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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 auto
