cloud was unique in its magnitude and potential toxic exposure, prior experience does not allow reliable prediction of the long-term risk
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of late-emerging diseases or the relative importance of acute high-level versus cumulative low-level exposures without carefully designed long-term monitoring and treatment programs. Our initial effort clearly shows the importance of a structured monitoring program leading to an early diagnosis and treatment.
References 1. Lioy PJ, Weisel CP, Millette JR, et al. Characterization of the dust/smoke aerosol that settled east of the World Trade Center (WTC) in lower Manhattan after the collapse of the WTC 11 September 2001. Environ Health Perspect 2002; 110:703–714. 2. Prezant DJ, Levin S, Kelly K, et al. Upper and lower respiratory diseases after occupational and environmental disasters. Mt. Sinai Med J (in press). 3. Brackbill R, Thorpe L, DiGrande L, et al. Surveillance for World Trade Center heath effects among survivors of collapsed and damaged buildings. Morb Mortal Wkly Rep 2006; 55:1–18. 4. Banauch GI, Dhala A, Prezant DJ. Pulmonary disease in rescue workers at the World Trade Center site. Curr Opin Pulm Med 2005; 11:160–168. 5. McGee JK, Chen LC, Cohen MD, et al. Chemical analysis of World Trade Center fine particulate matter for use in toxicologic assessment. Environ Health Perspect 2003; 111:972–980. 6. Edelman P, Osterloh J, Pirkle J, et al. Biomonitoring of chemical exposure among New York City firefighters responding to the World Trade Center fire and collapse. Environ Health Perspect 2003; 111:1906–1911. 7. Prezant DJ. WTC Cough Syndrome and its Treatment. Lung 2008; 186:945–1025. 8. Prezant DJ, Weiden M, Banauch GI, et al. Cough and bronchial responsiveness in firefighters at the World Trade Center site. N Eng J Med 2002; 347:806–815. 9. Kelly KJ, Niles J, Corrigan M, et al. FDNY WTC health effects. A six year assessment: September 2001–September 2007. New York: Fire Department of the City of New York, 2007. 10. Herbert R, Moline J, Skloot G, et al. The World Trade Center disaster and health of workers; five year assessment of a unique medical screening program. Environ Health Perspect 2006; 114:1853–1858. 11. Toren K, Brisman J, Hagberg S, et al. Improved nasal clearance among pulp-mill workers after the reduction of lime dust. Scand J Work Environ Health 1996; 22:102–107. 12. Fireman EM, Lerman Y, Ganor E, et al. Induced sputum assessment in New York City firefighters exposed to World Trade Center dust. Environ Health Perspect 2004; 112:1564–1569. 13. Centers for Disease Control and Prevention. Physical Health Status of World Trade Center rescue and recovery workers and volunteers––New York City, July 2002–– August 2004. Morb Mortal Wkly Rep 2004; 53:807–812. 14. Salzman SH, Moosavy FM, Miskoff JA, et al. Early respiratory abnormalities in emergency services police officers at the World Trade Center site. J Occup Environ Med 2004;46:113–122.
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15. Buyantseva LV, Tulchinsky M, Kapalka GM, et al. Evolution of lower respiratory symptoms in New York police officers after 9/11: a prospective longitudinal study. J Occup Environ Med 2007; 49:310–317. 16. Skloot G, Goldman M, Fischler D, et al. Respiratory symptoms and physiologic assessment of ironworkers at the World Trade Center disaster site. Chest 2004; 25: 1248–1255. 17. Tapp LC, Baron S, Bernard B, et al. Physical and mental health symptoms among NYC transit workers seven and one half months after the WTC attacks. Am J Ind Med 2005; 47:475–483. 18. Herbstman JB, Frank R, Schwab M, et al. Respiratory effects of inhalation exposure among workers during the clean-up effort at the WTC disaster site. Environ Res 2005; 99:85–92. 19. Centers for Disease Control and Prevention. Self-reported increase in asthma severity after the September 11 attacks on the World Trade Center—Manhattan, New York, 2001. Morb Mortal Wkly Rep 2002; 51:781–784. 20. Reibman J, Lin S, Hwang S, et al. The World Trade Center residents’ respiratory health study: new onset respiratory symptoms and pulmonary function. Environ Health Perspect 2005; 113:406–411. 21. Szema AM, Khedkar M, Maloney PF, et al. Clinical deterioration in pediatric asthmatic patients after September 11, 2001. J Allergy Clin Immunol 2004; 113:420–426. 22. Banauch GI, Alleyne D, Sanchez R, et al. Persistent bronchial hyperreactivity in New York City firefighters and rescue workers following collapse of World Trade Center. Am J Respir Crit Care Med 2003; 168:54–62. 23. Melvin R, Pratter Christopher E, et al. An empiric integrative approach to the management of cough: ACCP evidence-based clinical practice guidelines. Chest 2006; 129:222S–231S. 24. Friedman S, Cone J, Eros-Sarnyai M, et al. Clinical guidelines for adults exposed to World Trade Center Disaster (Respiratory and Mental Health). City Health Information. New York: NYC Department of Health and Mental Hygiene, September 2006. 25. Brooks SM, Weiss MA, Bernstein IL. Reactive airways dysfunction syndrome. Chest 1985; 88:376–384. 26. Gavett S, Haykal-Coates N, Highfill J, et al. World Trade Center fine particulate matter causes respiratory tract hyperresponsiveness in mice. Environ Health Perspect 2003; 111:981–991. 27. Banauch GI, Dhala A, Alleyne D, et al. Bronchial hyperreactivity and other inhalation lung injuries in rescue/recovery workers after the World Trade Center collapse. Crit Care Med 2005; 33:S102–S106. 28. Banauch GI, Dhala A, Prezant DJ. Airway dysfunction in rescue workers at the World Trade Center site. Curr Opin Pulm Med 2005; 11:160–168. 29. Wheeler K, McKelvey, Thorpe L, et al. Asthma diagnosed after September 11, 2001 among rescue and recovery workers: findings from the World Trade Center registry. Environ Health Perspect 2007; 115(11):1584–1590. 30. Reed CE. The natural history of asthma. J Allergy Clin Immunol 2006; 118:543–548. 31. Feldman DM, Baron S, Mueller CA, et al. Initial symptoms, respiratory function and respirator use in New York City firefighters responding to the World Trade Center (WTC) disaster. Chest 2004; 125:1256–1264.
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32. Banauch GI, Hall C, Weiden M, et al. Pulmonary function loss after World Trade Center exposure in the New York City Fire Department. Am J Respir Crit Care Med 200; 174:312–319. 33. Wagner VL, Radigan MS, Roohan PJ, et al. Asthma in Medicaid managed care enrollees residing in New York City: results from a post-World Trade Center disaster survey. J Urban Health 2005; 82:76–89. 34. Izbicki G, Chavko R, Banauch GI, et al. World Trade Center ‘‘sarcoid-like’’ granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest 2007; 131:1414–1423. 35. Culver DA, Newman LS, Kavuru MS. Gene-environment interactions in sarcoidosis: challenge and opportunity. Clin Dermatol 2007; 25:267–275. 36. Prezant D, Dhala A, Goldstein A, et al. The incidence, prevalence and severity of sarcoidosis in New York City firefighters. Chest 1999; 116:1183–1193. 37. Rom WN, Weiden M, Garcia R, et al. Acute eosinophilic pneumonia in a New-York city firefighter exposed to World Trade center dust. Am J Respir Crit Care Med 2002; 166:797–800. 38. Mann JM, Sha KK, Kline G, et al. World Trade Center dyspnea: bronchiolitis obliterans with functional improvement: case report. Am J Ind Med 2005; 48: 225–229. 39. Safirstein BH, Klukowitcz A, Miller R, et al. Granulomatous pneumonitis following exposure to the World Trade center collapse. Chest 2003; 123:301–304. 40. DePalma Anthony. Medical views of 9/11 dust shows big gaps. New York Times. October 26, 2006. 41. American Thoracic Society. Guidelines for methacholine and exercise challenge testing–1999. Am J Respir Crit Care Med 2000; 161:309–1329. 42. Mulshine J, Sullivan D. Lung cancer screening. N Engl J Med 2005; 352: 2714–2720. 43. Gwaltney JM Jr., Jones JG, Kennedy DW. Medical management of sinusitis: educational goals and management guidelines. The International Conference on sinus disease. Ann Otol Rhinol Laryngol Suppl 1995; 167:22–30. 44. DeVault KR, Castell DO, et al. American College of Gastroenterology: updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005; 100:190–200. 45. Bars MP, Banauch GI, Appel DW, et al. ‘‘Tobacco Free with FDNY’’–The New York City Fire Department World Trade Center tobacco cessation study. Chest 2006; 129:979–987. 46. Irwin RS, Madison JM. Diagnosis and treatment of chronic cough due to gastroesophageal reflux disease and postnasal drip syndrome. Pulm Pharmacol Ther 2002; 15:261–266. 47. Banauch GI, McLaughlin M, Hirschhorn R, et al. Injuries and illnesses among New York City Fire Department rescue workers after responding to the World Trade Center attacks. Morb Mortal Wkly Rep 2002; 51:1–5. 48. Centers for Disease Control and Prevention. Rapid assessment of injuries among survivors of the terrorist attack on the World Trade Center–New York City, September 2001. Morb Mortal Wkly Rep 2002; 51:1–5. 49. Berrı´os-Torres SI, Greenko JA, Phillips M, et al. World Trade Center rescue worker injury and illness surveillance, New York, 2001. Am J Prev Med 2003; 25:79–87.
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24 Pathogenesis and Epidemiology of ANCA-Associated Vasculitides
J. CHARLES JENNETTE and RONALD J. FALK University of North Carolina, Chapel Hill, North Carolina, U.S.A.
I.
Introduction
Vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCAs) manifests as a spectrum of clinicopathologic syndromes including microscopic polyangiitis, Wegener’s granulomatosis, Churg-Strauss syndrome, and organlimited disease (Tables 1 and 2) (1,2). Microscopic polyangiitis is characterized by systemic small-vessel vasculitis and no evidence for granulomatous inflammation (3). Wegener’s granulomatosis has small-vessel vasculitis that is indistinguishable from the small-vessel vasculitis of microscopic polyangiitis, but in addition, it has necrotizing granulomatous inflammation, which most often affects the upper and lower respiratory tracts (3). Churg-Strauss syndrome has small-vessel vasculitis and necrotizing granulomatous inflammation with the additional defining features of asthma and blood eosinophilia (3). However, it is important to note that limited forms of Wegener’s granulomatosis and ChurgStrauss syndrome occur, for example, limited to the respiratory tract, which are less likely to have circulating ANCAs in the absence of systemic vasculitis and glomerulonephritis (4–6).
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Table 1 Definitions of Wegener’s Granulomatosis, Microscopic Polyangiitis, and Churg-Strauss Syndrome Adopted by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis Microscopic polyangiitis
Necrotizing vasculitis with few or no immune deposits affecting small vessels, i.e., capillaries, venules, or arterioles. Necrotizing arteritis involving small and medium-sized arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels, e.g., capillaries, venules, arterioles, and arteries. Necrotizing glomerulonephritis is common. Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small- to medium-sized vessels, and associated with asthma and blood eosinophilia
Wegener’s granulomatosis
Churg-Strauss syndrome
Table 2 Comparison of Approximate Frequency of Manifestations of Microscopic Polyangiitis to Several Other Forms of Small-Vessel Vasculitis Microscopic polyangiitis (%)
Wegener’s granulomatosis (%)
Churg-Strauss syndrome (%)
50 90 35 40 60 30 50
90 80 90 40 60 50 50
70 45 50 60 50 70 50
Pulmonary Renal ENT Cutaneous Musculoskeletal Neurologic Gastrointestinal Source: Modified from Ref. 21.
II.
Epidemiology
ANCA-associated vasculitis can occur at any age but is most common in older individuals with a mean age at diagnosis of 58 years (7). Males and females are affected equally. ANCA-associated vasculitis has an incidence in North America and Europe of approximately 10 to 25 per million among Caucasians, with a lower frequency in African-Americans, and the incidence may be increasing (1,8–10). The incidence of Wegener’s granulomatosis in Europe ranges from approximately 10 per million in northern countries (e.g., Norway and the United Kingdom) to 5 per million in southern countries (e.g., Spain). In contrast,
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microscopic polyangiitis has a lower incidence in northern European countries with an incidence of approximately 3 to 6 per million and a higher incidence in southern countries with an incidence of approximately 12 per million (9). Churg-Strauss syndrome has a much lower overall incidence in Europe of 0.5 to 4 per million (9). Compared to North America and Europe, patients in Asia have a higher incidence and prevalence of myeloperoxidase (MPO)-ANCA disease compared to proteinase-3 (PR3)-ANCA disease (11,12). Environmental and genetic factors appear to influence the risk for ANCAassociated vasculitis (1). For example, silica exposure appears to be a risk factor for ANCA-associated vasculitis (13,14). ANCA and ANCA-associated vasculitis can be induced by exposure to certain drugs, best documented for propylthiouracil and hydralazine (15–19). ANCAs are more frequent in patients treated with propylthiouracil, which is used to treat thyroid disease; however, ANCAs are more frequent in patients with thyroid disease irrespective of treatment regimen (20), thus the respective roles of treatment for thyroid disease versus thyroid disease in risk for ANCA disease is difficult to discern.
III.
Pathology of ANCA-Associated Vasculitis
Any organ of the body and any type of vessel can be affected by ANCA-associated vasculitis (Table 2) (21). Capillaries, venules, arterioles, and small arteries are the most frequent targets; however, medium sized arteries, large arteries, and veins may be affected in a minority of patients (21,22). Although any organ can be affected, the lungs and kidneys are most often involved (Table 2), probably because of the high volume of blood flow and high density of small vessels, especially the pulmonary alveolar capillaries and renal glomerular capillaries, which are frequently involved in ANCA-associated vasculitis. ANCA-associated vasculitis, not anti-glomerular basement membrane (anti-GBM) disease, is the most common cause for pulmonary-renal syndrome (23). Of note, patients with pulmonary-renal syndrome may have concurrent ANCA and anti-GBM antibodies (23). Acute ANCA-associated vasculitis is characterized pathologically by neutrophil-rich inflammatory infiltrates, leukocytoclasia, and focal fibrinoid necrosis (22). Monocytes and eosinophils also may be present in acute lesions. Eosinophils are especially conspicuous in acute vasculitic and granulomatous lesions of Churg-Strauss syndrome. Within a few days of onset of lesions, macrophages and T lymphocytes replace the acute inflammatory cells, and the lesion progresses from a necrotizing to a sclerosing process. A very distinctive immunopathologic characteristic of ANCA-associated vasculitis is the frequent absence or paucity of immunohistologic staining for immunoglobulins in vessel walls, which distinguished ANCA-associated vasculitis from immune complex vasculitis and anti-GBM disease (21,22). However, a minority of patients have concurrent anti-GBM or immune complex disease and thus are not pauciimmune, but rather have substantial vascular deposition of immunoglobulins and
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complement. Approximately 30% of patients with anti-GBM disease have concurrent ANCA or will develop ANCA at a later time (23,24). Usually, antiGBM antibodies disappear after treatment, whereas ANCA antibodies tend to persist and are associated with recurrences of ANCA-associated vasculitis (24). Pulmonary lesions caused by ANCA-associated vasculitis are quite variable and range from acute vasculitic and necrotizing granulomatous lesions to chronic sclerotic vascular, interstitial, and airway lesions. For example, an evaluation of pathologic lesions in lung tissue from 27 patients with ANCAassociated vasculitis identified alveolar capillaritis in 63%, necrotizing granulomatous inflammation not involving major airways in 30%, bronchocentric necrotizing granulomatous inflammation in 15%, bronchiolitis obliterans organizing pneumonia in 19%, and interstitial fibrosis in 48% (25). Each type of lesion was identified in patients with either MPO-ANCA or PR3-ANCA. IV.
ANCA Serology
In patients with small-vessel vasculitis, the two major autoantigen specificities for ANCAs are for MPO-ANCA (26) and PR3-ANCA (27–30). MPO and PR3 are enzymes in the primary granules of neutrophils and the lysosomes of monocytes. As discussed in detail later, ANCAs can interact with MPO or PR3 and cause activation of neutrophils and monocytes, which appears to be a primary event in the pathogenesis of vasculitis in patients with ANCAs (30). As summarized in Table 3, all patients with the categories of vasculitis associated with ANCAs do not have identifiable ANCAs in the circulation. Pauci-immune small-vessel vasculitis that is ANCA positive has no fundamental pathologic differences, whether it is ANCA positive or ANCA negative. ANCAnegative patients may have circulating autoantibodies that activate leukocytes just as MPO-ANCAs and PR3-ANCAs, but these autoantibodies are not detected Table 3 Approximate Frequency of ANCA with Specificity for PR3-ANCA or MPO-ANCA in Patients with Active Untreated Wegener’s Granulomatosis (Systemic, Not Limited), Microscopic Polyangiitis, Churg-Strauss Syndrome, and Renal-limited Pauci-immune Crescentic Glomerulonephritis Wegener’s granulomatosis MPO-ANCA PR3-ANCA ANCA Negative
20% 75% 5%
Microscopic polyangiitis 50% 40% 10%
Churg-Strauss syndrome 40% 5% 55%
Renal-limited vasculitis 65% 25% 10%
Note that Wegener’s granulomatosis limited to the upper respiratory tract has a lower frequency of ANCA (approximately 70%) compared to systemic disease, and Churg-Strauss syndrome with systemic vasculitis and glomerulonephritis has a higher frequency of ANCA than Churg-Strauss syndrome without glomerulonephritis. Abbreviations: ANCA, antineutrophil cytoplasmic autoantibodies; MPO, myeloperoxidase; PR3, proteinase 3.
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in current assay systems. For example, autoantibodies to human lysosomalassociated membrane protein 2 (h-lamp-2) (31) may play pathogenic role in patients who lack MPO-ANCA or PR3-ANCA. Pauci-immune small-vessel vasculitis in ANCA-negative patients may be mediated by a very different mechanism that activates a pathway of injury similar to ANCA-mediated injury. For example, anti-endothelial autoantibodies (AECA) may play a pathogenic role in ANCAnegative vasculitis, although this has not been documented. AECA have been reported in ANCA-positive vasculitis where they may have a synergistic effect, however, the importance of AECA in the pathogenesis of vasculitis remains unclear (32). Patients who have Wegener’s granulomatosis with systemic vasculitis and glomerulonephritis are more likely to have ANCAs than patients with Wegener’s granulomatosis limited to the respiratory tract (6). Patients with Churg-Strauss syndrome with systemic vasculitis and glomerulonephritis are more likely to have ANCAs than patients with Churg-Strauss syndrome who do not have systemic vasculitis and glomerulonephritis (4,5). This implies that the pathogenesis of the granulomatous respiratory tract inflammation may be different from the pathogenesis of the systemic vasculitis and glomerulonephritis. V.
Pathogenesis
A.
Clinical Observations Suggesting Pathogenicity of ANCAs
In 1954, Godman and Churg proposed that microscopic polyangiitis, Wegener’s granulomatosis, and Churg-Strauss syndrome might have a common pathogenesis because of their many shared clinical and pathologic features (33). The association of these three clinicopathologic syndromes with ANCAs further supports this possibility and implicates ANCAs in their pathogenesis. Additional clinical observations that support but do not prove a role for ANCAs in pathogenesis include the correlation of ANCA titers with disease outcomes (34,35), the value of plasma exchange in treatment (36), the induction of ANCA accompanied by small-vessel vasculitis by drugs such as propylthiouracil, penicillamine, and hydralazine (15–19), and the correlation of ANCA-associated vasculitis with higher levels of ANCA antigens on the surface of circulating neutrophils where they are accessible to interact with ANCAs (37,38). Although so far only one case has been documented, the report of a neonate who apparently developed glomerulonephritis and pulmonary hemorrhage secondary to transplacental passage of MPO-ANCA immunoglobulin G (IgG) from a mother with microscopic polyangiitis is the strongest clinical evidence that ANCA IgG can cause ANCA-associated vasculitis (39). Shortcomings of this observation include the absence of pathologic confirmation of the lesions and the absence of corroborating case reports. This case also suggests that antigen-specific T cells are not required to cause the vasculitis or glomerulonephritis, although T cells are undoubtedly involved in the immunogenesis of the autoimmune response and may be involved in the progression of lesions.
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In Vitro Observations Supporting Pathogenicity of ANCAs
The pathogenic potential of ANCAs is supported by numerous in vitro experiments. For example, incubation of ANCA IgG with cytokine-primed neutrophils causes the release of toxic reactive oxygen species and destructive granule enzymes (40). Pretreatment of neutrophil with cytokines increases the expression of small amounts of ANCA antigens at the surface of neutrophils, which can interact with ANCAs (41). Monocytes as well as neutrophils contain MPO and PR3 (42,43). In vitro, ANCA IgG causes monocytes to release oxygen radicals (44) and inflammatory cytokines (45,46). However, on the basis of the numbers of monocytes compared to neutrophils available to become activated and on the appearance of acute lesions with prominent neutrophilic infiltration, neutrophils probably are more important than monocytes in mediating the acute inflammatory injury of ANCA-associated vasculitis. Once monocytes transform into macrophages, ANCA antigens (MPO and PR3) are lost, thus, macrophages cannot interact directly with ANCAs (43). Activation of neutrophils by ANCAs involves engagement of Fc receptors by immunoglobulin bound to MPO or PR3 on the surface of neutrophils or in the microenvironment adjacent to neutrophils (47–49), as well as by the interaction of bivalent antigen binding domains with ANCA antigens on the surface of neutrophils (50,51) (Fig. 1). The isotype of ANCAs modulates the nature of neutrophil activation (49). At sites of vasculitis, ANCAs probably bind not only to ANCA antigens at the surface of neutrophils and monocytes, but also to ANCA antigens that have adsorbed onto endothelial cells and exposed vessel wall matrix (51) (Fig. 1). In vitro studies have documented that activation of leukocytes by ANCAs can release factors that are injurious to endothelial cells (52–59). Endothelial injury by ANCA-activated leukocytes requires interplay between multiple cytokine and adhesion molecule ligands and their receptors in the microenvironment at the site of vasculitis (55–59). Overall, in vitro activation of neutrophils by ANCA IgG causes neutrophil adherence to endothelial cells, diapedesis through endothelial monolayers, and release of toxic factors that kill endothelial cells (Fig. 1). Similar events in vivo would result in histologic changes that are characteristic of early acute ANCA-associated vasculitis, including neutrophil margination and infiltration and vascular necrosis. C.
Experimental Animal Observations Supporting Pathogenicity of ANCAs
Direct experimental evidence for the pathogenicity of ANCA IgG is provided by the observation that intravenous injection of anti-MPO IgG into mice causes a pauci-immune necrotizing glomerulonephritis and a pauci-immune systemic small-vessel vasculitis that is pathologically identical to human ANCA-associated vasculitis (60–62). Lung involvement in this animal model usually manifests as hemorrhagic alveolar capillaritis, although a minority of mice develop necrotizing
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Figure 1 Diagram of likely events in the pathogenesis of ANCA-associated vasculitis based on in vitro and in vivo experimental observations. Beginning in the upper left and moving to the right, cytokines or other priming factors induce neutrophils to express more ANCA antigens at the cell surface where they are available for binding to ANCAs, which activates neutrophils by both Fc receptor engagement and Fab’2 binding. Factors released by neutrophils activate the alternative complement pathway, which generates factors that amplify recruitment and activation of neutrophils. Activated neutrophils adhere to endothelial cells via adhesion molecules and release toxic factors that cause apoptosis and necrosis. Abbreviation: ANCA, antineutrophil cytoplasmic autoantibodies. Source: From Ref. 64.
granulomatous inflammation resembling Wegener’s granulomatosis. Identical glomerulonephritis and vasculitis can be induced by injecting anti-MPO antibodies into wild type mice or Rag2– /– mice that lack immune-competent B cells and T cells of their own. Development of disease in the Rag2–/– mice demonstrates that antigen-specific T cells are not required for induction of the acute vasculitic lesions. Injection of mice with bacterial lipopolysaccharide (LPS) augmented the induction of disease by anti-MPO (61). This was accompanied by increased circulating tumor necrosis factor a (TNF-a), which has been shown in vitro to enhance activation of neutrophils by ANCA (40,41). Treatment with anti-TNF-a attenuated, but did not prevent, the LPS-mediated aggravation of anti-MPO IgGinduced glomerulonephritis. Thus, synergistic proinflammatory stimuli augment ANCA induced pathogenic events in vivo and in vitro. This corresponds to the
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clinical observation that infections, such as upper respiratory tract infections, correlate with the onset and exacerbation of ANCA-associated vasculitis (1). The importance of neutrophils as the primary effector cells in this mouse model was documented by demonstrating that neutrophil depletion with a rat monoclonal antibody (NIMP-R14) completely prevented the induction of glomerulonephritis by injection of anti-MPO IgG (62). Influx of neutrophils (and not T lymphocytes) was demonstrated by immunohistochemistry as the earliest cellular event in the evolution of microvascular lesions (62). A variation of this mouse model was produced by transplanting wild type (Mpoþ/þ) bone marrow cells into irradiated MPO knockout (Mpo – /–) mice or vice versa (63). When injected with anti-MPO IgG, chimeric Mpo – /– mice with circulating MPOþ/þ neutrophils developed glomerulonephritis, whereas chimeric Mpoþ/þ mice with circulating MPO – /– neutrophils did not. This demonstrates that bone marrow–derived cells are sufficient and also necessary for causing anti-MPO disease in this animal model (63). Although, as with human disease, complement deposition is not conspicuous in the vasculitic lesions, multiple experimental observations indicate that complement activation has an important pathogenic role in this model (64,65). Depletion of complement with Cobra venom factor completely prevents the development of glomerulonephritis and vasculitis after injection of MPO-IgG or transfer of anti-MPO splenocytes (64). Injection of anti-MPO IgG into mice with knockout of various complement genes demonstrates that the alternative complement pathway, but not the classic pathway or the lectin pathway, is required for anti-MPO IgG mediated disease induction (64). Specifically, C4 – /– mice with blockade of the classic pathway and the lectin pathway develop disease that is same as in wild type mice, whereas C5 – /– mice with blockade of all pathways and factor B – /– mice with selective blockade of the alternative pathway are completely protected from disease induction. In accord with an important role for complement, the C5-inhibiting monoclonal antibody (BB5.1) prevents the induction of glomerulonephritis in mice after injection of anti-MPO IgG and LPS (65). Even when the anti-C5 antibody is administered a day after the antiMPO, there is a marked reduction in disease induction. To test a hypothetical mechanism for complement involvement in ANCAmediated vasculitis, and to demonstrate that complement might be involved in human ANCA-associated vasculitis, MPO-ANCA and PR3-ANCA IgG isolated from patients were tested for the ability to activate neutrophils and the alternative complement pathway (64). In the presence of human MPO-ANCA and PR3ANCA IgG, but not control IgG, human neutrophils released factors that activated complement as measured by the generation of C3a. This supports the hypothesis that activation of neutrophils by ANCA IgG causes release of factors that activate complement via the alternative pathway. Activation of complement generates many inflammatory factors, including C5a, a potent neutrophil chemoattractant and activator that may be involved in the extremely aggressive necrotizing injury of ANCA-associated vasculitis (Fig. 1).
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A rat model of ANCA disease has been induced by immunizing rats with human MPO, which induces anti-MPO antibodies that cross-react with human and rat MPO (66). As detected by intravital microscopy, rats with circulating anti-MPO resulting from active immunization or passive administration developed firm adherence and transmigration of leukocytes in the mesenteric microvasculature when a synergistic chemokine was applied to exposed mesentery. Rats also developed focal hemorrhage in the mesenteric microvasculature at sites of chemokine application in the presence of circulating anti-MPO. The effect of TNF-a blockade on this rat model also has been tested (67). Anti-rat TNF monoclonal antibodies were administered after glomerulonephritis was established. This treatment significantly reduced albuminuria and prevented crescent formation (0% treated vs. 60% controls). Lung hemorrhage was also reduced. When analyzed by intravital microscopy, there was a 43% inhibition of leukocyte transmigration in mesenteric venules in response to topical cytokine stimulation. This amelioration of disease occurred with no difference in antiMPO antibody titers. This ameliorating effect of anti-TNF was similar to the affect of anti-TNF treatment in the mouse model of ANCA-associated vasculitis caused by injection of anti-MPO antibodies (61). VI.
Immunogenesis of the ANCA Autoimmune Response
A relatively novel and not definitively proven theory has been proposed for the origin of the ANCA autoimmune response (68). Patients with PR3-ANCA disease were found to have not only circulating antibodies against PR3 but also a separate set of circulating antibodies against peptides produced by the antisense strand of DNA that is complementary to the sense strand (anti-cPR3). Anti-PR3 and anti-cPR3 antibodies bind together as an anti-idiotypic pair, which is in line with a body of literature documenting that an immune response to one complementary peptide results in the production of anti-idiotypic antibodies that react with the other complementary peptide. This phenomenon has been confirmed in mice by immunization with cPR3 resulting in the development of not only anti-cPR3 antibodies but also anti-PR3 antibodies that react with PR3 and anti-cPR3 (68). These observations support the hypothesis that an immune response to a complementary PR3 peptide could result in the development of anti-idiotypic antibodies that recognize not only the idiotope on the anti-cPR3 antibodies but also the portion of the PR3 molecule to which the peptide is complementary. The cPR3 peptide could be derived endogenously, for example from PR3 anti-sense transcripts, or exogenously, for example from an infectious pathogen containing a peptide that mimics the antisense peptide of PR3. Such mimics of the antisense peptide would be advantageous to the pathogen because they could bind to the sense peptide on PR3 and inhibit its antimicrobial functions. Interestingly, mimics of the PR3 complementary peptide are present in several pathogens that have been associated with the development of PR3-ANCA and ANCA-associated vasculitis, including Ross river virus, Staphylococcus aureus,
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and Entamoeba histolytica (68). In fact, the first report of ANCA by David Davies in 1982 (69) was titled ‘‘Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology’’ because all of the patients had positive serology for Ross river virus, which carries a peptide mimic of complementary cPR3 (143). VII.
Summary
The collective clinical, in vitro experimental, and especially animal model data support a direct pathogenic role for ANCA in the pathogenesis of ANCAassociated vasculitis (Fig. 1). Data from multiple in vitro experiments indicate that ANCA IgG can activate neutrophils and monocytes through Fc receptor and Fab’2 binding resulting in adhesion to endothelial cells and release of cytotoxic factors. In vivo studies in experimental animals document that ANCA, represented by anti-MPO antibodies, can cause renal and systemic pauci-immune necrotizing vasculitis that closely resembles human ANCA-associated vasculitis. As with other autoimmune diseases, the overall development and progression of ANCA-associated vasculitis involves a complex interplay between multiple environmental, genetic, and biologic processes that initiate the autoimmune state, cause the specific immune pathogenesis of lesions, and, if resolution does not occur, lead to chronic progression of the lesions (Fig. 2).
Figure 2 Interrelationships between multiple etiologic and pathogenic factors in the development and progression of ANCA-associated vasculitis. Abbreviation: ANCA, antineutrophil cytoplasmic autoantibodies.
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References 1. Kallenberg CG. Antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Curr Opin Rheumatol 2007; 19:17–24 (review). 2. Jennette JC, Falk RJ. Nosology of primary vasculitis. Curr Opin Rheumatol 2007; 19:10–16 (review). 3. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37:187–192. 4. Sable´-Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med 2005; 143:632–638. 5. Sinico RA, Di Toma L, Maggiore U, et al. Renal involvement in Churg-Strauss syndrome. Am J Kidney Dis 2006; 47:770–779. 6. Finkielman JD, Lee AS, Hummel AM, et al. ANCA are detectable in nearly all patients with active severe Wegener’s granulomatosis. Am J Med 2007; 120:643, E9–E14. 7. Hogan SL, Falk RJ, Chin H, et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med 2005; 143:621–631. 8. Watts RA, Scott DG. Epidemiology of the vasculitides. Semin Respir Crit Care Med 2004; 25:455–464. 9. Watts RA, Lane S, Scott DG. What is known about the epidemiology of the vasculitides? Best Pract Res Clin Rheumatol 2005; 19(2):191–207. 10. Koldingsnes W, Nossent H. Epidemiology of Wegener’s granulomatosis in northern Norway. Arthritis Rheum 2000; 43:2481–2487. 11. Chen M, Yu F, Zhang Y, et al. Clinical [corrected] and pathological characteristics of Chinese patients with antineutrophil cytoplasmic autoantibody associated systemic vasculitides: a study of 426 patients from a single centre. Postgrad Med J 2005; 81:723–727. 12. Chen M, Yu F, Zhang Y, et al. Characteristics of Chinese patients with Wegener’s granulomatosis with antimyeloperoxidase autoantibodies. Kidney Int 2005; 68: 2225–2229. 13. Hogan SL, Satterly KK, Dooley MA, et al. Silica exposure in antineutrophil cytoplasmic autoantibody-associated glomerulonephritis and lupus nephritis. J Am Soc Nephrol 2001; 12:134–142. 14. Rihoza Z, Maixnerova D, Jancova E, et al. Silica and asbestos exposure in ANCAassociated vasculitis with pulmonary involvement. Ren Fail 2005; 27:605–608. 15. D’Cruz D, Chesser AM, Lightowler C, et al. Antineutrophil cytoplasmic antibodypositive crescentic glomerulonephritis associated with anti-thyroid drug treatment. Br J Rheumatol 1995; 34(11):1090–1091. 16. Morita S, Ueda Y, Eguchi K. Anti-thyroid drug-induced ANCA-associated vasculitis: a case report and review of the literature. Endocr J 2000; 47(4):467–470. 17. Dolman KM, Gans RO, Vervaat TJ, et al. Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet 1993; 342(8872): 651–652. 18. Vogt BA, Kim Y, Jennette JC, et al. Antineutrophil cytoplasmic autoantibodypositive crescentic glomerulonephritis as a complication of treatment with propylthiouracil in children. J Pediatr 1994; 124:986–988.
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19. Choi HK, Merkel PA, Walker AM, et al. Drug-associated antineutrophil cytoplasmic antibody-positive vasculitis: prevalence among patients with high titers of antimyeloperoxidase antibodies. Arthritis Rheum 2000; 43(2):405–413. 20. Lionaki S, Hogan SL, Falk RJ, et al. Association of thyroid disease and its treatment with ANCA small-vessel vasculitis: a case control study. Nephrol Dial Transplant 2007; 22(12):3508–3515. 21. Jennette JC, Falk RJ. Small vessel vasculitis. N Engl J Med 1997; 337:1512–1523. 22. Jennette JC, Falk RJ. The role of pathology in the diagnosis of systemic vasculitis. Clin Exp Rheumatol 2007; 25(1 suppl 44):S52–S56. 23. Niles JL, Bo¨ttinger EP, Saurina GR, et al. The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition. Arch Intern Med 1996; 156(4): 440–445. 24. Desai A, Goldschmidt RA, Kim GC. Sequential development of pulmonary renal syndrome associated with c-ANCA 3 years after development of anti-GBM glomerulonephritis. Nephrol Dial Transplant 2007; 22(3):926–929. 25. Gaudin PB, Askin FB, Falk RJ, et al. The pathologic spectrum of pulmonary lesions in patients with anti-neutrophil cytoplasmic antibodies specific for anti-proteinase 3 and anti-myeloperoxidase. Am J Clin Path 1995; 104:7–16. 26. Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 1988; 318:1651–1657. 27. Goldschmeding R, van der Schoot CE, ten Bokkel Huinink D, et al. Wegener’s granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils. J Clin Invest 1988; 4: 1577–15879. 28. Niles JL, McCluskey RT, Ahmad MF, et al. Wegener’s granulomatosis autoantigen is a novel neutrophil serine proteinase. Blood 1989; 74:1888–1893. 29. Jennette JC, Hoidal JH, Falk RJ. Specificity of anti-neutrophil cytoplasmic autoantibodies for proteinase 3. Blood 1990; 75:2263–2264. 30. Jennette JC, Xiao H, Falk RJ. The pathogenesis of vascular inflammation by antineutrophil cytoplasmic antibodies. J Am Soc Nephrol 2006; 17:1235–1242. 31. Kain R, Matsui K, Exner M, et al. A novel class of autoantigens of anti-neutrophil cytoplasmic antibodies in necrotizing and crescentic glomerulonephritis: the lysosomal membrane glycoprotein h-lamp-2 in neutrophil granulocytes and a related membrane protein in glomerular endothelial cells. J Exp Med 1995; 181:585–597. 32. Savage CO, Williams JM. Anti endothelial cell antibodies in vasculitis. J Am Soc Nephrol 2007; 18:2424–2426. 33. Godman GC, Churg J. Wegener’s granulomatosis. Pathology and review of the literature. Arch Pathol Lab Med 1954; 58:533–553. 34. Lurati-Ruiz F, Spertini F. Predictive value of antineutrophil cytoplasmic antibodies in small-vessel vasculitis. J Rheumatol 2005; 32:2167–2172. 35. Sanders JS, Huitema MG, Kallenberg CGM, et al. Prediction of relapses in PR3– ANCA associated vasculitis by assessing responses of ANCA titres to treatment. Rheumatology (Oxford) 2006; 45:724–729. 36. Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007; 18:2180–2188.
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37. Schreiber A, Busjahn A, Luft FC, et al. Membrane expression of proteinase 3 is genetically determined. J Am Soc Nephrol 2003; 14(1):68–75. 38. Schreiber A, Luft FC, Kettritz R. Membrane proteinase 3 expression and ANCAinduced neutrophil activation. Kidney Int 2004; 65(6):2172–2183. 39. Schlieben DJ, Korbet SM, Kimura RE, et al. Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs. Am J Kidney Dis 2005; 45(4):758–761. 40. Falk RJ, Terrell RS, Charles LA, et al. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A 1990; 87(11):4115–4119. 41. Charles LA, Caldas ML, Falk RJ, et al. Antibodies against granule proteins activate neutrophils in vitro. J Leukoc Biol 1991; 50(6):539–546. 42. van der Woude FJ, Rasmussen N, Lobatto S, et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet 1985; 1(8426):425–429. 43. Charles LA, Falk RJ, Jennette JC. Reactivity of antineutrophil cytoplasmic autoantibodies with mononuclear phagocytes. J Leukoc Biol 1992; 51(1):65–68. 44. Weidner S, Neupert W, Goppelt-Struebe M, et al. Antineutrophil cytoplasmic antibodies induce human monocytes to produce oxygen radicals in vitro. Arthritis Rheum 2001; 44(7):1698–1706. 45. Ralston DR, Marsh CB, Lowe MP, et al. Antineutrophil cytoplasmic antibodies induce monocyte IL-8 release. Role of surface proteinase-3, alpha1-antitrypsin, and Fcgamma receptors. J Clin Invest 1997; 100(6):1416–1424. 46. Casselman BL, Kilgore KS, Miller BF, et al. Antibodies to neutrophil cytoplasmic antigens induce monocyte chemoattractant protein-1 secretion from human monocytes. J Lab Clin Med 1995; 126:495–502. 47. Mulder AH, Stegeman CA, Kallenberg CG, et al. Activation of granulocytes by anti-neutrophil cytoplasmic antibodies (ANCA) in Wegener’s granulomatosis: a predominant role for the IgG3 subclass of ANCA. Clin Exp Immunol 1995; 101: 227–232. 48. Porges AJ, Redecha PB, Kimberly WT, et al. Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa. J Immunol 1994; 153(3):1271–1280. 49. Colman R, Hussain A, Goodall M, et al. Chimeric antibodies to proteinase 3 of IgG1 and IgG3 subclasses induce different magnitudes of functional responses in neutrophils. Ann Rheum Dis 2007; 66:676–682. 50. Kettritz R, Jennette JC, Falk RJ. Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils. J Am Soc Nephrol 1997; 8:386–394. 51. Williams JM, Ben Smith A, Hewins P, et al. Activation of the G(i) heterotrimeric G protein by ANCA IgG F(ab’)2 fragments is necessary but not sufficient to stimulate the recruitment of those downstream mediators used by intact ANCA IgG. J Am Soc Nephrol 2003; 14(3):661–669. 52. Savage CO, Gaskin G, Pusey CD, et al. Myeloperoxidase binds to vascular endothelial cells, is recognized by ANCA and can enhance complement dependent cytotoxicity. Adv Exp Med Biol 1993; 336:121–123. 53. Ewert BH, Jennette JC, Falk RJ. Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells. Kidney Int 1992; 41:375–383.
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54. Savage CO, Pottinger BE, Gaskin G, et al. Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells. Am J Pathol 1992; 141:335–342. 55. Radford DJ, Savage CO, Nash GB. Treatment of rolling neutrophils with antineutrophil cytoplasmic antibodies causes conversion to firm integrin-mediated adhesion. Arthritis Rheum 2000; 43:1337–1345. 56. Calderwood JW, Williams JM, Morgan MD, et al. ANCA induces beta2 integrin and CXC chemokine-dependent neutrophil-endothelial cell interactions that mimic those of highly cytokine-activated endothelium. J Leukoc Biol 2005; 77:33–43. 57. Ewert BH, Becker ME, Jennette JC, et al. Antimyeloperoxidase antibodies induce neutrophil adherence to cultured human endothelial cells. Ren Fail 1995; 17:125–133. 58. Radford DJ, Luu NT, Hewins P, et al. Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells. Arthritis Rheum 2001; 44:2851–2861. 59. Lu X, Garfield A, Rainger GE, et al. Mediation of endothelial cell damage by serine proteases, but not superoxide released from antineutrophil cytoplasmic antibodystimulated neutrophils. Arthritis Rheum 2006; 54:1619–1628. 60. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002; 110:955–963. 61. Huugen D, Xiao H, van Esch A, et al. Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-alpha. Am J Pathol 2005:167:47–58. 62. Xiao H, Heeringa P, Liu Z, et al. The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies. Am J Pathol 2005:167:39–45. 63. Schreiber A, Xiao H, Falk RJ, et al. Bone marrow-derived cells are sufficient and necessary targets to mediate glomerulonephritis and vasculitis induced by antimyeloperoxidase antibodies. J Am Soc Nephrol 2006; 17:3355–3364. 64. Xiao H, Schreiber A, Heeringa P, et al. Alternative complement pathway in the pathogenesis of disease mediated by antineutrophil cytoplasmic autoantibodies. Am J Pathol 2007; 170:52–64. 65. Huugen D, van Esch A, Xiao H, et al. Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice. Kidney Int 2007; 71:646–654. 66. Little MA, Smyth CL, Yadav R, et al. Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte–microvascular interactions in vivo. Blood 2005; 106:2050–2058. 67. Little MA, Bhangal G, Smyth CL, et al. Therapeutic effect of anti-TNF-alpha antibodies in an experimental model of anti-neutrophil cytoplasm antibodyassociated systemic vasculitis. J Am Soc Nephrol 2006; 17:160–169. 68. Pendergraft WF III, Preston GA, Shah RR, et al. Autoimmunity is triggered by cPR3(105-201), a protein complementary to human autoantigen proteinase-3. Nat Med 2004; 10(1):72–79. 69. Davies DJ, Moran JE, Niall JF, et al. Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? Br Med J (Clin Res Ed) 1982; 285(6342):606.
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25 Wegener’s Granulomatosis
FRANCISCO SILVA Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota, U.S.A.
JOSEPH P. LYNCH, III Department of Medicine, Division of Pulmonary and Critical Care Medicine, Clinical Immunology and Allergy, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
MICHAEL C. FISHBEIN Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
ULRICH SPECKS Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota, U.S.A.
I.
Introduction
Wegener’s granulomatosis (WG) is a multisystem autoimmune disease characterized by necrotizing granulomatous inflammation predominantly affecting the respiratory tract and a necrotizing small vessel vasculitis centered on capillaries, arterioles, and venules (1,2). Specific disease manifestations depend on the predominant type of histopathologic lesions and their location. The disease typically runs a relapsing and remitting course, with one or more relapses in approximately 50% of patients (1,3). The vasculitic disease manifestations of WG are shared with microscopic polyangiitis (MPA), but the presence of necrotizing granulomatous inflammation sets WG apart from MPA. WG and MPA also share the frequent presence of antineutrophil cyoplasmic autoantibodies (ANCAs) in the serum of patients (4). In WG, they are usually directed against the neutrophil granule protease, proteinase 3 (PR3), and cause a cytoplasmic immunofluorescence pattern (c-ANCA) on ethanol-fixed neutrophils (4). ANCAs occurring in MPA are more frequently directed against the 605
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neutrophil enzyme myeloperoxidase (MPO) and cause a perinuclear immunofluorescence pattern (p-ANCA) on ethanol-fixed neutrophils. Given the overlap of the histopathologic features and organ manifestations between WG and MPA, the separation of the syndromes is sometimes difficult. Similarly, the ANCA subtype does not allow a clear separation of the two. Consequently, these two ANCA-associated vasculitides (AAV) are often viewed as parts of a disease spectrum that shares pathogenic mechanisms and calls for the application of the same treatment strategies. Treatment strategies for WG and other AAV (discussed in detail later) developed in the 1970s and 1980s dramatically improved the prognosis of what previously was a fatal disease (3,5,6). II.
Clinical Features
WG, the most common of the pulmonary granulomatous vasculitides, typically involves the upper respiratory tract (e.g., sinuses, ears, nasopharynx, oropharynx, trachea), lower respiratory tract (bronchi and lung), and kidney, with varying degrees of disseminated vasculitis (1,3,5,7–10). Clinical manifestations of WG are protean; virtually any organ can be involved (1). Further, the spectrum and severity of the disease is heterogeneous, ranging from indolent disease involving only one site to fulminant, multiorgan vasculitis leading to death. Many of the ‘‘classical’’ features of the disease may be lacking early in the course, but may evolve months or even years after initial presentation (3,7,8,10). Given the rarity of WG, and nonspecificity of symptoms, the diagnosis is often missed for several months after the initial symptom(s). III.
Historic Aspects
WG was described in 1931 by Heinz Klinger. He reported a patient with severe destructive sinusitis and uremia who had glomerulonephritis (GN) and disseminated vasculitis at necropsy (11). In 1936, Wegener incorporated both clinical and histologic criteria to describe what he believed represented a unique and distinctive syndrome (12). In 1954, Godman and Churg established pathologic and clinical criteria for the diagnosis (13). The classic histopathologic criteria included three major features: (i) necrotizing granulomatous lesions in the upper or lower respiratory tract, (ii) generalized necrotizing vasculitis involving both arteries and veins, and (iii) glomerulitis (13). In 1966, Carrington and Liebow described 16 patients with classic histologic features of WG but sparing the kidneys (i.e., ‘‘limited WG’’) (14). Subsequent studies affirmed that this subset of patients had a more favorable prognosis compared with those with generalized WG (8,15,16). In 1990, the American College of Rheumatology (ACR) proposed clinical criteria (in addition to the presence of small vessel vasculitis) to establish the diagnosis of WG (9). Major diagnostic criteria included nasal or oral inflammation, abnormalities on chest radiographs, abnormal urine sediment, and granulomatous inflammation on biopsy. The
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criteria were sensitive (88%) and specific (92%) to differentiate WG from other specific vasculitides but were not reliable to differentiate from other nonvasculitic diseases. In 1994, experts at the Chapel Hill Consensus Conference defined the various types of vasculitides according to histologic criteria (17). Granulomatous inflammation was a requisite feature for the diagnosis of WG whereas granulomata were absent in MPA or classical polyarteritis nodosa (PAN) (17). By 1990s, it was recognized that c-ANCAs were present in the sera of most patients with WG, and often correlated with active disease (10,18,19). The Wegener’s Granulomatosis Etanercept Trial (WGET) study group (20) modified the ACR criteria to include a fifth element (i.e., positive ANCAs to PR3 in an enzyme immunoassay). However, c-ANCA is not specific for WG, and one should be cautious about relying on c-ANCA to diagnose WG in the absence of histologic confirmation. IV.
Epidemiology
The estimated annual incidence of WG has been rising over the decades from 0.5 to 0.7 per million during the 1970s and early 1980s to current estimates of >10 per million (21,22). Similar increases of annual incidence were observed for MPA and Churg-Strauss syndrome (CSS) (21). WG affects predominantly Caucasians, and northern Europeans appear more prone to develop WG (22,23). In contrast, individuals of southern European and Mediterranean descent appear to be relatively more likely to develop MPA (21). Annual incidence and prevalence vary between countries, with a North-South declining gradient in the disease risk in the Northern Hemisphere (24). Annual incidence rates of WG (per million) were 4.1 in Spain (25), 8.5 to 10.3 in England (25,26), and 12 in Norway (22). Published prevalence rates (per million) include 23.7 in Paris (27), 30 in the United States (28), 95.1 in Norway (22), 112 in New Zealand (29), 160 in southern Sweden (23). The peak incidence is in the fourth through sixth decades of life (3,8,28); children or adolescents are rarely affected (30,31). There is no gender predominance in adults (10), but a female predominance has been noted in children (32). V.
Histopathology
The cardinal histopathologic features of WG include a necrotizing vasculitis affecting arterioles, venules, and capillaries; granulomatous inflammation; foci of parenchymal necrosis; microabscesses; areas of fibrosis with acute and chronic inflammation (2,3,5,33) (Fig. 1A–F). Irregularly shaped (geographic) necrosis surrounded by granulomatous inflammation is characteristic. Wellformed sarcoid-like granulomas are rare, but multinucleated giant cells, epithelioid cells, and collections of histiocytes impart a granulomatous character to the inflammatory process (2,3,5,33). Vascular walls are infiltrated (and may be destroyed) by mononuclear cells and neutrophils, with occasional multinucleated
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Figure 1 (See color insert.) Patterns of pathology of WG. (A) ‘‘Blue necrosis’’ with many degenerating neutrophils characteristic of WG, a giant cell is also present (arrow) (H þ E stain, 100). (B) Capillaritis with pulmonary hemorrhage (200) (H þ E stain). (C) Vasculitis necessary for the diagnosis of WG (H þ E stain, 100). (D) Arteritis with numerous eosinophils present (eosinophilic variant) (H þ E stain, 100). (E). Biopsy of the nose showing venulitis (H þ E stain, 200). (F) Kidney biopsy showing crescentic glomerulonephritis (trichrome stain, 100). Abbreviation: H þ E, hematoxylin-eosin.
giant cells and eosinophils. Both acute and healing phases of the vasculitic lesions may be observed in individual patients. Fibrinoid necrosis and thrombosis within vascular lumens are early findings (2). Later, fibrosis of vascular walls may result in stenosis or obliteration of the lumens. Elastic stains may be
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required to identify remnants of destroyed vascular walls (5). A pronounced fibroblastic component, with concentric rings of collagen and connective tissue matrix, may be present. These histologic features may not be found if small or nonrepresentative biopsies are obtained. Granulomas and vasculitis of small vessels may be observed with infections (particularly due to mycobacterial and fungal etiologies) (34). Thus, special stains should be performed in any granulomatous or necrotic lesion to exclude infectious causes. With infectious granulomas, vasculitis is a secondary phenomenon contiguous with foci of necrosis; sarcoid-like granulomas are frequently observed (34). VI.
Specific Organ Manifestation
WG is the most common form of vasculitis to involve the lung. The Chapel Hill Consensus Conference defined WG as ‘‘granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels’’ (17). However, it is important to recognize that WG is a systemic disease that can affect almost any organ. The most frequently involved sites are the upper airways, lungs, and kidneys (1). Symptoms and clinical disease manifestations are the result of necrotizing granulomatous inflammation and small-vessel vasculitis. A.
Upper Airway Involvement
Upper respiratory tract (e.g., sinuses, ears, nasopharynx, oropharynx, trachea) symptoms occur in more than 90% of patients with WG and are often the presenting features (3,5,7,8,10). The upper respiratory tract is the predominant or only site of involvement in some patients (16,35). Chronic sinusitis, nasal congestion, nasal ulcers, epistaxis, or otitis media are often the presenting and dominant clinical features of WG (3,10). Sinus computed tomographic (CT) scans are abnormal in over 85% of patients with WG (3,5). Magnetic resonance imaging (MRI) scans of the sinuses and orbits may reveal mucosal thickening or granulomatous lesions but are less sensitive than CT in detecting bony destruction (36,37). Otologic involvement occurs in 30% to 50% of patients with WG (1,3,10). Manifestations include otalgia, refractory otitis media, chronic mastoiditis, and hearing loss (3,8). Salivary (38) and parotid (39,40) gland involvement is rare. The nasopharynx is involved in 60% to 80% of patients with WG (1,3,8). Clinical manifestations include epistaxis, nasal septal perforation, persistent nasal congestion or pain, nasal crusting, and mucosal ulcers (3,10,41). Saddle nose deformity, due to destruction of the nasal cartilage, occurs in 10% to 25% of patients with WG (1,3,8). Ulcerations or granulomatous involvement of the oropharynx or vocal cords may give rise to pain, crusting, bleeding, or hoarseness (3,41). ‘‘Strawberry gingival hyperplasia’’ is a rare, but nearly pathognomonic, oral lesion of WG (41). Consultation with an experienced otolaryngologist is warranted for patients with suspected WG to look for
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mucosal ulcerations or granulomatous inflammation; suspicious lesions should be biopsied (41). However, biopsies of upper airway lesions often demonstrate nonspecific findings of necrosis and chronic inflammation (42,43). The cardinal histologic features of vasculitis or granulomatous inflammation are often lacking (42,43). If upper respiratory tract biopsies are nondiagnostic, biopsies of other sites may be required. B.
Ocular Manifestations
Ocular involvement occurs in 20% to 50% of patients during the course of WG and is the presenting feature in 8% to 16% of cases (3,5,7,8,44–46). Manifestations include conjunctivitis and episcleritis, granulomatous necrotizing scleritis, uveitis, corneal uclerations or perforation, retinal or ciliary vasculitis, and retro-orbital mass lesions (44). Involvement of the lacrimal glands may result in epiphora, dacryocystitis, and fistula (45). Vision may be threatened by direct involvement of the eye or optic vessels, or by extension of the inflammatory process from contiguous sinuses (5,7). Retro-orbital inflammatory pseudotumors may lead to proptosis, oculomotor palsies, diplopia, or visual loss (5,30,44) and orbital socket contracture (47). Vasculitis or ciliary or retinal vessels may lead to ischemia of the optic nerves (48). Ocular WG may be difficult to diagnose as serum ANCA and systemic manifestations may be lacking in up to 30% of patients (45,49). Gadolinium-enhanced MRI or CT scans of the orbit and sinuses are critical to evaluate for inflammatory or mass lesions (36,45) Sinusitis is present in >85% of patients with proptosis due to WG (45). Orbital and/or sinus biopsies reveal granulomatous vasculitis or nonspecific findings of mixed inflammatory cells, areas of necrosis, and microabscesses (44,45,49). Topical corticosteroids (CS) may be adequate for superficial ophthalmic manifestations (e.g., conjunctivitis or episcleritis), but immunosuppressive therapy is warranted for other indications (1). Mass lesions leading to optic nerve compression may require surgical intervention (44). C.
Involvement of Trachea and Major Bronchi
Granulomatous involvement of the trachea or major bronchi leads to stenosis in 10% to 30% of patients with WG (3,10,50–52). Symptoms include dyspnea, wheezing, stridor, and change in voice (50,51,53). Stenosis of large airways may develop years after the initial diagnosis of WG, and may develop in the absence of manifestations of WG at other sites (51,53). The site of tracheal stenosis is usually localized, extending 3 to 5 cm below the glottis, but more extensive involvement can occur (50–52). Ulcerations and stenoses of trachea or mainstem bronchi may result in stridor or wheezing (51). When tracheobronchial involvement is suspected, flow-volume loops should be performed to detect airflow obstruction. With tracheal (subglottic) stenosis, both the inspiratory and expiratory loops are flattened or truncated (50). If the intrathoracic trachea or mainstem bronchi are affected, flattening of the expiratory curve may be found
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(50,53). However, pulmonary function and flow-volume tracings may be normal with mild degrees of tracheal or endobronchial stenosis (51,53). Further, early in the disease process, when active inflammation has not yet caused significant stenosis, even severe tracheobronchial inflammation may be reflected only in subtle abnormalities of the flow-volume tracing. When stenosis is suspected, flexible fiberoptic bronchoscopy (FFB) should be performed to assess the site and extent of narrowing (53). Endoscopic visualization of the airways not only assesses the trachea and lower airways, but examines the oropharynx, nasopharynx, epiglottic, glottis, and larynx. Bronchoscopy is the most important diagnostic procedure to assess the location and degree of airway involvement below the vocal cords, the nature of luminal abnormalities, and the feasibility of bronchoscopic therapy to restore functional airway patency (52). Bronchoscopy is also used for diagnostic tissue sampling and is invaluable in the evaluation of the efficacy of both pharmacologic and interventional therapy of the airway involvement in WG. A cursory bronchoscopy may overlook subtle changes in the airways, particularly in the subglottic trachea. The bronchoscopist should be cognizant of the possibility of WG affecting the tracheobronchial tree and carefully examine the airway lumen and describe the abnormalities. Virtual bronchoscopic imaging derived from CT technique has been used to create threedimensional projections of airway abnormalities in patients with WG. In a study of 11 patients with WG, 32 of 40 stenoses (80%) were detected by virtual bronchoscopy (54). However, even if the resolution of this novel CT technique improves, it is unlikely to replace the visual assessment of the mucosa by FFB and does not allow for sampling of diagnostic specimens. If mucosal abnormalities are detected, adequate tissue biopsies should be obtained. However, histologic confirmation of tracheal or endobronchial WG is difficult; biopsies usually reveal nonspecific findings of necrosis or inflammation. Dual features of vasculitis and granulomatous inflammation are identified in <20% of patients with tracheal or endobronchial WG (50,51,53). Serum titers of c-ANCA may be negative, even with endobronchial inflammation (51). Importantly, progressive subglottic or bronchial stenosis can develop even when WG is quiescent at other sites (50,51,53). The diagnosis of tracheal or endobronchial involvement in patients with known WG must be presumed in the appropriate clinical context, even when histology is nonspecific. The severity and extent of airway narrowing are best evaluated using multiplanar and three-dimensional reconstructions of spiral CT scans (54–56). Serial CT scans may be useful to follow patients longitudinally (56). Some patients require repeated, periodic, bronchoscopies to reevaluate the airway lumen and disease recurrence. Ideally, the findings should be recorded in the report and by photographic documentation. D.
Lung Involvement
Pulmonary involvement is noted in 55% to 80% of patients with WG (1,3,5,8,10). The spectrum of pulmonary manifestations includes asymptomatic
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Figure 2 Chest CT scan: cavitary lung masses. A 35-year-old woman with a 9-year history of relapsing WG. The left panel shows bilateral lung masses with and without cavitation at the time of disease flare before treatment. Because of multiple drug toxicities, remission induction therapy for this flare consisted of prednisone and rituximab (4 weekly infusions of 375 mg/m2). The right panel shows the follow-up CT scan after completion of the glucocorticoid taper.
nodules or infiltrates on chest radiographs or CT scans, cough, hemoptysis, dyspnea, impaired pulmonary function, parenchymal necrosis, and diffuse alveolar hemorrhage (capillaritis) (3,5,8,10). The most characteristic finding on chest radiographs or CT scans is single or multiple pulmonary nodules; cavitation is noted in 20% to 50% (usually in lesions >2 cm in diameter) (1,55,57) (Fig. 2). Other features include consolidation or ground-glass opacification, stenosis of trachea or bronchi, calcification and thickening of tracheal rings, bronchial wall thickening, bronchiectasis, pleural effusions, atelectasis, septal bands, parenchymal scarring, and irregular pleural thickening (55,57,58). Enlarged intrathoracic lymph nodes are uncommon (<2%) on conventional chest radiographs (59) but are detected on chest CT in 20% of patients with WG (57,58). Fluffy alveolar or mixed alveolar-interstitial infiltrates or consolidation may reflect alveolar hemorrhage (Fig. 3) or granulomatous inflammation (60,61) With treatment, ground-glass opacities, cavitating nodules, nodules >3 cm in diameter, or consolidation typically resolve or regress (55), whereas linear lines or smaller nodules persist, suggesting residual fibrosis (60). Pulmonary function testing is an integral part of the comprehensive approach to the diagnosis and management of WG (51,53). Pulmonary function tests (PFTs) may demonstrate airflow obstruction (particularly when tracheal or endobronchial involvement is prominent), restriction, or mixed patterns (1,62). Mechanisms responsible for airflow obstruction include diffuse or localized areas of bronchial narrowing, bronchiectasis, peribronchial scarring, bronchomalacia, and perhaps other
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Figure 3 Diffuse alveolar hemorrhage. A 39-year-old man with WG admitted to the medical intensive care unit with hemoptysis, respiratory failure, and renal insufficiency preceded by a five-month history of recurrent otitis media, epistaxis, nasal congestion, and leukocytoclastic vasculitis of the skin. The CT section shows a cavitary lung nodule (arrow) and diffuse patchy alveolar infiltrates consistent with DAH. Abbreviation: DAH, diffuse alveolar hemorrhage.
mechanisms. Reductions in lung volumes or diffusing capacity for carbon monoxide (DLCO) likely reflect pulmonary parenchymal involvement (62). Surgical lung biopsy (SLB) is optimal to establish a firm diagnosis of pulmonary WG. The gross pathology of pulmonary WG typically reveals bilateral cavitary nodules and zones of consolidation and geographic necrosis (2). A review of 87 SLBs from patients with pulmonary WG cited the following histologic features: vascular inflammation (acute or chronic) in 94%, parenchymal necrosis (84%), scattered giant cells (79%), areas of geographic necrosis (69%), granulomatous microabscesses with giant cells (69%), neutrophilic microabscesses (65%), poorly formed granulomata (59%), capillaritis (31%), and fibrinoid necrosis (11%) (33). Bronchiolar abnormalities cited included nonspecific chronic inflammation (64%), acute inflammation (51%), bronchiolitis obliterans (31%), and follicular bronchiolitis (28%) (33). The nodular/ cavitary lesions in WG are caused by necrotizing granulomatous inflammation. These lesions are not found in MPA (17). Small necrotizing microabscesses are an early lesion in WG; these enlarge and coalesce until geographic necrosis has developed (2). The necrotic center is surrounded by palisading histiocytes and scattered giant cells (2). In same cases, the necrosis is bronchocentric. The inflammatory background of the granulomatous necrosis and vasculitis consists of a mixed cellular infiltrate containing lymphocytes, plasma cells, scattered giant cells, and eosinophils. In some cases, extensive parenchymal consolidation mimics organizing pneumonia (OP). Confluent, sarcoid-like granulomas are rarely observed (<5%) in WG (2). Varying degrees of fibrosis may be observed in later phases of the disease (33). Less common features of WG include OP, eosinophilic infiltration, chondritis involving bronchial cartilage, and interstitial fibrosis (2,33).
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Because of small sample size, the yield of endobronchial or transbronchial lung biopsies to diagnose WG is low (3–18%) (1,33,51). Cytologies of BAL fluid may demonstrate nonspecific findings of necrotic debris, acute inflammation, multinucleated giant cells, epithelioid cells, and hemosiderin-laden macrophages (1). Transthoracic core needle biopsy (guided by CT or fluoroscopy) has demonstrated inflammation or vasculitis in a few cases (63), but specificity is suboptimal. With few exceptions, SLB is required to substantiate the diagnosis. E.
Diffuse Alveolar Hemorrhage
Diffuse alveolar hemorrhage (DAH) caused by capillaritis is a rare but potentially fatal complication of WG, reflecting diffuse injury to the pulmonary microvasculature (1,61,64). In this setting, rapidly progressive glomerulonephritis (RPGN) is present in more than 90% of patients (1,61,65). Chest radiographs in DAH demonstrate bilateral alveolar infiltrates; the classic nodular or cavitary lesions of WG are lacking (65). Rapidly progressive respiratory failure in common; mortality rate approximates 50% (1). DAH results from diffuse injury to the pulmonary microvasculature. The cardinal histologic finding in DAH is alveolar hemorrhage and a neutrophilpredominant capillaritis (Fig. 1B); fibrinoid necrosis of vessel walls, pyknotic cells, and nuclear fragments from neutrophils undergoing apoptosis (termed leukocytoclasis) is a key feature (2,61). Eosinophils or monocytes may also be present. Depending on the acuity and duration of alveolar hemorrhage, hemosiderinladen macrophages and interstitial hemosiderin deposits may be present (2). Granulomatous vasculitis or extensive parenchymal necrosis is not found in DAH (61). The diagnosis of DAH can usually be made on the basis of clinical features, chest radiographs, circulating c-ANCA, and bronchoscopy with BAL. Large numbers of hemosiderin-laden macrophages, bloody or serosanguinous BAL fluid, and absence of infectious etiologies support the diagnosis of DAH (1,65). For severe DAH, the risk of SLB outweighs the benefit. Percutaneous renal biopsy is warranted if microscopic hematuria or renal insufficiency is present. Crescentic RPGN, with negative immunofluorescent stains (i.e., pauciimmune), is characteristic of WG in the context of DAH (Fig. 1F) (1,65). DAH is a medical emergency requiring aggressive therapy with intravenous (IV) ‘‘pulse’’ methylprednisolone (1 g daily for 3 days) (1,65) while pursuing a diagnostic workup. Immediate therapy with cyclophosphamide (CYC) and CS is appropriate once the diagnosis of WG is confirmed. Plasmapheresis should be considered for life-threatening DAH refractory to standard therapy (66–68). F.
Renal Involvement
Glomerulonephritis (pauci-immune) occurs in 70% to 85% of patients at some point in the course of the disease (1,3,5,8,10). Extrarenal manifestations usually precede the renal manifestations, often by several months (1). Renal insufficiency
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is noted in only 11% to 20% of patients at presentation (1,3,5,69). The renal lesion of WG is a segmental focal GN (3,69). With more fulminant forms, a necrotizing, crescentic GN is observed (1,69) (Fig. 1F). These histologic findings are nonspecific and can be found in diverse immune-mediated or infectious disorders. Granulomatous vasculitis is observed in only 3% to 15% of renal biopsies from patients with WG (3,5,32,69). Microscopic hematuria, proteinuria, or red cell casts precede elevations in serum creatinine (3,5). The onset and course of renal involvement is variable. In some patients, the course is indolent (progressing over months to years) whereas others manifest RPGN, progressing to end-stage renal failure (ESRF) within days to weeks (1,3,69). Eleven percent to 32% of patients with WG develop ESRF requiring chronic dialysis (3,68–70). Aggressive and prompt institution of therapy with CS and cytotoxic agents (discussed in detail later) is mandatory to avert irreversible renal damage. Plasma exchange is indicated for patients with severe RPGN (68,71). In a recent randomized trial of 137 patients with AAV, RPGN, and serum creatinine >5.8 mg%, the addition of plasma exchange (PE) to CYC and CS increased the rate of renal recovery compared with IV pulse methylprednisone and immunosuppressive therapy (CYC þ CS) (68). Even in oliguric renal failure, substantial recovery of renal function can be achieved in many patients (1,69). Chronic renal failure months or years after the initial injury may reflect nephrosclerosis from the original renal injury rather than recurrent WG (1,5). Renal transplantation may be considered for patients with ESRF and no evidence for active WG (70,72). Mean one-year graft survival for patients with WG approximates 65% (72). The presence of serum ANCA should not preclude transplantation in patients who are in clinical remission (72). Recurrence of WG (renal or extrarenal) following transplantation has been noted in 10% to 30% of cases (72). Other rare urologic complications of WG include renal artery aneurysms (73,74), renal masses (75,76), necrotizing vasculitis involving the ureters (74), ureteral stenosis (72,77), penile necrosis (73) or ulcers (77), acute urinary retention (72), bladder pseudotumor (77), and involvement of the prostate (3,78). G.
Central or Peripheral Nervous System Involvement
Central nervous system (CNS) involvement occurs in 4% to 11% of patients with WG; the incidence is slightly higher (8–18%) when isolated cranial nerve palsies are included (3,5,79–81). Neurologic complications may arise at any time during the course of WG, but typically occur at later stages (3,80). Pathogenic mechanisms for CNS symptoms include (i) vasculitis affecting cerebral or spinal cord vessels; (ii) contiguous invasion of granulomata from nasal, paranasal, or orbital disease; and (iii) granulomatous lesions involving brain parenchyma or meninges (80). Predominant clinical patterns include chronic hypertrophic pachymeningitis (CHP), pituitary gland involvement, and cerebral vasculitis (80). CHP refers to an inflammatory thickening of the dura mater that results in severe,
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analgesic-resistant chronic headaches (80). CHP involving spinal cord presents with paraplegia (80). Meningeal thickening or enhancing lesions on CT are usually focal, adjacent to nasal, orbital, or sinus disease (81). Clinical manifestations include cranial nerve palsies (3), cerebral infarction or hemorrhage, transient ischemic attacks or strokes (82), arterial or venous thrombosis (80), generalized seizures (reflecting meningeal involvement) (80,83), altered mental status (82) or cognitive impairment (84), cortical atrophy (81), chronic headaches (80,81,85), oculomotor disturbances (86), and visual loss (from compression of the optic nerve or vasculitis of the vasculature) (3,5,81,85). Granulomatous involvement of the pituitary may give rise to pituitary insufficiency, hyperprolactemia, diabetes insipidus, or bitemporal hemianopsia (80). Involvement of the spinal cord microvasculature may give rise to myelopathy, quadriparesis or paraparesis (81,87,88). In WG involving the CNS, lumbar puncture demonstrates pleiocytosis with lymphocyte predominance and elevated protein concentrations (80). Vasculitis of the CNS is rarely confirmed histologically, because of inaccessibility or risks associated with biopsies (81,87). In a review of 20 patients with WG-associated CHP, meningeal biopsies uniformly revealed inflammation, but vasculitis was observed in only 5 patients (25%) (80). The diagnosis of WG is usually supported by histologic confirmation at extraneural sites or by noninvasive studies [e.g., electromyogram (EMG), MRI or CT scans of the brain or spinal cord] in patients with neurologic symptoms and previous documentation of WG (81,85,89). MRI scans reveal a wide spectrum of findings including diffuse or focal dural thickening and enhancement, discrete lesions, infarcts, nonspecific white matter areas of high signal intensity, enlarged pituitary gland with infundibular thickening, and cerebral atrophy (80,81,84,87,89,90). In some patients, MRI abnormalities persist, even after clinical recovery (80,85). Clinical and MRI findings of CNS vasculitis overlap with infectious etiologies (e.g., tuberculosis, toxoplasmosis, brain abscess, etc.) (80). Prior to instituting immunosuppressive therapy, CNS infections must be excluded. Cerebral angiography is not warranted, because the small vessels affected in WG are below the sensitivity of angiography (80,87). Peripheral neuropathy, due to involvement of the vasa vasorum, is noted in 30% to 43% of patients during the course of the disease (3,5,79–81,91). Most common manifestations include mononeuritis multiplex or polyneuritis (3,5,79). Peripheral neuropathy is more common in males, older age, greater extent of disease, and higher titers of ANCA (79). In some patients, biopsy of the sural nerve or other affected nerves may substantiate the diagnosis. Both peripheral and CNS manifestations may be associated with irreversible damage, persisting even after the acute inflammation is adequately controlled. H.
Involvement of Large Vessels
Involvement of medium-sized or large arteries is rare in WG. However, case reports of WG with aneurysms or macroscopic inflammatory lesions involving
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the aorta (92,93), internal carotid artery (94), intracerebral vessels (95), subclavian artery (96), mesenteric (97), hepatic (98), and renal arteries (73) have been published. Venous thrombotic events (VTE) are more common in WG, both in children (32,99) and adults (99,100), and may reflect venulitis. In addition, circulating cardiolipin antibody was noted in up to 19% of adults with WG (99,101), although this likely does not explain the increased incidence of VTE in WG (102). I.
Skin Involvement
Cutaneous lesions are present in 14% to 30% of patients with WG during the course of the disease (3,5,8,103,104). Leukocytoclastic vasculitis presenting as palpable purpura is most common (104), followed by pyoderma gangrenosumlike lesions (103,105,106). However, manifestations are protean and include subcutaneous nodules, papules, petechiae, ulcerations, nonspecific erythematous or maculopapular rashes, and gingival hyperplasia (3,103). Skin biopsies may demonstrate leukocytoclastic vasculitis, acute or chronic inflammation (with or without vasculitis), granulomatous inflammation (with or without vasculitis), palisading extravascular necrotizing granuloma (Churg-Strauss-like granuloma), and fibrinoid necrosis of vessel walls (3,104,107). Skin changes may be the presenting feature or may occur late in the course of the disease (3,103,107). Cutaneous lesions in WG are associated with a higher incidence of articular and renal involvement and more rapid progression of disease compared with patients without cutaneous involvement (103,107). J.
Cardiac Involvement
Cardiac involvement is rarely documented antemortem, but prevalence rates of 8% to 15% have been estimated (1,3,8,108). Any portion of the heart may be involved, but coronary arteritis and pericarditis are the most common features (108). Fatal arrhythmias (109), conduction defects (110), cardiomyopathies (3), and valvulitis (108) have been noted. K.
Gastrointestinal Involvement
Clinically significant gastrointestinal (GI) manifestations (e.g., abdominal pain, diarrhea, hemorrhage, perforation) were cited antemortem in 4% to 10% of patients with WG (3,8,111). However, the incidence of unrecognized GI tract disease is undoubtedly higher (1). Rare manifestations include intestinal involvement (e.g., colitis, bleeding, perforation, ischemia) (111–114), hepatic vasculitis or fibrosis (115), primary biliary cirrhosis (116), and splenic involvement (e.g., splenomegaly, hemorrhage, dysfunction, infarcts, rupture) (1,117–119).
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Other Organ Involvement
Constitutional symptoms (e.g., malaise, fatigue, fever, weight loss) occur in 30% to 80% of patients with WG and may be the presenting features (3,5). Nondeforming polyarthritis involving medium and large-size joints occurs in two-thirds of patients and parallels activity of the systemic disease (3,5). Articular symptoms usually remit with cytotoxic or CS therapy. VII.
Laboratory Features
Striking increases in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are characteristic of active, generalized disease and usually correlate with disease activity (1,3). However, ESR or CRP can be normal with active disease, particularly when only a single site is involved (51,120). Serial determinations of the ESR or CRP are useful in monitoring the disease, but are nonspecific since elevations may occur in the presence of coexisting infections. The cardinal laboratory aberration in WG is serum autoantibodies directed against cytoplasmic components of neutrophils (c-ANCA) (120). Increases in c-ANCA have been noted in more than 90% of patients with active generalized WG and in 40% to 70% of patients with active regional disease (1,10,120,121). Among WG patients with circulating ANCAs, >90% are directed against PR3 and <10% are directed against MPO or other antigenic epitopes (1,120). Changes in c-ANCA usually correlate with disease activity and are unaffected by intercurrent infections (1). However, c-ANCA titers may persist in 30% to 40% of patients even after complete clinical remissions have been achieved (1,10,121,122). Further, increases in c-ANCA titers do not necessarily presage relapse (121,122). Serial determinations of c-ANCA provide useful adjunctive information to the clinical data, but treatment decisions should not rely exclusively on c-ANCA titers (1,10). VIII.
Pathogenesis
The etiology of WG remains unknown, but both cell-mediated and neutrophilmediated mechanisms are operative (1). Circulating ANCAs suggest a critical role for neutrophils and these autoantibodies in the pathogenesis and evolution of WG (4,123–126). The role of ANCAs and other mediators in the pathogenesis of AAV is elegantly reviewed in the previous chapter by Drs. Jennette and Falk and will not be reiterated in detail here. However, abundant experimental, in vitro, and clinical data suggest that ANCA plays a key role in the pathogenesis and clinical expression of WG (4,120,124,125). Further, the presence or absence of ANCA and the specific type of ANCA (i.e., PR3-ANCA vs. MPO-ANCA) define the disease phenotype (120,127,128). In AAV and GN, renal function deteriorates more rapidly in patients with circulating PR3-ANCA compared with MPO-ANCA (127). In WG, the presence of PR3-ANCA is closely related to the development of vasculitic
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complications and propensity to relapse (120,124). Furthermore, relapses of systemic vasculitis nearly invariably are associated with circulating c-ANCA (120). By contrast, patients with limited WG who remain ANCA-negative rarely develop systemic vasculitic manifestations (120). However, remissions may be maintained for extended periods of time in up to half of patients with WG despite the presence of ANCA (120,122,127). These clinical observations suggest that ANCAs alone are not sufficient to cause disease activity, but ANCAs seem to be required for the development of vasculitic complications and systemic relapses in WG. Infection may be a trigger to relapses of WG. ANCA directed against a broad variety of target antigens have been documented with viral, fungal, bacterial, and protozoal infections (4). Most ANCA-mediated effects on neutrophils and monocytes require priming of the cells (4). This cytokine-dependent process is not unique to vasculitis. Infections elicit cytokine release [including tumor necrosis factor a (TNF-a)] that stimulates neutrophils and monocytes, resulting in increased surface expression of ANCA target antigens. Patients with active vasculitis display elevated levels of TNF-a and increased expression of ANCA target antigens on the surface of their neutrophils (4). These observations support the hypothesis that neutrophil priming in response to cytokine stimulation during infection enables ANCA to interact with target antigen(s) on the neutrophil surface. This in turn elicits the proinflammatory effects of ANCAs, which aggravate and perpetuate the inflammatory reaction at the endothelial cell interphase. In the rare instances of C-ANCA/PR3-ANCA observed in infections, the ANCA disappeared with appropriate antimicrobial therapy. These observations suggest that ANCA can occur transiently in the setting of infection, and the persistent ANCA response in patients with vasculitis may be the result of molecular mimicry in susceptible hosts. Subsequent diversification of T- and B-cell responses (‘‘epitope spreading’’) may lead to responses against different epitopes on the same target molecule (intramolecular spreading) or extend to other molecules (intermolecular spreading). Interestingly, chronic nasal carriage of Staphyloccus aureus is a risk factor for disease relapses in patients with WG (129). Further, S. aureus–specific T-cell clones from patients with WG were of the ab TCRþ CD4þ phenotype and were HLA-DR restricted (130). In addition, S. aureus– specific T-cell clones recognized the PR3 antigen (130). It is possible that HLADR-restricted CD4þ T cells play a key role in triggering immune responses in WG. By inducing potent T- and B-cell activity, superantigens produced during a S. aureus infection could initiate and maintain both ANCA production and cytokine release, resulting in necrotizing granulomatous inflammation and vasculitis. The role of genes in influencing susceptibility to WG has not been clarified (1), but genetic polymorphisms may be of importance (131). IX.
Treatment
Prior to the introduction of effective therapy, mean survival among patients with WG was less than six months (132); more than 80% of patients died within three years of onset of symptoms, usually of progressive renal failure (133). Over the
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past 30 years, therapeutic options were developed that allowed long-term survival (3,8). Seminal studies at the National Institutes of Health (NIH) in the 1970s employing daily CYC combined with CS fundamentally improved the prognosis of WG (1,3,5,134). With this regimen, favorable responses were noted in 70% to 95% of patients, with five-year mortality rates of <15% (1,3,5,8). Relapses were noted in 30% to 70% of patients following cessation or tapering of therapy, but reinstitution of therapy was usually efficacious (1,3,8,10,135). However, late sequelae of vasculitis (e.g., cerebrovascular accidents, myocardial infarction, renal failure, hypertension) or complications of CYC (e.g., opportunistic infections, neoplasms) contributed to long-term mortality and morbidity (3,8,135–137). The search has remained ongoing for safer and effective therapies associated with acceptable rates of relapse. Recognition of treatment-related toxicities and the chronically relapsing nature of the disease have driven the search for better-tolerated treatment alternatives. With the expansion of therapeutic alternatives, management decisions in WG are increasingly being guided by disease severity, organ manifestations, and individual patient factors that take into account past treatment history and drug toxicities (138). A.
Staging of Disease
Treatment options for WG are stratified according to acuity, extent, site(s), and severity of disease. To determine the appropriate therapeutic regimen, the European Vasculitis Study Group (EUVAS) developed a grading system for WG according to the following categories: (i) limited; (ii) generalized, early; (iii) generalized, active; (iv) severe; and (v) refractory. Although the original term limited WG referred to patients without renal involvement (14), patients may have severe, life-threatening pulmonary or neurologic disease in the absence of renal involvement. Therefore, patients with ‘‘lone’’ alveolar hemorrhage or other serious manifestations should never be classified as having limited WG. The current use of the term limited WG implies that (i) there is predominantly necrotizing granulomatous pathology and the vasculitis is of subordinate clinical significance and (ii) there is no immediate threat to the patient’s life or a disease manifestation that puts the affected organ(s) at risk for irreversible damage. By contrast, severe WG is defined as disease that is life-threatening or affects critical organs (e.g., kidneys, pulmonary hemorrhage, nervous system, etc.). These definitions and distinctions form the basis for stratification of current standard therapy (1). Further, treatment approaches can be classified as induction therapy or maintenance therapy. Preferred induction therapy for severe or generalized WG is oral CYC (1–2 mg/kg/day) and CS (prednisone or prednisolone 60 mg daily, with taper to 10–20 mg within 4 months if possible) (139). For fulminant cases, severe renal failure, or DAH, the combination of IV pulse methylprednisone (1000 mg daily for 3 days, with taper), CYC, and PE should be considered (68). CYC and CS are continued for three to six months until complete remissions have been achieved (139). At that point, less toxic agents
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[e.g., methotrexate (MTX), azathioprine (AZA), mycophenolate mofetil (MMF), or leflunomide (LEF)] can be substituted for CYC; this maintenance regimen is continued for a total of 12 to 18 months (1,140). Additionally, for patients with mild or limited disease and preserved renal function, MTX (138,141), MMF (142), or LEF (140) may be substituted for CYC for induction therapy (discussed later). Relapses or persistent, ‘‘grumbling’’ disease requires retreatment with CYC/CS or additional options (discussed later). Trimethoprim/sulfamethoxazole (T/S) may have an adjunctive role in reducing relapse rates (1,143). B.
Determining Extent and Activity of Disease
At the time of initiation of therapy, objective assessment of ‘‘activity’’ of the disease is critical, in order to assess response. The Birmingham Vasculitis Activity Score (BVAS) has been used as a disease-specific activity index for WG (7,144). Parameters are weighted according to minor or major components. A modified BVAS was shown to be a valid, disease-specific activity index for WG, with good inter- and intraobserver variability (145). Additionally, Exley and colleagues developed the Vasculitis Damage Index (VDI) in 1997 that incorporated sequelae of the disease or toxicities of treatment (146). The VDI consists of 64 items related to sequela of WG or its therapy. The use of objective scoring systems is invaluable in clinical trials and longitudinal follow-up (20,145,147). C.
Remission Induction
1.
Limited Disease
The limited disease includes manifestations of WG that bring no immediate threat to either the patient’s life or the function of a vital organ (148). Initial treatment for limited WG can utilize MTX, AZA, MMF, or LEF, usually combined with CS. On the basis of anecdotal responses in some patients with limited WG, T/S may be considered for mild disease (15), although we believe this option is distinctly less effective than traditional immunosuppressive or cytotoxic agents. Limited WG that fails to respond to initial therapy should be treated more aggressively with CYC and CS. Some manifestations (e.g., subglottic stenosis, proptosis, aggressive sinus or orbital involvement) may require surgical or interventional techniques as adjunctive therapy (50). 2.
Generalized Disease
Patients with generalized WG [i.e., compromise of one or more organ systems other than high airway, presence of constitutional symptoms, and/or elevated acute phase reactants (erythrocyte ESR or elevated CRP level); variable severity of organ compromise] should be treated with the combination of oral CYC (2 mg/kg/day) and CS (3,5,139). IV pulse CYC has been used to treat WG, primarily as a means to reduce late toxicity (e.g., bladder cancers and
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malignancies) (136,137). Remission rates were similar with daily oral or intermittent IV pulse CYC, but relapses were more common with pulse CYC (1,8,135,149). We believe daily oral CYC combined with CS remains the standard of care for severe or generalized WG. Alternative induction therapeutic options (e.g., MTX, MMF, or LEF) should be reserved for mild or moderate cases with no life-threatening manifestations or renal impairment (141,150). Importantly, MTX or AZA should be substituted for CYC as maintenance therapy after remissions have been achieved with CYC (8,139,141). We also add T/S double-strength twice daily in order to reduce relapse rates (15,143). 3.
Fulminant Generalized Disease
More aggressive therapeutic regimens may be necessary in patients with fulminant disease (e.g., RPGN, DAH with respiratory failure, or CNS vasculitis). In this context, higher initial doses of CS and CYC can be considered (5). Pulse methylprednisolone (1000-mg daily IV) combined with IV CYC (3–4 mg/kg/day) for three days, followed by CS taper and oral CYC (2 mg/kg/day) has been used, but data are limited to anecdotal cases. The role of PE in RPGN or DAH is controversial (66,151). However, in retrospective studies, PE compared with CYC/CS increased the rate of renal recovery in patients with AAV and severe RPGN (serum creatinine >5.7 mg%) compared with IV methylprednisolone plus CYC/CS (68). In the absence of prospective data establishing its efficacy apart from other modalities, PE should be reserved for patients with severe RPGN or life-threatening disease. D.
Maintenance Therapy
In this phase, less aggressive therapy is used to maintain the remissions achieved with CYC. MTX or AZA (combined with low-dose CS) have been utilized most often, but favorable responses have been noted with other agents (e.g., MMF, LEF, cyclosporine). The rationale for maintenance therapy with agents other than CYC is the potential for serious late toxicities associated with long-term cumulative use of CYC (particularly bladder carcinomas, malignancies, and myeloproliferative disorders) (3,136,137,152–155). Recent strategies advocate treating generalized WG with CYC and CS (to induce remission), followed by less toxic agents (e.g., AZA or MTX) to maintain remissions (139,156,157). A randomized trial by the EUVAS presented strong evidence in support of this ‘‘inductionmaintenance’’ approach in WG (139). In that study, 155 patients with AAV were treated with daily oral CYC/CS as induction therapy for a minimum of three to six months (139). Ninety-five patients (61%) had WG and 60 patients (39%) had MPA. Renal involvement was present in 94%. With this induction regimen, complete remissions (CRs) were achieved in 119 patients (77%) by three months and in 144 patients (93%) within six months. After CRs were achieved, patients were randomly assigned to continue oral CYC (1.5 mg/kg/day) (n ¼ 73) or switch to AZA (2 mg/kg/day) (n ¼ 71) in addition to low-dose prednisolone (10 mg/day) for maintenance therapy. After 12 months of therapy, both groups received AZA
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(1.5 mg/kg/day) and prednisolone (7.5 mg/day). Both groups were followed for 18 months from study entry. At 18 months, relapse rates (the primary end-point) were similar in the AZA cohort (15.5%) and CYC group (14%) (p ¼ 0.65). Relapses were more common among patients with WG (18%) compared with MPA (8%), p ¼ 0.03. Other outcome measures (e.g., VDI scores, quality of life, CRP or ESR) were similar between AZA and CYC cohorts. End-stage renal failure developed in only two patients in each group. The rate of adverse effects was similar between treatment groups. Only eight patients died (5% mortality). Seven of the eight fatalities occurred within the first three months, during the induction phase with CYC/CS. One patient died (from stroke) during the maintenance phase. Although the frequency of toxicity was similar between treatment arms, the short study duration was insufficient to examine the long-term consequences associated with chronic CYC use (particularly malignancies). This experience supports the use of CYC/CS for initial induction therapy, followed by early switch (within 3–6 months) to less toxic agents once CRs have been achieved. Although this study did not evaluate MTX, we believe either MTX or AZA can be utilized as long-term maintenance therapy. The decision about whether to use MTX or AZA for remission maintenance must be made on an individual patient basis, since no studies have directly compared these agents. However, MTX is contraindicated in patients with renal insufficiency, hepatic disease, or severe chronic pulmonary functional impairment. E.
Treatment of Refractory Disease
Disease unresponsive to conventional therapy can be treated with cytolytic agents or monoclonal antibodies (discussed later), but data are limited to small series and anecdotal case reports. Before discussing these novel approaches, we will briefly discuss the salient aspects of the conventional immunosuppressive and cytotoxic agents used to treat WG and AAV. 1.
Specific Therapeutic Agents
Cyclophosphamide
CYC, an alkylating agent with diverse effects on cellular and humoral immunity (136), is the initial treatment of choice for generalized WG and other severe vasculitides (1,139). However, given its myriad toxicities (136) [e.g., bone marrow suppression, heightened susceptibility to infections, bladder carcinoma (137), lymphoproliferative disorders (3), and other malignancies (158–160)], less toxic agents are preferred for patients with mild or localized disease. Methotrexate
Oral or IV MTX, administered once weekly, can be used as (i) maintenance therapy for patients who have achieved CRs after initial treatment with CYC (141,161–164), (ii) induction therapy for patients with mild-to-moderate (non
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life-threatening) WG, and (iii) induction or salvage therapy for patients experiencing adverse effects from CYC (157,164). Acute renal failure, DAH, serum creatinine >2.0 mg%, or chronic liver disease are considered contraindications to MTX (164). The dose of MTX is 15 to 25 mg once weekly; prednisone is usually administered concomitantly (initial dose 1 mg/kg/day, with gradual taper) (156,157,161,164). With this regimen, remissions were achieved in 59% to 88% of cases (8,141,156,163–165). Late relapses were noted in 36% to 66%, usually after dose reduction or discontinuation of MTX (8,141,156,163–165). In this context, reintroduction of MTX plus CS usually induced remissions (157,161). Five-year mortality rates with MTX were low (3.7–14%) (8,141,156,163–165). These data support the use of MTX plus CS in patients experiencing adverse effects from CYC or as initial therapy for mild WG. Additional data are required to evaluate the role of MTX as therapy for severe cases of WG. Since the kidneys are the major route of MTX elimination, toxicity is increased in the presence of renal insufficiency (136). The concomitant use of MTX and T/S 160 mg/800 mg twice daily may cause severe pancytopenia (162,166). However, low-dose T/S (80/400) thrice weekly is safe (1,157) and should be used for prophylaxis against Pneumocystis jiroveci (157,161,162,165). Azathioprine
AZA, a purine analogue, is less effective than CYC and should not be used as primary therapy for WG (5). However, AZA (1–3 mg/kg/day orally) is as effective as CYC as maintenance therapy in patients who remit with CYC and CS (139). High-dose, intermittent IV AZA (1200 mg/mo) was used to treat four patients with WG intolerant or refractory to prolonged CYC therapy; two patients remitted after an average of six course of monthly AZA (167). Given the small number of patients in the trial, we do not recommend this approach. Azathioprine has myriad toxicities (principally GI side effects and bone marrow suppression) but lacks bladder toxicity and has low oncogenic potential (136). Mycophenolate mofetil
MMF, an inhibitor of purine synthesis, has been used in small, nonrandomized trials both to maintain and induce remissions in WG (142,168,169). Nowack et al. treated nine patients with WG and renal involvement with MMF (2 gm/day) following induction of remission with CYC/CS (168). One patient relapsed during the 15-month study period. In a prospective study, Langford et al. treated 14 patients with daily CYC plus CS to induce CR, followed by MMF as maintenance therapy (142). Relapses occurred in six patients (43%) at a median of 10 months after achieving CR. In another trial, 12 patients with AAV (7 had WG) were treated with MMF, 10 had failed at least two courses of CYC and/or AZA (170). Oral MMF was escalated to a final dose of 1000 mg twice daily and continued for up to 12 months. All patients improved (by BVAS) at 24- and 52-week time points. MMF was discontinued in three patients, one relapsed. Another patient relapsed while on MMF and was treated with etanercept (170).
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Experience with MMF is limited and studies comparing MMW with other agents are lacking. Leflunomide
LEF, an inhibitor of the enzyme dihydroorotate dehydrogenase, was used as maintenance therapy for 20 patients with generalized WG in a phase II, openlabel study (171). All had remitted with CYC/CS. Overall, disease activity was unchanged during a median follow-up of 1.75 years (range 1–2.5 years) (171). A recent multicenter, prospective, randomized trial evaluated the efficacy of LEF versus MTX to maintain remissions in patients with WG following induction of remission with CYC (172). The study was terminated because there were more relapses within six months in the MTX group (13 of 28) compared with 6 of 26 receiving LEF. There were more adverse effects in LEF-treated patients. The dose of LEF in that study (30 mg/day) was higher than the recommended for rheumatoid arthritis, and the dose of MTX was lower than often used in WG (140). Additional studies are required to determine whether LEF is superior to MTX for WG. Trimethoprim/sulfamethoxazole
T/S may reduce relapse rates in patients with WG (143), but is of doubtful value as primary therapy (173). Nonrandomized studies suggested that T/S may have a role in patients with indolent but progressive WG (174) or for limited ‘‘initial phase’’ WG (15,175). By contrast, T/S did not induce remissions or reduce relapse rates in patients with generalized WG (15,173). Others reported that T/S was less effective than MTX in maintaining remissions following initial treatment with CYC and CS (156). Nonetheless, a role for T/S in ameliorating the course of the disease is plausible. One placebo-controlled, randomized trial suggested that T/S (160 mg/800 mg twice daily) reduced relapse rates in patients with WG who were in remission following treatment with CYC and CS (143). These data are intriguing, but the impact of T/S on modulating the course of WG remains controversial. In view of its low toxicity, T/S may be considered as adjunctive therapy for persistent, indolent disease despite CYC and CS. T/S has no primary role for treating WG involving kidney or other major organs. The most important role of T/S in WG is to prevent pneumonia due to P. jirovecii (PCP), a complication of immunosuppressive therapy (3,135). Prophylaxis against PCP with T/S is highly efficacious (176) and should be given to all patients treated with aggressive immunosuppressive therapy (provided no contraindications exist). Thrice weekly T/S (160 mg/800 mg) is cost-effective (176). Other prophylactic regimens employing dapsone (177), aerolized pentamadine (one monthly) (176), or atovaquone (177) are far more expensive and have a less favorable adverse effect profile. TNF-a inhibitors
Given the plausible role of TNF-a in the pathogenesis of AAV, inhibitors of TNF-a have been used to treat WG (178,179), but data are limited. Currently,
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three TNF-a antagonists are marketed for use: etanercept, infliximab, and adalimumab; none has an indication for use in WG. Etanercept is composed of two p75 TNF-a receptors coupled to the Fc portion of a monoclonal human IgG1, and binds TNF-a in a one-to-one fashion (179). An early pilot study treated 20 WG patients with etanercept (in addition to standard therapy) for six months (180). Remissions were achieved in 80% but major flares developed in three patients while on etanercept. The WGET randomized 180 patients with WG to either etanercept (25 mg subcutanenously twice weekly) or placebo in addition to standard therapy with CYC or MTX (20). Patients were followed for a minimum of 12 months. The rate of sustained remissions, number and severity of disease flares, and quality of life were similar between etanercept- and placebo-treated groups. Importantly, solid organ cancers developed in six patients in the etanercept group, while no cancers were observed among controls. On the basis of this study, etanercept has no role as therapy for WG. Conversely, infliximab, a chimeric mouse/human monoclonal antibody that inhibits TNF-a by binding to both soluble and transmembrane TNF-a, may be effective as therapy for WG. Four clinical trials (181–184) and anecdotal case reports (80,90,185) suggest benefit for patients with AAV failing conventional therapy. In one study, 10 patients with AAV refractory to conventional therapy (7 had WG) were treated with IV infliximab (5 mg/kg body weight) on days 0, 2 weeks, 6 weeks, and every 8 weeks thereafter; CS were continued (181). By six weeks, all patients had improved and CS dose had decreased. In a second openlabel trial (184), six WG patients refractory to CYC/CS were treated with infliximab [3 mg/kg body weight (n ¼ 2), 5 mg/kg body weight (n ¼ 4)] at time 0, 2 weeks, 6 weeks, and every 4 weeks thereafter; CYC and CS were continued. Complete remissions were achieved in five patients; infliximab was ineffective in one patient with an enlarging retro-orbital granuloma (184). In another study, six patients with AAV (3 had WG) who had 3 relapses while on conventional therapy were treated with infliximab (200 mg once monthly) for three months (182). Remissions were achieved in five of six patients. In a subsequent opentrial by these investigators, 32 patients (19 with WG, 13 with MPA) received infliximab (5 mg/kg body weight) plus conventional therapy to induce remission (n ¼ 16) or as adjunctive therapy in patients with persistent disease (n ¼ 16). For the first group, infliximab was administered on day 0, 2 weeks, 6 weeks, 10 weeks, and was then stopped. For the group with persistent disease, infliximab was continued every 6 weeks for a total of 12 months (183). Fourteen patients in each group achieved clinical remissions at a mean time of 6.4 weeks, mean BVAS scores declined from 12.3 at baseline to 0.3 at week 14. Two patients died during the trial (1 from DAH and one from pneumonia attributed to CYCinduced leukopenia); one patient developed lymphoma. Others cited responses to infliximab in three of four WG patients with CNS involvement refractory to conventional therapy (80,90). These various studies suggest that infliximab may have a role to treat selected WG patients’ refractory to conventional therapy. To our knowledge, adalimumab has not been studied in patients with WG or other
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AAV. However, all TNF-a inhibitors have potential serious toxicities including opportunistic infections; lymphoproliferative and solid malignancies (20,158); induction of autoimmune disorders, vasculitis, or interstitial lung diseases (186). Placebo-controlled trials are necessary to ascertain the role of infliximab or other TNF-a inhibitors for WG or AAV. Rituximab
Rituximab is a chimeric monoclonal antibody that binds CD20 on the surface of B cells and promotes B lymphocyte depletion (187). Since B cells are the primary sources of ANCA (4), eradication of the cellular source of ANCA is an appealing target. Although randomized trials have not been done, favorable responses to rituximab have been cited in patients with WG refractory to conventional therapy (often multiple therapeutic approaches) (188–196). Keogh et al. treated 11 patients with pR3-ANCA (þ) vasculitis with IV rituximab and CS; three also underwent PE (190). All had failed or were intolerant of prior treatment with CYC/CS. Remissions were achieved in all patients and were maintained during B-cell depletion. In another study, 10 patients with AAV (8 had WG) refractory to conventional therapy received IV rituximab (375 mg/m2 weekly for 4 consecutive weeks) (188); remissions were achieved in all 10 (9 complete); ANCA disappeared in 8. Three relapses were noted at a median of 33.5 months; all responded to retreatment (188). Rituximab may be less efficacious as therapy for granulomatous manifestations of WG. Aries et al. treated eight patients with active WG refractory to treatment with CYC/CS plus TNF-a blockade three months before inclusion in the study (189). Rituximab was administered every four weeks in combination with either CYC (n ¼ 5) or MTX (n ¼ 2). Granulomatous features were present in all eight [retro-orbital granulomas (n ¼ 5), bronchostenosis (n ¼ 2), pulmonary nodules (n ¼ 1)]. Despite disappearance of B lymphocytes, ANCA titers did not change and only three patients remitted (2 complete); the disease progressed in two patients. In a recent study, rituximab combined with CS and immunosuppressants induced remissions in six of eight patients; one relapsed one year after stopping rituximab and responded to a second cycle (195). Consistent with previous observations, ‘‘granulomatous’’ manifestations regressed more slowly than constitutional or ‘‘vasculitic’’ symptoms (189). Additional studies are required to assess the role of B-cell depletion to treat WG, predictors of response, appropriate dosing and frequency of administration, and long-term side effects. A prospective, randomized trial evaluating the efficacy of rituximab therapy for WG is pending (187). Antithymocyte globulin
Antithymocyte globulin (ATG) has been used to treat WG refractory to other agents. In one study, three of four patients with severe orbital WG responded to rabbit ATG (2 partial, 1 complete) (197). In an open-label study, 15 patients with active refractory WG were treated with ATG (198). The patients had received a mean of 5.2 different therapies without control of disease. Favorable responses to
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ATG were noted in 13 of 15 patients (partial in 9, complete in 4). Relapses occurred in 47% of patients during a follow-up of 22 months (198). High-dose intravenous immunoglobulin
High-dose (0.5 mg/kg/day for 4 days) IV immunoglobulin (IVIG) may have a role to treat AAV refractory to or intolerant of conventional therapy. Favorable responses were noted with IVIG (alone or combined with CS and/or immunosuppressive agents) in 45% to 77% of patients with AAV (199–205). One placebo-controlled trial assessed the efficacy of a single course of IVIG administered to patients with relapsing AAV (205). Responses were noted in 14 of 17 receiving IVIG and 6 of 17 receiving placebo. In a recent study, 22 patients with relapsing AAV (19 had WG) were treated with IVIG monthly for six months (204). All patients received concomitant CS; immunosuppression was maintained at existing levels or reduced. After nine months, 17 patients (77%) had achieved CR. Side effects of IVIG were mild and transient. These studies suggest that IVIG may have a role in selected patients with AAV refractory to conventional therapy, but comparative trials comparing IVIG with other salvage therapies have not been done. Other therapeutic options
Anecdotal responses have been cited with cyclosporin A (206), monoclonal antibodies targeted against T cells (207,208); humanized anti-CD4 antibodies (18), alemtuzumab (CAMPATH-1H), a monoclonal antibody directed against CD52 (81,209), 15-deoxyspergualin (210,211), and etoposide (180,212), and autologous hematopoietic stem cell transplants (213), but data are limited to a few cases in uncontrolled trials. 2.
Biologic Response Modifiers
The use of biologic agents in the treatment of WG is intriguing because of the potential to specifically target immunologic components involved in disease pathogenesis while leaving other host defense mechanisms intact (214). To date, the efficacy and safety profile associated with biologic agents to treat WG have not been established. F.
Surgical Management of Specific Complications of WG
Localized disease refractory to medical therapy or associated with compromise of organ function [e.g., tracheal or bronchostenosis (50–52), mass lesions encroaching the orbit or optic chiasm (44)] may require percutaneous or surgical management or intralesional CS therapy (3,50,52). For tracheobronchial WG, treatment modalities include CO2 or Nd:YAG laser, dilatation, intratracheal CS injections, placement of Silastic airway stents, tracheostomy, laryngeal-tracheal reconstruction, and partial tracheal resection (3,50,51,53,215–218). Silastic stents may provide sustained relief of symptoms in some patients, but are associated with
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numerous complications (e.g., migration of the stent, granuloma formation, mucus hypersecretion, fungal colonization, bronchomalacia in the area of the stent) (50,51,219). Intralesional injection with long-acting CS and intratracheal dilatation is preferred to more aggressive techniques (50,52,219). Tracheal reconstruction has been successfully performed in patients with severe tracheal stenosis refractory to medical therapy, but is a formidable undertaking (50,53). References 1. Lynch JP III, White E, Tazelaar H, et al. Wegener’s granulomatosis: evolving concepts in treatment. Semin Respir Crit Care Med 2004; 25(5):491–521. 2. Travis WD. Pathology of pulmonary vasculitis. Semin Respir Crit Care Med 2004; 25(5):475–482. 3. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener’s granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116:488–498. 4. Kallenberg CG. Pathogenesis of PR3-ANCA associated vasculitis. J Autoimmun 2008; 30(1–2):29–36. 5. Fauci AS, Haynes BF, Katz P, et al. Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983; 98(1):76–85. 6. Mukhtyar C, Flossmann O, Hellmich B, et al. Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the EULAR Systemic Vasculitis Task Force. Ann Rheum Dis 2007 (Epub ahead of print; Oct 2, 2007). 7. Luqmani RA, Bacon PA, Beaman M, et al. Classical versus non-renal Wegener’s granulomatosis. Q J Med 1994; 87(3):161–167. 8. Reinhold-Keller E, Beuge N, Latza U, et al. An interdisciplinary approach to the care of patients with Wegener’s granulomatosis: long-term outcome in 155 patients. Arthritis Rheum 2000; 43(5):1021–1032. 9. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990; 33(8):1101–1107. 10. Langford CA, Hoffman GS. Rare diseases. 3: Wegener’s granulomatosis. Thorax 1999; 54(7):629–637. 11. Klinger H. Grenzformen der Periarteritis Nodosa. Pathology 1931; 42:455–480. 12. Wegener F. Uber generarlisisierte, seeptische Gefaesserkrankungen. Verh Dtsch Ges Pathol 1936; 29:202–210. 13. Godman G, Churg J. Wegener’s granulomatosis: pathology and review of the literature. Arch Pathol 1954; 58:533–553. 14. Carrington CB, Liebow A. Limited forms of angiitis and granulomatosis of Wegener’s type. Am J Med 1966; 41(4):497–527. 15. Reinhold-Keller E, De Groot K, Rudert H, et al. Response to trimethoprim/sulfamethoxazole in Wegener’s granulomatosis depends on the phase of disease. Q J Med 1996; 89(1):15–23. 16. Ahmad I, Lee WC, Nagendran V, et al. Localised Wegener’s granulomatosis in otolaryngology: a review of six cases. ORL J Otorhinolaryngol Relat Spec 2000; 62(3):149–155.
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146. Exley AR, Bacon PA, Luqmani RA, et al. Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis Rheum 1997; 40(2):371–380. 147. Seo P, Min YI, Holbrook JT, et al. Damage caused by Wegener’s granulomatosis and its treatment: prospective data from the Wegener’s Granulomatosis Etanercept Trial (WGET). Arthritis Rheum 2005; 52(7):2168–2178. 148. Stone JH. Limited versus severe Wegener’s granulomatosis: baseline data on patients in the Wegener’s granulomatosis etanercept trial. Arthritis Rheum 2003; 48(8):2299–2309. 149. Hoffman GS, Leavitt RY, Fleisher TA, et al. Treatment of Wegener’s granulomatosis with intermittent high-dose intravenous cyclophosphamide. Am J Med 1990; 89(4):403–410. 150. De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005; 52(8):2461–2469. 151. Gallagher H, Kwan JT, Jayne DR. Pulmonary renal syndrome: a 4-year, singlecenter experience. Am J Kidney Dis 2002; 39(1):42–47. 152. Knight A, Askling J, Ekbom A. Cancer incidence in a population-based cohort of patients with Wegener’s granulomatosis. Int J Cancer 2002; 100(1):82–85. 153. Odeh M. Renal cell carcinoma associated with cyclophosphamide therapy for Wegener’s granulomatosis. Scand J Rheumatol 1996; 25(6):391–393. 154. Lee K, Baglin TP, Marcus RE. Therapy-related leukaemia in Wegener’s granulomatosis. Clin Lab Haematol 1991; 13(2):207–209. 155. Koldingsnes W, Gran JT, Omdal R, et al. Wegener’s granulomatosis: long-term follow-up of patients treated with pulse cyclophosphamide. Br J Rheumatol 1998; 37(6):659–664. 156. de Groot K, Reinhold-Keller E, Tatsis E, et al. Therapy for the maintenance of remission in sixty-five patients with generalized Wegener’s granulomatosis. Methotrexate versus trimethoprim/sulfamethoxazole. Arthritis Rheum 1996; 39(12): 2052–2061. 157. Langford CA, Talar-Williams C, Barron KS, et al. A staged approach to the treatment of Wegener’s granulomatosis: induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance. Arthritis Rheum 1999; 42(12):2666–2673. 158. Stone JH, Holbrook JT, Marriott MA, et al. Solid malignancies among patients in the Wegener’s Granulomatosis Etanercept Trial. Arthritis Rheum 2006; 54(5): 1608–1618. 159. Bernatsky S, Ramsey-Goldman R, Clarke AE. Malignancies and cyclophosphamide exposure in Wegener’s granulomatosis. J Rheumatol 2008; 35(1):11–13. 160. Faurschou M, Sorensen IJ, Mellemkjaer L, et al. Malignancies in Wegener’s granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol 2008; 35(1):100–105. 161. Sneller MC, Hoffman GS, Talar-Williams C, et al. An analysis of forty-two Wegener’s granulomatosis patients treated with methotrexate and prednisone. Arthritis Rheum 1995; 38(5):608–613. 162. Langford CA, Sneller MC, Hoffman GS. Methotrexate use in systemic vasculitis. Rheum Dis Clin North Am 1997; 23(4):841–853.
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163. de Groot K, Muhler M, Reinhold-Keller E, et al. Induction of remission in Wegener’s granulomatosis with low dose methotrexate. J Rheumatol 1998; 25(3): 492–495. 164. Villa-Forte A, Clark TM, Gomes M, et al. Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience. Medicine (Baltimore) 2007; 86(5):269–277. 165. Stone JH, Tun W, Hellman DB. Treatment of non-life threatening Wegener’s granulomatosis with methotrexate and daily prednisone as the initial therapy of choice. J Rheumatol 1999; 26(5):1134–1139. 166. Furst DE. Practical clinical pharmacology and drug interactions of low-dose methotrexate therapy in rheumatoid arthritis. Br J Rheumatol 1995; 34(suppl 2): 20–25. 167. Benenson E, Fries JW, Heilig B, et al. High-dose azathioprine pulse therapy as a new treatment option in patients with active Wegener’s granulomatosis and lupus nephritis refractory or intolerant to cyclophosphamide. Clin Rheumatol 2005; 24 (3):251–257. 168. Nowack R, Gobel U, Klooker P, et al. Mycophenolate mofetil for maintenance therapy of Wegener’s granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement. J Am Soc Nephrol 1999; 10(9):1965–1971. 169. Nowack R, Birck R, van der Woude FJ. Mycophenolate mofetil for systemic vasculitis and IgA nephropathy. Lancet 1997; 349(9054):774. 170. Joy MS, Hogan SL, Jennette JC, et al. A pilot study using mycophenolate mofetil in relapsing or resistant ANCA small vessel vasculitis. Nephrol Dial Transplant 2005; 20(12):2725–2732. 171. Metzler C, Fink C, Lamprecht P, et al. Maintenance of remission with leflunomide in Wegener’s granulomatosis. Rheumatology (Oxford) 2004; 43(3):315–320. 172. Metzler C, Miehle N, Manger K, et al. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener’s granulomatosis. Rheumatology (Oxford) 2007; 46(7):1087–1091. 173. Hoffman GS. Immunosuppressive therapy is always required for the treatment of limited Wegener’s granulomatosis. Sarcoidosis Vasc Diffuse Lung Dis 1996; 13(3): 249–252. 174. DeRemee RA. The treatment of Wegener’s granulomatosis with trimethoprim/ sulfamethoxazole: illusion or vision? Arthritis Rheum 1988; 31(8):1068–1074. 175. Georgi J, Ulmer M, Gross WL. [Cotrimoxazole in Wegener’s granulomatosis—a prospective study]. Immun Infekt 1991; 19(3):97–98. 176. Chung JB, Armstrong K, Schwartz JS, et al. Cost-effectiveness of prophylaxis against Pneumocystis carinii pneumonia in patients with Wegner’s granulomatosis undergoing immunosuppressive therapy. Arthritis Rheum 2000; 43(8):1841–1848. 177. El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group. N Engl J Med 1998; 339(26):1889–1895. 178. White ES, Lynch JP. Pharmacological therapy for Wegener’s granulomatosis. Drugs 2006; 66(9):1209–1228. 179. Mukhtyar C, Luqmani R. Current state of tumour necrosis factor {alpha} blockade in Wegener’s granulomatosis. Ann Rheum Dis 2005; 64(suppl 4):iv31–iv36.
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180. Stone JH, Uhlfelder ML, Hellmann DB, et al. Etanercept combined with conventional treatment in Wegener’s granulomatosis: a six-month open-label trial to evaluate safety. Arthritis Rheum 2001; 44(5):1149–1154. 181. Bartolucci P, Ramanoelina J, Cohen P, et al. Efficacy of the anti-TNF-alpha antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatology (Oxford) 2002; 41(10):1126–1132. 182. Booth AD, Jefferson HJ, Ayliffe W, et al. Safety and efficacy of TNFalpha blockade in relapsing vasculitis. Ann Rheum Dis 2002; 61(6):559. 183. Booth A, Harper L, Hammad T, et al. Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 2004; 15(3):717–721. 184. Lamprecht P, Voswinkel J, Lilienthal T, et al. Effectiveness of TNF-alpha blockade with infliximab in refractory Wegener’s granulomatosis. Rheumatology (Oxford) 2002; 41(11):1303–1307. 185. Cheung CM, Murray PI, Savage CO. Successful treatment of Wegener’s granulomatosis associated scleritis with rituximab. Br J Ophthalmol 2005; 89(11):1542. 186. Ramos-Casals M, Brito-Zeron P, Munoz S, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore) 2007; 86(4): 242–251. 187. Hinze CH, Colbert RA. B-Cell depletion in Wegener’s granulomatosis. Clin Rev Allergy Immunol 2008 (Epub ahead of print; Jan 3, 2008). 188. Stasi R, Stipa E, Del Poeta G, et al. Long-term observation of patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology (Oxford) 2006; 45(11):1432–1436. 189. Aries PM, Hellmich B, Voswinkel J, et al. Lack of efficacy of rituximab in Wegener’s granulomatosis with refractory granulomatous manifestations. Ann Rheum Dis 2006; 65(7):853–858. 190. Keogh KA, Wylam ME, Stone JH, et al. Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibodyassociated vasculitis. Arthritis Rheum 2005; 52(1):262–268. 191. Memet B, Rudinskaya A, Krebs T, et al. Wegener granulomatosis with massive intracerebral hemorrhage: remission of disease in response to rituximab. J Clin Rheumatol 2005; 11(6):314–318. 192. Tamura N, Matsudaira R, Hirashima M, et al. Two cases of refractory Wegener’s granulomatosis successfully treated with rituximab. Intern Med 2007; 46(7):409–414. 193. Specks U, Fervenza FC, McDonald TJ, et al. Response of Wegener’s granulomatosis to anti-CD20 chimeric monoclonal antibody therapy. Arthritis Rheum 2001; 44(12):2836–2840. 194. Omdal R, Wildhagen K, Hansen T, et al. Anti-CD20 therapy of treatment-resistant Wegener’s granulomatosis: favourable but temporary response. Scand J Rheumatol 2005; 34(3):229–232. 195. Brihaye B, Aouba A, Pagnoux C, et al. Adjunction of rituximab to steroids and immunosuppressants for refractory/relapsing Wegener’s granulomatosis: a study on 8 patients. Clin Exp Rheumatol 2007; 25(1 suppl 44):S23–S27. 196. Hermle T, Goestemeyer AK, Sweny P, et al. Successful therapeutic use of rituximab in refractory Wegener’s granulomatosis after renal transplantation. Clin Nephrol 2007; 68(5):322–326.
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197. Kool J, de Keizer RJ, Siegert CE. Antithymocyte globulin treatment of orbital Wegener granulomatosis: a follow-up study. Am J Ophthalmol 1999; 127(6):738–739. 198. Schmitt WH, Hagen EC, Neumann I, et al. Treatment of refractory Wegener’s granulomatosis with antithymocyte globulin (ATG): an open study in 15 patients. Kidney Int 2004; 65(4):1440–1448. 199. Jayne DR, Davies MJ, Fox CJ, et al. Treatment of systemic vasculitis with pooled intravenous immunoglobulin. Lancet 1991; 337(8750):1137–1139. 200. Richter C, Schnabel A, Csernok E, et al. Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin. Clin Exp Immunol 1995; 101(1):2–7. 201. Taylor CT, Buring SM, Taylor KH. Treatment of Wegener’s granulomatosis with immune globulin: CNS involvement in an adolescent female. Ann Pharmacother 1999; 33(10):1055–1059. 202. Blum M, Andrassy K, Adler D, et al. Early experience with intravenous immunoglobulin treatment in Wegener’s granulomatosis with ocular involvement. Graefes Arch Clin Exp Ophthalmol 1997; 235(9):599–602. 203. Ito-Ihara T, Ono T, Nogaki F, et al. Clinical efficacy of intravenous immunoglobulin for patients with MPO-ANCA-associated rapidly progressive glomerulonephritis. Nephron Clin Pract 2006; 102(1):c35–c42. 204. Martinez V, Cohen P, Pagnoux C, et al. Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective, open-label study of twenty-two patients. Arthritis Rheum 2008; 58(1):308–317. 205. Jayne DR, Chapel H, Adu D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 2000; 93(7): 433–439. 206. Ghez D, Westeel PF, Henry I, et al. Control of a relapse and induction of long-term remission of Wegener’s granulomatosis by cyclosporine. Am J Kidney Dis 2002; 40(2):E6. 207. Lockwood CM. New treatment strategies for systemic vasculitis: the role of intravenous immune globulin therapy. Clin Exp Immunol 1996; 104(suppl 1):77–82. 208. Lockwood CM, Thiru S, Stewart S, et al. Treatment of refractory Wegener’s granulomatosis with humanized monoclonal antibodies. Q J Med 1996; 89(12): 903–912. 209. Dick AD, Meyer P, James T, et al. Campath-1H therapy in refractory ocular inflammatory disease. Br J Ophthalmol 2000; 84(1):107–109. 210. Schmitt WH, Birck R, Heinzel PA, et al. Prolonged treatment of refractory Wegener’s granulomatosis with 15-deoxyspergualin: an open study in seven patients. Nephrol Dial Transplant 2005; 20(6):1083–1092. 211. Birck R, Warnatz K, Lorenz HM, et al. 15-Deoxyspergualin in patients with refractory ANCA-associated systemic vasculitis: a six-month open-label trial to evaluate safety and efficacy. J Am Soc Nephrol 2003; 14(2):440–447. 212. Papo T, Le Thi Huong D, Wiederkehr JL, et al. Etoposide in Wegener’s granulomatosis. Rheumatology (Oxford) 1999; 38(5):473–475. 213. Statkute L, Oyama Y, Barr WG, et al. Autologous non-myeloablative hematopoietic stem cell transplantation for refractory systemic vasculitis. Ann Rheum Dis 2007 (Epub ahead of print; Oct 18, 2007). 214. Langford CA. Biologic immunomodulatory therapies in the vasculitic diseases. Semin Respir Crit Care Med 2004; 25(5):595–607.
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26 Churg-Strauss Vasculitis
PHILIPPE GUILPAIN, CHRISTIAN PAGNOUX, and LOI¨C GUILLEVIN Department of Internal Medicine and Referral Center for Necrotizing Vasculitides and Systemic Sclerosis, Cochin Hospital, Assistance Publique-Hoˆpitaux de Paris, Paris, France
I.
Introduction
Churg-Strauss syndrome (CSS) is a primary small vessel necrotizing vasculitis characterized by asthma, lung infiltrates, extravascular necrotizing granulomas, and hypereosinophilia (1). Churg and Strauss, in 1951, individualized CSS from periarteritis nodosa on the basis of autopsy of 13 patients (1) and initially called it allergic granulomatosis and angiitis. Asthma (usually severe and of late onset) is a hallmark of CSS, present in almost all patients but other thoracic manifestations may occur, including lung infiltrates in about 70%, pleural effusions, and, more rarely, hilar lymphadenopathy and alveolar hemorrhage. CSS is one of the antineutrophil cytoplasm autoantibody (ANCA)-associated vasculitides (AAV), which also comprises microscopic polyangiitis (MPA) and Wegener’s granulomatosis. However, ANCAs are not always found in CSS patients. Two recent studies described two CSS phenotypes, on the basis of ANCA status, suggesting two distinct pathogenic mechanisms (2,3).
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Pathogenesis and Triggering Factors
According to the three successive phases of CSS described by Lanham et al. (4), an infectious agent or a foreign antigen could initiate allergic inflammation leading to rhinosinusitis and asthma in patients with predisposing genetic backgrounds. Eosinophilia and vasculitis could arise later, as a result of the inflammatory cascade. Several findings support the deleterious effect of activated eosinophils. Because hypereosinophilia and eosinophil tissue infiltration are key CSS features, activated eosinophils could be effector cells in this AAV. The high surface expression of the CD25 and CD69 antigens (5) suggests strong cell activation. Pertinently, elevated serum levels of interleukin-5 (IL-5), a cytokine essential for eosinophil maturation, activation, and survival, are found in CSS patients (5) and are closely associated with disease activity (6). Th2 pattern cytokines, e.g., IL-5, are probably involved in eosinophil activation and CSS development. Although some CSS patients improved under interferon-a (IFN-a) (7), the benefit of counteracting Th2 cytokines remains controversial. Upon activation, eosinophils release cytotoxic enzymes, e.g., eosinophil cationic protein (ECP), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase (EPO). Extravascular ECP (8) and MBP (9) deposits have been observed, and high levels of eosinophil cytotoxic enzymes are found in CSS patient’s sera, urine, and bronchoalveolar fluids (9–11). In addition, the results of a recent study suggested that EPO released by activated eosinophils could cause oxidative tissue damage (12). Taken together, these elements incriminate eosinophil cytotoxicity in CSS development. While all CSS patients may have activated eosinophils, those with ANCA also suffer from the deleterious effects of these antibodies (Ab), detected in MPA patients. Indeed, ANCA with anti-myeloperoxidase (MPO) activity can activate neutrophils in vitro leading to the release of reactive oxygen species, which are highly toxic to endothelium. More recently, the in vivo pathogenic role of antiMPO Ab was demonstrated by the immune transfer (13) of these Ab into Rag–/– mice, which induced vasculitis resembling MPA but not CSS. In addition, our group recently demonstrated that anti-MPO Ab act also through MPO activation and hypochlorous acid production to induce endothelial cells damage (14). The effects of anti-MPO Ab could explain the more pronounced vasculitic manifestations in ANCA-positive patients. However, the mechanisms initiating CSS remain incompletely understood, particularly for ANCA-negative patients, and other factors must be at work. Although CSS etiology remains unknown, some triggering factors have been identified or suspected, including drugs and/or environmental factors (15). First, vaccinations and desensitization were incriminated in several cases (16). We usually advise CSS patients to avoid vaccination and desensitization. Second, exposures to inhaled allergens and infections (parasitic or bacterial) were also described shortly before CSS onset (17). Third, several drugs [e.g., macrolides,
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carbamazepine, quinine, and corticosteroid (CS)-sparing agents for asthma] were implicated in CSS development (18). More recently, leukotriene receptor antagonists (LRA) (zafirlukast, montelukast, pranlukast) were suspected (19,20). LRA allowed substantial CS tapering or withdrawal, which could unmask an underlying and previously ‘‘incomplete’’ disease (19). LRA could also be given because of worsening asthma that may predate CSS. Finally, a direct LRA causative role cannot be excluded. Although their deleterious effect remains controversial, LRA should be used cautiously in asthma patients, especially when asthma is atypical or exacerbates. When CSS appears in LRAtreated asthma patients, these agents must be discontinued. However, in our experience, some CSS patients with very severe asthma benefited from these drugs, and we think that their prescription in this context should be discussed with a specialist. III.
Systemic Manifestations of CSS and Diagnosis
Mean age at the time of CSS diagnosis is 48 years, with a sex ratio of approximately 1:1. Most patients have general symptoms, like fever or weight loss, but pulmonary manifestations are core disease features, particularly asthma and patchy pulmonary infiltrates (Fig. 1) (about 100% and 70% patients, respectively) (2–4,16,21–25). Airways involvement, including ear, nose, and
Figure 1 Thoracic radiological findings: lung infiltrates and patchy multifocal peripheral consolidation.
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Figure 2 (See color insert.) ENT manifestations: bilateral maxillary sinusitis. Source: Courtesy of the French Vasculitis Study Group.
throat (ENT) manifestations, affects about 70% patients (Fig. 2). A history of allergic rhinitis or sinus polyposis is classical. Notably, sinus polyposis and asthma may be associated with intolerance to aspirin, which should be prescribed with caution and is contraindicated for intolerant patients. Neurological involvement is noted in 50% to 78% of patients (26,27). Mononeuritis multiplex is the most frequent (*70% patients with peripheral neuropathy) at CSS onset whereas symmetrical polyneuropathy can be seen in up to 30% of patients (26,27). Central nervous system (CNS) involvement (cranial nerves palsies, cerebral hemorrhage or infarction, convulsions, coma, and psychiatric features) is rarely seen (16). Heart involvement develops in up to 60% of CSS patients (1). In the French Vasculitis Study Group (FVSG) experience, heart disease was found in 39 of 112 (35%) patients, including 28 patients with pericarditis and 27 with cardiomyopathy (3). Heart disease can involve the myocardium, pericardium, and at lesser degree, endocardium (28) and, in earlier studies, represented the major cause of death, accounting for about 48% of deaths (28,29) and morbidity. Myocarditis (caused by different or perhaps associated mechanisms, including eosinophilia, coronary arteritis, and fibrosis) can lead to restrictive (29), congestive (30), or dilated cardiomyopathy (30,31). Pericardial effusion occurs in up to 22% of CSS patients. CS usually control pericarditis but relapses may occur.
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Endomyocardial involvement was also reported (29,30). Conduction disorders and supraventricular arrhythmias, which can be fatal, can respond to CS. New imaging methods to detect heart disease are under development, including cardiac magnetic resonance and gated single photon-emission computed tomography (SPECT) that provide functional information (32,33). Skin lesions develop in 40% to 75% of patients. Palpable (often necrotic) purpura, urticaria, and cutaneous nodules or papules on the limbs or fingers may be observed (34). Gastrointestinal (GI) tract symptoms have been reported in 37% to 62% of patients (35) and include abdominal pain (29–59%) and diarrhea (possibly bloody) (10–33%) (4,16,24,36). GI tract ulcerations and perforations, ischemic pancreatitis, and cholecystitis are other severe manifestations (16,24). Kidney disease is observed in 16% to 49% of CSS patients, usually presenting as rapidly progressive glomerulonephritis with necrosis, crescents, or both (2,3,37,38). Interstitial eosinophil and neutrophil infiltration with edema is also possible. Although mostly associated with anti-MPO Ab (2,3), it is a pauciimmune glomerulonephritis. Other renal manifestations include proteinuria, hypertension, renal insufficiency, and/or renal infarction with or without microaneurysms (1,4,16,22–24,36,38). Marked peripheral eosinophilia is observed in almost all patients and nonspecific elevated serum immunoglobulin E (IgE) in about 75% of patients. ANCA can be detected in 38% to 50% of patients, yielding a perinuclear immunofluorescent label pattern (P-ANCA) with 75% to 81% of ANCA-positive sera. P-ANCAs are mostly directed against MPO as assessed by enzyme-lined immunosorbent assay (ELISA) (92–100% of the P-ANCA) (2,3). Defining histological features of CSS (1) include eosinophil infiltrates, extravascular necrotizing granulomas, and small vessel angiitis, which may be granulomatous or not. Because the typical lesions rarely coexist temporally or spatially, histological documentation of CSS may be difficult. Neuromuscular biopsy may be highly informative when obvious clinical and electromyographic signs are present. Skin biopsy often lacks diagnostic specificity (34), and temporal artery involvement has been reported anecdotally (20).
IV. A.
Pulmonary Manifestations of CSS Asthma
Asthma is quasi-constant (4) and can be severe and become CS dependent with continuous dyspnea, and severe attacks are common. In the vast majority of cases, asthma develops before systemic signs of vasculitis. The time between asthma onset and CSS may be very long (up to 30 years). For 96 of our patients (16), this delay was 8.86 10.86 years (range: 0–61). The severity of asthma attacks usually increases before CSS onset. However, asthma appears after vasculitis (4) or simultaneously with it [about 20% of the patients described by
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Chumbley et al. (23)]. Vasculitis preceded asthma by 6 and 12 months, respectively, for two highly unusual patients (16). Only 1 of 23 CSS patients followed by Reid et al. (22) had no asthma, and this absence should always be interpreted as a possible argument against the diagnosis. In CSS, asthma may persist after treatment controls systemic vasculitis. About 75% of patients in long-term CSS remission have persistent asthma requiring low-dose prednisone and/or inhaled CS (16). B.
Specific Thoracic Involvement
Uni- or bilateral, symmetrical or not, lung infiltrates are found in about 70% of CSS patients (4) and may predate vasculitis in 40% of them. Fever, cough, and dyspnea are common clinical manifestations of these infiltrates. According to Choi et al. (39), patchy, multifocal, peripheral consolidation (67%) was the most common radiological finding (Fig. 1). Infiltrates are characterized by primary eosinophil penetration into interstitial lung tissue and alveoli, with subsequent development of necrotizing vasculitis (4). These infiltrates are transient and labile and can regress even without any treatment. Finally, lung infiltrates should be distinguished from interstitial edema secondary to congestive heart failure, which is also frequent in CSS. 1.
Symmetrical and Peripheral Infiltrates
According to Choi et al. (39), findings on thoracic thin-section CT scans include symmetrical and peripheral infiltrates that may mimic chronic eosinophilic pneumonia (39). Their peripheral location and lobular distribution are suggestive of vasculitis involving small- and medium-sized arteries. These infiltrates may be associated with subpleural thickening secondary to hemorrhagic necrosis, and they should be distinguished from those of chronic eosinophilic pneumonia (usually characterized by homogeneous peripheral airspace consolidation). However, consolidation can have a more lobular distribution and may be associated with other patterns. 2.
Centrilobular Perivascular Densities
This pattern, found in some patients (40,41), was described as diffusely scattered centrilobular nodules (5 mm) within ground glass opacities in eight of nine patients investigated by Choi et al (39). These lesions, located in centrilobular spaces, correspond to pulmonary vasculitis and perivascular infiltration. C.
Pleural Effusion
According to Lanham et al. (4) and Reid et al. (22), pleural effusions were present in 20% to 30% of their patients, but were less frequent in our patients (16). The pleural fluid is usually exudative and rich in eosinophils. Pleural biopsy might contain eosinophil infiltrates with necrotizing vasculitis (16) or
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granulomas (42). However, pleural effusions occurring in the context of CSS may also be a consequence of congestive heart failure, severe renal insufficiency, infection, or, more rarely, nephrotic syndrome. D.
Other Pulmonary Manifestations
In CSS, asthma, heart failure, pulmonary infiltrates, and alveolar hemorrhage may also cause dyspnea. Alveolar hemorrhage, which occurred in only 4% of our patients (16), resulted from lung capillary involvement, causing dyspnea, hemoptysis, anemia, and lung alveolar infiltrates. It is associated with the detection of antiMPO Ab (2,3). Phrenic palsy, probably because of phrenic nerve vasculitis (36), and enlarged mediastinal lymph nodes are rarely observed (39). V.
CSS Natural History, Classifications, and Phenotypes
According to Lanham et al. (4), CSS clinical manifestations follows three successive phases: first, the prodromic phase, consisting of asthma and allergic manifestations; second, eosinophil (granulomatous or not) infiltration of tissues (especially lung, myocardium, and/or GI tract); third, necrotizing vasculitis, preferentially affecting skin, peripheral nerves, and kidneys, possibly several years after asthma (mean: 3–4 years; range: 2 months–30 years) (16,25). Neither the American College of rheumatology (43) nor the Chapel Hill Consensus Conference (44) classification criteria (Table 1) distinguish patients according to the ANCA status. Furthermore, several studies focused on the possible clinical manifestation differences among CSS patients according to the ANCA status (2,3,25). The only difference found between ANCA-positive and ANCAnegative CSS patients by Keogh and Specks (25) was more frequent CNS involvement in the former (20% vs. 5%). Unexpectedly, the CNS involvement was present in 73% of the 93 patients included in that retrospective study (25).
Table 1 CSS Classification Criteria American College of Rheumatology Chapel Hill Conference nomenclature (1994) (ACR) criteriaa (1990) Asthma Asthma Blood eosinophilia > 10% Blood eosinophilia > 10% Mononeuropathy (including multiplex) Small- to medium-sized vessels necrotizing or polyneuropathy vasculitis Nonfixed pulmonary infiltrates on Eosinophil-rich respiratory tract inflammation roentgenography Paranasal sinus abnormality Granuloma-rich respiratory tract inflammation Biopsy containing a blood vessel with extravascular eosinophils a
4 criteria yielded a sensitivity of 85% and a specificity of 99.7%.
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Two recent retrospective studies (1 Italian series and 1 from the FVSG) (2,3) showed that ANCA-positive CSS patients (about 38% of all CSS patients) differed clinically from those without ANCA. Necrotizing crescentic glomerulonephritis, purpura, alveolar hemorrhage, and mononeuritis multiplex were more frequent in Italian ANCA-positive patients, while cardiomyopathy and pulmonary infiltrates were more frequent in ANCA-negative patients (2). In addition, vasculitis was detected more rarely in the latter patients (76% vs. 32% of those who underwent biopsy), while tissue infiltration by eosinophils was more prominent (14% vs. 59%). The FSVG obtained similar results (3) with French ANCA-negative patients having more frequent cardiac involvement (including pericarditis and cardiomyopathy), pleural effusion, fever and livido, and ANCA-positive patients also having more frequent renal involvement, peripheral neuropathy, purpura, and sinusitis (3). Histological examination detected vasculitis less frequently (79% vs. 39%) in ANCA-negative patients, while eosinophil infiltration rates were comparable for the two groups. Hence, we think that ANCA status might define two distinct CSS phenotypes. However, patient survival and relapse rates at three to five years were similar in both studies, regardless of ANCA status at diagnosis. VI.
Treatment
CSS prognosis has improved dramatically since the introduction of CS and, when indicated, cytotoxic drugs. Remission is rapidly obtained in greater than 80% of treated patients. However, 15% to 43% of patients relapse (3,16,25), and some suffer from several relapses. In our experience (16), *25% of CSS patients relapsed with *50% of those relapses occurring during the first year of followup and later in the other 50%. In the first FVSG study, the 10-year survival rate was 79% (16). More recently, the five-year survival rate was *95% for the Italian patients (2); 88% after a median follow-up of seven years for the Mayo Clinic cohort (25); and 95% after a mean follow-up of 34 months for the FVSG patients (3). Approximately 75% of deaths were directly attributable to vasculitis, with cardiac involvement being the primary cause of death. After recovery from vasculitis, asthma often persists. In long-term remission of vasculitis, 82% of surviving CSS patients have persistent asthma, which requires, for 73% of them, maintenance therapy with low-dose prednisone (mean dose: 8.9 7 mg/day) and/or inhaled CS (12% of our patients) (16). Congestive heart failure is also a major concern in the long term follow up, and some patients may require heart transplantation. A.
Current Therapeutic Recommendations
Therapeutic strategies depend on disease severity, assessed by well-established indicators of severity and prognostic factors. On the basis of the FVSG prospective study on 342 patients (45), the five factor score (FFS) comprising proteinuria greater
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than 1 g/day, renal insufficiency [creatininemia > 140 mmol/L (1.58 mg/dL)], specific cardiomyopathy, GI tract involvement, and CNS involvement, was established and shown to have significant prognostic value. In the absence of poor prognosis factors, vasculitis usually responds quickly to CS. Immunosuppressant [mainly cyclophosphamide (CYC)] should be added as first-line therapy for the most severe disease forms (i.e., FFS 1), representing approximately half of CSS patients (2,3). In all cases, the initial CSS management should include high-dose CS (1 mg/kg/day of prednisone or its methylprednisolone equivalent). Methylprednisolone pulses (usually 15 mg/kg IV repeated at 24-hour intervals for 1–3 days) are recommended at therapy onset for severe disease. Biological inflammation parameters usually return to normal within three weeks to one month, at which CS dose tapering started to reach less than 10 mg/day after several months. However, permanent discontinuation of CS is often impossible because of residual asthma (16). CYC is the criterion standard as immunosuppressant for CSS. It is combined with CS as first-line therapy for patients with at least one poor prognosis factor or as second-line therapy for patients with refractory or relapsing disease. Intravenous CYC pulses (600–750 mg/m2 given at 2-week intervals for 1 month and then once monthly, with appropriate hydration and bladder protection with sodium 2-mercaptoethanesulfonate) can be proposed instead of oral administration because of their lower toxicity. Oral CYC can be successfully given to patients with relapsing CSS and to those whose disease is refractory to CS and intravenous CYC. Treatment should not be interrupted before 18 months for patients with poor prognosis factor(s). Indeed, patients who received 12 CYC pulses had a lower relapse rate than those who received only 6 pulses (46). However, a prospective study on of AAV management (47) showed that the switch to a less toxic maintenance immunosuppressant can be made as soon as the patient enters remission, i.e., usually after three to six months of CYC. Therefore, for CSS patients with FFS 1, we now induce remission with a shorter CYC regimen than in the past and switch to another less toxic drug, like azathioprine, for maintenance therapy. B.
Alternative Therapies for Relapsing or Refractory Disease
Some patients with relapsing or refractory disease could benefit from intravenous immunoglobulins (IVIg), which have been successfully administered to AAV patients (48–50). According to the recent prospective, open, multicenter FVSG study on patients with relapsed AAV (but no CSS patients) (50), monthly infusions of IVIg (2 g/kg over 2 days) for six months could be added to conventional regimen for patients with relapsing disease or refractory disease. Similarly, CSS patients might benefit from plasma exchanges, which have been evaluated for AAV treatment (51–53). Plasma exchanges do not improve survival of AAV patients (51), but can reverse kidney damage in those with severe renal insufficiency at diagnosis (53). When added to the standard CS and CYC regimen, synchronized plasma exchanges with IVIg could improve clinical recovery, with a more rapid control of disease activity (54).
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Because it could reverse pathogenic Th2-mediated immune responses, IFNa has been used to treat refractory CSS. High IFN-a doses (9–63 million units/wk) obtained clinical responses in four CSS patients refractory to CS plus CYC, but most of them relapsed after its discontinuation (7). IFNa has also successfully treated skin lesions (6). Those promising results have not been confirmed, but IFNa might be useful in some patients. Rituximab, a B-cell-targeted therapy, seems promising in patients with refractory and/or relapsed AAV (55). Thus, B-cell depletion could be proposed for CSS ANCA-positive patients. When reported, only three patients had been successfully treated with rituximab for CSS refractory to conventional therapy, with follow-up of 3, 9, and 16 months (56,57). Although attractive, these successes should be viewed with caution, because the CSS phenotypes were not typical in all cases. Notably, eosinophil counts decreased after rituximab infusions in those patients. Further studies are needed to establish the role of rituximab as an alternative treatment for CSS. In the future, CSS therapeutic agents might also include IL-5-neutralizing agents and omalizumab, a murine antihuman IgE monoclonal antibody, which has been shown to be safe and effective in allergic asthma (18). Omalizumab might be useful in patients with persistent and CS-dependent asthma, but CSS developed in a patient taking it for asthma (58). Therefore, we cannot recommend this agent in CSS management. VII.
Conclusion
Several characteristics distinguish CSS from other AAV, particularly the pathogenic role of eosinophils, the low ANCA frequency, and severity of heart involvement associated with ANCA-negative forms. While induction therapy for CSS is the same as that prescribed for other AAV, long-term prognosis and management are specific, especially because persistent asthma and perhaps CSS relapses represent special therapeutic issues. References 1. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 1951; 27(2):277–301. 2. Sinico RA, Di Toma L, Maggiore U, et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum 2005; 52(9):2926–2935. 3. Sable-Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med 2005; 143(9):632–638. 4. Lanham JG, Elkon KB, Pusey CD, et al. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore) 1984; 63(2):65–81. 5. Tsukadaira A, Okubo Y, Kitano K, et al. Eosinophil active cytokines and surface analysis of eosinophils in Churg-Strauss syndrome. Allergy Asthma Proc 1999; 20(1): 39–44.
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6. Termeer CC, Simon JC, Schopf E. Low-dose interferon alfa-2b for the treatment of Churg-Strauss syndrome with prominent skin involvement. Arch Dermatol 2001; 137(2):136–138. 7. Tatsis E, Schnabel A, Gross WL. Interferon-alpha treatment of four patients with the Churg-Strauss syndrome. Ann Intern Med 1998; 129(5):370–374. 8. Tai PC, Holt ME, Denny P, et al. Deposition of eosinophil cationic protein in granulomas in allergic granulomatosis and vasculitis: the Churg-Strauss syndrome. Br Med J (Clin Res Ed) 1984; 289(6442):400–402. 9. Peen E, Hahn P, Lauwers G, et al. Churg-Strauss syndrome: localization of eosinophil major basic protein in damaged tissues. Arthritis Rheum 2000; 43(8):1897–1900. 10. Schnabel A, Csernok E, Braun J, et al. Inflammatory cells and cellular activation in the lower respiratory tract in Churg-Strauss syndrome. Thorax 1999; 54(9):771–778. 11. Guilpain P, Auclair JF, Tamby MC, et al. Serum eosinophil cationic protein: a marker of disease activity in Churg-Strauss syndrome. Ann N Y Acad Sci 2007; 1107:392–399. 12. Higashi N, Mita H, Taniguchi M, et al. Urinary eicosanoid and tyrosine derivative concentrations in patients with vasculitides. J Allergy Clin Immunol 2004; 114(6): 1353–1358. 13. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002; 110(7):955–963. 14. Guilpain P, Servettaz A, Goulvestre C, et al. Pathogenic effects of antimyeloperoxidase antibodies in microscopic polyangiitis. Arthritis Rheum 2007; 56(7):2455–2463. 15. Lane SE, Watts RA, Bentham G, et al. Are environmental factors important in primary systemic vasculitis? A case-control study. Arthritis Rheum 2003; 48(3): 814–823. 16. Guillevin L, Cohen P, Gayraud M, et al. Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients. Medicine (Baltimore) 1999; 78(1):26–37. 17. Mouthon L, Khaled M, Cohen P, et al. Systemic small sized vessel vasculitis after massive antigen inhalation. Ann Rheum Dis 2001; 60(9):903–904. 18. Pagnoux C, Guilpain P, Guillevin L. Churg-Strauss syndrome. Curr Opin Rheumatol 2007; 19(1):25–32. 19. Wechsler ME, Finn D, Gunawardena D, et al. Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma. Chest 2000; 117(3):708–713. 20. Guilpain P, Viallard JF, Lagarde P, et al. Churg-Strauss syndrome in two patients receiving montelukast. Rheumatology (Oxford) 2002; 41(5):535–539. 21. Haas C, Le Jeunne C, Choubrac P, et al. Churg-Strauss syndrome. Retrospective study of 20 cases [in French]. Bull Acad Natl Me´d 2001; 185(6):1113–1130. 22. Reid AJ, Harrison BD, Watts RA, et al. Churg-Strauss syndrome in a district hospital. QJM 1998; 91(3):219–229. 23. Chumbley LC, Harrison EG Jr., DeRemee RA. Allergic granulomatosis and angiitis (Churg-Strauss syndrome). Report and analysis of 30 cases. Mayo Clin Proc 1977; 52(8):477–484. 24. Solans R, Bosch JA, Perez-Bocanegra C, et al. Churg-Strauss syndrome: outcome and long-term follow-up of 32 patients. Rheumatology (Oxford) 2001; 40(7):763–771. 25. Keogh KA, Specks U. Churg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med 2003; 115(4): 284–290.
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27 Microscopic Polyangiitis
ALAN D. SALAMA and CHARLES D. PUSEY Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, London, U.K.
I.
Introduction
Microscopic polyangiitis (MPA) is a multisystem autoimmune vasculitis, associated with antineutrophil cytoplasm antibodies (ANCA), and characterized by pauci-immune necrotizing vasculitis of small blood vessels. It is one of three small vessel vasculitidies commonly associated with ANCA, the others being Wegener’s granulomatosis (WG) and Churg-Strauss syndrome (CSS). However, despite the common association with ANCA, these disease entities have significant differences in their clinical features and possibly in their underlying pathophysiology. As such, data on pathological mechanisms should be extrapolated from one disease to another with caution. In this review, we will provide an overview of MPA, with particular reference to its pulmonary manifestations. II.
Epidemiology
MPA has been defined according to the Chapel Hill Consensus Conference, with the size of the vessels affected differentiating it from classical polyarteritis nodosa (PAN). The former involves small vessels (but can affect medium-sized 657
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vessels) while a diagnosis of PAN requires that no small vessels are involved, making it a comparatively less common diagnosis (1). In addition, PAN is not associated with ANCA but may be related to hepatitis B infection in a subgroup of patients. The incidence of MPA appears to be increasing in Europe, not solely as a result of increased disease awareness (2). In part, this may reflect the increased longevity of the population with many more patients living long enough to develop vasculitis. There is a marked geographical variation in the incidence of MPA, with an apparent inverse reciprocal incidence with WG, so that MPA appears commoner in Southern Europe, with an incidence of up to 11/million in Spain, while it is comparatively less common in Norway, with an incidence of only 2.7/million population (2). Additionally, there appears to be a geographical skewing of disease in Asia, with the vast majority of primary systemic vasculitis in Japan being MPA (incidence 14/million population) but with very few cases of WG or CSS (3). Similarly, in China, approximately 80% of cases of ANCA-associated vasculitis (AAV) are classified as MPA (4). The predisposition for vasculitis in European Caucasian populations (particularly WG) appears to be genetic rather than environmental, as Caucasoids have a twofold increase in prevalence compared with fellow countrymen of non-European ancestry, suggesting that immigrant populations maintain their intrinsic risk rather than developing the local population’s risk (5). While the majority of reported patients with MPA are Caucasian (6), this could be, in part, a result of reporting bias as most series have originated in Europe and North America, and there is undoubtedly a lack of reporting of vasculitis from certain countries and ethnic groups. Familial cases of AAV (including MPA) have been reported infrequently (7), while other genetic associations with AAV include a1 antitrypsin deficiency (8,9), elevated monocyte membrane PR-3 (10), deficiency in alleles of the negative costimulatory molecule CTLA4 (11,12), and low FcgR3 copy number (13). Numerous negative genetic association studies have been reported, including those demonstrating no clear HLA association with disease (14,15). Environmental factors implicated in disease induction include silica exposure (although this is a ubiquitous substance) and certain drugs such as propylthiouracil, penicillamine, and minocycline. Overall, these observations suggest that there are important genetic and environmental factors, critical for the evolution of different forms of vasculitis (see below).
III.
Pathogenesis
Evidence for pathogenicity of ANCA in MPA comes from a single case of maternal transmission of myeloperoxidase (MPO)-ANCA associated with a pulmonary renal syndrome in a neonate. The mother, with known MPA, had a disease relapse during pregnancy with pulmonary hemorrhage, following which
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the neonate was delivered by caesarean section. The infant was found to have circulating cord blood IgG MPO-ANCA, pulmonary hemorrhage, renal dysfunction, and microscopic hematuria and proteinuria. Following steroid therapy and exchange transfusion, the infant showed signs of improved pulmonary function, normalization of renal impairment and dipstick abnormalities, as well as disappearance of ANCA (16,17). No clinical or serological relapses were subsequently recorded in the infant. In contrast to the paucity of in vivo human data, significant work in animal models has now confirmed the pathogenic capabilities of ANCA. Data from a recent murine model have shown that transfer of anti-MPO antibodies, raised in MPO-deficient mice, into syngeneic, naı¨ve C57BL/6 mice is sufficient for induction of a necrotizing glomerulonephritis and systemic vasculitis (18). Since the anti-MPO antibodies were generated by immunization of MPO-deficient mice using murine MPO, they represent alloantibodies rather than true autoantibodies, which would be expected to impact on the avidity of the antibodies toward the MPO antigen. Despite these reservations, this novel model demonstrates that if antibodies are of sufficient avidity and in sufficient dose, they are sufficient to induce disease. In another model, in which MPO-ANCA were induced following immunization of Wistar Kyoto (WKY) rats with human MPO, ANCA-rich antibody preparations were shown to induce alterations in leukocyte adhesion and transmigration, assessed using intravital microscopy of mesenteric vessels (19). Renal and lung disease in this model were largely inhibited by TNF-blocking monoclonal antibodies (20), potentially mediated through diminished leukocyte endothelial cell interactions. In vitro, ANCA have been shown to induce neutrophil degranulation and activation, which is most marked following cytokine priming with tumor necrosis factor (TNF), a process that upregulates expression of MPO on the neutrophil surface (21). Additionally, MPO-ANCA induce IL-8 production by neutrophils, as well as enhancing their phagocytic capacity (more so than PR3-ANCA) and promoting neutrophil activation-induced cell death (22) and accelerated secondary necrosis (23). Both the Fc and F(ab’)2 portions of the ANCA are required for full neutrophil activation, interacting with Fc receptors and autoantigen (MPO) on the cell surface, respectively. Phagocytosis of ANCA-opsonized neutrophils by monocytes in turn promotes pro-inflammatory cytokine release (24), potentially perpetuating a cycle of cell activation and inflammation. Subsequently, neutrophil activation within the vasculature can lead to bystander endothelial cell damage, clearly demonstrated by coculturing neutrophils and endothelial cells in vitro (25). Since ANCA promote firm neutrophil adhesion to activated endothelial cells under flow conditions, as well as their migration across an endothelial monolayer (26), they allow greater neutrophil interaction with the endothelial cells and heighten the potential for endothelial damage. Interestingly, it appears that neutrophil activation leading to serine protease release is more critical in promoting endothelial cell injury than the release of reactive oxidative species (27).
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Taken together these data demonstrate that MPO-ANCA have the capacity to induce many of the disease features found in patients with MPA. Whether this is also true of PR3-ANCA remains to be established. Interestingly, using an analogous model to the anti-MPO antibody transfer system, but with PR3 immunization of PR3-deficient mice to generate a source of anti-PR3 antibodies, antibody transfer into naı¨ve mice did not result in induction of systemic vasculitis (28). In addition to the humoral component of the autoimmune response, cellular immunity directed against the MPO antigen has been demonstrated in patients with MPA, with peripheral blood mononuclear cells proliferating to MPO, although less frequent responses can also be found in some healthy individuals (29,30). We have also demonstrated an increased frequency of IFNg-secreting T cells, reactive to MPO, in patients with acute MPA compared with those in remission or healthy controls (Salama ASN 2). In a recently reported animal model, using mice immunized with MPO, in which anti-MPO T- and B-cell responses can be demonstrated, administration of a subnephritogenic dose of anti-GBM serum resulted in neutrophil influx to the glomeruli and glomerulonephritis. Control animals in which the MPO immunization was omitted did not develop disease. Moreover, animals were protected from GN following CD4 T-cell depletion, but not B-cell deficiency, suggesting that cell-mediated antiMPO immunity can play a significant role in mediating organ damage in MPA (31). However, the more proximal steps of immune dysfunction, the underlying factors leading to the breakdown of immune tolerance toward MPO, still remain unclear.
IV.
Clinical Manifestations
MPA appears to affect men slightly more than women, with a mean age of more than 50 years. MPA presents most commonly with renal involvement, systemic symptoms with weight loss, fever, arthralgias and myalgias, mononeuritis multiplex, and, in approximately a quarter to a third of cases, lung involvement. Pulmonary hemorrhage is a significant feature in around half of these cases (32), and occurs in the older age groups (Fig. 1), the rest being made up of pneumonitis or pleuritis. Systemic features may appear many weeks prior to a diagnosis being made and, interestingly, in one series pulmonary hemorrhage preceded other vasculitic symptoms in 20% of cases (32), with hemoptysis occurring up to a year before the diagnosis of MPA was made. In some cases, patients may present with clinical and radiological features of interstitial lung fibrosis (see below). ANCA is positive in about 75% of cases of MPA, with the majority having a perinuclear staining pattern and antigen specificity directed toward MPO. Sensitivity for MPA is of the order of 35% to 75% (33). False-positive ANCAs may occur in which the specificity is not directed against MPO, or in a non-vasculitic clinical
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Figure 1 Age distribution of a cohort of patients with MPA, treated at Hammersmith Hospital, presenting with pulmonary hemorrhage. Pulmonary hemorrhage appears to manifest in a slightly younger age group.
context. Consequently, both indirect immunofluorescence testing for ANCA and anti-MPO assay by ELISA are used in combination to increase test sensitivity, in the at-risk populations (33). Relapses occur less frequently in MPA and in MPO-ANCA positive patients than in WG and in PR3-ANCA positive patients (34–36). In most cases, symptoms of relapse are similar to those at original presentation, although a third of patients may relapse with new signs and symptoms. A renal-limited form of MPA can also be recognized (Fig. 2), although it is less common, and patients may later relapse with systemic features suggesting that it may not be a distinct entity but a presentation of the same disease. The reason for the predilection in MPA for involvement of certain organs remains uncertain, and the differences in organ involvement between the different ANCA-associated vasculitidies is challenging to explain, given our current understanding of disease pathogenesis. Interestingly, in all the animal models of MPA induced by immunization with MPO or transfer of anti-MPO antibodies, renal disease is a common feature, while lung disease occurs less frequently. V.
The Spectrum of Lung Disease
Although less common than in WG, lung disease in MPA is associated with a poor clinical outcome. Those patients presenting with pulmonary hemorrhage have a significantly higher mortality than the whole MPA population (Fig. 3).
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Figure 2 (See color insert.) Renal biopsy from a patient with MPA demonstrating crescentic glomerulonephritis with focal and segmental change and an area of fibrinoid necrosis, shown by arrow. (Haematoxylin and Eosin 200).
Figure 3 Kaplan Meir survival curves of a cohort of 130 patients with MPA treated at Hammersmith Hospital, and the subgroup presenting with pulmonary hemorrhage. There is a statistically significant difference between the two curves (p ¼ 0.0021). Those patients with pulmonary hemorrhage demonstrate a markedly worse outcome with considerable early mortality.
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The commonest symptoms are hemoptysis, cough, chest pain, and breathlessness. The incidence of alveolar hemorrhage is up to 30% in some series, with 20% of our cohort of MPA patients at the Hammersmith Hospital presenting with symptoms and signs of pulmonary hemorrhage (Fig. 4A). While this may be overt, with signs of hemoptysis, it may also be subclinical, apparent only following radiological examination, bronchoscopy with bronchoalveolar lavage evidence of hemosiderin-laden macrophages, or with an elevated (>30% baseline) carbon monoxide gas transfer coefficient (KCO). Alveolar hemorrhage is a result of underlying pulmonary capillaritis. Other pulmonary manifestations of disease that are recognized include a subclinical but progressive interstitial fibrosis (37), obstructive lung disease, and less frequently pleurisy with pleural effusions.
Figure 4 (A) Chest radiograph of a patient with MPO-ANCA vasculitis who presented with pulmonary hemorrhage and renal failure, demonstrating diffuse alveolar shadowing. Additionally, a central venous dialysis catheter is visible in the right internal jugular vein. (B) CT scan of a patient with pulmonary fibrosis diagnosed concurrently with their renal failure due to MPO-ANCA-associated vasculitis, demonstrating the characteristic ‘‘honeycombing’’ pattern.
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Pulmonary interstitial fibrosis (PIF) coincident with the diagnosis of MPA has been reported by a number of groups, including our own (Fig. 4B) (37–40), and is usually associated with increased fatality. Indeed, PIF may precede the diagnosis of MPA by a considerable amount of time, with some cases manifesting three or four years prior to a diagnosis of MPA (37). In part, the delay in diagnosis of MPA may relate to the initial paucity of other clinical features (41), a situation reminiscent of patients with the renal limited form of MPA, in whom systemic features subsequently develop. The pathophysiology of PIF in patients with MPA remains uncertain, although it has been suggested that it may result from repeated episodes of subclinical pulmonary hemorrhage (42), evidenced by histological changes of chronic hemorrhage (with hemosiderin-laden macrophages) and paucicellular capillary injury, juxtaposed with foci of fibrosis (43). A similar association has been made in three siblings with an urticarial vasculitis syndrome (44), and these changes resemble the pathology of idiopathic hemosiderosis, in which pulmonary hemorrhage and restrictive lung disease due to interstitial fibrosis were found to coexist. Moreover, in a follow-up series of children with idiopathic hemosiderosis, 60% of children with evidence of lung hemorrhage progressed to pulmonary fibrosis (45). Repeated episodes of pulmonary hemorrhage have also been associated with the subsequent development of obstructive lung disease in patients with no other predisposing factors (46). Additionally, in a genetic animal model of PIF, endothelial injury and capillaritis led to pneumocyte proliferation and fibrosis, providing a mechanistic link between the two processes (47). The incidence of pulmonary fibrosis associated with MPA is difficult to estimate accurately. In one series of 85 MPA patients, none were reported to have pulmonary fibrosis (32), while a cohort of 90 MPA patients studied at our institution contained eight (9%) with pulmonary fibrosis, three at presentation, and five who developed it following pulmonary hemorrhage (Fig. 4B) (39). This relative paucity of pulmonary fibrosis in MPA, despite a much higher incidence of pulmonary hemorrhage, suggests that factors besides alveolar hemorrhage are required for the pathology to develop. Indeed, it appears that numerous pathways may lead to the common final picture of pulmonary fibrosis, which may result from preceding inflammation or follow aberrant epithelial responses to chronic alveolar injury (48). Interestingly, it may be that MPO-specific ANCA are more closely associated with interstitial fibrosis than the particular clinical syndrome, as Chinese patients with WG, but with pANCA and anti-MPO antibodies, were found to have coexistent pulmonary fibrosis in 28% of cases (49). Moreover, in a series of 31 patients with MPO-ANCA and pulmonary fibrosis (40), only eight (26%) had a clinical diagnosis of MPA, while the rest were associated with primary Sjogren’s syndrome (13%), systemic sclerosis (10%), rheumatoid arthritis (6%), other connective tissue disorders (16%), or no underlying disease (29%). Of these 31 patients, 26 had honeycombing on high-resolution CT scanning, while all of those examined at autopsy were found to have pathological fibrotic
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changes consistent with usual interstitial pneumonia (UIP). In five patients, there was evidence of vasculitis affecting alveolar capillaries, pulmonary arterioles, or bronchiole arteries. Clinical improvement following immunosuppression was no more common in those patients with MPA than with other underlying conditions. Although initial MPO-ANCA titer did not correlate with severity of pulmonary fibrosis, these data suggest that MPO-ANCA may be the critical link between MPA and pulmonary fibrosis. However, the mechanism through which they may mediate this effect remains unknown.
VI.
Therapy
The natural history of untreated AAV is not well documented, but in a frequently cited series of patients with WG, one-year mortality from all causes was in excess of 80% (50). In general, immunosuppression is the mainstay of treatment for active disease, with the intensity and duration of therapy dictated by the disease manifestations, in an attempt to balance damage from disease with complications related to therapy. At disease onset, a more aggressive induction protocol is utilized, followed by a maintenance protocol, generally consisting of less intensive immunotherapy. The standard treatment for MPA has been clarified following a number of European Vasculitis Study Group (EUVAS)-coordinated clinical trials that included both WG and MPA. The treatment for severe disease is generally cyclophosphamide and steroid induction, followed by azathioprine or methotrexate and steroids for maintenance. Pulsed intravenous cyclophosphamide appears equivalent to daily oral therapy, in terms of disease remission and adverse events at 18 months, but with significantly less total drug exposure (51). In patients with advanced renal failure (serum creatinine greater than 500 mcmol/L), plasma exchange in addition to immunosuppression with steroids and oral cyclophosphamide was shown to improve the outcome in terms of independent renal function at one year (52). Our own data demonstrate that the effect on renal function is preserved for at least five years. A similar regimen has been utilized at the Hammersmith Hospital for over 20 years, for patients with lung hemorrhage or other vital end organ damage (such as cerebral vasculitis). Although there are no controlled clinical trials of the treatment of pulmonary hemorrhage, our experience and that of others confirms a good outcome following plasmapheresis (36,39,53). Following three to six months of cyclophosphamide therapy, azathioprine may be safely substituted without increasing the risk of relapse (54). Less severe disease (localized or early generalized disease), with better-preserved renal function, can be successfully treated with methotrexate rather than cyclophosphamide (55). Certain patients require additional therapy, for refractory or grumbling disease or following significant relapses, and this may consist of deoxyspergualine or biological agents such as rituximab, infliximab, or IVIg. A number of other induction regimens are currently being tested and should provide novel combination therapies to cater for most clinical scenarios.
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Additional supportive treatment may also be required; for example, in patients with alveolar hemorrhage, preventing fluid overload may prevent further pulmonary bleeding, ventilation in the prone position may improve oxygenation, and treatment with activated factor VIIa may diminish bleeding from the capillaritis (56). VII.
Disease Outcome and Relapse
Overall prognosis in MPA appears to relate to presenting renal function and the severity of other clinical features, with pulmonary hemorrhage generally conferring a poor outcome (Fig. 3), especially if assisted ventilation is required (57). Respiratory failure occurs in 11% to 57% of patients with pulmonary-renal presentation (58,59). Approximately 80% of patients will enter remission with standard (cyclophosphamide and steroid) therapy within three months. At oneyear, data from the EUVAS trials demonstrate that in patients with severe disease (not all of whom had pulmonary hemorrhage) the survival is between 73% and 76% (52). In a single-center experience of 14 patients with pulmonary-renal syndrome, 13 of whom had MPA (two with concurrent anti-glomerular basement membrane disease), ventilation was required in 57%, and 50% had died by two years (58). Death in this cohort of patients is commonly as a result of sepsis, and in some cases due to alveolar hemorrhage or progressive fibrosis (6,52,58). In one series of 34 patients, 10 had frank pulmonary hemorrhage, of whom 4 required assisted ventilation and 3 died from hypoxia despite immunotherapy (6). The other fatalities were as a result of infectious complications or cardiovascular events. This pattern was mirrored in the recently reported MPEPEX study (52). Relapse rates from EUVAS trials and other cohort studies suggest that relapse is less common in MPA than WG (34–36), and occurs in approximately 8% to 10% cases with less severe disease at 18 months (54), while it reaches up to 35% in those with more complex disease including those with pulmonary hemorrhage (54,58). VIII.
Conclusions
MPA remains a challenge in terms of reaching a rapid diagnosis and with respect to successful therapy. Associated lung disease, manifesting acutely with pulmonary hemorrhage and chronically with pulmonary fibrosis, remains a critical component as it generally heralds a poorer prognosis for those patients. However, we remain ignorant about some of the pathophysiological links between the autoimmune vasculitis and the lung pathology. Although huge improvements have been made in patient outcome, there is still a significant morbidity and mortality associated with the disease and its treatment. Our increasing understanding of the pathogenesis of disease should allow for better stratification of disease and more focused, less toxic therapy.
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Acknowledgments We are grateful to Professor Terry Cook for providing the renal biopsy images, and to our colleagues at Hammersmith Hospital who have contributed to the care of these patients.
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30. King WJ, Brooks CJ, Holder R, et al. T lymphocyte responses to anti-neutrophil cytoplasmic autoantibody (ANCA) antigens are present in patients with ANCAassociated systemic vasculitis and persist during disease remission. Clin Exp Immunol 1998; 112:539–546. 31. Ruth AJ, Kitching AR, Kwan RY, et al. Anti-neutrophil cytoplasmic antibodies and effector CD4+ cells play nonredundant roles in anti-myeloperoxidase crescentic glomerulonephritis. J Am Soc Nephrol 2006; 17:1940–1949. 32. Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum 1999; 42:421–430. 33. Frankel SK, Cosgrove GP, Fischer A, et al. Update in the diagnosis and management of pulmonary vasculitis. Chest 2006; 129:452–465. 34. Booth AD, Almond MK, Burns A, et al. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis 2003; 41:776–784. 35. Hogan SL, Falk RJ, Chin H, et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med 2005; 143:621–631. 36. Salama AD, Ryba M, Little MA, et al. 30 year follow up of 400 patients with ANCA associated vasculitis: predictors of relapse and survival. JASN 2006; 17:733A. 37. Eschun, GM, Mink, SN, Sharma S. Pulmonary interstitial fibrosis as a presenting manifestation in perinuclear antineutrophilic cytoplasmic antibody microscopic polyangiitis. Chest 2003; 123:297–301. 38. Becker-Merok A, Nossent JC, Ritland N. Fibrosing alveolitis predating microscopic polyangiitis. Scand J Rheumatol 1999; 28:254–256. 39. El-Mistry N, Pusey CD, Gaskin G. Markers of pulmonary haemorrhage in microscopic polyangiitis. Sarcoidosis Vasc Diffuse Lung Dis 1996; 13:268. 40. Homma S, Matsushita H, Nakata K. Pulmonary fibrosis in myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitides. Respirology 2004; 9:190–196. 41. Mansi IA, Opran A, Sondhi D, et al. Microscopic polyangiitis presenting as idiopathic pulmonary fibrosis: is anti-neutrophilic cytoplasmic antibody testing indicated? Am J Med Sci 2001; 321:201–202. 42. Birnbaum J, Danoff S, Askin FB, et al. Microscopic polyangiitis presenting as a ‘‘pulmonary-muscle’’ syndrome: is subclinical alveolar hemorrhage the mechanism of pulmonary fibrosis? Arthritis Rheum 2007; 56:2065–2071. 43. Magro CM, Allen J, Pope-Harman A, et al. The role of microvascular injury in the evolution of idiopathic pulmonary fibrosis. Am J Clin Pathol 2003; 119: 556–567. 44. Al Riyami BM, Al Kaabi JK, Elagib EM, et al. Subclinical pulmonary haemorrhage causing a restrictive lung defect in three siblings with a unique urticarial vasculitis syndrome. Clin Rheumatol 2003; 22:309–313. 45. Le Clainche L, Le Bourgeois M, Fauroux B, et al. Long-term outcome of idiopathic pulmonary hemosiderosis in children. Medicine (Baltimore) 2000; 79:318–326. 46. Schwarz MI, Mortenson RL, Colby TV, et al. Pulmonary capillaritis. The association with progressive irreversible airflow limitation and hyperinflation. Am Rev Respir Dis 1993; 148:507–511. 47. Rossi GA, Hunninghake GW, Kawanami O, et al. Motheaten mice—an animal model with an inherited form of interstitial lung disease. Am Rev Respir Dis 1985; 131:150–158.
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48. Maher TM, Wells AU, Laurent GJ. Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Eur Respir J 2007; 30:835–839. 49. Chen M, Yu F, Zhang Y, et al. Characteristics of Chinese patients with Wegener’s granulomatosis with anti-myeloperoxidase autoantibodies. Kidney Int 2005; 68: 2225–2229. 50. Walton EW. Giant-cell granuloma of the respiratory tract (Wegener’s granulomatosis). Br Med J 1958; 2:265–270. 51. de Groot K, Adu D, Savage CO. The value of pulse cyclophosphamide in ANCAassociated vasculitis: meta-analysis and critical review. Nephrol Dial Transplant 2001; 16:2018–2027. 52. Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 2007; 18:2180–2188. 53. Klemmer PJ, Chalermskulrat W, Reif MS, et al. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis 2003; 42:1149–1153. 54. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349:36–44. 55. De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005; 52:2461–2469. 56. Betensley AD, Yankaskas JR. Factor viia for alveolar hemorrhage in microscopic polyangiitis. Am J Respir Crit Care Med 2002; 166:1291–1292. 57. Lauque D, Cadranel J, Lazor R, et al. Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review of the literature. Groupe d’Etudes et de Recherche sur les Maladies ‘‘Orphelines’’ Pulmonaires (GERM‘‘O’’P). Medicine (Baltimore) 2000; 79:222–233. 58. Gallagher H, Kwan JT, Jayne DR. Pulmonary renal syndrome: a 4-year, singlecenter experience. Am J Kidney Dis 2002; 39:42–47. 59. ter Maaten JC, Franssen CF, Gans RO, et al. Respiratory failure in ANCAassociated vasculitis. Chest 1996; 110:357–362.
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28 Anti-GBM Antibody Disease (Goodpasture’s Syndrome)
RALPH J. PANOS Cincinnati VAMC and University of Cincinnati Medical School, Cincinnati, Ohio, U.S.A.
PAUL BIDDINGER Medical College of Georgia, Augusta, Georgia, U.S.A.
I.
Introduction
During the influenza pandemic of 1919, Ernest Goodpasture described an 18-year-old man with fever and cough who developed hemoptysis and renal failure (1). At autopsy, this patient had histopathological evidence of vasculitis with focal necrosis within the spleen and intestinal hemorrhage. In 1958, Stanton and Tange (2) reported a series of men with glomerulonephritis and pulmonary hemorrhage and designated this constellation of symptoms, Goodpasture’s syndrome, based on Goodpasture’s earlier report. Subsequent investigations demonstrated linear deposition of antibodies along the glomerular basement membrane (GBM) in individuals with Goodpasture’s syndrome and that antibodies eluted from patients’ kidneys induced proliferative glomerulonephritis in primates (3,4). Although the patient originally described by Goodpasture had evidence of vasculitis, significant vascular inflammation is not characteristic of Goodpasture’s syndrome. Among the many different causes of pulmonaryrenal syndromes, Goodpasture’s syndrome is used to describe the triad of pulmonary hemorrhage, glomerulonephritis, and antiglomerular basement 671
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membrane antibodies (anti-GBMAs); Goodpasture’s disease is glomerulonephritis and anti-GBMAs without evidence of pulmonary hemorrhage; and anti-GBMA disease is the presence of circulating anti-GBMA in the presence or absence of pulmonary or renal pathology. Although Goodpasture’s syndrome is a rare disease, the research and investigation into the biochemical, cellular, and immune mechanisms causing this process have led to significant insights into many aspects of biology. Initial studies discovered multiple new types of collagen. Subsequent investigations identified the antigenic epitopes and unraveled the autoimmune processes stimulating the development of antibodies directed against type IV collagen. More recent studies have suggested that cellular-immune processes may be as important as the humoral-immune response. Goodpasture’s syndrome is considered as an archetypal autoimmune disease for which the antigenic epitopes have been carefully delineated at a molecular level. Animal models of Goodpasture’s syndrome are frequently used to investigate the cellular and cytokine pathways underlying autoimmune processes. Goodpasture’s syndrome is an exemplary rare or ‘‘orphan’’ disorder that has expanded our insights into multiple and diverse biological processes. This chapter will review the investigations that have elucidated the molecular and cellular mechanisms causing Goodpasture’s syndrome and then review its clinical presentation, evaluation, and management.
II.
Background: Basement Membrane and Type IV Collagen
Basement membrane is a complex system of macromolecular components within a collagen reticular network that supports overlying structures, usually glandular, epithelial, or endothelial cells. Type IV collagen is the major protein constituent of basement membrane. It aggregates into a highly regulated tertiary structure resembling ‘‘chicken wire’’ to which other proteins attach and intercalate (5). There are six genetically distinct type IV collagen chains that share a common tripartite structure: a short, 15-amino acid, 7S noncollagenous (NC) aminoterminus, a long collagenous domain, and a NC1 domain at the carboxyterminus (Fig. 1A). These type IV collagen molecules aggregate into triple helical structures (protomers) that are the fundamental building units of the basement membrane reticular network (Fig. 1B). Protomers are believed to be formed by only three combinations of collagen molecules: a1.a1.a2 (IV), a3.a4.a5 (IV), and a5.a5.a6 (IV). These protomers self-associate in an ordered manner to form a grid- or wire-like suprastructure that is the framework of the basement membrane (Fig. 1C). The three NC1 domains of each protomer dimerize with the NC1 terminus of another protomer forming a NC1 hexamer or NC1 box. This dimerization creates a linear array of protomers. Four 7S domains aggregate into a tetramer that creates the grid-like arrangement of the collagen IV network. The
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Figure 1 (A) Tripartite structure of type IV collagen: a short, 15 amino acid, 7S noncollagenous aminoterminus, a long collagenous domain, and a NC1 domain at the carboxyterminus. (B) Three type IV collagen molecules aggregate into a triple helical protomer that is the fundamental building element that forms the reticular network of the basement membrane. (C) Protomers assemble into a grid- or wire mesh–like suprastructure into which other proteins intercalate and attach. The three NC1 domains of a protomer dimerize with the NC1 terminus of another protomer to form a NC1 hexamer or NC1 box (an example is within the box). The cryptic antigenic domain recognized by antibodies from patients with Goodpasture’s syndrome is sequestered within the NC1 box. Four aminoterminal domains join into a tetramer (an example is within the oval) that creates the grid- or wire mesh–like structure of the type IV collagen matrix. Abbreviation: NC1, noncollagenous1.
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formation of these networks is restricted to three sets of NC1 hexamers: a1.a1. a2 (IV)–a1.a1.a2 (IV), a3.a4.a5 (IV)–a3.a4.a5 (IV), and a1.a1.a2 (IV)–a5.a5. a6 (IV). Only a1.a1.a2 (IV)–a1.a1.a2 (IV) and a3 a4.a5 (IV)–a3.a4.a5 (IV) networks are found in both lung and kidney.
III.
Pathogenesis
Experimental techniques causing the induction of antibodies to the GBM are welldescribed systems for investigating glomerulonephritis and, in some models, pulmonary hemorrhage. Immunohistochemical studies demonstrate linear distribution of antibodies along glomerular and alveolar basement membranes in these models and similar patterns of immune deposition are noted in patients with Goodpasture’s syndrome (3,4). Further studies showed that autoantibodies eluted from the kidneys of individuals with Goodpasture’s syndrome produced a similar linear deposition along normal renal GBM (4). Two subsequent serendipitous observations linked Goodpasture’s syndrome with Alport’s syndrome: (i) antibodies from patients with Goodpasture’s syndrome did not react with the GBM in renal specimens from individuals with Alport’s syndrome and (ii) Goodpasture’s syndrome was only observed in patients with Alport’s syndrome after renal transplantation (6,7). These observations suggested that the native kidney in individuals with Alport’s syndrome lacked an antigenic determinant found in the transplanted kidney. Intensive investigations by Hudson and others (8–13) showed that the GBM antigen recognized by antibodies from patients with Goodpasture’s syndrome was a NC peptide contained within the NC1 domain of a3 (IV) collagen. Subsequent investigations identified two cryptic antigenic epitopes (EA and EB) that are concealed within the NC1 box formed by the dimerization of two protomers (14–16). Evolutionary genetic studies suggest that genetic mutations causing the loss of asparagine and glutamine amino acid residues and the emergence of serine, aspartic acid, and lysine residues occurred over 450 million years ago as the a3(IV) collagen gene evolved from Danio rerio. These genomic mutations produced the cryptic antigenic epitopes that precipitate the development of Goodpasture’s syndrome (17). Recent studies have shown that the NC1 hexamers may be either M-hexamers containing only monomer subunits that are autoantibody reactive or D-hexamers containing both dimer and monomer subunits that are not autoantibody reactive (18). Disassociation of the NC1 hexamer is required to expose these epitopes. Although the process(es) leading to the revelation of these determinants is(are) not clear, clinical observations suggest factors such as infections, environmental toxins, ischemia, and neoplasms or mechanical factors such as lithotripsy (19) may disrupt the NC1 hexamer, exposing cryptic determinants, and precipitating an autoimmune reaction (20). Experimentally, sodium dodecyl sulfate (SDS), urea, reactive oxygen species, or guanidine exposure are required for antibody binding to the a3 NC1 domain (21).
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Alternatively, Arends and colleagues (22) suggest that single T-cell epitope mimicry by microbial antigens may precipitate glomerulonephritis and pulmonary hemorrhage similar to Goodpasture’s syndrome. They synthesized seven peptides derived from human-infection related microbes that were homologous to the a3 (IV) NC1 domain that has been identified as the antigenic determinant in Goodpasture’s syndrome. Three peptides induced severe proteinuria and glomerulonephritis after injection into rats. One of the peptides derived from Clostridium botulinum also caused pulmonary hemorrhage. These observations suggest that epitope mimicry by microbial proteins may be another potential stimulus for the production of antibodies that recognize the a3 (IV) NC1 domain of type IV collagen. In a study of 58 individuals with Goodpasture’s syndrome, every patient demonstrated antibodies binding to the a3 (IV) NC1 domain. In 85% of these patients, this antibody was the only autoantibody; 15% had additional antibodies to a1 (IV) NC1 and 4% to a4 (IV) NC1 (10). Most Goodpasture’s syndrome autoantibodies are IgG, usually subclasses IgG1 and IgG4 (23,24). Rarely, antiGBMAs are IgA (23,25–27). Kinetic binding studies demonstrate that antiGBMAs bind rapidly and tightly to a3(IV) collagen and once bound, they have slow dissociation rates (28). Genetic susceptibility studies show a very strong association between Goodpasture’s syndrome and the presence of DRB1 * 1501 (OR 8.5, 95% CI, 5.5–13.1, P < 0.0001) (29). After compensating for the increased presence of 1501 alleles, there is also a significant increase in the frequencies of DR3 (OR 1.7, 95% CI, 1.1–2.5, P ¼ 0.009) and DR4 (OR 2.5, 95% CI, 1.7–3.5, P < 0.001) and a decreased frequency of DR7 (OR 0.3, 95% CI, 0.1– 0.6, P ¼ 0.001), and DR1 (OR 0.6, 95% CI, 0.3–1.0, P ¼ 0.034) (29). These genetic studies as well as the observations that the mere presence of Goodpasture’s syndrome autoantibodies in patients with Alport’s syndrome who have undergone renal transplantation or in patients with anti-GBMA disease may not precipitate the development of renal or lung injury suggest, that factors beyond the presence of autoantibodies are required for the development of tissue injury. Demonstration of discordance for the development of Goodpasture’s syndrome in twins underscores the importance of environmental factors as well as suggesting a possible role for other immunogenic processes. Major histocompatibility complex (MHC) Class II molecules are believed to bind to a 3 (IV) NC1 epitopes stimulating T-cell recognition and modulating the humoral response. Using a mouse model of GBM disease, Kalluri and colleagues (30) showed that all mice strains immunized with a3 (IV) NC1 peptides developed anti a3 (IV) NC1 antibodies but the development of pulmonary and renal disease was restricted to Swiss James Lambert (SJL) mice that possessed MHC H-2s. B6 (H-2b), BALB/c (H-2d), DBA/2 (H-2d) mice developed only renal disease and A/J (H-2a), AKR (H-2k), and CBA (H-2k) mice showed no evidence of either renal or pulmonary disease. In addition, these investigators showed that passive transfer of isogenic a3 (IV) NC1 antibodies into T-cell receptor–deficient mice did not cause renal or pulmonary injury. Further immunohistochemical studies supported a Th1 response pattern with increased presence of interleukin (IL)-12, IL-4, IL-10, and
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interferon-g (IFN-g) within the kidneys of susceptible mice. These murine studies strongly support a genetic susceptibility to Goodpasture’s syndrome in humans because the murine H-SS MHC alleles map to the human HLA-DR and DQ loci that have been associated with the development of Goodpasture’s syndrome (29). Interestingly, between 15% and 35% of individuals with anti-GBMAs have normal renal function and minimal to no evidence of renal pathology in kidney biopsies (31). Unfortunately, the HLA phenotype of these patients was not reported. An intact Th-1 type immune response is required for the development of experimental anti-GBMA disease (32). IL-12 is required for the Th 1 response and mice lacking IL-12 do not develop renal disease in a model of antibody-induced glomerulonephritis (33). In contrast, mice that are genetically deficient of IFN-g / have increased renal damage in this model suggesting a protective effect for IFN-g. Bolton and colleagues (34) developed a model of glomerulonephritis by inoculating crude GBM extracts into chickens that had undergone bursectomy rendering them unable to produce antibodies but maintaining an intact cellular immune response. Transfer of mononuclear cells derived from these animals to naı¨ve chickens caused glomerulonephritis (35). Wu and colleagues (36) demonstrated disassociation between the presence of anti-GBMAs and renal pathology in a rat model. Animals were immunized with denatured recombinant mouse a3 (IV) NC1 peptides. All rats developed antibodies to a3 (IV) NC1 but only 20% had serum antibodies that reacted to isolated rat GBM by Western blot and no antiGBMAs were demonstrated by immunofluorescence. No antibodies or C3 binding was detected along the GBM of affected rats. However, T cells from immunized rats responded to both a3 (IV) NC1 peptide and isolated rat GBM. In subsequent experiments, these investigators showed that approximately half of rats that received a3 (IV) NC1-specific CD4þ T cells developed significant glomerulonephritis characterized by an absence of antibody or C3 deposition along with the GBM. The renal histopathology demonstrated an intense T-cell infiltration within the renal interstitium. Injection of fluorescence-labeled T cells demonstrated a significant increase in the number of transferred cells within the lungs but not other organs. The central role of T cells in the development of renal injury in these animal models of Goodpasture’s syndrome is corroborated further by the suppression of GBM disease after administration of anti-CD8 monoclonal antibodies (37). Using a model of anti-GBM disease induced by immunizing DBA/1 mice with recombinant human a3 (IV) NC1, Hopfer and coworkers (38) demonstrated a Th1-like antibody response and a marked splenocyte reaction to recombinant peptide. After stimulation, spleen cells secreted high levels of IL-2 and IFN-g but reduced amounts of IL-10 suggesting a robust Th1 response overwhelming a diminished Th2 response. The kidneys of affected animals showed increased numbers of CD3-positive T lymphocytes and macrophages. Peripheral blood mononuclear cells from patients with acute Goodpasture’s syndrome stimulated with recombinant a3 (IV) NC1 peptides proliferate vigorously and secrete IFN-g but diminished levels of IL-10 (39). IL-10 secretion increases during recovery but IL-4 production is absent indicating an increased regulatory but not Th2 response
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suggesting restoration of immunological tolerance to a3 (IV) NC1 antigens and resolution of the autoimmune reaction (39). Another series of experiments support a critical role for the activation of the cellular immune response in the renal and pulmonary tissue injury that characterize Goodpasture’s syndrome. Wu and colleagues (36,40,41) immunized mice with a synthetic polypeptide containing a T cell–specific epitope within amino acids 28–40 of a3 (IV) NC1. All of these animals developed severe glomerulonephritis and three-quarters developed anti-GBMAs. Elimination of B-cell epitopes within the protein sequence either by substitution or truncation did not prevent antibody production and antibody eluted from affected kidneys reacted with native GBM but not the synthetic peptide. Using a similar technique and mutated and truncated forms of a peptide corresponding to amino acids 14–34 of the a3 (IV) NC1 domain, Bolton and coworkers (42) demonstrated that this rat peptide uniformly induced renal disease in all immunized rats. Linear deposition of anti-GBMAs as well as lymph node enlargement occurred in all animals. Immunosorption studies demonstrated that even after removal of antibodies to the synthetic peptide from sera or kidney eluates, the sera and kidney eluates still contained antibodies reactive with native and recombinant collagen proteins and GBM in kidney sections. Administration of a monoclonal antibody to CD154 that blocks the interaction between CD154 on T helper cells and CD40 on antigen-presenting cells abrogates the development of experimental autoimmune glomerulonephritis (43). Lastly, Wu and colleagues (44) demonstrated that transfer of activated T cells generated from Th1 cell lines derived from rats immunized with recombinant a3(IV) NC1 into syngeneic rats caused severe proteinuria. Histopathology showed T-cell infiltration in the absence of IgG or C3 deposition. These findings strongly implicate a cellular immune mechanism in the pathogenesis of Goodpasture’s syndrome. The mechanism for the production of diverse autoantibodies remains unclear. Epitope spreading as well as T-cell activation of autoreactive B cells have been proposed (36,42). Local expression of CD80 and CD86, the major costimulatory ligands for the T-cell receptors CD28 and CTLA-4 that either promote or downregulate T-cell responses, respectively are expressed in the glomeruli of mice with crescentic anti-GMBA glomerulonephritis (45). Administration of anti-CD80/86 antibody reduces renal injury and the accumulation of CD4þ T cells suggesting that local expression of these ligands is critical to the processes regulating renal injury in this model (45). Tolerance to the Goodpasture antigen is tightly controlled through both central and peripheral mechanisms. Central eradication during depletion of the immune repertoire is suggested by thymic expression of the a3 (IV) NC1 antigen (46,47). Regulating CD25þ lymphocytes inhibit experimental autoimmune glomerulonephritis (48). Furthermore, regulating CD25þ cells are not present during the acute onset of Goodpasture’s syndrome but emerge approximately three months later (49). The presence of this regulating T-cell population may explain the extremely rare relapse of Goodpasture’s syndrome.
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Epidemiology
Because Goodpasture’s syndrome occurs so infrequently, the incidence is not known precisely. Estimates of the annual incidence range from 0.1–3.2 cases per million population (50–53). Approximate 1% to 2% of all cases of glomerulonephritis are due to Goodpasture’s syndrome (54). Many studies suggest that men are affected more frequently than women with gender ratios ranging from 3:2 to 9:1 (23,55,56). The age distribution demonstrates peaks between 20 and 30 and also between 60 and 70 years of age (57,52,23). Although Goodpasture’s syndrome occurs in many racial groups, whites are affected predominantly (23,58,59). Temporal clusterings of cases suggest possible environmental or infectious triggers but the disease does not appear to have a seasonal predilection (52,58,60). V.
Clinical Manifestations
Hemoptysis is the most common presenting symptom in Goodpasture’s syndrome and occurs in nearly 90% of patients (23,55,56,58). When present, it commonly precedes the development of renal disease (52,53,61). The degree of hemoptysis varies from minimal to massive hemorrhage (58). Other respiratory symptoms include cough and breathlessness. Chills, fevers, sweats, diaphoresis, chest discomfort, fatigue, lethargy, and flank tenderness may also occur. Rashes, arthralgias, and myalgias are less frequent and when present, suggest other types of rapidly progressive nephritis (62). Gross hematuria is present in less than half of all patients (58). The most common sign is pallor, which is present in up to 90% of cases (23,58). Between one-third and half of patients have crackles or rhonchi present on chest auscultation (58). Lower extremity edema occurs in 25% to 32% of patients (23,58). Other physical examination findings include tachycardia, tachypnea, and hepatosplenomegaly. Ophthalmic findings occur infrequently and include retinal hemorrhage and detachment with IgG deposition in Burch’s membrane and the basement membranes of the choroidal vessels (63,64). Breathlessness (79%), hemoptysis (75%), and cough (64%) were the most frequent respiratory symptoms in a series of 28 patients with anti-GBMAs and alveolar hemorrhage (65). The median age at diagnosis was 23 years and 89% of patients were active smokers. Approximately one-third of the patients had been exposed to vapors or fumes prior to disease onset. Chest examination revealed crackles in approximately half of them. Most patients were anemic but the serum creatinine was elevated in only 54%. Circulating anti-GBMAs were present in 64% and linear IgG deposition was demonstrated in all 23 patients with renal biopsies and in all the four lung biopsies (one patient had a lung biopsy but immunofluoresence was not performed). Approximately one-quarter of patients demonstrated a reduced diffusing capacity of lung for carbon monoxide (DLCO) or restriction on pulmonary function testing. Chest X-rays were abnormal due to consolidation and ground-glass opacities in 86%. Nodules, consolidation, or ground-glass opacities were present in 16 of 20 chest CT scans. Bronchoalveolar lavage (BAL) demonstrated pink or red
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fluid in all patients in whom this data was collected. Patients were treated with plasma exchange, corticosteroids, and immunosuppressive agents including cyclophosphamide, mycophenolate mofetil, and azathioprine. None of the patients died. Half had no sequelae, two developed mild renal insufficiency, and 10 required chronic dialysis. Subsequent chest X-rays were normal in all tested patients and pulmonary function testing revealed restriction in 20%, elevated residual volume to total lung capacity ratio, 30%, and reduced DLCO, 45%. Although the clinical manifestations of Goodpasture’s syndrome are usually limited to the lungs and kidneys, cerebral vasculitis occasionally associated with seizures has been described (66–68). Other autoimmune disorders that have been associated with anti-GBMAs include myasthenia gravis (69), primary biliary cirrhosis (70), polyarteritis nodosa (71), cardiac disease (72), and epidermolysis bullosa acquisita (72). VI.
Imaging Studies
Chest radiographs typically demonstrate diffuse alveolar opacifications due to pulmonary hemorrhage. (Fig. 2) With more severe bleeding, alveolar consolidation may occur. These findings are not specific for alveolar hemorrhage and may also be caused by pulmonary edema, infection, or atelectasis. Chest radiographs are normal in one quarter of patients (23). Chest CT scans frequently demonstrate alveolar ground-glass opacifications that are not specific. (Fig. 3A,B,C)
Figure 2 Chest X-ray demonstrating diffuse alveolar opacities with areas of consolidation. Bronchoalveolar lavage revealed pink hemorrhagic fluid that became bloodier as more aliquots of saline were instilled and recovered.
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Figure 3 Chest computed tomography scan at upper (A), middle (B), and lower (C) thoracic levels demonstrating areas of consolidation and ground-glass opacification.
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Laboratory Studies
Anemia is the most common laboratory abnormality on presentation in patients with Goodpasture’s syndrome. The hemoglobin has been reported to be less than 12 gram-percent (g%) in nearly 90% of patients (23); the mean value was 7.5 g% in another series (55). In Goodpasture’s syndrome, the erythrocyte sedimentation rate (ESR) is usually not elevated; and an elevated ESR suggests another cause of pulmonary-renal disease, especially vasculitis (73). The blood urea nitrogen and serum creatinine are frequently increased but may be normal in up to 30% to 40% of cases (23,31). Urinanalysis usually demonstrates an active urinary sediment due to proteinuria, granular casts, and hematuria (Figs. 4–6). Approximately 25% of patients with Goodpasture’s syndrome have antibodies to antineutrophil cytoplasmic antibody (ANCA) in addition to anti-GBMAs (74). In a 10-year period at the Hammersmith Hospital, United Kingdom, 5% of patients with detectable ANCA also demonstrated anti-AGBM whereas 32% of patients with anti-AGBM were also positive for ANCA (75). In 82% of patients with both antibodies, ANCA was peripheral and directed against myeloperoxidase (MPO). Approximately two-thirds of these patients presented with dialysisrequiring renal failure and most had extensive glomerular crescents on renal biopsy. Pulmonary hemorrhage was present in nearly half of the patients. Survival was only 52% at one year (75). Similar results were found in a series of 23 patients with Goodpasture’s syndrome in Nanjing, China (76). ANCA was present in 11 patients (48%) and there were no significant distinguishing clinicopathological features between this group and those who were ANCA negative. In another study of 889 consecutive patients with rapidly progressive glomerulonephritis, 2% had
Figure 4 (See color insert.) Medium-power photomicrograph of lung showing diffuse intra-alveolar hemorrhage [hematoxylin and eosin (H&E) stain].
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Figure 5 (See color insert.) High-power photomicrograph of lung showing intra-alveolar hemorrhage and hemosiderin-laden macrophages [hematoxylin and eosin (H&E) stain].
Figure 6 (See color insert.) High-power photomicrograph of lung showing capillaritis with neutrophils within widened alveolar septum [hematoxylin and eosin (H&E stain)].
both anti-GBMAs and positive ANCA, 65% had only anti-GBMAs; 28% were only positive for ANCA, and 5% had neither autoantibody (77). Of 1060 patients with suspected pulmonary renal syndromes or rapidly progressive glomerulonephritis, 10 demonstated both anti-GBMAs and ANCA; 133 were ANCA positive (60 PR3 and 73 MPO) and 19 had anti-GBMAs (78).
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The diagnosis of Goodpasture’s syndrome is usually established by the immunopathological demonstration of linear deposition of immunoglobulins along the basement membrane in either lung or kidney biopsies. Originally, circulating anti-GBMAs were detected by indirect immunofluorescence using patient sera and normal human or primate renal sections as substrate. These assays were neither quantitative nor sensitive, and were vulnerable to subjective interpretation. Several different commercial enzyme-linked immunosorbent assay (ELISA) kits are available that utilize recombinant human a3 (IV) collagen or the entire or parts of extracted human a3 (IV) collagen as substrate (79). The sensitivity of these assays ranges from 94.7% to 100% with a specificity of 90.9% to 100%. The area under the receiver operator curves varies from 0.953 to 0.991 suggesting that all assays perform well. An incorrect diagnosis of Goodpasture’s syndrome was made in an individual with lung adenocarcinoma and hemoptysis who had an elevated anti-GBMA performed in a commercial reference laboratory (80). Subsequent evaluation demonstrated that the antibodies were directed against a1(IV) rather than a3(IV) collagen. Anti-GBMAs may also be detected in individuals with human immunodeficiency virus (HIV) infection and no clinical renal or pulmonary disease (81,82).
VIII. A.
Histopathology
Renal
In longstanding Goodpasture’s syndrome, the kidneys are commonly small and shrunken whereas in more acute disease, they are pale and slightly enlarged (58). Renal biopsy is the preferred clinical test for the histopathological diagnosis of Goodpasture’s syndrome because lung tissue can have significant autofluorescence and the degree of renal pathological involvement is predictive of clinical prognosis and correlates with measures of renal function (24,74,75,83). Extremely rarely, patients with Goodpasture’s syndrome may have normal renal biopsies (84). The most common histopathological finding is necrotizing and crescentic glomerulonephritis involving over 50% of the glomeruli (83). In a series of 80 individuals with Goodpasture’s syndrome who had undergone renal biopsy, Fisher and colleagues (83) demonstrated crescentic glomerulonephritis involving half or more of the glomeruli in 88% of the renal specimens. The proportion of glomerular involvement correlated positively with the serum creatinine. Initially, mesangial expansion with hypercellularity due to proliferating epithelial cells and infiltrating lymphocytes, monocytes, and leukocytes, is present and progresses to segmental or global necrosis of the capillary tuft with disruption of both Bowman’s capsule and the GBM (24,83). The crescents usually have a homogeneous appearance distinguishing Goodpasture’s syndrome from other causes of crescentic nephritis (24). Periglomerular multinucleated giant cells, granulomas, or vasculitis involving the interstitial arterioles occur
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infrequently (83). In the latter stages of the disease, global and segmental sclerosis and interstitial fibrosis may be present. The hallmark of Goodpasture’s syndrome is the immunofluorescent (IF) demonstration of intense linear deposition of IgG along the GBM. Very infrequently IgA is detected rather than IgG. Discontinuous or granular deposition of C3 or C1q may be detected in up to one-third of patients (83). Leakage of fibrin and inflammatory cells through perforations within the GBM may be present on electron micrographs (83). Other ultrastructural findings include loss of podocytes, thickening of the basement membrane, and endothelial cell and capillary disruption (58,84). B.
Pulmonary
At autopsy, the lungs of patients with Goodpasture’s syndrome are most often consolidated and heavy with visually evident hemorrhage and petechiae (58). The most common and prominent pulmonary histopathological feature is widespread intra-alveolar hemorrhage (84–87). Intact erythrocytes are seen within alveolar spaces during periods of active hemorrhage. Variable numbers of hemosiderin-laden macrophages can be seen as the erythrocytes undergo lysis and phagocytosis. The hemosiderin-laden macrophages generally take at least two to three days to appear, and usually persist for two to eight weeks after cessation of hemorrhage (88,89). Alveolar septa may show some degree of expansion due to capillaritis, edema, and/or interstitial fibrosis (84,85). Capillaritis, characterized by neutrophils within the septa, is usually focal and of mild to moderate intensity. Diffuse or prominent capillaritis, or vasculitis of larger blood vessels is atypical, and if present, suggests another disease process. When interstitial fibrosis is present, it too is usually patchy and mild. Type II pneumocytes may show hyperplasia and reactive atypia in response to alveolar damage. In some cases, hyaline membranes are seen focally (85). Ultrastructural studies have shown fragmentation of alveolar septal basement membranes and wide gaps between endothelial cells (90). All of the pathological changes noted above are nonspecific and seen in other hemorrhagic disorders of the lungs (85,87). IF studies, however, are relatively specific. They demonstrate linear deposits along the alveolar septa (84–86,91). Deposits of IgG and complement are typically highlighted. Rare cases of IgM or IgA deposition have been reported (23,25–27). Other hemorrhagic lung diseases may show positivity for IgG by IF staining, but the pattern is granular, consistent with immune complex deposition (85,92,93). Similar to glomerular tissue in the kidney, a linear staining pattern along the alveolar septa is the key to the diagnosis of Goodpasture syndrome in a lung biopsy. Renal biopsies are more common than lung biopsies, probably reflecting the higher complexity of a surgical lung biopsy. Also, the IF staining seen in a lung biopsy may be technically inferior to that of a renal biopsy (84). Nevertheless, IF
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analysis of lung tissue can be helpful in the diagnostic evaluation of cases of hemorrhagic lung disease, particularly those with minimal or no renal abnormalities. Lung tissue to be used for IF studies must not be fixed, but rather fresh frozen with histological sections cut in a cryostat.
IX.
Treatment
Untreated, Goodpasture’s syndrome is nearly universally fatal. In a study of 52 patients reported by Benoit and colleagues in 1963 (55), the mortality rate was 96%. The earliest treatment was nephrectomy in an effort to remove the inciting antigen and prevent overwhelming pulmonary hemorrhage (94–96). However, increased knowledge of the pathogenesis of this disease has improved treatment strategies. Current therapeutic management strategies are based on the principles of removing circulating autoantibodies by plasmapheresis and preventing autoantibody production through immunosuppression. Plasma exchange is usually performed with large-volume plasmapheresis of four liters daily for two weeks. Human albumin is the usual replacement fluid and is supplemented with fresh frozen plasma when severe pulmonary or renal hemorrhage occurs or after invasive procedures. Johnson and colleagues (97) compared immunosuppression with corticosteroids and low-dose cyclophosphamide with plasma exchange combined with immunosuppressive therapy in a group of 17 patients with Goodpasture’s syndrome. The mortality rate was 11% in those treated with immunosuppressants alone and 0% in the group treated with plasma exchange combined with immunosuppressants (97). In patients with a serum creatinine less than 600 mmol/L, renal function generally improves in 80% of individuals within several days of the initiation of plasma exchange (24). Levy and coworkers (98) performed a retrospective review of patients with anti-GBMA disease treated with plasma exchange and immunosuppression at the Hammersmith Hospital, London from the year 1975 to 2000. All patients received plasma exchange for at least 14 days or until anti-GBMA was not detectable. In addition, they received immunosuppressant therapy with oral prednisolone (1 mg/kg of body weight daily to a maximum dose of 60 mg/d) and oral cyclophosphamide (2 to 3 mg/kg per day with a reduced dose in individuals older than 55 years of age). The one-year survival rate was 100% in individuals presenting with a creatinine concentration less than 500 mmol/L (5.7 mg/dL). However, in patients with a creatinine 500 mmol/L (5.7 mg/dL), the one-year survival was 83% and, in patients who presented with dialysis dependent renal failure, survival was only 65% in one year. Less that 20% of patients who were not dialysis-dependent at presentation required dialysis at one year whereas 92% of patients requiring dialysis at presentation continued to require dialysis at one year of follow-up. All patients requiring dialysis at presentation and having crescents in 100% of glomeruli on renal biopsy required chronic dialysis. The duration of immunosuppressant therapy has not been well studied. Corticosteroids are usually tapered over several months and cyclophosphamide
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continued for varying periods up to one year. In contrast with other autoimmune processes, Goodpasture’s syndrome does not usually recur and only several cases of recurrence after treatment with plasmapheresis and immunosuppressant therapy have been reported (99–104). Patients may be evaluated for renal transplantation after 6 to 12 months of suppression of anti-GBMA production. Newer treatments for Goodpasture’s syndrome include the use of rituximab, a chimeric monoclonal antibody that targets the pan-B lymphocyte antigen CD20 (105). Rituximab was used to treat a patient with recurrent Goodpasture’s syndrome that was refractory to cyclophosphamide, corticosteroids, and plasmapheresis. Treatment with rituximab and maintenance therapy with azathioprine successfully induced remission. Mycophenolate mofetil has been used to treat refractory hemorrhage in Goodpasture’s syndrome with rapid success (106). Staphylococcal protein A immunoadsorption rather than plasmapheresis has been used to remove specifically IgG antibodies in patients with Goodpasture’s syndrome with excellent efficacy (107). Experimental studies demonstrated that enteral administration of GBM ameliorates the development of Goodpasture’s disease (108) suggesting that oral recombinant a3 (IV) NC1 peptides might restore tolerance or prevent disease onset in patients with Alport’s syndrome who undergo renal transplantation (109).
X.
Summary
Goodpasture’s syndrome is an exemplary rare lung disease that has provided immense insight into numerous biological processes. The observations that Goodpasture’s syndrome did not occur in individuals with Alport’s syndrome until after renal transplantation and that antibodies from individuals with Goodpasture’s syndrome did not react with the GBM in renal tissue from patients with Alport’s syndrome, led to the realization that the antigenic determinant precipitating the development of Goodpasture’s syndrome was lacking in Alport’s syndrome. Subsequent investigations revealed that the GBM antigen was a NC peptide within the NC1 domain of a3 (IV) collagen. These experiments led to the discovery of new types of collagen and expanded the understanding of the genetic, biochemical, and molecular processes regulating the extracellular matrix. Experimental models inducing the production of anti a3 (IV) collagen antibodies have produced critical discoveries into the genetic and immune processes causing and regulating autoimmune diseases. Although the initial investigations suggested a predominant humoral immune mechanism in the development of Goodpasture’s syndrome, more recent studies demonstrate that the cellular immune process also is critically involved. Genetic susceptibility is also extremely important and the presence of DRB1 * 1501 is strongly associated with the development of Goodpasture’s syndrome. Management of Goodpasture’s syndrome is based upon elimination of circulating anti-GBMAs and cessation of their production. Antibodies are removed
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by large-volume plasmapheresis and production is reduced by corticosteroids and immunosuppressant medications. The prognosis of Goodpasture’s syndrome depends on the level of renal function at the time of presentation; better renal function portends an improved outcome. Although there are exceptions, Goodpasture’s syndrome does not usually recur.
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49. Salama AD, Chaudhry AN, Holthaus KA, et al. Regulation by CD25þ lymphocytes of autoantigen-specific T-cell responses in Goodpasture’s (anti-GBM) disease. Kidney Int 2003; 64:1685–1694. 50. Bolton WK, Goodpasture’s syndrome. Kidney Int 1996; 50(5):1753–1766. 51. Davison AM. Seasonal incidence of glomerulonephritis: findings of UK medical research council’s glomerulonephritis registry. IX International Congress of Nephrology, Los Angeles, 1984 (abstr). 52. Savage CO, Pusey CD, Bowman C, et al. Antiglomerular basement membrane antibody mediated disease in the British Isles 1980–1984. Br Med J 1986; 292 (6516):301–304. 53. Teague CA, Doak PB, Simpson IJ, et al. Goodpasture’s syndrome: an analysis of 29 cases. Kidney Int 1978; 13:392–504. 54. Wilson CB, Dixon FJ. Anti-glomerular basement membrane antibody-induced glomerulonephritis. Kidney Int 1973; 3:74–89. 55. Benoit FL, Rulon DB, Theil GB, et al. Goodpasture’s syndrome: a clinicopathologic entity. Am J Med 1963; 58:424–444. 56. Proskey AJ, Weatherbee L, Easterling RE, et al. Goodpasture’s syndrome: a report of five cases and review of the literature. Am J Med 1970; 48:162–173. 57. Daly C, Conlon PJ, Medwar W, et al. Characteristics and outcome of antiglomerular basement membrane disease: a single center experience. Ren Fail 1996; 18(1):105–112. 58. Kelly PT, Haponik EF. Goodpasture syndrome: molecular and clinical advances. Medicine 1994; 73:171–186. 59. Wakui H, Chubachi A, Asakura K, et al. Goodpasture’s Syndrome: a report of an autopsy case and a review of Japanese cases. Intern Med 1992; 31:102–107. 60. Perez GO, Bjornsson S, Ross AH, et al. A miniepidemic of Goodpasture’s syndrome. Nephron 1974; 13:161–173. 61. Briggs WA, Johnson JP, Teichman S, et al. Antiglomerular basement membrane antibody-mediated glomerulonephritis and Goodpasture’s syndrome. Medicine 1979; 58:348–361. 62. Turner AN, Rees AJ. Goodpasture’s disease and Alport’s Syndrome. Annu Rev Med 1996; 47:377–386. 63. Jampol LM, Lahov M, Albert DM, et al. Ocular clinical findings and basement membrane changes in Goodpasture’s syndrome. Am J Ophthalmol 1975; 79(3): 452–463. 64. Rowe, PA, Mansfield DC, Dutton, GN. Ophthalmic features of fourteen cases of Goodpasture’s syndrome. Nephron 1994; 68(1):52–56. 65. Lazor R, Bigay-Game L, Cottin V et al. Alveolar hemorrhage in anti-basement membrane antibody disease. Medicine 2007; 86(3):181–193. 66. Gittins N, Basu A, Eyre J, et al. Cerebral vasculitis in a teenager with Goodpasture’s syndrome. Nephrol Dial Transplant 2004; 19:3168–3171. 67. Rydel JJ, Rodby RA. An 18-year-old man with Goodpasture’s syndrome and ANCAnegative central nervous system vasculitis. Am J Kidney Dis 1998; 31:345–349. 68. Garnier P, Deprele C, Pilonchery B, et al. Cerebral angiitis and Goodpasture’s syndrome. Rev Neurol (Paris) 2003; 159:68–70. 69. Drube S, Maurin N, Sieberth HG. Coincidence of myasthenia gravis and antiglomerular basement membrane glomerulonephritis: combination of two antibody-mediated autoimmune diseases on day 15. Nephrol Dial Transplant 1997; 12:1478–1480.
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29 Behc¸et’s Disease
RULA A. HAJJ-ALI and CAROL A. LANGFORD Center for Vasculitis Care and Research, Cleveland Clinic, Cleveland, Ohio, U.S.A.
I.
Introduction
Behc¸et’s disease (BD) is a multisystem disease characterized by mucocutaneous, ocular, articular, vascular, intestinal, urogenital, and neurologic involvement. BD was first described as a triad of recurrent aphthous stomatitis, genital aphthae, and relapsing uveitis in 1937 by Hulusi Behc¸et, a Turkish dermatologist (1), but descriptions of the disease features date back to Hippocrates, from his third book of epidemiology written in the fifth century BC. BD can be associated with a wide range of manifestations affecting the lungs and pulmonary vasculature that occur in 1% to 10% of patients and are potentially life threatening (2–6). This chapter will seek to review the epidemiology, pathogenesis, diagnosis, pathology, and treatment of BD with a focus on its pulmonary manifestations. II.
Epidemiology
BD has a worldwide distribution, although most cases are reported from Japan, the Middle East, and the Mediterranean. This pattern of origin, corresponding to the 695
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ancient ‘‘silk route,’’ has raised important questions about disease pathogenesis. In examining frequency estimates, out of 100,000 people, the prevalence of BD has ranged from 0.3 in Northern Europe, 2 in Germany, 5 in Turkey, 10 in Japan, 20 in Saudi Arabia, and 16 to 100 in Iran (7). Its prevalence in Olmsted County, Minnesota, has been estimated to be from one-third to one-tenth of that observed in Japan (7). BD presents most commonly between 20 and 40 years, although the age at onset varies in different studies spanning infancy to more than 78 years (7). A male predominance is seen in the Arab, Jewish, Iranian, and Turkish populations, whereas women have more frequently been affected in series reported from Germany, Japan, Brazil, and the United States (7). III.
Pathogenesis
The etiology of BD is unknown, although available data from laboratory-based studies have led to several hypotheses. One proposed mechanism is that an external stimuli such as a viral or bacterial infection activates the macrophages of patients who are genetically predisposed to have BD (Fig. 1). The strong association between HLA-B51 and BD supports the potential for a genetic predisposition (8). The role for T cell–mediated immune responses in the pathogenesis of BD has also been suggested (9,10). It is speculated that the macrophages present the unknown antigen to CD4 þ T cells, which is recognized in the context of class II MHC antigens. This will in turn initiate a cascade of cytokines production including interleukin (IL)-2, interferon (IFN)-g, and tumor necrosis factor (TNF)-b, and lead to B-cell proliferation. In addition, IFN-g activates macrophages to release TNF-a, IL-1, and IL-8, which then induce the expression of adhesion molecules on endothelial cells. Neutrophils are then activated and chemotaxis is induced by IL-8, which facilitates the movement of polymorphonuclear neutrophils and activated T lymphocytes through the endothelium to the area of inflammation. Recent studies also suggest a possible pathogenic role of certain bacterial antigens that cross react with human peptides, which may include heat shock proteins (11). The underlying pathogenesis of most of the pulmonary lesions is believed to be an immune complex vasculitis affecting all types of blood vessels (12). IV.
Pathology
The main histologic finding in BD is a widespread vasculitis involving arteries, veins, and capillaries. Individual organs may additionally reveal other histologic findings beyond vasculitis. In the lung, the pathologic findings vary from aneurysms to pleural inflammation and vasculitis. Efthimiou et al. have reported findings of necrotizing vasculitis principally affecting the arteries in which the elastic fibers have a moth-eaten appearance (12). The principal site of involvement is the media of the pulmonary arteries, in which damage results in
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Figure 1 Suggested paradigm of pathogenesis in Behc¸et’s disease.
dilatation of the vessel wall. Pulmonary arteritis is the primary underlying pathology that will lead to thrombosed vessels and infarction. In situ thrombosis, secondary to venulitis (i.e., phlebitis), is a predominant feature in the development of major venous involvement in BD (13). V.
Diagnosis and Clinical Features
The clinical manifestations of BD are widespread and involve almost every organ (Table 1) (14). The diagnosis of BD in the individual patient is based on collective information gained from the pattern of clinical involvement, laboratory findings, tissue histology, and imaging, as there is no single study that alone is diagnostic. Many different classification criteria have been developed for the diagnosis of BD. The most commonly used criteria with the highest sensitivity
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Table 1 Frequency of Clinical Manifestations in Behc¸et’s Disease Features
Frequency (%)
Mucocutaneous features oral ulcers genital ulcers erythema nodosum folliculitis Ocular disease Arthritis Gastrointestinal Neurologic Vascular Pulmonary
96–100 65–90 25–80 40–50 35–70 30–80 5–60 10–50 5–30 1–10
Source: From Ref. 14.
Table 2 The International Study Group Criteria for Behc¸et’s Disease Recurrent oral ulcers Minor aphthous, major aphthous, or herpetifom ulceration which are recurrent at least three times in one 12-month period Plus two of the following: Recurrent genital ulceration Eye lesions Anterior uveitis Posterior uveitis Cells in vitreous on slit lamp examination Or retinal vasculitis observed by qualified physician Skin lesions Erythema nodosum like Pseudo folliculitis Papulopustular lesions Or acneiform nodules Positive pathergy test To be read by a physician at 48 hours, performed with oblique insertion of a 20–22 gauge or smaller needle under sterile conditions Source: From Ref. 15.
and specificity are the International Study Group (ISG) criteria for Behc¸et’s disease, summarized in Table 2 (15). These criteria were developed for the purpose of classifying patients for research studies and should not be used as diagnostic criteria. Pulmonary involvement occurs in 1% to 10% of patients and can affect the pulmonary vasculature, lung parenchyma, the airways, or the pleura (6). Dyspnea, chest pain, and hemoptysis are the major presenting symptoms of pulmonary involvement in BD.
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Pulmonary Manifestations Pulmonary Vascular Disease
Vasculitis in BD can affect multiple vessels and all vascular beds. Venous manifestations are more common than arterial involvement and their frequency tends to increase with the duration of the disease. Vascular involvement in BD can manifest as aneurysms, stenosis leading to occlusion, arterial and venous thrombosis, and varices. The prognosis for aneurysms is worse than that of occlusive lesions because of the risk of rupture that can result in severe hemorrhage. Aneurysms are more common than thrombosis and may coincide. Pulmonary artery aneurysms represent 34% of all pulmonary manifestations and may present with rupture or erosion into bronchi with hemoptysis (Figs. 2 and 3). The reported prevalence of pulmonary artery aneurysms in all patients with BD varies between 1% and 5% (5,16). Aneurysms can affect any part of the pulmonary arterial system and are most frequently located in the right lower lobar arteries, followed by the right and left main pulmonary arteries. The aneurysms can be associated with thrombosis and may contain gas bubbles reflecting a bronchoarterial fistula. The diagnosis of pulmonary aneurysms can be challenging, which leads to delayed recognition and to erroneous therapeutic decisions. Patients with BD can be erroneously diagnosed as having pulmonary emboli when they present with hemoptysis and have evidence of an associated deep venous thrombosis with the presence of mismatch on ventilation perfusion scan. The suspicion of a pulmonary artery aneurysm should be increased if there is hilar fullness on chest imaging, although pulmonary aneurysms may be poorly defined during an episode of acute hemoptysis. Koc et al. examined 137 patients with BD for the presence of vascular disease and compared their
Figure 2 Pulmonary artery aneurysms with mural thrombi in a patient with Behc¸et’s disease. Source: From Ref. 14.
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Figure 3 Fusiform aneurysm of the pulmonary artery in a patient with Behc¸et’s disease.
findings with the literature (17). Twenty-seven percent of their patients were found to have vascular involvement. Specifically, 47% had deep venous thrombosis, while only 0.05% had pulmonary thromboembolism. Eight percent had pulmonary arterial aneurysms; two of these had other arterial vascular disease. In their literature review of 728 BD patients with vascular involvement, 0.05% of the patients had pulmonary arterial occlusion or aneurysm. Interestingly, they observed that the presence of a positive pathergy test or eye involvement was higher in patients with vascular disease, which has also been confirmed in other studies (18). Efthimiou and colleagues reported five patients with BD who presented with hemoptysis and reviewed 25 other cases in the literature (12). They found that the presence of any pulmonary manifestation was associated with active BD at other sites. Patients with hemoptysis were more likely to be male and have evidence of deep venous thrombosis and thrombophlebitis as compared with patients who did not have hemoptysis. Pulmonary arteriography revealed occlusions of proximal vessels similar to that seen with pulmonary emboli. Thrombosis of large proximal or multiple peripheral arteries may lead to pulmonary hypertension, and single or multiple pulmonary aneurysms may be present. Pulmonary artery aneurysms have a poor prognosis, with more than onehalf of patients dying of pulmonary hemorrhage within three years (5).
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Nonvascular Lung Involvement
BD can have a diverse range of pulmonary parenchymal manifestations that include lung infarctions, or, less commonly, small-vessel vasculitis, eosinophilic pneumonia, interstitial pneumonitis, bronchiolitis obliterans organizing pneumonia, and pulmonary fibrosis (19,20). Obstructive lung disease has been rarely associated with BD as well as trachea-bronchial ulcerations and stenosis. Ulcerative lesions may be found in the trachea and proximal airways. Mucosal edema may result in irregular narrowing of the airway (21–23). Pleuritic involvement is uncommon in BD. Pleural effusion is thought to be secondary to superior vena cava thrombosis and pulmonary infarction. Very rarely can the pleura be involved by vasculitis, which can manifest as inflammation and effusions. Hydropneumothorax can result from rupture of peripheral subpleural opacities into the pleural space (24,25). Other rare thoracic manifestations include fibrosing mediastinitis. VII.
Imaging Techniques in the Evaluation of Behc¸et’s-Related Pulmonary Disease
Chest radiographs are usually the first imaging modalities to be performed in patients with pulmonary symptoms or signs. On chest radiographs, pulmonary artery aneurysms may appear as hilar enlargement or intraparenchymal round opacities. Pulmonary parenchymal disease can radiographically present as transient focal or diffuse alveolar infiltrates, wedge-shaped opacities, linear shadows, atelectasis, subpleural nodules, excavated nodules, rounded opacities, ill-defined or reticular infiltrates, and areas of parenchymal hypovascularization. Chest imaging may also demonstrate pulmonary infarctions presenting as atelectasis, wedge-shaped opacities, linear shadows, as well as pleural effusions. Helical computed tomography (CT) has been suggested as a safe method of investigation for vascular changes as this technique provides excellent vascular images with only a small amount of contrast material (26). High-resolution CT may also be more sensitive than chest radiographs and pulmonary function tests in detecting parenchymal changes in patients with BD (27). Magnetic resonance imaging (MRI) has been suggested as an alternative noninvasive method for the diagnosis of pulmonary aneurysms; however it may not be as sensitive as the helical CT for small-sized aneurysms (28). Scintigraphy, including ventilation perfusion scan, may play a role in the diagnosis BD and has been investigated for its ability to assess disease activity. Unlu and colleagues investigated the role of 123I-meta-Iodobenzylguanidine (123I-MIBG) scintigraphy scans in 25 patients with BD and 12 age-matched controls (29). Only two patients with BD had known pulmonary involvement, and disease activity was defined globally and was not specific to the lung. After
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intravenous injection of 123I-MIBG, thoracic images were taken at 15 minutes and four hours. Heart to mediastinum (H/M) ratios and lung retention indices (LRI) were calculated. The difference between the LRI of controls and patients was found to be significant. The LRIs of active and inactive states of BD were significantly different from each other. There was no significant difference between the H/M ratios of controls and patients or between patients who are active as compared with inactive disease. These authors concluded that there is prolonged lung retention of 123I-MIBG in BD probably reflecting the severity of the disease and that this may be a potential marker of prognosis in BD. These studies support the need for further evaluation and validation of this imaging modality in patients with BD. The use of invasive diagnostic imaging procedures should be carefully selected in BD patients with pulmonary disease, as these may carry significant risk. The frequency of pulmonary hypertension in patients with BD is high, and several reports have described this as a predisposing factor for catheter-induced pulmonary vascular injury. Raz et al. reported severe progression of the disease after contrast angiography in 11 of 13 patients with BD (2). There is a risk of aneurysm development with the injury to arteries after the contrast angiography. Venipuncture, intravenous infusion, rapid injection of large quantities of contrast material, or insertion of venous catheters may initiate or aggravate an already developed thrombosis in the peripheral veins (12,16). Thus, the use of alternative methods to diagnose pulmonary artery aneurysm in patients with BD should always be considered where possible. The need for pulmonary angiography could be obviated in certain cases with the use of high-precision MRI and ventilation/perfusion lung scanning, including radionuclide pulmonary angiography (30).
VIII.
Treatment
The current treatment of BD is based on the site and severity of disease. There have been very few randomized controlled trials in BD, and the approach to therapy has largely been based on small prospective open-label trials and retrospective case series. There are limited data on the specific treatment of pulmonary involvement in BD and the therapeutic approach has largely been based on patients who have multiple manifestations or other severe vascular features. Immunosuppression is the mainstay of treatment for many manifestations of BD. Glucocorticoids are the foundation of therapy but may not be sufficient for long-term immunosuppression or for severe disease involvement. Other immunosuppressive therapies, such as azathioprine (31), methotrexate (32), chlorambucil (33,34), cyclophosphamide, and penicillamine (35), have been studied in limited fashion. Anti-inflammatory drugs, such as colchicine (36), thalidomide (37), dapsone (38), and levamisole (39), have been shown to be effective on mucocutaneous
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lesions. Penicillin has been studied prospectively with favorable response in mucocutaneous lesions and arthritis, which may reflect the possible role of streptococci in the pathogenesis of BD (35). New alternatives, such as IFN-a in the treatment of eye involvement, have shown encouraging results (40). There is growing evidence in the literature about the successful use of antiTNF agents, in induction of remission in BD patients, especially in those with manifestations refractory to conventional treatments. The published evidence on the use of anti-TNF agents in BD is mainly derived from use of infliximab, which has been used in open-label studies and as an adjunctive therapy for posterior uveitis inadequately controlled with conventional immunosuppressive agents. Infliximab was effective in preventing ocular relapses, maintaining visual acuity, and tapering immunosuppressive therapy (41,42). However, the only randomized controlled trial of anti-TNF agents was a four-week study, in which etanercept suggested efficacy in mucocutaneous manifestations (42). To date, there are not enough data available about the efficacy of anti-TNF agents in vascular involvement in BD. Major vascular manifestations such as pulmonary artery aneurysm and superior vena cava occlusion are usually treated with a combination of cyclophosphamide and methylprednisolone, although there is no compelling evidence about the efficacy of this combination. There is no consensus on the role of anticoagulant and thrombolytic treatment in BD. It is important that pulmonary angiitis and aneurysms are not mistaken for thromboembolic disease, since fatalities have occurred in BD shortly after initiation of anticoagulation/thrombolytic treatment (6). The surgical treatment of aneurysms in BD should be considered carefully since the operative morbidity and mortality rates of surgical interventions for vascular involvement are very high. Complications include anastomotic aneurysm, arteriovenous fistulas, and thrombus (6). Lobectomy and pneumonectomy should be reserved only for urgent cases with massive hemoptysis. Other treatment modalities have involved embolization, but this procedure carries a risk of bleeding and other hazards (43). IX.
Summary
BD is a chronic systemic vasculitis that can be associated with pulmonary manifestations in up to 10% of patients. Pulmonary aneurysms are the most common form of pulmonary involvement and carry a poor prognosis. Further investigation is needed to better understand the pathogenesis of disease and to explore novel treatment options through the conduct of rigorous standardized trials. References 1. Behc¸et H. Uber rezidivierende aphthouse durch ein virus verursachte Geschwuere am Mund, am Auge und an den Genitalien. Derm Wochenschr 1937; 105:1152–1157. 2. Raz I, Okon E, Chajek-Shaul T. Pulmonary manifestations in Behc¸et’s syndrome. Chest 1989; 95(3):585–589.
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3. Yazici H, Tuzun Y, Pazarli H, et al. Influence of age of onset and patient’s sex on the prevalence and severity of manifestations of Behc¸et’s syndrome. Ann Rheum Dis 1984; 43(6):783–789. 4. Lakhanpal S, Tani K, Lie JT, et al. Pathologic features of Behc¸et’s syndrome: a review of Japanese autopsy registry data. Hum Pathol 1985; 16(8):790–795. 5. Hamuryudan V, Yurdakul S, Moral F, et al. Pulmonary arterial aneurysms in Behc¸et’s syndrome: a report of 24 cases. Br J Rheumatol 1994; 33(1):48–51. 6. Uzun O, Akpolat T, Erkan L. Pulmonary vasculitis in Behc¸et’s disease: a cumulative analysis. Chest 2005; 127(6):2243–2253. 7. Kaklamani VG, Vaiopoulos G, Kaklamanis PG. Behc¸et’s Disease. Semin Arthritis Rheum 1998; 27(4):197–217. 8. Yazici H, Yurdakul S, Hamuryudan V. Behc¸et’s syndrome. Curr Opin Rheumatol 1999; 11(1):53–57. 9. Emmi L, Brugnolo F, Salvati G, et al. Immunopathological aspects of Behc¸et’s disease. Clin Exp Rheumatol 1995; 13(6):687–691. 10. Hasan A, Fortune F, Wilson A, et al. Role of gamma delta T cells in pathogenesis and diagnosis of Behc¸et’s disease. Lancet 1996; 347(9004):789–794. 11. Pervin KCA, Shinnick T, Mizyshima Y, et al. T cells epitope expression of mycobacterial and homologous human 65-kilodalton heat shock protein peptides in short term cell lines from patients with Behc¸et’s disease. J Immunol 1993; 151:2273–2282. 12. Efthimiou J, Johnston C, Spiro SG, et al. Pulmonary disease in Behc¸et’s syndrome. Q J Med 1986; 58(227):259–280. 13. Kansu E, Ozer FL, Akalin E, et al. Behc¸et’s syndrome with obstruction of the venae cavae. A report of seven cases. Q J Med 1972; 41(162):151–168. 14. Hiller N, Lieberman S, Chajek-Shaul T, et al. Thoracic manifestations of Behc¸et’s disease at CT. Radiographics 2004; 24(3):801–808. 15. International Study Group for Behc¸et’s Disease. Criteria for diagnosis of Behc¸et’s disease. Lancet 1990; 335:1078–1080. 16. Chajek T, Fainaru M. Behc¸et’s disease: report of 41 cases and a review of the literature. Medicine (Baltimore) 1975; 54(3):179–196. 17. Koc Y, Gullu I, Akpek G, et al. Vascular involvement in Behc¸et’s disease. J Rheumatol 1992; 19(3):402–410. 18. Muftuoglu AU, Yurdakul S, Yazici H, et al., eds. Vascular Involvement in Behc¸et’s disease—a review of 129 cases. London: Royal Society of Medicine Services International Congress and Symposium Series; 1986; (103):255–260. 19. Ning-Sheng L, Chun-Liang L, Ray-Sheng L. Bronchiolitis obliterans organizing pneumonia in a patient with Behc¸et’s disease. Scand J Rheumatol 2004; 33(6):437–440. 20. Kim HK, Yong HS, Oh YW, et al. Behc¸et’s disease complicated by diffuse alveolar damage. J Thorac Imaging 2005; 20(1):55–57. 21. Ahonen AV, Stenius-Aarniala BS, Viljanen BC, et al. Obstructive lung disease in Behc¸et’s syndrome. Scand J Respir Dis 1978; 59(1):44–50. 22. Witt C, John M, Martin H, et al. Behc¸et’s syndrome with pulmonary involvementcombined therapy for endobronchial stenosis using neodym-YAG laser, balloon dilation and immunosuppression. Respiration 1996; 63(3):195–198. 23. Fairley C, Wilson JW, Barraclough D. Pulmonary involvement in Behc¸et’s syndrome. Chest 1989; 96(6):1428–1429. 24. Cadman EC, Lundberg WB, Mitchell MS. Pulmonary manifestations in Behc¸et’s syndrome. Case report and review of the literature. Arch Intern Med 1976; 136(8):944–947.
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25. Erkan F, Kiyan E, Tunaci A. Pulmonary complications of Behc¸et’s disease. Clin Chest Med 2002; 23(2):493–503. 26. Greene RM, Saleh A, Taylor AK, et al. Non-invasive assessment of bleeding pulmonary artery aneurysms due to Behc¸et’s disease. Eur Radiol 1998; 8(3):359–363. 27. Ozer C, Duce MN, Ulubas B, et al. Inspiratory and expiratory HRCT findings in Behc¸et’s disease and correlation with pulmonary function tests. Eur J Radiol 2005; 56(1): 43–47. 28. Tunaci A, Berkmen YM, Gokmen E. Thoracic involvement in Behc¸et’s disease: pathologic, clinical, and imaging features. AJR Am J Roentgenol 1995; 164(1):51–56. 29. Unlu M, Akincioglu C, Yamac K, et al. Pulmonary involvement in Behc¸et’s disease: evaluation of 123 I-MIBG retention. Nucl Med Commun 2001; 22(10):1083–1088. 30. Basoglu T, Canbaz F, Bernay I, et al. Bilateral pulmonary artery aneurysms in a patient with Behc¸et’s syndrome: evaluation with radionuclide angiography and V/Q lung scanning. Clin Nucl Med 1998; 23(11):735–738. 31. Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in Behc¸et’s syndrome. N Engl J Med 1990; 322(5):281–285. 32. Hirohata S, Suda H, Hashimoto T. Low-dose weekly methotrexate for progressive neuropsychiatric manifestations in Behc¸et’s disease. J Neurol Sci 1998; 159(2):181–185. 33. Mudun BA, Ergen A, Ipcioglu SU, et al. Short-term chlorambucil for refractory uveitis in Behc¸et’s disease. Ocul Immunol Inflamm 2001; 9(4):219–229. 34. Tricoulis D. Treatment of Behc¸et’s disease with chlorambucil. Br J Ophthalmol 1976; 60(1):55–57. 35. Calguneri M, Ertenli I, Kiraz S, et al. Effect of prophylactic benzathine penicillin on mucocutaneous symptoms of Behc¸et’s disease. Dermatology 1996; 192(2):125–128. 36. Aktulga E, Altac M, Muftuoglu A, et al. A double blind study of colchicine in Behc¸et’s disease. Haematologica 1980; 65(3):399–402. 37. Gardner-Medwin JM, Smith NJ, Powell RJ. Clinical experience with thalidomide in the management of severe oral and genital ulceration in conditions such as Behc¸et’s disease: use of neurophysiological studies to detect thalidomide neuropathy. Ann Rheum Dis 1994; 53(12):828–832. 38. Sharquie KE, Najim RA, Abu-Raghif AR. Dapsone in Behc¸et’s disease: a doubleblind, placebo-controlled, cross-over study. J Dermatol 2002; 29(5):267–279. 39. Lavery HA, Pinkerton JH. Successful treatment of Behc¸et’s syndrome with levamisole. Br J Dermatol 1985; 113(3):372–373. 40. Deuter CM, Kotter I, Gunaydin I, et al. Ocular involvement in Behc¸et’s disease: first 5-year-results for visual development after treatment with interferon alfa-2a. Ophthalmologe 2004; 101(2):129–134. 41. Sfikakis PP, Markomichelakis N, Alpsoy E, et al. Anti-TNF therapy in the management of Behc¸et’s disease–review and basis for recommendations. Rheumatology (Oxford) 2007; 46(5):736–741. 42. Melikoglu M, Fresko I, Mat C, et al. Short-term trial of etanercept in Behc¸et’s disease: a double blind, placebo controlled study. J Rheumatol 2005; 32(1):98–105. 43. Lacombe P, Frija G, Parlier H, et al. Transcatheter embolization of multiple pulmonary artery aneurysms in Behc¸et’s syndrome. Report of a case. Acta Radiol Diagn (Stockh) 1985; 26(3):251–253.
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30 Eosinophilic Pneumonias and Syndromes
VINCENT COTTIN Department of Respiratory Medicine, Reference Center for Orphan Pulmonary Diseases, Hospices Civils de Lyon, Louis Pradel University Hospital, University of Lyon, Lyon, France
ROMAIN LAZOR Department of Respiratory Medicine, University Hospital, Bern, Switzerland, and Department of Respiratory Medicine, Reference Center for Orphan Pulmonary Diseases, Louis Pradel University Hospital, Lyon, France
JEAN-FRANC ¸ OIS CORDIER Department of Respiratory Medicine, Reference Center for Orphan Pulmonary Diseases, Hospices Civils de Lyon, Louis Pradel University Hospital, University of Lyon, Lyon, France
I.
Introduction
The eosinophilic lung diseases and syndromes are characterized by prominent infiltration of the lung by polymorphonuclear eosinophils, often associated with marked peripheral blood eosinophilia and eosinophilia at bronchoalveolar lavage (BAL), and may include parenchymal lung diseases as well as diseases of the lower airways (1). The diseases associated with eosinophilic pneumonia developed in this chapter may be separated into eosinophilic pneumonia of undetermined origin and well-individualized syndromes, and eosinophilic pneumonia with a definite cause (mainly infection and drug reaction) (Table 1). II.
The Eosinophil Leukocyte
Eosinophil precursors originate in the bone marrow, where they divide and further differentiate into mature eosinophils, which shortly circulate in the bloodstream, and get recruited into target tissues such as the lung through cell attraction and adhesion to the endothelial cells (through adhesion molecules), diapedesis, and chemotaxis within tissues. Eosinophil recruitment to tissues 707
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Table 1 Clinical Classification of Eosinophilic Lung Diseases Eosinophilic lung disease of determined origin Eosinophilic pneumonias of parasitic origin and other infectious causes Allergic bronchopulmonary aspergillosis and related syndromes Iatrogenic and toxic agents–induced eosinophilic pneumonias Drugs Radiation therapy to the breast Toxic agents Eosinophilic lung disease of undetermined origin Limited to the lung Idiopathic chronic eosinophilic pneumonia Idiopathic acute eosinophilic pneumonia Associated with systemic disease Churg-Strauss syndrome Hypereosinophilic syndromes (lymphocytic and myeloproliferative variants) Lung diseases with possible and/or mild pulmonary eosinophilia Asthma, eosinophilic bronchitis Organizing pneumonia Idiopathic interstitial pneumonias Langerhans’ cell granulomatosis Sarcoidosis Lymphoma
especially occurs on cell activation in eosinophilic syndromes. While the initial steps of precursor differentiation are mostly under the action of interleukin (IL)-5, IL-3, and granulocyte macrophage colony-stimulating factor (GM-CSF), tissue recruitment of mature cells is mainly controlled by cytokines IL-5 and the eotaxin-1 chemokine (2). The physiological function of the eosinophil leukocyte is still poorly known, partly due to the lack of appropriate animal model (eosinophils do not degranulate in mice). The eosinophil has long been considered to be involved in innate immunity against infectious organisms and especially protection against parasites. However, a crucial role of eosinophils in defense against parasitic infections is not supported by the experimental model of eosinophil-deficient mice infected with Schistosoma (there is no impact of eosinophil ablation on traditional measures of disease in the S. mansoni infection model, such as liver granuloma and fibrosis formation, hepatocellular damage, worm burden, or on egg deposition) (3). Similarly, eosinophil-deficient mice may be protected against airway wall remodeling but not against allergen-induced upper airways dysfunction, leading to reevaluate the role of the eosinophil in allergic asthma. Participation of the eosinophil in inflammatory and allergic processes is mediated by the release upon activation of a variety of mediators including specific cationic proteins (through degranulation or the so-called piecemeal
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degranulation), proinflammatory cytokines, chemokines, complement proteins, arachidonic acid–derived mediators including leukotrienes, enzymes, and reactive oxygen species, as well as membrane expression of surface enzymes and receptors for cytokines and mediators (including expression of Toll receptors). Differential secretion of mediators by eosinophils may occur depending on the cell stimulus. In addition, emphasis has further been put on the involvement of this cell in acquired immunity, with many biological properties directed to T-helper-2 lymphocytes (through the expression of costimulatory molecules and major histocompatibility complex class-II molecules by eosinophils), and interaction of eosinophils with a variety of cell types (e.g., mast cells, basophils, endothelial cells, macrophages, platelets, and fibroblasts) mostly through cytokine secretion. Activation of the eosinophils in tissues is considered the major cause of tissue injury in eosinophilic disorders due to the release of nonspecific and the so-called eosinophil-specific cationic proteins, the physiological function of which is largely unknown. These cationic proteins include major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), enzymatic protein eosinophil peroxidase (EPO), and the recently described MBP homolog. III.
Histopathology of Eosinophilic Pneumonia
Eosinophilic pneumonia is characterized on histopathology by the prominent infiltration of the lung parenchyma by polymorphonuclear eosinophils, involving the lung interstitium and the alveolar spaces (together with a fibrinous exudate) (4–6) and often associated with some lymphocytes, plasma cells, and polymorphonuclear neutrophils. Occasional macrophages and scattered multinucleated giant cells may be present within the infiltrate. The global architecture of the lung is preserved. Although nonprominent, some eosinophilic microabscesses and a nonnecrotizing vasculitis are common in idiopathic chronic eosinophilic pneumonia (ICEP) and idiopathic acute eosinophilic pneumonia (IAEP). Parenchymal necrosis or interstitial fibrosis is seldom present, and most eosinophilic pneumonias heal without major sequelae. IV.
Diagnosis of Eosinophilic Pneumonia
The eosinophilic pneumonias may manifest by different clinical-imaging syndromes, namely Lo¨ffler syndrome, chronic eosinophilic pneumonia, or acute eosinophilic pneumonia, the diagnosis of which requires both characteristic clinical-radiological features and the demonstration of eosinophilia at BAL—or on histopathology—with or without peripheral blood eosinophilia. BAL is a good noninvasive surrogate of lung biopsy for the diagnosis of eosinophilic pneumonias, and surgical lung biopsy is rarely necessary, although
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usually safe. However, no study has formally studied the relationship between increased eosinophils at BAL and the finding of eosinophilic pneumonia at surgical lung biopsy. A percentage of eosinophils above 2% at BAL differential cell count is considered abnormal; a percentage of 2% to 25% may be found in nonspecific conditions; a percentage of 25% or more (7) and preferably 40% or more eosinophils at BAL (8,9) is mostly found in patients with eosinophilic pneumonias, therefore it is the recommended cutoff for their diagnosis, especially when the eosinophils are the predominant cell population in BAL (macrophages excepted). When present and associated with typical clinical-imaging features, markedly elevated peripheral blood eosinophilia (>1 109 eosinophils/L and preferably 1.5 109 eosinophils/L) contributes to the diagnosis of eosinophilic syndromes and may obviate the need for BAL, although it does not prove that the observed pulmonary opacities correspond to eosinophilic pneumonia. Peripheral blood eosinophilia rapidly drops to normal upon corticosteroid treatment. It is often absent at presentation in IAEP. V.
Eosinophilic Lung Diseases of Determined Origin
Once the diagnosis of eosinophilic pneumonia has been established, potential causes must be thoroughly investigated since identification of a cause may lead to effective therapeutic measures. When present, nonrespiratory manifestations contribute to the diagnosis of the possible clinical entity, especially for ChurgStrauss syndrome (CSS). A.
Eosinophilic Pneumonia in Parasitic Diseases
Parasite infestation (mostly by helminths) (10) represents the main cause of eosinophilic pneumonia in the world. The diagnosis may be difficult and requires appropriate serologies and repeated search of parasites in the feces. Tropical pulmonary eosinophilia (11) is transmitted by mosquito bites and caused by the filarial parasites Wuchereria bancrofti and Brugia malayi. Symptoms mainly result from an immune response of the host to the antigenic microfilariae trapped in the lung vasculature. The clinical features are nonspecific, with chronic cough, and frequently fever, weight loss, and anorexia. Chest-imaging features include bilateral infiltrative opacities predominating in the lower lobes (12,13). The diagnosis of tropical pulmonary eosinophilia may be established in patients residing in an endemic area (tropical and subtropical regions of the world) on the basis of persisting peripheral blood eosinophilia (>3 109 eosinophils/L), bilateral opacities at chest radiograph, a strongly positive specific serology for filariasis, and immunoglobulin (Ig)E levels exceeding 10,000 ng/mL; it is further supported by clinical improvement following treatment with diethylcarbamazine (14–17). In addition, the diagnosis
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may be considered in patients living in North America or Europe and who have lived in endemic areas several months or years previously; corticosteroids may also be beneficial in severe cases in addition to diethylcarbamazine (14). Infestation with Strongyloides stercoralis, an intestinal nematode that infects humans through the skin by contact with humid soil, may cause eosinophilic pneumonia with mild or moderate symptoms in recently infected immunocompetent individuals. Strongyloidiasis may also cause severe disseminated disease (hyperinfection syndrome) in immunocompromised patients, with various manifestations, including fever, abdominal pain, ileus or small bowel obstruction, jaundice, meningitis, cough, wheezing, dyspnea, or acute respiratory failure, with or without peripheral eosinophilia, and bilateral patchy infiltrates on chest X ray. This massive larval infection that may occur years after the initial infection may be diagnosed by the recovery of rhabditiform larvae in BAL, bronchial washing, or sputum. Because of this risk, treatment with thiabendazole is recommended in all infected patients diagnosed with strongyloidiasis, symptomatic or not, and especially before any immunosuppressive therapy is started (18). In nontropical areas, eosinophilic pneumonias usually of mild severity may be commonly caused by the nematode Ascaris lumbricoides, transmitted through food contaminated by human feces containing parasitic eggs (and migration of the larvae through the lung) (19), and by Toxocara canis (visceral larva migrans syndrome), which especially contaminates children after ingestion of eggs released in infected dog feces often in the soil of public playgrounds in urban areas. Pulmonary manifestations are nonspecific, and mostly consist in Lo¨ffler syndrome characterized by transient cough, wheezing, possible dyspnea, and pulmonary infiltrates at chest imaging. Symptoms are often limited to cough, and transient fever, seizures, fatigue, which resolve within a few days. Blood eosinophilia may develop only in the days following pulmonary manifestations, but it may last for several weeks. Treatment of intestinal ascariasis with mebendazole, pyrantel pamoate, or albendazole is recommended, while the use of antihelmintics is controversial in toxocariasis (20). B.
Allergic Bronchopulmonary Mycoses
Allergic bronchopulmonary aspergillosis (ABPA) and related mycoses result from a complex allergic and immune reaction to antigens from fungi colonizing the airways and mediated by immunoglobulin (Ig)E and IgG, and combining both type-I and type-III hypersensitivity (21–23). ABPA is mostly caused by Aspergillus fumigatus; however, a similar pattern of allergic bronchopulmonary mycosis has occasionally been reported with other fungi or yeasts (e.g., Pseudallescheria boydii, Candida albicans) (1). The immune and inflammatory chronic reaction takes place in the bronchi and the adjacent lung parenchyma and results in progressive tissue damage (24,25), especially with the development of proximal bronchiectasis predominating in the upper lobes. Mucous plugs
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Figure 1 Allergic bronchopulmonary aspergillosis. CT scan of the chest showing proximal bronchiectases and a mild infiltrate in the right middle lobe.
containing Aspergillus obstruct the airways with subsequent atelectasis and contribute to bronchial wall damage. ABPA occurs mainly in adults with preexisting asthma and in patients with cystic fibrosis (26,27). Exacerbations of ABPA are characterized initially by fever, expectoration of mucus plugs, and peripheral blood eosinophilia greater than 1 109 eosinophils/L (which rapidly resolves on corticosteroid treatment), in patients presenting with recurrent corticosteroid-dependent asthma (28). Chest imaging demonstrates segmental or lobar atelectasis due to mucus plugging, pulmonary infiltrates, or consolidation due to eosinophilic pneumonia. The chronic phase of ABPA is characterized by asthma, eosinophilia, and chronic bronchopulmonary manifestations, with expectoration of mucous plugs, and presence of Aspergillus in sputum. Proximal bronchiectasis present on CT scan and predominating in the upper lobes (Fig. 1) is highly suggestive of the diagnosis of ABPA in an asthmatic patient (Table 2) (29–33), but may be lacking (34), such cases being designated ABPA-seropositive (34). Late skin reactivity to Aspergillus antigen is common at this stage. Allergic Aspergillus sinusitis is frequently associated. The treatment of exacerbations of ABPA by oral corticosteroids may reduce lung damage and progression to fibrotic end-stage lung disease. Oral itraconazole allows the reduction of the doses of oral corticosteroids and reduces the frequency of exacerbations (35–38). Inhaled treatment of asthma including corticosteroids is a useful adjunct to oral therapy and may reduce the need for long-term oral corticosteroids. Treatment with an anti-IgE recombinant antibody may be useful in some cases (39). The newer agent voriconazole has been used in ABPA only in isolated case reports (40).
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Table 2 Diagnostic Criteria for Allergic Bronchopulmonary Aspergillosis in Asthmatic Patients Criteria for ABPA–central bronchiectasis 1. Asthma 2. Central bronchiectasis (inner two-thirds of chest CT field) 3. Immediate cutaneous reactivity to Aspergillus species or A. fumigatus 4. Total serum IgE concentration >417 kU/L (1000 ng/mL) 5. Elevated serum IgE–A. fumigatus and or IgG–A. fumigatus 6. Chest roentgenographic infiltrates 7. Serum precipitating antibodies to A. fumigatus Criteria for the diagnosis of ABPA-seropositive 1. Asthma 2. Immediate cutaneous reactivity to Aspergillus species or A. fumigatus 3. Total serum IgE concentration >417 kU/L (1000 ng/mL) 4. Elevated serum IgE–A. fumigatus and or IgG-A. fumigatus 5. Chest roentgenographic infiltrates
C.
Eosinophilic Pneumonias Secondary to Drugs, Toxic Agents, and Radiation Therapy
Drug-induced eosinophilic lung disease may present as transient pulmonary infiltrates with eosinophilia (Lo¨ffler syndrome), chronic eosinophilic pneumonia, or acute eosinophilic pneumonia sometimes requiring mechanical ventilation. Eosinophilic pneumonias due to drug exposure are usually indistinguishable from idiopathic eosinophilic pneumonias, although cutaneous rash or pleural effusion may increase the likelihood of the diagnosis when associated. As a result, all drugs taken in the weeks or months preceding the symptoms must be thoroughly investigated, including illicit drugs (especially cocaine or heroin). Eosinophilic pneumonia has been reported in association with more than 80 drugs, but causality has been confidently demonstrated in fewer than 20 drugs, which are mostly antibiotics as minocycline and anti-inflammatory drugs (Table 3) (1). Corticosteroids are often given concomitantly with drug withdrawal to accelerate clinical improvement. Reintroduction of the drug responsible for the eosinophilic pneumonia is potentially dangerous and thus must be avoided. Chronic eosinophilic pneumonia similar to ICEP has been described in women after up to 10 months after radiation therapy for breast cancer (41) [a syndrome comparable to the organizing pneumonia syndrome primed by radiation therapy to the breast (42)]. All patients had a history of asthma, allergy, or both, and it is hypothesized that eosinophilic pneumonia may develop preferentially in patients with preexisting T-helper type-2-oriented lymphocyte response (43,44), together with yet unidentified genetic predisposition, environmental factors, and/or additional triggers.
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Table 3 Drugs Commonly Causing Eosinophilic Pneumonia Anti-inflammatory drugs and related drugs
Antibiotics
Other drugs
Acetylsalicylic acid Diclofenac Ibuprofen Naproxen Phenylbutazone Piroxicam Sulindac Tolfenamic acid Ethambutol Minocycline Para (4)-aminosalicylic acid Penicillins Pyrimethamine Sulfamides, sulfonamides Trimethoprim-sulfamethoxazole Captopril Carbamazepine Granulocyte-monocyte colony-stimulating factor L-tryptophan
A more extensive list of drugs reported to cause eosinophilic pneumonia may be found at www.pneumotox.com and in Ref. 1.
D.
Other Lung Diseases with Associated Eosinophilia
Peripheral blood and (or) tissue eosinophilia may be found incidentally as an accessory finding in a variety of other bronchopulmonary disorders, including airway diseases and interstitial lung diseases. Asthma is a common cause of mild increase of eosinophils in peripheral blood and BAL differential cell counts (usually <5%), in the absence of eosinophilic pneumonia. Eosinophilia may also be found in induced sputum, a finding that may help in adapting the treatment and reduce asthma exacerbations and hospital admissions. Eosinophilic inflammation of the bronchial walls is very common at histopathology in asthmatics (45) and has been correlated with the severity of asthma, defining the eosinophilic variant of asthma (as opposed to the neutrophilic and pauci-leukocytic variants of asthma). The eosinophilic variant of asthma often begins late in adulthood, may be associated with aspirin intolerance, and may respond poorly to inhaled corticosteroids. More important, blood eosinophilia (i.e, >1.5 109 eosinophils/L) is present in a subset of asthmatics in the absence of any determined cause, defining so-called hypereosinophilic asthma, which should raise concern of an increased risk of evolution to ICEP or systemic disease such as CSS. We discourage the use of leukotriene inhibitors in this context as these drugs have
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been suspected to facilitate the onset of the vasculitis. Alternatively, hypereosinophilic asthma may remain solitary. It is characterized by frankly elevated eosinophils in the blood, induced sputum, and BAL, and frequent dependency on oral corticosteroids often requiring prolonged oral corticosteroid treatment. Bronchocentric granulomatosis is an extremely rare condition with clinical and imaging features resembling those of ABPA (lung masses may also be present), and diagnosed only by lung biopsy. Corticosteroids represent the mainstay of treatment, with good clinical efficacy and excellent prognosis. Eosinophilic bronchitis defined by a high percentage of eosinophils (up to 40%) in induced sputum is a cause of chronic cough, with normal lung function and absence of bronchial hyperreactivity (46–48). Prolonged treatment with inhaled corticosteroids may be beneficial. Eosinophilic bronchitis is distinct from bronchial asthma, although it may in some cases evolve over time to irreversible airflow obstruction without asthma or to genuine asthma (49,50). Eosinophilic pneumonia does not occur. Mild-to-moderate increase of eosinophil differential cell count may be found at BAL in idiopathic pulmonary fibrosis (a finding reported with a poor prognosis) (51–53), in desquamative interstitial pneumonia (54), and occasionally in pulmonary Langerhans’ cell histiocytosis and sarcoidosis. Although BAL eosinophilia is usually less than 20% in organizing pneumonia, some clinical and pathological overlap may occur between cryptogenic organizing pneumonia and ICEP, with possible eosinophils in organizing pneumonia and foci of organizing pneumonia in ICEP, respectively.
VI. A.
Eosinophilic Pneumonia of Undetermined Origin Idiopathic Chronic Eosinophilic Pneumonia
ICEP individualized by Carrington et al. (4) predominates in women (2:1 female to male ratio), with a mean age of 45 years at diagnosis, and is more common in nonsmokers (6,9,55). It is characterized by the progressive onset over several weeks of cough, dyspnea, and chest pain, often accompanied by constitutional symptoms (fatigue, malaise, fever, and weight loss) (6,9). The mean interval between the onset of symptoms and the diagnosis is four months. Crackles or wheezes are found at lung auscultation in one third of patients. In contrast to CSS, nonrespiratory manifestations are absent in ICEP, although some minor systemic manifestations (e.g., pericarditis, arthralgias, repolarization (ST-T) abnormalities on the electrocardiogram, altered liver biological tests, eosinophilic enteritis, etc.) are possible, therefore suggesting an overlap with—or formes frustes of—CSS (4,9,56). Prior asthma may antedate the diagnosis of ICEP, occur concomitantly, or develop in subsequent years (8). Overall, it is present in approximately two thirds of patients, and may get worse after the occurrence of ICEP, requiring prolonged
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Figure 2 Idiopathic chronic eosinophilic pneumonia. Chest radiograph demonstrating bilateral opacities with ill-defined margins and predominating in the upper lobes, with density varying from ground glass to consolidation.
inhaled and (or) oral corticosteroids. About half of patients also have a history of atopy, and 20% have chronic rhinitis or sinusitis. Imaging features of ICEP are often characteristic enough to suggest the diagnosis, especially in the case of migratory and bilateral alveolar opacities with ill-defined margins and peripheral predominance (described as the classic pattern of ‘‘photographic negative of pulmonary edema’’), but are seen in only onefourth of patients (4,6,9,32,57–59). Density may vary from ground glass to consolidation (Fig. 2). Radiological features may be similar to those of organizing pneumonia. On high-resolution computed tomography (HRCT), the opacities are almost always bilateral, predominate in the upper lobes and the periphery of the lungs, and generally associate early ground glass and late consolidation opacities (Fig. 3). In addition, band-like or streaky opacities parallel to the chest wall may be present (58), especially after corticosteroid treatment is started. Mediastinal lymph node enlargement and small-size pleural effusion may be seen (9). Peripheral blood eosinophilia is almost always present in ICEP when blood count is performed prior to corticosteroid treatment (systemic corticosteroids may decrease dramatically the eosinophil cell count within 24–48 hours), with a mean blood eosinophilia over 5 109 eosinophils/L in most series. Alveolar eosinophilia usually greater than 40% at BAL differential cell count is a hallmark of ICEP (9,60), with a mean of about 60% at differential cell count (9), and is key to the diagnosis. Total blood IgE level is increased in about half the cases. C-reactive protein is elevated. Urine excretion of the EDN/eosinophil protein X (EPX) is markedly increased, indicating active eosinophil degranulation (61).
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Figure 3 Idiopathic chronic eosinophilic pneumonia. CT scan of the chest showing multifocal alveolar consolidation in the periphery of the lung.
Lung function tests in ICEP show an obstructive ventilatory defect in about half the cases and a restrictive ventilatory defect in the other half (6,9). Usually mild hypoxemia is present in two thirds of patients. Although spontaneous resolution of ICEP may occasionally occur, treatment with oral corticosteroids is needed and is followed by dramatic clinical improvement and normalization of blood eosinophil level within 48 hours in about 80% of the patients (9). An initial dose of 0.5 mg/kg/day may be used for two weeks, followed by 0.25 mg/kg/day for two weeks, with further tapering of corticosteroids. Chest CT eventually returns to normal in almost all patients, but streaky or bandlike opacities may persist in a minority of patients. Pulmonary opacities rapidly decrease in both size and extent, with possible evolution from consolidation to ground glass opacities or inhomogeneous opacities, and clear within one week. Similarly, the spirometry returns to normal with treatment in most patients, although persistent airflow obstruction may develop in isolated cases (9,62). Relapse occurs in over half of the patients after stopping the corticosteroid treatment or under a low daily dose of prednisone (<10 mg/day) (6,9). Consequently, most patients require prolonged treatment for more than six months, and often several years. However, relapses respond very well to resumed corticosteroid treatment. Whether inhaled corticosteroids might reduce the rate of relapses of ICEP after stopping maintenance oral corticosteroids has not been demonstrated (8,9). B.
Idiopathic Acute Eosinophilic Pneumonia
IAEP strikingly differs from ICEP by its acute onset, its clinical severity with possible acute respiratory failure that may require tracheal intubation, the usual lack of increased blood eosinophilia at diagnosis (contrasting with marked
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Table 4 Diagnostic Criteria for Idiopathic Acute Eosinophilic Pneumonia 1. 2. 3. 4. 5.
Acute onseta with febrile respiratory manifestations Bilateral diffuse infiltrates on imaging PaO2 on room air 60 mmHg (8 kPa), or PaO2/FiO2 300 mmHg (40 kPa), or oxygen saturation on room air <90% Lung eosinophilia, with 25% eosinophils at BAL differential cell countb Absence of determined cause of acute eosinophilic pneumonia (including infection or exposure to drugs known to induce pulmonary eosinophilia). Recent onset of tobacco smoking or exposure to inhaled dusts may be present
a
One month or less, and especially 7 days duration before medical examination. Or eosinophilic pneumonia at lung biopsy when done. Source: From Ref. 69; modified from Ref. 70. b
alveolar eosinophilia), and by the absence of relapse after recovery (7,63–69). Current diagnostic criteria (70) are listed in Table 4. IAEP is not associated with asthma, and presents as an acute pneumonia in previously healthy individuals, mainly young adults with a male predominance (7,67). Symptoms usually appear in less than a week (and up to one month) and include dyspnea (often severe), dry cough, chest pain, and fever, sometimes with abdominal pain or myalgias. Tachypnea, tachycardia, and crackles are present on clinical examination. Chest X ray shows bilateral interstitial and alveolar opacities, often associated with bilateral pleural effusion and Kerley B lines. Chest CT mainly shows ground-glass opacities and bilateral airspace consolidation; the presence of interlobular septal thickening, bilateral pleural effusion (present in 70% of cases), and possibly poorly defined nodules (Fig. 4) (7,32,65,71,72) is suggestive of the diagnosis in the appropriate context, especially in the absence of left cardiac dysfunction.
Figure 4 Idiopathic acute eosinophilic pneumonia. CT scan of the chest demonstrating diffuse ground-glass opacities, poorly defined nodules, and bilateral pleural effusion.
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Because blood eosinophilia is usually lacking at presentation and clinicalradiological presentation is indistinguishable from that of infectious acute pneumonia and (or) the acute respiratory distress syndrome (ARDS), performing the BAL before treatment is critical for the diagnosis of IAEP. BAL analysis should include cultures and appropriate staining for infectious agents, and differential cell count (the latter being often overlooked). BAL demonstrates alveolar eosinophilia (usually >25%) together with absence of infection and obviates the need of a surgical lung biopsy (7,67). Eosinophilia may be also found in pleural effusion or sputum. The peripheral blood eosinophil count often rises during the course of disease despite corticosteroid treatment (7,64,67), an evolution which is opposite to that of the eosinophil count in ICEP, and which in fact is suggestive enough of IAEP to raise the suspicion of this diagnosis. High levels of IgE may be present. Elevated circulating TARC (thymus and activation-regulated chemokine) has been reported (73). Lung biopsy, seldom performed, may show acute and organizing diffuse alveolar damage together with interstitial alveolar and bronchiolar infiltration by eosinophils, intra-alveolar eosinophils, and interstitial edema (7,68,74). Hypoxemia is almost always present and is one of the diagnostic criteria (Table 4), with PaO2 on room air less than or equal to 60 mmHg (8 kPa), PaO2/ FiO2 less than or equal to 300 mmHg (40 kPa), and (or) oxygen saturation on room air less than 90%. A majority of patients fit with either the definition of acute lung injury (characterized by an acute onset, bilateral infiltrates on chest X ray, pulmonary artery wedge pressure 18 mmHg when measured or no evidence of left atrial hypertension, and a PaO2/FiO2 300 mmHg) or the definition of ARDS (patients with acute lung injury and with PaO2/FiO2 200 mmHg). In addition, mechanical ventilation is necessary in a significant proportion of patients, either noninvasive or with intratracheal intubation (63,67). In contrast with ARDS, extrapulmonary organ failure does not occur. When performed in less severe cases, lung function tests usually show a mild restrictive ventilatory defect (without obstructive ventilatory defect), with reduced carbon monoxide transfer factor and increased alveolar-arterial oxygen gradient. At long-term follow-up, spirometry is generally normal (7,75,76). Potential causes of eosinophilic pneumonia with acute onset should be carefully searched for, especially drug reactions and infections. Interestingly, IAEP may develop within days or weeks after the initiation of tobacco smoking, with potential relapse upon challenge with resumed cigarette smoking (77–82). In addition, a variety of respiratory exposures within days before disease onset have been reported (cave exploration, heavy dust inhalation due to motocross racing, plant repotting, wood pile moving, smoke-house cleaning, indoor renovation work, gasoline tank cleaning, explosion of a tear gas bomb, exposure to World Trade Center dust, etc) (7,67,83). These consistent observations suggest that IAEP may be triggered by nonspecific inhaled injurious agents, including tobacco smoking. Most patients are treated with oral corticosteroids for two to four weeks, allowing rapid and complete clinical and radiological recovery (67). In contrast
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with ICEP, IAEP does not relapse. Spontaneous recovery may occur without corticosteroid treatment (especially when IAEP is not diagnosed at presentation). C.
Churg-Strauss Syndrome
According to the Chapel Hill Consensus Conference on the nomenclature of systemic vasculitis (84), CSS belongs to the group of antineutrophil cytoplasmic antibodies (ANCA)-associated small-vessel vasculitis and is defined as an eosinophil-rich and granulomatous inflammation involving the respiratory tract, with necrotizing vasculitis affecting small- to medium-sized vessels, and associated with asthma and eosinophilia. Very rare among the group of vasculitides, CSS predominates in the fourth and fifth decades, with no gender predominance. Patients more often carry the DRB4 and DRB*07 alleles than control subjects (85), suggesting a genetic predisposition to the disease. Three phases have been described in the natural course of disease, although they are not always distinct: allergic rhinosinusitis and asthma, blood and tissue eosinophilia, and emergence of systemic vasculitis with eosinophilic disease. Blood eosinophil cell count is greater than 1.5 109 eosinophils/L (and generally between 5 109 eosinophils/L and 20 109 eosinophils/L) (86–88), and rapidly returns to normal upon corticosteroid treatment. Blood eosinophilia usually parallels disease activity. Eosinophilia, sometimes greater than 60%, is also present at BAL differential cell count. Eosinophilia may also be present in sputum and pleural fluid. IgE levels are usually markedly increased. High levels of urinary EDN excretion reflect eosinophil activation in vivo and might parallel disease activity (89). Chronic rhinosinusitis consists of so-called allergic and (or) eosinophilic rhinitis and paranasal sinusitis (present in 60% of cases), with frequent nasal polyposis (88). However, septal nasal perforation and saddle nose deformation are exceptional, contrasting with Wegener granulomatosis. Bronchial asthma usually precedes the onset of vasculitis by several years, although they may develop more closely and even simultaneously (86–88,90). Asthma progressively becomes corticodependent, and may attenuate with the onset of the vasculitis (86,87); long-term oral corticosteroid treatment is often required by the severity of asthma, even long after the active systemic phase of the disease has abated. Although the asthmatic phase of CSS has been considered allergic, only onethird of the patients have positive skin tests and (or) specific IgE for the common respiratory allergens, suggesting that mechanisms other than allergy (or allergy to unidentified allergens) may play a role in the chronic airway inflammation and asthma of CSS (91). Eosinophilic pneumonia may occur in about half of patients, especially at presentation. Alternatively, the chest radiograph may remain normal throughout the course of the disease (86,88). When present, pulmonary opacities are mainly transient ill-defined infiltrates, sometimes migratory (86,87,92,93), which rapidly
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Figure 5 Churg-Strauss syndrome. CT scan of the chest showing bilateral pleural effusion (related to cardiac eosinophilic involvement) and small-size airspace consolidation corresponding to eosinophilic pneumonia.
resolve upon corticosteroid treatment. On chest CT, the opacities consist of areas of ground-glass attenuation and (or) airspace consolidation, often with peripheral predominance, which may not be visualized on chest radiograph and may be accompanied by centrilobular nodules, bronchial wall thickening or dilatation, interlobular septal thickening, and hilar or mediastinal lymphadenopathy (32,93,94). Pleural effusion (usually mild) may be present (Fig. 5), often associated with pericardial effusion, either due to pleural involvement or associated with cardiac failure resulting from cardiac eosinophilic involvement. Constitutional symptoms (asthenia, weight loss, fever, arthralgias, and/or myalgias) and systemic manifestations of vasculitis are always present in CSS (86–88,90,95,96). Cardiac involvement, often asymptomatic for long and diagnosed only when left ventricular failure and severe dilated cardiomyopathy have developed, has become the primary cause of death (97). It mainly results from eosinophilic myocarditis and further heart failure that may lead to heart transplantation (and which may recur in the transplanted heart), although mild or moderate myocardial impairment may markedly improve with treatment. Pericarditis with limited effusion is frequent, whereas true coronary arteritis is rare. Digestive tract involvement present in one third of cases usually manifests as isolated abdominal pain or diarrhea, but intestinal vasculitis (with ulcerations, perforations, or hemorrhage) and cholecystitis may occur. Peripheral nervous system involvement with mononeuritis multiplex, or asymmetrical polyneuropathy, is highly suggestive of CSS in the clinical context of eosinophilic asthma. Cutaneous lesions present in about half of patients mainly consist of palpable purpura of the extremities, subcutaneous nodules, erythematous rashes, and urticaria. Renal involvement present in a quarter of cases is usually mild, in contrast to Wegener granulomatosis or microscopic polyangiitis. There is currently no consensus on diagnostic criteria for CSS. The three diagnostic criteria proposed by Lanham et al. (before ANCA were available)
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(86) are the most commonly used in clinical practice, and include (i) asthma, (ii) eosinophilia greater than 1.5 109 eosinophils/L, and (iii) systemic vasculitis of two or more extrapulmonary organs (proven or not by biopsy). When present, ANCA with specificity for myeloperoxidase or proteinase 3 on ELISA may also be considered a major diagnostic criterion (96). Lung biopsy and transbronchial biopsies are not indicated. The skin, nerve, and muscle are the most common sites where a pathological diagnosis of vasculitis may be obtained (88). However, obtaining a definite pathological diagnosis may be challenging in CSS, because all the pathological lesions are seldom found together on a single biopsy (98,99) and abnormalities are often limited to an eosinophilic perivascular infiltration of the tissues characteristic of the early (prevasculitic) phase of the disease. Therefore, the pathological criterion may not be mandatory in patients with characteristic clinical features and marked eosinophilia. The diagnosis of CSS is particularly difficult in the so-called ‘‘formes frustes’’ of CSS, without overt vasculitis involving several organs. Although CSS belongs to the pulmonary ANCA-associated vasculitides, which also include Wegener granulomatosis and microscopic polyangiitis, ANCA are present in only about 40% of patients and consist in 80% to 90% of cases of perinuclear ANCA (P-ANCA) with a specificity for myeloperoxidase on ELISA (88,90,100,101). Cytoplasmic ANCA with proteinase 3 specificity on ELISA are very rare in CSS, as opposed to Wegener granulomatosis. Interestingly, two recent studies have demonstrated that ANCA antibody status may characterize two distinct clinical phenotypes in CSS (Table 5) (100,101). Hence, patients with ANCA, representing 38% of patients in both studies, have a vasculitic phenotype of disease with an increased frequency of extracapillary glomerular lesions, peripheral neuropathy, purpura, and biopsyproven vasculitis. Conversely, CSS patients without ANCA have more frequent cardiac and pulmonary involvement (and fever), thus corresponding to an eosinophilic tissular disease phenotype of CSS, which might conceivably Table 5 Distinct Phenotypes of Churg-Strauss Syndrome
Respective frequency ANCA Predominant clinical and histopathological features
Vasculitic phenotype
Tissular disease phenotype
40% Present (mostly p-ANCA with anti-MPO specificity) Extraglomerular renal disease Peripheral neuropathy Purpura Biopsy-proven vasculitis
60% Absent Cardiac involvement (eosinophilic myocarditis) Eosinophilic pneumonia Fever
Abbreviations: ANCA, antineutrophil cytoplasmic antibodies; MPO, myeloperoxidase. Source: From Refs. 100, 101.
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represent a variant of the hypereosinophilic syndrome (HES) with systemic manifestations (100,102). The vasculitic phenotype of CSS is more frequent in patients carrying the major histopathology complex DRB4 allele (85). Corticosteroids are the mainstay of treatment of CSS (103,104). Treatment is started with 1 mg/kg/day of prednisone, together with initial intravenous methylprednisolone bolus in the most severe cases, then oral prednisone dose is progressively tapered over several months. Disease control must be balanced with treatment side effects. So-called difficult asthma and less commonly genuine relapse of CSS (with recurring peripheral blood eosinophilia >1 109 eosinophils/L and systemic manifestations) may occur when corticosteroid doses are reduced or stopped, and these must be clearly differentiated. While treatment with corticosteroids alone is sufficient to control disease in a large number of cases of CSS (105), additional immunosuppressive treatment (most commonly intravenous pulses of cyclophosphamide) is required for patients with manifestations associated with increased risk of mortality or severe morbidity at onset (105): cardiomyopathy, proteinuria greater than 1 g/day, renal insufficiency with serum creatinine greater than 15.8 mg/L, gastrointestinal tract involvement, and (or) central nervous system involvement. With treatment, a majority of patients achieve complete remission and do not relapse, but longterm corticosteroid treatment is often necessary to control the disease and especially asthma. Oral azathioprine in addition to corticosteroids may be useful in patients who relapse under 20 mg/day of prednisone or greater. The prognosis of CSS has considerably improved over the years with presently almost 80% of patients alive at five years (106). Subcutaneous interferon-a, high-dose intravenous immunoglobulins, and cyclosporin have been occasionally used successfully in CSS patients with severe or refractory disease (107–109). Vaccines and desensitization have been suspected to trigger or act as adjuvant factors in the development of CSS (110,111), and are thus considered contraindicated in patients with overt CSS. The possible responsibility of leukotriene-receptor antagonists (montelukast, zafirlukast, pranlukast) in the development of CSS has been debated (90,112), with no established causative role in epidemiological studies. However, some rather convincing case reports or personal observations lead us to consider that these agents should be avoided in asthmatic patients with eosinophilia and (or) extrapulmonary manifestations. Drug-induced eosinophilic vasculitis with pulmonary involvement has been occasionally reported. CSS has developed in an asthmatic patient a few months after starting omalizumab, an anti-IgE antibody (113). D.
Idiopathic Hypereosinophilic Syndromes
According to its historical definition (114), idiopathic HES is defined as the presence of persistent eosinophilia greater than 1.5 109 eosinophils/L for longer than six months, with no evidence for a known cause of eosinophilia and presumptive signs and symptoms of organ involvement (including hepatosplenomegaly, organic
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Table 6 Distinctive Characteristics of the Lymphocytic and the Myeloproliferative Variants of the Hypereosinophilic Syndromes Lymphocytic variant
Myeloproliferative variant
Distinctive clinical features
Cutaneous papules or urticarial plaques
Distinctive biological features
Clonal peripheral lymphocytes with aberrant immunological surface phenotype Elevated serum IL-5 and IgE Hypergammaglobulinemia (polyclonal)
Pathogeny
T-cell clonal proliferation producing the Th2 cytokine IL-5
Main treatment considerations
Corticosteroids Interferon-a Anti-IL-5 (mepolizumab)
Hepatomegaly, splenomegaly Cardiac involvement Mucosal ulcerations Activated tyrosine kinase fusion protein Increased serum tryptase Anemia, thrombocythemia Increased serum vitamin B12 and leukocyte alkaline phosphatase Circulating leukocyte precursors Fip1L1–PDGFRa fusion protein resulting from chromosomal interstitial deletion (4q12) Imatinib Hydroxyurea Interferon-a Anti-IL-5 (mepolizumab)
heart murmur, congestive heart failure, diffuse or focal central nervous system abnormalities, pulmonary fibrosis, fever, weight loss, or anemia). Although patients with HES share common complications, especially cardiac involvement, recent studies have demonstrated that the idiopathic HES is a heterogeneous disease, as it has been linked to clonal proliferation of lymphocytes (‘‘lymphocytic variant’’ of HES), or of the eosinophil cell lineage itself (‘‘myeloproliferative variant’’ of HES, sometimes referred to as chronic eosinophilic leukemia) (115) (Table 6). The term idiopathic might be abandoned in the classification of HES (116) and may be appropriate only for the proportion of cases that cannot be classified in either category. Cases of HES, which do not fit into either category, challenge the diagnosis and the pathophysiological analysis; innovative diagnostic tools such as the quantitative assessment of the WT1 transcript in peripheral blood may help differentiate HES from other determined causes of eosinophilia (117). Most clinical descriptions of the disease come from older series, and reported marked male predominance (9:1 male to female ratio) (118). HES generally presents in patients aged 20 to 50 years, with progressive weakness, fatigue, cough, and dyspnea. The mean eosinophil count at presentation is
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about 20 109 eosinophils/L (119), and values up to 100 109 eosinophils/L have been reported (114). Lung involvement present in 40% of patients is nonspecific (114,120). Cough may be the predominant feature, with severe coughing attacks (119), and possibly eosinophilic bronchitis revealing HES (121). The pulmonary manifestations of HES have not been reevaluated since the recent description of the two variants of HES. CT findings are poorly specific among eosinophilic diseases (32), with interstitial infiltrates, ground-glass attenuation, small nodules, but eosinophilic pneumonia with bilateral alveolar consolidation seems uncommon. Pleural effusion has been reported, and must be distinguished from those secondary to cardiac eosinophilic involvement. Cardiovascular involvement is present in about 60% of the patients (118). Endomyocardial fibrosis is a hallmark of HES (120,122) and is quite distinct from the eosinophilic myocarditis of CSS. Classical features at echocardiography include mural thrombus (resulting from an initial acute necrosis), ventricular apical thrombotic obliteration, and involvement of the posterior mitral leaflet (123). Clinical manifestations include dyspnea, congestive heart failure, mitral regurgitation, and cardiomegaly (120,124). Other nonrespiratory manifestations of the HES mainly target the skin (erythematous pruritic papules and nodules, urticaria, angioedema) and the nervous system (thromboemboli, central nervous system dysfunction, peripheral neuropathy). The lymphocytic variant of HES, which may account for about 30% of patients with HES, is a T-cell disorder resulting from the production of chemokines active on eosinophil proliferation and activation (especially IL-5) by clonal Th2 lymphocytes bearing an aberrant antigenic surface phenotype (such as CD3– CD4þ). Polymorphonuclear eosinophils accumulate in tissues in response to chemokine-mediated cell recruitment. Distinctive clinical features of the lymphocytic variant of HES include frequent cutaneous papules or urticarial plaques (infiltrated by lymphocytes and eosinophils at histopathology) (Table 6). IgE level is generally elevated as a consequence of IL-4 and IL-13 production by Th2 lymphocytes. Serum levels of IL-5 and TARC are increased (125). Lymphocyte phenotyping to detect a phenotypically aberrant T-cell subset, and analysis of the rearrangement of the T-cell receptor genes in search of T-cell clonality, should be performed on the peripheral blood and bone marrow. The myeloproliferative variant of HES, accounting for 20% to 30% of cases, is characterized by clinical and biological features common with the chronic myeloproliferative syndromes (Table 6). Hepatomegaly, splenomegaly, mucosal ulcerations, and severe cardiac manifestations resisting to corticosteroid treatment are common, while cutaneous manifestations are infrequent. Anemia, thrombocythemia, increased serum vitamin B12, leukocyte alkaline phosphatase and serum tryptase, and circulating leukocyte precursors are suggestive of the diagnosis. The myeloproliferative variant of HES or chronic eosinophilic leukemia is the consequence of a chromosomal interstitial deletion in the long arm of chromosome 4 (4q12), resulting in the translation of a fusion protein Fip1L1–PDGFRa with
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constitutively active tyrosine kinase activity (126,127) and transforming activity in hematopoietic cells. Accumulation of eosinophils in tissues results from the primitive proliferation of the eosinophil cell lineage characterizing the chronic eosinophilic leukemia. Imatinib, a 2-phenylaminopyrimidine-based drug used in treating chronic myelogenous leukemia and gastrointestinal stromal tumors, inhibits the tyrosine kinase activity of Fip1L1–PDGFRa, and proved efficient in the treatment of the myeloproliferative variant of HES in patients with a disease refractory to corticosteroids, hydroxyurea, and (or) interferon-a. Thus, chromosomal rearrangement analysis and transcript study of the Fip1L1–PDGFRa fusion gene should be systematically performed in patients with HES. Imatinib has become the first-line treatment in patients with the myeloproliferative variant of HES, especially (but not exclusively) when the Fip1L1–PDGFRa fusion protein is present (126,127). Other treatments include corticosteroids especially in the lymphocytic variant of HES (with only about half of the patients responding to corticosteroids), chemotherapeutic agents especially hydroxyurea particularly in the myeloproliferative variant, interferon-a, and the anti-IL-5 antibody mepolizumab (1,128). References 1. Cordier JF. Eosinophilic pneumonias. In: Schwarz MI, King TE, Jr., eds. Interstitial Lung Disease. 4th ed. London BC Dekker, 2003: 657–700. 2. Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol 2006; 24: 147–174. 3. Swartz JM, Dyer KD, Cheever AW, et al. Schistosoma mansoni infection in eosinophil lineage-ablated mice. Blood 2006; 108:2420–2427. 4. Carrington C, Addington W, Goff A, et al. Chronic eosinophilic pneumonia. N Engl J Med 1969; 280:787–798. 5. Liebow AA, Carrington CB. The eosinophilic pneumonias. Medicine (Baltimore) 1969; 48:251–285. 6. Jederlinic PJ, Sicilian L, Gaensler EA. Chronic eosinophilic pneumonia. A report of 19 cases and a review of the literature. Medicine (Baltimore) 1988; 67: 154–162. 7. Pope-Harman AL, Davis WB, Allen ED, et al. Acute eosinophilic pneumonia. A summary of 15 cases and a review of the literature. Medicine (Baltimore) 1996; 75:334–342. 8. Marchand E, Etienne-Mastroianni B, Chanez P, et al. Idiopathic chronic eosinophilic pneumonia and asthma: how do they influence each other? Eur Respir J 2003; 22:8–13. 9. Marchand E, Reynaud-Gaubert M, Lauque D, et al. Idiopathic chronic eosinophilic pneumonia. A clinical and follow-up study of 62 cases. Medicine (Baltimore) 1998; 77:299–312. 10. Chitkara RK, Krishna G. Parasitic pulmonary eosinophilia. Semin Respir Crit Care Med 2006; 27:171–184. 11. Vijayan VK. Tropical pulmonary eosinophilia: pathogenesis, diagnosis and management. Curr Opin Pulm Med 2007; 13:428–433.
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90. Keogh KA, Specks U. Churg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med 2003; 115:284–290. 91. Bottero P, Bonini M, Vecchio F, et al. The common allergens in the Churg-Strauss syndrome. Allergy 2007; 62:1288–1294. 92. Degesys GE, Mintzer RA, Vrla RF. Allergic granulomatosis: Churg-Strauss syndrome. AJR 1980; 135:1281–1282. 93. Choi YH, Im JG, Han BK, et al. Thoracic manifestation of Churg-Strauss syndrome: radiologic and clinical findings. Chest 2000; 117:117–124. 94. Worthy SA, Muller NL, Hansell DM, et al. Churg-Strauss syndrome: the spectrum of pulmonary CT findings in 17 patients. AJR 1998; 170:297–300. 95. Reid AJC, Harrison BDW, Watts RA, et al. Churg-Strauss syndrome in a district hospital. QJM 1998; 91:219–229. 96. Cottin V, Cordier JF. Churg-Strauss syndrome. Allergy 1999; 54:535–551. 97. Sable-Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med 2005; 143:632–638. 98. Garrell M. Lo¨ffler’s syndrome. Arch Intern Med 1960; 106:874–877. 99. Churg A. Recent advances in the diagnosis of Churg-Strauss syndrome. Mod Pathol 2001; 14:1284–1293. 100. Sinico RA, Di Toma L, Maggiore U, et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum 2005; 52:2926–2935. 101. Sable-Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med 2005; 143:632–638. 102. Kallenberg CGM. Churg-Strauss syndrome: just one disease entity? Arthritis Rheum 2005; 52:2589–2593. 103. Keogh KA, Specks U. Churg-Strauss syndrome. Semin Respir Crit Care Med 2006; 27:148–157. 104. Pagnoux C, Guilpain P, Guillevin L. Churg-Strauss syndrome. Curr Opin Rheumatol 2007; 19:25–32. 105. Cohen P, Pagnoux C, Mahr A, et al. Churg-Strauss syndrome with poor-prognosis factors: a prospective multicenter trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in forty-eight patients. Arthritis Rheum 2007; 57:686–693. 106. Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore) 1996; 75:17–28. 107. Tatsis E, Schnabel A, Gross WL. Interferon-alpha treatment of four patients with the Churg-Strauss syndrome. Ann Intern Med 1998; 129:370–374. 108. Kaushik VV, Reddy HV, Bucknall RC. Successful use of rituximab in a patient with recalcitrant Churg-Strauss syndrome. Ann Rheum Dis 2006; 65:116–117. 109. Koukoulaki M, Smith KG, Jayne DR. Rituximab in Churg-Strauss syndrome. Ann Rheum Dis 2006; 65:557–559. 110. Mouthon L, Khaled M, Cohen P, et al. Antigen inhalation as a triggering factor in systemic small-sized-vessel vasculitis. Four cases. Ann Med Interne (Paris) 2001; 152:152–156. 111. Guillevin L, Guittard T, Bletry O, et al. Systemic necrotizing angiitis with asthma: causes and precipiting factors in 43 cases. Lung 1987; 165:165–172.
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112. Lilly CM, Churg A, Lazarovich M, et al. Asthma therapies and Churg-Strauss syndrome. J Allergy Clin Immunol 2002; 109:S1–S19. 113. Winchester DE, Jacob A, Murphy T. Omalizumab for asthma. N Engl J Med 2006; 355:1281–1282. 114. Chusid MJ, Dale DC, West BC, et al. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975; 54:1–27. 115. Roufosse F, Goldman M, Cogan E. Hypereosinophilic syndrome: lymphoproliferative and myeloproliferative variants. Semin Respir Crit Care Med 2006; 27: 158–170. 116. Roufosse F, Cogan E, Goldman M. The hypereosinophilic syndrome revisited. Annu Rev Med 2003; 54:169–184. 117. Cilloni D, Messa F, Martinelli G, et al. WT1 transcript amount discriminates secondary or reactive eosinophilia from idiopathic hypereosinophilic syndrome or chronic eosinophilic leukemia. Leukemia 2007; 21:1442–1450. 118. Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood 1994; 83:2759–2779. 119. Spry CJF, Davies J, Tai PC, et al. Clinical features of fifteen patients with the hypereosinophilic syndrome. Q J Med 1983; 205:1–22. 120. Fauci AS, Harley JB, Roberts WC, et al. The idiopathic hypereosinophilic syndrome: clinical, pathophysiologic and therapeutic considerations. Ann Intern Med 1982; 97:78–92. 121. Chung KF, Hew M, Score J, et al. Cough and hypereosinophilia due to FIP1L1PDGFRA fusion gene with thyrosine kinase activity. Eur Respir J 2006; 27:230–232. 122. Roberts WC, Ferrans VJ. Pathologic anatomy of the cardiomyopathies. Idiopathic dilated and hypertrophic types, infiltrative types, and endomyocardial disease with and without eosinophilia. Hum Pathol 1975; 6:287–342. 123. Ommen SR, Seward JB, Tajik AJ. Clinical and echocardiographic features of hypereosinophilic syndromes. Am J Cardiol 2001; 86:110–113. 124. Lefebvre C, Bletry O, Degoulet P, et al. Facteurs pronostiques du syndrome hypere´osinophilique. Etude de 40 observations. Ann Med Interne (Paris) 1989; 140:253–257. 125. Kakinuma T, Nakamura K, Wakugawa M, et al. Thymus and activation-regulated chemokine in atopic dermatitis: serum thymus and activation-regulated chemokine level is closely related with disease activity. J Allergy Clin Immunol 2001; 107:535–541. 126. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003; 348:1201–1214. 127. Griffin JH, Leung J, Bruner RJ, et al. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome. Proc Natl Acad Sci U S A 2003; 100: 7830–7835. 128. Klion AD, Law MA, Noel P, et al. Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome. Blood 2004; 103:2939–2941.
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31 Langerhans Cell Histiocytosis
ROBERT VASSALLO, RAJESH PATEL, and MARIE CHRISTINE AUBRY Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A.
I.
Introduction
Pulmonary Langerhans’ cell histiocytosis (LCH) is an important consideration in the differential diagnosis of patients with diffuse lung disease, particularly in cigarette smokers. Pulmonary LCH refers to the same disease that was formerly known as eosinophilic granuloma or histiocytosis X, and is characterized by proliferation and infiltration of the lungs, and occasionally other organs, by specific dendritic cells of the Langerhans’ type (1). II.
Epidemiological Features
Pulmonary LCH is an uncommon disease and accounts for less than 5% of all interstitial lung diseases in some studies (2). The true prevalence may be higher, since a proportion of patients with less aggressive forms of pulmonary LCH will never undergo biopsy and may be misdiagnosed as having emphysema or bullous lung disease. Previously, pulmonary LCH was thought to occur more often in men, but a recent study reported a higher prevalence in women, potentially reflecting changes in smoking habits by women (3–5). Genetic factors are 733
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unlikely to be important in the development of adult pulmonary LCH, and the overwhelming majority of cases occur sporadically. Pulmonary LCH afflicts predominantly Caucasians and seems to be very uncommon in other ethnic groups. The reason for this racial predilection is undefined. There are many convincing lines of evidence that implicate a central role for cigarette smoking in pulmonary LCH. Multiple case series have reported tobacco use in the vast majority (>90%) of patients (3–7). Cigarette smoking has been described to precipitate pulmonary LCH in individuals with childhood LCH that had been in remission prior to the onset of smoking (8). Smoking cessation is associated with disease remission in some cases, suggesting a direct pathogenic role for smoking in pulmonary LCH (9,10). Apart from cigarette smoking, there are no other known environmental or occupational risk factors associated with pulmonary LCH.
III.
Pathogenesis
Langerhans’ cells are specialized dendritic cells that express the CD1a receptor and possess specialized intracellular organelles known as Birbeck granules (11). Langerhans’ cells are morphologically similar to macrophages (hence the term histiocyte or macrophage-like) but differ with respect to specific immuneregulatory functions. The primary function of these cells is to regulate pulmonary responses to exogenous (inhaled) and endogenous (self) antigens (12). Following internalization of antigen, dendritic and Langerhans’ cells migrate from the lung to regional and draining lymphoid tissues and present antigen to other immune cells. Accumulation of Langerhans’ cells is the earliest lesion described to occur in LCH lung tissue specimens (13). Biopsies of pulmonary LCH demonstrate accumulation of Langerhans’ cells around small airways, suggesting that an inhaled factor is involved in promoting local accumulation or expansion of these cells, which are believed to play a pivotal role in the pathogenesis. Since pulmonary Langerhans’ cells are critical regulators of lung immunity, it is tempting to speculate that pulmonary LCH represents an abnormal tobacco-induced immune-mediated process, characterized primarily by bronchiolar Langerhans’ cell infiltration and secondarily by recruitment of other inflammatory cells, eventually resulting in the formation of cellular loose granulomatous lesions around small airways. Although accumulation of Langerhans’ cells is an evident early event in the pathogenesis, the factor/s and mechanisms responsible for their accumulation and retention and the role of Langerhans’ cells in orchestrating subsequent recruitment of T cells, eosinophils, and other immune cells present in cellular pulmonary LCH lesions are unclear. Cigarette smoking has been demonstrated to increase Langerhans’ cell numbers in smokers, even in the absence of clinically evident lung disease (14). This may be partially explained by the capacity of soluble cigarette smoke constituents to induce epithelial cell production of
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essential Langerhans’ cell differentiating factors, such as granulocyte macrophage colony stimulating factor (GM-CSF) and transforming growth factor-beta (TGF-b) (13,15). However, the overwhelming majority of smokers do not develop pulmonary LCH, in spite of having an increased population of Langerhans’ cells in the lungs, suggesting that a ‘‘second-hit’’ is necessary for the disease to occur. Extensive searches for viral pathogen–associated genes or proteins have not led to any conclusive findings. Potentially, cigarette smoke– induced expansion of neuroendrocrine cells and subsequent generation of bombesin-like peptides may promote sustained Langerhans’ cell recruitment in the lungs of these patients (16). Another possible mechanism involves aberrant presentation of self-antigens from damaged lung tissues by abnormally activated Langerhans’ cells. This possibility is supported by the observation that T lymphocytes are very abundant in LCH lesions, both interspersed between LC and surrounding the lesions (17). More importantly, many T lymphocytes are CD4þ, and associate very closely with lesional Langerhans’ cells, suggesting local presentation of antigen at these sites (17). The potential source for antigen is unknown but could be derived from the cigarette smoke–damaged airway epithelium. Under light microscopy, pulmonary LCH is identical to LCH, affecting other organ systems. However, lesional Langerhans’ cells express significant differences at the cellular and molecular level, implying that the pathogenetic mechanisms responsible for pulmonary LCH are not the same as other types of LCH. For instance, Langerhans’ cells in lesional childhood and adult forms of multisystem LCH are clonally expanded (18). In contrast, the majority of lesional Langerhans’ cells in adult smoking-related pulmonary LCH are expanded in a polyclonal fashion, suggesting that factors exogenous to the Langerhans’ cell promote their expansion and retention (19). Furthermore, the lack of persistence of Langerhans’ cells in advanced pulmonary LCH lesions, the occurrence of disease remission following smoking cessation, and the low proliferative rate of Langerhans’ cells in pulmonary LCH lesions all suggest that isolated lung LCH is a reactive process rather than a type of malignancy (20,21).
IV.
Histological Characteristics
The earliest histological feature is proliferation of Langerhans’ cells found around terminal and respiratory bronchioles (3,21). These early cellular lesions expand to form nodules that are typically 1 to 6 mm in diameter (21). These bronchiolocentric nodules characteristically have a stellate configuration (Fig. 1a). The morphology of the nodules varies with the activity of the lesions. Early lesions are cellular. The peribronchiolar interstitium and adjacent alveolar septa are thickened by clusters of Langerhans’ cells admixed with variable numbers of eosinophils, neutrophils, lymphocytes, macrophages, and fibroblasts. Eosinophils are often numerous and can form eosinophilic abscesses but may be absent in up to 20% of
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Figure 1 (A) Low-power photomicrograph displaying the classic bronchiolocentric stellate shape of the nodules in pulmonary LCH. (B) High-power photomicrograph of strong positive immunoreactivity for CD1a antibody. (C) Ultrastructural image of Birbeck granules, pentalaminar inclusions present within the cytoplasm of Langerhans’ cells. (A. Hematoxylin-eosin, 40; B. Immunostain CD1a, 400; C. Electron microscopy, 98,000). Abbreviation: LCH, Langerhans’ cell histiocytosis.
cases (21). Although increased numbers of Langerhans’ cells may be seen in a variety of neoplastic and nonneoplastic lung diseases (22), clustering of Langerhans’ cells usually occurs in pulmonary LCH and is an important diagnostic criterion. Langerhans’ cells are recognizable by their characteristic delicate folded nuclei and pale cytoplasm. Immunohistochemical staining using antibodies for S-100 protein and CD1a can assist in the identification of Langerhans’ cells (Fig. 1b). Although ultrastructurally Langerhans’ cells are characterized by unique pentalaminar cytoplasmic inclusions called Birbeck granules (Fig. 1c), immunohistochemistry has supplanted electron microscopy as a diagnostic tool. In advanced lesions, fibroblastic proliferation develops in the center of the nodules and is followed by collagen deposition. This results in central scarring with peripheral cellularity. Ultimately, the nodules become completely scarred with scant inflammatory cells and no diagnostic Langerhans’ cell (21). Paracicatricial
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Figure 2 (A) CT of a 23-year-old woman with histopathologically proven pulmonary LCH showing multiple irregular thin-walled cysts bilaterally in the mid lungs. (B) CT of a 21-year-old man with surgical lung biopsy–proven pulmonary LCH demonstrating extensive cystic change in the mid-lung field. Abbreviation: LCH, Langerhans’ cell histiocytosis.
airspace enlargement (irregular or scar emphysema) affecting surrounding airspaces, as well as cavitation, are characteristic findings in fibrotic lesions and accounts for most of the ‘‘cysts’’ seen on high-resolution computed tomography (HRCT) (Fig. 2). Since most patients are active or former smokers, respiratory bronchiolitis is virtually always present (23). In some biopsies, the extent of respiratory bronchiolitis and airspace macrophage accumulation may be sufficiently severe to suggest desquamative interstitial pneumonia (23). Finally,
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involvement of vascular structures is increasingly appreciated in pulmonary LCH. Both venous and arterial abnormalities occur in some patients and may lead to a vasculopathy that mimics primary pulmonary hypertension (24). V.
Clinical Features
The main clinical features of pulmonary LCH are summarized in Table 1. The most frequent presenting symptoms include nonproductive cough and dyspnea, though approximately one-quarter of patients are asymptomatic at the time of presentation (Table 1). In 5% to 15% of patients, other presenting symptoms may be related to histiocytic involvement of other organs such as pain due to bone involvement, polyuria and polydipsia secondary to hypothalamic infiltration with associated diabetes insipidus, skin rashes related to cutaneous LCH, adenopathy from superficial lymph node involvement, and abdominal discomfort due to Langerhans’ cell infiltration of liver and spleen (4). Around 15% to 20% of the patients present with chest pain and dyspnea due to spontaneous pneumothorax (25). Hemoptysis is very uncommon and should not be attributed to LCH unless other causes—such as bronchogenic carcinoma or development of a fungus ball in a cystic cavity—have been carefully ruled out.
Table 1 Clinical and Functional Characteristics of Adults with Pulmonary LCHa Demographical features Gender (% male) Age (range in yr) Nonsmokers (% of total) Symptoms (%) Cough Dyspnea Weight loss/fever Chest pain Pneumothorax Hemoptysis Asymptomatic Pulmonary function test findingsb Normal study (%) Restriction (%) Obstruction (%) Mixed pattern (%) Isolated reduction in DLCO a
46 18–70 3 53 42 11 13 15 4 20 25 32 29 11 3
The table represents summary data of 337 patients with adult pulmonary LCH described in references 3–7. b The pulmonary function test findings are derived from Refs. 3, 4, and 7.
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Pulmonary Function Impairment
Pulmonary function may be normal or may demonstrate mild obstructive, restrictive, or mixed abnormalities (Table 1). At the onset of disease, normal or restrictive physiology predominates (4,26). As the disease progresses, obstruction or mixed abnormalities are commonly observed. The presence of obstructive change on lung function testing may be related to smoking-induced emphysema, which frequently coexists (23), or may reflect bronchiolar obstruction from the peribronchiolar inflammation and fibrosis. Physiological studies in pulmonary LCH have identified important limitations in the exercise capacity of these patients. Crausman et al. (26) studied lung mechanics and exercise physiology in 23 patients and found that exercise performance was severely limited in all patients. Abnormalities of ventilatory function and gas exchange did not appear to be exercise limiting. Rather, measurements of pulmonary vascular function correlated with overall exercise performance, suggesting that exercise impairment in these patients were likely a manifestation of pulmonary vascular dysfunction, at least in earlier stages of disease (3,26). In patients with more advanced disease, which is often accompanied by development of cystic abnormalities, exercise limitation is probably a result of both pulmonary vascular dysfunction and ventilatory limitation.
VII.
Radiographical Imaging
The chest radiograph (CXR) is abnormal in virtually all patients, but the appearance is often nonspecific. Micronodular and interstitial infiltration, often symmetric and bilateral with sparing of the costophrenic angles is commonly encountered. Cystic changes may be present, commonly superimposed on a background of reticular/nodular changes. Honeycombing may be observed in advanced cases. Lung volumes as assessed by the CXR may be either normal or increased, a feature helpful in distinguishing pulmonary LCH from other interstitial diseases, which are typically associated with reduced lung volumes. Infrequent findings on the CXR include alveolar infiltrates, hilar adenopathy, and pleural effusions. HRCT of the chest is a useful and sensitive tool in the diagnostic evaluation. The most common findings are nodules and cysts occurring in a middle and upper lobe distribution (Fig. 2a) (27–29). In the early stages, nodules predominate, whereas in the later stages of disease cystic change becomes more common (30). The lung cysts in pulmonary LCH are usually less than 20 mm in size, although large cysts are not uncommon (Fig. 2b). The combination of cystic lesions associated with nodules in the mid and upper lung regions results in a distinctive radiographical pattern. In some cases, the HRCT does not show a combination of cysts and nodules, resulting in a nonspecific radiographical pattern. Other less-common abnormalities appreciated on HRCT include
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ground-glass attenuation, adenopathy, and extensive cystic change with predominantly lower lobe involvement. VIII.
Lung Biopsy and Bronchoalveolar Lavage
Definitive confirmation of the diagnosis of pulmonary LCH may be obtained with bronchoalveolar lavage (BAL), transbronchoscopic lung biopsy (TBLB), or surgical lung biopsy (SLB). Increased numbers of Langerhans’ cells in BAL, identified by staining with antibodies to CD1a, is strongly suggestive (but rarely diagnostic) of pulmonary LCH (31). When the proportion of CD1a staining cells in the BAL is greater than 5%, the diagnosis of pulmonary LCH is extremely likely (31). Unfortunately, an indeterminate elevation (2–5%) of CD1a positive cells is present in the lavage of many patients. These modest elevations of CD1a cells should be interpreted with caution, since elevations in this indeterminate range may be present in normal smokers and in other interstitial lung diseases (31,32). Bronchoscopy with TBLB also has a low but discernable diagnostic yield in the range of 10% to 40% (4,33). This somewhat limited diagnostic utility of TBLB is related to the patchy distribution of nodular lesions and the small amounts of tissue obtained through standard TBLB approaches. SLB (either open or thoracoscopic) has the greatest diagnostic yield due to the relatively large portion of tissue obtained during the procedure resulting in a greater likelihood of sampling involved lung tissue. The site of lung biopsy should be guided by HRCT. IX.
Diagnostic Approach and Differential Diagnosis
The history and physical examination in patients with pulmonary LCH usually will not provide any specific pointers to the diagnosis, so a high index of suspicion is required. There are no serological studies that aid in the diagnostic evaluation. In addition to routine CXR and pulmonary function testing, all individuals suspected of having pulmonary LCH should undergo chest HRCT. As alluded to previously, characteristic HRCT findings of nodular or cystic changes predominating in the upper lung fields in the appropriate clinical context render the diagnosis of pulmonary LCH highly likely and in some cases obviate the need for lung biopsy. Since the CT findings are variable, other cystic lung diseases (including lymphangioleiomyomatosis and neurofibromatosis) or other interstitial pulmonary processes (sarcoidosis, vasculitis, hypersensitivity pneumonitis, idiopathic interstitial pneumonias, etc.) may need to be considered in the differential. In these cases, bronchoscopy or SLB is indicated to establish a definitive diagnosis and exclude other disease entities. Lung biopsy is usually also indicated if treatment with immunosuppressive or chemotherapy agents is contemplated. In our practice, bronchoscopy is usually performed prior to SLB, because a specific diagnosis may be established by BAL or TBLB in a small but appreciable percentage of patients. In the patient with biopsy-proven LCH
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outside the lung (such as skin or bone), the diagnosis may be established if HRCT shows features consistent with pulmonary LCH. A.
Management
In light of the undeniable association of pulmonary LCH with cigarette use, smoking cessation is a primary and essential component of the management program for all patients. Abstinence from tobacco leads to stabilization of symptoms in many patients and may be the only intervention required for improvement or stabilization of disease in a significant proportion, particularly for patients with limited symptoms. However, the natural course of pulmonary LCH is variable. Whereas in many patients the disease takes a relatively benign course, in others the disease is far more aggressive (4). The management of patients who suffer from progressive forms of pulmonary LCH is not established, but should include consideration of certain pharmacological agents in addition to smoking cessation. Historically, corticosteroids have been the primary therapeutic agent used to treat pulmonary LCH, in spite of limited data supporting their efficacy. Clinicians are often compelled to treat patients with progressive and symptomatic disease, and evidence from certain case series and anecdotal reports have suggested potential benefit from corticosteroid therapy with ‘‘stabilization’’ of the process and symptomatic improvement in some patients (5,6). Since there are no randomized trials that compare the efficacy of corticosteroids with smoking cessation, it is difficult to establish efficacy of corticosteroids, since many patients improve with smoking cessation alone. It is the authors practice to consider a trial of 0.5 to 1 mg/kg/day of prednisone in patients with severe or progressive lung disease. It is advisable to use corticosteroids only if smoking cessation has been achieved; in the absence of which, pulmonary LCH may progress despite any therapeutic maneuver. When steroids are prescribed for LCH, patients should be followed closely and rapidly tapered if there is no objective evidence of response following a 6- to 12-week course of moderate dose prednisone. A variety of chemotherapeutic agents such as vinblastine, methotrexate, cyclophosphamide, etoposide, thalidomide, and 2-chlorodeoxyadenosine (2-CdA) have been employed empirically in patients with either progressive disease, or in those with multisystem involvement. The role of these agents in the management of pulmonary LCH is not well defined. One agent that merits further investigation is 2-CdA, an antimetabolite that is equally active against dividing and resting lymphocytes and monocytes (34). There are now several reports describing efficacy of 2-CdA in the management of bony, skin, and other forms of LCH (34,35). There are also case reports of pulmonary LCH responding to 2-CdA, although none of the patients reported had isolated pulmonary LCH (35,36). Further studies are necessary to define the adverse effect profile, dosing schedule, and efficacy of 2-CdA in patients with progressive pulmonary LCH.
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The management of pulmonary LCH patients should include careful screening for pulmonary hypertension. Significant pulmonary hypertension is increasingly being recognized in patients with pulmonary LCH (24). A subgroup of patients with pulmonary LCH appears to have a primary pulmonary vasculopathy that mimics primary pulmonary hypertension and may respond to vasodilator therapy (24,37). Once a diagnosis of pulmonary LCH is established, all patients should be screened for pulmonary hypertension with trans-thoracic echocardiography and measurement of right ventricular systolic pressure (RVSP) (37). It is reasonable to consider further evaluation with right heart catheterization and vasodilator trial, if the RVSP is greater than 45 mmHg by echocardiography. Patients should not be treated empirically with vasodilators, as there are reported cases of veno-occlusive disease in pulmonary LCH (38). Pneumothoraces occur in around 15% of patients and may be recurrent. In one study, the rate of recurrent pneumothorax was 58% to the ipsilateral side when the episode was managed conservatively by observation or chest tube without pleurodesis (25). Early surgical therapy with pleurodesis is therefore justified in managing spontaneous pneumothorax in LCH patients, although pleurectomy is generally avoided in patients for whom lung transplantation may be eventually considered. Lung transplantation should be considered for patients with progressive disease associated with severe respiratory impairment and limited life expectancy. Transplantation evaluation should be considered if there is evidence of rapidly declining lung function or if the patient is severely limited by symptoms that do not respond to smoking cessation and/or immunosuppressive therapy. It is imperative that patients stop smoking prior to lung transplantation. There are no disease-specific guidelines for the referral, but UNOS guidelines for progressively declining pulmonary function can be applied to evaluate patients. A recent meta-analysis by Dauriat showed similar 2-, 5-, and 10-year mortality in transplant recipients with pulmonary LCH and other pulmonary disease (39). The disease may recur after lung transplant with resumption of smoking.
X.
Clinical Outcomes and Prognosis
Definitive longitudinal information on patient outcomes is limited. The frequency of respiratory failure, pulmonary hypertension, and cor pulmonale related to pulmonary LCH is not currently known. Several retrospective studies suggest that most patients have a reasonably good overall prognosis with a median survival of 12.5 years following diagnosis (4). A variety of factors are associated with adverse clinical outcome including extremes of age, multisystem involvement, prolonged constitutional disturbance, markedly reduced diffusing capacity, low FEV1/FVC ratio, corticosteroid therapy at time of follow-up, and a high RV/TLC ratio (4,7). These clinical parameters may be helpful to identify patients at risk of poor outcomes. Adult pulmonary LCH patients may also have an
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increased risk toward developing malignant neoplasms (4). Several investigations report that lymphoma and bronchial carcinoma may occur in greater frequency than in the general population; however, the increased incidence of bronchial carcinoma may be a reflection of heavy smoking rather than a predisposition due to pulmonary LCH. References 1. Tazi A. Adult pulmonary Langerhans’ cell histiocytosis. Eur Respir J 2006; 27(6): 1272–1285. 2. Gaensler EA, Carrington CB. Open biopsy for chronic diffuse infiltrative lung disease: clinical, roentgenographic, and physiological correlations in 502 patients. Ann Thorac Surg 1980; 30(5):411–426. 3. Travis WD, Borok Z, Roum JH, et al. Pulmonary Langerhans’ cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol 1993; 17(10):971–986. 4. Vassallo R, Ryu JH, Schroeder DR, et al. Clinical outcomes of pulmonary Langerhans’-cell histiocytosis in adults. N Engl J Med 2002; 346(7):484–490. 5. Schonfeld N, Frank W, Wenig S, et al. Clinical and radiologic features, lung function and therapeutic results in pulmonary histiocytosis X. Respiration 1993; 60(1): 38–44. 6. Friedman PJ, Liebow AA, Sokoloff J. Eosinophilic granuloma of lung. Clinical aspects of primary histiocytosis in the adult. Medicine (Baltimore) 1981; 60(6): 385–396. 7. Delobbe A, Durieu J, Duhamel A, et al. Determinants of survival in pulmonary Langerhans’ cell granulomatosis (histiocytosis X). Groupe d’Etude en Pathologie Interstitielle de la Societe de Pathologie Thoracique du Nord. Eur Respir J 1996; 9(10):2002–2006. 8. Bernstrand C, Cederlund K, Ashtrom L, et al. Smoking preceded pulmonary involvement in adults with Langerhans’ cell histiocytosis diagnosed in childhood. Acta Paediatr 2000; 89(11):1389–1392. 9. Mogulkoc N, Veral A, Bishop PW, et al. Pulmonary Langerhans’ cell histiocytosis: radiologic resolution following smoking cessation. Chest 1999; 115(5):1452–1455. 10. Von Essen S, West W, Sitorius M, et al. Complete resolution of roentgenographic changes in a patient with pulmonary histiocytosis X. Chest 1990; 98(3):765–767. 11. Jaksits S, Kriehuber E, Charbonnier AS, et al. CD34þ cell-derived CD14þ precursor cells develop into Langerhans’ cells in a TGF-beta 1-dependent manner. J Immunol 1999; 163(9):4869–4877. 12. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392(6673):245–252. 13. Tazi A, Bonay M, Bergeron A, et al. Role of granulocyte-macrophage colony stimulating factor (GM-CSF) in the pathogenesis of adult pulmonary histiocytosis X. Thorax 1996; 51(6):611–614. 14. Casolaro MA, Bernaudin JF, Saltini C, et al. Accumulation of Langerhans’ cells on the epithelial surface of the lower respiratory tract in normal subjects in association with cigarette smoking. Am Rev Respir Dis 1988; 137(2):406–411.
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15. Churg A, Tai H, Coulthard T, et al. Cigarette smoke drives small airway remodeling by induction of growth factors in the airway wall. Am J Respir Crit Care Med 2006; 174(12):1327–1334. 16. Aguayo SM, King TE Jr., Waldron JA Jr., et al. Increased pulmonary neuroendocrine cells with bombesin-like immunoreactivity in adult patients with eosinophilic granuloma. J Clin Invest 1990; 86(3):838–844. 17. Tazi A, Bonay M, Grandsaigne M, et al. Surface phenotype of Langerhans’ cells and lymphocytes in granulomatous lesions from patients with pulmonary histiocytosis X. Am Rev Respir Dis 1993; 147(6 pt 1):1531–1536. 18. Willman CL, Busque L, Griffith BB, et al. Langerhans’-cell histiocytosis (histiocytosis X)–a clonal proliferative disease. N Engl J Med 1994; 331(3):154–160 (comments). 19. Yousem SA, Colby TV, Chen YY, et al. Pulmonary Langerhans’ cell histiocytosis: molecular analysis of clonality. Am J Surg Pathol 2001; 25(5):630–636. 20. Brabencova E, Tazi A, Lorenzato M, et al. Langerhans’ cells in Langerhans’ cell granulomatosis are not actively proliferating cells. Am J Pathol 1998; 152(5): 1143–1149. 21. Colby TV, Lombard C. Histiocytosis X in the lung. Hum Pathol 1983; 14(10): 847–856. 22. Tazi A, Moreau J, Bergeron A, et al. Evidence that Langerhans’ cells in adult pulmonary Langerhans’ cell histiocytosis are mature dendritic cells: importance of the cytokine microenvironment. J Immunol 1999; 163(6):3511–3515. 23. Vassallo R, Jensen EA, Colby TV, et al. The overlap between respiratory bronchiolitis and desquamative interstitial pneumonia in pulmonary Langerhans’ cell histiocytosis: high-resolution CT, histologic, and functional correlations. Chest 2003; 124(4):1199–1205. 24. Fartoukh M, Humbert M, Capron F, et al. Severe pulmonary hypertension in histiocytosis X. Am J Respir Crit Care Med 2000; 161(1):216–223. 25. Mendez JL, Nadrous HF, Vassallo R, et al. Pneumothorax in pulmonary Langerhans’ cell histiocytosis. Chest 2004; 125(3):1028–1032. 26. Crausman RS, Jennings CA, Tuder RM, et al. Pulmonary histiocytosis X: pulmonary function and exercise pathophysiology. Am J Respir Crit Care Med 1996; 153(1): 426–435. 27. Bonelli FS, Hartman TE, Swensen SJ, et al. Accuracy of high-resolution CT in diagnosing lung diseases. AJR Am J Roentgenol 1998; 170(6):1507–1512. 28. Hidalgo A, Franquet T, Gimenez A, et al. Smoking-related interstitial lung diseases: radiologic-pathologic correlation. Eur Radiol 2006; 16(11):2463–2470. 29. Moore AD, Godwin JD, Muller NL, et al. Pulmonary histiocytosis X: comparison of radiographic and CT findings. Radiology 1989; 172(1):249–254. 30. Brauner MW, Grenier P, Tijani K, et al. Pulmonary Langerhans’ cell histiocytosis: evolution of lesions on CT scans. Radiology 1997; 204(2):497–502 (comments). 31. Chollet S, Soler P, Dournovo P, et al. Diagnosis of pulmonary histiocytosis X by immunodetection of Langerhans’ cells in bronchoalveolar lavage fluid. Am J Pathol 1984; 115(2):225–232. 32. Auerswald U, Barth J, Magnussen H. Value of CD-1-positive cells in bronchoalveolar lavage fluid for the diagnosis of pulmonary histiocytosis X. Lung 1991; 169(6):305–309.
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33. Housini I, Tomashefski JF, Jr., Cohen A, et al. Transbronchial biopsy in patients with pulmonary eosinophilic granuloma. Comparison with findings on open lung biopsy. Arch Pathol Lab Med 1994; 118(5):523–530. 34. Saven A, Foon KA, Piro LD. 2-Chlorodeoxyadenosine-induced complete remissions in Langerhans’-cell histiocytosis. Ann Intern Med 1994; 121(6):430–432. 35. Pardanani A, Phyliky RL, Li CY, et al. 2-Chlorodeoxyadenosine therapy for disseminated Langerhans’ cell histiocytosis. Mayo Clin Proc 2003; 78(3):301–306. 36. Goh NS, McDonald CE, MacGregor DP, et al. Successful treatment of Langerhans’ cell histiocytosis with 2-chlorodeoxyadenosine. Respirology 2003; 8(1):91–94. 37. Chaowalit N, Pellikka PA, Decker PA, et al. Echocardiographic and clinical characteristics of pulmonary hypertension complicating pulmonary Langerhans’ cell histiocytosis. Mayo Clin Proc 2004; 79(10):1269–1275. 38. Hamada K, Teramoto S, Narita N, et al. Pulmonary veno-occlusive disease in pulmonary Langerhans’ cell granulomatosis. Eur Respir J 2000; 15(2):421–423. 39. Dauriat G, Mal H, Thabut G, et al. Lung transplantation for pulmonary Langerhans’ cell histiocytosis: a multicenter analysis. Transplantation 2006; 81(5):746–750.
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32 Lymphangioleiomyomatosis
FRANCIS X. McCORMACK Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio, U.S.A.
I.
Introduction
Pulmonary lymphangioleiomyomatosis (or lymphangiomyomatosis) (LAM) is a rare disease of women, which is characterized by smooth muscle cell infiltration and cystic destruction of the lung and abdominal tumors including angiomyolipomas (AMLs) and lymphangiomyomas (1–3). LAM typically results in progressive dyspnea on exertion and recurrent pneumothoraces and is also occasionally associated with chylous fluid collections in the chest and/or abdomen. LAM was first described at autopsy in 1919, in a patient with tuberous sclerosis complex (TSC), a genetic disorder of highly variable penetrance associated with seizures, brain tumors, and cognitive impairment (4). For most of the 20th century, LAM was thought to affect only a few percent of patients with TSC. However, recent screening studies of women with TSC have revealed that about 30% to 40% have cystic changes in the lung consistent with LAM (5–7), placing the predicted number of patients with TSC-associated LAM (TSC-LAM) at about 200,000 worldwide. In 1937, in Germany, LAM was reported in a woman who did not have TSC (8); a form of LAM that is now termed ‘‘sporadic LAM’’ or ‘‘S-LAM.’’ The prevalence of S-LAM is difficult to determine, but registry data from various 747
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countries suggest a minimum prevalence of about one to three cases per million (9,10), or about 20,000 patients worldwide. For reasons that are not clear, S-LAM patients outnumber TSC-LAM patients in the LAM Foundation Registry, The National Heart, Lung and Blood Institute (NHLBI) Registry (11), and most pulmonary clinics by a factor of 7 to 10 to 1, despite the 10-fold lower prevalence of S-LAM. LAM has no clear ethnic or geographical predilection. It occurs predominantly in women between menarche and menopause, but it has been reported in prepubescent girls (12) and female octogenarians (13). Radiographic evidence of cystic lung disease has occasionally been described in men with TSC (14), but biopsy-documented LAM has only been reported in four men, three with TSC-LAM (15,16) and one with S-LAM (17). II.
Discovery in LAM
Ten years ago, despite powerful clues from nature including remarkable female gender restriction and a clear association with TSC, nearly nothing was known about the etiology of LAM. In 2008, more is known about the molecular pathogenesis of LAM than for any other interstitial lung disease. The first prospective clinical trial based on well-defined molecular targets has just been published (18). This remarkable progress is attributable to the monogenic nature of the disease, to synergy with the fast moving Drosophila and TSC research communities, and to well-organized and effective patient advocacy. The major discoveries are briefly outlined below, but the reader is referred to recent reviews for a more complete discussion of basic scientific advances in LAM (19,20). A.
The Role of TSC Proteins in the Regulation of Cellular Homeostasis
The genes associated with TSC were discovered in 1993 (TSC2) (21) and 1997 (TSC1) (22). The proteins they encode, hamartin (TSC1) and tuberin (TSC2), did not have many informative homologies to known proteins, and initially there were few clues about their functions. Serendipitously, an investigator searching for genes involved in the regulation of cell growth by random deletion mutagenesis of the Drosophila genome found that disruption of the homolog for tuberin produced an enlarged eye cell phenotype in flies (23). Additional epistatic experiments in Drosophila demonstrated that tuberin was downstream of the signaling protein, Akt (also known as PKB) and upstream of a protein called mTOR (mammalian target of rapamycin), which regulates protein translation (24,25) (Fig. 1). There has been an explosion of interest in the Akt/mTOR pathway because of its central importance in cellular homeostasis and the pathogenesis of common diseases and conditions including diabetes, obesity, and cancer (26). Subsequent experiments from TSC laboratories demonstrated that tuberin and hamartin form a complex, which regulates the transmission of growth signals
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Figure 1 Tuberous sclerosis proteins TSC1 and TSC2 regulate signaling through the Akt pathway. The binding of a ligand to a cell surface growth factor receptor activates PI3K, followed by Akt. Akt phosphorylates TSC2, which blocks its ability to maintain Rheb GTP–depleted state. Activated Rheb GTP phosphorylates mTOR, which in turn activates downstream targets S6K and 4EBP1. Phosphorylated S6 and liberated eIF4E activate the cellular translational machinery. Sirolimus (rapamycin) can block mTOR activation.
by blocking the activation of mTOR, through an intermediate signaling protein called Rheb (27). Mutations that cause deficiency or dysfunction of either member of the tuberin/hamartin complex result in loss of regulation of Akttransmitted signals arriving from upstream cell surface tyrosine kinase and G-protein-coupled receptors and constitutive activation of mTOR. The resultant hyperphosphorylation of the mTOR-regulated proteins that control protein translation, S6 and 4EBP1, causes an inappropriate increases in cell size, proliferation, and migration. Phospho-S6 also feeds back to the most proximal elements of the signaling pathway (such as IRS1) to inhibit the transmission of further growth stimuli, which may explain the rarity of malignant transformation of LAM (28). One possible role for estrogen in the pathogenesis of LAM is that
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it can signal through Akt, relieve the feedback inhibitory loop, and facilitate unregulated growth (29,30). B.
S-LAM Is Due to Acquired Mutations in Both Parental Copies of TSC2
Initially, there was no obvious link between S-LAM and TSC. Many pulmonary physicians were skeptical that a nonheritable disease such as S-LAM could have a genetic basis. In 1998, however, Smolarek and Henske reported genetic deletions (loss of heterozygosity or LOH) in the genes for tuberous sclerosis in the AMLs and lymph nodes of patients with S-LAM (31). Henske et al. subsequently reported that the lung lesions and kidney lesions of five patients with S-LAM harbored mutations in both parental copies of the TSC2 gene (32). These data were consistent with a tumor-suppressor model for LAM, in which two genetic hits that inactivate both copies of a gene responsible for the control of cell growth result in tumor formation. Henske found no evidence of TSC mutations in the blood, the normal kidney, or the normal lung of patients with S-LAM, which indicated that there were no TSC mutations in the germ line (32–35). A low level of mosaicism, in which only rare cells contain mutations and detection is difficult, could not be completely excluded. Collectively, the data suggested that S-LAM is caused by somatic (i.e., nongerm cell) mutations in TSC genes, which occur post conception. In essence, S-LAM is tuberous sclerosis in two organs, the kidney and lung, due to dual random mutational events that inactivate both parental copies of one (either TSC1 or TSC2, but not both) of the tuberous sclerosis genes. S-LAM has been only associated with TSC2 mutations to date, but it is likely that S-LAM due to TSC1 mutations also occurs. C.
LAM Metastasizes to the Lung
There are many other examples of involvement of tumor suppressor genes in the formation of sporadic neoplasms that are similar to the mechanism described above for S-LAM, such as the identification of neurofibromatosis gene (NF2) mutations in Schwannoma’s of patients who do not have neurofibromatosis (36). The mystery in LAM was the relationship between the lesions in the lung, the kidney, and the lymphatics. One of the surprises in the genetic analysis of LAM patients was that the TSC2 mutations were identical in the kidney and lung of each individual, suggesting that the cells in the LAM lesions in different organs were derived from a common precursor (32). This could be consistent with metastasis from a primary kidney tumor (AML) to the lung, or from the LAM lung lesion to the kidney, or to both sites from another visceral organ or the bone marrow (37). Alternatively, the lung and the kidney could have been seeded with cells that harbored mutations and then were disseminated during development, as occurs during implantation of neural crest cells in multiple tissues (38). The recurrence of LAM in the grafts of patients with LAM who had undergone lung transplant, proven by genetic techniques to have derived from the cells of the
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recipient (39), supports the metastatic theory (39–42). The source of LAM cells that populate the lung remains unclear; speculation beyond the AML has included pericytes, cells of neural crest origin, the uterus, and the bone marrow. D.
LAM Cells Spread Through Lymphatics by Induction of Lymphangiogenesis
Recent data from Japan suggest that the most likely mechanism of spread of LAM is through the lymphatics (43–45). Approximately 30% of LAM patients have axial abdominal or thoracic lymphadenopathy (46). In some cases, LAM is restricted to the abdomen or pelvis and is associated with normal lung structure on HRCT or only a very few lung cysts, consistent with regional spread from a subdiaphragmatic source (47). Multiple case reports of LAM in the uterus with regional lymph node involvement have been described (48). Kumasaka et al. found that LAM cells form clusters enveloped by lymphatic endothelial cells and bud from lymphatic vessel walls into the lumen (49). They migrate upstream and infiltrate axial and supraclavicular lymph nodes. LAM cells clusters are also found in chylous effusions in patients with LAM (45). Induction of lymphangiogenesis appears to play an important role in this process on the basis of abundant expression of lymphatic endothelial markers such as podoplanin (D2-40), vascular endothelial cell growth factor receptor-3 (VEGFR-3), and VEGF-C (49). Two separate laboratories have recently reported that VEGF-D is elevated over three- to eightfold in the serum of patients with LAM (50,51). Cells containing LOH for TSC genes have been isolated from the blood of LAM patients (52), suggesting that the spread through the systemic circulation is also possible. The mechanisms of matrix remodeling that are required for migration, implantation, and cyst formation in LAM are not clear, but metalloproteinase imbalance involving overexpression of MMP-2 and MMP-9 and low levels of TIMP-3 has been described in LAM lesions (53–55). E.
LAM as Benign Metastasizing Cancer
The National Cancer Institute defines cancer as a disease in which abnormal cells divide without control, invade nearby tissues, and spread to other parts of the body through the blood and lymph systems. The data outlined above is generally consistent with this definition; LAM is caused by mutations in tuberous sclerosis genes, is associated with loss of growth control through constitutive activation of mTOR, spreads regionally, and metastasizes to lung and lymph nodes (37). The features of LAM which are atypical for metastatic cancers that involve the lung, are the slow rate of progression, the diffuse rather than macronodular and basilar radiological presentation, the remarkable gender restriction, predilection for a single organ, the lack of a known source, and the benign histological appearance of the cells. Other examples of benign metastasizing disorders include benign metastasizing leiomyoma (which can cavitate) (56), leiomyomatosis peritonealis
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disseminata (57,58), and pulmonary meningotheliomatosis (59). Although not a complete fit as a classification of LAM, approaching LAM as ‘‘cancer’’ provides a conceptual framework for trials targeting each stage of pathogenesis; somatic mutation, proliferation, migration/dissemination, implantation/infiltration, and cystic destruction.
III. A.
Clinical Features Presentation, Diagnosis, and Differential Diagnosis
The average age at diagnosis of LAM is approximately 35 years, usually three to five years after symptoms first develop (9,10,60–62). Most patients present with exertional dyspnea and first receive an erroneous diagnosis of asthma or chronic obstructive pulmonary disease (COPD), on the basis of evidence of airflow obstruction on pulmonary function tests and an unremarkable (from the standpoint of cystic change) or uninformative chest radiograph. It is often recurrent pneumothorax and screening by high-resolution computed tomography (HRCT) scanning after an average of 2.2 pneumothoraces per patient that leads to consideration of LAM (63). Workup of chylous fluid collections or abdominal or retroperitoneal masses suspected to be lymphoma or ovarian cancer can lead to the diagnosis of LAM (64). Finally, screening of asymptomatic women with TSC, as recommended by the Tuberous Sclerosis Alliance (65), reveals LAM in approximately 30% to 40% of cases. Biopsy-documented LAM has been reported in only four men; three with definite or probable TSC (15,16,66) and one without TSC (17). The diagnosis of pulmonary LAM is typically on the basis of a HRCT demonstrating thin-walled cystic change and one of the following; (i) a positive tissue biopsy of lung, kidney, lymphangiomyoma, or lymph node (including immunohistochemical reactivity with HMB-45); (ii) chylothorax, optimally complemented by the finding of HMB-45-positive LAM cell clusters on cytological evaluation of the fluid (67); (iii) tuberous sclerosis complex; and (iv) pathologically or radiographically confirmed AML. The diagnosis can occasionally be made by transbronchial biopsy (68), but there is no good data about rates of success, and the yield from this technique is generally thought to be low (69). The two diseases that are most commonly considered in the differential diagnosis of patients with cystic lung disease who smoke or have smoked are pulmonary Langerhan’s cell histiocytosis (PLCH) (70) and emphysema. Diffuse nodular changes are often present in PLCH, but can also occur in TSC and TSC-LAM, where they represent micronodular pneumocyte hyperplasia (71). Compared to LAM cysts, the cysts of PLCH are thicker walled, more bizarrely shaped, and generally spare the bases, while the cysts of emphysema have indiscernible walls and are most frequently upper lobe predominant (72). LAM cysts are devoid of internal structure; the finding of internal septae or blood vessels is a useful clue that points toward emphysema or bronchopulmonary dysplasia. The HRCT alone
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is not sufficient for a definite diagnosis; blinded expert radiologists correctly identify LAM less than 80% of the time (72). Diseases that can mimic LAM and should also be considered include amyloidosis, light chain deposition disease (73), bronchopulmonary dysplasia, metastatic endometrial stromal cell sarcoma and low grade leiomyosarcomas (74), and follicular bronchiolitis and lymphocytic interstitial pneumonitis (75), both in the presence and absence of Sjogren’s syndrome (76). Birt-Hogg-Dube (BHD) syndrome is a rare tumor-suppressor syndrome caused by mutations in the folliculin gene, which is associated with familial spontaneous pneumothorax, skin lesions, pulmonary cysts, and inherited renal cell cancer (77,78). It appears that BHD syndrome is also associated with aberrant signaling through the Akt pathway, but the loss of regulation occurs upstream of mTOR (79). Interestingly, sporadic mutations in folliculin have been associated with pulmonary cysts and spontaneous pneumothorax (80). Lymphangiomatosis is a like-sounding illness that is commonly confused with LAM, because it can produce chylous pleural effusions, chylous ascites, and smooth muscle–rich (HMB-45-negative) lymphangiomyomas (81,82). Although lymphangiomatosis can produce scarring along bronchovascular bundles and in the lung parenchyma, it does not cause lungs cysts or pneumothorax, and the lesions do not stain with HMB-45. Serum VEGF-D is elevated in LAM but not in emphysema, PLCH, or lymphangiomatosis and may prove to be a useful diagnostic tool for LAM (51). B.
Natural History
There is significant variability in the rate of progression in LAM. Ten years following the onset of symptoms, approximately 55% of patients with LAM have developed Medical Research Council (MRC) grade 3 dyspnea (shortness of breath walking on flat ground), 23% require supplemental oxygen, and 10% are housebound (83). Lung function declines at about three times the normal rate in patients with LAM. In a series of 275 patients with LAM followed at the National Institutes of Health for an average of four years, the mean rates of decline in forced expiratory volume in one second (FEV1) and diffusing capacity for carbon monoxide (DLco) were 75 9 mL/yr and 0.69 mL/min/mmHg/yr, respectively (84). Retrospective studies from Europe suggested higher rates of decline in FEV1 of 118 142 mL/yr (85) and 106 143 mL/yr, respectively (86). In the Japanese population, lung function declined more rapidly in patients who presented with shortness of breath than in patients who were ascertained through a sentinel pneumothorax (87). Previous estimates of 10-year survival in LAM on the basis of series of women with advanced disease ranged from 40% to 80% (9,60,61). More recent data suggest that 10-year survival from onset of symptoms is about 90% (10,83) and from the time of biopsy is 70%, but there is a wide variation on the basis of histological severity (88) and mode of presentation. Japanese patients who present
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Figure 2 (See color insert.) Expanded alveolar septa due to smooth muscle infiltration in a patient with LAM.
with pneumothorax as their sentinel event have 5-, 10-, and 15-year survivals of 95%, 89%, and 89%, respectively, while patients who present with shortness of breath have 5-, 10-, and 15-year survivals of 85%, 60%, and 47%, respectively (87). Cases of LAM in octogenarians (13) and of over 30 years in duration (89) have also been documented. C.
Pathology
Grossly, LAM lungs are enlarged and diffusely cystic. Microscopic examination of LAM lesions reveals nodular collections of spindle-shaped and epithelioid cells along cyst walls, blood vessels, lymphatics, and bronchioles, which react with antibodies for smooth muscle actin, vimentin, and desmin, suggesting a smooth muscle lineage (Fig. 2). The epithelioid cells also react with HMB-45, an antibody that recognizes a protein member of the melanogenesis pathway (90). Receptors for estrogen and progesterone are variably present in LAM cells (91). The histological and immunophenotypic patterns described above are characteristic of a larger pathological family of perivascular epithelioid cell (PEC) tumors or PEComas, which in addition to LAM also include AMLs, clear cell carcinomas, and some rare malignancies of the gastrointestinal (GI) tract and uterus (92). PEComas are most common in women and in patients with tuberous sclerosis and can be associated with malignant transformation and pulmonary metastasis (93–96). D.
Physiology
Evidence of airflow obstruction is present in approximately 70% of patients with LAM (11,97). The earliest changes found are an increase in residual volume and a
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reduction in DLco. With disease progression, hyperinflation and progressive airflow limitation occur. Restrictive or combined restrictive and obstructive abnormalities are present in about 15% to 20% of patients. Approximately 20% of patients with LAM have reversible airflow obstruction, which responds to bronchodilators. Exercise-induced hypoxemia out of proportion to reduction in DLco and FEV1 is not uncommon in LAM (84,98). Resting pulmonary hypertension appears to be unusual in LAM, but elevations with exercise frequently occur and may contribute to dyspnea (98,99). E.
Radiology
The chest radiograph in LAM is often normal early in the disease. Pleural effusions may be apparent in patients with lymphatic involvement. Diffuse bilateral and symmetrical reticulonodular infiltrates, cysts, bullae, or a honeycomb appearance may evolve over time but are virtually never specific enough to suggest LAM in the absence of other data. The HRCT scan of the chest is much more sensitive than the chest radiograph in detecting cystic change and can be markedly abnormal even in asymptomatic patients and those with normal pulmonary physiology (100). The CT shows diffuse, thin-walled cysts of numbers ranging from a few scattered cysts to near complete replacement of the lung and in varying sizes ranging from a few millimeters to many centimeters (Fig. 3) (101,102). Ground glass densities, nodular densities, hilar or mediastinal adenopathy, pleural effusion, and dilated thoracic ducts are additional features identified on CT. A dedicated CT scan or MRI of the abdomen should be obtained in all patients with LAM (46,103–105). Renal AMLs are present in most (~80%) patients with TSC-LAM and 25% to 50% of patients with S-LAM (106). Fat
Figure 3 Diffuse cystic changes on a high-resolution computed tomography scan of a patient with LAM.
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Figure 4 Retroperitoneal adenopathy and cystic lymphangiomyomas on an abdominal CT scan of a patient with LAM.
density within renal tumors is pathognomonic for LAM. AMLs may also be found in spleen, liver, and lymph nodes. Cystic lymphangiomyomas, retroperitoneal adenopathy, and ascites are other common findings (Fig. 4). A CT or MRI should be offered to S-LAM patients at least once in a lifetime to rule out subclinical TSC, which may have greater implications for family members than for the patient. IV. A.
Special Issues Pleural Manifestations
Pneumothoraces occur in approximately 60% to 70% of patients with LAM at some point in their disease course (10,107). The recurrence rate following conservative therapy such as aspiration or chest tube drainage is about 66%, and the average number of subsequent pneumothoraces for those who have had a sentinel pneumothorax is 2.5 (63). The failure rate of chemical or surgical pleurodesis are 27% and 32%, respectively, higher than for any other cystic lung disease (70). The reason for the poor response to pleural fusion in LAM is unclear, but it is possible that the cysts on the surface of the LAM lung or the infiltration of the pleura with LAM cells prevent apposition and fusion of the visceral and parietal pleura. Despite the partial response, the LAM Foundation Pleural Disease Consensus Group recommends that pneumothorax should be treated with ipsilateral pleurodesis on the first event (63). Patients who were surveyed did not always agree with this aggressive approach, however (108). Mechanical abrasion is preferred over talc or pleurectomy in patients who may be candidates for lung transplantation, since these interventions ablate tissue planes and are associated
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with higher rates of perioperative bleeding. Chylous pleural effusions occur in about one-third of LAM patients and may be unilateral or bilateral (109). Chylous fluid can also collect in the peritoneum (chylous ascites) or the pericardium (chylopericardium) and can appear in the sputum (chyloptysis), the urine (chyluria), or in vaginal discharge. Pleurodesis is generally an effective approach for chylothorax, but less invasive treatments are often attempted first, such as observation, low fat, medium chain triglyceride—enriched diets, repeated thoracentesis, and shunts. Octreotide is a somatastatin analogue (110,111) which reduces splanchnic blood flow and is currently being tested in a clinical trial in patients with chylous effusions (www.clinicaltrials.gov; NCT00005906). B.
Renal Manifestations
Renal AMLs are benign tumors composed of dysplastic blood vessels, smooth muscle, and variable amounts of fat (46,112) which occur in about 93% of patients with TSC-LAM and 30% to 50% of patients with S-LAM. AMLs most commonly occur in the kidney but have also been reported in the liver, spleen, lung, lymph nodes, and skin. The AMLs in patients with S-LAM are usually unilateral, small, solitary, and restricted to the kidney, while in TSC-LAM they are more often large, bilateral, multiple, and multiorgan (involving the spleen or liver) (46). AMLs are usually clinically silent, however, flank pain, hydronephrosis, hematuria, life-threatening hemorrhage, and loss of renal function can all occur. The risk of renal hemorrhage from AMLs is positively associated with size and with profusion of aneurysms (113) and can be increased by the use of birth control pills and pregnancy. Lesion approaching 4 cm in size should be followed with periodic ultrasonography or CT scanning, and intervention should be considered when the tumor exceeds this threshold. Selective, nephron-sparing techniques, such as embolization, enucleation, radioablation, electrocautery, or partial nephrectomy rather than total nephrectomy, are recommended. Unfortunately, many TSC and LAM patients have unnecessary nephrectomies for AMLs, because clinicians are often unfamiliar with the diagnostic implications of radiographically identified fat density within a renal tumor. Atypical AMLs with malignant potential and frank renal cell carcinomas can occur in TSC and LAM, but are uncommon (114). Polycystic kidney disease due to large gene deletions, which include both the TSC2 gene and the adjacent PKD1 gene can also occur in TSC-LAM patients (115). C.
Comparison of TSC-LAM and S-LAM
TSC-LAM can be discovered by screening TSC patients with HRCT, while S-LAM almost always comes to attention in patients undergoing clinical evaluation for a medical problem. It is not surprising, therefore, that LAM manifestations in published TSC-LAM series (5,116) are generally milder than in studies with S-LAM. Alternatively, TSC-LAM may be an inherently milder condition. Patients with TSC-LAM have a lower frequency of abdominal
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lymphangioleiomyomas (9% vs. 29%), thoracic duct dilation (0% vs. 4%), pleural effusion (6% vs. 12%), and ascites (6% vs. 10%) than patients with S-LAM (46). Patients with TSC-LAM had a higher frequency of noncalcified pulmonary nodules consistent with multifocal, micronodular, pneumocyte hyperplasia, hepatic and renal AMLs, and prior nephrectomy (46). D.
Lifestyle Issues
1.
Air Travel
Pollock-Bar Ziv et al. found that 35% of LAM patients are advised by medical caregivers to avoid air travel, because of the theoretical risk of lung cyst rupture associated with atmospheric pressure changes during flight (117). In responses from 276 patients who answered a questionnaire, there were eight cases of radiographically documented pneumothorax in 454 flights. In five cases, however, symptoms that were consistent with pneumothorax may have been present prior to boarding. Other symptoms also occurred, including anxiety (22%), chest pain (12%), shortness of breath (14%), cyanosis (2%), and hemoptysis (0.4%) in 10% to 20% of flights. The conclusion from the study was that although adverse events occurred during flight in patients with LAM, air travel is well tolerated by most LAM patients. 2.
Pregnancy
Pregnancy has been associated with pneumothorax and persistent bronchopleural fistulas in patients with LAM. Of 318 patients who indicated on their LAM Foundation intake forms that they had had at least one pregnancy, 163 patients responded to a second inquiry regarding pneumothorax (118). A total of 38 patients reported that they had a pneumothorax during pregnancy, consistent with a minimum incidence of approximately 10% (38 of 318). In one-third of patients, the pneumothorax during pregnancy led to the diagnosis of LAM. Pneumothoraces occurred almost twice as frequently on the right as on the left lung and four women presented with bilateral spontaneous pneumothorax. Most pneumothoraces occurred during the second and third trimesters. This study and others (9,10) suggest that pregnancy is associated with pleural complications in patients with LAM. Unfortunately, the more pressing question of whether pregnancy accelerates the decline in lung function in LAM may never be fully addressed, since so few women with LAM choose to become pregnant, and patients who are diagnosed with LAM during pregnancy rarely have baseline pulmonary function tests available. V.
Treatment
A.
Pharmacological and Surgical Therapies
The remarkable gender restriction in LAM, though unexplained, has provided the rationale for the empiric antiestrogen strategies that have dominated the approach
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to the disease for the last several decades. The results have been almost uniformly disappointing, and because proper trials with hormonal therapies have never been conducted, there remain no proven therapies for LAM based on antagonism of estrogen action. Bilateral oophorectomy has not been demonstrated to slow the rate of decline in lung function in LAM and is much less frequently recommended than in the past (119). Enthusiasm for the use of progesterone, which became the standard of care following a positive outcome published in a case report in 1987 (120), has likewise waned over time. In a retrospective study of 275 patients, Taveira-DaSilva et al. found that progesterone treatment failed to slow the decline in FEV1 (121). In fact, in that study, intramuscular (IM) or oral (PO) progesterone therapy was associated with an acceleration in the rate of decline in diffusing capacity compared to untreated patients. The rate of decline in FEV1 and DLco was also no different in 10 patients treated with the GnRh agonist, triptorelin for three years compared to a well-characterized cohort of historical controls (122). Other case series of gonadotropin-releasing hormone (GnRh) agonist treatment yielded conflicting results (123–125). A trial of sirolimus in 20 patients with AMLs and either TSC or LAM was recently completed (18). Patients were treated for one year with escalating doses of sirolimus, and AML volume was measured on treatment and for a year after the drug was discontinued. Lung function tests, volumetric chest CT, and six minute walk testing were also conducted in the 11 TSC-LAM and S-LAM patients who were enrolled over this interval. The AML burden was reduced by approximately 50% on therapy, but returned to near baseline levels within a year of drug withdrawal. FEV1 and forced vital capacity (FVC) increased by 118 330 cc and 390 570 cc on treatment, and remained 62 411 cc and 346 412 cc above baseline, respectively, one year post withdrawal. Residual volume was reduced by an average of 439 493 cc on therapy and remained 333 570 cc below baseline at the end of the year off drug. There was a trend toward reduction in the percent of the thoracic volume that was cystic on the basis of volumetric CT measurements, but statistical significance was not reached. Total lung capacity, six minute walk distance, and DLco did not change. There were six serious adverse events on the drug, including hospitalizations for respiratory infections, cellulitis, stomatitis, palpitations, diarrhea, and pyelonephritis. The interim analysis from a parallel trial in England revealed similar effects of sirolimus on AML volume, but there were too few patients with lung function data to reach a conclusion about pulmonary effects of the drug (126). B.
Lung Transplantation
A recent study reported that one-third of the 243 patients that were enrolled in the NHLBI LAM Registry from 1998 to 2001 have either been transplanted or were being considered for transplant. In the period from October 1987 to December 2002, 79 women with LAM underwent lung transplant for LAM, representing 0.008% of all patients who received lung transplants during that period (127). The average age at transplant was 41.1 years. Bilateral grafts were
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placed in 57% patients over this period, and were performed in nearly 75% of patients in the interval from 1998–2002. There were two intraoperative deaths and 20 late deaths. The actuarial Kaplan Meier survival for LAM patients transplanted in the United States was 85.75% at one year, 76.35% at three years, and 64.95% at five years, which is equal to or better than the rate for other lung disease groups who had transplantation during the same period. There was a trend toward better survival in patients who had received bilateral lung transplants, but statistical significance was not achieved. Recurrence of LAM has been reported in the donor allograft in three patients who died of infectious complications at 2, 22, and 30 months posttransplant (39–42). The recurrence did not seem to contribute to death in these patients, and there have been no reports of retransplant for LAM recurrence. Therefore, at this time, recurrence should not be a consideration in transplant candidacy decisions for LAM patients. Some patients with LAM develop disabling dyspnea on exertion, hypoxemia, and reduced DLco in the absence of marked airflow obstruction; this ‘‘vascular presentation’’ of LAM may require transplantation evaluation before FEV1 reaches the typical threshold of 30% of predicted. The average FEV1 at transplant for LAM in the 126 patients who have been transplanted to date is 36%; considerably higher than for other obstructive lung diseases such as smokingrelated emphysema (24.3%) or a-1 antitrypsin deficiency (22.3%). Prior pleurectomy or talc pleurodesis can create difficulties with tissue plane dissection and bleeding during removal of the native lung. In the Almoosa study, 45 of 80 transplanted patients had a prior pleural fusion procedure (63) and 14 reported pleura-related postoperative bleeding, all but one of whom had a prior pleurodesis. However, these perioperative complications are generally manageable, and most centers do not consider even bilateral prior pleurodesis to be a contraindication to lung transplantation. As of February 2004, 130 women with LAM were awaiting lung transplant.
VI.
Future Directions
LAM and TSC research have identified a wealth of potential molecular targets and experimental therapies that may be appropriate for testing in clinical trials. These include mTOR inhibitors (e.g., sirolimus, everolimus), Rheb inhibitors (e.g., farnesyltransferase inhibitors and statins), selective estrogen antagonists (e.g., fispemifene), tyrosine kinase inhibitors (e.g., imatinib mesylate), metalloproteinase inhibitors (e.g., doxycycline), angiogenesis inhibitors (e.g., bevacizumab), and lymphangiogenesis inhibitors (e.g., anti-VEGF-D antibody). At the time of this writing, the open interventional trials for LAM patients that include lung function endpoints are the double blind, placebocontrolled Multicenter International LAM Efficacy of Sirolimus (MILES) trial (NCT 00414648) and the open label trials of mTOR inhibitors for AMLs in patients with LAM and TSC in the United Kingdom (NCT 00490789), Boston
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125. Schiavina M, Contini P, Fabiani A, et al. Efficacy of hormonal manipulation in lymphangioleiomyomatosis. A 20-year-experience in 36 patients. Sarcoidosis Vasc Diffuse Lung Dis 2007; 24(1):39–50. 126. Davies DM, Johnson SR, Tattersfield AE, et al. Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N Engl J Med 2008; 358(2): 200–203. 127. Kpodonu J, Massad MG, Chaer RA, et al. The US experience with lung transplantation for pulmonary lymphangioleiomyomatosis. J Heart Lung Transplant 2005; 24(9):1247–1253.
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33 Pulmonary Alveolar Proteinosis
TISHA WANG and S. SAMUEL WEIGT David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
MICHAEL C. FISHBEIN Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
JOSEPH P. LYNCH, III Department of Medicine, Division of Pulmonary and Critical Care Medicine, Clinical Immunology and Allergy, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
I.
Introduction
Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by the accumulation of surfactant-like material in the alveolar spaces, with resultant impairment in gas exchange (1–8). Since the sentinel description of PAP by Rosen and colleagues in 1958 (9), fewer than 500 cases have been reported in the literature (5). The clinical syndrome of PAP is likely a heterogeneous group of disorders with several discrete biochemical defects (1,5). In murine models, local deficiency of granulocyte/macrophage colony–stimulating factor (GM-CSF) has been implicated (either by GM-CSF gene deletion or deletion of the b-subunit of GM-CSF/IL-3/IL-5 receptor) (10,11). In humans, three major forms of PAP exist: (i) congenital forms (2% of total cases), (ii) secondary forms (<10% cases, principally in patients with hematological malignancies), (iii) idiopathic acquired form in adults (90% cases) (1). Congenital forms are caused by mutations in the genes encoding surfactant protein B or C or the b chain of the receptor for GMCSF (5,12–15). These inherited disorders typically lead to severe respiratory failure in infants soon after birth (11). Secondary forms due to defects in alveolar 769
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macrophage (AM) function or numbers may occur (1,11). These secondary conditions include hematological malignancies (16,17), toxic exposures (18), or pulmonary infections (1,19). Since > 90% of PAP cases are idiopathic (or primary) (1–3,5,11), this chapter focuses on idiopathic PAP (iPAP). As will be discussed in detail later, iPAP is caused by antibodies to GMCSF (1–5). Over the past decade, the discovery of anti-GM-CSF antibodies in bronchoalveolar lavage fluid (BALF) and serum of patients with PAP provided a key insight into the pathogenesis of this rare disease (20–26). GM-CSF is crucial for the differentiation of AMs, which in turn, are necessary for the clearance of surfactant from the alveolar spaces (11). II.
Epidemiology
Estimated incidence of iPAP ranges between 0.2 and 0.37 per 1,000,000 patients per year with a prevalence of 3.7 per 1,000,000 patients per year (1,5,6,27–29). A comprehensive review of the literature up to 2002 identified 410 cases of PAP in 241 publications (11). In that review, the median age at diagnosis of PAP was 39 years for males and 35 years for females. There was a male predominance of 2.7:1; 72% of patients with PAP were smokers. PAP has been reported in North America, Europe, Asia, and Australia (11), and a true racial predilection is unknown. III.
Clinical Features
Progressive dyspnea of insidious onset and nonproductive cough are the most common presenting symptoms (1,4,11) (Table 1). Symptoms typically progress over weeks to months, but up to 20% of patients are asymptomatic (2,4,5). Table 1 Salient Features of Pulmonary Alveolar Proteinosis (PAP) Accumulation of surfactant-like material in alveolar spaces Insidious onset of dyspnea and cough Hypoxemia and intrapulmonary shunting Elevated serum lactate dehydrogenase (LDH) and surfactant proteins (SP-A and SP-D) Neutralizing autoantibodies to granulocyte/macrophage colony–stimulating factor (GM-CSF) Histology: granular acidophilic material on hematoxylin and eosin stains; stains bright pink with periodic acid–Schiff (PAS) and negative with alcian blue Bronchoalveolar lavage fluid (BALF): thick, viscid, opaque, milky; sediments on standing High-resolution computed tomography (HRCT) chest scan: ‘‘crazy paving’’ pattern; ground-glass opacities (GGO) Disease may progress to respiratory failure Heightened susceptibility to opportunistic infections Treatment: whole lung lavage (WLL) current standard. Subcutaneous or aerosolized GM-CSF promising
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Hemoptysis has been noted in 3% to 24% of patients (2,4,5). Constitutional symptoms (e.g., low grade fevers, fatigue, and weight loss) may occur, but extrapulmonary involvement is lacking (1,4,5,11). The clinical presentation is often nonspecific and thus, the diagnosis is frequently missed (30); median duration of symptoms prior to diagnosis was seven months in a large retrospective review (11). Physical examination reveals inspiratory crackles in 50%, cyanosis in 20%, and digital clubbing in 29% to 40% (1,2,4).
IV.
Pulmonary Function Tests
Hypoxemia, due to intrapulmonary shunting, is the cardinal physiological aberration (2,4,5,31–33). Among 410 published cases of PAP, the mean partial pressure of oxygen in arterial blood (PaO2) at diagnosis was 58.6 mmHg (11). Pulmonary function tests typically show a restrictive ventilatory defect with a disproportionate reduction in the diffusing capacity of lung for carbon monoxide (DLCO) (5,11). Expiratory flow rates and forced expiratory volume in one second (FEV1) are usually normal. Cardiopulmonary exercise testing typically reveals a severe impairment in aerobic capacity and gas exchange during exercise (34). Physiological aberrations may improve or normalize after treatment with whole lung lavage (WLL) (discussed later) (2,4,5,11). V.
Laboratory Studies
Serum lactate dehydrogenase (LDH) is elevated in 80% of patients with iPAP (1,4,5,11,32). Concentrations of carcinoembryonic antigen (CEA) (5), cytokeratin (11), Kreb von den Lungen-6 (KL-6), a mucin-like protein secreted by type II pneumocytes (35–37), and surfactant proteins-A (SP-A) and SP-D (37–40) are elevated in serum and BALF in iPAP. However, these various laboratory findings are not specific for PAP (5,40). Neutralizing antibodies against GM-CSF are invariably present in sera and BALF from patients with iPAP and are absent in other lung disorders (20,21,23,24,41) (discussed in detail in the section on pathogenesis). Characteristically, patients with iPAP also lack a hematopoietic response to exogenous GM-CSF and do not show expected increases in their peripheral white blood cell count (32,41).
VI.
Histopathological Features
Grossly, the lungs in PAP are consolidated (2,4). Under light microscopy, the alveolar spaces and bronchioles are filled with granular acidophilic material on hematoxylin and eosin stains, which stain bright pink with periodic acid–Schiff (PAS) and
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Figure 1 (See color insert.) Histologic findings in PAP: (A) low power showing eosinophilic proteinaceous material filling alveoli; (B and C) higher magnification showing foamy macrophages (arrow), and cholesterol clefts (asterisks) typically present within the proteinaceous material [all hematoxylin and eosin (H&E) stain, (A) 40, (B and C) 400].
negative with alcian blue (2,4) (Fig. 1A–C). The alveoli maintain their normal architecture, and interstitial inflammation and fibrosis are minimal or absent (2,3,5,11). The major constituent of the intraalveolar material is lecithin, the main component of surfactant (4). The intraalveolar material in PAP stains
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uniformly for surfactant-specific apoprotein (42). Electron or transmission microscopy (performed for research purposes only) reveals lamellar bodies within alveolar lumens, complex inclusions, cholesterol inclusions, AMs containing phospholipoprotein inclusions, and lipid droplets (4). Historically, open lung biopsy was considered the gold standard. However, bronchoscopy with BAL and transbronchial biopsies can substantiate the diagnosis in up to 75% of cases (11,43). BALF is thick, opaque, milky (yellowish-white colored), and sediments in multiple layers upon standing (2,4,11). Microscopic analysis of BALF in PAP reveals large numbers of eosinophilic acellular bodies and ‘‘foamy’’ AMs containing granular eosinophilic material within phagocytosomes or cytoplasm (4). Positive PAS and negative alcien blue stains of BALF confirm the diagnosis (11). Papanicolaou-stained smears of BAL fluid may also be valuable in the diagnosis of PAP, especially when there are abundant globules (stained orange or green) (5,44). When bronchoscopy is non-diagnostic, surgical biopsy should be performed. VII.
Radiographic Features
Chest radiographs usually show bilateral symmetric alveolar infiltrates, but asymmetric, unilateral, and chronic patchy patterns can also occur (2,4,11). A perihilar distribution resembling a butterfly or batwing pattern is often seen and can be mistaken for pulmonary edema (2) (Fig. 2). The extent of radiographic
Figure 2 Pulmonary alveolar proteinosis (PAP). PA chest radiograph reveals bilateral pulmonary infiltrates but with more extensive disease noted in the right lung.
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Figure 3 (A) HRCT from a patient with PAP demonstrating classic features of thickened interlobular septa against a background of ground-glass opacities with a “crazy-paving” appearance. The lung architecture is preserved. (B) Coned down view highlighting the thickened interlobular septa with a “crazy-paving” appearance. Abbreviation: HRCT, highresolution computed tomography; PAP, pulmonary alveolar proteinosis.
abnormalities is often disproportionate to the relatively modest pulmonary symptoms and physical findings (5). High-resolution computed tomography (HRCT) of chest reveals patchy or geographic widespread ground-glass opacities (GGO) and airspace consolidation; air bronchograms are not present (4,45–47). An alveolar pattern dominates, but interstitial (reticular) patterns may be present in areas of GGO or consolidation (45,46). There is no particular anatomic or zonal predominance in PAP (45,46,48). The lung architecture is preserved in PAP and fibrosis is rare (48). The extent of CT abnormalities correlates with impairment in pulmonary function (oxygenation and spirometry) (46). The most characteristic feature of PAP (present in nearly all cases) is what has been termed the ‘‘crazy paving’’ pattern. This represents thickened interlobular septa against the background of GGO or air space opacities (Figs. 3 and 4) (4,45–48). As was discussed in chapter 2 by Lynch et al., this ‘‘crazy paving’’ pattern is nonspecific (49,50). Intrathoracic lymphadenopathy or pleural effusions are not features of PAP (4,48). VIII.
Natural History and Clinical Course
The clinical course of PAP is variable, ranging from spontaneous resolution to death secondary to pneumonia or respiratory failure (1,2,4,11). Spontaneous resolution occurs in 8% to 25% of cases (11,51). The five-year survival in a retrospective analysis of 343 cases of PAP was approximately 75% (11). With the therapeutic use of WLL (discussed below), fatalities are rare now. More recent data suggests a survival rate of close to 100% in the last 10 years (11), compared to *70% prior to the use of WLL (52).
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Figure 4 HRCT from a patient with PAP shows a background of ground-glass opacities with some areas of relatively spared lung parenchyma. The lung architecture is preserved and honeycomb cysts are not present. Abbreviation: HRCT, high-resolution computed tomography; PAP, pulmonary alveolar proteinosis.
Patients with PAP are at an increased risk of infections not only with common respiratory pathogens but also opportunistic organisms such as Mycobacterium tuberculosis, Mycobacterium avium-intracellulare (MAI), Aspergillus spp. Pneumocystis carinii, and Nocardia spp. (11,53). Seven cases of lung cancer in patients with iPAP have been reported (54), but whether or not this is a true association is not known. IX.
Pathogenesis
Defective clearance of surfactant, mediated by circulating antibodies against GM-CSF, is the cardinal pathogenetic mechanism responsible for iPAP (5,23). AMs in iPAP exhibit defects in chemotaxis, phagocytosis, and phagolysosomal fusion and clearance of surfactant (4,5). Pulmonary surfactant, a complex mixture of phospholipids and proteins synthesized and secreted by alveolar type II cells, functions to keep alveoli from collapsing during expiration (55). Surfactant is composed of 90% to 95% lipids and 5 to 10% proteins including SP-A, -B, -C, and -D (5,56,57). All four of the SP accumulate within the alveolar spaces in PAP (57). The two hydrophilic SP, A and D, have been the most studied. SP-A and SP-D belong to the collectin family and play roles in the innate immunity of the lung (55). Pulmonary collectins have antimicrobial effects and display both inflammatory and anti-inflammatory properties (55). In iPAP, AMs exhibit defective clearance of surfactant; however,
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in addition, abnormal secretion of transport vesicles containing precursors of SP-B may play a role in the pathogenesis (57). Cholesterol/disaturated phospholipid ratios (CHOL/DSP) are elevated sevenfold in BALF from patients with PAP, whereas the SP-A/DSP and SP-B/DSP ratios are elevated 40- and approximately 100-fold, respectively (58). Serum and BAL fluid SP-D are consistently elevated in PAP and appear to reflect disease severity (40). Many advances have been made in characterizing the pathogenesis of PAP in recent years (59,60). The sentinel breakthrough came unexpectedly in 1994, when development of gene knock-out mice lacking the hematopoietic growth factor GMCSF was studied (61,62). Mice lacking the GM-CSF gene (GM/) did not show defects in hematopoiesis but had intraalveolar accumulation of surfactant lipids and proteins, similar to PAP in humans (61). Extensive lymphoid hyperplasia associated with lung airways and blood vessels was also noted (61,63). In addition to PAP, GM–/– mice manifested subtle extrapulmonary features (e.g., disturbed macrophage function (64), heightened susceptibility to infections (65), reduced fertility (10), T-cell dysfunction (66), and reduced survival) (10). Subsequent investigations supported the concept that the accumulation of surfactant in GM-CSF knock-out mice (GM–/–) was secondary to reduced clearance rather than overproduction (67). Exogenous administration of aerosolized (but not intraperitoneal) GM-CSF corrected the lung lesions in GM–/– mice (68). Further, reconstituting the gene for CM-CSF to the respiratory epithelia of GM–/– mice corrected the PAP lesion (69). Further, bone marrow or stem cell transplantation and hematopoietic reconstitution of GM–/– mice reversed the PAP lesion (70,71). These discoveries implicated the role of GM-CSF in normal surfactant homeostasis and suggested the possibility of GM-CSF deficiency in PAP in humans. In 1999, Japanese investigators identified a GM-CSF neutralizing antibody in serum and BALF of patients with acquired (idiopathic) PAP but not in patients with congenital or secondary PAP (72) (20). These findings were confirmed by others (21) (24,73). In contrast to the murine model or in congenital forms of PAP, defects in the GM-CSF b receptor (74,75) or gene sequence (75) were not identified in adults with iPAP. These findings supported the concept that iPAP was an autoimmune disease characterized by circulating GM-CSF antibodies (24). GM-CSF stimulates the terminal differentiation of AMs that are necessary to clear the surfactant (31,76). AMs in GM–/– mice displayed reduced capacity for surfactant catabolism, cell adhesion, phagocytosis, bacterial killing, toll-receptor signaling, and expression of various pathogen-associated molecular-pattern recognition receptors, suggesting arrest at an early stage of differentiation (77). Further, AMs from GM–/– mice lack PU.1 protein expression, which correlated with decreased maturation, differentiation, and surfactant metabolism (76). Similarly, AMs obtained by BAL from humans with iPAP display deficient PU.1 mRNA expression compared to healthy controls (76). PU.1-dependent terminal differentiation markers CD32 and macrophage colony–stimulating factor receptor
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(M-CSFR) are decreased in AMs from iPAP patients (60,76). Among patients with iPAP, absence of GM-CSF was associated with elevated levels of M-CSF, monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (24). Iyonaga et al. reported marked elevation of MCP-1 in four patients with iPAP compared to controls (78). MCP-1 may serve as an amplification mechanism to recruit additional macrophages to the alveoli in PAP. Contrary to the murine model, GM-CSF levels in patients with iPAP were higher than those in normal subjects (22). Most iPAP patients exhibited intact GM-CSF synthesis and normal AM responses to GM-CSF (22). Further, GMCSF bioactivity was completely abrogated in the BALF from patients with iPAP (26). This led to the identification of neutralizing antibodies of the immunoglobulin G isotype in BALF and serum of all patients with PAP compared to healthy subjects and subjects with other lung diseases (20,24). Importantly, these anti-GM-CSF antibodies were not found in congenital cases of PAP or in murine models (20,21). BALF levels of anti-GM-CSF antibodies correlated with increased disease severity in patients with iPAP whereas serum antibodies did not (23). These autoantibodies in iPAP bind GM-CSF with high specificity and high affinity and block GM-CSF binding to its receptor, thereby resulting in inhibition of AM differentiation and function (26). Administration of GM-CSF in patients with iPAP restores PU.1-dependent terminal differentiation markers CD32 and M-CSFR (76). Recent studies cited immune dysfunction in iPAP resulting from anti-GM-CSF antibodies. In humans with iPAP (as well as GM–/– mice), neutrophils exhibited impairments in basal phagocytosis, adhesion, oxidative burst, and bactericidal activity (25). These immune defects were also observed in normal human neutrophils after incubating them with anti-GM-CSF antibodies from subjects with iPAP (25). AMs in PAP are also dysfunctional with decreased phagolysosome fusion resulting in the decreased ingestion of yeast (79). Similarly, GM–/– mice displayed immune defects and an impaired ability to resolve a variety of infections including group B streptococcus, Listeria, adenovirus, Pneumocystis carinii, and malaria (80). These observations are consistent with the known propensity of patients with PAP to develop a wide range of opportunistic infections (53,80). One study reported isolation of MAI from BALF in 8 of 19 consecutive patients with PAP who underwent WLL for the treatment of symptomatic PAP (53). Interestingly, a recent study cited elevated BALF concentrations of a- and b-defensins in patients with PAP compared to controls (81). BALF from PAP patients, but not controls, expressed antimicrobial activity against S. aureus and Pseudomonas aeruginosa (81); this may be a mechanism to protect against bacterial airway infections in PAP. Inciting stimuli for PAP are not known. However, a history of exposure to hydrocarbons, chemicals, fiberglass, metals, dusts, or solvents has been elicited in up to 50% of cases (2,4). In animal models, inhalation of dust particles elicits a PAP-like syndrome (4). One patient with silicosis, PAP, and circulating GMCSF antibodies was reported (82).
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Treatment
Treatment is not required in every patient with PAP, as some patients have minimal or no symptoms (5,11). Currently, the standard of care for treatment of PAP remains sequential WLL (11). The technique, first described in the mid1960s (83,84), involves ‘‘repeated segmental flooding’’ of the lungs in order to physically remove the accumulated alveolar material (83,84). In current practice, WLL is performed under general anesthesia via a double-lumen endotracheal tube (2,5). The most severely affected lung is allowed to deflate and the opposite lung is ventilated. Large volumes of sterile saline (15–40 liters) are instilled into the diseased lung until the lavage effluent is grossly clear (31). This process generally takes three to four hours. This process removes the viscid, thick material, allowing the alveolar spaces to re-expand and participate in gas exchange. Most patients can be extubated within one hour of WLL. Typically, one lung is lavaged per session but two sequential WLLs during one anesthesia session may be as efficacious and without increased adverse effects (5,85). Some centers incorporated chest percussion and prone positioning to standard WLL with additional improvement in the clearance of the intraalveolar lipoproteinaceous material (86). WLL was associated with an initial increase in SP-A in the airways within the first two hours, followed by rapid clearance, supporting the concept that WLL accelerates clearance of surfactant-like material in the alveolar spaces (87). WLL is generally well tolerated, but potential risks include complications of general anesthesia, worsening hypoxemia, flooding of the contralateral lung, pneumonia, acute respiratory distress syndrome (ARDS), laryngospasm, bronchospasm, arrhythmias, and pneumothorax (88). The absolute indications for WLL remain unclear, but WLL is generally performed for intractable symptoms or significant hypoxemia (PaO2 < 60 mmHg) (88). Given the complexity of this procedure, WLL should be performed by individuals in centers with special expertise. Following WLL, symptoms, oxygenation, and chest radiographs improve in 75% to 95% of patients over the next few weeks (2,4,11) (Fig. 5). The average improvement in PaO2 levels after WLL is 12 to 19 mmHg (overall mean 14.5 mmHg) (11). In a retrospective review of 55 iPAP who had WLL, the median duration of clinical benefit was 15 months and relapses occurred in >70% by three years (11). Importantly, WLL was associated with improved five-year survival compared to patients not receiving WLL (94% vs. 85%, p ¼ 0.04) (11). A recent study of 21 patients noted that the benefit of one session of bilateral WLL was durable, with 70% of patients remaining free of recurrent PAP at three years (89). In that study, most of the improvement in spirometry occurred in the immediate post-WLL period due to efficient clearance of the alveoli (89). Relapses requiring repeated WLL occur in 15% to > 70% of treated patients (2,11,31,37). When occupational exposure is believed to play a causative role, withdrawal from that occupation is advised (2).
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Figure 5 (A) PA chest radiograph from a patient with pulmonary alveolar proteinosis (PAP) shows extensive alveolar opacification involving all lung fields. The patient was severely hypoxemic. (B) PA chest radiograph from the same patient 4 weeks following bilateral whole lung lavage shows marked, albeit partial, clearing.
XI.
Exogenous GM-CSF
Following the discovery of anti-GM-CSF antibodies in serum and BALF from patients with iPAP, treatment with exogenous GM-CSF has been tried (24,41,90). In 1996, Seymour et al. reported a patient treated successfully with subcutaneous recombinant human GM-CSF (rhGM-CSF) (91). Following this sentinel report, two prospective but nonrandomized trials of subcutaneous rhGM-CSF were performed. After 12 weeks of therapy, favorable responses were noted in 3 of 4 patients (41) and 6 of 14 patients (74), respectively. GM-CSF-induced eosinophilia correlated with favorable response (74). In a subsequent paper, these authors noted that a normal LDH level predicted a higher likelihood of response to treatment with subcutaneous GM-CSF (90). Other favorable responses were cited in case reports (92–95) or small nonrandomized trials (41,90,96). In some patients, responses were dramatic (41,74). However, improvement was usually gradual, over four to eight weeks. The delay in response is consistent with the hypothesis that GM-CSF recruits immature precursor cells to the lung, which later differentiate into functional AMs. Longer time from diagnosis, higher vital capacity, normal serum LDH, and high plasma level of SP-B were each associated with a response to rhGM-CSF (dose 5 mg/ kg/day) (74). The largest human clinical trial of GM-CSF was published in 2006 and treated 25 patients with moderate-to-severe PAP (defined by need for supplemental oxygen), with escalating doses of subcutaneous GM-CSF until clinical improvement occurred (97). Of the 21 patients who completed the trial, 12 were clinical responders with significant improvements in paO2, alveolar-arterial O2 gradient, DLCO, total lung capacity, and six-minute walk distance (97). During a mean 39-month follow-up, WLL or home oxygen was required in 4 of the 12 (33%) responders compared to 5 of 9 (56%) nonresponders. The anti-GM-CSF
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titers at baseline were lower and decreased further in the responder group (97). To date, toxicities associated with GM-CSF have been minimal (41,74), but long-term follow-up (beyond five years) data are limited (5,11). XII.
Aerosolized GM-CSF
Initial animal studies revealed that aerosolized (but not intraperitoneal) GM-CSF corrected the lung lesions in GM-CSF knock-out mice (68). In humans with iPAP, aerosolized GM-CSF has been used in small series (98–100) and anecdotal case reports (3101). Aerosolized GM-CSF markedly reduced anti-GM-CSF antibodies in three patients with iPAP (98). Inhaled GM-CSF was shown to decrease the amount of autoantibody in BALF and improve pulmonary function in patients with iPAP (98–100). Although GM-CSF appears promising in a subset of patients with moderate-to-severe PAP, many important questions remain unanswered including the optimal dose, duration, and route of administration. Importantly, which patients are candidates for therapy remains unclear. Additionally, markers to predict response to GM-CSF therapy need to be identified. To date, studies suggest that titers of circulating anti-GM-CSF, a normal LDH level, and GM-CSF-induced eosinophilia predict a higher level of success with GM-CSF (24,74,90,96). XIII.
Other Therapies
Anecdotal responses to plasmapheresis were noted in two patients with iPAP (96,99). Importantly, one patient had failed prior treatment with GM-CSF and multiple sessions of WLL (99). Anecdotal responses were cited in two patients with oral ambroxol, a surfactant activator (102,103), but a controlled study is required to confirm these findings, given the potential for spontaneous resolution in iPAP. Bone marrow transplantation reversed PAP in GM-CSF-deficient mice, supporting the hematopoietic pathogenesis in that PAP model (70). To our knowledge, this has not yet been attempted in humans. Corticosteroids are contraindicated in PAP. Corticosteroids can be deleterious via interference of surfactant maturation and secretion (5) and impair immune responses (11). In addition, in the early literature on PAP, the use of corticosteroids was associated with fatal opportunistic infections due to cryptococcosis, nocardiosis, and mucormycosis (104). Given the presence of circulating autoantibodies in iPAP, immunosuppressive agents may have a theoretical role in refractory cases of PAP, but data are lacking. Lung or heart-lung transplantation has been performed for refractory PAP, but data are limited to case reports (105,106) and a small series in infants (n ¼ 3) (107). Recurrent (and ultimately fatal) PAP developed in a child with lysinuric protein intolerance and PAP within 18 months of heart-lung transplantation (105). In an adult who underwent bilateral lung transplant for refractory PAP, the
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disease (PAP) recurred three years following transplantation (106). Further, PAP was described in three lung allograft recipients with no prior history of PAP; repeat bouts of alveolar damage due to ischemic reperfusion injury, rejection, or infection preceded the intraalveolar accumulation of surfactant-like material (108). Gal et al. reported a patient who developed PAP 66 days after lung transplantation for idiopathic pulmonary fibrosis (109). Severe PAP developed in the lung allograft of a patient with acute myeloid leukemia following chemotherapy (110). In light of these findings and the fact that iPAP is an autoimmune disease with circulating antibodies, we see no role of lung transplantation for this disorder. Further research needs to be performed on the optimal therapeutic regimen including WLL, GM-CSF (subcutaneous or aerosolized), and alternative therapeutic agents, but much progress has been made in the past decade. References 1. Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med 2003; 349(26):2527–2539. 2. Prakash UB, Barham SS, Carpenter HA, et al. Pulmonary alveolar phospholipoproteinosis: experience with 34 cases and a review. Mayo Clin Proc 1987; 62(6): 499–518. 3. Mazzone PJ, Jane Thomassen M, Kavuru MS. Pulmonary alveolar proteinosis: recent advances. Semin Respir Crit Care Med 2002; 23(2):115–126. 4. Shah PL, Hansell D, Lawson PR, et al. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax 2000; 55(1):67–77. 5. Ioachimescu OC, Kavuru MS. Pulmonary alveolar proteinosis. Chron Respir Dis 2006; 3(3):149–159. 6. Du Bois RM, McAllister WA, Branthwaite MA. Alveolar proteinosis: diagnosis and treatment over a 10-year period. Thorax 1983; 38(5):360–363. 7. Kariman K, Kylstra JA, Spock A. Pulmonary alveolar proteinosis: prospective clinical experience in 23 patients for 15 years. Lung 1984; 162(4):223–231. 8. Selecky PA, Wasserman K, Benfield JR, et al. The clinical and physiological effect of whole-lung lavage in pulmonary alveolar proteinosis: a ten-year experience. Ann Thorac Surg 1977; 24(5):451–461. 9. Rosen SH, Castleman B, Liebow AA. Pulmonary alveolar proteinosis. N Engl J Med 1958; 258(23):1123–1142. 10. Seymour JF, Lieschke GJ, Grail D, et al. Mice lacking both granulocyte colonystimulating factor (CSF) and granulocyte-macrophage CSF have impaired reproductive capacity, perturbed neonatal granulopoiesis, lung disease, amyloidosis, and reduced long-term survival. Blood 1997; 90(8):3037–3049. 11. Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med 2002; 166(2):215–235. 12. Williams GD, Christodoulou J, Stack J, et al. Surfactant protein B deficiency: clinical, histological and molecular evaluation. J Paediatr Child Health 1999; 35(2): 214–220. 13. Teja K, Cooper PH, Squires JE, et al. Pulmonary alveolar proteinosis in four siblings. N Engl J Med 1981; 305(23):1390–1392.
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84. Ramirez J. Pulmonary alveolar proteinosis. Treatment by massive bronchopulmonary lavage. Arch Intern Med 1967; 119(2):147–156. 85. Kavuru MS, Popovich M. Therapeutic whole lung lavage: a stop-gap therapy for alveolar proteinosis. Chest 2002; 122(4):1123–1124. 86. Perez A 4th, Rogers RM. Enhanced alveolar clearance with chest percussion therapy and positional changes during whole-lung lavage for alveolar proteinosis. Chest 2004; 125(6):2351–2356. 87. Alberti A, Luisetti M, Braschi A, et al. Bronchoalveolar lavage fluid composition in alveolar proteinosis. Early changes after therapeutic lavage. Am J Respir Crit Care Med 1996; 154(3 pt 1):817–820. 88. Menard KJ. Whole lung lavage in the treatment of pulmonary alveolar proteinosis. J Perianesth Nurs 2005; 20(2):114–126. 89. Beccaria M, Luisetti M, Rodi G, et al. Long-term durable benefit after whole lung lavage in pulmonary alveolar proteinosis. Eur Respir J 2004; 23(4):526–531. 90. Seymour JF, Doyle IR, Nakata K, et al. Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis. Thorax 2003; 58(3):252–257. 91. Seymour JF, Dunn AR, Vincent JM, et al. Efficacy of granulocyte-macrophage colony-stimulating factor in acquired alveolar proteinosis. N Engl J Med 1996; 335(25):1924–1925. 92. Schoch OD, Schanz U, Koller M, et al. BAL findings in a patient with pulmonary alveolar proteinosis successfully treated with GM-CSF. Thorax 2002; 57(3):277–280. 93. Barraclough RM, Gillies AJ. Pulmonary alveolar proteinosis: a complete response to GM-CSF therapy. Thorax 2001; 56(8):664–665. 94. de Vega MG, Sanchez-Palencia A, Ramirez A, et al. GM-CSF therapy in pulmonary alveolar proteinosis. Thorax 2002; 57(9):837. 95. Khanjari F, Watier H, Domenech J, et al. GM-CSF and proteinosis. Thorax 2003; 58(7):645. 96. Bonfield TL, Kavuru MS, Thomassen MJ. Anti-GM-CSF titer predicts response to GM-CSF therapy in pulmonary alveolar proteinosis. Clin Immunol 2002; 105(3): 342–350. 97. Venkateshiah SB, Thomassen MJ, Kavuru MS. Pulmonary alveolar proteinosis. Clinical manifestations and optimal treatment strategies. Treat Respir Med 2004; 3(4):217–227. 98. Tazawa R, Hamano E, Arai T, et al. Granulocyte-macrophage colony-stimulating factor and lung immunity in pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2005; 171(10):1142–1149. 99. Kavuru MS, Bonfield TL, Thomassen MJ. Plasmapheresis, GM-CSF, and alveolar proteinosis. Am J Respir Crit Care Med 2003; 167(7):1036; author reply 1036–1037. 100. Wylam ME, Ten R, Prakash UB, et al. Aerosol granulocyte-macrophage colonystimulating factor for pulmonary alveolar proteinosis. Eur Respir J 2006; 27(3): 585–893. 101. Arai T, Hamano E, Inoue Y, et al. Serum neutralizing capacity of GM-CSF reflects disease severity in a patient with pulmonary alveolar proteinosis successfully treated with inhaled GM-CSF. Respir Med 2004; 98(12):1227–1230. 102. Hashizume T. Pulmonary alveolar proteinosis successfully treated with ambroxol. Intern Med 2002; 41(12):1175–1178.
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103. Shiratori M, Takahashi H. Development of treatment for pulmonary alveolar proteinosis. Intern Med 2002; 41(12):1090–1091. 104. Robertson HE. Pulmonary alveolar proteinosis. Can Med Assoc J 1965; 93(18): 980–983. 105. Santamaria F, Brancaccio G, Parenti G, et al. Recurrent fatal pulmonary alveolar proteinosis after heart-lung transplantation in a child with lysinuric protein intolerance. J Pediatr 2004; 145(2):268–272. 106. Parker LA, Novotny DB. Recurrent alveolar proteinosis following double lung transplantation. Chest 1997; 111(5):1457–1458. 107. Hamvas A, Nogee LM, Mallory GB Jr., et al. Lung transplantation for treatment of infants with surfactant protein B deficiency. J Pediatr 1997; 130(2):231–239. 108. Yousem SA. Alveolar lipoproteinosis in lung allograft recipients. Hum Pathol 1997; 28(12):1383–1386. 109. Gal AA, Bryan JA, Kanter KR, et al. Cytopathology of pulmonary alveolar proteinosis complicating lung transplantation. J Heart Lung Transplant 2004; 23(1): 135–138. 110. Du EZ, Yung GL, Le DT, et al. Severe alveolar proteinosis following chemotherapy for acute myeloid leukemia in a lung allograft recipient. J Thorac Imaging 2001; 16(4):307–309.
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34 Pulmonary and Tracheobronchial Involvement with Amyloidosis
JOHN L. BERK Amyloid Treatment and Research Program, Department of Medicine, Boston University Medical Center, Boston, Massachusetts, U.S.A.
I.
Introduction
The amyloidoses are a collection of disorders arising from protein misfolding and misassembly into insoluble b-rich sheets. Extracellular deposition of the resulting amyloid fibrils disrupts organ function, producing clinical disease. Originally identified as carbohydrate by Virchow in 1854 (1), amyloid deposits consist of linear arrays of subunit proteins complexed with glucosaminoglycans and serum amyloid P (SAP) that stabilize the b-sheet conformation. Amyloid deposition occurs in systemic and organ-limited or localized forms. More than 20 proteins form amyloid fibrils (2). In systemic amyloidosis, the precursor proteins forming amyloid fibrils dictate organ involvement and the resulting clinical syndrome. Consequently, typing the amyloid allows disease classification, prediction of disease progression, and basis for therapeutic intervention. II.
Classification
By definition, amyloid deposits stained with Congo red dye express green birefringence under polarized light microscopy (3). Electron microscopy 789
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identifies amyloid fibrils as 8- to 10-nm wide structures of variable length (4). Typically, standard immunohistochemistry can type the precursor protein. Immunogold electron microscopy may be necessary in more challenging cases (5). The nomenclature includes an ‘‘A’’ for amyloid and a letter designating the precursor protein composing the deposits. Four major systemic designations exist (Table 1): primary or immunoglobulin light chain (AL) disease, secondary or amyloid A protein (AA) disease, familial or transthyretin (ATTR) disease, and dialysis-related or b2 microglobulin disease (AB2M). Localized amyloid disorders affect a variety of organs (Table 1); however, isolated lung involvement is restricted to precursor proteins expressed in systemic amyloidosis.
Table 1 Classification of Amyloid Diseases Disease
Type
A. Systemic syndromes Primary systemic AL Secondary
AA
Familial
ATTR
Senile systemic Dialysis related
ApoAI ApoAII AFibA ALys AGel ACys ATTR AB2M
B. Localized syndromes Localized AL Alzheimer’s Creutzfeldt-Jakob Type 2 diabetes Atrial amyloidosis
ApoAI Ab APrP AIAPP AANF
Protein subunit
Organs affected
Monoclonal Ig light chain Kidney, heart, GI, neurologic, soft tissues, lungs, endocrine Serum amyloid A protein Kidney, GI, neuropathy— rarely heart or lung Transthyretin (mutant) Peripheral/autonomic neuropathy, heart, kidney—rarely lung Apolipoprotein AI Apolipoprotein AII Fibrinogen Aa chain Lysozyme Gelsolin Cystatin C Transthyretin (wild type) Heart, soft tissues b2 microglobulin Articular deposits, bone— rarely pleura Monoclonal Ig light chain Airway, lung, bladder, skin, soft tissue, brain, eye Apolipoprotein AI Knee—rarely Ab protein Brain Prion protein Brain Islet amyloid polypeptide Pancreas Atrial natriuretic factor Cardiac atria
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Primary Systemic (AL) Amyloidosis Demographics
The true incidence of AL amyloidosis, an orphan disease, remains unknown. Extrapolating a 30-year experience at the Mayo Clinic, Gertz et al. (6) estimated that 3200 new cases occur annually in the United States. The National Center for Health reported an incidence of 4.5 cases per 100,000 population in the United States—or nearly 13,500 cases per year (7). Between 1994 and 2002, we evaluated 701 patients with AL amyloidosis at Boston University Medical Center (8). B.
Pathogenesis
AL amyloidosis arises from clonal expansion of plasma cells. In systemic AL amyloidosis, the expanded clone of plasma cells resides in the bone marrow, expressing monoclonal k or l light chain immunoglobulin (Ig) in the blood and urine. AL amyloid fibrils represent intact 23-kDa monoclonal light chains or fragments of the Ig variable region (9). AL deposits are most frequently made up of the variable regions of lVI or kI light chain Ig. Gene rearrangements appear responsible for production of amyloidogenic light chain Ig leading to AL disease. Whether extracellular amyloid deposits or soluble precursors induce cell and organ dysfunction is debated. Notably, exposure to purified amyloid fibrils alters cardiac function ex vivo and myocardial contractility in vivo by augmenting oxidant stress (10,11), supporting a role for soluble amyloidogenic proteins in organ disruption. C.
Parenchymal Lung Disease
Clinically evident amyloid lung disease is not a prominent feature of systemic AL amyloidosis. Among 701 consecutive AL patients assessed by Skinner et al. (8), clinical organ involvement included the kidney (80%), heart (54%), GI tract and liver (63%), nervous system (53%), and soft tissues (24%). The Mayo Clinic reported similar findings among 474 AL patients with kidney (28%), heart (17%), and peripheral nerves (17%) most often affected (12). Neither series noted lung disease. Between 1996 and 2001, we assessed 492 new AL patients at Boston University, identifying 138 (28%) with lung involvement—9% of whom had amyloid lung disease in the absence of heart infiltration. Two autopsy series address AL lung disease. Celli et al. (13) reported findings from 15 AL individuals, all with extensive amyloid deposits in lung vessels, airway walls, and interstitium—between alveolar epithelial and vascular endothelial cells. In contrast to the ubiquitous histologic findings, only 53% had signs or symptoms of lung disease. Lung involvement appeared to determine clinical outcome in just one case. To define the contributions of lung and heart involvement on AL disease course, Smith et al. (14) reviewed autopsy findings in 26 AL patients at Johns Hopkins Hospital. Ninety-two percent had moderate-to-severe heart infiltration
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while 73% had significant alveolar-septal deposition, a statistically significant association by pair-wise analysis ( p < 0.01). Heart deposition exceeded lung involvement in nearly all cases. The authors concluded that while lung involvement may contribute, heart disease determined clinical course. Subsequent Kaplan-Meier analyses of AL patients by organ involvement support these conclusions. Patients with AL cardiomyopathy (left ventricular ejection fraction <40%) had median survival of 12 weeks versus 16 months in those with interstitial amyloid lung disease and normal heart function (12,15). Hemoptysis, hemothorax, or alveolar hemorrhage may occur suddenly. In a case of massive hemoptysis, histologic examination of a resected lower lobe revealed dissection of a medium-sized pulmonary artery containing amyloid deposits (16). D.
Pleural Effusions
Systemic amyloidoses are rarely complicated by pleural effusions. A seven-year experience evaluating 636 AL patients at Boston University identified large persistent pleural effusion in 6% of cases, with an additional 5% to 10% exhibiting smaller pleural fluid collections (17). From 1977 to 2007, 29 case reports of pleural effusion were recorded in the English literature from multiple medical centers (17–19). A detailed analysis of 35 additional cases with large pleural effusions in AL patients was published from one center (17). Taken together, these data provide insights into the clinical course and pathophysiology of amyloid-related pleural effusions. Among the 29 case reports over the past 30 years (17–19), 19 cases provide sufficient data to establish the diagnosis of AL amyloidosis. Pleural biopsies documented amyloid deposits in 13 (68%) of these cases. Although 16 of 19 cases (84%) had concomitant congestive heart failure (CHF), 56% expressed exudative pleural fluid chemistries, suggesting disruption of pleural membrane mechanics. 1.
Physiology
The physiology of amyloid pleural effusions is complex. AL amyloidosis can alter the function of several organs that could contribute to effusion formation including the heart (infiltrative cardiomyopathy—48% cases), kidneys (nephrotic syndrome—65% cases), and thyroid (hypothyroidism—4% cases) (20). The retrospective analysis of 35 cases of large persistent AL pleural effusions versus 120 AL cardiomyopathy patients without effusions offers perspective on the role of cardiac dysfunction and elevated filling pressures on amyloid pleural effusions. No differences in multiple echocardiographic parameters (interventricular septal thickness, left ventricular ejection fraction, or sensitive measures of diastolic function) could be identified between the pleural effusions group and the effusion-free cardiomyopathy group (21). Ironically, nephrotic range proteinuria and hypoalbuminemia were more prevalent in the
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effusion-free cardiomyopathy group. Pleural fluid chemistries revealed exudative character in over one-third of the cases, confirming the findings of the case series review (17–19). Pleural biopsies from six consecutive cases with pleural effusions exhibited amyloid infiltration; negative biopsies were obtained at autopsy from two effusion-free cardiomyopathy cases (21). Taken together, these data indicate that left ventricular dysfunction and elevated cardiac filling pressures, hypothyroidism, and nephrotic syndrome/ hypoalbuminemia may all contribute but are not sufficient for the formation and maintenance of large persistent pleural effusion in AL amyloidosis. The incidence of exudative chemistries and the presence of amyloid deposits on pleural biopsies suggest that amyloid infiltrates and disrupts pleural mechanics, inducing fluid secretion and impairing parietal membrane drainage from the pleural space. 2.
Survival
Large persistent pleural effusions are associated with limited survival in AL amyloidosis. Untreated patients with large effusions lived a median of 1.6 months (1–18.5 months, range) versus 6 months (0–29 months, range) in untreated effusion-free cardiomyopathy patients ( p ¼ 0.031) (21). Chylothorax is rarely reported (21–23). The low incidence of chylous effusions despite the frequent appearance of mediastinal and hilar adenopathy in AL amyloidosis raises the possibility that direct amyloid infiltration of pleural lymphatics causes chylous effusions, not lymph node compression of mediastinal lymphatics. 3.
Management
High cardiac filling pressures and unusually permeable pleural membranes make management of persistent AL pleural effusions challenging. Although these effusions typically do not diminish with diuretic therapy, large volume drainage prior to optimizing filling pressures offers transient benefits with pleural fluid reaccumulating over 24 to 72 hours. Aggressive diuresis will slow or prevent the recollection of the effusion; however, the hypotensive effects of autonomic neuropathy or low cardiac output may limit this strategy. When clinical symptoms require weekly thoracenteses, pleurodesis by tube thoracostomy or video-assisted pleuroscopy should be considered. In patients with severe cardiomyopathy or hypotension who may not tolerate significant sedation or anesthesia required for a video-assisted procedure, placement of sterile silastic tubes (PleuRx1 tubes, Denver Biomaterials, Colorado, U.S.) are a viable alternative. Chest tube placement effectively drains the pleural space; however, large volume (>500 cc/day) collection persists for at least 5 to 12 days. Among 18 patients treated with chest tubes, 8 patients had tube-directed talc sclerosis, which did not achieve symphysis with pretreatment drainage >200 cc; those with drainage <100 cc/day sealed appropriately. Chest tubes
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were removed and sclerotherapy abandoned in seven patients with unrelenting high drainage. Two patients underwent successful video-assisted thoracostomy talc sclerosis, and one patient had bilateral PleuRx tubes placed and maintained for 12 months (21). Vascular endothelial cell growth factor (VEGF) is highly expressed in malignant (1290 pg/mL) and benign pleural effusions and ascites (250 pg/mL), potentially stimulating fluid formation by its effects on cell permeability (24). Pichelmayer et al. (25) and Hoyer et al. (18) administered bevacizumab (Avastin1), a monoclonal anti-VEGF antibody, 5 mg/kg intravenously to five patients with AL amyloidosis and persistent pleural effusion. Diuresis and fluid retention improved with initiation of bevacizumab in four of five cases; however, administration of multiple concomitant medications (diuretics, glucocorticoids, angiotensin-converting enzyme inhibitors) confounded assessment of the antibody effect. At present, no data exist on VEGF expression in AL pleural effusions.
E.
Pulmonary Hypertension
The literature includes eight case reports of pulmonary hypertension in AL amyloidosis attributed to pulmonary vascular amyloid deposition (Table 2). Autopsies confirmed pulmonary artery amyloid deposits in four out of four cases. The prevalence of restrictive cardiomyopathy and diastolic dysfunction in AL patients predisposes them to secondary forms of pulmonary vascular disease. Direct measurements of pulmonary artery pressures (PAP) were obtained in five cases (3 pulmonary arteriograms, 2 right heart catheterizations); however, only two reports include direct measures of left atrial filling pressures. Echocardiographic estimates of elevated right ventricular systolic pressures and normal diastolic function were reported in all cases. An autopsy series of 15 individuals with AL amyloidosis or multiple myeloma/AL amyloid found mild-to-severe pulmonary vessel amyloid deposition in >90% of cases (13). The ubiquity of pulmonary vascular amyloid in AL patients is in stark contrast to the small number of clinically recognized cases of amyloid-mediated pulmonary hypertension. It appears, therefore, pulmonary vascular amyloid deposition is required, but not sufficient, for inducing pulmonary hypertension in AL patients. Treatment recommendations cannot be derived from such limited experience. Individual cases have been treated with ‘‘calcium channel blockers and diuretics’’ (26), nifedipine and diuretics (27), or sildenafil (27). Nifedipine decreased echo estimated RV systolic pressures from 90 to 84 mmHg (27). Median survival for all reported cases was 157 days (range 19–1036 days). Calcium channel blockers (28) and digoxin (29) avidly bind amyloid fibrils, producing locally toxic drug-myocardial interaction. Calcium channel blockers can worsen CHF in patients with amyloid cardiomyopathy and should be used cautiously (30).
1 3 1 1 1 1 1 1 1
Shiue and McNally (75) Dingli et al. (26)
AL AL/MM AL AA AL AL AL/MM AB2M AA/FMF
Type Yes No Yes No No No Yes Yes
LVH/RVH
Cath
RV dil RV dil No RV dil RV dil PAS 90 RV dil
Echo
Path
None
Yes
None Yes CCB, diuretics, dig Yes (all) CCB CCB None Yes CCB, diuretics No Sildenafil No
Rx
Died several months after dx
Unavailable Died *180 days post dx Alive 1 year later
Died hospital day 39 Died after median 73 days (range 19–1036 days)
Outcome
Abbreviations: MM, multiple myeloma; RV dil, right ventricular dilatation; Cath, right heart catheterization; CCB, calcium channel blocker; dig, digoxin; dx, diagnosis; LVH/RVH, left ventricular hypertrophy/right ventricular hypertrophy.
Chapman et al. (76) Eder et al. (27) Lehtonen (77) Lutz et al. (78) Johnson et al. (43)
n
Study (reference)
Table 2 Pulmonary Hypertension in Systemic Amyloidosis
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Diaphragm Dysfunction
Two cases of weakened diaphragms by fluoroscopic testing and maximal inspiratory pressure generation in patients with (i) apparent AL disease and (ii) k light chain AL amyloidosis/multiple myeloma document extensive amyloid infiltration of the diaphragm (31,32). We reported unilateral diaphragm paralysis by AL-induced mononeuropathy multiplex (33). Balloon manometry documented a gastric Pdimax of 5.64 cmH2O. Nocturnal bilevel positive airway pressure (BiPAP) has preserved the patient’s daytime functional status. IV. A.
Secondary Amyloidosis (AA) Demographics
Approximately 1% of patients with chronic inflammatory conditions (connective tissue disease, malignancy, infection, cystic fibrosis, Castleman’s disease) express AA amyloid (34). The incidence of AA amyloid increases 5- to 10-fold in Europe due to larger number of patients with chronic inflammatory disease. In the Western world, AA amyloidosis occurs in 0.5% to 0.86% of autopsies (7). In contrast to AL amyloidosis, we evaluated only 31 patients with AA amyloidosis at Boston University Medical Center between 1994 and 2002. Familial Mediterranean Fever (FMF), an autosomal recessive trait transmitted by a gene (MEFV) on the short arm of chromosome 16, constitutes up to 64% of AA amyloid cases in endemic areas such as Turkey (35,36). B.
Pathogenesis
Long-standing inflammatory conditions induce acute phase reactants such as interleukin-1b, interleukin-6, and tumor necrosis factor that, in turn, stimulate hepatic expression of serum amyloid A (SAA), the precursor of AA amyloidosis. AA amyloid fibrils are derived from an 8-kDa amino-terminal fragment of SAA (37). A number of hepatic SAA genes express a variety of apoproteins that complex high-density lipoproteins during blood stream transport. Interestingly, survival with AA amyloidosis is determined by renal involvement. Among 64 patients with AA amyloid, patients with normal renal function lived 57 months versus 11 months survival in patients with kidney failure (38). Cardiac or lung involvement did not influence survival. C.
Parenchymal Lung Disease
Clinical lung disease attributed to AA amyloid rarely occurs. The Mayo Clinic described 64 patients with AA amyloid, none of whom exhibited clinical heart or lung involvement (38). A more recent 14-year review at the Mayo Clinic reported two patients with diffuse interstitial opacities and AA amyloid (15). AA amyloid–induced interstitial lung disease has been reported after 28 years of
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rheumatoid arthritis (39) and in systemic lupus erythematosus (40). However, not all amyloid lung disease occurring in immunologically mediated disorders proves to be AA amyloid. Kobayashi et al. (41) reported k light chain amyloid nodular disease in a patient with Sjogren’s syndrome, while Orriols et al. (42) documented hypersensitivity pneumonitis complicated by Ig light chain alveolarseptal amyloid deposition. Pathology series confirm the clinical scarcity of lung disease in AA amyloidosis. Celli et al. (13) reported autopsy findings in seven patients with AA amyloid, none of who had signs or symptoms of lung disease. Amyloid deposits were identified in only three out of seven cases, limited to either lung vessels or airway walls. No interstitial amyloid was detected. An 88-year autopsy experience at Johns Hopkins included 113 cases of AA amyloid, with interstitial disease in one case (14). D.
Pleural Effusions
Four cases of pleural effusion and biopsy-proven pleural amyloid infiltration in patients with AA amyloidosis have been reported in the past 30 years (17–19). Three cases occurred in patients with long-standing rheumatoid arthritis and the remaining patient had cystic fibrosis. No amyloid-related pleural effusions have been reported in FMF. The rarity of pleural effusions in AA amyloidosis is further evidenced by the absence of pleural disease at autopsy in 113 AA patients (14), a registry of 287 Turkish AA patients (36), or autopsies of 7 patients— despite bronchial wall or pulmonary vessel amyloid deposition in over 70% (13). Amyloid cardiomyopathy is extremely unusual in AA amyloidosis, emphasizing the importance of pleural disruption by amyloid deposition in the formation of pleural effusions. Given the paucity of reports documenting amyloid-related pleural disease in this population, pleural effusions in AA patients should generally be ascribed to other causes. E.
Pulmonary Hypertension
One case of AA amyloid–induced pulmonary hypertension has been reported in a patient with FMF after 38 years of disease (43). Although pulmonary wedge pressures were mildly elevated (17 mmHg), PAP and PAP diastolic-wedge differentials (27 mmHg) greatly exceeded CHF-related pulmonary hypertension. The patient died before treatment could be initiated.
V.
Familial Amyloidosis
A.
Demographics
Familial amyloidoses are rare autosomal dominant disorders encompassing more than seven different genes and protein products. Transthyretin amyloidosis (ATTR) is the most common hereditary form of the disease, newly affecting
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1:100,000 to 1:1 million population or 2000 to 3000 ATTR cases each year in the United States (44). This incidence and the limited survivorship associated with the disease projects a total ATTR population of less than 200,000 patients in the United States—qualifying familial amyloidosis as an orphan disease. Portugal has the greatest world focus of ATTR (V30M) with over 100:100,000 population afflicted in two northern districts of Portugal (45). Gene carriers represent 1:625 population (46). Sweden represents the second largest world focus of V30M, with 3% to 5% of the population in Skelleftea and Pitea being affected (47). Untreated, death typically occurs within 5 to 15 years after disease onset. B.
Pathogenesis
Over 100 variant transthyretin (TTR) have been identified, each arising from different point mutations of a single gene located on chromosome 18 (18q11.2q12.1). The one amino acid substitutions alter the quaternary conformation of the 127 amino acid, 55-kDa TTR protein, destabilizing the native homotetramer configuration of TTR. Release of TTR monomers from the clusters of four molecules allows protein misfolding and amyloid fibril formation. Interestingly, many amino acid substitutions alter target organ involvement, producing different constellations of clinical disease. C.
Parenchymal Lung Disease
A large autopsy series from Johns Hopkins reporting findings in 223 patients collected over 88 years identified only three cases of familial (ATTR) amyloidosis (14). Two of these cases had alveolar-septal amyloid deposition but no pleural disease. A 14-year review of cases at Mayo Clinic Rochester had similar findings (15), reporting one patient with diffuse nodular radiographic opacities. In contrast, Ueda et al. (48) examined the lungs of 19 autopsied individuals with V30M ATTR amyloidosis ranging from 35 to 63 years old, documenting consistent amyloid deposition in bronchial walls and/or pulmonary vessels. Alveolar-septal deposits were restricted to individuals 47 years. Duration of clinical disease did not predict alveolar amyloid deposition. In the youngest cases, amyloid deposition in pulmonary arteries significantly exceeded pulmonary vein involvement. These data suggest that age of clinical disease onset influences the distribution of amyloid deposits in the lungs of ATTR patients. D.
Pleural Effusions
The Ueda et al. (48) autopsy series reported pleural effusions in all 19 individuals; however, hypoproteinemia was credited for the fluid collections, not ATTR amyloid.
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Pulmonary Hypertension
The data on amyloid infiltration of pulmonary arteries presented by Ueda et al. (48) predicts pulmonary hypertension in large numbers of ATTR amyloid patients. The absence of pulmonary hypertension publications, however, indicates that many of these autopsy findings represent clinically silent disease. VI. A.
Senile Systemic Amyloidosis Demographics
Senile systemic or age-related amyloidosis (SSA) results from the misfolding of wild-type transthyretin protein. Age-related amyloidosis occurs in systemic and localized (isolated atrial amyloid, senile aortic amyloidosis) forms. Elderly men are almost uniformly involved. Ng et al. (49) recently reported 18 SSA patients ranging in age from 67 to 86 years. B.
Parenchymal Lung Disease
Kunze (50) examined autopsied lung and heart tissue from 340 octogenarians, finding two predominant patterns of amyloid deposits in 49 cases: (i) combined vascular and alveolar-septal or (ii) isolated alveolar-septal disease. Typically concurrent heart and lung involvement occurred. The incidence of lung amyloid deposits increased with age, from 2% of cases <80 years old to 10% in cases 80 to 84 years old, and 20% in those older than 85 years. Alveolar-septal deposition always accompanied vascular deposits. Bronchial walls were never involved. Pitkanen et al. (51) performed detailed histologic evaluations of 24 organs harvested at autopsy in 13 patients with SSA. In all cases, nodular amyloid deposits occurred in alveolar septae and vessel walls. In advanced cases, amyloid deposits were also detected in the lamina propria of bronchi. Westermark et al. (52) examined 33 Swedes with advanced senile cardiac amyloidosis at autopsy, confirming the ubiquitous presence of alveolar septal amyloid in these cases. C.
Pleural Effusions
Three autopsy series including 33 Swedish SSA cases (52), 13 Swedish and American cases (51), and 50 lung-restricted dissections (50) did not report any pleural amyloid deposition.
VII. A.
Dialysis-Related Amyloidosis Demographics
A direct correlation between years of dialysis, prolonged exposure to b2 microglobulin (B2M), and dialysis-related amyloidosis (DRA) exists. In 54
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patients on hemodialysis (HD) for 2 to 163 months, articular biopsies demonstrated amyloid deposits in 21% after <2 years, 50% after 4 to 7 years, and 90% on HD for 7 to 13 years (53). Amyloid deposition is largely restricted to joints and bones, initially affecting knee and sternoclavicular synovium, carpal tunnel, and small hand joints.
B.
Pathogenesis
DRA is the product of exposure to high concentrations of B2M, an 11.8-kDa major histocompatibility glycoprotein expressed on cell surfaces and normally cleared by the kidney—but not by low-flux HD membranes. Recent data demonstrates that B2M clearance by high-flux membrane dialysis exceeds that achieved by peritoneal dialysis, intimating that peritoneal dialysis may be associated with a similar incidence of DRA if employed long enough.
C.
Parenchymal Lung Disease
Two forms of AB2M have been described: articular and visceral. Autopsy examination of 20 dialysis patients found AB2M in seven cases with 10 or more years of HD (54). Visceral deposition was greatest in the heart and GI tract, with less frequent lung involvement. Interestingly, only severe cases of GI deposition had clinical consequences; heart and lung deposition were clinically silent.
D.
Pleural Effusions
Suzuki et al. (19) reported right-sided pleural effusions, elevated pleural fluid protein (3.3 g/dL and 5.2 g/dL), parietal pleural thickening, and AB2M amyloid infiltration in two patients. In one case, the effusion occurred as the first manifestation of amyloidosis after 5 years of HD, and in the other case following carpal tunnel syndrome and 16 years of HD. In both instances video-assisted thoracoscopic biopsies were needed to establish the pleural diagnosis. The novelty of AB2M-related pleural effusions despite large numbers of patients undergoing long-term HD emphasizes the selectivity of AB2M organ deposition and the infrequency of DRA pleural disease.
E.
Pulmonary Hypertension
The one published case of AB2M pulmonary hypertension was attributed to amyloid-induced mitral valve insufficiency—not pulmonary artery amyloid deposition.
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Radiology of Systemic Amyloidosis (Table 3)
Table 3 Radiographic Manifestations of Systemic Amyloidosis Disease form
CXR
CT
AL (light chain)
Normal Interstitial opacities Pulmonary edema Pleural effusions
Normal airways Interstitial or alveolar opacities Minimal pleural thickening Dense lymph node calcifications Serosal surface calcification (rare)
Diaphragm elevation AA (secondary)
ATTR (hereditary) AB2M (dialysis related)
Calcified adenopathy Normal Diffuse interstitial opacities Pleural effusion (rare) Bronchiectasis Normal Cardiomegaly/CHF Interstitial opacities Normal Pleural effusion (rare)
Normal Interstitial/interlobular thickening Bronchiectasis Normal CHF/ground-glass opacities Alveolar-septal prominence Normal Pleural effusion
Abbreviations: CXR, chest X ray; CT, computed tomography; CHF, congestive heart failure.
VIII. A.
Localized Amyloidosis
Demographics
The incidence and prevalence of localized pulmonary amyloidosis is unknown. Lower respiratory (subglottic) amyloid disease presents in three localized forms: (i) tracheobronchial amyloid (TBA), (ii) nodular lung disease, and (iii) diffuse interstitial lung disease. An exhaustive compilation documented 290 cases of localized amyloidosis, including 138 cases of laryngeal, airway, and parenchymal lung disease (55). The median age for lower respiratory sites was 58.5 years (27– 80 year range) versus 49 years (33–77 years range) for sinonasal and laryngeal diseases (55–57). Follow-up ranged from 6 months to 23 years in 190 cases of localized disease, with 3 of 290 (1.0%) cases reportedly progressing to systemic disease (58,59). Thompson and Citron (60) reviewed 126 cases of localized lung amyloid finding 53% TBA, 44% nodular disease, and 3% interstitial disease. B.
Pathophysiology
Amyloid fibril protein typing in 132 localized cases revealed 120 AL (91%), 8 AA (6%), 3 ATTR (2%), and 1 AB2M (55). All analyzed lung-related cases have been composed of light chain (AL) immunoglobulin, typically encompassing the variable region of kI or lIII (61–63). The presence of clonal plasma
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cells expressing the same protein and DNA sequence as the amyloid deposits they surround implies a localized production and deposition process (64,65). ‘‘Progression’’ from localized to systemic disease most likely reflects failure to detect systemic biomarker expression at initial presentation. C.
Tracheobronchial Amyloidosis
TBA constitutes 23% of benign airway lesions assessed for laser surgery and 0.5% of symptomatic tracheal disease (66). Women experience earlier onset (52 vs. 59 years old) and more extensive disease than men (56,66,67). Symptoms of wheezing, dyspnea, cough, and hemoptysis typically prompt treatment for asthma and airway infections before establishing diagnosis a mean of 17 months later (56). Precipitants of disease onset remain undefined, although smoking does not appear causally related (56). In our experience at Boston University, patients with systemic AL disease do not manifest TBA disease—and those with TBA do not progress to systemic disease. The presence of monoclonal Ig protein in serum or urine has been reported in TBA (67,68). In the absence of other biomarker expression and amyloid biopsies documenting extrathoracic disease, these faint monoclonal bands appear to represent ‘‘leak’’ into capillary systems from the localized airway process. Three anatomic patterns of TBA exist, each with distinct pulmonary function test characteristics: (i) proximal trachea, (ii) mainstem bronchi, and (iii) distal airways. Proximal disease limits expiratory airflows, producing flowvolume loop changes consistent with extrathoracic upper airway obstruction. Mainstem bronchial disease affects large airways flow, decreasing FEV1/FVC ratio. In contrast, distal airway involvement results in decreased small airway or FEF 25 to 75 flows (56). Bronchoscopically, TBA appears as submucosal plaques or diffuse infiltration in 44% cases, nodular disease in 28%, and circumferential lesions in 28% (58). Treatment, historically, has focused on Nd:YAG and rigid bronchoscopic debridement to maintain airway patency (56,58,69). Kurrus et al. (70) successfully employed low-dose external beam radiation therapy (EBRT) on TBA with local disease control and durable effect over three years follow-up (personnel communications). In 2004, Berk et al. (71) reported a seven-patient experience treating TBA with 20-Gy EBRT over 10 sessions. Median follow-up was 12.7 months (range 5.6–27.2 months), with maximal clinical and physiologic benefit expressed at 12 to 16 months. Recently, Neben-Wittich et al. (72) reported a second sevenpatient experience using the 20-Gy regimen, detecting clinical effect at 4.1 months median follow-up. At present, we recommend laser therapy to maximize airway patency followed by EBRT to eradicate amyloidogenic clonal plasma cells and prevent disease progression. D. Nodular Lung Disease
Amyloid nodules are usually clinically silent and incidental radiographic findings, generally presenting at 64 years (73). Consequently, the true prevalence
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of amyloid nodules remains undetermined. Although occasionally diagnosed in systemic AL disease, amyloid nodules typically represent localized disease. Amyloid nodules range in size from 0.6 to 15 cm (3 cm, mean) (15,60,73), predominantly occur in subpleural areas of the lower lung fields as single (52%) or multiple nodules (48%), frequently calcify (26%), and may cavitate (10%) (73,74). Pulmonary nodules do not induce respiratory insufficiency or require specific therapy. When multiple nodules exist, surveillance for dyssynchronous nodule growth is important to identify cancers masquerading as amyloid. E.
Diffuse Interstitial Disease
This form represents 5% to 12% of localized disease in large series (73,74). The localized and systemic forms of diffuse interstitial (alveolar-septal) amyloidosis have nearly indistinguishable radiographic features, histology, and risk for developing respiratory insufficiency—with steroid unresponsiveness and 50% dying rapidly of respiratory failure (73,74). In our experience, patients with systemic AL amyloidosis and diffuse interstitial deposition have shorter survival than those with localized disease due to concomitant amyloid cardiomyopathy. Progressing localized diffuse interstitial amyloid warrants consideration of systemic therapy—despite the absence of biomarkers of systemic disease—to extinguish clonal plasma cell expansion and prevent further amyloid fibril formation. F.
Radiology of Localized Amyloidosis (Table 4)
Table 4 Radiographic Manifestations of Localized Amyloidosis Disease form
CXR
CT
Tracheobronchial
Normal Hyperinflation Airway calcification
Airway wall thickening Airway lumen narrowing Amyloid deposit calcification Irregular endolumenal surfaces Interstitial/interlobular thickening Adenopathy þ/ focal calcifications Smooth/lobulated lesions
Parenchymal
Nodular (AA and AL)
Volume loss/focal atelectasis Diffuse interstitial opacities Unilateral alveolar opacities 5 mm to 5 cm lesions Lower lung field predominance Calcification (29%) Cavitation (10%)
Often subpleural
PET
Variable FDG uptake
Solitary or multiple lesions
Abbreviations: CXR, chest X ray; CT, computed tomography; PET, positron emission tomography.
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35 Drug-Induced Pulmonary Disorders
FABIEN MALDONADO and ANDREW H. LIMPER Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A.
I.
Introduction
Interstitial lung diseases encompass a heterogeneous group of disease processes characterized by a variety of clinical, radiographical, and histopathological manifestations. The term ‘‘diffuse parenchymal lung diseases’’ may be preferred as it reflects more accurately the wide range of changes that can be observed histologically. Considerable efforts have been made to develop a coherent and organized classification of these disorders, but as our understanding of the various pathogenic mechanisms broadens, more unanswered questions appear both for clinicians and their patients. A new diagnosis of diffuse parenchymal lung disease triggers a battery of laboratory, microbiological, and histological investigations, which sometimes point to a defined etiological agent that can guide therapy. In virtually all cases of diffuse parenchymal lung disease, the possibility of drug-induced pulmonary toxicity should be systematically entertained and appropriate history obtained from the patient, including not only prescription medications, but also over-thecounter and herbal medications. This may represent a time-consuming task for the clinician as these histories are notoriously incomplete or unreliable, and as the use of some agents, such as illicit drugs, may not be easily volunteered. It is, however, a 809
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crucial step in the evaluation of a patient as it may preclude other onerous and lengthy investigations, and will lead to necessary therapeutic measures including discontinuation of the drug, and occasionally, the administration of corticosteroids.
II.
Diagnosis
The diagnosis of drug-induced lung disease nearly always remains a diagnosis of exclusion. To this day, no established criteria for the diagnosis of drug-induced lung diseases have been officially established, although several criteria have been suggested (1). Several factors may explain these limitations. First, except for rare situations where suggestive clues may be present (e.g., hilar lymphadenopathy in methotrexate toxicity), the pulmonary manifestations are rarely specific enough to clearly point to the suspected drug. The time frame in which pulmonary drug-induced toxicity occurs is also highly variable, ranging from acute hypersensitivity reactions (e.g., methotrexate, nitrofurantoin toxicities) to delayed presentations (e.g., nitrosoureas, or ‘‘radiation recall’’ seen with bleomycin, as discussed below). This along with the fact that combination treatments have become commonplace, in particular in the context of chemotherapy protocols, may further hamper the clinician’s ability to identify the culprit medication. In addition, several drugs may be implicated in an additive or synergistic fashion and further confuse the clinical picture. The patients’ underlying medical conditions should also be taken into consideration as coexisting cardiac or respiratory diseases may delay the recognition of a possible adverse drug reaction. Immunosuppressed patients represent a particularly complex situation as they are also predisposed to a myriad of opportunistic infections with various presentations and to uncommon presentations of typical infections. Finally, although some drugs with cumulative toxicity may have very predictable consequences (e.g., bleomycin), most druginduced pulmonary adverse reactions occur in a more randomly fashion and may be a function of the patient’s susceptibility profile, the chemical properties of the drug and other environmental factors (2). A great deal of research is being conducted to try to explain some of these inter- and intra-individual differences and may eventually explain why, for example, rechallenge with the same drug may not lead to the same disease process. As new classes of medications are discovered or engineered, new adverse pulmonary reactions are identified and explain the ever increasing list of agents, which have been linked to this type of reactions. A review of this topic in 1972 reported 19 drugs with potential pulmonary toxicity (3). Currently, more than 350 drugs have been identified, since less than 5% of all drug-induced respiratory complications may be reported (4). The mechanisms by which drugs may lead to adverse pulmonary reactions are still incompletely understood. Several types of pulmonary toxicity have however been described in details and are thought to explain most of these
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adverse drug effects. Direct cytotoxicity is frequently cited for chemotherapeutic agents although other mechanisms may also occur. Hypersensitivity reactions, oxidative injury, and immune-mediated tissue insult have also all been demonstrated with various agents. Virtually all histopathological patterns described in diffuse parenchymal lung diseases have been reported with drug-induced pulmonary toxicity: diffuse alveolar damage (DAD), nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, eosinophilic pneumonia, organizing pneumonia with or without bronchiolitis obliterans, and diffuse alveolar hemorrhage (1). Even druginduced noncaseating granulomas, reminiscent of sarcoidosis, and a form of alveolar proteinosis have been described. For the reasons explained above, the diagnosis is often difficult to make and requires a high level of clinical suspicion. Indeed, various histological presentations may be induced by one drug and may sometimes coexist in the same pathological sample. In every case, alternative explanations for the respiratory symptoms observed must be carefully excluded. A constellation of suggestive clinical and radiographical findings, and if necessary, supported by a compatible histopathological diagnosis should alert the clinician and prompt discontinuation of the drug. In selected cases, the initiation of judicious corticosteroid therapy may also be indicated.
III. A.
Chemotherapeutic Agents Bleomycin
Bleomycin is an antibiotic chemotherapeutic agent, which has been used since 1966 for the treatment of various neoplastic conditions including lymphomas, germ cell tumors and carcinomas of the head and neck. Bleomycin’s propensity to cause pulmonary toxicity was recognized early following its introduction and remains the main limiting factor of this chemotherapeutic agent. Although it is by far the most studied model of drug-induced lung disease in animals, all the mechanisms by which it exerts adverse reactions are not completely understood. Bleomycin accumulates in the lungs and in the skin due to a relative deficit of an enzyme responsible for its metabolism (bleomycin hydrolase) in these tissues (5). It is also eliminated by the kidneys. As a result, uremia may potentiate its toxicity. Extreme of age seems to worsen lung toxicity as well. Bleomycin is a direct cytotoxic agent and leads to the formation of characteristic atypical type 2 pneumocytes and a relative paucity of type 1 pneumocytes. These changes, although suggestive of bleomycin-induced lung toxicity, are not diagnostic, for example, bleomycin complexes, ferrous ions, and oxygen promoting the generation of oxygen free radicals. These highly reactive agents lead to a fragmentation of the cell’s DNA in a cycle-dependent fashion and cellular death ensues (6). Supplemental oxygen, a commonly used adjunct therapy, can worsen
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this process. Radiation therapy may also have a synergistic effect with bleomycin toxicity by enhancing the production of free radicals. Inflammatory cells and fibroblasts are subsequently recruited into injured airspaces and the interstitium with initiation of collagen deposition. Bleomycin may also activate pulmonary fibroblasts directly, and has been used in animal models as a reliable and consistent promoter of pulmonary fibrosis. Finally, angiogenesis may be impaired by bleomycin, another mechanism by which it may exert its antitumoral effects. This effect may act to inhibit the repair and clearance of lung injury induced by bleomycin, leading to irreversible scarring. Importantly, the toxicity of bleomycin is cumulative. Total doses in excess of 450 units are associated with a significantly increased incidence of adverse lung reactions and death. The incidence of bleomycin-induced lung toxicity has been reported between 0% and 46% with a mortality rate of 3% (5,7). As mentioned above, high cumulative dose, extreme of age, uremia, the use of supplemental oxygen, and radiation therapy are well-documented risk factors for bleomycin toxicity. Other chemotherapeutic agents (cyclophosphamide and vincristine) may also have a synergistic effect with bleomycin. Finally, bleomycin may occasionally reactivate a prior radiation-induced pneumonitis, a phenomenon known as ‘‘radiation-recall.’’ The subacute onset of respiratory symptoms is the common clinical presentation observed with bleomycin toxicity. Pulmonary function studies (PFT) typically demonstrate a restrictive pattern, with decreased diffusing capacity of lung for carbon monoxide (DL CO). Although of questionable benefit, serial screening PFT’s are still recommended by some experts. Vital capacity and pulmonary capillary blood flow, rather than DLCO, may be valuable prognostic tools (5). Imaging studies typically show a nonspecific interstitial pattern with basal and subpleural predominance. Nodular infiltrates may be seen and mistaken for metastatic lung disease. Bronchoscopy with biopsies is usually recommended to rule out alternative diagnoses such as infections. However, a pathology sample is not absolutely required for the diagnosis. Histopathologically, the lesions may have the appearance of either a usual interstitial pneumonitis or nonspecific interstitial pneumonitis pattern. The lung nodule form of bleomycin toxicity is typical due to organizing pneumonia when biopsied. The nodular forms, hence, often respond dramatically to corticosteroid therapy. Alveolar infiltration by eosinophils and peripheral eosinophilia may be seen in the hypersensitivity pneumonitis form of bleomycin toxicity, representing less than 10% of cases. Pulmonary veno-occlusive disease has also been described with bleomycin and may present clinically with pulmonary edema and pulmonary hypertension. Successful therapy of bleomycin toxicity hinges on early recognition. Immediate discontinuation of the drug is mandatory. A trial of corticosteroid is a reasonable option and may prevent the progression to pulmonary fibrosis, although supported by anecdotal evidence only. Unfortunately, despite these measures, some patients experience progressive lung fibrosis.
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Mitomycin C
Between 8% and 39% of patients treated with mitomycin C have the evidence of pulmonary toxicity. This alkylating agent is used for a variety of tumors including bladder, prostate, breast, and lung cancer. Its use is also mainly limited by its pulmonary side-effect profile. Like bleomycin, the toxicity of mitomycin C is cumulative and pulmonary fibrosis is rare at doses less than 30 mg/m2 (8). The typical presentation is similar to that observed with bleomycin with the subacute development of an interstitial pneumonitis usually within the first year of initiation of therapy. Increased fraction of inspired oxygen, radiotherapy or concomitant administration of certain chemotherapeutic agents may also be synergistic with this agent. Dry cough and shortness of breath are typically reported by the patient. Imaging studies demonstrate the presence of nonspecific interstitial infiltrates with basal and subpleural predominance. PFT generally show a restrictive pattern with decreased DLCO, although rarely an obstructive component secondary to bronchospasm may be present instead. Screening PFT are of uncertain value. Histologically, these lesions correspond to UIP or NSIP. The administration of high doses of steroids may prevent the progression to fibrosis, although the evidence remains scarce. Combination therapy with vinca alkaloids has been associated with a more acute presentation, which histologically corresponds to DAD. The response to steroids is incomplete but may prevent progression to fibrosis. Diffuse alveolar hemorrhage and pulmonary veno-occlusive disease have also been reported (1). One specific manifestation of mitomycin C is the development of a thrombotic microangiopathy similar to the hemolytic and uremic syndrome. It is associated with noncardiogenic pulmonary edema in 50% of the cases. Mortality is high from 50% to 95% when associated with pulmonary edema. Treatment is supportive with plasmapheresis, steroids, and occasionally dialysis. C.
Busulfan
The pulmonary toxicity of busulfan was first reported in 1961. No clear risk factors for the development of lung toxicity have been consistently identified. The reported incidence of lung toxicity is 6% (4). The onset is typically subacute with fever and dry cough. Bleomycin is histologically characterized by NSIP or UIP. Pulmonary veno-occlusive disease and DIP have also been reported (1). Occasionally, busulfan may lead to alveolar proteinosis secondary to massive deposition of intracellular debris. This form of alveolar proteinosis is poorly responsive to whole lung lavage, and the role of steroids is not clearly established (9). D.
Cyclophosphamide
Cyclophosphamide is an alkylating agent used in a variety of malignant, inflammatory, and autoimmune diseases. The prevalence of drug toxicity is low, likely
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occurring in less than 1%. Two temporal patterns of injury have been described; early toxicity, occurring during the first 6 months of therapy, and late toxicity, which may occur years after initiation of therapy (10). The early form may respond to discontinuation of the drug and administration of corticosteroids. The later form tends to be more resistant to such maneuvers. Histologically, they typically correspond to NSIP or UIP. Cyclophosphamide has sometimes been reintroduced without recurrence of lung toxicity, although this is generally not recommended. E.
Other Alkylating Agents
Chlorambucil, melphalan, ifosfamide, and procarbazine have rarely been associated with the development of interstitial pneumonia (4). Discontinuation of the drug with or without corticosteroid therapy is recommended. F.
Methotrexate
Methotrexate is a frequently encountered drug used to treat a number of inflammatory conditions including rheumatoid arthritis, sarcoidosis, and psoriasis. Methotrexate-induced lung toxicity is thought to occur in approximately 10% of patients (11). A recent case-control study suggests that the relative risk of developing methotrexate-induced interstitial lung disease in patients with rheumatoid arthritis that take methotrexate may be 1.5 to 6.4 fold higher than in similar patients who do not use this agent (11). It usually consists of a hypersensitivity reaction characterized by the sudden onset of fever, cough and shortness of breath. Hypereosinophilia is present in more than 50% of the cases, and mediastinal lymphadenopathy may strongly suggest the diagnosis. PFT show restriction and decreased DLCO. Lung biopsies when obtained, may demonstrate the presence of ill-defined granulomas. Less commonly, the onset is subacute and NSIP or UIP patterns may be observed. Opportunistic infections secondary to T-cell deficiency need to be excluded, particularly Pneumocystis jireveci pneumonia (12). Non-Hodgkin’s lymphomas have also been described in the setting of methotrexate usage. G.
Carmustine (BCNU) and Other Nitrosoureas
These alkylating agents are related to nitrogen mustard, a chemical warfare agent subsequently discovered to be effective for the treatment of lymphoma in the early 1940’s. Their ability to cross the blood-brain barrier makes them agents of choice for the treatment of brain tumors. The cumulative dose of carmustine appears to be the most reliable predicting factor of lung toxicity, which occurs in 1.5% to 20% of the cases, especially when the dose exceeds 1400 mg/m2 (13). Toxicity can either occur acutely during the active phase of treatment, but may also occur in a delayed fashion years and sometimes decades after discontinuation of the drug, leading to irreversible fibrosis, which preferentially targets the lung apices (Fig. 1). Lung biopsies reveal either UIP or NSIP, when obtained, though tissue examination is often not necessary for the diagnosis.
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Figure 1 Chest radiograph in a male with carmustine-induced pulmonary toxicity. Note the predominant upper lobe distribution of the pulmonary infiltrates typical of nitrosourea toxicity.
Pulmonary veno-occlusive disease has also been reported with these agents (1). The role of corticosteroid therapy is unclear, though often proves ineffective. Cases of pulmonary fibrosis and pneumothoraces have rarely been reported with other nitrosourea agents (CCNU, methyl-CCNU, and DCNU). H.
Other Antimetabolites
Cytosine arabinoside has been associated with noncardiogenic pulmonary edema and diffuse alveolar hemorrhage (Fig. 2). Gemcitabine, a pyrimidine analog recently introduced in the treatment of non–small cell lung cancers, causes pulmonary toxicity in about 1% of the cases. Interstitial fibrosis, pulmonary edema, diffuse alveolar hemorrhage, and veno-occlusive disease have been described. More recently, fludarabine, a nucleoside analog, may also induce nonspecific interstitial pneumonitis in up to 8.6% of the cases. Affected individuals experience dyspnea as early as three days after the first round of fludarabine therapy, though later onset of pulmonary symptoms have also been reported. The chest radiograph often demonstrates either interstitial or mixed alveolar-interstitial infiltrates. Most patients respond to discontinuation of this drug and receive symptomatic and objective benefits from additional corticosteroid therapy. Finally, there have been a few reports to suggest that azathioprine and its metabolite, 6-mercaptopurine, may also induce pulmonary fibrosis.
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Figure 2 Computerized tomography image of a patient with pulmonary toxicity related to cytosine arabinoside. Alveolar ground-grass infiltrates are present, which correspond to regions of acute lung injury.
I.
Novel Agents
Transretinoic acid has dramatically changed the management of acute promyelocytic leukemia. It allows the maturation of leukemic cells and induces remission. It is typically used in association with daunorubicin and cytosine arabinoside. The retinoic acid syndrome occurs in 25% of patients and consists of a capillary leak syndrome with noncardiogenic pulmonary edema (14). Diffuse alveolar hemorrhage is also a well-documented complication. Gefitinib is a tyrosine kinase inhibitor used in the treatment of refractory non–small cell carcinoma of the lung. Respiratory failure has been observed in 1% of the cases with a 30% fatality rate and corresponds histologically to DAD with possible progression to fibrosis (4). Diffuse alveolar hemorrhage has also been reported. Rare cases of pulmonary complications with imatinib mesylate (used in chronic myelogenous leukemia) have also been described. Bevacizumab is a monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). It is used for treatment of patients suffering from advanced cancers including metastatic colorectal cancer, metastatic breast, and locally advanced nonsquamous, non–small small cell lung cancer. Dyspnea and life-threatening hemoptysis with or without pulmonary infiltrates is the most serious adverse effect of bevacizumab (15). The inhibition of VEGF is a likely mechanism involved in the destruction of normal lung tissue and subsequent hemoptysis. Squamous cell lung cancer seems to be particularly prone to this complication and this treatment should be avoided in this subgroup of patients. A granulomatous reaction indistinguishable from sarcoidosis has been described with the use of interferons (16). A subacute progression to fibrosis has
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also been reported. Other immune modulatory agents like interleukin 2 and TNFa may induce pulmonary edema. Diffuse alveolar hemorrhage has also been reported with TNF-a. J.
Other Agents
Irinotecan, a semisynthetic camptothecin, is used in the treatment of metastatic colorectal cancer. The rate of pulmonary toxicity is estimated around 1%. Pulmonary fibrosis and noncardiogenic pulmonary edema have been described. Topotecan is a similar agent that has rarely been associated with bronchiolitis obliterans. Vinblastine, a tubulin-binding agent, may induce interstitial pneumonitis, bronchospasm, lung nodules, and pulmonary edema. Paclitaxel, used in the treatment of breast and ovarian cancer, may induce hypersensitivity pneumonitis, pulmonary fibrosis, and pulmonary edema. Though uncommon, prolonged use of etoposide (VP-16) for the treatment of lung cancer may also trigger DAD. Finally, zinostatin may cause interstitial pneumonitis and induce pulmonary endothelial hypertrophy (4). IV.
Antibiotics
A.
Nitrofurantoin
Pulmonary toxicity is a commonly encountered side effect of nitrofurantoin thought to occur in 1% of the cases (3). It is typically used prophylactically to prevent urinary tract infections and understandably, most patients are older female patients (17). This information may not be systematically volunteered by the patients. Hence, a high degree of suspicion is required to make the diagnosis. Two temporal patterns of pulmonary toxicity have been described. The common scenario is the acute development of a hypersensitivity reaction characterized by sudden onset of fever, rash, and peripheral eosinophilia. Respiratory symptoms consist of dry cough and shortness of breath. This reaction usually occurs within a few hours to a few days after initiation of therapy. Imaging studies demonstrate nonspecific diffuse alveolar and interstitial infiltrates with basal predominance. Pleural effusions are present in one-third of the cases and may be clinically responsible for severe pleuritic chest pain. The delayed form of nitrofurantoin toxicity may occur years after initiation of therapy. It is a rather infrequent presentation that does not seem to be related to the acute presentation. Histologically, UIP or NSIP are commonly observed, although other less common patterns have been described including organizing pneumonia, desquamative interstitial pneumonia, DAD, and diffuse alveolar hemorrhage (17). The treatment is essentially supportive and consists of discontinuation of the drug. Corticosteroids are not thought to be helpful and are generally not recommended. B.
Sulfasalazine
Sulfasalazine is an antibiotic used in the treatment of inflammatory diseases such as inflammatory bowel diseases and rheumatoid arthritis. Several forms of
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pulmonary toxicities have been reported and include pulmonary fibrosis, pulmonary infiltrates with eosinophilia, desquamative interstitial pneumonia, druginduced lupus with pleural and pericardial effusions, and vasculitis. It is important to keep in mind that both inflammatory bowel disease and rheumatoid arthritis are also independently associated with a host of respiratory manifestations, which may have confounded these reports. Nevertheless, an adverse reaction should be considered and the drug discontinued. Corticosteroids may offer additional benefit in most cases (4). C.
Other Antibiotics
Various antibiotics, in particular sulfonamides, beta-lactam compounds, tetracycline and ethambutol, may induce pulmonary toxicities, which usually consist of pulmonary infiltrates with eosinophilia. Drug-induced lupus states have also been reported with minocycline and tetracycline, nalidixic acid, sulfonamides, and nitrofurantoin (1). V.
Cardiovascular Medications
A.
Amiodarone
Amiodarone-induced pulmonary toxicity (APT) is one of the most frequently encountered drug reactions, and occurs in 1% to 15% of treated patients (18). Other adverse reactions related to amiodarone include thyroid dysfunction, liver toxicity, skin changes, and corneal deposits. Several mechanisms of toxicity have been described. Amiodarone is an amphiphilic compound, which binds phospholipids leading to their accumulation in tissues, with subsequent disruption of the membranous and cytoplasmic cellular functions. The high turnover of phospholipids may explain why the lungs seem preferentially involved (4). Histologically, this results in the characteristic appearance of foamy macrophages. Amiodarone may also induce the generation of oxygen free radicals, resulting in direct cytotoxicity. Hypersensitivity reactions with eosinophilia may also be seen in about 10% of cases. Doses in excess of 400 mg/day for a period of at least two months are typically required for toxicity to occur. However, respiratory complications have been reported with much lower doses and some presentations are independent of the cumulative effect. For instance, the development of acute respiratory distress syndrome characterized microscopically by DAD may follow surgical procedures and heart catheterization, in particular when high fractions of inspired oxygen are used, suggesting a synergistic effect of oxygen and radiocontrast agents. Organizing pneumonia can also occur in a subacute fashion with the insidious onset of fever, cough and shortness of breath, and is typically responsive to discontinuation of the drug and corticosteroids. Because of the long half-life of the drug, short courses of steroids have been associated with recurrance, on completion of therapy. Solitary pulmonary nodules, usually pleural
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based, may suggest malignancy but often are due to localized organizing pneumonia and resolve after discontinuation of the drug. Pulmonary fibrosis is an infrequent complication of long-term amiodarone therapy. Cases of diffuse alveolar hemorrhage have also been described. As always, the diagnosis remains a diagnosis of exclusion. The presence of foamy macrophages on lung biopsies is characteristic, although not pathognomonic of APT. Such macrophages represent exposure to the agent rather than toxicity. Likewise, low-attenuation infiltrates on CT scan without contrast explained by the high iodine content of amiodarone may also be seen but are nonspecific. Gallium scans have been suggested to differentiate APT from noninflammatory infiltrates secondary to congestive heart failure but are not routinely performed. Screening PFTs do not seem to predict lung toxicity (18,19). The diagnosis is sometimes difficult to make but should prompt discontinuation of the drug and initiation of corticosteroids as clinically indicated. B.
Other Cardiovascular Drugs
Hydrochlorothiazide has been associated with the onset of noncardiogenic pulmonary edema. There are well-documented cases of recurrence of symptoms after rechallenge with the drug. Protamine, used to reverse the anticoagulant effects of heparin, may also induce noncardiogenic pulmonary edema. Procainamide may induce nonspecific intersitial pneumonia and drug-induced lupus. Tocainide may induce pulmonary fibrosis (4). Angiotensin-converting enzyme antagonists, though strongly associated with the development of cough, do not usually result in diffuse pulmonary infiltrates. More recently, statins used in the treatment of hypercholesterolemia, have been preliminarily associated with lung infiltrates and interstitial lung disease in a few patients (20). While these initial reports are intriguing, the relative incidence of this reaction appears to be fairly unusual, based on the widespread use of these agents. VI. A.
Anti-inflammatory Medications Penicillamine
D-Penicillamine is used in the treatment of rheumatoid arthritis. Several types of pulmonary toxicities have been described with this agent. A pulmonary-renal syndrome similar to Goodpasture’s syndrome has been rarely described and is fatal in *50% of the cases. Hemoptysis and hematuria are present in an acute fashion and warrant prompt discontinuation of the drug. Anti-glomerular basement membrane antibodies are not found and the role of plasmapheresis in undetermined. Treatment with corticosteroids or immunosuppressive agents may be of benefit (21). Bronchiolitis obliterans with or without organizing pneumonia has also been reported, but is also described with rheumatoid arthritis. Hypersensitivity pneumonitis and the subacute onset of pulmonary fibrosis have been
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reported in 3% of the patients and are usually responsive to discontinuation of the drug and initiation of corticosteroids. B.
Gold
Gold is an immunomodulatory agent, still occasionally used in the treatment of refractory rheumatoid arthritis. Pulmonary complications are more commonly seen in women (women to men ratio of 4:1), and typically consists of a hypersensitivity reaction heralded by the sudden onset of cough, shortness of breath, and peripheral eosinophilia. A more subacute presentation is also possible with the insidious onset of dry cough and shortness of breath with progression to diffuse fibrosis. Bronchiolitis obliterans with or without organizing pneumonia has also been reported. Discontinuation of the drug and corticosteroids are indicated. C.
Other Anti-inflammatory Agents
Nonsteroidal anti-inflammatory medications may occasionally induce pulmonary infiltrates and eosinophilia. Drug-induced lupus erythematosus and noncardiogenic pulmonary edema have also been described. Leukotriene inhibitors have been extensively used in the treatment of asthma and may be associated with the development of Churg-Strauss syndrome including pulmonary infiltrates, eosinophilia, and cardiac dysfunction, though this relationship is controversial and not definitively established. These manifestations have been attributed to the discontinuation of systemic or inhaled steroids leading to a flare of a previously clinically silent vasculitis rather than to the leukotriene inhibitors themselves (22). VII.
Illicit Drugs
The pulmonary complications of heroin use continue to represent a major source of mortality and morbidity (23). Noncardiogenic pulmonary edema is seen in up to 40% of patients hospitalized for heroin intoxication. Treatment is essentially supportive and consists of supplemental oxygen, and if clinically indicated, endotracheal intubation and mechanical ventilation. Intravenous naloxone may help. Bronchiectasis and necrotizing bronchitis have also been reported but may be secondary to recurrent aspirations rather than to an effect of the drug itself. Similar manifestations have been reported with other opioid derivatives such as methadone and propoxyphene. Intravenous injections on methylphenidate for intoxication purposes have been associated with the development of panacinar emphysema. Intravenous use of drugs mixed with talc may induce talc granulomatosis in 15% to 80% of the cases. Micronodular-calcified infiltrates are seen on imaging studies. PFT may show restriction or a mixed obstructive-restrictive pattern. Biopsies are characterized by the presence of strongly birefringent crystals within granulomas.
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Pulmonary hypertension may result from granulomatous infiltration of the pulmonary arteries with progression to plexiform lesions and irreversible pulmonary hypertension. Cocaine can cause of host of respiratory complications, including noncardiogenic pulmonary edema with DAD, hemoptysis, hypersensitivity pneumonitis, diffuse alveolar hemorrhage, and bronchiolitis obliterans with or without organizing pneumonia. Black carbonaceous material in the sputum can be a useful clinical finding suggesting the diagnosis. In addition, Valsalva maneuvers frequently used to enhance absorption of crack cocaine may precipitate pneumothoraces or pneumomediastinum. A.
Miscellaneous Agents
A host of other medications may lead to pulmonary complications. An exhaustive analysis of these medications is beyond the scope of this review. The adverse effect of supplemental oxygen is worth mentioning. Pulmonary toxicity is well established in animal models, but difficult to assess and quantify in patients treated for prolonged periods with high fraction of supplemental oxygen. Noncardiogenic pulmonary edema with DAD and secondary progression to pulmonary fibrosis are possible. Extrinsic lipoid pneumonia may be caused by aspiration of mineral oil–based laxatives or oil nose drops. Histological findings are characteristic and show abundance of lipid-laden macrophages. Imaging studies typically show alveolar consolidation in the lower lung zones with low-attenuation infiltrates on the CT scan. VIII.
Conclusions
Drug-induced pulmonary toxicity should systematically be considered when investigating intersitial lung diseases and bronchiolar disorders. The list of drugs is ever expanding and it may be necessary for the clinician to refer to exhaustive sources of information such as the web site pneumotox.com, where the updated information on drug-induced pulmonary toxicity is compiled. It is sometimes helpful to directly contact the drug manufacturer. A high degree of suspicion is required to make the diagnosis. Discontinuation of the drug with judicious initiation of corticosteroids, when clinically indicated, are the treatment of choice. Rechallenge after resolution of the pulmonary complications is rarely justified. References 1. Camus P, Fanton A, Bonniaud P, et al. Interstitial lung disease induced by drugs and radiation. Respiration 2004; 71(4):301–326. 2. Delaunois LM. Mechanisms in pulmonary toxicology. Clin Chest Med 2004; 25:1–14.
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3. Rosenow EC. The spectrum of drug-induced pulmonary disease. Ann Intern Med 1972; 77:977–991. 4. Limper AH. Drug-induced pulmonary disease. In: Murray JF, Nadel J, eds. Textbook of Respiratory Medicine, 4th ed. Philadelphia: WB Saunders; 2005. 5. Sleijfer S. Bleomycin-induced pneumonitis. Chest 2001; 120:617–624. 6. Chandler DB. Possible mechanisms of bleomycin-induced fibrosis. Clin chest Med 1990; 11:21–30. 7. Simpson AB, Paul J, Graham J, et al. Fatal bleomycin pulmonary toxicity in the west of Scotland 1991–1995: a review of patients with germ cell tumors. Br J Cancer 1998; 78:1061–1066. 8. Verweij J, van Zenten T, Souren T, et al. Prospective study on the dose relationship of mitomycin C-induced interstitial pneumonitis. Cancer 1987; 60:756–761. 9. Aymard JP, Gyger M, Lavallee R, et al. A case of pulmonary alveolar proteinosis complicating chronic myelogenous leukemia. Cancer 1984; 53:954–956. 10. Malik SW, Myers JL, DeRemee RA, et al. Lung toxicity associated with cyclophosphamide use. Two distinct patterns. Am J Respir Crit Care Med 1996; 154: 1851–1856. 11. Suissa S, Hudson M, Ernst P. Leflunomide use and the risk of interstitial lung disease in rheumatoid arthritis. Arthritis Rheum 2006; 54:1435–1439. 12. Kaneko Y, Suwa A, Ikeda Y, et al. Pneumocystis jiroveci pneumonia associated with low-dose methotrexate treatment for rheumatoid arthritis: report of two cases and review of the literature. Mod Rheumatol 2006; 16:36–38. 13. Weinstein AS, Diener-West M, Nelson DF, et al. Pulmonary toxicity of carmustine in patients treated for malignant glioma. Cancer Treat Rep 1986; 70:943–946. 14. De Botton S, Dombret H, Sanz M, et al. Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1998; 92:2712–2718. 15. Cohen MH, Gootenberg J, Keegan P, et al. FDA drug approval summary: bevacizumab plus carboplatin and paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non–small cell lung cancer. Oncologist 2007; 12:713–718. 16. Rubinowitz AN, Naidich DP, Alinsonorin C. Interferon-induced sarcoidosis. J Comput Assist Tomogr 2003; 27:279–283. 17. Mendez JL, Nadrous HF, Hartman TE, et al. Chronic nitrofurantoin-induced lung disease. Mayo Clin Proc 2005; 80:1298–1302. 18. Camus P, Martin WJ II., Rosenow EC. Amiodarone pulmonary toxicity. Clin Chest Med 2004; 25:65–75. 19. Gleadhill IC, Wise RA, Schonfeld SA, et al. Serial lung function testing in patients treated with amiodarone: a prospective study. Am J Med 1989; 86:4–10. 20. Walker T, McCaffery J, Steinfort C. Potential link between HMG-CoA reductase inhibitor (statin) use and interstitial lung disease. Med J Aust 2007; 186:91–94. 21. Camus P, Reybet Degat O, Justrabo E, et al. D-penicillamine induced severe pneumonitis. Chest 1982; 81:376–378. 22. Weller PF, Plaut M, Taggart V, et al. The relationship of asthma therapy and ChurgStrauss syndrome: NIH workshop summary report. J Allergy Clin Immunol 2001; 108:175–183. 23. Wolff AJ, O’Donnell AE. Pulmonary effects of illicit drug use. Clin Chest Med 2004; 25:203–216.
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Index
ABPA. See Allergic bronchopulmonary aspergillosis (ABPA) ACE. See Angiotensin-converting enzyme (ACE) Acquired immune deficiency syndrome (AIDS), and LIP, 406, 407, 409 Acute beryllium disease, 295–296 Acute exacerbations, of IPF, 347 Acute fibrinous and organizing pneumonia (AFOP), 392 Acute interstitial pneumonia (AIP), 20, 389–396. See also Pneumonia clinical features, 390–392 current case definition, 390 differential diagnosis, 394–395 historical perspective, 389–390 management, 395 pathogenesis, 392–394 pathology, 392 pathology of, 100–101 published case series of, 396 radiographic findings, 391–392 survival rates, 395–396 thoracic imaging for, 20 Acute pulmonary edema, in BMT, 563–564 Acute rheumatoid pneumonitis, 493 Adults infectious and postinfectious bronchiolitis in, 533–535 LIP in, 407, 409 Aerosolized GM-CSF, in PAP, 780 AFP. See Alpha-fetoprotein (AFP)
AIDS. See Acquired immune deficiency syndrome (AIDS) AIP. See Acute interstitial pneumonia (AIP) Airways obstruction. See also Lower airway; Upper airway in LAM, 754–755 in rheumatoid arthritis, 489 Alkylating agents, in pulmonary toxicity, 814 Allergic bronchopulmonary aspergillosis (ABPA), 711–712 Allergic bronchopulmonary mycoses. See Allergic bronchopulmonary aspergillosis (ABPA) Alpha-fetoprotein (AFP), 252 Alport’s syndrome, Goodpasture’s syndrome in, 674 Alveolar-arterial oxygen gradient [P(A-a)O2], 275 Alveolar hemorrhage, diffuse in BMT, 565–566 in SLE, 495–496 Wegener’s granulomatosis in, 614 Alveolar macrophages (AM), in sarcoidosis, 168–169 Alveolitis, 438 American College of Rheumatology (ACR), on Wegener’s granulomatosis, 606–607 Amiodarone, in pulmonary toxicity, 818–819 Amiodarone-induced pulmonary toxicity (APT), 818–819
823
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824 Amyloidosis classification of, 789–790 localized syndromes demographics, 801 diffuse interstitial disease, 803 nodular lung disease, 802–803 pathophysiology, 801–802 radiology of, 803 TBA, 802 overview, 789 systemic syndromes dialysis-related amyloidosis, 799–800 familial amyloidosis (AA), 797–799 primary systemic (AL), 791–796 radiology, 801 secondary amyloidosis (AA), 796–797 SSA, 799 Amyopathic dermatomyositis, 453 ANCA. See Antineutrophil cytoplasmic autoantibodies (ANCA) Ancillary tests, of patients with DPLD, 8–9 Anemia, in Goodpasture’s syndrome, 681 Angioimmunoblastic lymphadenopathy (AIBL), 412 Angiotensin-converting enzyme (ACE), 78 Animal experiments, for ANCA, 596–599 Antibiotics, in pulmonary toxicity nitrofurantoin, 817 sulfasalazine, 817–818 Anticoagulants, for IPF, 351 Anti-endothelial autoantibodies (AECA), 595 Anti-GBM antibody disease. See Goodpasture’s syndrome Anti-glomerular basement membrane (anti-GBM) disease, 593–594 Anti-inflammatory agents for Behc¸et’s disease (BD), 702–703 in pulmonary toxicity gold, 820 leukotriene inhibitors, 820 penicillamine, 819–820 Antimalarial agents. See Hydroxychloroquine/chloroquine
Index Antineutrophil cytoplasmic antibodies (ANCA) in Goodpasture’s syndrome, 681, 682 immunoglobulin G (IgG), 595 microscopic polyangiitis, 658–660 vasculitis associated with, 591–600 autoimmune response, 599–600 epidemiology, 592–593 interrelationships between multiple factors, 600 pathogenesis, 595–599 pathology, 593–594 serology, 594–595 in Wegener’s granulomatosis, 618–619 Anti-synthetase syndrome, 454, 497 Antithymocyte globulin (ATG), for Wegener’s granulomatosis, 627–628 Anti-TNF, 599 Apical fibrobullous disease, in rheumatoid arthritis, 492 Arava1. See Leflunomide ARDS clinical research network (ARDSnet), for corticosteroids in AIP, 395 Arterial blood gas, in DPLD, 7 Arthritis, 251 rheumatoid. See Rheumatoid arthritis Asbestos deposition during inhalation of, 318–319 fibers role in pathogenesis of asbestosis, 323–325 Asbestosis, 317–328 asbestos fibers in, 322–325 inhaled particles’ deposition, 318–319 pathobiological responses of, 319–328 ROS and, 327–328 Ascaris lumbricoides, 711 Aspiration pneumonia, 497 Asthma and CSS, 647–648 post-WTC attacks, 579–581 Azathioprine (AZA) for ILD, 131–133 for IPF, 349–350 for systemic sclerosis-ILD, 440 for Wegener’s granulomatosis, 624 Azithromycin, treating OB, 552–553
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Index BAL. See Bronchoalveolar lavage (BAL) BALT. See Bronchus-associated lymphoid tissue (BALT) Basement membrane Goodpasture’s syndrome, 672–674 inflammation in IPF and alveolar-capillary, 340–342 Battery Park residents study, 581 B-cell lymphomas, and LIP, 409 Behc¸et’s disease (BD) anti-inflammatory drugs for, 702–703 clinical manifestations of, 697–698 computed tomography (CT) for, 701 epidemiology, 695–696 etiology of, 696 HLA-B51 and, 696 immunosuppression for, 702 invasive diagnostic imaging, 702 ISG criteria for, 698 MRI, 701 pathology, 696–697 penicillin, 703 pleural effusion, 701 pulmonary vascular disease, 699–700 scintigraphy, 701–702 surgical treatment, 703 Berylliosis. See Chronic beryllium disease (CBD) Beryllium. See also Chronic beryllium disease (CBD) diseases caused by, 295–299 disease susceptibility, 293–297 exposure and toxicology of, 291–293 historical perspective of exposure, 291 immunopathogenesis and, 293–295 industries using, 290 sensitization, 296–297 Beta-human chorionic gonadotrophic (b–HCG), 252 b–HCG. See Beta-human chorionic gonadotrophic (b–HCG) Bevacizumab, in pulmonary toxicity, 816 BHD. See Birt-Hogg-Dube (BHD) syndrome Biologic agents, for Wegener’s granulomatosis, 628
825 Biopsy, of DPLD, 9 Birmingham Vasculitis Activity Score (BVAS), 621 Birt-Hogg-Dube (BHD) syndrome, 753 Bleomycin, pulmonary toxicity of, 811–812 Blue necrosis, 608 B lymphocytes, 277 BMT. See Bone marrow transplantation (BMT) Bone and joint, sarcoidosis of, 251 Bone marrow transplantation (BMT) in PAP, 780 pulmonary complications of, 559–569 noninfectious, 560–569 Brain natriuretic peptide (BNP), in IPF, 348 Breast, sarcoidosis of, 252 Bronchiectasis, in rheumatoid arthritis, 492–493 Bronchiolar fibrosis, 537 Bronchiolar metaplasia, 529 Bronchioles, 526 Bronchiolitis, 525–526 cellular, 527–528 cicatricial, 528–529 clinical classification of, 526–527 connective tissue diseases (CTD) and, 535 constrictive. See Constrictive bronchiolitis cryptogenic constrictive, 538 follicular. See Follicular bronchiolitis histopathologic classification of, 527–529 infectious and postinfectious in adults, 533–535 with inflammatory/intraluminal polyps, 528 lymphocytic, 546 obliterans. See Obliterative bronchiolitis (OB) practical clinical approach to patients with, 539–540 pulmonary function impairment in, 532 radiographic findings, 529–532 respiratory, 104
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826 Bronchoalveolar lavage (BAL) for CBD, 301–302 for hypersensitivity pneumonia, 276–279 for IPF, 346 in polymyositis/dermatomyositis, 461 proteins, 278–479 in rheumatoid arthritis-ILD, 446 in sarcoidosis, 201 in Sjo¨gren’s syndrome, 451–452 in systemic sclerosis-ILD, 438 Bronchoscopy, 611 for NSIP, 370–371 for patients with DPLD, 8–9 Bronchostenosis, 208 Bronchus-associated lymphoid tissue (BALT), 403–414, 442–443 follicular hyperplasia of. See Follicular bronchitis/bronchiolitis lymphomas, 452 Busulfan, pulmonary toxicity of, 813 Calcium, serum, 249 Calcium metabolism, 248–249 Cancer, LAM as, 751–752 Carcinogenesis, beryllium, 298–299 Cardiac manifestations, of Wegener’s granulomatosis, 617 Cardiac sarcoidosis, 241–244 diagnosis of, 241–242 epidemiology/demographics of, 241 manifestation of, 241 treatment of, 242–244 Cardiopulmonary exercise tests (CPET) of IPF, 343 of patients with DPLD, 7–8 of sarcoidosis, 199 Cardiovascular drugs, in pulmonary toxicity amiodarone, 818–819 hydrochlorothiazide, 819 CARD 15 mutation, 164 Castleman disease, 416, 418–420 CBD. See Chronic beryllium disease (CBD) CCR2. See Chemokine (C-C motif) receptor 2 (CCR2)
Index CD4+/CD8+, and HP, 276–277 1 Cellcept . See Mycophenolate mofetil (MMF) Cell differentiation, 174 Cellular bronchiolitis, 527–528 Cellular homeostasis, TSC in, 748–750 Cellular migration, chemokines regulators of, 174–175 Central nervous system (CNS), in Wegener’s granulomatosis, 615–616 Centrilobular perivascular densities, 648 CEP. See Chronic eosinophilic pneumonia (CEP) Cerebral sarcoidosis lesions, 256 Chapel Hill Consensus Conference definition of different types of vasculitides, 592, 607 ‘‘Check-valve’’ effect, 451 Chemokine (C-C motif) receptor 2 (CCR2), 79 regulators of cellular migration, 174–175 Chemotherapeutic agents for LCH, 741 in pulmonary toxicity alkylating agents, 814 bleomycin, 811–812 busulfan, 813 cyclophosphamide, 813–814 cytosine arabinoside, 815 methotrexate, 814 mitomycin C, 813 novel agents, 816–817 Children, LIP in, 406–407, 409 Chlorambucil, for sarcoidosis, 141 Chronic beryllium disease (CBD), 297. See also Beryllium BAL for, 301–302 chest radiography for diagnosis of, 299–301 compensation, 305 diagnostic evaluation of, 303–304 laboratory abnormality tests, 302 natural history in, 304 pathology of, 302–303 pulmonary physiology in, 299 treatment of, 304–305
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Index Chronic eosinophilic pneumonia (CEP) in BMT recipients, 569 HRCT of, 24–25 Chronic hypertrophic pachymeningitis (CHP), 615–616 Chronic rejection, OB pathologic manifestation, 546–547 risk factors, 547–548 Chronic rhinosinusitis, 578 Churg-Strauss syndrome (CSS), 591, 643–652, 720–723 classification criteria, 649 definitions of, 592 diagnosis, 645–647 frequency of ANCA in, 594–595 frequency of manifestations of, 592 histological features of, 647 natural history, classifications, and phenotypes, 649–650 pathogenesis and triggering factors, 644–645 pulmonary manifestations of, 647–649 systemic manifestations of, 645–647 treatment, 650–652 Chylous pleural effusions, and LAM, 757 Cicatricial bronchiolitis, 528–529 Cirrhosis, in hepatic sarcoidosis, 235 Citrullinated proteins, 443 Clinically amyopathic, 453 Clinical prognostic factors, of pulmonary sarcoidosis, 195–196 Cobra venom factor, 598 Cocaine, in pulmonary toxicity, 821 Collagen vascular diseases (CVD), pulmonary fibrosis in, 108–112 Colony-stimulating factors, in sarcoidosis, 174 Composite scoring systems, in IPF, 346 Computed tomography (CT) for Behc¸et’s disease (BD), 701 high-resolution. See High-resolution computed tomography (HRCT) scans of pulmonary sarcoidosis, 196–198 Connective tissue diseases (CTD), 429–430 and bronchiolitis, 535 ILD associated with, 429–466
827 [Connective tissue diseases (CTD)] classification of the idiopathic interstitial pneumonias (IIP), 430–431 detection and management of, 432–434 detection of unsuspected CTD, 430–431 frequency of different patterns of, 436 mixed, 465–466 polymyositis/dermatomyositis, 453–462 rheumatoid arthritis, 441–447 Sjo¨gren’s syndrome, 448–453 systemic lupus erythematosus (SLE), 462–464 systemic sclerosis, 434–441 involved thoracic anatomical structures in, 430 pleuropulmonary complications of, 487–501 Constrictive bronchiolitis, 528–529. See also Bronchiolitis associated with paraneoplastic pemphigus, 536–537 following infection, 534 COP. See Cryptogenic organizing pneumonia (COP) Corticosteroids for DIP management, 384–385 for ILD, 120–125 for LCH, 741 for neurosarcoidosis, 247 for organizing pneumonia, 515–516 in PAP, 780 for PERDS, 395, 566 for pulmonary sarcoidosis, 209–210 RB-ILD management, 382 for skin sarcoidosis, 232 for systemic sclerosis associated COP, 499 for Wegener’s granulomatosis, 620–623 CPET. See Cardiopulmonary exercise tests (CPET) Crazy paving pattern, 30 Cricoarytenoid arthritis, 489–492 Crohn’s diseases, amd bronchiolitis obliterans, 536
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828 Cryptogenic constrictive bronchiolitis, 538 Cryptogenic organizing pneumonia (COP), 392, 506. See also Organizing pneumonia; Pneumonia clinical course and outcome, 516–517 HRCT of, 23–24 and inflammation, 341 pathology of, 101–103 in systemic sclerosis, 498–499 CSS. See Churg-Strauss syndrome (CSS) CTD. See Connective tissue diseases (CTD) CVD. See Collagen vascular diseases (CVD) Cyclophosphamide (CYC) for CSS management, 651 for ILD, 134–136 for IPF, 349–350 lung toxicity of, 813–814 for polymyositis/dermatomyositisILD, 462 for pulmonary sarcoidosis, 211 for systemic sclerosis-ILD, 440 for Wegener’s granulomatosis, 620–623 Cyclosporine, for ILD, 141 Cytokines IIP and, 56–57 role in pathogenesis of sarcoidosis, 170–175 sarcoidosis and receptors of, 79–80 Cytotoxic agents for ILD, 125–136 for IPF, 349–350 Cytoxan1. See Cyclophosphamide Delayed pulmonary toxicity syndrome (DPTS) in BMT recipients, 567 Dendritic cells (DC) role in pathogenesis of sarcoidosis, 169 Dermatitis, 298 Dermatomyositis, 111, 496–497 auto-antibodies in, 454 diffuse alveolar damage pattern in, 458 ILD associated with, 453–462 bronchoalveolar (BAL) in, 461 clinical features of, 457–459
Index [Dermatomyositis ILD associated with] epidemiology and risk factors of, 454 evolution and prognosis of, 461 imaging of, 459–461 pathogenesis of, 454–457 pathology of, 457 treatment of, 461–462 Desquamative interstitial pneumonia (DIP), 379, 382–385. See also Pneumonia diagnosis, 384 epidemiologic and clinical features, 382 histopathology of, 384 HRCT for, 18 management and prognosis, 384–385 pathology of, 104–106 pulmonary function testing for, 383 radiologic features, 383 Dialysis-related amyloidosis, 799–800 Diffuse alveolar damage (DAD), 392, 393 Diffuse alveolar hemorrhage (DAH) following BMT, 565–566 in SLE, 495–496 Wegener’s granulomatosis in, 614 Diffuse panbronchiolitis, 537–538 in rheumatoid arthritis, 492 Diffuse panbronchiolitis (DPB), 47–48 Diffuse parenchymal lung diseases (DPLD) accurate diagnosis in, 1–3 ancillary tests in, 8–9 history and physical examination, 3–6 multidisciplinary approaches for diagnosis of, 10–11 physiological testing of, 7–8 screening for common comorbidities in, 9–10 Diffuse skin disease, 434 Diffusing capacity for carbon monoxide (DLCO) in DPLD, 7 and sarcoidosis, 199–200 DIP. See Desquamative interstitial pneumonia (DIP) DLCO. See Diffusing capacity for carbon monoxide (DLCO) DNA microarrays, of ILD, 81
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Index Doppler echocardiography (DE), for PAH, 206 Dosage azathioprine, 132 cyclophosphamide, 135 of glucocorticoids in ILD, 123 hydroxychloroquine/chloroquine, 137 infliximab, 139–140 of leflunomide, 130 MMF, 133 of MTX for ILD, 127 DPB. See Diffuse panbronchiolitis (DPB) DPLD. See Diffuse parenchymal lung diseases (DPLD) Drug-induced bronchiolitis obliterans, 535 Drug-induced pulmonary disorders. See Pulmonary toxicity Dyskeratosis congenita, 55 Ear, nose and throat (ENT) manifestations, of CSS, 645–646 Echocardiography Doppler, 206 transthoracic, 348 Edema, 563–564 ELMOD2, 48 Emphysema, 275 Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) biopsy, 204 Endothelin-1 (ET-1), for PAH, 142 Energy Employees Occupational Illness Compensation Act (EEOICPA), 305 Eosinophilic granuloma. See Pulmonary Langerhans cell histiocytosis (PLCH) Eosinophilic pneumonia ABPA, 711–712 asthma in, 714–715 bronchocentric granulomatosis, 715 clinical classification of, 708 CSS, 720–723 diagnosis, 709–710 drug-induced, 713–714 histopathology of, 709 IAEP and, 717–720
829 [Eosinophilic pneumonia] ICEP and, 715–717 idiopathic HES, 723–726 in parasitic diseases, 710–711 Eosinophil leukocyte, 707–709 Epitope spreading, 619 Epstein-Barr virus (EBV), and LIP, 405–406 Erythema nodosum, 228, 231 Erythrocyte sedimentation rate (ESR), in Goodpasture’s syndrome, 681 Esophageal disease in systemic sclerosis, 498 Esophageal muscular weakness, 497 Etanercept, 626 European Vasculitis Study Group (EUVAS)-coordinated clinical trials, 665, 666 EUSTAR (Eular Scleroderma Trials and Research) group study, 435 Everolimus, 552 Exacerbations, acute, 347 Exercise testing, for systemic sclerosis-ILD, 437 Exhaled nitric oxide (eNO) measurements, 532 Extranodal marginal zone lymphoma, 411 Extrapulmonary sarcoidosis bone and joint, 251 calcium metabolism and, 248–249 differential diagnosis of, 253 eye, 224–227 heart, 241–244 liver, 233–241 manifestations and treatment of, 254 skin, 228–233 spleen, 249–250 upper respiratory tract, 250 Eye sarcoidosis, 224–227 diagnosis of, 226–227 epidemiology/demographics of, 224 manifestation of, 224–226 treatment of, 227 Familial amyloidosis (AA) demographics, 797–798 parenchymal lung disease, 798
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830 [Familial amyloidosis (AA)] pathogenesis, 798 pleural effusions, 798 pulmonary hypertension, 799 Familial interstitial pneumonia (FIP), IPF and, 337–338 FAST. See Fibrosing Alveolitis in Scleroderma (FAST) trial FBN1. See Fibrillin1 (FBN1) FEV1. See Forced expiratory volume in one second (FEV1) FEV1/FVC ratio in PFT of HP, 275 of sarcoidosis, 199–200 Fibrillin1 (FBN1), 63 Fibroblastic foci (FF), in UIP, 335 Fibronectin, 435 Fibroproliferative bronchiolitis obliterans syndrome (fBOS), 548–549 Fibrosing Alveolitis in Scleroderma (FAST) trial, 440 Fibrosis bronchiolar, 537 of organizing pneumonia, intraalveolar, 506–507 mechanisms, 507–508 peribronchial, 529 pulmonary interstitial, 664 FIP. See Familial interstitial pneumonia (FIP) Five factor score (FFS), 650–651 Fludarabine, in pulmonary toxicity, 815 Follicular bronchiolitis, 416–418, 528. See also Bronchiolitis clinical features, 417 definition, 416–417 differential diagnosis, 411, 417–418 in HIV patients, 534 pathologic features, 417 radiologic features, 417 in rheumatoid arthritis, 492 in Sjo¨gren’s syndrome, 450 Folliculin gene, 753
Index Forced expiratory volume in one second (FEV1) in lung transplantation for sarcoidosis, 212 in obliterative bronchiolitis, 544–545 diagnosis criteria, 549–551 French Vasculitis Study Group (FVSG) trial, 646, 650 Fundoplication, 547 Gastroesophageal reflux disease (GERD) risk factor for OB, 547, 548 Gastroesophageal reflux disease (GERD) and IPF, 337 in patients with DPLD, 9 post-WTC attacks, 579 Gastrointestinal manifestations, of Wegener’s granulomatosis, 617 Gefitinib, in pulmonary toxicity, 816 Gemcitabine, in pulmonary toxicity, 815 GER. See Gastroesophageal reflux disease (GERD) GERD. See Gastroesophageal reflux disease (GERD) Giant lymph node hyperplasia. See Castleman disease Glucocorticoids. See also Corticosteroids dosage and route of administration in ILD, 123 mechanisms of action of, 120 toxicity risk of, 123–124 Gold, in pulmonary toxicity, 820 Goodpasture, Ernest, 671 Goodpasture’s syndrome basement membrane, 672–674 clinical manifestations, 678–679 epidemiology, 677 imaging studies, 679–680 kidneys in, 684 laboratory studies, 681–683 pathogenesis, 674–677 pulmonary system in, 684–685 treatment of, 685–686 type IV collagen, 672–374 Granulocyte/macrophage colony– stimulating factor (GM-CSF), in PAP aerosolized, 780 exogenous, 779–780
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Index Granulomas, 176–178 Granulomatous hepatitis, 240 Granulomatous inflammation and extrahepatic organs biopsy, 236 and liver biopsy, 235–236 and manifestation of cardiac sarcoidosis, 241 Head cheese pattern, in bronchiolitis, 531 Healthy-worker effect, 583 Heart-lung transplantation obliterative bronchiolitis (OB) following, 543–553 survival rate, 543–544 Heart manifestations, of CSS, 646 Hemorrhage in BMT recipients, diffuse alveolar, 565–566 in microscopic polyangiitis, pulmonary, 660, 661 Hepatic sarcoidosis, 233–241 diagnosis of, 235–239 epidemiology/demographics, 233 manifestation of, 233–235 treatment of, 240–241 Hermansky-Pudlak syndrome, 55 HHV-8, 406 High-dose intravenous immunoglobulin, 628 High-resolution computed tomography (HRCT) for acute interstitial pneumonia (AIP), 392 for bronchiolar diseases, 529–531 for desquamative interstitial pneumonia (DIP), 383 for DPLD, 8 for follicular bronchitis/ bronchiolitis, 417 of hypersensitivity pneumonia (HP), 28–29, 274 of IIP, 15–25 of LAM, 32–33 for LCH, 739–740 for mixed connective tissue disease, 465 for NSIP, 368–370 in PAP, 774
831 [High-resolution computed tomography (HRCT)] of PAP, 29–30 of PLCH, 30–31 polymyositis/dermatomyositis-ILD, 459–461 rheumatoid arthritis-ILD, 445–446 sarcoidosis, 25–27 scans for diagnosis of IPF, 344–345 for sclero(dermato)myositis, 466 for Sjo¨gren’s syndrome, 450–451 and MALT lymphoma, 453 for SLE-ILD, 464 systemic sclerosis, 431–438 High-throughput genotyping, of ILD, 81 Histiocytosis X. See Pulmonary Langerhans cell histiocytosis (PLCH) HLA-B5, and Behc¸et’s disease (BD), 696 Hot tub lung, 534 HP. See Hypersensitivity pneumonia (HP) HRCT. See High-resolution computed tomography (HRCT) HTERT. See Telomerase reverse transcriptase (hTERT) Human immunodeficiency virus (HIV) infection and sarcoidosis, 209 and LIP, 406, 407 Hyaline membrane, 100 Hydrochlorothiazide, in pulmonary toxicity, 819 Hydroxychloroquine/chloroquine for ILD, 136–137 for skin sarcoidosis, 232 Hypercalcemia, mild, 249 Hypercalcuria, 248 Hypereosinophilic syndrome (HES), 723–726 Hyperplasia giant lymph node. See Castleman disease neuroendocrine cell, 537 nodular lymphoid. See Nodular lymphoid hyperplasia (NLH) Hypersensitivity pneumonia (HP) BAL for, 476–479 chest radiography of, 273 clinical manifestations of, 271–272 diagnostic criteria for, 280–281 factors promoting, 269–270
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832 [Hypersensitivity pneumonia (HP)] genetics of, 80 HRCT scans of, 274 laboratory tests of, 272–273 pathology of, 99–100 PFT of, 275–276 sources and antigens involved in, 268 thoracic imaging for, 28–29 treatment and outcomes of, 281–282 Hypersensitivity pneumonitis, 412 Hypertension, pulmonary, 10 and systemic sclerosis-ILD, 437 Hypoamyopathic dermatomyositis, 453 IAEP. See Idiopathic acute eosinophilic pneumonia (IAEP) ICEP. See Idiopathic chronic eosinophilic pneumonia (ICEP) Idiopathic acute eosinophilic pneumonia (IAEP), 717–720 and asthma, 718 diagnostic criteria for, 718 Idiopathic chronic eosinophilic pneumonia (ICEP), 715–717 Idiopathic hypereosinophilic syndromes, 723–726 Idiopathic inflammatory myopathies, 455–456 Idiopathic interstitial pneumonia (IIP) classification of, 334 versus CTD associated ILD, 430–431 genetics of, 48–57 complement and coagulation cascade, 57 cytokine genes, 56–57 familial disease, 48–56 MHC genes, 56 thoracic imaging of, 15–25 acute interstitial pneumonia (AIP), 20 chronic eosinophilic pneumonia (CEP), 24–25 cryptogenic organizing pneumonia (COP), 23–24 desquamative interstitial pneumonia (DIP), 18 lymphocytic interstitial pneumonia (LIP), 20–22
Index [Idiopathic interstitial pneumonia (IIP) thoracic imaging of] nonspecific interstitial pneumonia (NSIP), 16–18 RB-ILD, 18–20 usual interstitial pneumonia (UIP), 15–16 Idiopathic pneumonia syndrome (IPS) following BMT, 564–565 Idiopathic pulmonary fibrosis (IPF) ancillary staging in, 346 chest radiography in, 344–346 clinical features of, 334–335 complications of, 347–349 epidemiology of, 336–337 GERD, 337 risk factors, 336 and histopathology of UIP, 335–336 lung transplantation for, 351–352 pathogenesis of, 337–342 genetic factors, 337–339 FIP and, 337–338 inflammation, 340–342 mechanisms of lung injury and fibrosis, 339–340 physiological aberrations in, 343–344 therapeutic treatment of, 349–351 IFNa for CSS, 652 IFN-g. See Interferon-g (IFN-g) IIP. See Idiopathic interstitial pneumonia (IIP) ILD. See Interstitial lung disease (ILD) Imaging studies, of Goodpasture’s syndrome, 679–680 Immunoglobulin, high-dose intravenous, 628 Immunoglobulin G (IgG) ANCA, 595 pathogenicity of, 596–599 Immunosuppressive therapy for Goodpasture’s syndrome, 685–686 for IPF, 349–350 for systemic sclerosis-ILD, 439–441 Imuran1. See Azathioprine (AZA) Induction therapy, for Wegener’s granulomatosis, 620–621, 622 Infiltrates, 510, 648
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Index Inflammatory bowel disease (IBD), and bronchiolitis obliterans, 536 Inflammatory myopathies, idiopathic, 455–456 Infliximab, 626 for ILD, 138–141 for skin sarcoidosis, 233 Inhaled particles deposition on alveolar surface, 318–319 Interferon-g (IFN-g) 1b in IPF, 350 in ILD, 142 role in sarcoidosis pathogenesis, 173 Interleukins (IL) IL-1, 173–174 IL-2, 172–173 IL-10, 171–172 IL-12, 171–172 IL-15, 172–173 IL-18, 171–172 Intermediate uveitis, 225 International Society for Heart and Lung Transplantation (ISHLT) registry, 351–352 Interstitial lung disease (ILD) associated with CTD, 429–466 corticosteroids for, 120–125 cyclosporine for, 141 cytotoxic agents for, 125–136 DLCO reduction in, 7 DNA microarrays and high-throughput genotyping, 81 genetics of, 43–81 approaches for, 46 complex traits, 45–46 defining disease, 46–47 DPB, 47–48 HP, 80 IIP, 48–57 sarcoidosis, 64–80 systemic sclerosis, 57–64 hydroxychloroquine/chloroquine for, 136–137 pathology of diffuse, 93–112 pentoxifylline for, 142–143 pirfenidone for, 141 post-WTC attacks, 581–582 thoracic imaging for diffuse, 13–33 TNF-a in, 138–141
833 Intra-alveolar fibrosis of organizing pneumonia, 506–507 mechanisms, 507–508 Invasive diagnostic imaging, Behc¸et’s disease (BD), 702 IPF. See Idiopathic pulmonary fibrosis (IPF) Irinotecan, in pulmonary toxicity, 817 Irritants inhalation, bronchiolitis obliterans (BO), 532–533 ISHLT registry. See International Society for Heart and Lung Transplantation (ISHLT) registry Japanese Ministry of Health and Welfare, 242 Kaplan Meir survival curves, for microscopic polyangiitis, 662 Kveim-Siltzbach-antigen, 176 LAM. See Lymphangioleiomyomatosis (LAM) Lambertosis, 99 Laminin-5, 508 Langerhans’ cell histiocytosis (LCH) chemotherapeutic agents for, 741 chest radiograph (CXR), 739 clinical features, 738 corticosteroids for, 741 diagnosis, 740–741 epidemiology, 733–734 histological features, 735–738 HRCT, 739–740 lung biopsy, 740 lung transplantation, 742 pahogenesis, 734–735 pulmonary function, 739 pulmonary hypertension, 742 radiographical imaging, 739–740 smoking cessation for, 741 Langerhans cells, 106–107. See also Langerhans’ cell histiocytosis (LCH) Large vessels, Wegener’s granulomatosis in, 616–617
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834 LDH. See Plasma lactate dehydrogenase (LDH) Leflunomide, 446 for ILD, 130–131 for Wegener’s granulomatosis, 625 Lesions in lungs, LAM, 750–751 Leukotriene inhibitors, in pulmonary toxicity, 820 Leukotriene receptor antagonists (LRA), 645 Limited skin disease, 434 LIP. See Lymphocytic interstitial pneumonia (LIP) Liver sarcoidosis. See Hepatic sarcoidosis Localized syndromes, amyloidosis demographics, 801 diffuse interstitial disease, 803 nodular lung disease, 802–803 pathophysiology, 801–802 radiology of, 803 TBA, 802 Lofgren’s syndrome, 76 and arthritis, 251 Lower airway reactive airways dysfunction syndrome (RADS), 579–581 WTC-related diseases of, 576–577 for cough syndrome, 586 Lung biopsy of DPLD, 9 DPLD and surgical, 9 photomicrograph of CBD patient, 303 Lung biopsy, for LCH, 740 Lungs biopsy. See Lung biopsy cancer beryllium and risk of, 298–299 in patients with pulmonary sarcoidosis, 209 in systemic sclerosis, 499 and UIP, 347 diseases interstitial, post-WTC attacks, 581–582 in microscopic polyangiitis, 661–665 MALT-type lymphomas of, 452 toxicity. See Pulmonary toxicity transplantation. See Lung transplantation vasculitis, 500 Wegener’s granulomatosis in, 611–614
Index Lung transplantation for IPF, 351–352 for LAM, 759–760 for LCH, 742 obliterative bronchiolitis (OB) following, 543–553 in PAP, 780–781 for pulmonary sarcoidosis, 211–212 survival rate, 543–544 Lupus pernio lesions, 229–230 Lupus pneumonitis, 494, 495 Lymphadenopathy angioimmunoblastic differential diagnosis, 412 mediastinal, 342 sarcoidosis and peripheral, 251 Lymphangioleiomyomatosis (LAM) airflow obstruction in, 754–755 as cancer, 751–752 chylous pleural effusions, 757 diagnosis of, 752–753 HRCT of, 32–33 lesions in lungs, 750–751 lifestyle issues, 758 and lymphatics, 751 natural history of, 753–754 overview, 747–748 pathology, 754 pneumothoraces in, 756–757 radiology in, 755–756 renal tumor, 757 treatment for lung transplantation, 759–760 pharmacological therapies, 758–759 surgical therapies, 758–759 and TSC cellular homeostasis, 748–750 S-LAM, 750, 757–758 Lymphatics, and LAM, 751 Lymph node enlargement (LNE), 342, 345 Lymphocyte costimulatory molecules, 78 Lymphocytic bronchiolitis, 546 Lymphocytic interstitial pneumonia (LIP), 405–413, 449 clinical features, 406–408 definition, 405 differential diagnosis, 410–413
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Index [Lymphocytic interstitial pneumonia (LIP)] etiology/pathogenesis, 405–406 HRCT of, 20–22 in lungs, diseases associated with, 404 versus malignant lymphoma, 22 pathologic features, 409–410 pathology of, 103–104 radiologic features, 408–409 treatment, 409 Lymphoid interstitial pneumonia. See Lymphocytic interstitial pneumonia (LIP) Lymphomas B-cell, association with LIP, 409 extranodal marginal zone, 411 differential diagnosis, 411 of lung, MALT-type, 452 malignant, 22 MALT. See Maltoma Lymphoproliferative disorders posttransplant, 420–421 pulmonary, 403–421 Macrolides, for organizing pneumonia, 516 Macrophages, 277 alveolar, 168–169 Major bronchi, Wegener’s granulomatosis in, 610–611 Major histocompatibility complex (MHC) genes and systemic sclerosis, 58 genes in sporadic IIP, 56 and HP, 269–270 region and DPB, 47 sarcoidosis, 75–77 in sporadic IIP, 56 Malignant lymphoma, 22 MALT lymphoma. See Maltoma Maltoma, 415–416, 452 differential diagnosis, 411, 412 Masson bodies, 392 Mast cells, 278 Matrix metalloproteinases (MMP), 507–508 Mediastinal lymphadenopathy, 342 Metaplasia, bronchiolar, 529
835 Methotrexate (MTX) for ILD, 125–129 pulmonary toxicity of, 814 for skin sarcoidosis, 232 for Wegener’s granulomatosis, 623–624 MHC. See Major histocompatibility complex (MHC) Microscopic polyangiitis, 591, 657–667 clinical manifestations, 660–661 definitions of, 592 epidemiology, 657–658 frequency of ANCA in, 594–595 frequency of manifestations of, 592 lung diseases in, 661–665 outcome and relapse, 666 pathogenesis, 658–660 treatment, 665–666 Migratory pulmonary infiltrates, 510 Mikulicz’s syndrome, 231 Mild hypercalcemia, 249 Mimickers, of bronchiolitis obliterans (BO), 538–539 Minocycline, for sarcoidosis, 143 Mitomycin C, lung toxicity of, 813 Mixed connective tissue disease, 465–466 MMF. See Mycophenolate mofetil (MMF) MTX. See Methotrexate (MTX) 6MWT. See Six-minute walk test (6MWT) Mycetomas in patients with sarcoidosis, 208 Mycobacterium avium, 100 complex infection, 534 Mycobacterium tuberculosis, 124, 167 catalase-peroxidase (mKatG), 167, 176 Mycophenolate mofetil (MMF) for ILD, 133–134 for systemic sclerosis-ILD, 440 for Wegener’s granulomatosis, 624–625 Myeloperoxidase (MPO) ANCA, 594–595, 663 human, 599 Myositis syndromes, 497 NAC. See N-acetyl cysteine (NAC) N-acetyl cysteine (NAC), for IPF, 350 Necrotizing sarcoid angiitis and granulomatosis (NSG), 207–208
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836 Neomacrolide antibiotics, 552 Nephrectomy, for Goodpasture’s syndrome, 685 Neuroendocrine cell hyperplasia, 537 Neurosarcoidosis diagnosis of, 247 epidemiology/demographics of, 244 manifestations of, 244–247 treatment of, 247 Neutrophilic reversible allograft dysfunction (NRAD), 548–549 Neutrophils, 277–278 New York Heart Association (NYHA), 242 NF-kB. See Nuclear factor kappa B (NF-kB) Nitrofurantoin, in pulmonary toxicity, 817 Nodular lymphoid hyperplasia (NLH) of the lung, 413–416 clinical features, 413 definition, 413 differential diagnosis, 411, 412, 415–416 etiology/pathogenesis, 413 pathologic features, 414–415 radiologic features, 413–414 Nodules, rheumatoid, 493 Nonmajor histocompatibility complex genes DPB and, 47–48 sarcoidosis, 77–80 and systemic sclerosis, 58–64 Nonspecific interstitial pneumonia (NSIP), 365–374 diagnosis of, 367–371 bronchoscopy/SLB for, 370–371 clinical characteristics, 367–368 radiographic, 368–370 epidemiology of, 366 histology of UIP and, 335–336 histopathology of, 371–373 HRCT for, 16–18, 368–370 natural history and prognosis of, 373–374 pathogenesis of, 373 pathology of, 97–98 treatment of, 374
Index North-American Scleroderma Lung Study, 440 Novel agents, in pulmonary toxicity, 816–817 bevacizumab, 816 gefitinib, 816 transretinoic acid, 816 NSG. See Necrotizing sarcoid angiitis and granulomatosis (NSG) NSIP. See Nonspecific interstitial pneumonia (NSIP) Nuclear factor kappa B (NF-kB), 78 NYC firefighter WTC study, 583 NYHA. See New York Heart Association (NYHA) OB. See Obliterative bronchiolitis (OB) Obliterative bronchiolitis (OB). See also Bronchiolitis associated inflammatory bowel disease (IBD), 536 drug-induced, 535 fibroproliferative bronchiolitis obliterans syndrome (fBOS), 548–549 following BMT, 560–563 following lung/heart-lung transplantation, 543–553 classification, 550 diagnosis, 549–551 pathologic manifestation of chronic rejection, 546–547 pathophysiology, 548–549, 550 phenotypes of, 548–549 prevalence and clinical presentation, 544–546 risk factors for chronic rejection, 547–548 treatment, 551–553 mimickers of, 538–539 in rheumatoid arthritis, 492 secondary to irritants inhalation, 532–533 Obstructive lung disease, in systemic sclerosis, 498 Obstructive sleep apnea, in DPLD, 10 Occupational Safety and Health Administration (OSHA), 291
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Index Ocular manifestations, of Wegener’s granulomatosis, 610 Ocular sarcoidosis. See Eye sarcoidosis Organic dust toxic syndrome (ODTS), 271 Organizing pneumonia. See also Cryptogenic organizing pneumonia (COP); Pneumonia clinical and imaging characteristics of, 509–512 atypical forms, 512 classical multifocal form, 509–510 diffuse infiltrative form, 511–512 localized form, 510–511 clinical course and outcome, 516–517 diagnosis, 512–515 clinicopathological, 513–514 differential, 514–515 histopathological, 512–513 epidemiology, 506 intra-alveolar fibrosis of, 506–507 mechanisms of, 507–508 pathogenesis, 506–507 pattern in polymyositis, 458 in systemic sclerosis, 498–499 terminology used for, 505–506 treatment, 515–516 Osteoporosis, 123
P. acnes. See Propionibacterium acnes P(A-a)O2. See Alveolar-arterial oxygen gradient [P(A-a)O2] Pachymeningitis, chronic hypertrophic, 615–616 Paclitaxel, in pulmonary toxicity, 817 PAH. See Pulmonary arterial hypertension (PAH) Panbronchiolitis, diffuse, 537–538 genetics of, 47–48 in rheumatoid arthritis, 492 PAP. See Pulmonary alveolar proteinosis (PAP) Paraneoplastic pemphigus, 536–537 Parasitic diseases, eosinophilic pneumonia in, 710–711 Pathogenesis, for LCH, 734–735 Pauci-immune small-vessel vasculitis, 594, 595
837 Pemphigus, paraneoplastic, 536–537 Penicillamine, in pulmonary toxicity, 819–820 Penicillin, Behc¸et’s disease (BD), 703 Pentoxifylline, for ILD, 142–143 PERDS. See Periengraftment respiratory distress syndrome (PERDS) Peribronchial fibrosis, 529 Periengraftment respiratory distress syndrome (PERDS), 566 Peripheral nervous system, in Wegener’s granulomatosis, 615–616 Peritoneal sarcoidosis, 252 PFT. See Pulmonary function tests (PFT) Pharmacokinetics azathioprine, 132 corticosteroids, 124–125 cyclophosphamide, 136 hydroxychloroquine/chloroquine, 137 infliximab, 140–141 leflunomide, 130–131 MMF, 134 MTX, 129 Pirfenidone for ILD, 142 for IPF, 350–351 Plasma exchanges, for CSS, 651 Plasma lactate dehydrogenase (LDH), 272 Plasmapheresis, for Goodpasture’s syndrome, 685 PLCH. See Pulmonary Langerhans cell histiocytosis (PLCH) Pleural effusions and Behc¸et’s disease (BD), 701 in CSS, 648–649 rheumatoid, 488–489 Pleural manifestations, in sarcoidosis, 208–209 Pleurisy, SLE, 495 Pleuropulmonary manifestations, of rheumatoid arthritis, 488 Pneumocystis jiroveci infection, 625 Pneumonia acute fibrinous and organizing, 392 AIP. See Acute interstitial pneumonia (AIP) aspiration, 497
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838 [Pneumonia] in BMT recipients, chronic eosinophilic, 569 cryptogenic organizing. See Cryptogenic organizing pneumonia desquamative interstitial. See Desquamative interstitial pneumonia (DIP) IIP. See Idiopathic interstitial pneumonias (IIP) LIP. See Lymphocytic interstitial pneumonia (LIP) mixed nonspecific interstitial, 437 organizing. See Organizing pneumonia Pneumonitis acute rheumatoid, 493 differential diagnosis of hypersensitivity, 412 lupus, 494, 495 Pneumothoraces, in LAM, 756–757 Polychondritis, relapsing, 500–501 Polymyositis, 496–497 auto-antibodies in, 454 ILD associated with, 453–462 bronchoalveolar (BAL) in, 461 clinical features of, 457–459 epidemiology and risk factors of, 454 evolution and prognosis of, 461 imaging of, 459–461 pathogenesis of, 454–457 pathology of, 457 treatment of, 461–462 organizing pneumonia pattern in, 458 Portal hypertension in patients with hepatic sarcoidosis, 235 teatment of, 240 Posterior uveitis, 225 Postinfectious bronchiolitis obliterans (PBO), 533–534 Posttransplant lymphoproliferative disorders (PTLD), 420–421 ‘‘potential’’ bronchiolitis obliterans syndrome, 549–551 Pregnancy and azathioprine, 132–133 cyclophosphamide and, 136 hydroxychloroquine/chloroquine during, 137
Index [Pregnancy] infliximab and, 141 leflunomide, 131 MMF and, 131 MTX and, 129 use of corticosteroids during, 125 Primary systemic (AL), amyloidoses demographics, 791 diaphragm dysfunctiom, 796 parenchymal lung disease, 791–792 pathogenesis, 791 pleural effusions, 792–794 pulmonary hypertension in, 794–795 Progressive systemic sclerosis (PSS), 111 Propionibacterium acnes, 176 Propylthiouracil, 593 Prostaglandin E2, 80 Proteinase 3 (PR3)-ANCA, 594–595 Proton pump inhibitor (PPI), 498 ‘‘pseudo-restriction,’’ 583 Pulmonary alveolar proteinosis, in BMT recipients, 569 Pulmonary alveolar proteinosis (PAP) chest radiographs, 773–774 clinical course of, 774–775 clinical features, 770–771 epidemiology, 770 histopathological features, 771–773 HRCT in, 774 infections in, 775 laboratory studies, 771 overview, 769–770 pathogenesis of, 775–777 pulmonary function tests, 771 surfactants, 775–776 thoracic imaging for, 29–30 treatment of bone marrow transplantation, 780 corticosteroids in, 780 GM-CSF, 779–780 lung transplantation, 780–781 WLL in, 778 Pulmonary arterial hypertension (PAH) endothelin-1 (ET-1) receptor antagonist for, 142 and IPF, 347–349 lung transplantation for, 352 and sarcoidosis, 205–206
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Index Pulmonary complications of bone marrow transplantation, 559–569 diagnostic approach to, 561 non-infectious, 560–569 timing of the major non-infectious, 561 in CSS, 647–649 post-WTC attacks, 573–587 Pulmonary cytolytic thrombi (PCT) in BMT recipients, 567–568 Pulmonary functions abnormalities following BMT, 560 in desquamative interstitial pneumonia (DIP), 383 for LCH, 739 during LIP, 407–408 during RB-ILD, 381 test for Wegener’s granulomatosis, 612–613 Pulmonary function tests (PFT) for hypersensitivity pneumonia, 275–276 in PAP, 771 of patients with DPLD, 7 in patients with IPF, 343 in sarcoidosis, 198–200 Pulmonary hemorrhage, in microscopic polyangiitis, 660, 661 Pulmonary hypertension association with systemic sclerosisILD, 437 in LCH, 742 in patients with DPLD, 10 Pulmonary interstitial fibrosis (PIF), 664 Pulmonary Langerhans cell histiocytosis (PLCH) pathology of, 106–107 thoracic imaging for, 30–31 Pulmonary lymphoid hyperplasia (PLH), 416–417 Pulmonary lymphoproliferative disorders, 403–421 Pulmonary sarcoidosis, 189–190 and bronchostenosis, 208 chest radiographic, 190–195 features, 190 staging system, 190–195
839 [Pulmonary sarcoidosis] clinical features of, 190 clinical prognostic factors, 195–196 CT scans, 196–198 diagnosis of, 204–205 effects of pulmonary function on prognosis of, 200 in HIV-infected patients, 209 lung cancer in, 209 lung transplantation for, 211–212 and mycetomas, 208 and NSG, 207–208 pathogenesis of, 201 pathology of, 202–204 radionuclide techniques for diagnosis of, 201–202 SACE in, 200 treatment of, 209–212 corticosteroids for, 209–210 vascular involvement in, 205–207 Pulmonary toxicity antibiotics in nitrofurantoin, 817 sulfasalazine, 817–818 anti-inflammatory agents in gold, 820 leukotriene inhibitors, 820 penicillamine, 819–820 cardiovascular drugs, 818–819 chemotherapeutic agents alkylating agents, 814 bleomycin, 811–812 busulfan, 813 cyclophosphamide, 813–814 cytosine arabinoside, 815 methotrexate, 814 mitomycin C, 813 novel agents, 816–817 cocaine, 821 diagnosis, 810–811 illicit drugs, 820–821 Pulmonary vascular disease, Behc¸et’s disease (BD), 699–700 Pulmonary veno-occlusive disease (PVOD) in BMT recipients, 568 Pulmonary Wegener’s granulomatosis, 611–614
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840 Radiology in LAM, 755–756 in LCH, 739–740 of localized amyloidosis, 803 in PAP, 773–774 of systemic amyloidosis, 801 Radionuclide techniques for IPF, 346 for pulmonary sarcoidosis, 201–202 RADS. See Reactive airways dysfunction syndrome (RADS) Rapamycin, 552 RB-ILD. See Respiratory bronchiolitisassociated interstitial lung disease (RB-ILD) Reactive airways dysfunction syndrome (RADS), post-WTC attacks, 579–581 Reactive oxygen species (ROS), 327–328 Reactive upper airway dysfunction syndrome (RUDS). See Chronic rhinosinusitis Refractory Wegener’s granulomatosis, 620 treatment, 623–628 Relapsing polychondritis, 500–501 Renal manifestations in Goodpasture’s syndrome, 684 in LAM, 757 of Wegener’s granulomatosis, 614–615 Reproductive organs, sarcoidosis of, 252 Respiratory bronchiolitis–associated interstitial lung disease (RB-ILD), 379–382 diagnosis, 381 epidemiologic and clinical features, 380 HRCT for, 18–20 management and prognosis, 382 pathology of, 104–106 pulmonary function testing for, 381 radiologic features, 380 Respiratory bronchiolitis (RB), 104 Rheumatoid arthritis, 108, 487–494 acute pneumonitis, 493 airways obstruction, 489–492 apical fibrobullous disease in, 492 bronchiectasis, 492–493
Index [Rheumatoid arthritis] ILD associated with, 441–447 bronchoalveolar (BAL) in, 446 clinical features of, 443–444 diagnosis of, 446–447 epidemiology and risk factors of, 442 evolution and prognosis of, 447 imaging of, 445–446 pathogenesis of, 442–443 pathology of, 443 treatment of, 447 pleural effusions, 488–489 pleuropulmonary manifestations of, 488 pulmonary nodules, 493 treatment, 493–494 ‘‘rheumatoid lung,’’ 446 Rhinosinusitis, chronic, 578 Right ventricular (RV) dysfunction, 347–349 Rituximab for CSS treatment, 652 for Goodpasture’s syndrome, 686 for Wegener’s granulomatosis, 627 ROS. See Reactive oxygen species (ROS) Ross river virus, 599, 600 RUDS. See Chronic rhinosinusitis Saccharopolyspora rectivirgula, 270 SACE. See Serum angiotensin–converting enzyme (SACE) Sarcoid-like granulomatous pulmonary disease WTC associated, 581–582 Sarcoidosis, 163–178 BAL in, 201 in BMT recipients, 569 of breast, 252 chlorambucil for, 141 CPET of, 199 epidemiology of, 164–165 extrapulmonary. See Extrapulmonary sarcoidosis genetics of, 64–80 MHC genes, 75–77 nonmajor histocompatibility complex genes, 77–80
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Index [Sarcoidosis] granulomas in, 176–178 immunopathogenesis of, 165–175 role of cytokines in, 170–175 role of T-cells in, 165–169 as mimicker of bronchiolitis obliterans, 538–539 minocycline for, 143 neurologic. See Neurosarcoidosis pathology of, 107–108 PFT in, 198–200 pleural manifestations in, 208–209 pulmonary. See Pulmonary sarcoidosis of reproductive tracts, 252 skin lesions, 229–231 thalidomide for, 141–142 thoracic imaging for, 25–27 type 1 IFN and, 209 of upper respiratory tract, 250 Sauropus androgynus, 535 Scintigraphy, in Behc¸et’s disease (BD), 701–702 Scleroderma. See Systemic sclerosis Scleroderma. See Systemic sclerosis Sclero(dermato)myositis, 466 Sclerosis genetics of systemic, 57–64 progressive systemic, 111 systemic. See Systemic sclerosis Secondary amyloidosis (AA) demographics, 796 parenchymal lung disease, 796–797 pathogenesis, 796 pleural effusion, 797 pulmonary hypertension, 797 Secondary organizing pneumonia, 506 causes of, 514 Secreted protein, acidic and rich in cysteine (SPARC), 63–64 Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology, 600 Senile systemic amyloidosis (SSA) demographics, 799 parenchymal lung disease, 799 pleural effusions, 799 Sensitization, beryllium, 296–297
841 Serology, in DPLD, 9 Serositis, 498 Serum angiotensin–converting enzyme (SACE), 200 Serum calcium, 249 SFTPC genes. See Surfactant protein C (SFTPC) genes Shrinking lung syndrome, 496 Silica crystal role in silicosis, 325–327 deposition during inhalation, 318–319 risk factor for ANCA-associated vasculitis, 593 Silicosis, 317–328 and deposition of inhaled particles, 318–319 pathobiological responses in, 319–328 ROS and, 327–328 silica crystals role in, 325–327 Silo filler’s disease, 533 Six-minute walk test (6MWT) of IPF, 343–344 for patients with DPLD, 8 Sjo¨gren’s syndrome, 407, 499–500 follicular bronchiolitis in, 450 ILD and, 448–453 bronchoalveolar (BAL) in, 451–452 clinical features of, 441 diagnosis of, 452 epidemiology and risk factors of, 448 evolution and prognosis of, 452 imaging of, 450–451 pathogenesis of, 448–449 pathology of, 449 treatment of, 452–453 Sjo¨gren syndrome (SS), 111–112 Skin sarcoidosis, 228–233 diagnosis of, 231 epidemiology/demographics of, 228–229 manifestation of, 229–231 treatment of, 231–233 SLB. See Surgical lung biopsy (SLB) SLE. See Systemic lupus erythematosus (SLE) Smoking cessation, in LCH, 741 and chronic HP, 272
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842 [Smoking] emphysema and, 275 and RB-ILD, 380, 382 SPARC. See Secreted protein, acidic and rich in cysteine (SPARC) Spirometry, for WTC-related diseases, 583–584 Spleen sarcoidosis, 249–250 Splenectomy, 250 SSA. See Senile systemic amyloidosis (SSA) Staphyloccus aureus infection risk factor for Wegener’s granulomatosis, 619 ‘‘strawberry gingival hyperplasia,’’ 609 Strongyloides stercoralis, 711 Sulfasalazine, in pulmonary toxicity, 817–818 Surfactant protein C (SFTPC) genes, 55–56 Surfactant proteins, 55–556 Surgical lung biopsy (SLB) for diagnosis of pulmonary Wegener’s granulomatosis, 613 for NSIP, 370–371 Swyer-James syndrome, 534 Systemic lupus erythematosus (SLE), 111 alveolar hemorrhage in, 495–496 ILD associated with, 462–464 lupus pneumonitis, 494, 495 pleurisy, 495 shrinking lung syndrome in, 496 thoracic manifestations of, 494 Systemic sclerosis, 497–499 genetics of, 57–64 MHC genes, 58 nonmajor histocompatibility complex genes, 58–64 ILD associated with, 434–441 bronchoalveolar (BAL) in, 438 clinical features of, 436–437 diagnosis of, 438–439 epidemiology and risk factors of, 434–435 evolution and prognosis of, 439 imaging of, 437–438 pathogenesis of, 435–436
Index [Systemic sclerosis ILD associated with] pathology of, 436 treatment of, 439–441 progressive, 111 treatment response of, 64 typical pattern of mixed nonspecific interstitial pneumonia in, 437
T. cutaneum. See Trichosporon cutaneum TBA. See Tracheobronchial amyloidosis (TBA) TBLB. See Transbronchial lung biopsy (TBLB) TBNA. See Transbronchial needle aspiration biopsy (TBNA) T-cells axis of stimulatory, 168–169 role in immunopathogenesis of sarcoidosis, 165–169 Telomerase reverse transcriptase (hTERT), 54 Telomerase RNA (hTR), 54 Tetracycline, for skin sarcoidosis, 232 Thalidomide, for sarcoidosis, 141–142 T-helper 1 (TH1) cytokines, 171–173 TIMP. See Tissue inhibitors of metalloproteinases (TIMP) Tissue inhibitors of metalloproteinases (TIMP), 80 TLC. See Total lung capacity (TLC) T lymphocytes, in organizing pneumonia, 508 TNF. See Tumor necrosis factor (TNF) TNF-a. See Tumor necrosis factor alpha (TNF-a) TNF-a inhibitors for ANCA-associated vasculitis, 625–627 for Wegener’s granulomatosis, 625–627 Topical/intralesional therapy for skin sarcoidosis, 232 Total lung capacity (TLC) in patients with NSIP, 368 Toxicity. See also Pulmonary toxicity azathioprine, 132 of cyclophosphamide, 135 glucocorticoids, 123–124
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Index [Toxicity. See also Pulmonary toxicity] hydroxychloroquine/chloroquine, 137 infliximab, 140 leflunomide, 130 of MMF, 133–134 of MTX, 127–129 Trachea, in Wegener’s granulomatosis, 610–611 Tracheobronchial amyloidosis (TBA), 802 Transbronchial biopsy (TBBx) for NSIP, 370 in patients with uveitis, 227 Transbronchial lung biopsy (TBLB) for pulmonary sarcoidosis, 204 Transbronchial needle aspiration biopsy (TBNA) for pulmonary sarcoidosis, 204–205 Transforming growth factor, beta 1 (TGFb). See also Cytokines in sarcoidosis, 173–174 Transfusion-related acute lung injury (TRALI), 569 Transretinoic acid, in pulmonary toxicity, 816 Transthoracic echocardiography (TTE) for PAH, 348 of PAH, 348 ‘‘tree in bud’’ pattern, in bronchiolitis, 529, 530 Trichosporon cutaneum, 281 Trimethoprim/sulfamethoxazole for Wegener’s granulomatosis, 625 TSC. See Tuberous sclerosis complex (TSC) Tuberous sclerosis complex (TSC) in cellular homeostasis, 748–750 and S-LAM, 750, 757–758 Tumor necrosis factor alpha (TNF-a) antagonists for ILD, 138–141 antagonists for skin sarcoidosis, 233 HP and polymorphisms of, 270 IIP and, 56 for IPF, 350 Tumor necrosis factor (TNF), in sarcoidosis, 170–171 Type 1 IFN. See Type 1 interferons (IFN)
843 Type 1 interferons (IFN) therapy and sarcoidosis, 209 Type IV collagen, 672–674 UIP. See Usual interstitial pneumonia (UIP) Upper airway abnormalities following BMT, 560 WTC-related diseases of, 576–577 treatment algorithm for cough syndrome, 585 Upper respiratory tract, sarcoidosis of, 250 Usual interstitial pneumonia (UIP) HRCT for, 15–16 IPF and histopathology of, 335–336 lung cancer and, 347 pathology of, 94–97 Uveitis, 224–227 differential diagnosis of, 226 intermediate, 225 posterior, 225 Vasculitis associated with ANCA, 591–600 lung, 500 pauci-immune small-vessel, 594, 595 Vasculitis Damage Index (VDI), 621 Venous thrombotic events (VTE), 617 Ventilation-perfusion scans for bronchiolitis, 532 Viral infections relation with LIP, 405–406 Vital capacity (VC) measurements, 532 Wegener’s granulomatosis, 591, 605–629, 620, 621–622 clinical features, 606 definition of, 592 epidemiology, 607 frequency of manifestations of, 592 histopathology, 607–609 historic aspects, 606–607 laboratory features, 618 pathogenesis, 618–619 role of ANCA in, 618–619 specific organ manifestations, 609–618 treatment, 619–629
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844 [Wegener’s granulomatosis] determining extent and activity of disease, 621 remission induction, 621–622 staging of disease, 620–621 surgical management, 628–629 Wegener’s Granulomatosis Etanercept Trial (WGET), 607 Whole lung lavage (WLL), in PAP, 778 World Trade Center (WTC) asthma and RADS post attacks on, 579–581 chronic rhinosinusitis post attacks on, 578
Index [World Trade Center (WTC)] cough syndrome, 574–578 treatment algorithm for, 585–586 diagnostic evaluation of diseases related to, 582–584 gastroesophageal reflux disease (GERD) post attacks on, 579 interstitial lung diseases post attacks on, 581–582 treatment of diseases related to, 585–587 WTC. See World Trade Center (WTC) WTC Health Registry study, 575
LBH_6x9_Walsworth_Template.indd
Volume
Pulmonology
227
Lung Biology in Health and Disease
Volume 227
Executive Editor: Claude Lenfant
about the book…
about the editor... JOSEPH P. LYNCH, III is Professor of Clinical Medicine in the Division of Pulmonary and Critical Care Medicine, Clinical Immunology and Allergy, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. Dr. Lynch received his M.D. from Harvard Medical School, Boston, Massachusetts, USA. He is a member and fellow of several professional organizations, including the American Thoracic Society and the American College of Chest Physicians. Dr. Lynch has been invited to speak at more than 400 seminars and lectures, and he currently serves as the editor in chief of the publication Seminars of Respiratory and Critical Care Medicine. Dr. Lynch is also on the editorial board of other publications, such as Clinical Pulmonary Medicine, Pulmonary Infections Forum, and Clinical Medicine: Respiratory and Pulmonary Medicine. From 1992–2008, he has been cited in The Best Doctors in America and from 2001–2007, he has been cited in America’s Top Doctors. Dr. Lynch is also the editor of Informa Healthcare’s Idiopathic Pulmonary Fibrosis and Lung and Heart-Lung Transplantation. Printed in the United States of America
Lynch
edited by
Joseph P. Lynch, III
DESIGNER: XX
H5342
Interstitial Pulmonary and Bronchiolar Disorders FILE NAME: XXXXX DATE CREATED: XXXXX DATE REVISED: XXXX NOTES:
The only text on the market today that deals with the entire spectrum of ILDs, this handy, one-stop reference includes: • a special focus on treatment and the proper use of treatment options, including in depth coverage of the most common and potentially dangerous means of treatment • emerging concepts in patient care • discussion of lung diseases affecting the survivors of 9/11
Interstitial Pulmonary and Bronchiolar Disorders
Removing the guesswork associated with Interstitial Lung Disorders (ILDs) and bronchiolar disorders, Interstitial Pulmonary and Bronchiolar Disorders addresses the issues faced by pulmonologists in treating these disorders. Divided into sections based on the disease type (granulomatous, pneumonias, bronchiolar disorders, vasculitis, and orphan lung disease), each disorder is covered from epidemiological, pathogenic, clinical, and radiographic perspectives.
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