Diffuse Parenchymal Lung Disease (Progress in Respiratory Research)

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Author: U. Costabel | R. M. du Bois | J. J. Egan

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Diffuse Parenchymal Lung Disease

Progress in Respiratory Research Vol. 36

Series Editor

Chris T. Bolliger, Cape Town

Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Singapore · Tokyo · Sydney

Diffuse Parenchymal Lung Disease

Volume Editors

Ulrich Costabel, Essen Roland M. du Bois, London Jim J. Egan, Dublin

144 figures, 15 in color, and 47 tables, 2007

Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Singapore · Tokyo · Sydney

Prof. Dr. Ulrich Costabel

Prof. Dr. Roland M. du Bois

Department of Pneumology and Allergy Ruhrlandklinik Tueschener Weg 40 DE–45239 Essen (Germany)

Interstitial Lung Disease Unit & Clinical Genomics Group Royal Brompton Hospital Sydney Street London SW3 6NP (UK)

Dr. Jim J. Egan The Mater Misericordiae Hospital University College Dublin Eccles Street Dublin 7 (Irland)

Library of Congress Cataloging-in-Publication Data Diffuse parenchymal lung disease / volume editors, Ulrich Costabel, Roland M. du Bois, Jim J. Egan. p. ; cm. – (Progress in respiratory research, ISSN 1422-2140 ; v. 36) Includes bibliographical references and indexes. ISBN-13: 978-3-8055-8153-0 (hard cover : alk. paper) 1. Interstitial lung diseases. I. Costabel, Ulrich. II. Du Bois, Roland M. III. Egan, Jim J. IV. Series. [DNLM: 1. Lung Diseases. 2. Lung Diseases, Interstitial. W1 PR681DM v.36 2007 / WF 600 D5695 2007] RC776.I56D54 2007 616.2⬘4–dc22 2007010588

Disclaimer. The statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in

indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.

© Copyright 2007 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 978–3–8055–8153–0, ISSN 1422–2140

Contents

VII Foreword VIII Preface General Aspects 2 Classification of Diffuse Parenchymal Lung Disease Gomez, A.D.; King, T.E., Jr. 11 Diagnostic Approach to Diffuse Parenchymal Lung Disease Lynch, J.P., III; Weigt, S.S.; Fishbein, M.C. 22 Clinical Evaluation Yang, S.; Raghu, G. 29 Imaging Desai, S.R.; Wells, A.U. 44 Diffuse Parenchymal Lung Diseases – Histopathologic Patterns Chilosi, M.; Murer, B.; Poletti, V. 58 Bronchoalveolar Lavage Drent, M.; Baughman, R.P.; Meyer, K.C. Basic Aspects 70 Genetics of Interstitial Lung Disease du Bois, R.M. 87 Granuloma Formation Facco, M.; Miorin, M.; Agostini, C.; Semenzato, G. 101 Pathogenesis of Idiopathic Pulmonary Fibrosis Noble, P.W. 110 Basics of Pulmonary Vasculitis Cohen Tervaert, J.W.; Damoiseaux, J.G.M.C. 117 Novel Aspects of Treatment for Interstitial Lung Diseases Behr, J.

V

Diseases 128 Sarcoidosis Newman, L.S.; Wasfi, Y.S. 139 Hypersensitivity Pneumonitis Vogelmeier, C. 148 Idiopathic Pulmonary Fibrosis Keating, D.T.K.; McCullagh, B.; Egan, J.J. 160 Nonspecific Interstitial Pneumonia Flaherty, K.R.; Martinez, F.J. 175 Diseases: Other Entities of the Idiopathic Interstitial Pneumonias Collard, H.R. 185 Pulmonary Fibrosis in Collagen Vascular Disease Hoyles, R.K.; Wells, A.U. 196 Pulmonary Vasculitis Lynch, J.P., III; Fishbein, M.C.; White, E.S. 212 Drug-Induced and Iatrogenic Infiltrative Lung Disease Camus, P. 238 Idiopathic Eosinophilic Pneumonias Lazor, R.; Cordier, J.-F. 250 Diffuse Alveolar Hemorrhage Olson, A.L.; Schwarz, M.I. 264 Pulmonary Langerhans’ Cell Histiocytosis Harari, S.; Caminati, A. 275 Lymphangioleiomyomatosis Johnson, S.R. 285 Acquired Idiopathic Pulmonary Alveolar Proteinosis Costabel, U.; Bauer, P.C.; Guzman, J. 292 Bronchiolitis Poletti, V.; Casoni, G.; Zompatori, M.; Chilosi, M. 307 Lymphoproliferative Lung Disorders Poletti, V.; Zinzani, P.L.; Tomassetti, S.; Chilosi, M. Special Considerations 324 Interstitial Lung Diseases in Children Clement, A.; Fauroux, B. 332 Lung Transplantation for Diffuse Parenchymal Lung Disease Irani, S.; Boehler, A.

341 Author Index 342 Subject Index

VI

Contents

Foreword

The book series Progress in Respiratory Research was started in 1963 and is enjoying increasing success. Since I took over from my predecessor Prof. H. Herzog in 1997, my vision was to cover the whole area of thoracic medicine. In contrast to standard text books, however, this series aims at providing cutting-edge knowledge including the most recent advances in the field discussed. This necessitates three preconditions: top quality experts as volume and chapter authors, a strict enforcement of submission deadlines, and a fast printing process by the publisher. I am happy to say that all of these requirements have been ful-filled in this current 36th volume of Progress in Respiratory Research devoted to diffuse parenchymal lung disease (DPLD). The choice of the topic was made easy as none of the previous volumes have ever addressed DPLD, an important area in pulmonary medicine, where a lot of progress has been made during the last couple of years. It was therefore a timely topic to choose. The choice of terminology for the volume title was a deliberate one; the classic designation interstitial lung disease has been replaced by the more modern and more accurate term DPLD. As usual, the most important task of the Editor-in-Chief after the choice of the topic of a volume was the choice of

the volume editor(s). I was fortunate enough to have the immediate support of three well-known experts in DPLD – Ulrich Costabel, Jim Egan and Ron Dubois – who shared the task of compiling the content and choosing the best possible authors to write the individual book chapters. As you the reader can easily see, the result has been a fantastic book covering all the important aspects and including the majority of leaders in DPLD at a global level. True to the vision of the book series, authors were instructed to include the latest references available at the time of writing. The book is aimed at all doctors from general practitioners to pulmonary physicians with a special interest in DPLD; there is something for everyone. For a more specific introduction of the various topics please see the preface by the volume editors. My thanks go to the three editors as well as all the chapter authors, and, once again, to the editorial staff at the publishing house, S. Karger AG, Basel, Switzerland. The publisher has proved his quality once again by printing a high-quality book in the shortest possible time after receipt of the final manuscript, well done guys! C.T. Bolliger Cape Town

VII

Preface

Diffuse parenchymal lung diseases (DPLD) represent a large and heterogeneous group of disorders, many of them belonging to the category of orphan diseases. Our knowledge on DPLD has expanded greatly during the last decade. New insights into the pathogenesis and new techniques such as high-resolution CT scanning have made significant contributions to a better understanding of these less common disorders which remain an intellectual challenge to clinicians, radiologists and pathologists. DPLD comprise over 200 entities of known and unknown causes, with or without associated systemic disease, of acute or chronic onset, of indolent or rapidly progressive course, and wide variations in treatment response. The management of DPLD remains difficult, but correct diagnosis, appropriate treatment and a balanced assessment of prognosis are important. This issue of Progress in Respiratory Research aims to provide valuable information on the rapid advances in this field. The first section covers general topics including the most recent classification system, the general diagnostic approach, and the clinical evaluation of the patient including radiology, histopathological patterns, and bronchoalveolar lavage findings. The concept of classification of DPLD has undergone significant change over recent years. The idiopathic interstitial pneumonias now comprise seven distinct diagnoses which have all been previously regarded as forms of idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis. Even the current classification is controversial, since disorders related to cigarette smoking such as DIP and RBILD are included without being truly idiopathic. In the diagnostic evaluation CT scanning can sometimes provide highly disease-specific information so that

VIII

surgical lung biopsy can be avoided. Diagnosis cannot, however, be based on imaging or histopathology alone, but needs precise clinical information, so that the necessity of a multidisciplinary clinical/radiological/pathological approach in making the final diagnosis has been emphasized. Several chapters deal with the basic aspects of DPLD. Genetic factors that pre-dispose to DPLD and define clinical disease phenotypes have been characterized in sarcoidosis and systemic sclerosis, whereas this is far less advanced in idiopathic fibrosing lung diseases. The basics of granuloma formation, fibrogenesis in idiopathic pulmonary fibrosis, and mechanisms of vasculitis are highlighted. A special chapter addresses novel aspects of treatment for interstitial lung diseases with an emphasis on idiopathic pulmonary fibrosis. A large section of the book is devoted to specific diseases, covering granulomatous disorders, idiopathic pulmonary fibrosis and other idiopathic interstitial pneumonias, collagen vascular diseases, drug-induced infiltrative lung disease, diffuse alveolar hemorrhage, and even rarer disease entities such as the eosinophilic pneumonias, Langerhans’ cell histiocytosis, lymphangioleiomyomatosis and pulmonary alveolar proteinosis. Bronchiolitis and lymphoproliferative lung disorders are also included, since their clinical and radiological manifestations mimic diffuse parenchymal lung disease. The last two chapters are focused on DPLD in children and lung transplantation for end-stage fibrosis, two topics which deserve special consideration. The editors have recruited international experts from the various disciplines involved in these disorders to

U. Costabel, Essen

R.M. du Bois, London

contribute state-of-the-art reviews to this book. We hope that the readers will find it a helpful tool in the daily management of their patients with DPLD and an invaluable information source. We thank Chris Bolliger for providing us with the opportunity to update a very exciting area in the field of lung diseases. We are grateful to S. Karger publishers for

Preface

J.J. Egan, Dublin

being extremely supportive in getting the book published. Our special thanks go the authors; we appreciate the high quality of their contributions and also their willingness to add the latest and hottest news to the bibliography of their chapters. Ulrich Costabel, Roland M. du Bois, Jim J. Egan

IX

General Aspects

Costabel U, du Bois RM, Egan JJ (eds): Diffuse Parenchymal Lung Disease. Prog Respir Res. Basel, Karger, 2007, vol 36, pp 2–10

Classification of Diffuse Parenchymal Lung Disease Antonio D. Gomez

Talmadge E. King Jr.

San Francisco General Hospital, San Francisco, Calif., USA

Abstract The diffuse parenchymal lung diseases (DPLD) comprise an extremely wide spectrum of pathologies, presentations, and outcomes. Many different approaches to the classification of DPLDs exist.The most common classification scheme divides the DPLD into 4 broad categories based on whether or not the cause is known. The ATS/ERS classification focused on the idiopathic interstitial pneumonias and combined the histopathologic pattern seen on lung biopsy with clinical and radiological information to arrive at a final diagnosis. This approach made it such that lung biopsy was no longer considered the ‘gold standard’ for the diagnosis but was one integral part of the diagnosis. The new ‘gold standard’ for the diagnosis of the diffuse parenchymal lung diseases, in particular, the idiopathic interstitial pneumonias (IIPs), is a combination of ‘clinical-radiographic-pathological’ features arrived at by a dynamic, integrated process among clinicians, radiologists and pathologists. Much has been learned about the IIPs since the publication of the ATS/ERS classification. Therefore, we propose a revised classification scheme for these diffuse parenchymal lung diseases.

years. Cases of DPLD are relatively uncommon and few clinicians have extensive experience diagnosing this group of diseases. However, DPLDs account for about 15% of diseases seen in pulmonary medicine practice [1]. Because of this, consensus on how to classify the DPLDs has been controversial. Nonetheless, the evolution in the classification of these disorders has been driven by epidemiologic, clinical, radiologic, biochemical, genetic, and pathological investigation. Recently, there has been significant change in the way we think about DPLD, both from an etiologic and pathophysiologic standpoint. Most of the recent work has centered on defining and characterizing the idiopathic forms of DPLD, the so called idiopathic interstitial pneumonias (IIPs). In 2001, the American Thoracic Society (ATS)/ European Respiratory Society (ERS) consensus panel provided a standardized nomenclature and diagnostic criteria for the IIPs in the hope this would provide a framework for the future study of these entities and lead to improved understanding of the causes of these disorders and ultimately to improved treatments [2].

Copyright © 2007 S. Karger AG, Basel

Historical Background

The diffuse parenchymal lung diseases (DPLDs) comprise over 200 entities and include a wide spectrum of diseases, many uncommon and many of unknown etiology [1]. The classification of DPLD, also known as interstitial lung disease (ILD), has challenged clinicians and investigators for many

The concept of DPLD has been described in the medical literature for over a century (fig. 1). In 1892, Osler [3] described the lungs of patients with chronic interstitial pneumonia as having ‘a fibrinoid change, which may have its starting point in the tissue about the bronchi and bloodvessels, the interlobular septa, the alveolar walls of the

1890s: ‘Cirrhosis’ of the lung

1940s: Acute ‘Hamman-Rich’ Syndrome (Acute diffuse interstital fibrosis of lungs)

1950s: Chronic ‘Hamman-Rich’ Syndrome (Synonyms: Chronic interstitial pulmonary fibrosis Cryptogenic fibrosing alveolitis)

1960s: Widespread pulmonary fibrosis (Diffuse fibrosing alveolitis)

Pulmonary granulomata (many causes)

Pulmonary exudates (many causes)

Inorganic dust inhalation

Other types of lung injury (e.g. infections)

Fig. 1. Historical progression of the classification of the diffuse parenchymal lung diseases. Adapted from Turner-Warwick [17] and King [18].

pleura’. He used the term ‘cirrhosis of the lung’ to describe this finding. Even then, it was recognized that the classification of these entities was difficult. with inhaled dusts was well known by this time, but that was the extent of what was understood and was not the focus of investigation. Osler [3] stated, ‘…So diverse are the different forms and so varied the conditions under which this change occurs that a proper classification is extremely difficult’. Decades later, Hamman and Rich [4] described 4 cases of acute diffuse interstitial fibrosis in which ‘…the lungs were the seats of a widespread connective tissue hyperplasia throughout the interstitial structures. The alveolar walls were tremendously thickened; in the early stages of the process crowded with fibroblasts’. Although these cases were acute and rapidly progressive, the term Hamman-Rich syndrome was coined to describe any diffuse idiopathic fibrotic lung disease, whether chronic or acute. Over the next several decades, progress was made in defining the etiology of many DPLDs. Most notable were the associations made with systemic disease (collagen-vascular diseases), drugs, inherited conditions and occupational or environmental exposures (organic and inorganic dust). Despite these advances, there was still a significant group of interstitial pneumonias not clearly linked to any causative agent and remained idiopathic (fig. 2). Several terms were

Classification of DPLD

used to describe this group, such as chronic idiopathic interstitial fibrosis, diffuse fibrosing alveolitis, Hamman-Rich syndrome, idiopathic pulmonary fibrosis, diffuse alveolar pulmonary fibrosis, and idiopathic interstitial pneumonia. In the years that followed and up to the present, classifying and further refining this idiopathic group from an epidemiologic, etiologic, and histopathologic basis became the main focus. In 1964, Scadding [5] introduced the term ‘diffuse fibrosing alveolitis’. He defined this as ‘…widespread fibrosis in that part of the lungs beyond the terminal bronchioles, which is concerned with gas exchange’. He later divided this category between entities with a defined etiology (inhaled dusts, ingested toxic substances, and infections) versus those with a defined histopathology and no known etiology. The histopathologic group was further subdivided into systemic diseases with similar histology (i.e. sarcoidosis, tuberous sclerosis, etc.) and into those only affecting the lungs. He also defined two distinct histologic patterns: desquamative (lacking fibrosis or changes to lung architecture) and mural (fibrosis with architectural distortion) [5]. In the same decade, Liebow and Carrington [6] subdivided the chronic idiopathic interstitial pneumonias based on histopathology. They described five distinct groups: the classical ‘undifferentiated’ or ‘usual’ interstitial pneumonia

3

Idiopathic interstitial pneumonias Fig. 2. Historical progression of the classifi-

cation of the idiopathic interstitial pneumonias. AIP ⫽ Acute interstitial pneumonia; BOOP ⫽ bronchiolitis obliterans organizing pneumonia; DAD ⫽ diffuse alveolar damage; DIP ⫽ desquamative interstitial pneumonia; GIP ⫽ giant cell interstitial pneumonia; IPF ⫽ idiopathic pulmonary fibrosis; LIP ⫽ lymphocytic interstitial pneumonia; NSIP ⫽ nonspecific interstitial pneumonia; OP ⫽ organizing pneumonia; RB-ILD ⫽ respiratory bronchiolitis interstitial lung disease; UIP ⫽ usual interstitial pneumonia. Adapted from King [18].

Acute 1986: ‘Hamman-Rich’ Syndrome = AIP (DAD)

Gomez/King

Subacute

1960s: UIP, DIP, BIP, LIP, GIP

1970s: IPF (UIP, DIP, NSIP)

1985: BOOP 1987: RB-ILD 1994: NSIP

DAD

OP

NSIP

Acute and subacute IIPs

(UIP), bronchiolitis obliterans interstitial pneumonia and diffuse alveolar damage (termed bronchiolitis interstitial pneumonia, BIP), desquamative interstitial pneumonia (DIP), lymphoid interstitial pneumonia (LIP), and giant cell interstitial pneumonia (GIP). Under their scheme, HammanRich syndrome was considered the acute form of UIP. They believed that classifying the idiopathic forms histologically, when correlated with the clinical and radiographic data, would eventually lead to a particular etiology. They also reasoned that this ‘…should be a stimulus to intensive investigation…’ and the basis for new treatment approaches [7]. American and European investigators did not always agree on the classification schemes or the pathophysiology of DPLD, but in retrospect, it is appears their differences were relatively minor. For example, the Scadding and Liebow classification schemes, while appearing different on the surface are actually complementary and easily related. The chronic IIPs as described by Liebow and Carrington are basically Scadding’s histopatholgic group subdivided into five groups. Despite this, few investigators other than Liebow’s students used this histopathologicbased classification of the idiopathic forms of DPLD. In 1998, Katzenstein and Myers [8] redefined the classification scheme including two of Liebow’s categories and incorporating two other patterns. Their four subdivisions included UIP, DIP and a related form termed ‘respiratory-bronchiolitis-associated interstitial lung disease’ (RB-ILD), acute interstitial pneumonia (essentially bringing Hamman-Rich syndrome back into the classification), and the newer nonspecific interstitial pneumonia (NSIP). By this time, the etiologic agent in GIP was known to be

4

Chronic

LIP

DIP, RB-ILD

UIP

Chronic IIPs

hard-metal exposure and LIP was considered a lymphoproliferative disorder. Consequently, both were excluded from the IIP classification. In addition, BIP was excluded because it was predominantly an intraluminal rather than interstitial process now recognized as two separate processes: organizing pneumonia (also called bronchiolitis obliterans organizing pneumonia, BOOP) and diffuse alveolar damage (DAD). They identified several key histologic features that allow these entities to be separated one from the others, such as, temporal heterogeneity of inflammation and fibrosis, extent of inflammation and fibroblast proliferation, accumulation of intra-alveolar macrophages, and the presence of honeycombing or hyaline membranes.

Current Classification Schemes for DPLD

Classification of DPLD There have been many different approaches to the classification of DPLD and there is no universally accepted format. The scheme that has gained recent popularity breaks DPLD into 4 broad categories: DPLD of known causes, IIPs, granulomatous, and other forms (fig. 3). The advantage of this method is that the IIPs are given a separate subdivision (see below). This classification scheme conveys more about the clinical history and histopathology than the tempo of disease [2]. Another useful scheme is to categorize DPLD based on the pace of clinical presentation, drug exposures, and the presence of organ system involvement outside of the lung (table 1): (1) acute DPLD (excluding infections); (2)

Diffuse parenchymal lung disease

DPLD of known cause (e.g. drugs or association e.g. collagen vascular disease)

Idiopathic interstitial pneumonias

Idiopathic pulmonary fibrosis (Usual interstitial pneumonia)

Granulomatous DPLD (e.g. sarcoidosis)

Other forms of DPLD (e.g. LAM, PLCH, etc.)

IIP other than idiopathic pulmonary fibrosis

Desquamative interstitial pneumonia

Respiratory bronchiolitis interstitial lung disease

Acute interstitial pneumonia (Diffuse alveolar damage)

Cryptogenic organizing pneumonia

Nonspecific interstitial pneumonia (Provisional)

Lymphocytic interstital pneumonia

Fig. 3. ATS/ERS classification of diffuse parenchymal lung diseases. DPLDs consist of disorders of known causes (collagen vascular disease, envi-

ronmental or drug related) as well as disorders of unknown cause. The latter include IIPs, granulomatous lung disorders (e.g. sarcoidosis), and other forms of ILD including lymphangioleiomyomatosis (LAM), pulmonary Langerhans’ cell histiocytosis/histiocytosis X (PLCH), and eosinophilic pneumonia. The most important distinction among the idiopathic interstitial pneumonias is that between idiopathic pulmonary fibrosis and the other IPs, which include nonspecific interstitial pneumonia (a provisional term), desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, acute interstitial pneumonia, cryptogenic organizing pneumonia, and lymphocytic interstitial pneumonia. Adaped from [2].

episodic DPLD (can overlap with acute); (3) chronic DPLD secondary to occupational, environmental or drug exposures; (4) chronic DPLD in the setting of systemic disease, and (5) chronic DPLD that is idiopathic, confined to the lung or has no clearly identifiable exposure [1]. This scheme is easier to follow from a clinical point of view, but lumps the IIPs with disorders such as lymphangioleiomyomatosis (LAM), pulmonary alveolar proteinosis (PAP) and Langerhans’ cell histiocytosis based on the time course and organ involvement of the particular disorder. The disadvantage here is that entities like PAP or LAM share almost none of the same pathophysiology with IPF/UIP or DIP, but are placed in the same subdivision – this classification scheme tells you very little about the pathophysiology of these disorders. Classification of IIPs In an attempt to standardize the classification of IIPs, an American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus panel published a revised classification system 2001. The panel expanded the Katzenstein


and Myers scheme to include seven different entities which comprises the current group of IIPs (table 2). They stressed the importance of an integrated multidisciplinary approach to the diagnosis and the difference between the clinico-radiologic diagnosis and the histopathologic entity seen on biopsy. The idea behind distinguishing the two, was to highlight the fact that a ‘final diagnosis should be rendered only after the pulmonologist, radiologist, and pathologist have reviewed all of the clinical, radiological, and pathological data obtained from the patient.’ While the panel emphasized the need for a surgical lung biopsy to make a firm histopathological diagnosis, they also established a set of clinico-radiologic criteria by which a diagnosis of idiopathic pulmonary fibrosis (IPF) could be made without a surgical lung biopsy [2]. Controversies in the Classification Unclassifiable Interstitial Pneumonia. Despite the widespread acceptance of the current classification system, controversy still exists. Specifically, the relationships, if any,

5

Table 1. Classification scheme for DPLDa

Acute DPLD Cause Allergy Toxins Hemodynamic Vasculitis/hemorrhageb

Example drugsb (e.g. penicillin); fungi (e.g. aspergillosis); helminths (e.g. Toxocara) drugsb (e.g. cytotoxics, amiodarone); toxic gases, fumes (e.g. chlorine) left ventricular failureb, fluid overload, renal failure Goodpasture’s syndrome, idiopathic hemosiderosis, Behcet’s syndrome, systemic lupus erythematosus, Wegener’s granulomatosis, Churg-Strauss syndrome trauma, septicemia cryptogenic organizing pneumoniab, cryptogenic pulmonary eosinophiliab

ARDS Unknown Episodic DLPD Eosinophilic pneumonia Vasculitides/pulmonary hemorrhage Churg-Strauss syndrome Hypersensitivity pneumonitis Cryptogenic organizing pneumonia

Chronic DPLD secondary to occupational or environmental agents Agent inhaled Example Inorganic dusts Fibrogenic asbestosis, silicosis Non-fibrogenic siderosis (iron), stannosis (tin), baritosis (barium) Granulomatous/fibrogenic berylliosis Organic dusts (hypersensitivity pneumonitis) Bacteria farmers’ lung (thermoactinomycetes in moldy hay); bagassosis (thermoactinomycetes in mouldy sugar cane) Fungi suberosis (in cork workers); Cheese workers’ lung (moldy cheese) Animal protein Bird fanciers’ lung (avian protein on feathers) Chemicals isocyanates Drug and toxin-induced DPLD Drug class Antibiotics Anti-inflammatory agents Cardiovascular agents Chemotherapeutic agents Drug-induced SLE Illicit drugs Miscellaneous Chronic DPLD with evidence of systemic disease Connective tissue disorders Systemic sclerosis Systemic lupus erythematosus Sjögren’s syndrome Ankylosing spondylitis Neoplastic Lymphomac Micrometastates Vasculitisc Wegener’s granulomatosis Goodpasture’s syndrome Sarcoidosisc Inherited disorders Tuberous sclerosis Lipid storage disease

6

Gomez/King

Example nitrofurantoin, sulphasalazine gold, penicillamine, aspirin amiodarone bleomycin, methotrexate hydralazine heroin, methadone, talc oxygen, radiation, lipoid pneumonia

Rheumatoid arthritis Polymyositis Mixed connective tissue disorders Behcet’s disease Lymphangitic carcinomac

Microscopic polyangiitis

Neurofibromatosis Hermansky-Pudlak syndrome

Table 1. (continued)

Other miscellaneous Inflammatory bowel disease After bone marrow transplantation Langerhans’ cell histiocytosisc

HIV associated Amyloidosisc Miliary tuberculosis Pulmonary eosinophiliac

Chronic DPLD with no evidence of systemic disease or external agent exposure Idiopathic interstitial pneumonias Sarcoidosisd Cryptogenic organizing pneumoniad Pulmonary Langerhans’ cell histiocytosisd Alveolar proteinosisd Bronchocentric granulomatosis Chronic aspiration Pulmonary veno-occlusive disease Alveolar microlithiasis Idiopathic pulmonary hemosiderosis Lymphangioleiomyomatosis Bronchoalveolar carcinoma Pulmonary eosinophiliad a

Does not include infections or neoplasms. May also present with chronic disease. c May be confined to the lung. d May be associated with systemic disease or external agents. Adapted from British Thoracic Society [1]. b

Table 2. Histopathological classifications schemes of idiopathic interstitial pneumonias

Liebow and Carrington [6]

Usual interstitial pneumonia Desquamative interstitial pneumonia

Katzenstein and Myers [8]

Usual interstitial pneumonia Desquamative interstitial pneumonia Respiratory bronchiolitis interstitial lung disease

Lymphoid interstitial pneumonia Giant cell interstitial pneumonia Bronchiolitis obliterans interstitial pneumonia and diffuse alveolar damage Acute interstitial pneumonia Nonspecific interstitial pneumonia

between the various entities within the IIPs have been the subject of much debate, especially the relationship of UIP to the other form of DPLD. For some time, investigators had considered UIP as the ‘end-stage’ form of the other DPLDs. The idea was that, depending on the time of diagnosis, chronic interstitial inflammation from any cause could lead to the same clinical and histopathologic pattern of UIP. Indeed,


ATS/ERS [2] Histologic patterns

Clinical-radiographic-pathologic diagnosis

Usual interstitial pneumonia Desquamative interstitial pneumonia Respiratory bronchiolitis Lymphoid interstitial pneumonia

Idiopathic pulmonary fibrosis Desquamative interstitial pneumonia Respiratory bronchiolitis interstitial lung disease Lymphoid interstitial pneumonia

Organizing pneumonia


Diffuse alveolar damage Nonspecific interstitial pneumonia

Acute interstitial pneumonia Nonspecific interstitial pneumonia

finding end-stage fibrosis and honeycomb lung makes rendering a specific diagnosis virtually impossible, however, most experts no longer label these cases as UIP but rather they are called ‘unclassifiable interstitial pneumonia’ [2]. In this circumstance, the ATS/ERS consensus statement recommends that the clinician determine the most probable diagnosis after detailed clinico-radiological-pathological case

7

discussion with the pathologist and radiologist. Importantly, this category designation should not be used for cases of clearly defined NSIP or cases in which the distinction between the UIP and fibrosing NSIP patterns is difficult. In such cases, one should make the best possible diagnosis given the available information, realizing the differential diagnosis may be a challenge. Finally, the purpose of the concept of unclassifiable interstitial pneumonia to acknowledge that uncertainty may remain in individual cases [2]. Relationship between DIP and UIP. Desquamative interstitial pneumonia (DIP) is a term that has been used for many years, but until recently it was not clear whether investigators were referring to the same process. Fortunately, the criteria for the histopathologic diagnosis of DIP have become more stringent. An important controversy centered on the belief that DIP was a precursor of UIP. This hypothesis was largely supported by the observation that DIP had a greater cellularity than UIP on biopsy and that a DIP pattern could be found in the lungs of patients with clearly defined UIP pattern of lung injury, i.e. supporting the notion that DIP was an earlier stage of UIP and that patients with the DIP pattern would evolve into UIP [8]. To date, little evidence has appeared to support this idea, i.e. no one has been able to show the development of a UIP pattern in a patient previously diagnosed with DIP. More importantly, it has become clear that a DIP-like reaction (usually with respiratory bronchiolitis) is commonly seen in smokers and should therefore be expected in smokers with UIP (or any other lung disease). Also, it is clear that DIP and RB-ILD improve with smoking cessation, and carries a much better prognosis than UIP [2]. Currently, DIP/ RB-ILD and UIP are considered two separate entities within the IIPs. The NSIP and UIP Debate. Originally introduced as a ‘wastebasket’ category, NSIP as a distinct entity has been the topic of many discussions [9]. Collagen vascular disease, hypersensitivity pneumonitis, drug-induced pneumonias, infections and immunodeficient states (HIV or after bone marrow transplant) have all been associated with a NSIP-like pattern on lung biopsy. The remaining cases without a clear association are considered truly ‘idiopathic NSIP’. In some cases, the associated diseases are obvious before NSIP is found on biopsy specimens, but many times the finding of NSIP on lung biopsy is the first manifestation of systemic disease. Currently, no one really knows whether NSIP eventually becomes the clinical, radiologic, and pathologic entity that is IPF/UIP. The general thought is that they are distinct entities with the evidence for this mainly being the difference in response to therapy and mortality. Because most studies have been cross-sectional and not longitudinal in study

8

Gomez/King

design, it has been difficult to answer this question with much certainty. Katzenstein et al. [10] examined the surgical lung biopsy specimen of 20 patients who then went on to have lung transplant, and compared the histological pattern seen on the previous biopsy to the explanted specimen. They found that 12 of 15 biopsies and 13 of 15 explants diagnosed with UIP, had NSIP-like areas found both in the same area as UIP and in areas that were not clearly diagnosable as UIP. Interestingly, no explant showing UIP was preceded by biopsy findings of NSIP, and the one NSIP case appeared similar at biopsy and explant. Also, other patterns of lung injury could be found in many cases, i.e. diffuse alveolar damage and organizing pneumonia. In a study of 109 patients who had biopsies taken from more that one lobe at the time of surgery, Flaherty and colleagues showed that patients with UIP often have areas resembling NSIP occur in a background of otherwise typical UIP (labeled ‘discordant UIP)’ [11]. They demonstrated that these cases of ‘discordant UIP’ had the same survival rates as patients with ‘concordant UIP’ (all sites showing UIP pattern). Patients with ‘concordant NSIP’ (all biopsy sites showing NSIP pattern) had a much better prognosis than the cases with UIP (more in keeping with the results of other studies comparing UIP to NSIP) [12–14]. These studies show that NSIP-like areas are commonly seen in patients with diagnostic features of UIP. However, they do not answer the question of whether or not one evolves from or into the other. They do support the notion that surgical lung biopsy must be performed such that biopsies are taken from more than one lobe of the lung in an effort to avoid a sampling error that might lead to an incorrect diagnosis, especially of UIP – the lesion with the worse prognosis. Several critical questions regarding NSIP remain to be answered [15]. Should NSIP continue be a ‘provisional’ diagnosis until an association is found, and then placed into the idiopathic category [2]? Does idiopathic NSIP carry a worse prognosis and response to treatment than NSIP secondary to other causes such as rheumatologic disease for example? The answers to these questions have implications in the classification of the IIPs and ultimately in discovering an etiology.

A New Look at the Classification of DPLD

The goal of any classification system should be to convey information about the etiology, pathophysiology and prognosis of the diseases in question. This is no simple task in DPLD – the number of diseases is broad, the etiology is not known in many cases, some entities can be both acute

Diffuse parenchymal lung disease

DPLD of known cause (e.g. drugs or association e.g. collagen vascular disease)

Smoking-related DPLD

Idiopathic pulmonary fibrosis (Usual interstitial pneumonia)

Idiopathic interstitial pneumonias

Granulomatous DPLD (e.g. sarcoidosis)

Nonspecific interstitial pneumonia

Acute interstitial pneumonia (Diffuse alveolar damage)

Other forms of DPLD


Respiratory bronchiolitis interstitial lung disease

Lymphocytic interstitial pneumonia

Pulmonary Langerhans’ cell histiocytosis

Other forms of DPLD (e.g. LAM, vasculitis, etc.)

Fig. 4. Revised ATS/ERS classification of diffuse parenchymal lung diseases. DPLDs consist of disorders of known causes (collagen vascular

disease, environmental, smoking related or drug related) as well as disorders of unknown cause. The latter include IIPs, granulomatous lung disorders (e.g. sarcoidosis), and other forms of ILD. The idiopathic interstitial pneumonias consist of three entities: nonspecific interstitial pneumonia, acute interstitial pneumonia, and idiopathic pulmonary fibrosis (usual interstitial pneumonia).

and chronic, and entities within the same sub-category have varying rates of progression and pathophysiology. Many workers in this field believe that the ATS/ERS classification system needs revision, given the knowledge gained since its publication in 2001. Using the ATS/ERS classification system as a guide (fig. 4), some of the entities in the IIP category can be moved to other categories. DIP and RB-ILD along with Langerhans’ cell histiocytosis are only seen in patients who smoke tobacco and can be moved to the ‘Known Cause’ category. To avoid confusion, DIP is removed from the classification in favor of the broader and more useful category of RB-ILD. It should be noted that cases of DIP have been described in patients without a proven prior history of smoking. Pathophysiologically, LIP is a lymphoproliferative disorder which can be replaced in the ‘Other’ or ‘Known Cause’ category (associated with HIV, lymphoma, plasma cell dyscrasia, collagen vascular disease, etc.). Histologically, COP is an alveolar process with preservation of the underlying lung architecture and should be taken out of the classification of


DPLD altogether. The end result of this reorganization would leave the IIPs with AIP, IPF/UIP, and NSIP.

Conclusion

DPLD is a diverse group of nonmalignant, noninfectious processes with multiple causative agents, both known and unknown. The classification of DPLD has undergone major shifts based on clinical investigation, improvements in radiologic evaluation (e.g. CT technology), and collaboration with the pathologist. The strict diagnostic criteria set forward by the ATS/ERS consensus panel simplified the process and ensured that investigators were all referring to the same disease entity. Over time, application of these criteria will help to shorten the idiopathic list which will have implications for treatment. Furthermore, the use of biochemical markers and markers of gene expression, could aid in refining the classification of DPLD in the future [16].

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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/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002;165:277–304. 3 Osler W: The Principles and Practice of Medicine. New York, Appleton, 1892. 4 Hamman L, Rich AR: Acute diffuse interstitial fibrosis of the lungs. Bull Johns Hopkins Hosp 1944;74:177–212. 5 Scadding JG: Diffuse pulmonary alveolar fibrosis. Thorax 1974;29:271–281. 6 Liebow AA, Carrington DB: The interstitial pneumonias; in Simon M, Potchen EJ, LeMay M (eds): Frontiers of Pulmonary Radiology. New York, Grune & Stratteon, 1969, pp 102–141. 7 Liebow AA: Definition and classification of interstitial pneumonias in human pathology. Prog Respir Res 1975;8:1–33. 8 Katzenstein ALA, Myers JL: Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998;157:1301–1315.

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9 Katzenstein AL, Fiorelli RF: Nonspecific interstitial pneumonia/fibrosis: histologic features and clinical significance. Am J Surg Pathol 1994;18:136–147. 10 Katzenstein AL, Zisman DA, Litzky LA, Nguyen BT, Kotloff RM: Usual interstitial pneumonia: histologic study of biopsy and explant specimens. Am J Surg Pathol 2002;26: 1567–1577. 11 Flaherty KR, Travis WD, Colby TV, et al: Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 2001;164:1722–1727. 12 Nicholson AG, Colby TV, Dubois RM, Hansell DM, Wells AU: The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 2000;162:2213–2217. 13 Daniil ZD, Gilchrist FC, Nicholson AG, et al: A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1999;160:899–905. 14 Bjoraker JA, Ryu JH, Edwin MK, et al: Prognostic significance of histopathologic

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subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;157:199–203. du Bois RM, King TE J: The NSIP/UIP debate. Thorax 2006. Selman M, Pardo A, Barrera L, et al: Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med 2006;173: 188–198. Turner-Warwick M: A perspective view on widespread pulmonary fibrosis. Br Med J 1974;2:371–376. King TE Jr: Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am J Respir Crit Care Med 2005;172:268–279.

Talmadge E. King Jr., MD San Francisco General Hospital The Constance B. Wofsy Distinguished Professor and Vice-Chairman Department of Medicine UCSF 1001 Potrero Avenue Room 5H22 San Francisco, CA 94110 (USA) Tel. ⫹1 415 206 3465, Fax ⫹1 415 206 4890 E-Mail [email protected]


Diagnostic Approach to Diffuse Parenchymal Lung Disease Joseph P. Lynch IIIa S. Sam Weigta Michael C. Fishbeinb a

Division of Pulmonary, Critical Care Medicine and Hospitalists, Department of Internal Medicine, Department of Pathology and Laboratory Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, Calif., USA b

Abstract Diffuse parenchymal lung disease (DPLD) encompasses a wide array of disorders, characterized by inflammatory and fibrotic changes affecting alveolar walls and airspaces. DPLD may be caused by myriad etiologies, with differing prognoses, natural history, and therapies. In this review, we focus on diverse immune-mediated, environmental, and idiopathic causes of DPLD. We present a comprehensive diagnostic approach that includes a careful occupational and environmental history, physical examination, radiographic and physiologic studies, and lung biopsy (selected patients). We discuss the salient characteristic of many DPLDs, and the role and limitations of surgical lung biopsies to diagnosis DPLD.

[4]. Although diverse infections (particularly tuberculosis and fungal diseases) may cause DPLD, this chapter does not address infectious causes. Rather, we briefly discuss a diagnostic approach to the diverse immune-mediated, environmental, and idiopathic causes of DPLD. Clinical signs and symptoms overlap between differing diseases, but salient differences in clinical, demographic, radiographic, and histopathological patterns distinguish these diverse entities. An initial approach to diagnosis requires incorporating these various facets.

Initial Approach to Establishing a Specific Cause of DPLD


Diffuse parenchymal lung disease (DPLD) encompasses a heterogenous group of disorders, characterized by a spectrum of inflammatory and fibrotic changes affecting alveolar walls and airspaces [1–3]. Clinical manifestations are protean, but progressive dyspnea, parenchymal infiltrates on chest radiographs, and pulmonary dysfunction are characteristic. DPLD may be caused by myriad etiologies (⬎150 causes), with differing prognoses, natural history, and treatment approaches. Causative agents include specific exposures or antigens (e.g. pneumoconiosis, hypersensitivity pneumonia (HP), infections) as well as disorders of unknown cause [e.g. idiopathic interstitial pneumonias (IIPs), cryptogenic organizing pneumonia (COP), sarcoidosis]

More than 150 causes of DPLD exist [2, 5]. Recent guidelines endorsed by the American Thoracic Society (ATS) and European Respiratory Society (ERS) recommended classifying DPLD into several broad categories as follows: (1) DPLDs of known cause; (2) granulomatous DPLDs; (3) rare DPLDs but with well-defined clinicopathologic features; (4) IIPs [2]. This classification schema is discussed in detail by King in this book. In this chapter, we present our approach to diagnose these diverse DPLDs. A comprehensive evaluation requires the following: (1) a methodical history to include demographics, family history, and occupational and environmental exposures; (2) physical examination; (3) chest radiographs; (4) high resolution computed tomographic (CT) scans; (5) blood tests; (6) fiberoptic bronchoscopy with bronchoalveolar lavage

(BAL) or transbronchial lung biopsies (selected patients); (7) surgical lung biopsy (selected patients).

Clinical History

Demographics Gender is rarely discriminatory, but some disorders (e.g. sarcoidosis [6, 7], chronic eosinophilic pneumonia (CEP) [8], systemic lupus erythematosus (SLE) [9], and progressive systemic sclerosis (PSS) [10]) are more common in females. Lymphangioleiomyomatosis (LAM) is exclusively seen in females [11, 12]. By contrast, pulmonary Langerhans cell granulomatosis (LCG) [13] and idiopathic pulmonary fibrosis (IPF) [1] are more common in males [1]. Age may narrow the differential diagnosis. Sarcoidosis typically presents between age 25 and 45 (but may affect all ages) [6], whereas IPF is rare in adults under age 50 [1]. When patients under age 50 present with features mimicking IPF, we aggressively search for specific causes or associations (e.g. pneumoconiosis, connective tissue disorder, drug or toxin exposures). Genetics A family history may identify patients with inheritable DPLD, but this is unusual. A positive family history can be elicited in only 1–3% of patients with IPF [14, 15] and 6–19% of patient with sarcoidosis [6, 16]. Examples of genetic ILDs include Hermansky-Pudlak syndrome [17]; Gaucher’s disease; lysosomal storage disorders; hypocalciuric hypercalcemia and interstitial lung disease [15, 18]; tuberous sclerosis complex (TSC) (associated with LAM) [11, 19]. These disorders are exceptionally rare. Exposures (Occupational, Hobbies, Home Environment) A thorough occupational and environmental history is critical to evaluate DPLD. Cigarette smoking has been strongly linked to pulmonary LCG [13], desquamative interstitial pneumonia (DIP) [20, 21], and respiratory bronchiolitis-interstitial lung disease (RB-ILD) [21], but appears to be protective against HP [22, 23]. Certain pharmacological agents or drugs may evoke airway (e.g. bronchiolar) or lung injury. Commonly recognized associations include: methotrexate; amiodarone; bleomycin; busulfan; chemotherapeutic and cytotoxic drugs; crack cocaine; intravenous illicit drugs [24, 25]. A careful work and environmental history is important to determine a possible cause of DPLD. Exposure to asbestos, silica, beryllium, tungsten carbide (hard metals) may suggest diagnoses such as asbestosis, silicosis, chronic beryllium disease, hard

12

Lynch/Weigt/Fishbein

metal pneumoconiosis, etc. The link between exposure to a noxious agent, irritant, or allergen may not be obvious, since clinical manifestations may be delayed for months or even years. It is likely that many cases of presumed IPF in fact reflect reactions to diverse occupational or environmental exposures that are not recognized. Inhaled environmental agents may cause HP, also termed extrinsic allergic alveolitis [23]. HP is a cell-mediated response to a variety of inhaled organic dusts or inorganic chemicals. Lung biopsy in HP demonstrates dense lymphocytic infiltrates, poorly formed granulomas, and foamy macrophages [23]. In North America, the most common causes of HP are: Farmer’s Lung Disease (caused by thermophilic actinomyces or molds in hay) and Pigeon Breeder’s or Bird Fancier’s Disease (caused by avian antigens) [23]. Other syndromes elicited by thermophilic actinomycetes include air conditioner (humidifier) lung, mushroom worker’s lung, and bagassosis (from exposure to sugar cane) [4]. Other causes of HP include: hot tub lung (from Klebsiella oxytoxa or Mycobacterium avium); contaminated heated swimming pools; machine operator’s lung (from Pseudomonas fluorescens); contamination with mold (in homes or buildings) [4]. The diagnosis of HP may be missed unless a detailed environmental history is obtained. Recent reports of unrecognized environmental lung diseases among workers in the nylon flocking industry and HP among workers in a peat moss packing plant underscore the need to seek the offending antigen(s). Importantly, repetitive exposures to the relevant antigen(s) may cause chronic HP, which can be fatal [26]. Treatment of HP requires removing the patient from the workplace or offending environment. Serum precipitating antibodies to the offending antigen(s) are present in a majority of patients with HP [23]. In patients with DPLD of unknown cause, we routinely screen for HP utilizing a panel of common antigens tested in commercial labs. These include precipitating antibodies to the most commonly implicated antigens (e.g. thermophilic Actinomycetes, Aspergillus spp, Micropolyspora faenii, avian antigens). Unfortunately, HP serological screens are negative in up to 40–60% of proven cases of chronic HP [26].

Physical Examination

Physical examination in patients with DPLD is usually nonspecific. Digital clubbing is more common in IPF, but can be found in nonspecific interstitial pneumonia (NSIP) [1, 27]. Bibasilar crackles are found in ⬎85% of patients with IPF, but may be found in virtually all DPLDs [1, 27]. Cutaneous findings (e.g. telangiectasis, sclerosis, digital

Fig. 1. Stage II sarcoidosis. Postero-anterior (PA) chest radiograph reveals massive bilateral hilar lymphadenopathy as well as bilateral parenchymal infiltrates. Note the predilection for mid and upper lung zones. Reproduced with permission from Lynch and Kazerooni [32].

Fig. 2. Idiopathic pulmonary fibrosis (IPF). PA chest radiograph demonstrates diffuse interstitial infiltrates, with a basilar and subpleural predominance, and reduced lung volumes. Note the predominant involvement of the basilar regions.

ulcerations, heliotrophic rash) may identify cases of PSS [10] or dermatomyositis [28]. Extrapulmonary features may suggest sarcoidosis [29] or collagen vascular disease (CVD) [30].

Chest Imaging

Abnormalities on chest radiographs are often the first clue to the presence of DPLD. Parenchymal infiltrates, cystic radiolucencies, or nodules can be identified in most patients with DPLD. The location, extent and pattern of abnormalities on conventional chest radiographs may be helpful in suggesting or refuting specific diagnoses. Certain diseases have a predilection for specific lung regions. Sarcoidosis [31, 32], chronic beryllium disease, silicosis, and pulmonary LCG [13] typically involve upper and mid lung zones, often with a nodular component (fig. 1). In striking contrast, IPF [33], NSIP [34], and collagen vascular disease-associated pulmonary fibrosis (CVD-PF) preferentially involve the basilar regions, with a proclivity for the subpleural (peripheral) regions [33–35] (fig. 2). COP most often presents with solitary or multiple foci of consolidation, often in a peripheral location [36–38]. However patchy interstitial or reticulonodular infiltrates, mimicking IPF or NSIP, may also be observed in COP (fig. 3). Chronic eosinophilic pneumonia presents as ground glass opacities (GGO) or

Diagnostic Approach to DPLD

Fig. 3. Cryptogenic organizing pneumonia. PA chest radiograph

demonstrates patchy bilateral lower infiltrates in the lower lobes, with air bronchograms. These features are nonspecific, and overlap with radiographic features of IPF and NSIP.

consolidation, with an affinity for the upper lobes [8, 39]. More fulminant CEP may present with diffuse airspace disease. However, the peripheral location has been termed the ‘photographic negative’ of pulmonary edema [8]. Irrespective of the cause of DPLD, review of old films may be invaluable to assess the pace and evolution of the disease. High resolution thin-section CT scans are superior to chest X-rays in depicting fine parenchymal details, and are

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Fig. 4. Usual interstitial pneumonia (UIP). HRCT scans reveals a few honeycomb cysts in the subpleural regions but most of the lung parenchyma appears normal. This marked heterogeneity is typical of UIP. Ground glass opacities are absent.

Fig. 6. Lymphangioleiomyomatosis (LAM). HRCT scan shows scattered cystic lesions with well-defined walls. Also note the chylous pleural effusion layering in the right minor fissure.

Fig. 5. Pulmonary Langerhans’ cell granulomatosis (LCG). HRCT

scans demonstrates multiple nodular lesions, thickened bronchial walls, and a few cavitary lesions are evident. Reproduced with permission from Lynch and Myers [3]. Fig. 7. Pulmonary alveolar proteinosis (PAP). HRCT scan demonstrates diffuse ground glass opacities with a background showing the ‘crazy paving’ pattern.

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Fig. 8. a Pulmonary sarcoidosis. HRCT

at the level of the carina demonstrates perihilar infiltrates, thickened bronchovascular bundles, and parenchymal nodules. Reproduced with permission from Lynch [31]. b Pulmonary sarcoidosis. HRCT demonstrates extensive cystic change and antatomic distortion. Note the predominant distribution around the central hilar regions. The subpleural and basilar regions were spared, in striking contrast to IPF.

a

Fig. 9. LAM. HRCT demonstrates innumerable cystic radiolucencies with well-defined walls. The intervening lung parenchyma is normal. In contrast to LCG, nodules are not evident. This HRCT appearance is virtually pathognomonic for LAM.

invaluable in supporting or refuting specific diagnoses [40]. The type of CT abnormality [i.e. cystic versus alveolar (GGO or consolidation)] has important implications in the differential diagnosis. Cystic radiolucencies are cardinal findings in usual interstitial pneumonia (UIP) [33] (fig. 4), LCG [13] (fig. 5), and LAM (fig. 6), [11], whereas consolidation or GGO are absent or minimal in these disorders. In striking contrast, focal areas of consolidation or GGO are characteristic of COP [37], CEP [8], or pulmonary alveolar proteinosis (PAP) [41]. Cysts are not found in those disorders. HRCT features of PAP are variable, and may include focal or diffuse GGO or consolidation and a ‘crazy-paving’


b

pattern [41, 42] (fig. 7). Some disorders such as sarcoidosis [31], NSIP [35, 43], or CVD-PF [30] may have both cystic and alveolar components. In pulmonary sarcoidosis, HRCT scans may demonstrate a wide spectrum of aberrations. Typical features in sarcoidosis include: parenchymal opacities or nodules in the mid or upper lung zones; distribution along bronchovascular bundles; focal or confluent alveolar opacities with consolidation; fibrosis, distortion, cysts [31] (fig. 8a, b). Extensive GGO may be found in myriad etiologies including acute HP [44, 45], COP [36], CEP [8], PAP [41, 42], etc. In some cases, the HRCT may be pathognonomic (obviating the need for lung biopsy). Such disorders include LAM [11] and usual interstitial pneumonia (UIP) [46, 47]. Innumerable cystic radiolucencies with diffuse involvement and no specific lobar or anatomical distribution are virtually specific for LAM [11, 12] (fig. 9). Similarly, a predominantly reticular pattern, with patchy involvement, subpleural and basilar predominance, honeycomb change (HC), and minimal or no GGO is pathognomonic for UIP (fig. 10a–d) [33, 43, 47]. It should be emphasized that UIP is a histological pattern that can be seen not only with IPF, but also with CVD-PF and asbestosis [1]. Although lung biopsy is not necessary for patients exhibiting classical features of LAM or UIP, biopsy (either transbronchial or thoracoscopic) is required to substantiate a specific histological diagnosis when CT is nondiagnostic. Importantly, NSIP cannot be diagnosed by CT. Features of NSIP on CT are variable and include: focal GGO; bibasilar predominance; reticulation; traction bronchiectasis; minimal or no HC [35, 43] (fig. 11a, b). However, these features overlap with UIP and other interstitial lung diseases and are nonspecific [35, 43, 46]. Surgical lung biopsy (SLB) is required to substantiate the diagnosis of NSIP [35, 43].

Clinical Features

Some DPLDs such as IIPs [2] or HP [23] are limited to the lung. Weight loss, malaise, and fatigue may be present,

15

a

b

c

d

Fig. 10. UIP. HRCT demonstrates a

patchy, reticular pattern, with subpleural honeycombing and a predilection for the basilar region. Ground glass opacities are minimal. Note the relative sparing of the upper lung fields (a, b) compared to lower lobes (c, d). Further, the heterogenous (patchy) nature of involvement is striking.

but these disorders do not affect extrapulmonary organs. By contrast, sarcoidosis [29], vasculitis [48], CVD [30], LAM [11, 12, 49], and LCG [13] may be associated with extrapulmonary manifestations. Pulmonary complications of CVD are protean and include: fibrosing alveolitis; diffuse alveolar damage (DAD); cellular or follicular bronchiolitis; obliterative bronchiolitis (with or without organizing pneumonia); alveolar hemorrhage [50, 51]. Progressive PF, indistinguishable from IPF, may complicate any of the CVDs [28, 51–53]. The course of PF complicating CVD is typically indolent [10], but progressive, fatal respiratory insufficiency can occur [54].

Blood Studies

Serological studies are rarely diagnostic in the setting of DPLD. However, we include the following studies in new patients with DPLD of unknown etiology: (1) HP screen (this incorporates the 7 or 8 most common antigens, measured by commercial laboratories); (2) connective tissue

16


screen [e.g. antinuclear antibody (ANA); rheumatoid factor (RF) for rheumatoid arthritis; Jo-1 antibody and creatine phosphokinase (for polymyositis/dermatomyositis); antibody to double stranded DNA (for SLE); Scl-70 (for PSS); anti-Smith (Sm) and Ro antibodies (for mixed connective tissue disease); SSA and SSB (for Sjogren’s syndrome)]; (3) erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). In selected patients (e.g. patients with upper or mid-lung zone predominant disease), serum angiotensinconverting enzyme (SACE) may be useful to support the diagnosis of sarcoidosis [6]. However, low titer positive ANA or RF are common in IIPs, and are nonspecific. Antibodies directed against the cytoplasmic components of neutrophils (e.g. ANCA) suggest the diagnosis of vasculitis [48], but such cases usually differ from chronic ILDs.

Pulmonary Function Tests (PFTs)

We routinely obtain PFTs to assess the extent of pulmonary functional impairment in patients with DPLD.

Fig. 11. Nonspecific interstitial pneumonia (NSIP). HRCT scan. a An example of ‘cel-

lular’ NSIP with diffuse patchy ground glass opacities (GGO) and minimal or no fibrosis. b An example of ‘fibrotic’ NSIP. Note the patchy GGO, reticulation, and traction bronchiecstasis. A few small honeycomb cysts are present but this is not a prominent feature.

12. Photomicrographs. Common nonspecific patterns in DPLD: a NSIP, cellular pattern; b NSIP, fibrotic pattern; c NSIP pattern with poorly-formed granuloma, consistent with HP; d UIP pattern. All HE. a, b ⫻100; c ⫻400; d ⫻40. All of these patterns may be idiopathic or associated with known diseases such as allergies, drug reactions, and connective tissue disorders.

a

b

a

b

c

d

Fig.


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13. Photomicrographs. Common nonspecific patterns in DPLD: a COP pattern; b NSIP and chronic inflammation; c eosinophilic pneumonia with numerous eosinophils in alveolar spaces and septae; d DAD with hyaline membranes and interstitial fibrosis. All HE. a ⫻40; b ⫻100; c, d ⫻200. These patterns are not only nonspecific, but more than one pattern can occur for any given etiologic agent. For example, a and b are from 2 different patients with amiodarone toxicity, and c and d are from 2 different patients with bleomycin toxicity.

a

b

c

d

Fig.

Initially, we perform spirometry, lung volumes, and diffusing capacity for carbon monoxide (DLco). Most DPLDs give rise to a restrictive pattern, so PFTs cannot establish a specific etiological diagnosis [5]. Disproportionate reduction in DLco is characteristic of IPF (compared to other ILDs) but may also reflect pulmonary vascular involvement or pulmonary arterial hypertension (PAH) in patients with diverse lung disorders. Thus, aberrations on PFTs are nonspecific. Nonetheless, PFTs are helpful to determine the severity of disease. A 6-min walk test (6MWT) may be helpful to assess the extent of impairment, need for supplemental oxygen, and gauge evolution of the course of the disease [55, 56]. Formal cardiopulmonary exercise tests (CPETs) are expensive, logistically difficult, and lack practical value.

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Bronchoscopy

Fiberoptic bronchoscopy with BAL or transbronchial lung biopsy (TBBs) may substantiate specific diagnoses in some patients [e.g. sarcoidosis, LCG, LAM, CEP, COP (provided the clinical context is appropriate)]. BAL may be adequate to diagnose specific infections (e.g. tuberculosis, histoplasmosis, coccidioidomycosis, endemic fungal infections) and selected non-infectious diseases (e.g. LCG [13] or LAM [49]). Further, BAL cell profiles may narrow the differential diagnosis [57, 58]. Increases in BAL lymphocytes suggest sarcoidosis [6], HP [23], or other granulomatous processes [57]. When BAL lymphocytes exceed 50%, HP is likely [57]. Further, marked increases in BAL eosinophils (⬎25%) strongly suggest

acute or chronic eosinophilic pneumonia [8, 39]. However, mild increases in lymphocytes or eosinophils have no diagnostic value [58]. Increases in neutrophils can be seen in a wide array of fibrotic disorders as well as bacterial pneumonia [58]. Due to small sample size and sampling variability, BAL and TBBs cannot establish the diagnosis of IPF or IIPs [1, 2, 59].

Surgical Lung Biopsy

Video-assisted thoracoscopic surgical (VATS) biopsy should be performed in patients with DPLD when BAL or TBBs are not definitive (unless specific contraindications exist) [60, 61]. Given the potential morbidity (and rarely, mortality) associated with SLB, this procedure is not warranted in debilitated or elderly patients. Surgical lung biopsy achieves three purposes: (1) establishes a precise diagnosis; (2) assesses the extent of inflammation and fibrosis; (3) identifies a histopathological pattern (i.e. in the context of IIP) [2, 59]. In the setting of IIPs, distinguishing NSIP from UIP may be difficult, even with experienced pulmonary pathologists [62, 63]. Hence, when SLB is performed in patients with DPLD, at least two biopsies should be obtained from different lobes to assure diagnostic accuracy [64, 65]. Further, the finding of NSIP on SLB does not imply idiopathic NSIP but should prompt further evaluation to rule out CVD, drug exposures, or HP (figs. 12a–d, 13a–d). Similarly, some patients with a clinical syndrome similar to IPF exhibit histopathological changes on SLB consistent with HP [45]. In this setting, an aggressive search for environmental allergen(s) is critical to avoid continued injury and further loss of lung function [26].

Response to Therapy In some patients, clinical, radiographic, and bronchoscopic findings (including BAL or TBB) may strongly suggest a specific diagnosis but are not entirely specific. For example, extensive GGO on CT without HC and TBBs demonstrating organizing pneumonia may justify an empirical trial of corticosteroids. Similarly, pronounced eosinophilia on BAL, and the finding of eosinophilic aggregates on TBBs, supports the diagnosis of CEP. In both instances, response to corticosteroids (assessed at 1–2 weeks) may affirm the putative diagnosis. Treatment is largely ineffectual for UIP [27, 66] whereas CEP [8] or COP [37] usually exhibit rapid and dramatic improvement within days of institution of corticosteroid therapy.

Conclusion

The diagnostic approach to DPLD requires a close interaction between clinicians, radiologists, and pathologists. A meticulous medical history, incorporating demographic features, occupational and environmental exposures, is essential. High resolution CT scan (HRCT) is an integral part of the evaluation of any patient with DPLD. The pattern of CT can narrow the differential diagnosis. In some cases, HRCT is pathognomonic, obviating the need for lung biopsy. However, when clinical and CT findings are nonspecific, an aggressive approach to include either bronchoscopic or surgical lung biopsy is warranted. Fiberoptic bronchoscopy with BAL and TBBs can establish a precise etiological diagnosis in some patients (e.g. LCG, CEP), but cannot substantiate the diagnosis of IIPs and myriad other etiologies. Surgical lung biopsy is the ultimate procedure in the diagnostic approach to DPLD, but integration of histopathological, radiographic, and clinical features is essential to guide management.

References 1 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. 2 American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias: This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee,

June 2001. Am J Respir Crit Care Med 2002; 165:277–304. 3 Lynch JP III, Myers JL: Interstitial lung diseases; in Bone RC, Campbell GD Jr, Payne DK (eds): Bone’s Atlas of Pulmonary and Critical Care Medicine. Baltimore, Williams & Wilkins, 1999, pp 1–12. 4 Lynch J III, Keane M: Treatment of parenchymal lung diseases; in Spina D, Page CP, Metzger WJ, O’Connor BJ (eds): Drugs for the Treatment of Respiratory Diseases. Cambridge, Cambridge University Press, 2003, pp 247–335. 5 Martinez FJ: Idiopathic interstitial pneumonias: usual interstitial pneumonia versus nonspecific


interstitial pneumonia. Proc Am Thorac Soc 2006;3:81–95. 6 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: Statement on Sarcoidosis. Am J Respir Crit Care Med 1999;160: 736–755. 7 Lynch JP III, Kazerooni EA, Gay SE: Pulmonary sarcoidosis. Clin Chest Med 1997;18: 755–785.

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38 Schlesinger C, Koss MN: The organizing pneumonias: an update and review. Curr Opin Pulm Med 2005;11:422–430. 39 Philit F, Etienne-Mastroianni B, Parrot A, Guerin C, Robert D, Cordier JF: Idiopathic acute eosinophilic pneumonia: a study of 22 patients. Am J Respir Crit Care Med 2002; 166:1235–1239. 40 Koyama M, Johkoh T, Honda O, Tsubamoto M, Kozuka T, Tomiyama N, Hamada S, Nakamura H, Akira M, Ichikado K, Fujimoto K, Rikimaru T, Tateishi U, Muller NL: Chronic cystic lung disease: diagnostic accuracy of high-resolution CT in 92 patients. AJR Am J Roentgenol 2003;180:827–835. 41 Trapnell BC, Whitsett JA, Nakata K: Pulmonary alveolar proteinosis. N Engl J Med 2003;349:2527–2539. 42 Shah PL, Hansell D, Lawson PR, Reid KB, Morgan C: Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax 2000;55:67–77. 43 Hartman TE, Swensen SJ, Hansell DM, Colby TV, Myers JL, Tazelaar HD, Nicholson AG, Wells AU, Ryu JH, Midthun DE, du Bois RM, Muller NL: Nonspecific interstitial pneumonia: variable appearance at high-resolution chest CT. Radiology 2000;217:701–705. 44 Hartman TE: The HRCT features of extrinsic allergic alveolitis. Semin Respir Crit Care Med 2003;24:419–426. 45 Lynch DA, Newell JD, Logan PM, King TE Jr, Muller NL: Can CT distinguish hypersensitivity pneumonitis from idiopathic pulmonary fibrosis? AJR Am J Roentgenol 1995;165: 807–811. 46 Flaherty KR, Thwaite EL, Kazerooni EA, Gross BH, Toews GB, Colby TV, Travis WD, Mumford JA, Murray S, Flint A, Lynch JP 3rd, Martinez FJ: Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003;58:143–148. 47 Hunninghake GW, Lynch DA, Galvin JR, Gross BH, Muller N, Schwartz DA, King TE Jr, Lynch JP 3rd, Hegele R, Waldron J, Colby TV, Hogg JC: Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest 2003;124: 1215–1223. 48 Lynch JP, White E, Tazelaar H, Langford CA: Wegener’s granulomatosis: evolving concepts in treatment. Semin Respir Crit Care Med 2004;25:491–521. 49 Johnson SR, Tattersfield AE: Clinical experience of lymphangioleiomyomatosis in the UK. Thorax 2000;55:1052–1057. 50 Lynch JP III, Belperio J, Flilnt A, Martinez FJ: Bronchiolar complications of connective tissue disorders. Semin Respir Crit Care Med 1999;20:149–168. 51 Tansey D, Wells AU, Colby TV, Ip S, Nikolakoupolou A, du Bois RM, Hansell DM, Nicholson AG: Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis. Histopathology 2004;44:585–596. 52 Bouros D, Wells AU, Nicholson AG, Colby TV, Polychronopoulos V, Pantelidis P, Haslam PL, Vassilakis DA, Black CM, du Bois RM: Histopathologic subsets of fibrosing alveolitis

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57 Welker L, Jorres RA, Costabel U, Magnussen H: Predictive value of BAL cell differentials in the diagnosis of interstitial lung diseases. Eur Respir J 2004;24:1000–1006. 58 Veeraraghavan S, Latsi PI, Wells AU, Pantelidis P, Nicholson AG, Colby TV, Haslam PL, Renzoni EA, du Bois RM: BAL findings in idiopathic nonspecific interstitial pneumonia and usual interstitial pneumonia. Eur Respir J 2003;22:239–244. 59 Katzenstein A, Myers J: Idiopathic pulmonary fibrosis. Clinical relevance of pathological classification. Am J Respir Crit Care Med 1998;157: 1301–1315. 60 Lettieri CJ, Veerappan GR, Helman DL, Mulligan CR, Shorr AF: Outcomes and safety of surgical lung biopsy for interstitial lung disease. Chest 2005;127:1600–1605. 61 Tiitto L, Heiskanen U, Bloigu R, Paakko P, Kinnula V, Kaarteenaho-Wiik R: Thoracoscopic lung biopsy is a safe procedure in diagnosing usual interstitial pneumonia. Chest 2005;128:2375–2380. 62 Nicholson AG, Colby TV, du Bois RM, Hansell DM, Wells AU: The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 2000;162:2213–2217. 63 Nicholson AG, Fulford LG, Colby TV, du Bois RM, Hansell DM, Wells AU: The relationship between individual histologic features and


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Joseph P. Lynch III, MD Division of Pulmonary, Critical Care Medicine, and Hospitalists The David Geffen School of Medicine at UCLA 10833 Le Conte Avenue, Room CHS 37–131 Los Angeles, CA 90095 (USA) Tel. ⫹1 310 825 8599, Fax ⫹1 310 206 8622 E-Mail [email protected]

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Clinical Evaluation Steve Yanga Ganesh Raghub a

Department of Respiratory and Critical Care Medicine, Block 6, Level 6, Singapore General Hospital, Singapore, Singapore; bDivision of Pulmonary and Critical Care Medicine, Departments of Medicine and Laboratory Medicine, Seattle,Wash., USA

Abstract Interstitial lung disease (ILD) encompasses a wide range of pulmonary disorders that affect the lung parenchyma and distal airspaces which result in disrupted gas exchange across the alveolar septa. An assessment of a patient with ILD includes a thorough medical history, detailed physical examination and diagnostic testing (laboratory tests, chest radiograph, high-resolution CT (HRCT) scan, and pulmonary function tests). To increase the diagnostic yield when assessing a patient with interstitial lung disease, dynamic interactions between pulmonologists, chest radiologists and pulmonary pathologists are important. Copyright © 2007 S. Karger AG, Bael

Interstitial lung disease (ILD) encompasses more than 150 distinct acute and chronic pulmonary disorders that affect the lung parenchyma, resulting in disrupted gas exchange across the alveolar septa. ILD commonly involves cellular and acellular components beyond the interstitial space and extends into the alveolar space, with some diseases affecting the distal small airways, blood vessels and pleura. ILD usually present with characteristic features which include: exertional dyspnea or cough, bilateral diffuse interstitial infiltrates on chest radiographs, physiologic and gas exchange abnormalities, which include a decreased diffusion capacity for carbon monoxide (DLCO) and abnormal alveolar arteriolar PO2 difference [P(A-a)O2] at rest or with

exertion, and histopathological abnormalities of the pulmonary parenchyma characterized by varying degrees of inflammation, fibrosis and remodeling.

Incidence and Prevalence Rates of ILD

The incidence and prevalence rates of ILD have not been precisely estimated due to difficulties in ascertaining a specific diagnosis on a specific disease. Moreover, ILD usually remains a diagnosis of exclusion requiring extensive investigations to differentiate ILD from other diseases [1]. In addition, available data from registries or hospitals suffer from selection biases, making them unrepresentative of the general population. In a study undertaken in the Bernalillo County, New Mexico, USA, data from a dedicated ILD registry estimated the incidence of ILD at 30 per 100,000 per year, with approximately one-third in the idiopathic pulmonary fibrosis (IPF) category. The estimated incidence was higher for men than women [2]. International differences in the prevalence of IPF exist: in Japan it was estimated to be 4.1 per 100,000 [3]; whereas in Finland it was estimated to be 7–12 per 100,000 [4]. Comparing data from the Bernalillo County with earlier US estimates, there are suggestions that IPF rates are increasing from 3–5 per 100,000 in 1984 [5] to 30 per 100,000 in 1994. This might reflect a true increase in IPF prevalence rates over 10 years, but it is more likely that the earlier studies underestimated the prevalence of IPF.

Medical History

To obtain an accurate diagnosis, a detailed clinical evaluation is vital. This includes a thorough history elicitation, a comprehensive review of multiple systems, identification of all medications or drugs, and a detailed review of past medical, social, family, and occupational histories with exploration of all potential environmental exposures. History of Onset of Pulmonary Symptoms The presenting respiratory system complaints of a patient with suspected ILD should begin with the onset and duration of symptoms, rate of progression, and any associated extrathoracic and constitutional symptoms. Acute symptoms (days to a few weeks) of cough, dyspnea, and fever necessitate evaluation for an infective agent. In the absence of infection, possible causes of acute ILD include cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), acute eosinophilic pneumonia (AEP), drug-induced pulmonary injury and hypersensitivity pneumonitis (HP). Acute symptoms that rapidly progress to respiratory failure raise the possibility of AIP and AEP. Subacute (weeks to months) presentations include COP, acute HP, chronic eosinophilic pneumonia (CEP), druginduced ILD and connective tissue disease (CTD) induced ILD. Chronic symptoms (months to years) usually indicate IPF, non specific interstitial pneumonia (NSIP) of the fibrotic variety, chronic HP, chronic occupation-related lung disease (e.g. asbestosis), and CTD-induced ILD. The rate of progression of disease is of equal importance as patients with IPF, pulmonary Langerhans cells granulomatosis (LCG) and ILD associated with CTD present with insidious onset of symptoms. The presence of cough raises the possibility of coexisting airway disease that is associated with respiratory bronchiolitisinterstitial lung disease (RB-ILD), sarcoidosis, HP, and acid gastroesophageal reflux (GER). A chronic irritable cough has been associated with lymphangitic carcinomatosis; mucoid or ‘salty’ sputum is suggestive of bronchoalveolar cell carcinoma. In long-standing ILD or advanced pulmonary fibrosis that is associated with traction bronchiectasis, cough may become productive and purulent. Hemoptysis is suggestive of a diffuse alveolar hemorrhage syndrome (DAH) such as pulmonary capillaritis or of vasculitides such as Wegener’s granulomatosis or Goodpasture syndrome. The absence of hemoptysis does not exclude DAH (especially chronic) or other underlying conditions that are associated with microscopic hemorrhage (e.g. systemic lupus erythematosus [SLE]).

Clinical Evaluation

Pleuritic chest pain raises the possibility of a pneumothorax which is usually seen in patients who have lymphangioleiomyomatosis (LAM), pulmonary LCG, neurofibromatosis, and catemenial syndrome. Alternatively, pleuritis can be seen in the CTD, such as SLE. Wheezing is suggestive of ILD that involves the airway, such as allergic bronchopulmonary aspergillosis (ABPA), Churg-Strauss syndrome, CEP, and parasitic disease. Rarely endobronchial lesions may result in wheezing (e.g. sarcoidosis, Wegener’s granulomatosis, amyloidosis). Extrapulmonary Symptoms Several extrapulmonary (gastrointestinal tract, rheumatologic, cutaneous, musculoskeletal, neurologic, renal) symptoms may provide useful clues. A history of dyspepsia or GERD may suggest scleroderma-related ILD. Overt aspiration or dysphagia may suggest scleroderma or mixed connective tissue disease (MCTD). Lower gastro-intestinal symptoms may suggest inflammatory bowel disease. The presence of arthritis may suggest a CTD or sarcoidosis, and combined muscle and skin symptoms suggest polydermatomyositis. Skin lesions such as lupus pernio suggest sarcoidosis. Other skin lesions can occur in neurofibromatosis (NF), tuberous sclerosis (TS) or SLE. Albinism can occur in patients with the Hermansky-Pudlak syndrome. Neurologic symptoms (cranial nerve involvement, Bell’s palsy) suggest the possibility of vasculitis or sarcoidosis. Polyuria and polydyspsia of diabetes insipidus is suggestive of sarcoidosis or pulmonary LCG. Hematuria raises the possibility of pulmonary-renal syndromes. Demographics and Family Medical History The patient’s age, cigarette-smoking status and gender may provide important clues. IPF is always an adult disorder and typically occurs in patients who are older than 60 years of age. Patients with NSIP are usually younger than the IPF patient. Although pulmonary sarcoidosis can manifest in the elderly patient, it is more common in the young and middle-aged. Pulmonary LCG typically occurs in young, cigarette-smoking men. RB-ILD is seen exclusively in cigarette smokers and desquamative interstitial pneumonia (DIP) is frequently seen in active smokers. LAM is a rare disorder that occurs exclusively in women, most often in those of childbearing age. ILD can also occur in patients who have a known inherited disease, including neurofibromatosis, TS, HermanskyPudlak syndrome and metabolic storage disorders. History

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Table 1. Diffuse lung diseases and selected occupational causes

Clinical entity

Pathologic description

Occupational causes

IPF NSIP DIP Bronchiolitis obliterans and organizing pneumonia (BOOP) Pulmonary alveolar proteinosis GIP ARDS/AIP

usual interstitial pneumonia nonspecific interstitial pneumonia desquamative interstitial pneumonia bronchiolitis obliterans and organizing pneumonia alveolar proteinosis giant cell interstitial pneumonia diffuse alveolar damage

asbestosis, uranium mining, plutonium, mixed dusts organic antigens textile work, aluminum welding, inorganic particles spray painting textiles – acramin-FWN; NOx

Bronchiolitis obliterans (BO) Bronchiolitis Sarcoidosis Lipoid pneumonia

constrictive bronchiolitis cellular bronchiolitis granulomatous inflammation lipoid pneumonia

high-level silica exposure, aluminum dust cobalt (in hard metal) irritant inhalational injury – NOx, SOx, cadmium, beryllium, chlorine, acid mists NOx, chlorine gas organic antigens beryllium, organic antigens, zirconium, aluminum, titanium oil-based fluid exposure

ARDS/AIP Acute respiratory distress syndrome/acute interstitial pneumonitis; IPF idiopathic pulmonary fibrosis; NOx oxides of nitrogen; SOx oxides of sulphur. Adapted from Glazer CS: Clin Chest Med 2004:467–478.

of a documented ILD among first-degree biologic relatives (siblings, parents, children) raises the strong possibility of the ILD being hereditary (e.g. familial pulmonary fibrosis) [6]. Environmental/Occupation/Medication History: Identifying Exposures A detailed environmental and occupational exposure history is essential as it may lead to identification of a cause of ILD. At-risk occupations include miners (pneumoconiosis); sandblasters and granite workers (silicosis); welders, shipyard workers, pipe fitters, electricians, automobile mechanics (asbestosis); farm workers, poultry workers, bird fanciers, bird breeders (hypersensitivity pneumonitis); and workers in aerospace, nuclear, computer, and electronic industries (berylliosis). History of existing, persistent environmental ‘fibrogenic’ factors at home; in the workplace; in automobiles; in frequently visited facilities/homes; associated with hobbies, such as exposure to birds, molds, woodworking; or the use of saunas and hot tubs often are ignored but are equally important and may provide useful clues (table 1). Several drugs are well-known causes of ILD [7]. These include chemotherapeutic and cytotoxic agents, nonsteroidal anti-inflammatory agents, antibiotics, narcotic analgesics, amiodarone, tricyclic antidepressants, methotrexate, and penicillamine. Over the counter medications and ‘alternative medicines’ must not be overlooked.

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Yang/Raghu

Physical Examination

Pulmonary Signs Crackles on lung auscultation, described as ‘dry’, ‘Velcrostrap’, end-inspiratory, and predominantly basilar, are detected in more than 80% of patients who have IPF [8]. Crackles due to other ILD auscultated on physical examination despite a normal chest radiograph can occur in granulomatous ILDs (e.g. sarcoidosis). Mid-inspiratory high-pitched squeaks are reported in the primary bronchiolitides and other diseases with airway-centered pathology (e.g. HP). Signs of pulmonary hypertension may be encountered in the later stages of all chronic ILDs as a result of progressive interstitial fibrosis and alveolar hypoxemia, but have been identified more specifically as part of the pathogenesis in CTD-associated ILD and pulmonary veno-occlusive disease. In patients with advanced IPF (extensive bilateral honeycomb cysts with traction bronchiectasis) demonstrating hypoxia at rest, secondary pulmonary hypertension maybe present. Such patients usually have FVC 50% predicted and/or DLCO 30% predicted. Extrapulmonary Signs Clubbing may be seen in patients who have IPF [8], but can also occur in patients who have asbestosis, chronic HP and DIP. Skin abnormalities, peripheral lymphadenopathy, and hepatosplenomegaly are associated with sarcoidosis.

Table 2. Clues from blood and urine tests for patients who have interstitial lung disease

Laboratory test

Indications

Interpretation

CBC count, LFT, creatinine, BUN

all patients suspected to have ILD

Aldolase, creatine kinase, Jo-1 antibody Immunoglobulins

muscle pain, weakness clinically suspected or histopathologic diagnosis of LIP suspected vasculitis (CTD, WG, MPA, Goodpasture syndrome) suspected IIP, IPF, CTD or ILD for which CTD cannot be ruled out suspected WG or MPA (lung nodules, sinusitis, DAH)

eosinophilia (CEP, drugs), normocytic anemia (CTD), Fe-deficiency anemia (DAH), leukopenia/ thrombocytopenia (CTD, sarcoidosis, lymphoma), liver disease (sarcoidosis, amyloidosis), renal disease (CTD, amyloidosis, WG, Goodpasture’s syndrome) elevated values are supportive of PM low levels of immunoglobulins may indicate a diagnosis of CVID RBC casts or dysmorphic RBCs suggest systemic vasculitis low titers of ANA (1:160) and RF occur in 10–20% of patients who have IPF positive C-ANCA or antiproteinase 3 is most suggestive of WG; P-ANCA may be seen in WG, but suggests MPA Positive result in patient who has DAH is diagnostic of Goodpasture’s syndrome interpret within clinical context; a negative result does not rule out HP; a positive result is not diagnostic of HP suggests possibility of sarcoidosis, but is insensitive and nonspecific for sarcoidosis

Urinary sediment ANA, RF C-, P-ANCA

Anti-GBM antibody Specific serum precipitins

suspected Goodpasture syndrome (i.e. DAH) exposure history appropriate for HP

Serum ACE

sarcoidosis

ACE Angiotensin-converting enzyme; ANA anti-nuclear antibody; BUN blood urea nitrogen; C-ANCA cytoplasmic antineutrophil cytoplasmic antibody; CBC complete blood count; CEP chronic eosinophilic pneumonia; Cr creatinine; CTD connective tissue disease; CVID common variable immunodeficiency; DAH diffuse alveolar hemorrhage; GBM glomerular basement membrane; HP hypersensitivity pneumonitis; IIP idiopathic interstitial pneumonia; ILD interstitial lung disease; IPF idiopathic pulmonary fibrosis; LFT liver function test; MPA microscopic polyangiitis; P-ANCA perinuclear antineutrophil cytoplasmic antibody; PM polymyositis; RBC red blood cell; RF rheumatoid factor; WG Wegener’s granulomatosis. Adapted from Fessler M, Brown K: Approach to patients with interstitial lung disease; in Lillington GA (ed): Best Practice of Medicine. Available at: http://www.praxis.md/index.asp?pagebpm_1stgi

Characteristic skin rashes and lesions also occur in CTD, amyloidosis, pulmonary LCG, TS and neurofibromatosis. Subcutaneous nodules (especially around the elbow and metacarpophalangeal joints) are suggestive of rheumatoid arthritis (RA). Muscle tenderness and proximal weakness raise the possibility of polymyositis. Signs of arthritis may be associated with sarcoidosis or CTD. Fever, erythema nodosum, and arthritis raise the likelihood of Löfgren’s syndrome. Sclerodactyly, Raynaud’s phenomenon and telangiectatic lesions are characteristic features of scleroderma and CREST syndrome. Iridocyclitis, uveitis, or conjunctivitis may be associated with sarcoidosis, Behcet’s disease, inflammatory bowel disease and autoimmune syndromes. Oculo-cutaneous albinism raises the possibility that ILD is associated with Hermansky-Pudlak syndrome.

Clinical Evaluation

Abnormalities of the central nervous system suggest the diagnosis of sarcoidosis (cranial nerve abnormalities, diabetes insipidus, anterior pituitary dysfunction), pulmonary LCG (diabetes insipidus), or TS (epilepsy, mental retardation).

Diagnostic Tests

Laboratory Testing Laboratory blood testing alone is rarely diagnostic, but may be strongly supportive in the appropriate clinical setting (table 2). Routine laboratory tests include a complete blood count with leukocyte differential, platelet count, erythrocyte sedimentation rate (ESR), chemistry profile (serum

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electrolytes, serum urea nitrogen, creatinine, liver function tests, and calcium). Antinuclear antibody (ANA), rheumatoid factor (RF) should be obtained in the setting of history or physical findings that are suggestive of CTD. Low titers of ANA (1:160) and RF occur in 10–20% of patients who have IPF. Such patients may manifest other typical clinical features of CTD later in the course of the disease. Slightly elevated ESR, C-reactive protein, and hypergammaglobulinemia are common and non-specific findings. An elevated level of angiotensin-converting enzyme may be seen with sarcoidosis, but is insensitive and nonspecific as it is also abnormal in other disease (e.g. silicosis, HP, LIP, acute respiratory distress syndrome). Serum precipitins that are focused on known exposures may be considered if the environmental history suggests HP; however, false-negative results may be encountered, and similarly, the presence of precipitating antibody may represent sensitization to an environmental antigen and not disease. Random ‘HP panels’ are almost never helpful in the absence of a specific exposure and seldom provides useful information. A careful history elucidation is key to diagnosing HP. If pulmonary vasculitis or DAH is suspected, antineutrophil cytoplasmic antibody (C-ANCA, P-ANCA), antiglomerular basement membrane antibody, ANA, and urine sediment should be checked. Proximal muscle weakness or tenderness should prompt measurement of aldolase, creatine kinase, anti-Jo-1 antibody, and possibly an electromyogram and muscle biopsy to rule out polymyositis. A clinically suspected or histopathologic diagnosis of LIP should prompt measurement of serologies to rule out a CTD, particularly Sjögren’s syndrome, immunoglobulin levels (to evaluate for associated common variable immunodeficiency) and a HIV test. Peripheral blood lymphocyte proliferation that is stimulated by the antigen that may cause the ILD (e.g. the beryllium lymphocyte proliferation test) has high sensitivity for chronic berylliosis.

PFT abnormalities generally reflect the effects of elevated elastic recoil (restrictive lung defect) and alveolarcapillary dysfunction (decreased DLCO), although increased lung volume (e.g. LAM) and increased DLCO (e.g. DAH) can be seen. A typical PFT pattern in ILD is a restrictive lung defect with symmetrically decreased lung volumes (total lung capacity [TLC], functional residual capacity [FRC], and residual volume [RV] 80% predicted); decreased forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) decreased in parallel with a normal or elevated FEV1/FVC ratio; and a decreased DLCO. Co-existing obstructive airflow defect, when present can aid with diagnosis. A mixed pattern of restriction and obstruction (decreased FEV1/FVC ratio, elevated RV, lack of supranormal airflows on a flow-volume loop, or a significant response to bronchodilator) in the patient without coexisting emphysema may suggest sarcoid, HP, RB-ILD, pulmonary LCG, LAM and ILD associated with asthma (chronic eosinophilic pneumonia, Churg-Strauss syndrome). An obstructive defect without significant restriction may reflect obliterative bronchiolitis (without associated organizing pneumonia) and constrictive bronchiolitis. A DLCO that is decreased out of proportion to other tests may indicate concomitant pulmonary vascular disease such as in scleroderma, CREST syndrome, pulmonary venoocclusive disease, and chronic pulmonary emboli, and can be seen occasionally in pulmonary alveolar proteinosis, pulmonary LCG and LAM. Since TLC and FVC are effort and muscle strengthdependent maneuvers, occasionally a restrictive pattern (TLC 80%) may be due in part or wholly to respiratory muscle weakness (e.g. polymyositis), and will be revealed by decreased maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and decreased maximum minute ventilation (MVV). Presence of air-trapping (↑ RV) in the absence of significant airflow obstruction (↓ FEV1/ FVC) should raise the possibility of underlying respiratory muscle weakness.

Pulmonary Function Testing Initial pulmonary function tests (PFTs) should include a spirometry (with and without bronchodilator challenge), plethysmographic lung volumes, and DLCO (corrected to hemoglobin). PFTs cannot diagnose a specific ILD and cannot distinguish between active lung inflammation versus fibrosis, but are important in the objective assessment of respiratory symptoms as well as in paring the differential diagnosis, grading the severity of disease, and monitoring response to therapy or progression.

Chest Radiograph: Useful Diagnostic Patterns A diffusely abnormal chest radiograph is often the initial finding that alerts the physician to the possibility of ILD. The clinician should make every effort to obtain previous chest radiographs for review. This may allow one to ascertain the onset, chronicity, rate of progression, or stability of the patient’s disease. Classification of abnormalities on routine chest radiograph that are based on distribution, location, and overall appearance are useful in narrowing the differential diagnosis (table 3).

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Table 3. Useful chest radiographic patterns

Pattern

Suggested diagnosis

Low lung volumes

IPF, CTD-related, chronic hypersensitivity pneumonitis, asbestosis, NSIP, chronic drug-induced, subgroup of chronic COP, CEP, DIP RB-ILD, IPF with coexisting emphysema, sarcoidosis, acute hypersensitivity pneumonitis, LAM, TS, pulmonary LCG, neurofibromatosis, bronchiolitis, cigarette smoking sarcoidosis, silicosis, coal workers pneumoconiosis, hypersensitivity pneumonitis, pulmonary LCG, chronic berylliosis, AS, CEP, Caplan syndrome, nodular rheumatoid arthritis IPF, CTD-related, asbestosis, DIP, chronic hypersensitivity pneumonitis COP, IPF, CEP Infection, sarcoidosis, hypersensitivity pneumonitis malignancy, chronic congestive heart failure, infection, pulmonary veno-occlusive disease IPF, asbestosis, CTD-related, sarcoidosis, chronic hypersensitivity pneumonitis COP, hypersensitivity pneumonitis, APBA, Löffler’s syndrome lymphagitic carcinomatosis CTD-related, asbestosis, malignancy, radiation-induced, sarcoidosis LAM, pulmonary LCG, TS, neurofibromatosis, catamenial syndrome sarcoidosis, malignancy, silicosis, infection, chronic beryllium disease, CTD hypersensitivity pneumonitis, NSIP (cellular), CTD-related, bronchiolitis, RB-ILD, sarcoidosis

Increased or preserved lung volumes Upper zone predominance Lower zone predominance Peripheral predominance Micronodular Septal thickening Honeycombing Migratory infiltrates Kerley B lines Pleural disease Pneumothorax Mediastinal/hilar lynphadenopathy Normal (encountered rarely)

Adapted from Schwarz M, King TE, Raghu G: Approach to the evaluation and diagnosis of interstitial lung disease; in Schwarz MI, King TE (eds): Interstitial Lung Disease. Hamilton, Decker, 2003, and Lynch D: Imaging of diffuse parenchymal lung disease; in Schwarz MI, King TE (eds): Interstitial Lung Disease, ed 4. Hamilton, Decker, 2003.

Table 4. Useful high-resolution CT patterns in interstitial lung disease

Findings

Common clinical disorders/syndromes

Reticular lines, honeycombing, traction bronchiectasis Airspace opacity, ‘ground-glass’ Nodular pattern Septal thickening Cystic changes Mosaic patterns

CTD-related, IPF, asbestosis, sarcoidosis COP, CEP, AIP, PAP, consolidation, lymphoma, sarcoidosis granulomatous diseases, pneumoconiosis, malignancy, rheumatoid arthritis infection, edema, malignancy, drug reaction, pulmonary veno-occulsive disease LAM, LIP, pulmonary LCG (emphysema must be distinguished) air-trapping (constrictive bronchiolitis)

Adapted from Schwarz M, King TE, Raghu G: Approach to the evaluation and diagnosis of interstitial lung disease; in Schwarz MI, King TE (eds): Interstitial Lung Disease. Hamilton, Decker, 2003, and Lynch D: Imaging of diffuse parenchymal lung disease; in Schwarz MI, King TE (eds): Interstitial Lung Disease, ed 4. Hamilton, Decker, 2003.

High-Resolution CT HRCT has evolved into a standard procedure during the evaluation of almost all patients who have ILD. It is a more sensitive test than plain chest radiograph in identifying ILD (sensitivity greater than 90%) and the image pattern of parenchymal abnormalities on HRCT often suggest a particular set of diagnostic possibilities (table 4). HRCT also identifies ‘mixed’ patterns of disease

Clinical Evaluation

(e.g. ILD plus emphysema) or additional pleural, hilar or mediastinal abnormalities. It has a better correlation with physiologic impairment and is especially useful in guiding the site of bronchoalveolar lavage (BAL) or lung biopsy. A completely normal HRCT of the chest essentially rules out IPF but does not rule out microscopic inflammation and granulomatous changes.

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Exercise Testing Occasionally, PFTs and resting arterial blood gas (ABG) analysis may be entirely normal in patients who in the early stages of ILD, with the only physiologic abnormality being an abnormal ABG sampling obtained during exercise (decreased PaO2, widening P(A-a)O2 gradient). Hence gas exchange evaluation at rest and with ambulation using pulse oximetry (i.e. 6-minute or modified walk test) should

be initially performed as they guide diagnostic and therapeutic interventions and also direct the use of oxygen therapy. A formal cardiopulmonary exercise testing allows measurement of peak oxygen consumption, exercise gas exchange, and dead space ventilation in patients with early ILD with minimal or no symptoms and who do not demonstrate significant oxygen desaturation while undergoing a 6-minute walk test.

References 1

2

3

4

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Mapel DW, Hunt WC, Utton R, Baumgartner KB, Samet JM, Coultas DB: Idiopathic pulmonary fibrosis: survival in population based and hospital based cohorts. Thorax 2000;53: 469–476. Coultas DB, Zumwalt RE, Black WC, Sobonya RE: The epidemiology of interstitial lung disease. Am J Respir Crit Care Med 1994; 150:967–972. Munakata M, Asakawa M, Hamma Y, Kawakami Y: Present status of idiopathic interstitial pneumonia: from epidemiology to etiology. Nihon Kyobu Shikkan Gakkai Zasshi 1994;32(suppl):187–192. Hodgson U, Laitnen T, Tukiainen P: Nationwide prevalence of sporadic and familial

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6

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idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland. Thorax 2000;57:338–342. Crystal RG, Bitterman PB, Rennard SI, Hance AJ, Keogh BA: Interstitial lung diseases of unknown cause: disorders characterized by chronic inflammation of the lower respiratory tract (second of two parts). N Engl J Med 1984;310:235–244. Raghu G, Mageto Y: Genetic predisposition of interstitial lung disease; in Schwarz M, King T (eds): Interstitial Lung Disease, ed 3. Hamilton, Mosby Yearbook, 1998, pp 119–132. Foucher P, Camus P, and the GEPPI: The druginduced lung diseases. Available at http://

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www.pneumotox.com. Accessed July 15, 2004. ATS International Consensus Statement. Idiopathic pulmonary fibrosis: diagnosis and treatment. Am J Respir Crit Care Med 2000;161: 646–664.

Ganesh Raghu, MD Division of Pulmonary and Critical Care Medicine, University of Washington Medical Center 1959 NE Pacific Street, Campus Box 356522 Seattle, WA 98195–6522 (USA) Tel. 1 206 543 3166, Fax 1 206 685 8673 E-Mail [email protected]


Imaging Sujal R. Desai Athol U.Wells Department of Radiology, King’s College Hospital, Denmark Hill, and Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK

Abstract Imaging tests are central to the investigation of patients with diffuse interstitial lung disease (DILD). For decades, the chest radiograph has been the primary imaging test. However, radiologists and clinicians alike have long sensed that the plain chest radiograph is an imprecise tool: a confident and, more importantly, accurate diagnosis of a specific interstitial lung disease can seldom be made from chest radiographic appearances alone.With clinical validation of the diagnostic accuracy of high-resolution computed tomography (HRCT) images, the role of the plain chest radiograph has been largely superseded. This chapter will focus on the imaging features of the DILDs with particular emphasis on the HRCT features and, where relevant, the relationship between HRCT appearances and macroscopic histopathological features. Copyright © 2007 S. Karger AG, Basel

A Practical Classification for Radiological Diagnosis

The diverse range of clinico-pathological entities captured within the umbrella of DILD (fig. 1), can usefully be broken down into four sub-groups, based upon the contribution made by HRCT to diagnosis (table 1). Firstly, a great many DILDs occur in association with an obvious potential cause, most often drug treatments known to cause lung toxicity or a collagen vascular disease such as rheumatoid arthritis or systemic sclerosis. In this setting, the diagnostic

contribution made by HRCT is often relatively slight. Pathognomonic HRCT abnormalities are not required; HRCT findings need only to be compatible with the likely cause and not strongly indicative of an alternative diagnosis. By contrast, HRCT makes a greater diagnostic contribution in the idiopathic interstitial pneumonias (IIPs) because an obvious aetiological factor is lacking. The recent ATS/ERS reclassification of the IIPs [1, 2] has now been very widely adopted. Characteristic HRCT patterns have now been defined and their recognition usually makes a large contribution to diagnosis. The diagnostic contribution of HRCT is highly variable in granulomatous DILDs (sarcoidosis, hypersensitivity pneumonitis). In many cases, the diagnosis is obvious clinically and HRCT is merely confirmatory. However, in an important subset, the clinical presentation is not definitive and diagnostic HRCT findings are extremely influential. Finally, HRCT plays an important diagnostic role in a highly heterogeneous group of rare disorders, including pulmonary Langerhans’ cell histiocytosis, lymphangioleiomyomatosis, alveolar proteinosis and lymphangitis carcinomatosis.

Plain Chest Radiography in the Diagnosis of DILD

The chest radiograph has limited sensitivity and specificity in the diagnosis of DLD. One key limitation is anatomical superimposition due to the two-dimensional nature of radiographic film. Thus, overlying soft tissue renders subtle diffuse lung disease invisible and may also create the spurious

impression of lung disease. At least 10% of patients ultimately found to have diffuse disease at biopsy will have an apparently normal chest radiograph [3]. This reflects the fact that, at a microscopic level, many millions of foci of disease are required before there is any appreciable alteration in lung density. Conversely, even when extensive disease is apparent on the chest radiograph, careful analysis of the radiographic pattern alone will seldom allow the radiologist to make a histologically specific diagnosis. Despite these limitations, it is surprising how often a sensible list of differential diagnoses can be proposed from a review of radiographic appearances. Regardless of the initial insult, the repertoire of histopathological responses in the lung is relatively restricted and, therefore, the spectrum of patterns on chest radiography is generally narrow. The description of radiographic patterns should be confined to a relatively short list of objective terms: such as ‘reticular’ (referring to a fine net-like appearance), nodular, linear (fine lines), ground-glass opacification (in which there is a ‘veil-like’ opacification of the lungs that renders vessels indistinct), and air-space opacification or consolidation (defined as poorly defined areas of increased density in which an air bronchogram may or may not be visible) [4]. Because different diseases have a propensity for particular lung zones, an evaluation of the distribution of the disease (e.g. upper, mid versus lower zones or central versus peripheral lung), is crucial. The predominantly bronchocentric upper zone distribution of sarcoidosis contrasts with the lower zone and peripheral predominance of idiopathic pulmonary fibrosis (IPF). The differential diagnosis of DILDs may be further refined by taking into account the ancillary radiographic abnormalities: for example, the presence of symmetrical hilar lymph node enlargement in a patient with a reticular pattern and volume loss in the upper zones should, first and foremost, suggest a diagnosis of sarcoidosis. Similarly, a diffuse reticulo-nodular pattern in the mid and lower zones associated with the presence of an erosive arthropathy involving the lateral ends of the clavicles should raise the possibility of lung fibrosis related to rheumatoid arthritis. Alternatively, the observation that the oesophagus is dilated should prompt the radiologist to consider a diagnosis of lung fibrosis secondary to systemic sclerosis. Finally, it must be stressed that the relevant clinical information can have crucial effect on radiological evaluation: for example, the absence of significant symptoms despite apparently extensive disease on the radiograph should suggest sarcoidosis and alveolar proteinosis. Similarly, whilst diffuse ground-glass opacification is a wholly non-specific radiographic sign, knowledge that the

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patient is immunocompromised should alert the radiologist to the possibility of an opportunistic infection. Plain chest radiography remains important, and often more useful than HRCT, in monitoring changes in disease severity, because of a relatively low radiation burden. By contrast, frequent repeated HRCT examinations (particularly in patients in whom the diagnosis is no longer in doubt), are difficult to justify. A further advantage of serial chest radiography is that the complications of diffuse lung disease, such as pneumothoraces, intercurrent infections and pulmonary malignancy may be detected. Although the sensitivity and specificity of serial chest radiography in these specific scenarios has not been formally tested, the value of serial chest radiography has been validated by widespread clinical experience. In summary, although it has shortcomings, a chest radiograph is (and will continue to be) the primary radiological investigation for a patient with suspected or clinically obvious diffuse lung disease. In addition, plain chest radiography continues to have a role in monitoring disease progression and in the detection of complications.

HRCT in the Diagnosis of DILD

Technical Considerations Two features of the HRCT technique differ from conventional (i.e. 10 mm collimation) CT imaging. Firstly, the collimation of the X-ray beam is significantly narrower (1–2 mm compared to 10 mm). As collimation is reduced, the likelihood that small structures will have dimensions comparable to the size of a voxel (the basic volume element of the CT image) is increased. In this way, spatial resolution is enhanced. The second key difference is that a dedicated algorithm is used to reconstruct the data. The ‘high-frequency’ algorithm takes advantage of the intrinsically high contrast milieu of the lung so that the natural density differences between aerated lung and the interstitium are enhanced [5]. The conspicuity of vessels, small bronchi and interlobular septa is increased as compared to conventional (thick-section) CT images [6]. An important downside of high-frequency algorithms is the increased visibility of image noise. However, in practice, this rarely hampers radiological interpretation. In routine HRCT protocols, 1-mm-thick images are acquired with 10- or 20-mm interslice spacing, as diffuse lung abnormalities are adequately ‘sampled’ with this approach. The acquisition of interspaced sections reduces the radiation burden substantially. Conventional (10-mm slice thickness) CT scanning, routinely used in the late 1980s, generated a radiation dose roughly equivalent to 100 chest

Diffuse parenchymal lung diseases

DILD of known cause

Granulomatous DILDs

Examples: Drug-induced Collagen vascular diseases

Examples: Sarcoidosis Hypersensitivity pneumonitis

The idiopathic interstitial pneumonias

Fig. 1. Classification of diffuse interstitial

lung diseases. Adapted from the American Thoracic Society/European Respiratory Society International Multidiscplinary Consensus Classification of the Idiopathic Interstitial Pneumonias [Am J Respir Crit Care Med 2002;165:277].

UIP NSIP RBILD/DIP COP AIP LIP

Miscellaneous DILDs

Examples: Langerhans’ cell histiocytosis Lymphangioleiomyomatosis Alveolar proteinosis Wegener’s granulomatosis

Table 1. DILDs with sufficiently recognisable HRCT features in many cases

DILD

Key HRCT features

Idiopathic pulmonary fibrosis Sarcoidosis

predominantly subpleural and basal reticular pattern with honeycombing highly variable appearances but typically, bronchocentric and interlobular septal nodularity, subpleural nodules; upper zone fibrosis, hilar and mediastinal lymph node enlargement

Extrinsic allergic alveolitis Subacute: Chronic: Langerhans’ cell histiocytosis Respiratory bronchiolitis-associated interstitial lung disease Lymphangioleiomyomatosis Lymphocytic interstitial pneumonia Alveolar proteinosis Cryptogenic organizing pneumonia

Imaging

variable combinations of ground-glass opacification, centrilobular nodules and foci of decreased attenuation (and air trapping on expiratory CT); occasional thin-walled cysts fibrosis, parenchymal distortion and honeycombing cavitating nodules in early stages; thin-walled cysts with bizarre outlines in late disease; sparing of extreme bases and medial tip of middle lobe and lingula ground-glass opacification, centrilobular nodules, thickened interlobular septa, mosaic attenuation, signs of fibrosis (minimal) and limited centrilobular emphysema multiple uniform thin-walled cysts; no zonal sparing and no nodules diffuse ground glass opacification, centrilobular nodules and thickened interlobular septa; cysts and (calcified) deposits of amyloid in some patients crazy-paving appearance: geographical areas of ground-glass opacification containing smoothly thickened interlobular septa patchy bilateral areas of consolidation/ground-glass opacification typically in mid and lower zones

31

radiographs. This contrasts strikingly with the estimated 4–6 chest radiograph equivalents from an HRCT study using 20-mm interslice spacing [7]. There is also the potential with HRCT to reduce radiation exposure further without major effects on image quality, by using low-dose protocols [8]. Diagnostic Utility of HRCT in DILDs The utility of HRCT reflects the close relationship between macroscopic histopathological changes and HRCT abnormalities [9], evident in many disease. Because the features of certain diseases are sufficiently characteristic (table 1) and there is now well over 15 years of accumulated radiological experience, a confident HRCT diagnosis is often correct. The diagnostic potential of HRCT was first highlighted by a study published in 1989 [10] and has, to a greater or lesser extent, been corroborated by subsequent series [11, 12]. In the study by Mathieson et al. [10], chest radiographs and HRCT images of 118 patients with a variety of (biopsy-proven) diffuse lung diseases were presented separately and in random order to experienced thoracic radiologists. On each modality, observers were asked to make up to three diagnoses (in decreasing order of likelihood) and were required to assign a level of confidence to the first choice diagnoses. Radiologists were confident nearly twice as often using HRCT. More importantly, when observers were confident of the CT diagnosis, they were nearly always correct, whereas the same was not true of chest radiography. Although the early diagnostic series were undoubtedly important, the limitations of HRCT literature need to be emphasized. Firstly, the results of diagnostic series are necessarily based on the observations of experienced thoracic radiologists and the findings of these studies may not be easily extrapolated to the wider body of general radiologists. Secondly, the population of patients in diagnostic series is usually highly selected and common mimics of diffuse lung disease (such as heart failure and malignancy) tend to be excluded. Thirdly, diagnostic series, by their very nature, become dated as experience increases and ‘new’ clinico-pathological entities (such as non-specific interstitial pneumonia) are recognized. Fourthly, the critical importance of radiological confidence is only partially addressed and in most series, the expression of diagnostic accuracy, using sensitivity alone, is inappropriate. Finally, the basic design of these studies has meant that the evaluation of diagnostic accuracy is divorced from the clinical act of diagnosis and, until recently, the role of the clinician in integrating data (including HRCT) has not been captured. However, on this last point, Aziz et al. [13] have evaluated the value of HRCT in the clinical diagnostic process. In this

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study, six respiratory physicians were first presented with the clinical details, results of pulmonary function tests and chest radiographs in 168 patients with a suspected DILD. The authors then quantified alterations in clinical perception and management after HRCT reports from two experienced thoracic radiologists were provided. With clinician access to HRCT data, there was a change in the first choice diagnosis in just over half the cases and substantial improvement in agreement on the first-choice diagnosis. Another important finding was that, after the assimilation of HRCT data, there were significant decreases in the proportions of patients thought to need more invasive procedures (lavage and lung biopsy) [13].

Radiological Abnormalities in Specific DILDs

DILDs of Known Cause Because the diagnostic role of HRCT is less crucial than in apparently idiopathic disease, the wide diversity of HRCT appearances in drug-induced lung disease and connective tissue disease is not discussed in detail. The list of drugs capable of causing lung damage is large [14] and the reported histological responses include the patterns of usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), diffuse alveolar damage (DAD), organizing pneumonia (OP), lymphocytic interstitial pneumonia (LIP) and eosinophilic pneumonia. Similarly, all the histological entities grouped as IIPs are reported to occur in the connective tissue diseases. CT findings corresponding to these histological patterns are discussed later in this chapter; lung disease in connective tissue disease is the subject of a separate chapter.

Idiopathic Interstitial Pneumonias HRCT appearances have been studied more closely in the IIPs than other DILDs. Compatible CT features are a key diagnostic criterion for the non-invasive diagnosis of IPF, as defined by consensus groups [1, 2]. The typical CT features of other IIPs have also been characterised, although these have yet to be integrated into formal non-invasive diagnostic criteria in these disorders. Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia IPF is characterised on surgical biopsy by a pattern of UIP, with temporally heterogeneous regions of interstitial

Thus, the possibility of IPF should always be considered in idiopathic disease when HRCT abnormalities are suggestive of NSIP or are not strongly indicative of an alternative disorder.

Fig. 2. CT demonstrating the typical appearances of a usual interstitial pneumonia pattern: there is a coarse sub-pleural reticular pattern with honeycombing but minimal ground-glass opacification. Traction bronchiectasis is also seen within regions of lung fibrosis.

fibrosis comprising varying proportions of inflammation and honeycombing that merge with zones of normal lung parenchyma [15]. On plain chest radiography, there is a coarse peripheral reticulo-nodular pattern which predominates in the mid and lower zones [1]. The cardinal HRCT finding is an approximately symmetrical reticular pattern with honeycombing which has a propensity for the subpleural and basal lung [16] (fig. 2). As the disease becomes more extensive, the anterior upper zones tend to be involved. There may be associated ground-glass opacification but this is seldom the dominant pattern. It is likely that many historic cases with prominent ground-glass attenuation, previously classified as UIP/IPF, would now be reclassified as alternative IIPs (especially NSIP). Whilst the typical HRCT pattern is highly predictive of a histological diagnosis of UIP, it should never be forgotten that in approximately one third of patients with IPF, the characteristic HRCT features of UIP are not present [17–19]. In a study of 98 patients, Flaherty et al. [20] showed that 26/73 patients with UIP on biopsy had CT appearances more akin to NSIP. This apparent discrepancy may, in part, reflect the fact that UIP and NSIP may coexist in the same patient, with the histological diagnosis critically dependent upon the site sampled. The important clinical message is that, although HRCT appearances typical of IPF have a very high positive predictive value, a large subgroup of IPF patients are not identified by HRCT findings.

Imaging

Non-Specific Interstitial Pneumonia Over the last decade, NSIP has evolved from a perceived pathological ‘waste-basket’ (DILDs not classifiable as one of the then recognised patterns [21]), to an important IIP [2]. In the process, some of the apparent confusion surrounding early CT findings in NSIP has been unravelled. In the study of Hartman and colleagues, the CT features of NSIP were highly variable [22], with findings variably suggestive of UIP, hypersensitivity pneumonitis and organising pneumonia. Thus, it is not surprising that in a study of 129 subjects with IIPs, radiologists were unable to consistently identify patients with NSIP [12]. It is likely that the wide spectrum of CT features in early reports reflects the multiplicity of clinico-radiological contexts in which an NSIP pattern may occur. The seeming non-specificity of HRCT patterns largely reflected the prevailing view of NSIP as a single entity. Put simply, NSIP should be sub-categorised according to the clinical context and, in this regards, HRCT has a crucial role. Recognised NSIP sub-groups, based upon the clinico-radiologic profile, include patients with the features of hypersensitivity pneumonitis, organizing pneumonia and IPF, in addition to patients with connective tissue disease. Based on early reports (in particular from radiological series from South Korea and Japan), consolidation was a key CT feature of NSIP in some patients [23, 24], in keeping with the relatively frequent finding of a component of organizing pneumonia at biopsy [24]. These patients can now be viewed as having the ‘organizing pneumonia variant of NSIP’, which is most commonly associated with a good treated outcome. For the clinician, a particular diagnostic dilemma in relation to NSIP is the patient presenting with clinical features typical of IPF. The distinction between NSIP and UIP is important in this context, since patients with the histopathological pattern of NSIP have significantly better survival overall, even though a subset of these patients have a bad (UIP-like) outcome [25, 26]. In this variant of NSIP, CT abnormalities overlap with those of UIP and consist of a variable mixture of ground-glass attenuation and a reticular pattern, although honeycombing is seldom evident. However, on average, NSIP is characterised by more ground-glass attenuation and finer fibrosis (with a much lower prevalence of honeycombing) [27] (fig. 3). In routine practice, radiologists find it easier to specify whether honeycombing is present or absent than to quantify the extent

33

Fig. 3. CT in 2 patients with non-specific

idiopathic pneumonia. a Targetted image of the right lung shows a subtle but definite ground-glass infiltrate. There is a subtle and limited fine reticular pattern but no honeycombing. b Image at the level of the pulmonary venous confluence demonstrating an asymmetrical reticular pattern with a roughly equal proportion of ground-glass opacification. Some traction bronchiectasis is also seen.

of ground-glass attenuation. Thus, for practical purposes, the absence of honeycombing remains the most useful CT feature in suggesting a diagnosis of NSIP, rather than UIP, in this difficult clinical context. Desquamative Interstitial Pneumonia (DIP) and Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RBILD) Because of a common association with smoking and overlapping microscopic features, DIP and RBILD are often discussed together. Indeed, it has been suggested that the all-encompassing term ‘smoking-related interstitial lung disease’ should be used when referring to these two patterns of IIP [28]. However, recent data suggest that it may still be appropriate to regard RBILD and DIP as separate processes with different pathogenetic mechanisms [29]. Furthermore, whilst RBILD is almost invariably associated with a smoking history, the link between tobacco smoke and DIP is less constant [29]. The chest radiograph is often abnormal in symptomatic patients with RBILD. In two small series, 17 of 24 patients (70%) had a fine diffuse or basal reticulonodular infiltrate [30, 31]. In contrast to CT, ground-glass opacification is surprisingly uncommon on chest radiography, occurring in none of 18 patients [31] and in 3 of 10 patients [28]. The chest radiograph in the strikingly less common entity of DIP also tends to be non-specific. In the original report lower zone ground-glass opacification was the dominant abnormality [32]. A reticulo-nodular pattern may also be seen and it is noteworthy that, the chest radiograph may

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Desai/Wells

b

a

be entirely normal despite histopathologically confirmed disease [33]. In RBILD there are variable CT findings [28, 34]. However, a ground-glass infiltrate (of variable intensity and distribution) is common. Superimposed on this pattern, there may be more ill-defined centrilobular nodules and a few secondary pulmonary lobules of decreased attenuation, both of which reflect the airway-centred nature of RBILD (fig. 3). Mild thickening of interlobular septa may also be seen but more overt features of interstitial fibrosis are uncommon [28]. Similarly, whilst emphysema is rarely extensive, the co-existence of the typical ‘permeative’ destruction pattern in the upper zones, in what is otherwise a non-specific abnormality on CT, may be a useful diagnostic clue. Diffuse ground-glass opacification in the mid and lower zones is the characteristic abnormality in DIP with predominant upper zone disease seen in a minority of cases [34, 35]. A predilection for the subpleural lung is seen in just under two thirds of patients but the distribution of ground-glass opacification may be entirely random. Other findings at CT in DIP include irregular lines, signs of parenchymal distortion, traction bronchiectasis, cystic spaces, emphysema and parenchymal nodules [35]. It will be clear from the above discussion that there are overlapping features on imaging in RBILD and DIP: ground-glass opacification (reflecting alveolar macrophage accumulation and alveolar wall thickening) is the dominant CT abnormality in both entities [36]. However, in RBILD, the intensity of ground-glass infiltration is generally more

Fig. 4. CT in respiratory bronchiolitis-

associated interstitial lung disease. a Section at the level of the aortic arch showing diffuse ground-glass opacification. There is also limited paraseptal emphysema in both lungs. b Image through the lower zones. There is ground-glass opacification, thickening of interlobular septa and parenchymal distortion. A few lobules of lower attenuation are present and taken to reflect the small airways component of RBILD.

a

b

a

b

Fig. 5. a Typical peripheral foci of consoli-

dation in cryptogenic organizing pneumonia. b CT through the lung bases demonstrating the bronchocentric disribution which is a feature in some patients with COP.

subtle than in DIP. Additional CT features in RBILD, not usually evident in DIP, include the ill-defined centrilobular nodules, interlobular septal thickening and the mosaicism indicative of small airways disease (fig. 4). Although the morphological distinction between DIP and RBILD is not always straightforward, in practical terms, it is often of minor clinical importance, since smoking cessation is the key to clinical management in both and the use of corticosteroids is usually guided by the severity of physiological impairment. Cryptogenic Organizing Pneumonia Cryptogenic organizing pneumonia (COP), first reported by Davison et al. [37], is characterised by buds of proliferating granulation tissue within terminal bronchioles and air-spaces. It is important to realise that organizing pneumonia is simply a histological pattern and not a diagnosis in itself; the label ‘cryptogenic’ being applied when other potential causes of this pattern (including a host of infections, certain drugs and connective tissue disorders) have been excluded [38]. In the past, the term idiopathic bronchiolitis obliterans organizing pneumonia (BOOP) has also been used [39]. However, because the airway changes

Imaging

are thought to be secondary to the dominant process in the air spaces and there is no evidence of a true ‘bronchiolitis obliterans’, COP is now the preferred term [2]. Bilateral patchy and peripheral areas of consolidation are the cardinal findings on chest radiography [40]. A predilection for the mid and lower zones was emphasised in early reports of COP. However, CT has clearly shown that all lung zones may be affected [41]. The changes of COP may be confined to one lung but this is an uncommon pattern [40]. Consolidation in COP has a propensity for the subpleural lung and may be peribronchovascular [42] (fig. 5). Cavitation is exceedingly rare. More recently, multifocal areas of ground-glass opacification with a surrounding rim of consolidation (termed the ‘reverse halo’ sign) have also been described [43]. Nodules, sometimes measuring up to 1 cm in diameter are a feature in some patients and, occasionally, these may be the sole radiographic manifestation of COP [41]; as with areas of consolidation, there is no definite zonal predilection. In some patents nodules may large and irregular enough to simulate a neoplasm [44]. A linear pattern is also a recognised manifestation of COP: Murphy et al. [45] reported two types of opacity in patients with COP. Type I opacities were related to bronchi

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and orientated in a radial manner towards the pleura and may co-exist with foci of consolidation. Type II opacities were subpleural and, unlike the Type I pattern, not related to airways. Type II linear opacities tended to be parallel to the pleural surface and also commonly associated with multifocal consolidation. Importantly, regardless of the type of opacity, there was radiological resolution on follow-up in the majority of patients. Another unusual manifestation of COP on CT, recently reported by Ujita et al. [46], is a perilobular pattern in which curvilinear opacities (of greater thickness but less well-defined than interlobular septa) give rise to an arcade-like appearance on HRCT. In general, the outlook for patients with COP is good with complete regression of radiological abnormalities. However, in a small proportion of COP patients the clinical course of may be complicated by moderately or severely extensive fibrosis, which may stabilise or progress inexorably. Evolution from organizing pneumonia at initial biopsy to fatal pulmonary fibrosis at autopsy has been reported in a small group of patients [47], and there is a further sub-group of COP patients in which less progressive fibrosis is present; it is likely that some patients with the ‘organizing pneumonia variant of NSIP’ fall into this group. HRCT may be useful in identifying fibrotic abnormalities when the response to treatment is sub-optimal in COP. Acute Interstitial Pneumonia (AIP) The histopathological, clinical and radiological features of AIP are virtually identical to those seen in the acute respiratory distress syndrome (ARDS) [48]. The plain radiographic appearances are non-specific: diffuse and apparently symmetrical air space opacification is the rule in most patients. By contrast, ground-glass opacification may be surprisingly patchy on CT with regions of consolidation and ground-glass attenuation admixed with apparently normal lung (fig. 6). Honeycombing (a testament to the exquisitely fibrotic nature of AIP) is more prevalent than in ARDS [49]. Consolidation, which is occasionally sub-pleural, is present in over two thirds of cases. In a minority, there is septal thickening with ground-glass attenuation, representing limited alveolar collapse. The extents of various CT patterns may have prognostic significance in patients with AIP: a poorer outcome is linked to more extensive ground-glass opacification or consolidation with evidence of traction bronchiectasis/bronchiolectasis and more severe achitectural distortion [50]. Lymphocytic Interstitial Pneumonitis (LIP) The idiopathic form of LIP is astonishingly rare and most proven cases are associated with dysproteinaemic

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Fig. 6. CT at the level of the venous confluence in a patient with biopsy-proven acute interstitial pneumonia. There is bilateral patchy ground-glass opacification and marked traction bronchiectasis of segmental and subsegmental airways.

states, immunologic diseases (including connective tissue disorders) and HIV infection [51]. At microscopy, there is diffuse pulmonary lymphocytic infiltration (with or without histiocytic and multinucleated giant cell infiltration) which tends to be centred on small airways. In a small proportion of patients with LIP there is also pulmonary amyloid deposition. Although the term LIP seems to suggest benignity, it is important to appreciate that a spectrum of lymphoproliferative disorders, ranging from relatively indolent to frankly malignant, is recognised. As with many of the other IIPs, the CT features of LIP (diffuse ground-glass opacification, centrilobular nodules and thickened interlobular septa) are variable and wholly non-specific [52]. However, in some patients with LIP these changes are associated with sparse thin-walled pulmonary cysts [52] (fig. 7). The presence of these lesions (giving rise to a ‘soap-bubble’ pattern of lung destruction) should prompt consideration of LIP in the differential diagnosis.

Granulomatous DILDs In this section, the radiological features of sarcoidosis and hypersensitivity pneumonitis (synonymous with extrinsic allergic alveolitis) will be discussed. In sarcoidosis patients without characteristic clinical features, radiological findings are of paramount diagnostic importance.

Fig. 7. Subtle ground-glass opacification and multiple thin-walled

cysts in a patient with lymphocytic interstitial pneumonia.

Hypersensitivity pneumonitis often presents as an apparently idiopathic disease; a causative exposure is often lacking or of marginal significance and, therefore, HRCT findings are often central to the diagnosis. Sarcoidosis The hallmark of sarcoidosis on histopathological examination is the presence of non-caseating granuloma. Although many organs may be affected, the lungs are the principal site of disease in most patients. The CT features of sarcoidosis vary according to the stage at which patients present and it is must be mentioned that, in many cases, the diagnosis of sarcoidosis is established without recourse to CT. Thus, CT has may have limited utility, once the diagnosis of sarcoidosis has been secured. The best recognised and most common CT pattern in sarcoidosis is a widespread nodular infiltrate which typically follows a bronchovascular distribution, giving rise to bronchial wall thickening and so-called ‘beading’ (fig. 8). Nodules also tend to aggregate in the interlobular septae and may be concentrated sub-pleurally. A second pattern, comprising regular and irregular linear opacities, denotes fibrosis and is generally associated with bilateral upper zone volume loss, parenchymal distortion and posterior traction of the larger upper lobe airways (fig. 9). Lymph node enlargement is common and calcification of enlarged nodes is a relatively frequent CT finding. Interestingly, the size of calcified nodes (larger in sarcoidosis), the pattern of calcification (focal as opposed to complete) and distribution of calcification (generally bilateral) may distinguish the nodes of sarcoidosis from those following tuberculosis [53].

Imaging

Extensive ground-glass attenuation is less common and but generally indicates fine fibrosis which is below the limits of HRCT resolution. It will be clear that the range of CT patterns in sarcoidosis is wide and atypical manifestations are frequent. In many cases, nodules do not have a bronchocentric distribution but are focal or have no obvious sub-pleural predilection. Intense micro-nodular infiltration with an entirely uniform distribution, mimicking military tuberculosis, is also recognised. Large masses (‘nodular’ sarcoid) and foci of consolidation (erroneously termed ‘air space sarcoid) are also rare manifestations. Furthermore, in occasional patients there are appearances which simulate IPF [54], although honeycombing is seldom striking. Because of the wide range of appearances, the integration of CT into a simple diagnostic algorithm is problematic. However, despite this variation, abnormalities virtually pathognomonic of sarcoidosis are present in many cases. Thus, CT is highly useful, when performed in appropriately selected cases. Furthermore, it is increasingly the practice in some centres (rightly or wrongly) to forgo biopsy confirmation of the diagnosis when the clinical presentation is typical; in this context, pathognomonic HRCT appearances are highly reassuring. Hypersensitivity Pneumonitis (HP) Traditionally, HP has been considered in acute, subacute and chronic clinical stages. Since patients with acute HP have non-specific symptoms (pyrexia, cough and malaise) which are attributed to a ‘flu-like’ illness, medical advice is rarely sought and imaging tests are seldom requested. By contrast, patients with subacute and chronic HP commonly have troublesome respiratory symptoms. It is worth briefly reviewing the histopathological features since they have a bearing on the CT patterns: the key findings in subacute HP are a bronchiolocentric lymphoplasmacytic cellular infiltrate with granuloma formation and fibrosis of varying severity [15]. In continued chronic exposure to the antigen, there is a inflammatory infiltration (again airway centred) and poorly-formed granulomata may be seen. With time there may be progression to end-stage fibrosis. The characteristic CT appearances of subacute HP comprise varying proportions of ground-glass opacification (due to lymphoplasmacytic infiltration), ill-defined centrilobular micronodules (reflecting the bronchiolocentric nature of the inflammation) and foci of decreased attenuation with air trapping on expiratory CT (due to the associated small airways obstruction) [55–57] (fig. 10). Emphysema may also be evident on CT in some patients with HP (even in the absence of a smoking history) [58]. Furthermore, in

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Fig. 8. Characteristic CT features in two

patients with sarcoidosis. a There is a nodular infiltrate in both upper zones. More confluent areas of opacification, with a striking bronchocentric distribution are present in the right upper lobe and there are some small sub-pleural nodules. Enlarged and calcified mediastinal nodes are also present. b There is a fine nodular infiltrate leading to irregular thickening of the oblique fissure in a patient with extensive mediastinal and symmetrical hilar lymph node enlargement.

b

a

associated with regions of ground-glass opacification, illdefined parenchymal micronodules and lobular areas of decreased attenuation and air trapping (fig. 10). The sometimes striking appearance of chronic EAA (reflecting both fibrotic and obstructive disease), has been termed the ‘head cheese’ sign because of the likeness to the cut surface of a sausage made from the blended components of a pig’s head [61].

Miscellaneous DILDs

Fig. 9. CT in sarcoidosis. There is coarse bronchocentric scarring in the

upper zones. There are dilated bronchi within regions of fibrosis and evidence of posterior traction of airways most noticeable on the right.

some patients a few thin-walled cysts will been seen [59], an interesting parallel with the appearance in patients with lymphocytic interstitial pneumonia (see above). Not surprisingly, in the chronic HP, there is evidence of fibrosis as judged by a reticular pattern, parenchymal distortion and honeycombing [56]. On occasion, the pattern of fibrosis is such that the distinction from IPF becomes difficult [60]. The features of fibrosis, described above, may be variably

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Langerhans’ Cell Histiocytosis (LCH) In the pulmonary form of LCH (now widely regarded as a form of smoking-related lung damage), the earliest histological abnormality is a small airway-centred interstitial infiltrate [62]. With progression, the infiltrate becomes nodular. Cavitation is a typical feature in nodules and the classical histopathological lesion of LCH is a broadly symmetrical scar with a stellate outline. Another characteristic finding on histopathological examination is the temporal heterogeneity: thus, cellular lesions may co-exist with fibrotic nodules. However, in the end-stages, there is often scarring associated with widespread emphysema. One of the difficulties for the pathologist (and for that matter, radiologists) in pulmonary LCH is that other patterns of interstitial lung disease frequent co-exist. Thus, features of RBILD/DIP and emphysema, for example, are often admixed with the obvious lesions of pulmonary LCH [63]; indeed, the macrophage accumulation around the lesions of LCH is sometimes so excessive that the distinction from DIP becomes almost impossible [62]. The CT features of LCH (fig. 11) generally mirror the macroscopic findings and depend, to a large extent on disease stage. Small irregular pulmonary nodules are characteristic,

Fig. 10. CT in a patient with subacute

hypersensitivity pneumonitis. a Images at the level of the aortic arch showing diffuse ground-glass opacification and ‘soft’ centrilobular nodules representing the interstitial lymphoplasmacytic and brochiolocentric infiltration (respectively). b Image through the lower zones showing similar features but in addition there are localised regions of decreased attenuation (conforming roughly to the outlines of secondary pulmonary lobules in the right lower lobe) denoting the small airways obstructive disease component of HP.

b

a

Fig. 11. CT through upper zones in pulmonary Langerhans’ cell histiocytosis. There is a combination of small nodules, cavities and irregular cysts within both lungs.

Lymphangioleiomyomatosis In lymphangioleiomyomatosis (LAM), there is proliferation of smooth muscle cells (called LAM cells) around small airways, vessels, lymphatics and the alveolar septa [15]. The classical presentation is in females of child-bearing age typically with a history of recurrent pneumothoraces, chylous effusions and/or haemoptyses. The pulmonary pathology of LAM is similar to those seen in patients with tuberose sclerosis. Multiple thin-walled cysts of roughly uniform size are the striking finding on CT (fig. 12). In contrast to LCH, the cysts of LAM tend to be uniform and round [65]. Another important distinguishing feature from LCH, except in very exceptional cases [66], is the absence of nodules in LAM. The cysts of LAM range in size from 2 mm to 5 cm and there is generally no regionally sparing (again unlike LCH). There may be evidence of (chylous) pleural fluid and pneumothoraces.

in the earlier stages. Since the disease is bronchiolocentric, some nodules do indeed appear to be centred within individual secondary pulmonary lobule [64]. The identification of cavitation on CT is a helpful diagnostic feature. Eventually, multiple cysts are seen which are initially small (typically ⬍1 cm in diameter) and an important finding is that cysts sometimes have an bizarre outline (presumably because of the coalescence of adjacent cysts). A useful diagnostic feature, unlike some other diseases in which cysts are a dominant finding, is the sparing of costophrenic recesses and the tips of the middle lobe and the lingula. Except for this particular regional sparing, the lesions in LCH are randomly distributed.

Pulmonary Alveolar Proteinosis Alveolar proteinosis (synonymous with alveolar lipoproteinosis and alveolar phospholipoproteinosis) is a rare disease characterised by the accumulation of a periodic acid-Schiff-positive lipoproteinaceous material within the alveoli [67]. In some cases, there is history of a definite pulmonary insult following exposure to inorganic dusts or infections. As with many of the DILDs, the chest radiographic appearances of alveolar proteinosis are non-specific: there is air space opacification in both lungs and the changes tend to be more pronounced centrally. The HRCT features of alveolar proteinosis are more striking and suggestive: the so-called ‘crazy-paving’ pattern (comprising a geographical ground-glass opacification and thickened

Imaging

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Fig. 12. Numerous thin-walled cysts in a patient with lymphangioleiomyomatosis. Most cysts are of relatively uniform size and there are no nodules. In this patient, who presented acutely with pleuritic chest pain, there is a shallow posterior pneumothorax on the left.

Fig. 13. CT appearances in a patient with alveolar proteinosis. There

interlobular septa) is a characteristic finding [68] (fig. 13). It is important to note that the crazy paving pattern on CT is not confined to cases of alveolar proteinosis: indistinguishable CT appearances have been reported be seen in some patients with mucinous bronchioloalveolar carcinoma, exogenous lipoid pneumonia and a variety of other diffuse lung diseases [69].

Cavitation is a characteristic radiological feature. However, this is by no means an invariable finding and thus, the absence of cavitation does not preclude a diagnosis of Wegener’s granulomatosis. Consolidation and ground-glass opacities are recognized features on CT but are less common than nodules. Interestingly, the converse is true in children, in whom nodules are seen less frequently [74]. As with nodules, foci of consolidation may cavitate. Some of the less common findings in Wegener’s granulomatosis include bronchovascular thickening and frank bronchiectasis. The other recognised ancillary features of Wegener’s granulomatosis are areas of lobar or segmental atelectasis, pleural effusions or thickening and rarely, hilar and mediastinal lymph node enlargement.

Wegener’s Granulomatosis Wegener’s granulomatosis is a multisystem disease of unknown aetiology in which the dominant histopathological changes are a necrotizing vasculitis involving medium- and small-sized vessels, granulomatous necrosis, and elements of both acute and chronic inflammation [70]. As with sarcoidosis, the spectrum of radiological appearances is relatively broad. Nevertheless, nodules (with no particular zonal predilection) are almost the rule in Wegener’s granulomatosis and vary in size from a few millimeters up to several centimeters in diameter [71]. The majority of patients have multiple nodules but in occasional cases, there may be a solitary pulmonary lesion. With treatment, nodules usually regress [72]. There may be residual parenchymal scarring on CT despite resolution of nodules and pulmonary consolidation [73].

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is a background of interlobular septal thickening with superimposed ground glass opacification (a combination commonly known as a ‘crazy paving’ pattern). Image courtesy of Dr. Susan Copley, London.

Lymphangitis Carcinomatosis In lymphangitis carcinomatosis there is typically, nodular thickening of the interlobular septae and the bronchovascular bundles usually associated with patchy ground-glass attenuation or widespread nodular infiltrates. The distribution is highly variable, ranging from diffuse involvement to a central or peripheral predominance, often in one lung, or even in a single lobe. Pleural effusions occur commonly. In advanced disease (and in the appropriate clinical setting),

the CT appearances of lymphangitis carcinomatosis are virtually pathognomonic. Chronic Eosinophilic Pneumonia Typically there is a history of fever, cough, breathlessness, weight loss with occasional patients also reporting haemoptysis and chest pain [75]. There is frequently eosinophilia in the peripheral blood and lung function tests reveal a restrictive defect with impaired gas transfer. The prognosis for most patients is good and there is a satisfactory respond to corticosteroid therapy. Unfortunately, relapses are common on withdrawal or even a dose reduction in such therapy. The plain radiographic abnormalities in chronic eosinophilic pneumonia may be characteristic: patchy, nonsegmental areas of consolidation are typical in the mid and upper zones [76]. A distinctive feature is that the opacities are peripheral and appear to parallel the chest wall, a finding that has been referred to as the ‘photographic negative’ of pulmonary oedema [76]. Not surprisingly, the peripheral

location of the air-space opacities is more readily appreciated on CT.

Conclusions

HRCT is now a key diagnostic tool in diffuse lung disease. In many cases, HRCT appearances are pathognomic for histospecific diagnoses and when the clinical presentation is also characteristic, a surgical lung biopsy is seldom required, especially when clinical and HRCT features are both typical of IPF. However, the limitations of HRCT should not be forgotten. In many cases, an HRCT diagnosis is probable, rather than definite, and often, HRCT appearances are inconclusive. Careful integration with the clinical presentation is essential, with early recourse to a surgical biopsy if uncertainty persists. In this regard, HRCT diagnosis must be viewed as a ‘silver standard’, along with clinical and histopathologic evaluation.

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Müller NL, Colman N, Paré PD (eds): Diagnosis of Diseases of the Chest, ed 4. Philadelphia, Saunders, 1999, pp 2699–2735. Murch CR, Carr DH: Computed tomography appearances of pulmonary alveolar proteinosis. Clin Radiol 1989;40:240–243. Johkoh T, Itoh H, Müller NL, Ichikado K, Nakamura H, Ikezoe J, et al: Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings. Radiology 1999;211:155–160. DeRemee RA, Colby TV: Wegener’s granulomatosis; in Thurlbeck WM, Churg AM (eds): Pathology of the Lung, ed 2. New York, Thieme Medical Publishers, 1995, pp 401–402. Lohrmann C, Uhl M, Kotter E, Burger D, Ghanem N, Langer M: Pulmonary manifestations

Imaging

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of Wegener granulomatosis: CT findings in 57 patients and a review of the literature. Eur J Radiol 2005;53:471–477. Grotz W, Mundinger A, Würtemberger G, Peter HH, Schollmeyer P: Radiographic course of pulmonary manifestations in Wegener’s granulomatosis under immunosuppressive therapy. Chest 1994;105:509–513. Attali P, Begum R, Ben Rhomdhane H, Valeyre D, Guillevin L, Brauner MW: Pulmonary Wegener’s granulomatosis: changes at followup CT. Eur Radiol 1998;8:1009–1113. Wadsworth DT, Siegel MJ, Day DL: Wegener’s granulomatosis in children: chest radiographic manifestations. AJR Am J Roentgenol 1994; 163:901–904. Fraser RS, Müller NL, Colman N, Paré PD: Eosinophilic lung disease; in Fraser RS, Müller

NL, Colman N, Paré PD (eds): Diagnosis of Diseases of the Chest, ed 4. Philadelphia, Saunders, 1999, pp 1743–1756. 76 Gaensler EA, Carrington CB: Peripheral opacities in chronic eosinophilic pneumonia: the photographic negative of pulmonary oedema. AJR Am J Roentgenol 1977;128:1–13.

Dr. Sujal R. Desai Department of Radiology King’s College Hospital Denmark Hill London SE5 9RS (UK) Tel. ⫹44 207 346 3526, Fax ⫹44 207 346 3157 E-Mail [email protected]

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Diffuse Parenchymal Lung Diseases – Histopathologic Patterns Marco Chilosia Bruno Murerb

Venerino Polettic

a

Department of Pathology, University of Verona,Verona, bDepartment of Pathology, Mestre Hospital, Mestre, and cDepartment of Diseases of the Thorax, Ospedale G.B. Morgagni, Forlì, Italy

Abstract Modifications of the lung structure in diffuse parenchymal lung diseases (DPLD) depend on the site of involvement (centrilobular, diffuse, focal/patchy, lymphangitic, sub-pleural, etc.) and on the type and extent of damage and repair. Recognizing histological patterns is a major task for pathologists, and these patterns contribute with other information derived from functional, clinical, laboratory and imaging studies to the definite diagnosis. The morphologic pattern is recognized in most cases by traditional histology using H&E staining, but more sophisticated studies, including immunohistochemistry, in situ hybridization and molecular studies can help in characterizing the qualitative and quantitative distribution of inflammatory cells, in recognizing the presence of infective agents, and also in demonstrating subtle tissue and molecular modifications. Advances in the understanding of the diversity of pathogenic mechanisms are rapidly progressing, and new morphologic and molecular markers are under investigation, that could potentially provide more reproducible diagnostic criteria. A pattern is defined on the basis of a variety of morphological features including the distribution of relevant tissue changes, the amount of architectural distortion, the presence, type and location of fibrosis, the epithelial modifications suggesting damage and repair processes (e.g. pneumocyte hyperplasia, bronchiolar distortion, basal cell hyperplasia), and the quantitative evaluation of different inflammatory cells (lymphocytes, granulocytes, macrophages, eosinophils). In this review the key morphologic and immunophenotypic features of the most relevant DPLD are described following the recent ATS/ERS consensus classifications of

idiopathic interstitial pneumonias. A new class of distinct smoking-related diseases has more recently emerged. Copyright © 2007 S. Karger AG, Basel

Usual Interstitial Pneumonia

Idiopathic pulmonary fibrosis (IPF) is the most common and severe form of idiopathic interstitial pneumonia (IIP) [1–4]. It is associated with the histological features of usual interstitial pneumonia (UIP), and demonstration of the UIP pattern on a surgical lung biopsy is either useful or fundamental for a definitive diagnosis [5]. The diagnosis of IPF can be obtained in a significant proportion of cases on the basis of clinical and imaging data, but when these data are not consistent or ambiguous, a histological confirmation is recommended. The differential diagnosis of IPF includes a variety of different lung diseases where severe distortion of the tissue architecture can occasionally take place. During the last few years the pathogenesis of IPF has been the subject of intense discussion, and new models have been proposed [6]. The ‘inflammatory theory’ of IPF/UIP has been challenged, assuming that abnormal epithelial-mesenchymal interactions and aberrant wound healing are in fact the crucial events in its pathogenesis. These new schemes must be taken into account when defining the changes of the ‘UIP pattern’. The UIP pattern has been classically described also in diseases other than IPF, including collagen vascular diseases, hypersensitivity pneumonitis, drug toxicity, asbestosis, Langerhans cell histiocytosis, and others. We believe that

hc

df

a

b

c

d

nal

Fig. 1. UIP pattern: all the major features of the UIP pattern are shown, including peripheral dense fibrosis with sub-pleural, paraseptal, peri-bronchiolar distribution (df), numerous honeycomb cysts (hc), and contiguous areas of normal alveolated lung (nal). HE. The patchy/focal involvement of the lung is evident.

FF

e

the pathogenic events leading to IPF are unique of this disease, and specifically linked to the remodeling processes morphologically recognized as the ‘UIP pattern’. If this is correct, the morphologic changes occasionally observed in other DPLD can only mimic the UIP pattern, especially when chronic inflammatory mechanisms induce severe structural changes in the lung, and the clinical significance of these changes is different. Accordingly, in collagen vascular diseases the prognostic relevance of defining the histologic pattern of UIP versus nonspecific interstitial pneumonia (NSIP) is not as crucial as in idiopathic interstitial pneumonias [7]. Taking into account these considerations, the UIP pattern should be limited to describe the morphologic appearance of IPF [1] whereas similar changes observed in other DPLD (connective tissue disease, chronic hypersensitivity pneumonitis, certain druginduced lung diseases, asbestosis) should be described as UIP-like. This is not a trivial point, since the notion that the ‘UIP-pattern’ can occur in different diseases can limit the understanding of pathogenic diversity.

Histological Features of the UIP Pattern The morphologic criteria for defining the UIP pattern have been well established since early descriptions of the disease (figs. 1, 2). Central to the pattern recognition is the demonstration of heterogeneity of the observed abnormalities affecting different sites at different times, with preferential

Diffuse Parenchymal Lung Diseases

f

Fig. 2. UIP pattern. At higher magnification, the severe remodelling

of lung structure is evidenced, with contiguous areas of normal lung, dense scarring and bronchiolar abnormal proliferation (a and b). HE. c Tenascin immunostaining highlights the presence of numerous interstitial deposits, corresponding to foci of early fibrotic reaction (fibroblast foci). Note that many of these foci are located within bronchiolar honeycomb lesions. d Cytokeratin 5, a marker of bronchiolar basal cells, is expressed in abnormally proliferating bronchiolar epithelium and honeycomb cysts. e Tenascin expression in a large fibroblast focus localized within the wall of a bronchiolar honeycomb cyst (arrow). f The same focus (FF) with abnormal expression of laminin-5-␥2 chain in bronchiolar basal cells overlying the myofibroblasts (arrow).

distribution to subpleural-paraseptal zones at lower lobes. This heterogeneity is in contrast to most of the other DPLD such as NSIP, DAD and desquamative interstitial pneumonia (DIP), where lung tissue modifications usually appear homogeneously distributed, as if evolving after a single damaging episode. Alveolar epithelium is progressively lost in the pathologic process, and evidence of patchy alveolar damage can be observed, including pneumocyte type II hyperplasia and occasional cytologic atypia. A major element for defining the UIP pattern is the presence of ‘normal’ or minimally affected alveolar tissue contiguous to areas where alveolated tissue is obliterated by dense fibrosis. Areas of preserved alveoli can be observed also in many other DPLD,

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but peculiar to the UIP pattern is the vicinity of normal and severely abnormal pulmonary tissue. Bronchiolar injury and repair are also evident in UIP, and abnormal bronchiolar proliferating lesions are common [8, 9]. These encompass basal cell hyperplasia, bronchiolization, squamous metaplasia and atypia. These abnormalities are also characterized by patchy distribution and heterogeneous extent. Bronchiolar scarring and prominent smooth muscle hyperplasia are common. Fibrosis and remodelling: The evaluation of fibrotic changes is also crucial for defining the UIP pattern. Fibrosis in UIP must be ‘temporally’ and ‘spatially’ heterogeneous. This means that old scarring fibrosis (recognized as thick collagen bands) needs to be present together with ‘young’ fibrosis, represented by collections of active myofibroblasts embedded in a myxoid milieu (fibroblast foci). Fibrosis can be also extensive in other DPLD, but it is usually characterized in these diseases by uniformity in distribution and age (e.g. mostly active in AIP/DAD and organizing pneumonia (OP), mainly old fibrosis with collagen deposition in fibrotic NSIP). In UIP, areas of advanced remodeling are common, where alveolar parenchyma is completely substituted by thick collagen scarring and smooth muscle fibers. These lesions can be observed in other DPLD, but are particularly prominent in UIP. The significance of this smooth muscle hyperplasia has been not defined, but likely is secondary to an abnormal regeneration of bronchiolar walls. Accordingly, the accumulating smooth muscle cells are not myofibroblasts, but exhibit a marker profile consistent with bronchiolar-wall derivation (␣-SMA⫹, caldesmon⫹) [9]. Fibroblast foci: Active fibrosing lesions (fibroblast foci) are another key element for defining the UIP pattern, since they give the appearance of temporal heterogeneity and represent the leading edge of ongoing lung injury and abnormal repair, responsible for the progressive obliteration of pulmonary structure and eventual tissue remodeling. Fibroblast foci are morphologically distinctive collections of loose organizing connective tissue formed by spindle cells immunophenotypically recognized as myofibroblasts (contractile fibroblasts expressing ␣-SMA). The fibroblast foci characterizing UIP are similar to those observed in OP (the so-called Masson’s body), but have different location (interstitial/ intramural versus alveolar), and biological features, such as the absence of blood vessels and inflammatory cells. The pathogenic relevance of these differences is currently unknown, but molecular abnormalities characterizing the myofibroblasts have been described in UIP [8, 9]. Fibroblast foci occur in the majority of UIP samples, and their frequency seems to be related to disease severity and prognosis [10].

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Chilosi/Murer/Poletti

The epithelial cells overlying fibroblast foci of UIP are frequently ‘cuboidal’ epithelial cells of undetermined nature. These epithelial cells, that likely represent target cells in the injury-repair sequence occurring in IPF, have been recognized as either alveolar or bronchiolar in different studies. At immunophenotypic analysis the majority of fibroblast foci are covered by bronchiolar epithelium [8, 9], and honeycomb cysts have frequently fibroblast foci in their wall (fig. 2). Inflammation is usually described as inconsistent in UIP, this in agreement with the new pathogenetic schemes. Nevertheless, various inflammatory cells can be observed in UIP samples, including lymphoid follicles, clusters of alveolar macrophages, scattered granulocytes and variable amounts of T cells. In a few cases eosinophils may be a prominent part of the inflammatory infiltrate. These inflammatory elements have no diagnostic significance and can be considered as secondary changes to lung tissue damage. Honeycombing is a major feature of the UIP pattern, although it is not specific for this disease. At histology, three different types of honeycomb lesions can be recognized: (1) Those formed by large emphysematous spaces (covered by alveolar epithelium) surrounded by dense collagen scarring. (2) Cysts formed by large dilated bronchiolar structures. (3) Areas of dense fibrosis including irregular bronchiolar structures, frequently filled by mucus and inflammatory cells, and showing features of hyperplasia and bronchiolization (so-called ‘microscopic’ honeycombing). Fibroblast foci are frequently found within the wall of microscopic honeycomb lesions, and the epithelial cells overlying these foci is, in most instances, bronchiolar (as defined by the presence of cilia and/or basal cells). In many cases, microscopic honeycomb cysts can be observed very close to the pleural surface. When end-stage fibrosis is the prevalent finding in a tissue sample, and only severe honeycombing can be documented, the differential diagnosis can be difficult or impossible. Acute exacerbation of IPF is characterized by the presence of morphological features of UIP with superimposed features of acute lung injury, such as diffuse alveolar damage, with or without hyaline membranes, type II reactive cells hyperplasia and numerous fibroblastic foci. Immunohistochemistry: Studies are in progress to verify the possible utility of molecular markers to improve the diagnostic accuracy of histological analysis. Although reproducible criteria have not been so far provided for the utilization of immuno-markers, some stains may be of help in difficult cases, highlighting subtle modifications that are not easily observed at routine HE staining. Tenascin, an

extracellular matrix protein, has been utilized to better visualize and reproducibly quantitate fibroblast foci (fig. 2c, e) [11]; low-molecular-weight cytokeratin immunostaining better visualizes the parenchymal organization; basal cell markers such as cytokeratin-5 and ⌬N-p63 can be used to precisely demonstrate abnormalities of bronchiolar regeneration (fig. 2d) [12]. Bronchiolar epithelial basal cells overlying fibroblast foci in UIP abnormally express laminin-5-␥2 chain and heat-shock protein-27, this suggesting an abnormal migratory/invasive phenotype (fig. 2f). This expression pattern is not observed in other DPLD and represents a promising differential marker for UIP [13]. Key morphologic features characterizing the UIP pattern: • Patchy/focal involvement of the lung (dense fibrosis and honeycombing with areas of ‘normal lung’ adjacent to heavily involved areas). • Distribution: sub-pleural, paraseptal, peri-bronchiolar. • Fibrosis, temporally heterogeneous (fibroblast foci, dense collagenous scarring). • Alveolar component: reduced or completely lost in affected areas, normal lung (no fibrosis, no inflammation) adjacent to end-stage fibrosis, focal alveolar damage, and occasional NSIP-like areas. • Bronchiolar component: damage and abnormal regeneration (basal cell hyperplasia, bronchiolization, squamous metaplasia, smooth-muscle scars and hyperplasia).

Acute Interstitial Pneumonia – Diffuse Alveolar Damage

When idiopathic, a rapidly progressive lung disease with features of the acute respiratory distress syndrome is recognized as acute interstitial pneumonia (AIP). Thus, the histological features of AIP are those of diffuse alveolar damage (DAD), with different changes in the different phases of the disease. The changes are diffuse, and fibrosis has a uniform temporal appearance. In the acute phases edema and exudative changes are prominent, and hyaline membranes are commonly found. In the organizing phases, the interstitial spaces are thickened and myofibroblasts accumulate in the alveolar walls. Prominent pneumocyte type II hyperplasia and atypia are evident (fig. 3a, b). Endo-alveolar organization similar to that observed in OP and areas of NSIP can be observed. Immunohistochemistry. Myofibroblast accumulation in the enlarged interstitial spaces is highlighted by ␣-SMA immunostaining (fig. 3d). Tenascin deposits are also found in the same location [unpubl. data]. Pneumocyte type II abnormal regeneration appears as hyperplasia and atypia,


a

b

c

d

e

f

Fig. 3. AIP/DAD-pattern. Diffuse homogeneous thickening of alveolar interstitial walls (a), with evidence of pneumocyte type II hyperplasia and atypia (b). Hyaline membranes (c) containing surfactant

proteins (SPA-1 immunostaining) and cellular debris. Fibrosis of uniform temporal appearance with myofibroblast accumulation within alveolar interstitial spaces is better evidenced by ␣-SMA immunostaining (d). Molecular markers of enhanced pneumocyte regeneration after acute damage include laminin-5-␥2 chain (e), and p53 (f).

and laminin-5-␥2 chain expression (fig. 3e) is increased in proliferating pneumocytes [13]. Activation of the p53p21waf1 pathway is also observed in AIP/DAD (fig. 3f). Key morphologic features characterizing the DAD/AIP pattern: • Diffuse involvement of the lung parenchyma. • Fibrosis of uniform temporal appearance with myofibroblast accumulation within alveolar interstitial spaces. • Diffuse features of acute alveolar damage with pneumocyte type II hyperplasia, atypia and hyaline membranes. Cryptogenic Organizing Pneumonia

Cryptogenic organizing pneumonia (COP) (formerly known as bronchiolitis obliterans OP or BOOP) is recognized

47

a

b

c

d

e

f

Fig. 4. OP pattern. The morphologic hallmark of the OP pattern is

the presence of polyps of organizing tissue composed of myofibroblasts and inflammatory cells within a myxoid stroma. Organization is patchy with centrilobular distribution and involves alveolar ducts, sometimes protruding within bronchiolar lumens. HE. (a). The loose appearance of polyps is due to the large amounts of extracellular matrix proteins, and in particular tenascin (b). A large intra-alveolar polyp is shown, adhering to epithelial layers of hyperplastic pneumocytes (cytokeratin 8/18 immunostaining). Note the presence of inflammatory cells within the polyp (c). Myofibroblasts are contractile, since they express at high level ␣-SMA (d). Intralveolar fragments of polyps digested by alveolar macrophages are observed in e (HE) and f (tenascin immunostaining). This phenomenon can explain the reversibility of the intralumenal fibrotic process characterizing COP.

in the ATS/ERS international Consensus Classification as a distinct clinicopathologic entity morphologically characterized by the presence of widespread organization within the alveolar ducts and alveoli, with or without bronchiolar intralumenal involvement (fig. 4) [14]. The OP pattern is produced by the reparative accumulation of granulation tissue within affected alveoli following widespread subacute injury, and focal signs of alveolar damage. Pneumocyte

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hyperplasia is common. The fibrosing process appears as uniform in age, and is mainly airway centered. The alveolar filling process is produced by the accumulation of contractile fibroblasts (myofibroblasts), which form branching or isolated polypoid formations (previously known as Masson’s bodies). The loose appearance of polyps is due to the large amounts of extracellular matrix proteins, and in particular tenascin (a reliable marker of early phases of fibrotic processes) (fig. 4b). The polyps of OP are similar to fibroblast foci of UIP. The main differences are in the location (mural versus intra-alveolar), the close relationship between myofibroblasts and overlying epithelial cells characterizing the UIP fibroblast foci, and other subtle features characterizing OP polyps, such as the presence of inflammatory cells (fig. 4c) and blood vessels. These features are in line with the divergent pathogenic mechanisms leading to the formation of fibroblast foci (proliferative) of UIP and OP polyps (inflammatory). The reversibility of OP lesions is suggested by the occasional finding of intra-alveolar fragments of polyps ingested by alveolar macrophages (fig. 4e, f). Interstitial infiltration of lymphocytes, plasma cells, scattered eosinophils, neutrophils and mast cells and intra-alveolar foamy macrophages are usually evident. Differential diagnosis. The inflammatory polyps of OP are the morphologic appearance of a stereotypic response to alveolar damage and this lesion is focally observed in a variety of lung diseases including infections, systemic collagen-vascular lung diseases, hypersensitivity pneumonitis, NSIP, DAD, DIP, eosinophilic pneumonia, and also UIP. Since polyps are easily to be found at the first screening of a pulmonary biopsy, careful investigation of the entire spectrum of diagnostic features is warranted to avoid over-diagnosis of COP. Key morphologic features characterizing the OP pattern: • Organizing tissue (polyps) within alveolar ducts and alveoli. • Mild interstitial inflammatory infiltrate/intra-alveolar foamy macrophages. • Focal alveolar damage with pneumocyte type II hyperplasia. • Preservation of lung structure, the process appears mainly centered on small airways.

Nonspecific Interstitial Pneumonia

Nonspecific interstitial pneumonia (NSIP) has only recently been recognized as a distinctive interstitial pneumonia [14, 15] that can occur either as an idiopathic disease

or associated with a variety of conditions such as collagenvascular diseases, slowly resolving DAD, drug reactions, exposure to different substances and also as a lone histological feature in hypersensitivity pneumonitis. NSIP has been included in the International Consensus Classification of IIP, where it is subdivided into the ‘cellular’ and the ‘fibrosing’ pattern [14]. The NSIP pattern was originally introduced in order to identify cases of interstitial pneumonias not fitting into well-defined histological patterns (UIP, DIP, AIP and COP), hence the term ‘non-specific’. Nevertheless, this pattern has been recognized as relevant and frequent in patients suffering of diseases where chronic inflammation occurs, and likely it occurs as a defined response of the alveolar interstitial compartment after chronic inflammatory injuries. Accordingly, NSIP is the pattern that most closely corresponds to the modifications observed in experimental lung fibrosis.

a

Histological Features of the NSIP Pattern The most relevant feature of the NSIP pattern is the uniformity of inflammatory and fibrosing changes observed in the alveolar septa (fig. 5). The relative amounts of cellular infiltrate and collagen fibers determines the assignment to the ‘cellular’ and ‘fibrotic’ variants of NSIP, and this grading is prognostically relevant [16]. Nevertheless, since a continuous spectrum from cellular to fibrosing patterns exists, the precise assignment can be occasionally challenging. Typically the lungs are uniformly involved, but the distribution and severity of changes are patchy. Inflammatory reaction. The interstitial infiltrate, described as mild to moderate, is mainly composed of lymphocytes and occasional plasma cells. Lymphoid follicles are common, mainly localized around airways. Information regarding the immunophenotypic profiles of infiltrating lymphocytes in NSIP is scanty, and apparently discrepant between studies on tissue and BAL samples [17]. Variable results can be explained by the differential distribution of T cell subsets in different compartments: CD8 in fact predominate in alveolar interstitial spaces, whereas CD4⫹ cells are mainly found in lymphoid follicles [17]. A predominance of plasma cells and lymphoid follicles suggest an autoimmune nature of the disease. Intra-alveolar accumulation of macrophages may occur, but it is not as prominent as in the DIP pattern. Fibrosis. Varying degrees of connective tissue accumulation is observed in alveolar septa, which is characteristically temporally homogeneous. Accordingly, fibroblast foci are


b

c

Fig. 5. NSIP pattern. Homogenous involvement of the lung, with

thickening of the alveolar walls and variable inflammatory infiltration characterizes the NSIP pattern (a). In the fibrotic type of NSIP dense collagen is present within the interstitial spaces, with focal sign of activity (b), arrow. HE. Alveolar damage is widespread, as evidenced in c, by cytokeratin 8/18 immunostaining.

inconspicuous or absent, and the variegated appearance observed in the UIP pattern is not present. In fibrosing NSIP the alveolar walls are uniformly thickened by dense collagen and inflammatory cells are scanty. Occasional intra-alveolar polyps are common in both types of NSIP. Areas of sub-acute alveolar damage, with patchy alveolar pneumocyte hyperplasia are common (fig. 5c), but severe damage and hyaline membranes are absent. Honeycombing is rare, but architecture distortion can occur in the fibrotic type of NSIP. Differential diagnosis. The variety of histological presentations of NSIP render the differential diagnosis a frequent challenge for the pathologist, and all the other IP patterns must be taken into account. When the NSIP pattern is encountered, a careful search of features suggesting other diseases (e.g. granulomas, eosinophils, viral inclusions) is needed. When histological variability is present, with the NSIP and UIP patterns observed in specimens

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from multiple lobes in a patient with IIP, the case should be classified as having UIP [18]. Immunohistochemistry. The number and type of inflammatory cells can be precisely evaluated using lymphoid markers such as CD3, CD8, CD20, CD138, etc. Tenascin immunostaining can better evidence the presence of active foci of fibrogenesis. Laminin-5-␥2 chain expression can help defining the extent of pneumocyte damage. Macrophage markers can more precisely detect the presence of small interstitial granulomas, this suggesting hypersensitivity pneumonitis. Key morphologic features characterizing the NSIP pattern:

• • • • • •

Cellular Pattern Interstitial chronic inflammatory infiltrate (lymphocytes, plasma cells), focal alveolar collections of macrophages. Homogenous involvement of the lung. Focal alveolar damage with pneumocyte type II hyperplasia and OP. Fibrosing Pattern Dense or loose interstitial fibrosis with homogenous involvement of the lung. Mild inflammatory infiltrate. No evidence of fibroblast foci or honeycombing.

Lymphoid Interstitial Pneumonia

In a clinical setting of profound immune disturbance, as observed in systemic autoimmune disorders, immunodeficiency syndromes, and bone marrow transplantation, the lung can be involved in an inflammatory infiltration presenting as lymphoid interstitial pneumonia (LIP). In this pattern, an intense and diffuse chronic accumulation of lymphocytes occurs in alveolar interstitial spaces, with important follicular reaction along lymphatic routes. The infiltrate is so intense that a low-grade marginal cell lymphoma can be suspected [see chapter by Poletti et al., p. 307]. The rarity of idiopathic LIP suggests that this diagnosis should be made with caution if underlying immune defects are not evident, and only after using investigations to rule out the diagnosis of lymphoma.

Granulomatous Interstitial Pneumonias and Sarcoidosis

Sarcoidosis is a chronic granulomatous disease involving several organs, and the lung is the most frequent target

50


Fig. 6. Sarcoidosis. Non-necrotizing granulomas localize in intersti-

tial spaces following lymphatic routes in intralobar septa, along bronchovascular bundles and the pleura. HE.

of disease. To obtain a definite diagnosis of sarcoidosis, the demonstration of granulomas is needed and histologic investigation is usually performed on pulmonary biopsies when easier sites for biopsy are not available (e.g. skin lesions or conjunctiva) [19]. Bronchoscopy can provide diagnostic transbronchial biopsies and BAL samples in most cases, hence the examination of surgical specimens is extremely rare. In the sarcoid lung, non-necrotizing granulomas localize in interstitial spaces following lymphatic routes in intralobar septa, along bronchovascular bundles and the pleura (fig. 6). The granulomas are formed by collections of epithelioid macrophages and multinucleated giant cells, admixed with lymphocytes mostly exhibiting the CD3⫹, CD4⫹ helper/inducer immunophenotype. A variable lymphoid infiltrate is also frequent in alveolar interstitial spaces, corresponding to the CD4⫹ alveolitis documented in BAL preparations [20]. Sarcoid granulomas are usually larger and more numerous than in hypersensitivity pneumonitis, and smaller than those observed in tuberculosis. In addition, sarcoid granulomas do not necrotize, although small necrotic areas containing a few apoptotic cells can occasionally be found. A rare necrotizing variant of sarcoidosis has been described [21]. The macrophages that form epithelioid granulomas in the lung do not likely arise from alveolar macrophages, but from monocytes imported from blood circulation [22]. Accordingly, macrophages exhibiting the Mac387 (a marker of monocytes that is down-modulated and lost during histiocyte differentiation) are frequently observed in the areas of ongoing granuloma formation [23]. Key morphologic features characterizing sarcoidosis: • Interstitial epithelioid granulomas associated with CD4⫹ T lymphocytes and scattered Mac387⫹ monocytes. • Granulomas are distributed along lymphatic routes (intralobar septa, bronchovascular bundles and the pleura).

•

Granulomas are usually non-necrotizing and special stains for infectious organisms are negative.

Hypersensitivity Pneumonitis/Extrinsic Allergic Alveolitis

Hypersensitivity pneumonitis/extrinsic allergic alveolitis (HP/EAA) comprises a group of allergic lung diseases occurring after inhalation of antigens contained in organic dusts (e.g. the ‘farmer’s lung’ after exposure to moulds, bird fancier’s lung after exposure to avian antigens, and many others), but also after inhalation or ingestion of organic chemicals and some drugs. The diagnosis of HP/EAA can be extremely difficult, since the number of triggering agents is large and anamnestic information regarding exposure is evident only in a proportion of cases. In addition, the disease, occurring as acute and chronic forms, can present with ambiguous clinical and imaging features, mimicking a variety of others conditions ranging from viral infections to IPF [24]. The diversity of clinical presentations corresponds to significant heterogeneity at histological investigation, and histological diagnosis can occasionally represent a critical challenge. Two different mechanisms of hypersensitivity are classically considered to be contemporaneously involved in HP/EAA: a type IV cell-mediated hypersensitivity (characterized by a cellular inflammatory reaction inducing a heavy infiltration of T lymphocytes exhibiting a CD8⫹ phenotype, and a type III humoral response, as evidenced by the accumulation of immune complexes in the alveolar septa.

Histological Features of HP/EAA HP/EAA is characterized by a chronic inflammatory infiltration of the alveolar septa, typically exhibiting centrilobular accentuation and bronchiolar involvement [25] (fig. 7). The inflammatory cells are mainly T lymphocytes exhibiting the CD8⫹ phenotype as also observed in BAL [26]. Small non-necrotizing granulomas and isolated giant cells (multinucleated macrophages) are a major histopathological feature of HP/EAA, but can be very few in some cases and difficult to be found. Collections of foamy macrophages within the alveolar spaces are likely consequences of some degree of obstruction occurring where bronchioles are involved in the inflammatory process. In fact, evidence of bronchiolar damage and repair is frequent, including epithelial fragmentation, inflammatory infiltration of the bronchiolar wall (at times resembling follicular


a

b

c

Fig. 7. Hypersentivity pneumonitis. The process is patchy and mainly characterized by centrilobular distribution (a). HE. Interstitial spaces are thickened by a heterogeneous infiltration of lymphocytes, and small non-necrotizing granulomas or isolated giant cells (b). Focal alveolar damage and OP lesions are often evident (c).

bronchiolitis), bronchiolization, smooth-muscle hyperplasia and/or smooth-muscle scars. Epithelial cell subacute damage is focally evident with pneumocyte type II hyperplasia and OP. HP/EAA can present with morphological features of idiopathic interstitial pneumonias, and this must be taken into account to avoid misdiagnosis. Interestingly, as evidenced in a recent clinicopathological correlation study on patients with chronic bird fancier’s lung, the histopathological patterns as described in the 2002 ATS/ERS consensus classification (UIP-like, NSIP-like, BOOP-like) correlate with the clinical course of the disease and with response to treatment and prognosis [27]. Differential diagnosis. HP/EAA must be distinguished from NSIP, where a similar interstitial inflammatory infiltrate can be seen, but without the centrilobular distribution and granulomatous response (nevertheless, the NSIP pattern can be observed as a lone histopathologic presentation of HP/EAA) [28]. In chronic HP/EAA the remodeling of lung structure can be so severe to appear as indistinguishable from UIP. Airway-centered interstitial fibrosis (ACIF),

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a recently described fibrosing disease with prevalent centrilobular distribution, is another disease sharing histopathological features with HP/EAA (and some cases could represent in fact cases of HP/EAA) [29]. Rarely, when the granulomatous reaction is exuberant, the differential diagnosis of sarcoidosis or infection can be taken into account. Nevertheless, in sarcoidosis the granulomatous infiltration characteristically follows lymphatic routes, there is usually a sclerotic reaction surrounding granulomas, and the lymphocyte infiltration is predominantly of the T helper/ inducer CD4⫹ subtype. Key morphologic features characterizing HP/EAA: Interstitial chronic inflammatory infiltrate with centri• lobular distribution (lymphocytes, mostly CD8⫹, some plasma cells and eosinophils). • Small interstitial epithelioid non-necrotizing granulomas and/or isolated multinucleated giant cells. • Evidence of bronchiolar damage and regeneration (airway-centered inflammation, smooth-muscle scars, bronchiolization). • Evidence of alveolar damage and regeneration (pneumocyte type II hyperplasia, focal OP).

CD68

a

b

c

d

Fig. 8. Smoking related pneumonias. RB-ILD is characterized by an inflammatory process centered on respiratory bronchioli (a), with clusters of pigmented alveolar macrophages; variable wall thickening and lymphoid infiltration of the bronchiolar wall is also evident (b, CD68 immunostaining). c A case of DIP is shown, exhibiting diffuse alveolar filling by pigmented alveolar macrophages. Diffuse pneumocyte type II hyperplasia is evidenced by cytokeratin immunostaining (d).

Smoking-Related Interstitial Lung Disorders

In lungs, cigarette smoking has generally been considered to be a risk factor for COPD and carcinomas. However, a group of interstitial lung diseases have been linked to cigarette smoking in recent years [30–32]. These have been considered as separate entities, within a spectrum of diseases with overlapping symptoms, radiological findings and histopathologic manifestations. Smokingrelated diseases include four entities: respiratory bronchiolitis (RB), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), DIP, and pulmonary Langerhans cell histiocytosis (PLCH) [33]. Although the pathogenic mechanisms have not been explained, there is some evidence that in all these entities the target of damage is the terminal and/or respiratory bronchioles.

Respiratory Bronchiolitis and Respiratory Bronchiolitis-Interstitial Lung Disease

RB, first described by Niewoehner in young male smokers, is now recognized as extremely common in cigarettes smokers [34–36]. RB is most commonly seen as an incidental finding in lung tissue from smokers, primarily affecting respiratory bronchioles. A mild chronic inflammation is

52


found in the wall of the respiratory and terminal bronchioles associated with slight fibrosis, smooth muscle hypertrophy, and thickening of the adjacent alveolar walls, which also may show mild chronic inflammation. The most characteristic (but not completely specific) feature of RB is the accumulation of pigmented macrophages in the lumen of respiratory bronchioles and the adjacent alveoli. These macrophages contain dark particulate material, stain with PAS after digestion, and may stain with iron. RB may persist for many years after stopping smoking. Accordingly, pigmented macrophages can be detected for at least 2 years after smoking has ceased, which is considerably longer than the estimated life span of the alveolar macrophages [37]. RB-ILD can be considered as an evolution of the RB reaction, sufficient to result in clinical and radiological evidence of interstitial lung disease [34, 36]. RB-ILD is a patchy process, restricted to the regions around respiratory bronchioles (fig. 8). It presents the typical changes of RB, with marked increase in pigmented macrophages that fill the lumen of the respiratory bronchioles and the surrounding alveoli, focally producing a DIP-like pattern. Greater extent of fibrosis, lymphoid follicles and eosinophilic infiltration characterizes DIP compared with RB-ILD [35].

Key morphologic features characterizing the RB and RB-ILD pattern: • Bronchiolocentric alveolar macrophages accumulation. • Macrophages with dusty brown appearance (may be positive with D-PAS and iron stain). • Mild bronchiolar and peribronchiolar fibrosis and chronic inflammation. • Some centrilobular emphysema. Desquamative Interstitial Pneumonia

In contrast to RB-ILD, DIP is a diffuse process mainly involving the lower lobes. Initially, DIP was considered to be an idiopathic interstitial pneumonia related to UIP [2]. That concept is not accepted today, and UIP and DIP are considered unrelated diseases. Currently, it has been suggested that RB, RB-ILD and DIP represent diverse degrees of evolution and severity of the same process. Nevertheless, it is important to lay stress on that DIP usually involves lower lobes, can be occasionally observed in non smokers (it represents one of the most common form of interstitial lung disease in children), and the DIP pattern can occur as familial DPLD [38]. These findings suggest that individual susceptibility has a relevant role in the occurrence and severity of the spectrum of smoking-related diseases, with DIP as the most severe. The classic DIP pattern shows uniform diffuse involvement of the lung by numerous macrophages that fill the peripheral airspaces, giving sometime a ‘paving stone’ appearance (fig. 8c). Sometimes, the changes may be not entirely uniform and centrolobular. Macrophages are generally round, with a light brown and finely granular cytoplasm (‘smokers macrophages’) that can be slightly positive to iron stain, reflective of the underlying influence of smoking. The alveolar septa show a mild thickening and a sparse chronic inflammatory infiltrate mainly composed of lymphocytes and plasma cells, sometimes forming nodular aggregates. Sparse eosinophils are seen in most cases; in a minority of cases eosinophils may be more prominent. Many alveolar spaces are lined by hyperplastic type 2 pneumocytes (fig. 8d). Associated emphysema or airspaces enlargement with fibrosis is commonly present. Differential diagnosis. Macrophage accumulation within the alveolar spaces is a nonspecific response to particular inflammatory stimuli, and this finding can occur in different pulmonary diseases including UIP, RB, chronic hemorrhage, hemosiderosis, veno-occlusive disease, and others. In contrast to UIP, DIP shows a uniform involvement of the lung parenchyma and lacks fibroblastic foci


and honeycombing changes. RB-ILD and DIP may overlap and the key feature to differentiate the two entities is the extension and distribution of the lesions: bronchocentric in the RB-ILD, diffuse in DIP. DIP and RB-ILD should be separated from haemosiderosis and chronic hemorrhage in which numerous hemosiderin-laden macrophages are seen. In contrast to hemosiderin, smoker’s pigment is indistinct and finely dispersed. In veno-occlusive disease the diagnostic changes are in the veins showing intimal fibrosis and recanalized thrombi. Intra-alveolar macrophage accumulation can also be seen in other lung diseases that must not be erroneously interpreted as DIP. An appearance very like DIP accompanies endogenous lipid pneumonia, lipid storage diseases, and also reactions to drugs (e.g. amiodarone). Clinical and radiological data are crucial to reach the correct diagnosis in these cases. Identification of the cytoplasmic vacuoles and lipid inclusions is necessary, and cytochemical stains (e.g. oil-red-O on BAL) can be useful. Macrophages can accumulate in giant cell pneumonia (GIP), but the distinctive exposure history and the high frequency of characteristic giant cells distinguish this disease. Pulmonary siderosis observed in iron pneumoconiosis can simulate a DIP or RB-ILD pattern. The abundance of iron pigment-containing macrophages, the presence of ferruginous bodies and clinical history are helpful in distinguishing this entity. Key morphologic features characterizing the DIP pattern: • Uniform involvement of lung parenchyma. • Prominent accumulation of alveolar macrophages. • Mild to moderate fibrosis and thickening of alveolar septa. • Mild interstitial inflammation.

Pulmonary Langerhans Cell Histiocytosis

This disease is characterized by the abnormal accumulation of Langerhans cells (LC) admixed to variable numbers of eosinophils (hence the previous term of pulmonary eosinophilic granuloma). The lesions of Pulmonary Langerhang cell histiocytosis (PLCH) are similar to those observed in extrapulmonary LCH, but, at variance with this latter disease that is considered to be clonal/neoplastic, the pulmonary form is considered to be caused by a reactive proliferative response of LC to cigarette smoke [39, 40]. LC are bone-marrow-derived specialized antigen-presenting histiocytes normally homing in the skin, scattered among epidermal keratinocytes. The relevant function of LC in skin immunopathology is well established, but less clear is the significance of these cells within the pulmonary microenvironment and the role of smoking in LC recruiting

53

a

b

c

d

Fig. 9. Pulmonary Langerhans cell histocytosis. The process is firstly focused on bronchiolar structures, which appear focally thickened (a, HE), and infiltrated by CD1a⫹ LC (b). Formation of large nodules of LC follows, as shown in c (S100 protein immunostaining). A fibrotic

process eventually develops, producing severe remodelling of the pulmonary structure (d).

Table 1. Classification of DPLD included in this review

Idiopathic interstitial pneumonias Usual interstitial pneumonia (UIP) Acute interstitial pneumonia (AIP) Cryptogenic organizing pneumonia (COP) Nonspecific interstitial pneumonia (NSIP) Lymphocytic interstitial pneumonia (LIP) Granulomatous DPLD Sarcoidosis Hypersensitivity pneumonitis/extrinsic allergic alveolitis Smoking-related pneumonias Desquamative interstitial pneumonia (DIP) Respiratory bronchiolitis interstitial lung disease (RB-ILD) Langerhans cell granulomatosis Other forms of DPLD Lymphangioleiomyomatosis (LAM) Erdheim-Chester disease Rosai-Dorfman disease DPLD of known cause Connective/vascular disease (rheumatoid arthritis, systemic sclerosis, Sjogren syndrome) Reaction to drugs

54


[41]. Different phases of the disease occur, one early cellular phase and one chronic fibrotic phase, which can be concomitantly present at different sites in the same patient, producing a variegated pattern at histological examination. The cellular presentation is characterized by centrilobular nodular accumulations of LC (fig. 9a, b). In chronic lesions LC can be few and scattered, and can be easily missed at morphologic analysis. Cystic lesions can be also produced by central splitting of large nodules, and by dense fibrosis surrounding dilated alveolar spaces (fig. 9d). Fibrosis follows the evolution of the disease, and stellate scars substitute the LC nodules. Diffuse interstitial fibrosis can eventually develop, with severe impairment of respiratory functions. In more chronic cases the fibrosis and structure remodeling is so severe to give a pattern similar to UIP. PLCH is a smoking-related disease, and other features of smoking damages are usually evident in the same biopsy, such as variable macrophage accumulations providing the pattern of respiratory bronchiolitis, RB-ILD, or DIP [42]. Immunohistochemistry. The cytological morphology of LC is characteristic (large mildly eosinophilic cytoplasm, pale nuclei with clear-cut infolding), but confirmation of the typical immunophenotype of LC (S100, CD1a, Langerin) (fig. 9b, c) is highly recommended, especially when the diagnosis is performed on small transbronchial biopsies and in chronic fibrotic cases. Nevertheless, it has to be stressed that in most cases a pulmonary biopsy is not needed, and the diagnosis of PLCH can be obtained on clinical and radiological grounds, with the immunocytological confirmation on BAL samples of more than 5% CD1a⫹ LC. Key morphologic features characterizing PLCH: • Centrilobular nodules of Langerhans cells (typical cytology, CD1a⫹, S100⫹, Langerin⫹) admixed with eosinophils. Cystic bronchiolar lesions. • • Stellate fibrotic scars. • Smoke-related modifications (pigmented macrophage accumulation). • Interstitial fibrosis in chronic forms. Others (Proliferative DPLD)

A group of DPLD is included in the ATS/ERS Classification as ‘others’ [14]. Within this group miscellaneous diffuse lung diseases are included (pulmonary lymphangioleiomyomatosis (LAM), Erdheim-Chester disease, Rosai-Dorfman and others), characterized by the similneoplastic accumulation of different cell types within the pulmonary tissue, inducing reactive stromal responses

and leading to a life-threatening functional respiratory impairment. Although the non-neoplastic nature of these entities is suggested by a number of molecular studies, definite understanding of their pathogenesis is not fully elucidated.

Lymphangioleiomyomatosis

This disease, occurring either sporadically or associated with TSC, has been related to mutations of the tuberous sclerosis complex gene (TSC2), and is restricted to women. The aberrant LAM-cells belong to a newly recognized cell family (the perivascular epithelioid cells – PEC cells expressing markers of contractile and melanocytic differentiation: S100, HMB45, ␣-SMA) [43] (fig. 10). In the lung, the LAM cells appear as plump, spindle-shaped eosinophilic cells, forming sheets and nodules around the bronchioli, which are often dilated and appearing as small cysts. LAM cells are also observed along lymphatic vessels (fig. 10d). LAM cell accumulations can be easily missed in early phases of the disease, and immunophenotypic confirmation can be crucial, especially on transbronchial biopsies [44].

a

b

c

d

Fig. 10. Lymphangioleiomyomatosis (LAM) is characterized by the interstitial accumulation of plump, spindle-shaped eosinophilic cells, forming sheets and nodules around bronchioli, which are often dilated and appearing as small cysts (a, HE). The spindle cells exhibit a specific immune-profile including ␣-SMA (b) and the melanocyteassociated antigen HMB45 (c). LAM cells characteristically infiltrate the interstitial spaces following lymphatic routes, as highlighted by the lymphatic marker podoplanin (d).

Erdheim-Chester Disease

This is a rare systemic histiocytosis of unknown etiology that usually affects the long bones and can present with pulmonary involvement (about 30% of cases). For many years, this disease has been considered a variant of Langerhans cell histiocytosis, but it is now recognized as a distinct entity [45, 46]. In the lung, the disease is characterized by thickening of the visceral pleura and interlobular septa, with formation of wide sclerotic bands containing variable numbers of histiocytes with large foamy cytoplasms (xanthomatous histiocytes) [47] (fig. 11). These cells exhibit a macrophage immunophenotypic profile, characterized by the expression of CD68, FXIIIa, distinct from that of Langerhans cells (lack of S100, CD1a and Langerin) [47]. Rosai-Dorfman Disease

Pulmonary involvement of Rosai-Dorfman disease (RDD, also known as sinus histiocytosis with massive lymphadenopaty) is rare, but should be taken into account in the differential diagnosis of DPLD. This disorder is suggested


a

b

c

d

Fig. 11. Erdheim-Chester disease. In this disease a striking fibrotic

process causes subpleural thickening of the visceral pleura and interlobular septa, forming wide sclerotic bands (a, b) containing variable numbers of histiocytes with large foamy cytoplasms (xanthomatous histiocytes) (c, HE). These cells exhibit a macrophage immunophenotypic profile, characterized by the expression of CD68 (d, arrow).

55

to arise from an immune dysfunction [48]. The main feature of RDD is the infiltration of lung tissue, preferentially located along lymphatic routes, by histiocytes characterized by unusual morphology and immunophenotype. Morphologically, RDD cells appear as large histiocytes containing intact T lymphocytes (a phenomenon known as emperipolesis). The phenotype of RDD histiocytes is peculiar (S100⫹, CD68⫹, CD1a-negative), and suggests

that they can represent abnormally stimulated antigenpresenting cells [49].

Acknowledgments Supported by Fondazione Cassa di Risparmio, Verona.

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45 Veyssier-Belot C, Cacoub P, CaparrosLefebvre D, Wechsler J, Brun B, Remy M, Wallaert B, Petit H, Grimaldi A, Wechsler B, Godeau P: Erdheim-Chester disease: clinical and radiologic characteristics of 59 cases. Medicine (Baltimore) 1996;75:157–169. 46 Kenn W, Eck M, Allolio B, Jakob F, Illg A, Marx A, Mueller-Hermelink HK, Hahn D: Erdheim-Chester disease: evidence for a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis. Hum Pathol 2000;31:734–739. 47 Rush WL, Andriko JA, Galateau-Salle F, Brambilla E, Brambilla C, Ziany-bey I, Rosado-de-Christenson ML, Travis WD: Pulmonary pathology of Erdheim-Chester disease. Mod Pathol 2000;13:747–754. 48 Maric I, Pittaluga S, Dale JK, Niemela JE, Delsol G, Diment J, Rosai J, Raffeld M, Puck JM, Straus SE, Jaffe ES: Histologic features of sinus histiocytosis with massive lymphadenopathy in patients with autoimmune lymphoproliferative syndrome. Am J Surg Pathol 2005; 29:903–911. 49 Bonetti F, Chilosi M, Menestrina F, Scarpa A, Pelicci PG, Amorosi E, Fiore-Donati L, Knowles DM: Immunohistological analysis of Rosai-Dorfman histiocytosis: a disease of S-100⫹ CD1⫺ histiocytes. Virchows Arch [A] 1987;411:129–135.

Marco Chilosi, MD Anatomia Patologica, Dipartimento di Patologia, Università di Verona Policlinico G.B. Rossi P. le L. Scuro IT–37134 Verona (Italy) Tel. ⫹39 045 8027616, Fax ⫹39 045 8027136 E-Mail [email protected]

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Bronchoalveolar Lavage Marjolein Drenta Robert P. Baughmanb

Keith C. Meyerc

a

Department of Respiratory Medicine, University Hospital, Maastricht,The Netherlands; bInterstitial Lung Disease and Sarcoidosis Clinic, University of Cincinnati Medical Center, Cincinnati, Ohio, c Department of Medicine, University of Wisconsin Medical School, Madison,Wisc., USA

Abstract Bronchoalveolar lavage (BAL) – an easily performed and well-tolerated procedure – can retrieve cells and solutes from the lower respiratory tract. When applied according to standardized protocols and considered in the context of other information (gained from conventional ancillary diagnostic tests combined with a thorough clinical evaluation), BAL can be very useful in the diagnostic work-up of diffuse infiltrative lung disease. In selected cases, BAL has the benefit of avoiding more invasive diagnostic procedures, such as tissue biopsies. Even when not diagnostic, BAL is often supportive of a specific diagnosis. Nonetheless, if a thorough clinical evaluation that includes bronchoscopy with BAL has not secured a confident diagnosis, a biopsy should be considered as the final diagnostic step. Bronchoalveolar lavage will undoubtedly continue to serve as an important procedure for clinical purposes as well as a method that facilitates our understanding of the pathological processes that cause inflammation and fibrosis in diffuse lung disease. Copyright © 2007 S. Karger AG, Basel

Pulmonary diseases have traditionally been evaluated by laboratory tests, lung function tests, imaging procedures and tissue biopsies. Bronchoalveolar lavage (BAL) represents an additional tool for pulmonologists that can aid in the assessment of the health status of the lung [1–5]. The application of BAL for diagnostic purposes has significantly improved the diagnostic work-up of diffuse parenchymal lung diseases, which are collectively referred

to as diffuse interstitial lung diseases (DILDs). Identifying the underlying disorder poses a significant challenging task for the clinician and requires a multidisciplinary approach with optimal resources. These disorders may be of infectious, noninfectious immunologic, malignant, environmental or occupational etiology. To establish the diagnosis, a thorough history is essential as it may identify a potential etiological factor (e.g. drug reaction, environmental and/or occupational exposures). Lung parenchymal evaluation by high-resolution CT scanning (HRCT) of the chest may provide virtually diagnostic images in certain forms of DILDs. However, other testing including BAL and lung biopsy may be required to secure an accurate diagnosis. The differential diagnosis rests on the clinician’s interpretation of the patient’s history, additional tests including BAL and, if necessary, tissue sampling. Provided that its limitations are kept in mind, there appears to be a place for BAL in the evaluation of DILDs. The pattern of inflammatory cells may be helpful in narrowing the differential diagnosis [1–5]. In this chapter, the potential practical value of BAL in the diagnostic work-up of DILD will be discussed.

Clinical Use of Bronchoalveolar Lavage

In the diagnostic work-up of specific DILDs the additional usefulness of BAL fluid (BALF) analysis has been widely appreciated [1–6]. Careful analysis of the BALF cell profile – together with an extensive evaluation of clinical

and radiological features – allows prediction of the underlying disorder with a high sensitivity and specificity. Moreover, in selected cases, BAL is useful for establishing or ruling out a diagnosis with only a low risk of misdiagnosis [1–7]. In this respect, it has the advantage of avoiding more invasive diagnostic procedures, such as tissue biopsies. Even in conditions in which lavage is not diagnostic, the results may be inconsistent with the suspected diagnosis, and then focus attention on more appropriate, further investigations. Furthermore, BAL was anticipated to help with management by assessing disease activity, determining prognosis, and guiding therapy [8–11]. These possible uses of BAL are, however, controversial and the most critically discussed aspects of BAL. To explore the possible role for BALF analysis in the management and care of individuals with DILD, future studies should be directed toward a prospective assessment of the interrelationship among BALF parameter changes over the course of a certain disease and how these reflect treatment response.

Diagnostic Applications of Bronchoalveolar Lavage Fluid Features

Thorough clinical assessment should be considered as the key diagnostic procedure. Even when lung biopsy is performed, an accurate diagnosis is dependent on optimal usage of all available clinical information [12]. When evaluating a patient with suspected diffuse interstitial disease the diagnostic approach should include: • full (medical) history including all available details about possible occupational and/or environmental exposures; • physical examination, assessing whether the disorder is multisystemic (skin lesions, arthralgia, ocular inflammation); • lung function tests and evaluation of arterial blood gases; • chest radiography and often a HRCT scan; • selected blood tests where appropriate, including autoantibodies, precipitins, ANCA, angiotensine converting enzyme (ACE), lactate dehydrogenase (LDH) and interleukin (IL)-2R. If these do not establish a likely diagnosis, more invasive diagnostic tests are required and include: • bronchoalveolar lavage, • transbronchial lung biopsy, • surgical lung biopsy.

Bronchoalveolar Lavage

Bronchoalveolar Lavage: Procedure and Confounding Factors

In general, BAL is a safe, noninvasive and generally welltolerated procedure. Most of the reported side effects are closely related to the endoscopic procedure, volume and temperature of the instilled fluid [1, 13]. Common complications or side effects associated with the lavage itself include coughing during the procedure, transient fever, chills and marked malaise occurring some hours after the performance of the BAL. Some complications are simply due to the bronchoscopy itself, while others are more likely to occur as a result of the lavage or personal characteristics of the patient like smoking and/or drug-use. Smoking has been shown to adversely affect the alveolar micro-environment both in health and disease. Smokers tend to have more neutrophils in their BALF. The major change seen in smokers is a marked increase in macrophages. There are often 10-fold more macrophages retrieved in smokers compared to nonsmokers. Since the cellular BALF population is usually reported as a percentage of retrieved cells, this absolute increase in macrophages will lead to a proportional drop in the percentage of lymphocytes. These macrophages often contain pigmented material related to the inhaled smoke. The macrophages are often activated, releasing increased amounts of oxygen free radicals for example. Cigarette smoking influences the recovery of the fluid, the viability and quantity of the cells, as well as amount of solutes [5, 14]. Fever and hypoxia are more commonly encountered with BAL. Hemoptysis is rarely caused by lavage and pneumothorax is unlikely to be caused by lavage itself. Although mortality has been associated with BAL, the overall complication rate of BAL was reported to be less than 3%, compared to 7% when combined with transbronchial biopsies [1, 13]. Various technical aspects of BAL are critical in obtaining representative samples [15]. Some intrinsic variability of the BAL procedure and results of the interpretation of the BALF profile can be limited by using a standard approach. The use of guidelines and recommendations for a standardized approach regarding the procedure as well as processing the material and use of central laboratories have reduced variations in obtaining samples and analyzing and interpreting data. Attempts have been made to set up a framework for the different steps of the procedure, such as the amount and temperature of fluid injected, the number of aliquots used (usually 4 of 50 ml), the ‘dwelling time’, and aspiration pressure [16]. The basic goal is to ensure that the injected fluid reaches the appropriate pathological area. In addition, the aspirate has to be a representative sample, containing cells and solutes, reflecting the pathophysiological

59

Table 1. Recommendations for acquiring and handling bronchoalveolar lavage fluid: comparison of three recommendations

Source of variability

US BAL Cooperative [13]

ERS 1999 [15]

ATS Task Force on BAL in ILD [unpublished data]

Disease process itself

stated

state underlying disease

state underlying disease

Suction pressure during the procedure

‘gently’ aspirate by hand held syringe

keep to a minimum (25–100 mm Hg)

keep below 100 mm Hg; avoid visible airway collapse

The handling of fluid: filtered/nonfiltered; concentrated

no comment

state technique specifically

no filtering with gauze

Volume instilled

240 ml

instil at least 100 ml

instil at least 100 ml

Handling of first aliquot recovered

poole all samples

specify

pool all samples unless specified

Number of aliquots

four

four

specify and standardize

Position of patient

semi-recumbent

specify

specify

Area that is lavaged

right middle lobe/lingula

specify

specify

Number of areas lavaged

one

specify

specify

Variability of lavage return

discontinue lavage if difference between instilled and aspirated was ⬎100 ml

report volume and percent of fluid returned establish minimal percent recovered

report volume and percent of fluid returned at least 10% of instilled volume must be recovered (still under discussion)

Reporting measurements of acellular components

report per ml of fluid recovered



Sample storage

specify

specify

specify

process of the inflammation. In general, fluid obtained at one site is representative for the whole lung as inflammation in DILD is not limited to one site. While this is true, for example, in sarcoidosis, differences in lavage population have been reported in studies of patients with idiopathic pulmonary fibrosis (IPF). Several groups have made specific recommendations about the acquiring and handling of BAL [13, 15, 16]. These are summarized in table 1. From an anatomic point of view the middle lobe or lingula is most convenient to access, and, therefore, routinely used. However, review of the chest CT scan may help in selecting the best areas to be lavaged. It has been shown that similar results for BAL are usually seen in different lobes in sarcoidosis patients but not in cases of pulmonary fibrosis [17]. For example, lavage performed in an area with extensive honeycombing will yield a smaller return of fluid and different cells than a lavage that is performed in an area of ground glass changes. In general, it is advisable to avoid areas of extensive honeycombing. This is similar to the logic of avoiding these end stage areas when performing an open lung biopsy. In localized disease, however,

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Drent/Baughman/Meyer

such as malignant lesions and infectious lesions, lavage at the site of abnormality is mandatory [16].

Processing of Bronchoalveolar Lavage Fluid

The obtained cells can be evaluated by cytological techniques and immunohistochemical procedures. Interpretation of data assessed from BALF – distribution of cells as well as fluid constituents – is complicated by confounding factors such as age, smoking history and use of drugs, principally, immunoregulators, as well as the lavage technique [1–7]. Various technical aspects of BAL are critical in obtaining representative samples. The epithelial cell layer is vulnerable to trauma. Damage caused by insertion of the fiberoptic bronchoscope into the airways may result in a number of confounding aspects including an increase of the amount of erythrocytes in the BALF. Repeated lavage within a few days may reveal increased neutrophils as a result of the previous lavage.

The retrieved BALF is prepared for total and differential cell counts and, when possible, the determination of lymphocyte subsets by monoclonal antibody techniques. Cell counts can be performed by a hemacytometer and should be performed on unconcentrated samples. For differential cell count most laboratories prepare the slides using a cytocentrifuge. There are some changes in the cell population due to the use of the cytocentrifuge. However, the ease of preparing the slides and the reproducibility of a good cell separation explains the popularity of this technique. Cytocentrifuge-prepared slides are usually stained with Wright’s or May-Grünwald-Giemsa (MGG) stains [16]. Both Wright and MGG stains render nuclear features in less detail as compared to Papanicoulaou stains and are therefore less suitable for the detection of malignancy and viral inclusion bodies. They are, however, excellent for identification of leukocytes and macrophages and they obviously stain extracellular substances such as mucus. Since these staining methods are performed on air-dried materials, fewer cells are lost than with the Papanicoulaou stain and no shrinkage secondary to wet-alcohol fixation occurs. If, after complete drying, the stained slides are mounted with a cover glass, they do not fade and the slides can be stored for years. Rapid substitutes are available, such as the Field’s stain and the Dif-Quik stain. The use of the former stain is mainly restricted to blood film parasitology, but the DifQuik stain (originally designed as a rapid and simple staining method for blood films in the physician’s office laboratory) is commonly used in BALF cytology. This stain, however, is not able to stain mast cells [16]. In addition to the usual MGG staining, which allows enumeration of cells containing intracellular micro-organisms, special stains and culture of BALF samples have increased the accuracy of diagnosing (opportunistic) infections [18, 19]. The use of immunologic markers allows staining for cell markers. These are most commonly performed on lymphocytes. The T cell is the most common lymphocyte found in BALF. Studies of the CD4 and CD8 positive cells can be performed on cytocentrifuge prepared slides. Another common method is performing flow cytometry, but this method usually requires at least a million cells for an adequate analysis. The most common application of the CD4:CD8 ratio has been in sarcoidosis and extrinsic allergic alveolitis. Initial reports concentrated on the increased CD4:CD8 ratio seen in sarcoidosis and the low ratio seen in extrinsic allergic alveolitis [20, 21]. However, it is clear that many patients with sarcoidosis have normal or even reduced CD4:CD8 ratio [20–23]. In addition, some cases of extrinsic allergic alveolitis have been reported to have normal or elevated CD4:CD8 ratios [24, 25]. While some feel that


CD4:CD8 ratios add considerably to the diagnostic reliability of BAL [26], others feel that CD4:CD8 ratios can provide prognostic information [21]. In cases of possible lymphoma, B cell markers such as lambda and kappa surface membrane immunoglobulin can be performed. The presence of a high proportion of either kappa or lambda implies a monoclonal population, usually indicating lymphoma or leukemia in the lung [27, 28]. Because of autofluorescence of macrophages, immunochemistry is less commonly used for markers of macrophages.

Cellular BALF Features that Are Useful in the Evaluation of DILD

Normally, BALF samples, obtained from healthy nonsmoking controls, contain 80–90% alveolar macrophages (AMs), 5–15% lymphocytes, 1–3% polymorphonuclear neutrophils (PMNs), ⬍1% eosinophils and ⬍1% mast cells [5, 13]. The aforementioned cell populations present within the lung are all potentially inflammatory cells. In patients with DILD marked changes in cell yield and cell differentiation may occur (table 2). The presence of squamous epithelial cells points to oropharyngeal contamination of the BALF [29]. Alveolar Macrophages Normally, BALF consists of predominantly AMs. The cytoplasm is pale and may contain phagocytized material such as carbon, hemosiderin, cell fragments or other foreign body material. Dust particles in AMs or elevated asbestos body counts in BALF and/or the presence of birefringent material or inclusion bodies, point towards dust or fiber exposure that may cause illness [7]. Foamy or ‘lipidladen’ AMs are macrophages that display clear and complete cytoplasm vacuolization. Although this finding usually is nonspecific, it might be indicative of extrinsic allergic alveolitis (EAA) or hypersensitivity pneumonitis (HP), drug-induced pneumonitis, or lipoid pneumonia either caused by injection or inhalation of oil substrates [5]. Occasionally, specially in Th1 mediated disorders, multinucleated giant AMs can be found in BALF [1]. Macrophages retrieved by BAL may be activated and release among others cytokines and oxygen free radicals. However, these products of AMs and other airway cells have not proved to be useful in the differential diagnosis of DILD or in evaluating therapy. In pulmonary alveolar proteinosis, BALF analysis may obviate the need of biopsy in almost all cases. The gross appearance of the fluid is milky and turbid. Light microscopy reveals acellular oval bodies; few

61

Table 2. Cellular bronchoalveolar lavage fluid (BALF) profile characteristics of the most common (diffuse) lung diseases.

AMs Noninfectious diseases Sarcoidosis Extrinsic allergic alveolitis Drug-induced pneumonitis Idiopathic pulmonary fibrosis COP Eosinophilic pneumonia Alveolar proteinosis Connective-tissue disorders Pneumoconiosis Diffuse alveolar hemorrhage Acute interstitial pneumonia ARDS

‘foamy’ aspect ‘foamy’ aspect ‘foamy’ aspect ‘foamy’ aspect inclusion particles Fe-staining ⫹⫹⫹ Fe-staining ⫹⫹ Fe-staining ⫹

Malignancies Bronchus carcinoma Lymphangitis carcinomatosa Hematologic malignancies Infectious diseases Bacterial Viral Tuberculosis HIV infection (AIDS)

intracellular bacteria inclusion bodies inclusion bodies (viral infections)

Lym

PMNs

Eos

PC

MC

CD4:CD8 ratio

⫹ ⫹⫹ ⫹⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⬇/⫹ ⬇/⫹ ⫹

⬇ ⫹ ⫹ ⫹/⫹⫹ ⫹ ⬇ ⬇ ⬇/⫹ ⫹ ⫹ ⫹⫹ ⫹⫹

⬇/⫹ ⬇/⫹ ⫹ ⫹ ⫹ ⫹⫹ ⬇ ⬇/⫹ ⬇/⫹ ⬇/⫹ ⬇/⫹ ⫹

0 1/0 1/0 0 0/1 1/0 0 0 0 0 –/⫹ 0

⬇/⫹ ⫹⫹ ⫹⫹ ⫹ ⬇/⫹ ⬇/⫹ ? ⬇/⫹ ⬇/⫹ ? ⬇ ⬇/⫹

⫹/⬇/– –/⬇ –/⬇ ⬇ – – ⫹/⬇ ⫹/⬇/– ⫹/⬇/– ⬇ ⬇ –/⬇

⬇ ⫹ ⫹

⬇ ⫹/⬇ ⫹

⬇ ⫹/⬇ ⫹

0 0/1 0/1

⬇ ⫹/⬇ ⫹

⬇ –/⬇ ⫺/⬇

⬇ ⫹ ⫹ ⫹

⫹⫹ ⫹ ⬇ ⫹

⫹ ⫹ ⬇/⫹ ⫹/⬇

0 0 0 0

? ? ⫹ ?

⬇ –/⬇ ⬇ –

? ⫽ Not known; ⫹, ⫹⫹ ⫽ increased; ⬇ ⫽ normal; – ⫽ decreased; 0 ⫽ not present; 1 ⫽ present; AMs ⫽ alveolar macrophages; ARDS ⫽ adult respiratory distress syndrome; COP ⫽ cryptogenic organizing pneumonia; Eos ⫽ eosinophils; Lym ⫽ lymphocytes; MC ⫽ mast cells; PC ⫽ plasma cells; PMNs ⫽ polymorphonuclear neutrophils.

and ‘foamy’ macrophages; and a dirty background due to large amounts of amorphous debris [30]. Lymphocytes Mature lymphocytes are the smallest nucleated cells in BALF. Granulomatous lung inflammatory disorders such as sarcoidosis and EAA, associated either with a drug reaction or inhalation of antigens causing a host response may display similarities in clinical presentation. However, these latter disorders demonstrate a different cellular profile in BALF [14, 31]. Clinical manifestations of sarcoidosis depend on the intensity of the inflammation and organ systems affected. In BALF an increased number of lymphocytes, predominantly activated T-helper cells were found. Furthermore, diseases with an increased number of lymphocytes in BALF can be further differentiated into those with an elevated, normal, or decreased CD4:CD8 ratio. However, neither the number of lymphocytes nor the CD4:CD8 ratio in BALF are specific features of any lung disease [8–10, 32–34]. In a fresh wet mount BALF cell preparation, viewed under phase contrast

62


microscopy, from a patient with active sarcoidosis, the appearance of lymphocytes stuck to the surface of AMs – rosettes – is striking [2]. The cells adhere and do not fall off and are not phagocytosed by the AM. In some cases, the alveolitis remains subclinical, whereas others present with pulmonary symptoms [35, 36]. This alveolitis reflects a local expression of a disseminated immunological reaction. Also, in case of extrathoracic manifestations such as ocular sarcoidosis and erythema nodosum features of an alveolitis suspected of sarcoidosis can be found, and, therefore, BALF analysis may be of additional diagnostic value. However, other DILD, such as Wegener’s granulomatosis, as well as extra thoracic granulomatous diseases, such as Crohn’s disease and primary biliary cirrhosis may demonstrate a (subclinical) lymphocyte alveolitis similar to sarcoidosis [37, 38]. There is no single cell type present in BALF that appeared to be predictive for sarcoidosis or EAA. A grouping of features, an elevated total cell count, predominantly lymphocytes, together with a nearly normal percentage of eosinophils and PMNs and the absence of plasma cells,

distinguish the most likely diagnosis sarcoidosis from EAA [20, 39]. In sarcoidosis the majority of cases have an increase of the number of lymphocytes and a normal amount of eosinophils and neutrophils [14]. Only in severe cases the number of neutrophils can be increased as well [11]. In contrast, in BALF obtained from EAA patients not only the number of lymphocytes but also the number of eosinophils and neutrophils are increased substantially [14]. Moreover, the clinical manifestation of EAA shows considerable variation as it is related to the frequency and intensity of exposure to the causative agent. The cellular profile in BALF obtained from EAA patients was found to be related to the time elapsed between termination of antigen exposure and the actual performance of BAL. The different phases of the immune responses involved in EAA are reflected in a varying composition of BALF samples [39]. So, no model BALF cell profile exists in EAA. In the cellular variant of nonspecific interstitial pneumonia (NSIP) a lymphocytosis has been observed [40]. However, an increase in lymphocytes is quite rare in IPF, and other diseases should then thoroughly be excluded [5, 31, 41]. Plasma Cells Normally, plasma cells – recognized by an eccentric nucleus – are absent in BALF. The presence of plasma cells together with ‘foamy macrophages’ and an increase of the number of lymphocytes in BALF is very suggestive of the diagnosis EAA or drug-induced hypersensitivity pneumonitis [39]. Moreover, patients with plasma cells in BALF showed signs of a more active alveolitis and a positive relation between the number of plasma cells and immunoglobulin levels in BALF. Other diseases that are associated with the presence of plasma cells in BALF include bronchiolitis obliterans with organizing pneumonia (BOOP), cryptogenic organizing pneumonia (COP), chronic eosinophilic pneumonia (CEP), Legionella pneumonia, Pneumocystis carinii pneumonia [42], and malignant non-Hodgkin’s lymphoma [39]. Polymorphonuclear Neutrophils The PMN has a characteristic segmented, multilobe nucleus, which contains densely clumped chromatin and no nucleoli, the cytoplasm contains fine granules. Elevation of the BALF PMNs count may occur in several clinical conditions, such as IPF, asbestosis, ARDS, Wegener’s granulomatosis, and predominantly in pulmonary infections [5, 13, 14, 40]. To date, the lavage profile alone is nonspecific in IPF [13, 40]. An increase in the number of PMNs in 70–90% of the cases, together with a mild increase in the number of eosinophils, and, sometimes an increase in lymphocytes


was reported [5, 41]. However, the cellular BALF profile appeared to be quite different from the BALF profile assessed from patients suffering from disorders with similar clinical presentation, e.g. sarcoidosis or EAA [14]. Previously, it was demonstrated that the cellular profile of BALF samples of bacterial infectious etiology appeared to be significantly different from samples of noninfectious etiology [29, 41]. Notably, just one variable, e.g. the percentage of PMNs (cut-off value for the percentage PMNs in BALF 65%), could distinguish between bacterial infections and noninfectious disorders [43]. Moreover, the extent of the increase of PMNs in BALF appeared to be associated with severity and prognosis of several disorders [8, 11, 44]. Eosinophils Eosinophils show bilobed nuclei rather than the more complexly lobulated nuclei of PMNs. The most distinctive feature of eosinophils is the presence of cytoplasmatic granules. A predominant eosinophilia is indicative of an eosinophilic pneumonia, the Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis, or a drug-induced eosinophilic lung reaction [45, 46]. In addition, using monoclonal antibody techniques, pulmonary histiocytosis X can be identified by HRCT together with appropriate BALF analysis (CD1⫹ Langerhans cells ⬎4% in 50% of patients) [2]. The diagnosis of lung eosinophilia can usually be made quickly and safely with BALF analysis (BALF differential with ⱖ25% eosinophils). Because it may be mistaken for other diseases, especially severe community-acquired pneumonia, the diagnosis may be missed or delayed [45, 46]. An increased number of eosinophils can be seen in a variety of interstitial lung diseases, including EAA, IPF, collagen vascular disease associated pulmonary fibrosis and P. carinii pneumonia [14, 40, 47]. However, these conditions rarely include more than 10% eosinophils. Patients with a higher percentage of eosinophils most likely have an eosinophilic lung disease. Mast Cells Mast cells or basophils possess a single eccentrically located nucleus and membrane-bound (histamine-containing) cytoplasmatic granules. It has been suggested that lung mast cells play a role in the pathogenesis of lung inflammation, the stimulation of collagen deposition and fibrosis [48]. Release of mediators by mast cells may increase lung capillary permeability and allow increased access of inflammatory cells into the interstitium. These relatively large cells are found to be increased in BALF obtained

63

from patients with EAA, especially in those cases suffering from the acute form [49]. Furthermore, increases in BALF mast cells have been reported in tuberculosis, malignant lymphomas and IPF as well as asthma, and, although to a much lesser extent, in sarcoidosis. Moreover, the presence and raised levels of mediators released by mast cells was suggested to be indicative of more advanced or progressive disease. Culture and Special Stains Lavage has probably achieved the most potential practical value in identifying infections including P. carinii, fungi and mycobacteria, especially in immunocompromized hosts and in distinguishing them from alveolar hemorrhage and drug-induced pneumonitis [29, 47]. Diffuse alveolar hemorrhage (DAH) or the alveolar hemorrhage syndromes, are associated with disorders such as Goodpasture’s syndrome, Wegener’s granulomatosis and other vasculitides, idiopathic pulmonary hemosiderosis, collagen vascular diseases, congestive heart failure and drug reactions. As many syndromes may cause DAH other clinical and laboratory features are required to establish the cause of the bleeding. The occurrence of DAH can be established by BAL, even if the bleeding is occult by identifying numerous hemosiderin-laden macrophages [37, 48]. The color of the BALF specimen obtained from these patients might change from light red (first fraction) to full red (last fraction). In contrast, in case of a proximal bleeding from the bronchi, the first fraction is dark red and the last one less intensive red. In general, the differential cell count in BALF is not abnormal. However, many inclusion bodies representing fragmented red blood cells can be found in the AMs.

Disease-Specific Features in Bronchoalveolar Lavage Fluid

In a number of diseases such as alveolar proteinosis, pulmonary Langerhans cell histiocytosis, EAA and druginduced pneumonitis, eosinophilic pneumonia, pulmonary hemosiderosis, occupationally induced diseases, and infections which can mimic diffuse lung disease, lavage can be diagnostic [1–7]. Lavage has probably achieved the most potential practical value in identifying infections including opportunistic infections such as P. carinii, cytomegalovirus, fungal infections and M. tuberculosis, and, differentiating them from alveolar hemorrhage, pulmonary involvement by an underlying malignancy, and drug-induced pneumonitis [19].

64


For some DILDs, abnormal BALF findings alone do not mean disease. Dairy farmers in Quebec with pulmonary symptoms, an abnormal chest roentgenogram, and a lavage showing increased lymphocytes are felt to have hypersensitivity pneumonitis [35, 36]. However, an asymptomatic farmer may have the same BALF findings, indicating focal lung sensitization [36]. These asymptomatic farmers do not necessarily progress to symptomatic disease, even after six years of follow-up [36]. The clinician therefore has to recognize that BALF findings are of limited prognostic value in this situation. In line with this, patients treated with amiodarone without pulmonary damage might have signs of a subclinical alveolitis demonstrated by the presence of ‘foamy alveolar macrophages’ and a high amount of lymphocytes and sometimes plasma cells in their BALF. However, the early diagnosis of lung toxicity due to a certain drug such as amiodarone is crucial and mandates the immediate cessation of therapy with the drug and sometimes treatment with corticosteroids [50, 51]. An early diagnosis of such pneumonitis is of interest because early drug cessation obviates installation of irreversible fibrosis. Moreover, it is important to consider each drug to be a potent agent, as not every drug is recognized to be liable to induce sudden and severe respiratory disorders [51, 52]. The lavage profile alone is nonspecific in idiopathic interstitial pneumonias (IIP). However, the cellular BALF profile in IPF appears to be quite different from the profile assessed from patients suffering from disorders with similar clinical presentation, e.g. sarcoidosis or EAA. Moreover, signs of diffuse alveolar damage (DAD) and the presence of reactive type II pneumocytes indicative more or less acute damage and acute interstitial pneumonia (AIP) can present in BALF [53, 54]. Distinguishing IPF from NSIP using the pattern of inflammatory cells in BALF is far more difficult. Patients with NSIP have a relative hypercellularity. A BALF lymphocytosis with a predominance of a suppressor subset of T lymphocytes in BALF is more suggestive of NSIP, cellular variant than IPF [40]. In BALF obtained from a group of patients with the clinical features of IPF, lymphocytes were no more frequent than in IPF. The clinical value of BALF analysis to stage or monitor DILDs is of limited value. Increases in the number of PMNs and/or eosinophils have been associated with a worse prognosis, whereas a lymphocytosis in general has been noted to be associated with a better outcome and a greater responsiveness to corticosteroids. Given the value of BAL in diagnosing some specific diseases, bronchoscopy with lavage has often been

Clinical and radiographic evidence of acute diffuse infiltrative lung disease (Illness ⱕ4 weeks duration, dyspnea, hypoxemia, radiographic infiltrates, ⫾fever)

⫾ High-resolution CT scan*

Diffuse bilateral airspace opacity

Bronchoalveolar lavage**

Eosinophils ⱖ25%

Bloody lavage (persists or increases on sequential aliquots) siderophages ⬎20%

Diffuse alveolar hemorrhage

Eosinophilic pneumonia

Other findings

Specific diagnosis

Nondiagnostic

Fig. 1. Approach to a patient who presents with diffuse interstitial lung disease with less than 4 weeks of symptoms. The HRCT scan (*) may

not be necessary but may be useful to identify the bronchoalveolar lavage (BAL) target area. In patients who can tolerate bronchoscopy, BAL (**; exclusion of infection mandated) should be performed.

Clinical evidence of diffuse infiltrative lung disease (DILD): physical examination, chest radiograph, pulmonary function testing

High-resolution CT scan

Extensive honeycomb change throughout lung End-stage lung

HRCT pattern typical for specific ILD

Atypical HRCT pattern

End-stage lung UIP

Non-UIP IIP

Non-IIP ILD*

Supportive care and lung transplant as appropriate Bronchoalveolar lavage

Inconsistent BALF findings and/or cell profile

Consistent BALF findings and cell profile

Reevaluate and consider alternative diagnosis

Bronchoalveolar lavage

Specific diagnosis

Nondiagnostic

Surgical lung biopsy

Fig. 2. Evaluation of a patient with chronic interstitial lung disease. In a patient with severe, advanced disease and extensive honeycombing, diagnostic procedures may be deemed too risky to perform. In other situations, the HRCT scan may be considered classic for a specific interstitial lung disease, such as idiopathic pulmonary fibrosis. Further evaluation, including bronchoalveolar lavage may be done to support the diagnosis and to rule out other processes. *Includes sarcoidosis, extrinsic allergic alveolitis (EAA), Langerhans’ cell Histocytoisis (LCH), eosinophilic pneumonia, etc. BALF ⫽ Bronchoalveolar lavage fluid; IIP ⫽ idiopathic interstitial pneumonia; UIP ⫽ usual interstitial pneumonia.


65

recommended as part of the routine evaluation of interstitial lung disease [6]. The role of lavage in the evaluation of interstitial lung disease has recently been summarized by a task force report [44]. The evaluation is based on whether the presentation is acute or chronic. While in some cases, the duration of symptoms may not be clear, many patients with interstitial lung disease have had gradually progressive symptoms over weeks or months. In patients with acute symptoms, one has to consider infection, pulmonary

hemorrhage, and other conditions. This evaluation is summarized in figure 1. For the usual patient with DILD, symptoms have been chronic. Figure 2 summarizes the proposed evaluation. There are several practical features included in this figure. For the patient with end-stage lung disease, invasive procedures may be of more risk than of potential benefit. In that case, further diagnostic procedures including bronchoscopy may not be performed [55, 56].

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Lavage in Evaluation of Interstial Lung Disease (in preparation). Allen JN, Davis WB: Eosinophilic lung diseases. Am J Respir Crit Care Med 1994;150: 1423–1438. Newman Taylor A: Pulmonary eosinophilia: the eosinophilic pneumonias; in Olivieri D, du Bois RM (eds): Interstitial Lung Diseases. Sheffield, European Respiratory Monograph, 2000, chap 213, pp 206–225. Jacobs JA, Dieleman MM, Cornelissen EI, et al: Bronchoalveolar lavage fluid cytology in patients with Pneumocystis carinii pneumonia. Acta Cytol 2001;45:317–326. Cordier JF: Pulmonary vasculitis. Rev Med Interne 2002;23(suppl 5):547s–548s. Pesci A, Bertorelli G, Gabrielli M, et al: Mast cells in fibrotic lung disorders. Chest 1993; 103:989–996. Costabel U, Uzaslan E, Guzman J: Bronchoalveolar lavage in drug-induced lung disease. Clin Chest Med 2004;25:25–35. Camus P, Foucher P, Bonniaud P, et al: Druginduced infiltrative lung disease. Eur Respir J 2001;18:93s–100s. Israel Biet D, Labrune S, Huchon GJ: Druginduced lung disease: 1990 review. Eur Respir J 1991;4:465–478. Linssen KC, Jacobs JA, Poletti VE, et al: Reactive type II pneumocytes in bronchoalveolar lavage fluid. Acta Cytol 2004;48: 497–504.

54 Bonaccorsi A, Cancellieri A, Chilosi M, et al: Acute interstitial pneumonia: report of a series. Eur Respir J 2003;21:187–191. 55 Hunninghake GW, Zimmerman MB, Schwartz DA, et al: Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001;164: 193–196. 56 Lynch DA, David Godwin J, Safrin S, et al: High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med 2005;172: 488–493.

Marjolein Drent, MD, PhD Professor of interstitial lung diseases Head of the sarcoidosis management team and ild care team Department of Respiratory Medicine University Hospital Maastricht PO Box 5800 NL-6202 AZ Maastricht (The Netherlands) Tel. ⫹31 43 387 7043, Fax ⫹31 43 387 5051 ⫹31 43 387 5051 E-Mail [email protected] www.pul.unimaas.nl

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Basic Aspects


Genetics of Interstitial Lung Disease Roland M. du Bois Interstitial Lung Disease Unit and Clinical Genomics Group, Royal Brompton Hospital, London, UK

Abstract The approach to demonstrating genetic factors that predispose to interstitial lung disease (ILD) is in an early phase. A number of key findings have, however, already emerged. These include the observation that disease pattern does not always remain consistent in different affected members of families with familial pulmonary fibrosis; that children have different manifestations of ILD from adults and may have different genetic predisposition; and that defining subsets or specific clinical phenotype enhances the significance of case/control genetic association studies as seen in sarcoidosis and systemic sclerosis. The failure to define clinical phenotype in studies of fibrosing lung disease has likely contributed to why we understand relatively little of the genetic determinants to date. With these caveats, the most promising studies in fibrosing lung disease are the co-operative familial study in the USA and the increasingly numerous reports on alleles of the surfactant protein C gene. In systemic sclerosis, strong associations are being identified with autoantibody status, particularly with the MHC/TNF extended haplotype and in sarcoidosis, robust associations are being found with specific disease subsets, most notable Löfgren’s syndrome, and chronic lung disease and MHC/TNF haplotypes but also chemokine receptor genes. Copyright © 2007 S. Karger AG, Basel

Four prerequisites are needed for genetic studies in interstitial lung disease (ILD) where cohorts often comprise small numbers: (1) precise clinical phenotype;

(2) index (indices) of disease severity; (3) family ⫾ case control studies; (4) obsessively accurate databases. It is erroneous to believe that huge patient numbers are required for case/control studies but confidence intervals usually narrow with greater numbers and p values become more significant. Even with the small numbers that are generally available in ILD, significance can still be found as long as higher odds ratios are sought. Four main groupings of ILD can be defined: granulomatous; associated with environmental exposures (such as inhaled inorganic dusts or ingested drugs) or systemic diseases (particularly rheumatological disease); the idiopathic interstitial pneumonias (IIPs); and a mixed collection of rare diseases with no common factor except the rarity (such as Langerhans cell histiocytosis) [1]. Many of these ILDs can result in ‘pulmonary fibrosis’. One of these groups, the IIPs, and more specifically idiopathic pulmonary fibrosis (IPF), was historically (and even now occasionally) considered as a single entity termed ‘pulmonary fibrosis’, and inappropriate attempts were made to derive meaningful correlations of treatment response and outcome in this population. This is inappropriate and the term ‘lung/pulmonary fibrosis’ should not be used as a diagnostic label. Recent refinement in the classification of the IIPs has provided an important first step in attempting to categorise them [1]. Despite this, heterogeneity is still apparent especially in non-specific interstitial pneumonia (NSIP) and this will need to be addressed in the future. Fibrosing interstitial lung diseases are ‘complex diseases’; they are the product of susceptibility factors from multiple genetic loci, each

exerting variable, relatively small effects, and environmental triggers. This review will focus on the familial and idiopathic forms of IIP together with the diffuse lung disease of systemic sclerosis and subsets of sarcoidosis as examples of how such disease subsets, when well-defined, can be used to explore genetic influence. It will also outline childhood ILD disease associations; phenotypes are often quite different from those found in adults but despite this genetic studies in children have highlighted potential candidates that would be logical to explore in adults.

Genetic Approaches

Individual ILD are rare and susceptibility does not follow single-gene inheritance patterns. Two approaches can be taken to investigating genetic predisposition. The first is the study of families in which linkage of a genetic marker or markers to disease trait is tracked and susceptibility gene(s) are identified by positional cloning. The second is an approach that tests association of genetic polymorphism in a gene or genes that are plausible candidates from a pathogenesis standpoint, in specific diseases and compares allele or genotype frequency with an ethnically matched control population. These two approaches can be used in tandem: familial studies can generate hypotheses that, inevitably larger, case control studies can test. However, it must not be presumed that familial and sporadic disease is necessarily the same; clinical features especially age at presentation and disease course can be different. Families with defined diffuse lung disease are rare and thus the majority of studies reported to date are case control association studies using single nucleotide polymorphism (SNP) analysis. There will likely be a number of genes that enhance susceptibility to disease and also polymorphisms at one or more genetic loci that will affect severity and progression of disease once it has manifest. In this regard, it is possible that this is due to combinations of genes, not all on the same chromosome that may be ‘linked’ to provide a complex genotype. Finally (and ideally from the purest viewpoint), specific genetic polymorphisms will be identified that affect function of the gene product in a way that modulates biological outcome.

Familial Lung Fibrosis

Children Familial IIP occurring in infants is well documented [2–4]. In one study, an apparently novel diffuse lung

Genetics of ILD

disease, pulmonary interstitial glycogenosis is reported that was likely a more detailed description of the entity previously known as infantile cellular interstitial pneumonitis [4]. The disorder was characterised by the presence of glycogen within the cytoplasm of immature interstitial cells. In the same issue of the American Journal of Respiratory and Critical Care Medicine, Fan and Langston [5] pointed out that paediatric disease should not be made to ‘fit’ the patterns seen in adults. Importantly usual interstitial pneumonia does not seem to exist in children and this suggests that we treat with caution descriptions of ‘familial IPF’ in which children are included in the cohorts. Surfactant Surfactant protein abnormalities exist in the lungs of adults with IPF [6–8] but it is studies of children that have highlighted a genetic basis to variations in surfactant proteins and diffuse lung disease. Major interest has focussed on the surfactant protein C gene over recent years. Surfactant Protein C Nogee et al. [9] reported an association between a mutation in the SP-C gene and ILD in a mother and baby. The baby, born to a woman with a history of desquamative interstitial pneumonia, which was diagnosed when she was 1 year old, was normal at birth but developed respiratory symptoms at age 6 weeks. Lung biopsy revealed non-specific interstitial pneumonia. The infant improved with oxygen and corticosteroid therapy. A mutation was found in one allele of the surfactant protein C gene in both mother and child. The substitution of A for G was located in the first base of intron 4 abolishing the normal donor splice site, resulting in the skipping of exon 4 and the deletion of 37 amino acids in the SP-C precursor protein. Such changes in protein structure can result in abnormal tertiary folding and protein transport. Mature surfactant protein C was completely absent from the BAL and lung tissue. The complete absence of protein with the mutation of a single allele is possibly due to a dominant negative effect in which the mutant allele produces an aberrant protein that precludes the normal processing and secretion of the normal allele product. Subsequent studies of an infant with a deletion in exon 3 of SP-C confirmed that abnormal SP-C accumulation in the cytoplasm of epithelial cells is associated with a progressive ILD and provides further support for the concept of a dominant negative effect [10]. A study of the SP-C gene in 34 infants with non-familial chronic lung disease of unknown origin identified mutations of the SP-C gene in 11 infants that resulted in a phenotype similar to the index patient [11]. This suggests

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further that SP-C is necessary for normal functioning of the lung in the postnatal period. Adults Familial Disease The true prevalence of familial pulmonary fibrosis is unknown but in the most thorough study to date, Hodgson et al. [12] evaluated hospital databases from all 29 Finnish respiratory clinics during 1997–1998 to identify individuals with idiopathic pulmonary fibrosis. A pulmonary specialist, using the ATS/ERS guidelines to define IPF, reviewed a sample of these. 1,212 living patients with IPF were contacted and asked about a family history and 675 replies received from which 88 familial pedigrees were identified. Disease prevalence was calculated to be 16–18/100,000 and to be 5.9/106 for familial IPF based on data from 17 multiplex families with 2–5 affected members. These studies will hopefully provide the platform for genetic evaluation of predisposition but as yet, no detailed genetic studies of adult familial IPF have been reported. In a more recent study, Steele et al. [13] report the results of a nationwide collaborative approach in the USA. Families with at least two affected members were recruited through a network of collaborators. 111 families with familial interstitial pneumonia (FIP) having 309 affected and 360 unaffected individuals were identified. Key findings from this study included: 45% of pedigrees were phenotypically heterogeneous; the commonest disease was, nonetheless, IPF; 20 pedigrees had a vertical transmission consistent with their disease being autosomal-dominant with incomplete penetrance; and smoking appeared to increase the risk of familial pulmonary fibrosis although the incomplete data from all unaffected family members casts a degree of uncertainty about this finding due to possible ascertainment bias. The numbers of affected individuals varied considerably in each pedigree.

Genetic Studies of Familial Disease A study of surfactant protein C polymorphisms in 14 individuals in a family kindred spanning 6 generations identified the transmission of a single SNP in all affected family members; an exon 5 ⫹ 128 T → A transversion that results in a glutamine for leucine substitution at amino acid position 188 in the proSP-C region was responsible [14]. Again, phenotypic heterogeneity was observed in the affected members of the pedigree; 6 had IPF and 3 NSIP (all 3 were children). The authors further demonstrated that the mutation affected processing of the protein, resulting in

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abnormal and disorganised cytoplasmic accumulation, cell injury and death. Do the findings of Steele et al. [13] and Thomas et al. [14] mean that there is likely a fibrosis gene that predisposes an individual to develop scarred lungs and that other factors determine which disease will result? Possibly, but the intense complexity of gene/environment interactions that may provoke the same outcome have yet to be elucidated and it would be a mistake to abandon precise phenotyping of patients with fibrosing lung disease on this evidence alone; better perhaps to analyse data grouped as interstitial pneumonias (‘lumping’) and also as individual diseases (‘splitting’). Hermansky-Pudlak Syndrome This is a clinical syndrome characterised by oculocutaneous albinism, a platelet defect and internal organ involvement primarily affecting the lungs, causing fibrosis, and bowel disease. The major histopathological feature is the accumulation of ceroid (a chromolipid, related to lipofuscin). It is inherited in an autosomal-recessive pattern. Lung fibrosis is associated in affected individuals, mainly from Puerto Rico. Four disease phenotypes are presently recognised, i.e. HPS type 1 (HPS-1), type 2 (HPS-2), type 3 (HPS-3), and type 4 (HPS-4), of which HPS-1 and HPS-4 are associated with severe pulmonary fibrosis. The HPS phenotypes result from mutations in seven genes: HPS1, AP3B1/HPS2, HPS3, HPS4 HPS, HPS6, and HPS7/Dysbindin [15]. To date, only AP3B1 produces a product with a known function. This gene codes for the ␤3A subunit of the AP-3 coat protein, a heterotetrameric complex that mediates vesicle formation [16, 17].

Non-Familial (Sporadic) ILD

Most studies of the genetics of ILDs have used the case/control candidate gene approach. Either relatively large numbers are needed or a two-set approach (raising hypotheses with a first set of patients and confirming with a second set) must be used to obtain meaningful results and significance is more plausible if high odds ratios are found. Findings that can be reproduced in a geographically distinct cohort provide strong support and polymorphisms that have relevant functional changes are even more supportive. Most studies have addressed ‘IPF’ but many were done before the new classification of the idiopathic interstitial pneumonias was published and almost certainly included patients with a range of IIPs.

Microsatellite Instability and DNA Repair A number of studies have explored somatic DNA injury. One such study from Crete investigated DNA sputum cells from 26 IPF patients and compared them with cells from 26 normal individuals using 10 microsatellite markers to identify variations in microsatellite length (microsatellite instability) or the loss of microsatellite heterozygosity [18]. Thirteen patients had either microsatellite instability or loss of heterozygosity by comparison with no abnormalities in controls. Mori et al. [19] studied microsatellite instability in the TGF-␤ receptor type II gene, the TGF axis being known to play a pivotal role in wound repair in IPF. DNA analysis of alveolar lining epithelial cells from 11 patients with IPF was performed. A single base pair deletion in exon 3 was found in multiple epithelial cell sites from 5 patients and this was associated with a decrease in the expression of the mature protein. Other evidence for DNA damage comes from genetic studies of the tumour suppressor factor p53, a transcriptional factor that plays a role in the DNA damage response, including the induction of the p21 tumour suppressor 20. DNA strand breaks were associated with p53 and p21 immunohistochemistry in alveolar and bronchial epithelial cells from 10 of 14 biopsies from patients with IPF by comparison with controls where p53 and p21 were present in scant amounts. The authors concluded that these findings might predispose to abnormalities possibly leading to tumorigenesis in these cells. Support for the concept that mutations in p53 may be important in IPF comes from studies reported by Hojo et al. [21]. In ten tissue samples evidence for point mutations scattered throughout the p53 gene in bronchoepithelial cells were identified and A:T and G:C transitions were also observed in the samples of 9 patients. The interpretation of these findings is not unequivocally clear. The evidence would support somatic rather than germ line mutations and are likely the result of injury. Whether the consequences of the change in cell phenotype that results from these changes in DNA is central to disease evolution or is simply another measure of injury, remains to be determined. Surfactant Proteins Selman and colleagues evaluated gene polymorphisms in SP-A1, SP-A2, SP-B, SP-C and SP-D genes [22]. Stratification of the study cohort based on their smoking habit demonstrated associations for the 6A4 haplotype of SFTPA1 with non-smoking IPF patients and for the 1580C allele of SFTPB with smoking IPF patients. More recently,

Genetics of ILD

Lawson et al. [23] reported SFTPC sequence results in 89 patients with sporadic IPF and found evidence for the role of genetic mutations in 1% of cases. These findings may be in line with results of Amin et al. [24] who demonstrated preserved SP-C expression in bronchoalveolar lavage fluid and lung biopsy specimens from 19 unrelated IPF patients. In a more recent study from Japan [25], two missense mutations were identified in the SP-C gene in exon 4 and exon 5 from 11 cases with familial interstitial pneumonia. The exon 5 mutation was also seen in patients with sporadic interstitial pneumonia. Cytokine Genes IL-1 Gene Cluster IL-1 has been shown to be prominently expressed in IPF. The genes encoding IL-1␣ and IL-1␤, and their naturally occurring inhibitor IL-1 receptor antagonist (IL-1RN) are localised in a cluster on chromosome 2q14. Whyte et al. [26] have demonstrated an association between IL-1RN and IPF; the rarer allele of the ⫹2018C ⬎ T polymorphism conferred increased risk for IPF in subjects from England and Italy but an IL-1RN association with susceptibility for IPF could not be confirmed by others [27]. These latter investigators studied polymorphisms in the IL-1␣, IL-1␤, and IL-1RN genes in IPF [27]: the IL-1␣ ⫺889, IL-1␤ ⫺511, IL-1␤ ⫹3,953, and IL-1RN intron 2 VNTR polymorphisms in 54 West Slavonic patients with IPF, and 199 healthy control subjects. By contrast with the Whyte study, no IL-1RN associations were found with IPF and similarly, no associations were observed in either IL-1 gene. However, an association between the ⫺889T allele in IL-1A and severity of gas transfer deficits in patients with IPF has been reported [28]. Tumour Necrosis Factor (TNF) and Related Genes TNF has been shown in many studies to be an early cytokine in IPF. In one study, carriage of the TNF ⫺308A allele was associated with increased risk of IPF in both a United Kingdom (OR 1.85) and an Italian (OR 2.50) cohort [26]. This association was confirmed in 22 Australian IPF patients but not by Pantelidis et al. [29, 30] in United Kingdom patients. In addition, no association was found for multiple other polymorphisms in the TNF gene, and polymorphisms in the genes encoding TNF-receptor II and lymphotoxin (LT)-␣ in the same cohort of United Kingdom patients. Interestingly, the G allele of the IL-6 intron 4 A ⬎ G polymorphism was associated with lower DLco levels, and co-carriage of the TNF-RII 1690C allele and the IL-6 intron 4G allele was associated with the presence of even more severe disease, defined by DLco, suggesting a combinatory effect of these two genes in IPF progression [30].

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There is evidence that IL-10 gene haplotypes and promoter polymorphisms are associated with differential IL-10 production and that approximately 75% of interindividual variation in IL-10 production appears to be genetic [31, 32]. Whittington and colleagues have screened the coding sequence and 3⬘ untranslated region of IL-10 for polymorphisms in 96 patients with IPF. Although they identified a novel polymorphism at nucleotide position ⫹43 from the start (G⬎A) causing an amino acid change and resulting in lower levels of IL-10 protein secretion, no difference in allele frequency between patients and controls was observed [33]. Chemokine Genes IL-8 has been found increased in the lungs of patients with IPF, and several studies have shown a correlation between the levels of IL-8 in BAL fluid or the expression of alveolar macrophages mRNA IL-8 and BAL neutrophil content in this disease. Only one study has investigated single-nucleotide polymorphisms in the genes encoding IL-8 and its receptor but no association was found [34].

on erythrocytes it has been speculated that putative immune complex bound microbial triggers might persist and cause recurrent lung injury. This genotype result could not however be reproduced in other cohorts [38]. The same negative conclusion was drawn in Finland; in a study of 96 patients with IPF and 164 geographically matched controls, Hodgson et al. [39] showed that all patients and controls were CR1 C5507 homozygous suggesting that either the Finns do not carry the G5507 polymorphism or it is extremely rare. Coagulation Cascade The concentrations of tissue factor, plasminogen activator inhibitor (PAI)-1 and PAI-2 are significantly elevated in bronchoalveolar lavage obtained from IPF patients, which is an index of a likely hypercoagulable state in IPF lungs. Kim and colleagues have evaluated a polymorphism in the PAI-1 gene but did not find an association with idiopathic interstitial pneumonia [40].

Genes Involved in Th1/Th2 Response Functional polymorphisms in genes encoding cytokines influencing Th1/Th2 balance, and especially IFN-␥ and its receptors have been studied in IPF. IL-12 plays a key role in inducing IFN-␥ production and a single nucleotide polymorphism in the 3⬘ untranslated region (UTR) of the IL12 p40 gene at position 1,188 has been shown to correlate with increased IL-12 secretion [35]. Latsi et al. [36] found no association of this polymorphism with susceptibility to IPF. Similarly, they found equal distribution of a potentially functional polymorphism in the IFN-␥ gene (position 5,644 in the 3⬘ UTR) in IPF and control subjects. However, absence of an association with just a single nucleotide polymorphism does not exclude a role for this gene in the genetic susceptibility of IPF.

Fibroblast Related Pathways TGF-␤ Serum TGF-␤1 concentrations appear to be under some genetic control [41]. As TGF-␤1 is implicated in IPF, Xaubet et al. [42] have assessed polymorphisms in TGF-␤1 in a Spanish cohort of Catalans. They studied two exon 1 polymorphisms, at position ⫹869 (T ⬎ C) and ⫹915 (G ⬎ C), both of which result in amino acid substitutions. No association was found with susceptibility to IPF. A greater rate of lung decline as measured by gas exchange was, however, associated with the ⫹869C allele (⬃codon 10 proline). Although this allele was not associated with other functional indices of IPF severity, and the levels of TGF-␤ in both cases and control subjects were not determined, the study provides the first evidence for the TGF-␤1 gene as a potential determinant of disease progression in IPF.

Complement Receptor Genes Complement receptor 1 (CR1, CD35, C3b/C4b receptor) is important in the clearance of immune complexes. The C ⬎ G polymorphism at nucleotide position ⫹5507 in exon 33 has been correlated with the levels of CR1 expressed on erythrocytes that may directly affect the clearance of immune complexes. Zorzetto et al. [37] studied the ⫹5507 SNP and two other polymorphic sites of the CR1 gene using an Italian IPF cohort. They demonstrated a significant association between the GG genotype of the C5507G polymorphism and IPF. As this GG genotype is thought to be resulting in low expression of CR1 molecules

Conclusion The data for genetic associations with sporadic IIPs are disappointing (for overview see table 1). Specifically, most reported associations cannot be substantiated by subsequent studies. This is probably due to a combination of poor phenotyping, low patient numbers, poor control matching and choice of candidate. It is hoped that ongoing positional cloning studies from the USA will provide other candidates for future work. In the meantime, larger numbers of welldefined phenotypes, ideally including cohorts from distinct ethnic backgrounds, need to be evaluated through international networking.

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Table 1. Genes and gene polymorphisms in IPF

Gene group

Gene

Association with disease

Population (number of cases/controls)

Surfactant proteins Surfactant protein

SP-A1

Mexican (84/194)

[22]

Mexican (84/194) Mexican (84/194)

[22]

SP-C SP-D SP-C

6A4 in nonsmoking subjects only no 1580C in smoking subjects only no no no

Mexican (84/194) Mexican (84/194) United Kingdom (135/104)

[22] [22] [23]

Coagulation Plasminogen activator inhibitor

PAI-1

no

United States White (62/2,120)

Fibrogenesis Transforming growth factor-␤

TGF-␤1

no

Spanish Catalan (128/140)

association between ⫹869C and deterioration of gas exchange

[42]

IL-1A

no

Czech Republic (54/199)

association between ⫺889T and lower DLCO levels [29]

[27]

IL-1B IL-1RN

no ⫹2018T

Czech Republic (54/199) United Kingdom White (88/88); Italian (61/103) Czech Republic (54/199); Australia White (22/140)

[27] [26]

United Kingdom White-1 (88/88); Italian (61/103); Australia White (22/140) United Kingdom White (74/192) United Kingdom White (74/192) United Kingdom White (74/201) United Kingdom White (74/201); Australia White (22/140)

[26, 29]

SP-A2 SP-B

Cytokines IL-1 cluster

no TNF superfamily

TNF

⫺308A

TNFR2 LTA IL-6

no no no no

Other

10 SNPs found; all different only in IPF; 0/46 NSIP

References

[40]

[27, 29]

association between IL-6 intron 4GG genotype and lower DLCO levels

[30] [30] [30] [29, 30]

IL-10

no

United Kingdom White (96/96)

[33]

Chemokines/receptors

IL-8 CXCR-1 CXCR-2

no no no

United Kingdom White (71/194) United Kingdom White (71/194) United Kingdom White (71/194)

[34] [34] [34]

Immune genes

IL-12p40 no IFN-␥ no

United Kingdom White (73/157) United Kingdom White (73/157)

[36] [36]

Complement receptor

CR1

Italian (74/166) Finnish (96/164)

[37] [39]

⫹5507G no

Genetics of ILD

75

Systemic Sclerosis

A number of rheumatological diseases have genetic predisposing factors, including systemic sclerosis (table 2). Despite pulmonary fibrosis being one of the defining criteria of systemic sclerosis, the internal manifestations of disease, including the extent of the pulmonary abnormality are widely variable. The histopathological pattern of lung disease in systemic sclerosis is most commonly NSIP [43]. Major Histocompatibility Complex (MHC) Systemic sclerosis is an immune based disease. Early phases of pathogenesis are thought to involve a T cell mediated response to an antigenic trigger, possibly epitopes of the DNA topoisomerase I enzyme that results in the production of the autoantibody anti-topoisomerase (Scl 70). Many studies have therefore focussed on the MHC to identify genetic predisposition factors and variable results have emerged. Arguably the strongest associations have been those with autoantibody status and this is of particular interest because the pattern of extractable nuclear antigen carried by an individual associates with the pattern of internal organ involvement and their presence is mutually exclusive i.e. no individual carries more than one. In this regard, studies have consistently shown that HLA-DR11 (previously included as part of HLA-DR5) and in particular the HLA-DRB1*1104 subtype is significantly increased in scleroderma patients with the anti-topoisomerase antibody (ATA) in European and North American populations. Our studies have confirmed these associations between HLA-DR11 but have also shown more strongly than previously an association between HLA-DPB1*1301 and the presence of anti-topoisomerase. This is in contrast with some previous negative studies at the HLA-DPB1 locus and is significantly stronger than previous positive studies. In the studies reported by Gilchrist et al. [44], 47 of 53 individuals with the ATA had diffuse lung disease whereas 43 of 52 patients with the anti-centromere antibody appeared to be ‘protected’ from lung fibrosis. Furthermore, the presence of the HLA-DPB1*1301 allele was highly associated with the presence of ATA. Other studies have, however, suggested that HLA-DR and HLA-DQ are important alleles in the production of this autoantibody. It is possible that there is a common amino acid motif, shared by the different class II susceptibility alleles that may be the unifying factor in these apparently discordant findings [44–46]. There appears, therefore, to be a very strong genetic influence on the production of autoantibody that in turn is a specific predictor of diffuse

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lung disease in systemic sclerosis. By contrast, the anticentromere antibody appears to be ‘protective’ of lung fibrosis but susceptible for vascular disease and is associated with a TNF haplotype [47]. Other Genetic Factors in Diffuse Lung Disease in Systemic Sclerosis Fibronectin Associations between lung fibrosis in systemic sclerosis and other genes have been few. Growth factors are attractive candidates and Avila et al. [48] reported that the coexistence of two fibronectin polymorphisms was more prevalent in individuals with lung fibrosis than those with systemic sclerosis but without fibrosis and controls. Chemokine Receptors Renzoni et al. [49] studied variations in the CXCR-2 receptor for the CXC chemokines. An increase in the frequency of the CXCR-2 ⫹785 CC homozygote and of the CXCR-2 ⫹1208 TT homozygote was found compared with controls, in the systemic sclerosis patients. However, this was not found to be specific for those with lung disease, occurring in systemic sclerosis patients both with and without diffuse lung disease. TNF-␣/LT-␣: Therapeutic Implications Because of the findings from other studies of chronic inflammation, of disease associations with complex haplotypes including TNF and lymphotoxin in the MHC region, future studies will inevitably further explore and fine map this region to define more precisely the nature of any associations that emerge from previous studies of classes I and II MHC. Any TNF-related associations might have immense practical implications now that anti-TNF strategies, using either the chimaeric mouse/human monoclonal antibody (infliximab) or the anti-TNF receptor fusion product (etanercept), have been proven to be highly effective in rheumatoid arthritis and Crohn’s disease and are being applied increasingly to other chronic inflammatory processes. This has important implications for potential intervention with specific strategies such as TNF-␣ blockade in systemic sclerosis provided it can be directed to those clinical phenotypes most affected by the effects of this early cytokine.

Sarcoidosis

Of all of the ILD, the evidence that supports the concept that sarcoidosis has strong genetic susceptibility is most

Table 2. Genes and gene polymorphisms in systemic sclerosis-associated lung fibrosis

Gene group

Gene

Association with disease

Population (number of cases/controls)

MHC HLA

DRB1 DPB1

DR11; DRB1*1104 DPB1*1301

United Kingdom (202/307); GRC (98/130) United Kingdom (202/307)

TNF

TNF

⫺857T


Non-MHC Extracellular matrix

Chemokines/receptors

Cytokines

FN1

Hae III genotype AB

United Kingdom (161/253)

SPARC

⫹1922T

FBN1

no Hap-5

United States White (94/70); African-American (33/28); Mexican-American (51/45) United Kingdom White (121/200) Japan (106/100)

IL-8 CXCR-1 CXCR-2

no no ⫹785C

United Kingdom White (128/194) United Kingdom White (128/194) United Kingdom White (128/194)

⫹1208T


⫺509T ⫹869C (OR 2.0)

Japan (87/110) Japan (87/110); United Kingdom (152/147)

no

United Kingdom (152/147)

TGF-␤1

compelling. In this T cell driven granulomatous disease, it is not surprising that the MHC region associations are most robust especially across ethnic boundaries but other gene groups have also been studied. Although most of these are negative or not reproducible, some interesting associations have been found. Furthermore, it is clear that disease subgroups carry different susceptibilities raising the notion that sarcoidosis might comprise a number of distinct diseases that may have quite individual triggers. Familial Sarcoidosis Familial clustering of disease has been reported in several populations including Germany, Northern Sweden,

Genetics of ILD

Other

References

[44] [44] ⫺857T is in LD with DR11 ⫺863A strongly associates with ACA⫹

[47] [47]

co-carriage of genotypes [48] MspI CD ⫹ HaeIII AB showed twofold increased risk of developing lung fibrosis weak association [118]

Hap-5 ⫹ 6 associated with SSc in Japan and Choctaw population

also associated with SSc without lung fibrosis also associated with SSc without lung fibrosis weak association also associated with SSc without lung fibrosis in United Kingdom patients

[119] [120]

[49] [49] [49] [49] [117] [116, 117]

[116]

Hokkaido and Furano in Japan, USA, United Kingdom and Ireland [50–55] with prevalences varying from 3.6 to 10%. In the ACCESS study (A Case-Control Etiologic Study of Sarcoidosis) of 10,862 first-degree and 17,047 second-degree relatives identified by 706 sarcoidosis case control pairs, the familial relative risk to siblings was larger than to parents (odds ratio (OR) ⫽ 5.8 versus 3.8) [56]. To date there have been only a few linkage studies in sarcoidosis. Schürmann et al. [57] reported his findings in 122 affected siblings from 55 families for seven DNA markers in the MHC region. Analysis showed linkage for the entire MHC region, with the peak score identified at a

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marker locus in the class III region (D6S1666). A follow-up genome-wide study using 225 microsatellite markers in 63 families – by the authors’ admission, very widely spaced and therefore of only modest sensitivity – with 138 affected siblings found the most prominent peak at the class II MHC loci [58]. Six other, less prominent peaks (p ⬍ 0.05) were found on chromosomes 1, 3 (close to the chemokine receptor genes CCR2 and CCR5), 7 (two peaks, one close to the T cell receptor B gene), 9 (close to the gene for TGF-␤ receptor I), and the X chromosome (close to the gene coding for the IL-2 receptor gamma chain). However, the wide spacing between the markers means that spurious positive and negative findings could have occurred. Other studies have indicated an association between the butyrophilin-like 2 (BTNL2) gene BTNL2, a member of the B7 receptor family, likely important in T cell co-stimulation, and sarcoidosis [59, 60]. In the first study, a three tier approach was taken that involved a combination of family and case control studies that identified a region of the MHC that included BTNL2. The authors concluded that the BTNL2 rs2076530A susceptibility allele was a risk factor independent of the known MHC associations despite the known strong linkage disequilibrium in the region. The finding appeared even more attractive when it seemed that this allele was associated with aberrant protein expression although other centres have not been able to confirm this. The same genetic association was also noted in the USA in an African-American familybased study population (n ⫽ 219 nuclear families) and two case-control populations – one African-American (n ⫽ 295 pairs) and one White (n ⫽ 366 pairs). The association was found to be stronger in Whites than African– Americans, again underscoring the impact of race on genetic susceptibility. Although both of these studies came to the same conclusion regarding a BTNL2 susceptibility allele neither study resolved satisfactorily the issue of whether the BTNL2 associations are entirely explicable on the basis of linkage disequilibrium with MHC. In this regard we have preliminary data from our studies on two of our cohorts from the United Kingdom and the Netherlands. We found comparable odds ratios (ORs) for the putative rs2076530A susceptibility allele to the reported studies. However, we found higher ORs on regression analysis for disease susceptibility association with HLA-DR-12 (OR 3.14) and ⫺14. Furthermore, using multivariate analysis, the rs2076530 association does not persist whereas a novel BTNL2 polymorphism haplotype (BTNL2 haplotype 4) appears to be independently associated with disease protection. These variable conclusions support strongly the need for finer mapping and more

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robust linkage disequilibrium analyses across the HLA region in this disease.

Case/Control Association Studies Major Histocompatibility Complex (MHC) HLA Class I The earliest studies explored the class I group of alleles (HLA-A, B, C) and produced variable results likely due to methodology, together with ethnic and phenotypic diversity [61–69]. Of the alleles that emerged from these reports, HLA-B8 has been most consistent across racial boundaries, but it has not been found in all studies and other reported associations are even weaker; it has been associated with disease of acute onset and short duration [67]. Many of the other reported associations are due to linkage with HLA class II molecules that fits better with the concept of HLA class II molecule presentation of antigen at the onset of disease pathogenesis. In this regard, however, a study of Scandinavian patients found that both HLA-B*07 and HLA-B*08 independently increased the risk of sarcoidosis [70]. Other class I associations were secondary to their linkages to class II alleles. The common allele combination A*03, B*07, DRB1*15 was most strongly associated with persistent disease and was found in 25.3% of such patients against 7.1% of healthy controls. The authors conclude that HLA class I alleles may have more influence on disease susceptibility and prognosis than has been previously thought.

HLA Class II HLA-DR-associated antigens have attracted most attention in recent years. Examples of ethnic differences in allele frequency include: HLA-DR5, -DR6 -DR8 and -DR9 in Japanese [71, 72]; HLA-DR5 with chronic disease and HLA-DR3 with acute disease in Germans [73, 74]; HLADR14, –DR15 with chronic disease while (-DR17 (3)) is linked with acute disease in Scandinavia [75]; HLA-DR14 with chronic disease in a study of Asian Indians [76]. Despite some variability across the globe, some transethnic patterns have been emerging especially when organ of involvement ⫾ severity have been considered. Some attempt has been made to arrive at a consensus from this sometimes confused picture. HLA-DR1 and -DR4 have been found to be protective in Scandinavians, Japanese, Italians, and in a study of United Kingdom, Polish and Czech patients [77]. This study showed position 11 of the HLA-DRB1 amino acid sequence to be the most variable, with 3 susceptibility

alleles all coding for small hydrophilic amino acids, and 2 protective alleles coding for amino acids with bulky, hydrophobic, aliphatic side chains. As the position 11 amino acid is located at a crucial interface between the HLA-DR ␣ and ␤ chains, it is possible to speculate that this position might influence antigen binding. In the first 474 patients and case-matched controls from one of the largest collaborative studies to date, the ACCESS (A Case Control Etiologic Study of Sarcoidosis) study, HLA-DPB1, HLA-DQB1, HLA-DRB1 and HLADRB3 alleles were evaluated [78]. The HLA-DRB1*1101 allele was associated with sarcoidosis in both AfricanAmericans and Whites, with a population attributable risk of 16% in African-Americans and 9% in Whites. The only class II allele differentially distributed between African-Americans and Whites with respect to disease was HLA-DRB1*1501, being associated with controls in African-Americans and with sarcoidosis in Whites. This caused the authors to speculate that broadly similar HLA class II alleles may be associated with sarcoidosis in both populations. The HLA-DP locus was also of interest due to the finding that chronic beryllium disease (a chronic multisystem granulomatous disease with many clinical and immunopathological similarities to sarcoidosis) is associated strongly with the presence of a glutamic acid residue at position 69 of the HLA-DPB1 ␤ chain. However, this association has not been found in two studies in sarcoidosis [79, 80], although the latter study in African-Americans did find an increased risk of disease associated with the Val36⫹ and Asp55⫹ alleles. Furthermore, in the ACCESS study, the HLA-DPB1 locus also contributed towards susceptibility, but with the HLA-DPB1*0101 allele conveying most of the risk [78]. In another study in African-Americans, 225 sarcoidosis patients with family members as controls were genotyped for six microsatellite markers covering the MHC region [81]. An association was observed between disease and the marker closest to HLA-DQB1; further analysis of other markers at this locus confirmed that in this AfricanAmerican cohort, it is HLA-DQB1 and not HLA-DRB1 that confers susceptibility to sarcoidosis. A follow-up study found that HLA-DQB1*0201 was transmitted to affected offspring only half as often as expected, whereas DQB1*0602 was transmitted to affected offspring about 20% more than expected, and was associated with radiographic disease progression [82]. In a study in a population of 149 Dutch Caucasian sarcoidosis patients an association was found between severe disease and the haplotype DRB1*1501/ DQB1*0601; due to the tight

Genetics of ILD

linkage disequilibrium of the alleles in the Caucasian population it is not possible to assign the primary association [83]. These DQB1 associations are consistent with a European study of the HLA-DQB1 locus in 235 Dutch and United Kingdom patients. DQB1*0201 was found to be strongly protective against severe sarcoidosis (i.e. it was associated with stage I disease) whereas the DQB1*0602 allele tended to have the opposite effect [84]. Furthermore the patient group included 15 patients with Löfgren’s syndrome and 23 patients with erythema nodosum – carriage of the DQB1*0201 allele was greatly increased in these subgroups. In a follow-up study based on this finding and the previously reported associations between Löfgren’s and the DRB1*0301 allele and the A allele at position ⫺307 of the TNF-␣ gene (TNF2), 37 Dutch Löfgren’s patients were genotyped for all three alleles [85]. The associations were confirmed; because there was 100% linkage disequilibrium between DQB1* 0201 and DRB1*03, and 70% LD between these alleles and TNF2 it is difficult to assign the primary association. This paper therefore identified the DQB1*0201-DRB1* 03(01)-TNF2 haplotype as an extended MHC haplotype that was present in 76% of Löfgren’s (versus 24% of controls). Löfgren’s syndrome is extremely rare in Japanese patients; this fits well with the above study, as the Japanese do not have the HLA-DR3 allele. However, cardiac sarcoidosis is more common than in Caucasians. One group reported an association between cardiac sarcoidosis and the TNFA2 allele [86]. Further studies from the same group [87] concluded that the strongest association was in fact with the HLA-DQB1*0601 allele, with homozygosity for this allele conferring a relative risk of 29.5 compared to healthy controls. The TNFA2 allele was not in LD with the class II allele, so the authors suggested that this allele might confer an additional genetic risk for cardiac sarcoidosis. Small fibre neuropathy has recently been identified as a relatively common problem in a cohort of Dutch chronic sarcoidosis patients. Sarcoidosis patients suffering from small fibre neuropathy showed an increased prevalence of DQB1*0602 suggesting a possible genetic relationship [88]. These studies all demonstrate one of the most taxing issues – that of primary association or association through linkage disequilibrium. Tight phenotyping of different ethnic groups with different linkage profiles, in concert with extended haplotyping and sequence data across the whole MHC region is needed to provide more complete clarification of this issue.

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Table 3. Key class II studies of association in sarcoidosis

Susceptibility alleles

Protection alleles

Population

Phenotype associations

Reference

DRB1*11 DRB1*14

DRB1*07 DQB1*0201

Asian Indians Asian Indians

DRB1*14 severe disease

[76]

DRB1*1101 DRB1*1501 DRB1*1401 DRB1*0402

DQB1*0602

American Whites American Whites American Whites American Whites

DRB1*0401 ocular

[78]

African-American

DRB1*0401 parotid/salivary glands

DRB1*1101 DRB1*1201 DPB1*0101 DQB1*0502 DQB1*0602 DR17(3)

hypercalcemia [78]

DRB3 bone marrow DQB1*0602 severe disease DQB1*0201 Swedish

DRB1*11 (DR5) DRB1*14 (DR6) DRB1*08 (DR8)

DRB1*0101 DQB1*0501 DPB*0402

DRB1*12 DRB1*14 DRB1*08

DR17(3) acute disease DR14, DR15 chronic disease

Japanese

[72]

Japanese

[71]

UK and Dutch

DQB1*0201–DRB1*03(01) DR3

DR4

[82] [75]

[84]

Caucasians Dutch Caucasians

DQB1*0201 mild disease including Löfgren’s syndrome DQB1*0602 severe disease DQB1*0201–DRB1*03(01) Löfgren’s

Czech and Italian Caucasians

DR3 mild disease

[66]

German Caucasians

DR4 severe disease DR3 Löfgren’s DR5 chronic disease

[74]

– [78]

DRB1*12 DRB1*14 DRB1*15 DQB1*0602 DQB1*0301/4

DRB1*01 DRB1*04

UK Caucasians

[73] [77]

DRB1*15 DQB1*0602

DRB1*01 DQB1*05

Polish

[77]

DRB1*14 DQB1*02 DQB1*04 DRB1*150101/DQB1*0602

DR7

Czech

[77]

Dutch Caucasian

Other Innate and Adaptive Immunity Genes The gene encoding for NRAMP was first identified in a murine model resistant to infection by the intracellular parasites leishmania, salmonella and mycobacteria. Maliarik et al. [89] analysed several NRAMP1 gene polymorphisms in 157 African-Americans with sarcoidosis and 111 ethnically matched controls. They identified the commonest 120-bp allele was over-represented in the sarcoidosis

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severe disease

[83]

patients, suggesting that the polymorphism at this site is protective against sarcoidosis. Interestingly, the 2 variants that were associated with susceptibility to tuberculosis did not affect susceptibility to sarcoidosis in this study. Its role in sarcoidosis susceptibility is uncertain. Toll-like receptors (TLR) are signal molecules essential for the cellular response to bacterial cell wall components. Two TLR4 gene polymorphisms (Asp299Gly and Thr399Ile)

have been described that have functional consequences. In a study of 141 Caucasian patients with sarcoidosis and 141 healthy unrelated controls an association was found for patients with chronic disease and TLR4 gene polymorphisms [90]. CARD 15 (NOD2) is a protein involved in innate immunity identifying microbial moieties. Polymorphisms in this gene have been found in two other granulomatous diseases – Blau syndrome and Crohn’s disease. However, several studies including those from Denmark [91–94] and our own unpublished observations have failed to identify an association in sarcoidosis. Transporter associated with antigen processing (TAP) gene studies have been evaluated with mixed results. TAP1 and TAP2 genes, located in the Class II MHC region, encode subunits of a heterodimeric complex that function in the endogenous antigen-processing pathway. One study examined 2 single nucleotide dimorphisms in TAP1 and 3 single nucleotide dimorphisms in TAP2, in 117 United Kingdom Caucasoids with 290 United Kingdom controls and in 87 Polish Slavonic patients with 158 Polish controls [95]. Different TAP2 variant associations were found in the two ethnically diverse populations studied. In Japanese patients, however, no associations were found between TAP1 or TAP2 polymorphisms and disease susceptibility [96]. B7 proteins (CD80, CD86) are co stimulatory molecules expressed on antigen-presenting cells and are essential factors for T cell activation. Handa et al. [97] showed no significant differences in the distribution of genotypes or allele frequencies between sarcoidosis and controls for all polymorphisms studied. Cytotoxic T lymphocyte antigen 4 (CTLA-4) is another co-stimulatory molecule, expressed on activated T cells, and functions as a regulator of T cell-dependent immune responses. In a study of 106 sarcoidosis patients and 100 healthy control subjects no differences in genotype frequency in a single promoter SNP and an exon 1 SNP were found between the healthy control subjects and sarcoidosis. However, there were differences observed for both loci in patients with ocular involvement compared with those patients without [98]. Complement receptor 1 (CR1) is a membrane protein expressed on erythrocytes, phagocytes, lymphocytes and dendritic cells that plays a number of roles in the complement system. A study of 91 Italian sarcoidosis patients compared to ethnically matched controls demonstrated a significant association between the GG genotype at the C5507G polymorphism and sarcoidosis [99]. This allele is known to be associated with low CR1 expression on

Genetics of ILD

erythrocytes, and could result in reduced clearance of immune complexes in sarcoidosis. However, these findings have not been confirmed in other studies [unpubl. personal observations]. In general, therefore, studies of non-MHC immune genes have not provided much insight into other genetic risk factors for sarcoidosis. Nuclear Transcription Inhibitor Kappa B-Alpha (I␬B-␣) Activation of the nuclear factor kappa B (NF-␬B) signalling pathway occurs in several of the components of the sarcoidosis pathogenetic process. In the resting cell, NF␬B is retained in the cell cytoplasm by the bound inhibitor protein ␬B (I␬B). The inhibitor protein I␬B-␣ is released from NF-␬B on phosphorylation and is essential for normal termination of the NF-␬B response. In a study of 3 promoter SNPs in 205 United Kingdom and Dutch sarcoidosis patients, the T allele at position ⫺297 was associated with disease susceptibility and the T allele at position ⫺826 progressively decreased in frequency across the chest radiographic stages of sarcoidosis from II to IV, suggesting that it could be protective against fibrotic disease [100]. The functional effects of these polymorphisms are not known. Cytokines TNF The TNF gene complex is located within the MHC complex, and includes the TNF-␣ and TNF-␤ (lymphotoxin ␣) genes. TNF is an early cytokine in the pathogenetic cascade in sarcoidosis, and the many studies linking sarcoidosis to the MHC complex have aroused much interest in the genes of the TNF gene complex as further candidate susceptibility genes. The association between Löfgren’s syndrome and TNFA2 has been confirmed in a more recent study of 196 British and Dutch patients and 576 controls [101]. A highly significant increase in the TNF-␣ ⫺857T allele was found in the sarcoidosis patient group overall. This allele has been associated with higher transcriptional promoter activity. In a follow-up study of 228 sarcoidosis patients including 46 Löfgren’s, 6 haplotypes were constructed across the 5 polymorphisms studied in the TNF-␣ promoter [85]. The ⫺307A allele associated with Löfgren’s syndrome occurred exclusively in haplotype 2. The ⫺857T allele associated with sarcoidosis susceptibility but under-represented in the Löfgren’s group occurred exclusively in haplotype 4. There was a very strong association between

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haplotype 2 and stage I disease with erythema nodosum, including Löfgren’s patients and with favourable radiological evolution over 4 years. By contrast, haplotype 4 was strongly associated with stages II–IV disease and with unfavourable radiological evolution over 4 years. Mrazek et al. [102] confirmed the TNF association with Löfgren’s syndrome and extended this association to include the ⫹252*G allele of the lymphotoxin-alpha gene in a large group of Czech Republic sarcoidosis patients and controls. It remains unclear whether TNF associations are functional polymorphisms, or whether one or both are in linkage disequilibrium with another site elsewhere in the MHC region. IL-1 A Czech case-control study investigated polymorphisms within the IL-1 gene cluster on chromosome 2q13–21 [103]. They studied biallelic polymorphisms in the IL-1␣ and IL-1␤ genes, and an 86-bp variable number tandem repeat polymorphism in intron 2 of the IL-1 receptor antagonist (IL-1RN) gene. They found an increase in the IL-1␣ ⫺889 1.1 genotype (C/C homozygotes) in 95 patients with sarcoidosis compared to 199 controls. This IL-1 association is consistent with the marker study by Rybicki et al. [104] in African-Americans that found an association with an IL-1␣ marker. However, a study of this same polymorphism in 147 United Kingdom patients with 101 United Kingdom controls and 102 Dutch patients with 166 controls failed to reproduce this association in either population [105]. This led the authors to surmise that the previously reported associations may have been due to linkage disequilibrium within the IL-1 gene cluster between the IL-1␣ ⫺889C allele and the unidentified locus that actually confers the risk of sarcoidosis. Population-dependent differences in linkage could explain the failure to reproduce this finding in United Kingdom and Dutch populations. IL-18 IL-18 is known to act synergistically with IL-12 to induce IFN-␥ production from TH1 cells. Serum and bronchoalveolar lavage levels of IL-18 are high in sarcoidosis patients. It is therefore an attractive candidate. One Japanese study genotyped 119 patients with sarcoidosis and 130 controls for two polymorphisms in the gene promoter known to affect promoter activity after stimulation [106]. They found a significant increase in the percentage of patients carrying the C allele at position ⫺607. This association was not confirmed in a second Japanese

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study although the promoter activity of the haplotype ⫺137G/⫺607C/⫺656G, was significantly higher than that of the other common haplotype ⫺137G/⫺607A/⫺656T, that explained the association between serum IL-18 levels and the G/C/G haplotype [107]. Similar negative findings emerged from a study from the Netherlands that also include haplotype analysis [108]. Chemokines Chemokines and their receptors are upregulated at disease sites in sarcoidosis and are therefore good candidate genes for study. Furthermore, the linkage study by Schürmann et al. [58] flagged up the presence of linkage on chromosome 3, the location of the chemokine receptor 2 and 5 genes. CCR2 The C-C chemokine receptor CCR2 is a receptor for the MCP family. This receptor also acts as a co receptor for human immunodeficiency virus (HIV) infection. A single nucleotide polymorphism in the CCR2 gene at position 64 substitutes isoleucine for valine (V64I). This polymorphism has a protective effect against progression of HIV infection to acquired immunodeficiency syndrome (AIDS). It was first studied in sarcoidosis in a Japanese population, and the V64I allele was found to be associated with a lower risk of sarcoidosis in 100 patients compare to 122 controls [109]. This same polymorphism was studied in 65 Czech patients and 80 controls [110]. The allelic frequency of the polymorphism was again reduced in patients compared to controls, but did not reach statistical significance. Spagnolo et al. [111] investigated the CCR2 gene in more detail, genotyping 304 Dutch individuals (90 nonLöfgren’s sarcoid, 47 Löfgren’s syndrome, 167 controls) for eight single-nucleotide polymorphisms (including V64I) across the whole gene. When analysing all sarcoidosis patients together, no statistically significant differences in any of the allele frequencies were found. However, analysing the Löfgren’s syndrome patients separately, strongly significant associations were found with 5 of these alleles when compared both to the healthy controls and also when compared to the non-Löfgren’s sarcoidosis patients. The V64I polymorphism was not one of the alleles showing association with Löfgren’s syndrome. They were able to construct 9 haplotypes from the 8 polymorphisms. In patients with Löfgren’s syndrome, a strongly significant increase in the frequency of CCR2-haplotype 2, which includes four unique alleles (A at nucleotide position

⫺6,752, A at 3,000, T at 3,547, and T at 4,385), was observed compared with control subjects whereas no difference was found between non-Löfgren’s sarcoidosis and control subjects. It is not certain whether this CCR2 haplotype predisposes to Löfgren’s in all carriers, or only in those positive for HLA DRB1*0301–DQB1*0201. In Löfgren’s patients negative for HLA DRB1*0301– DQB1*0201, the CCR2 haplotype did not appear to be more common – but the number of subjects in this subgroup was too small for definitive statistical conclusions to be drawn.

CCR5 CCR5 acts as a receptor for the chemokines RANTES and MIP-1␣. A 32-bp deletion in the gene (CCR5⌬32) renders the surface receptor molecule non-functional. In a study of 66 Czech sarcoidosis patients and 386 controls, this allele was significantly more common in patients [110]. Furthermore, this allele was associated with clinically more apparent disease; it was present in 39.1% of patients requiring corticosteroids but in only 16.7% of patients who needed no treatment. This study implicates the CCR5 gene as affecting both disease susceptibility and severity. Spagnolo et al. [111] report that the frequency of a CCR5 haplotype (HHC) was strongly associated with the presence of parenchymal disease (radiographic stage ⱖII versus stages 0 and I) at presentation and even more

strongly associated at 4 years follow-up in United Kingdom and Dutch cohorts of patients. Angiotensin-Converting Enzyme (ACE) Concentrations of serum ACE have been used to aid diagnosis but are elevated in only 60% of cases but, when elevated, it can be used as a marker of active disease. A 287-bp insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene has a major effect on serum levels; the DD genotype is associated with the highest serum levels the II genotype with the lowest [112]. However, no consistent correlation between ACE I/D polymorphisms and disease prevalence or severity has been demonstrated in several studies worldwide [113] other than in an African-American population, where an excess of D alleles was found in 183 cases compared to 111 controls, and DD homozygotes were at higher risk of sarcoidosis than ID heterozygotes [114]. ACE genotype did not appear to influence disease severity or progression. The latter study showed no difference in allele distribution between 60 Caucasian cases and 48 controls. In summary, there is little strong evidence to relate this particular polymorphism with either disease presence or severity. A recent study from the Netherlands of 148 sarcoidosis patients and 328 controls has, however, shown that a haplotype (haplotype 4) of seven SNPs in the gene of a homologue of ACE, ACE2 was associated with a gender dependent increased risk of parenchymal lung disease [115].

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27 Hutyrova B, Pantelidis P, Drabek J, Zurkova M, Kolek V, Lenhart K, Welsh KI, du Bois RM, Petrek M: Interleukin-1 gene cluster polymorphisms in sarcoidosis and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2002;165:148–151. 28 du Bois RM: The genetic predisposition to interstitial lung disease: functional relevance. Chest 2002;121:14S–20S. 29 Riha RL, Yang IA, Rabnott GC, Tunnicliffe AM, Fong KM, Zimmerman PV: Cytokine gene polymorphisms in idiopathic pulmonary fibrosis. Intern Med J 2004;34:126–129. 30 Pantelidis P, Fanning GC, Wells AU, Welsh KI, du Bois RM: Analysis of tumor necrosis factor-alpha, lymphotoxin-alpha, tumor necrosis factor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001;163: 1432–1436. 31 Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW: Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci USA 1998;95: 9465–9470. 32 Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV: An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997;24:1–8. 33 Whittington HA, Freeburn RW, Godinho SI, Egan J, Haider Y, Millar AB: Analysis of an IL-10 polymorphism in idiopathic pulmonary fibrosis. Genes Immun 2003;4:258–264. 34 Renzoni E, Lympany P, Sestini P, Pantelidis P, Wells A, African American C, Welsh K, Bunn C, Knight C, Foley P, du Bois RM: Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis. Arthritis Rheum 2000;43:1633–1640. 35 Seegers D, Zwiers A, Strober W, Pena AS, Bouma G: A TaqI polymorphism in the 3⬘UTR of the IL-12 p40 gene correlates with increased IL-12 secretion. Genes Immun 2002;3:419–423. 36 Latsi P, Pantelidis P, Vassilakis D, Sato H, Welsh KI, du Bois RM: Analysis of IL-12 p40 subunit gene and IFN-gamma G5644A polymorphisms in Idiopathic Pulmonary Fibrosis. Respir Res 2003;4:6. 37 Zorzetto M, Ferrarotti I, Trisolini R, Agli LL, Scabini R, Novo M, De Silvestri A, Patelli M, Martinetti M, Cuccia M, Poletti V, Pozzi E, Luisetti M: Complement receptor 1 gene polymorphisms are associated with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003;168:330–334. 38 Mrazek F, Kvezereli M, Garr E, Kubistova Z, Arakelyan A, Drabek J, Ruven HJT, van den Bosch JMM, Kolek V, Grutters JC, Welsh KI, du Bois RM, Petrek M: The complement receptor 1 polymorphisms are not involved in susceptibility to sarcoidosis: a case control association study in Czech and Dutch populations. Submitted. 39 Hodgson U, Tukiainen P, Laitinen T: The polymorphism C5507G of complement receptor 1 does not explain idiopathic pulmonary fibrosis among the Finns. Respir Med 2005;99: 265–267.

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110 Petrek M, Drabek J, Kolek V, et al: CC chemokine receptor gene polymorphisms in Czech patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 2000;162: 1000–1003. 111 Spagnolo P, Renzoni EA, Wells AU, et al: C-C chemokine receptor 2 and sarcoidosis: association with Lofgren’s syndrome. Am J Respir Crit Care Med 2003;168:1162–1166. 112 Arbustini E, Grasso M, Leo G, et al: Polymorphism of angiotensin-converting enzyme gene in sarcoidosis. Am J Respir Crit Care Med 1996;153:851–854. 113 McGrath DS, Foley PJ, Petrek M, et al: Ace gene I/D polymorphism and sarcoidosis pulmonary disease severity. Am J Respir Crit Care Med 2001;164:197–201. 114 Maliarik MJ, Rybicki BA, Malvitz E, et al: Angiotensin-converting enzyme gene polymorphism and risk of sarcoidosis. Am J Respir Crit Care Med 1998;158:1566–1570. 115 Kruit A, Ruven HJ, Grutters JC, van den Bosch JM: Angiotensin-converting enzyme 2 (ACE2) haplotypes are associated with pulmonary disease phenotypes in sarcoidosis patients. Sarcoidosis Vasc Diffuse Lung Dis 2005;22: 195–203. 116 Crilly A, Hamilton J, Clark CJ, Jardine A, Madhok R: Analysis of transforming growth factor beta1 gene polymorphisms in patients with systemic sclerosis. Ann Rheum Dis 2002;61:678–681. 117 Sugiura Y, Banno S, Matsumoto Y, Niimi T, Yoshinouchi T, Hayami Y, Naniwa T, Ueda R: Transforming growth factor beta1

gene polymorphism in patients with systemic sclerosis. J Rheumatol 2003;30: 1520–1523. 118 Zhou X, Tan FK, Reveille JD, Wallis D, Milewicz DM, Ahn C, Wang A, Arnett FC: Association of novel polymorphisms with the expression of SPARC in normal fibroblasts and with susceptibility to scleroderma. Arthritis Rheum 2002;46:2990–2999. 119 Lagan A, Lagan AL, Pantelidis P, Renzoni EA, Fonseca C, Beirne P, Taegtmeyer AB, Denton CP, Black CM, Wells AU, du Bois RM, Welsh KI: Single-nucleotide polymorphisms in the SPARC gene are not associated with susceptibility to scleroderma. Rheumatology 2005;44:197–201. 120 Tan FK, Wang N, Kuwana M, Chakraborty R, Bona CA, Milewicz DM, Arnett FC: Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations. Arthritis Rheum 2001;44:893–901. R.M. du Bois, MD Asmarley Professor of Respiratory Medicine Interstitial Lung Disease Unit and Clinical Genomics Group, Royal Brompton Hospital Sydney Street London SW3 6NP (UK) Tel. ⫹44 20 7351 8327, Fax ⫹44 7351 8336 E-Mail [email protected]


Granuloma Formation Monica Facco

Marta Miorin

Carlo Agostini

Gianpietro Semenzato

Padua University School of Medicine, Department of Clinical and Experimental Medicine, Clinical Immunology and Hematology Branch, Padova, Italy

Abstract This chapter reviews the cellular and molecular components that lead to delayed-type hypersensitivity granuloma formation during interstitial lung diseases. Granuloma formation is comprised of four main steps: (1) the triggering of T cells by antigenpresenting cells, represented by alveolar macrophages and dendritic cells; (2) the release of cytokines and chemokines by macrophages, activated lymphocytes, dendritic cells, and polymorphonuclear cells. Cytokines and chemokines attract and retain in the lung the immuno-inflammatory cell populations in the lung, inducing their survival and in situ proliferation at the site of ongoing inflammation, favoring (3) the stable and dynamic accumulation of immunocompetent cells and the formation of the organized structure of the granuloma. In granulomatous diseases, the last phase (4) of granuloma formation generally ends in fibrosis. The persistence of a chronic inflammatory response, in addition to the failure of immune-regulatory mechanisms, leads to the invasion of pulmonary tissues by granulomas and the derangement of alveolar structures. The exaggerated production of collagen, associated with fibroblast migration and proliferation during the repair processes, abnormally increases the extracellular matrix with resultant fibrosis. Copyright © 2007 S. Karger AG, Basel

In 1976, Adams [1] defined the granuloma as ‘a compact (organized) collection of mature mononuclear phagocytes (macrophages and/or epithelioid cells) which may or may not be accompanied by accessory features such as necrosis

or the infiltration of other inflammatory leukocytes’. Since then our knowledge, in terms of the network of interactions between inflammatory and immunocompetent cells that set the stage for the granuloma formation, has continuously improved, however, Adams’ granuloma definition is still appropriate. Granulomas are pathologically defined by the presence of macrophage-derived epithelioid cells and giant cells, whose organization can be modified by the cells of acquired immunity. The structural similarity in granulomas of diverse etiology suggests that a common set of pathophysiological signals regulates granulomatous inflammation. From a physiological point of view, the granuloma is a protective response to chronic infections with persistent pathogens, including Mycobacterium tuberculosis, Schistosoma species, and fungal organisms. Furthermore, granulomas can be observed in acute infections caused by Listeria [2] or Salmonella [3]. During infections, the function of the granuloma is to contain the pathogenic agent in order to prevent the dissemination of the organism and to contain the inflammatory reactions to confined sites. Nevertheless, granulomatous inflammation can also occur in the absence of an infectious microorganism, associated with autoimmune diseases such as Crohn’s disease [4] or Wegener’s granulomatosis [5], and associated with cancers [6, 7], including lymphoma as well as epitheliod tumors such as breast and lung cancer [8, 9]. Finally, granuloma can represent the hallmark of the disease, in absence of a known underlying agent, as in granuloma annulare [10] and sarcoidosis [11]. Although the identification of critical determinants of granuloma formation and evolution remains elusive, the

Secondary lymphoid tissue and pheripheral blood

Pulmonary parenchyma

Endothelial and epithelial cells

Lymphocytes

Antigen(s) (1)

Alveolar macrophages

Cytokines and Chemokines (2)

Polymorphonuclear cells

Pulmonary dendritic cells In situ proliferation (3) Cell recruitment (3)

Fig. 1. The process of granuloma forma-

tion. (1) Triggering of T cells by antigenpresenting cells; (2) release of cytokines and chemokines with multiple and overlapping functions; (3) accumulation and in situ proliferation of immunocompetent cells at sites of ongoing inflammation; (4) organized structure of granuloma.

Granuloma formation (4)

aim of this chapter is to provide the reader with an overview of the available knowledge concerning the cellular and molecular interactions that govern the dynamics of granuloma formation in the lung during interstitial lung diseases. Particularly, the attention has been focused on immunoinflammatory mechanisms that play a part in the development of pulmonary sarcoid granulomas. Sarcoidosis, extensively described in Part 3 of this volume, is a disorder characterized by an exaggerated CD4⫹, Th1-biased, T cell response to an unidentified antigen, resulting in the formation of organized immune granuloma. Sarcoidosis is the commonest interstitial lung disease in the western world [12]; it also represents the archetype of immune granulomatous disorders and several of its immunoregulatory mechanisms modulate the pathogenic events taking place in other interstitial lung diseases.

Immuno-Inflammatory Cellular Initiation of the Granuloma

The lung is one of the most immunologically challenged organs of the body, continuously exposed to both innocuous

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and pathogenic environmental antigens. The local pulmonary immune response against organic and inorganic agents is critical for host defense. Immune granulomatous inflammation represents a response to a known or unidentified antigen which has persisted at sites of lung involvement, perhaps because of its low solubility and degradability. The process of granuloma formation (fig. 1) can be divided into the following phases: (1) the triggering of T cells by antigen-presenting cells; (2) the release of cytokines and chemokines with multiple and overlapping functions; (3) the accumulation of immunocompetent cells at sites of ongoing inflammation, and (4) the final evolution of granuloma in the presence of a chronic inflammatory response (fig. 2). Each of these events involves T cells, which are absolutely required for the formation of the delayed-type hypersensitivity (DTH) granuloma. The sarcoid granuloma morphologically represents a typical DTH granuloma. In particular, it is a noncaseating granuloma, whose central core is made up of a number of mononuclear phagocytes and their progeny (epithelioid and multinucleated cells) surrounded by a rim of T cells, consisting mostly of CD4⫹ T helper 1 (Th1) cells but also containing rare CD8⫹ T cells, B cells and plasma cells [13].

Granuloma evolution

TNF-␣, IL-4, IL-13, deficit of immune regulation

IL-10, IL-12,IL-18, regulatory T cells Resolution

Fibrosis (chronic disease)

Fig. 2. The granuloma evolution derives from a delicate balance

between Th1 (resolution) and Th2 (fibrosis) cytokines. The presence and the compartmentalization of regulatory/suppressor T cells modulate the evolution of the granuloma. This regulatory activity does not occur in granulomatous chronic disorders, with the collateral maintenance of chronic inflammation that sets the stage of fibrosis.

From a pathogenic point of view, two mechanisms account for the increased number of inflammatory cells at granuloma sites: a cellular redistribution from the peripheral blood to the lung and an in situ proliferation [14]. All of these events ultimately lead to the organization of the local inflammatory process into granuloma. Dendritic Cells The presence of effective antigen-presenting cells (APCs) is mandatory to trigger the immune response. Dendritic cells (DCs) are efficient professional APCs with the unique ability to induce primary immune responses in T cells [15]. Despite their capacities, the role of DCs in the pulmonary granulomatous immune response has been overlooked until a few years ago. Two major subsets of DC precursors have been identified in human peripheral blood [16]: the CD11c⫹ subset, belonging to the myeloid lineage [17], and the CD11c-plasmacytoid subset, of lymphoid lineage [18]. On the basis of the DC1/DC2 paradigm, two populations regulate different Th response. The CD11c⫹ myeloid subset (DC1) has the capacity to polarize naïve CD4⫹ T cells towards IFN-␥ producing-Th1 cells, depending on interleukin (IL)-12 production, while the CD11c– plasmacytoid subset (DC2) drives IL-4 producing-Th2 cells upon IL-13 exposure [19]. Both DC populations may migrate to various organs, including the lung. Within unaffected lungs, immature DCs locate in airway epithelium, lung parenchyma, connective tissue surrounding major airways and vessels, pleura, and in the pulmonary vascular bed [20, 21]. Pulmonary DCs are functionally immature, specialized for antigen uptake, and express low surface amounts of MHC class II and costimulatory molecules. In the presence of inflammatory stimuli, DCs increase expression of these molecules and mature

Granuloma Formation

into functional APCs [22, 23]. Furthermore, lung DCs, retaining on their surface the antigenic peptide, upregulate CCR7 and, under the influence of the CCR7 ligands CCL19 and CCL21 [24], rapidly migrate into the T cell areas of regional lymph nodes [25]. Pulmonary DCs migrating to draining lymph nodes are replaced by peripheral blood precursors which are recruited into the lung in a chemokine/ chemokine receptor-dependent way. Experimental models on transgenic mice have observed that the CCR2/CCR2 ligand interactions are necessary to recruit DCs from the bloodstream to lung interstitium, while the crossing of DCs from the epithelial barrier into the alveoli is mediated by the CCR6/CCL20 axis [26]. DCs are well-recognized components of granuloma [21], whose recruitment at granulomatous lesions occurs both in pulmonary tuberculosis [27] and sarcoidosis [28]. The recent investigations on the contribution of DCs in the pulmonary granulomatous immune response show the premature and rapid involvement of DCs at the sites of inflammation and in the formation of granuloma [28, 29]. The detection of DCs throughout the granuloma, 3 days after granuloma-induced formation, suggest that these cells actively traffic into and out of the granuloma. Furthermore, a number of mature DCs infiltrate exclusively into the lymphocyte layer of granuloma, and interact functionally with T cells. The recent finding of IFN-␥ and IL-4 producing T cells in sarcoid Th1 granuloma suggests that the two populations of T lymphocytes are generated by the interaction with DC1 and DC2, respectively [28]. Interestingly, experimental murine models of granuloma formation induced by bead immobilized Th1- and Th2-inducing pathogen antigens, such as Mycobacteria bovis purified protein derivative (PPD) and Schistosoma mansoni soluble egg antigen (SEA), demonstrated that the transfer of mature granolumatous PPD-bead-DCs to naïve recipients induces a Th1 response, stimulating a PPD-specific T cell proliferation, while the SEA-bead-DCs do not initiate any Th2 differentiation [29]. Therefore, blood DC subsets can migrate into the inflamed lung tissues, contributing to the formation of granuloma, and may regulate the T cell response at least in the granulomatous lesions. Macrophages The present knowledge of the network of interactions underlying the mechanisms accounting for lung granulomatous reaction has been mostly acquired from the evaluation of cell populations retrieved from bronchoalveolar lavage (BAL) fluid and from immunohistologic analysis of tissues involved by the granulomatous inflammation.

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A macrophagic alveolitis is a common finding in patients with interstitial lung diseases. Macrophages, as part of the innate immune system, are recruited early to the inflammatory sites, without the need for specific antigen recognition. This is particularly evident in non-DTH granulomas, such as foreign body granulomas, which consist almost exclusively of macrophages and represents an example of frustrated phagocytosis as the crucial factor in initiating granuloma formation [30]. Once mononuclear inflammatory cells accumulate in the lung, macrophages aggregate and differentiate into epithelioid and multinucleated giant cells. The representatives of the mononuclear phagocyte system in the lung arise from circulating monocytes that migrate through the alveolar walls into the lungs [31, 32]. The compartmentalization of macrophages at sites of disease activity is confirmed by the surface phenotypic analysis of macrophages. In their steady state, alveolar macrophages (AMs) express class II MHC-related determinants and show high affinity receptors for the Fc portion of immunoglobulin (Ig)G (CD64), IgE (CD23), and complement (CD11b) [33], [34]. Unlike peripheral blood monocytes, they either bear or do not bear the CD14 determinant (LPS-binding protein) and express low levels of molecules involved in cell-to-cell, cell-to-endothelium, or cell-tomatrix contact [33, 34]. For these reasons, under normal conditions, AMs are poor antigen-presenting cells. Mature AMs show a suppressive action on local T cell immune responses, which is directly proportional to local TGF-␤ secretion and lack of expression of counter-receptors that are needed to provide costimulatory signaling to lung T cells, including CD80 [35, 36]. The daily contribution rate of monocyte traffic in the homeostatic maintenance of the AM population, which is relatively low in healthy individuals (1.25% day), markedly increases in the lung of patients with granulomatous diseases like sarcoidosis. Most events responsible for the recruitment of sarcoid monocytes from the bloodstream to sites of inflammation have been identified. High levels of monocyte chemoattractants, including CCL2, CCL3 and CCL5 have been demonstrated both in BAL fluid and the lung of patients with sarcoidosis. Once attracted by relevant chemotactic stimuli, monocytes acquire the ability to release type IV collagenase, an enzyme that is capable of binding and degrading the major structural component of the basement membrane of vessel walls (i.e. type IV collagen) [37]. Following the secretion of this enzyme, a massive monocyte influx takes place and is responsible for the release of an array of biologic mediators of the immune response, including IL-1, IL-6, IL-8, IFN-␥, GM-CSF,

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TNF-␣ [38, 39]. These molecules favor the expansion of AM, T cell, and neutrophil pools as well as the enhancement of local effector cell functions. In this regard, recent studies have shown that sarcoid AMs exhibit activation of NFkappa B and deficiency of PPAR␥, suggesting that insufficient PPAR␥ activity contributes to ongoing inflammation in pulmonary sarcoidosis by failing to suppress proinflammatory transcription factors, such as NF-kappa B [40]. A constitutive or dysregulated NF-kappa B activation caused by Nod2/CARD15 receptor mutations has been shown in other inflammatory granulomatous disorders, such as Crohn’s disease [41, 42], Blau syndrome [43], and earlyonset sarcoidosis [44]. Macrophages in early granulomatous lesions and around blood vessels in the inter-granulomatous areas express the calcium binding protein calgranulin Mac387 (an antigen shared by granulocytes and circulating monocytes but only by a minimal proportion of tissue macrophages), thus confirming that the recruitment of adherent cells drives the development of the core of the granuloma. Furthermore, the local release of macrophage growth factors also leads to the increase in self-renewal of the resident macrophage pool. According to the status of proliferating cells, AMs from patients with active sarcoidosis show enhanced expression of the M-CSF and GM-CSF receptors and are equipped with the CD71 antigen [45, 46]. In sarcoidosis as in other granulomatous diseases, the complex network of cytokines and chemokines triggers macrophages to become ‘primed’. This activation state of macrophages is indicated by an increased metabolic activity and by an enhanced secretion of immunomodulatory molecules, some of the most important are briefly listed below. Interleukin-1 The role of IL-1 in the lung is to provide accessory growth factor activity for T cells. It is involved in the regulation of alveolar inflammation (alveolitis) promoting the adhesion of neutrophils, monocytes, and T lymphocytes by enhancing the expression of adhesion molecules such as CD54/ICAM-1 and CD62E/ELAM (endothelial leukocyte adhesion molecule). IL-1 promotes DC maturation in vitro and contributes to the control of DC migration at the sites of inflammation [47]. Furthermore, IL-1 is capable of stimulating granuloma formation and fibrosis development by inducing fibroblast proliferation and increasing collagen production. Interleukin-6 IL-6 stimulates B cell growth and T cell proliferation. It is produced by AMs, lung T cells, endothelial cells, and

fibroblasts. A variety of pulmonary inflammatory diseases, including sarcoidosis, tuberculosis, and berylliosis are characterized by a dysregulated production of IL-6 [29]. The cytokine is involved in the control of the in situ proliferation of sarcoid fibroblasts. Interleukin-12 Produced by DCs and macrophages, IL-12 is involved in Th1 immune responses, inducing the Th0 versus Th1 shift. It stimulates the proliferation of activated T and NK cells. In synergy with IL-18, IL-12 induces IFN-␥ production in sarcoid BAL Th1 cells [48]. Interleukin-15 In the lung, IL-15 is mainly produced by DCs and macrophages and supports the growth and the chemotaxis of T cells, favoring the development of the alveolitis. At the same time, IL-15 down-modulates the apoptosis rate of lung T cells [49, 50]. It also behaves as a costimulatory factor for the production of other cytokines and chemokines (IL-17, CXCL8, CCL2, GM-CSF, IFN-␥, and TNF-␣). Interleukin-18 Mainly produced by monocytes and macrophages, IL18 is expressed at sites of chronic Th1 mediated inflammatory diseases such as Crohn’s disease, rheumatoid arthritis, and sarcoidosis. It acts synergistically with IL-12, stimulating IFN-␥ production by T cells. Interleukin-23 Secreted by DCs and other antigen presenting cells, IL23 is a novel member of IL-12 cytokine family. IL-23 stimulates the production of IFN-␥ and induces the proliferation of activated T cells. AMs exposed to mycobacterial antigens rapidly express IL-23, suggesting an immune-stimulatory role for this cytokine during infections [51]. Colony-Stimulating Factors GM-CSF is able to induce the growth and differentiation of sarcoid macrophages, facilitating the development of the macrophage-derived core of the sarcoid granuloma. Furthermore, GM-CSF modulates cytokine production and enhances the antigen presenting capacity of sarcoid macrophages [52]. Tumor Necrosis Factor-␣ TNF-␣ is a proinflammatory cytokine actively produced by sarcoid macrophages [39]. It plays a critical role in pulmonary injury and in the regulation of fibroblast growth via the induction of IL-6. Furthermore, TNF-␣ stimulates and

Granuloma Formation

regulates the synthesis and release of other lymphokines (IL-1, GM-CSF, platelet-activating factor and IL-6) and increases prostaglandin production (PGE2). There are data suggesting that the chronic overexpression of TNF-␣ and IFN-␥ sets the stage for the persistence and the progression of inflammatory events and tissue damage during sarcoidosis [53], suggesting the importance of anti-TNF strategies in the treatment of sarcoidosis. Chemokines The superfamily of chemokines consists of an array of chemoattractant proteins that can be divided into four main groups (C, CC, CXC, and CX3C), according to variations in a cysteine position. Most chemokines are highly expressed during inflammatory responses taking place in granulomatous diseases. The chemoattractant CCL2, CCL3, CCL4, and CCL5 cooperate to immobilize several leukocyte subpopulations in perivascular foci of inflammation. CCL2 and CCL5, interacting with CCR1/CCR2 or CCR1/CCR3/CCR5, respectively, may be chemoattractant for different cell targets, including macrophages and T lymphocytes, that characterize the different phases of the inflammatory process of sarcoidosis, including macrophages and T lymphocytes [38, 54]. CCL19 and CCL20 are also expressed in the macrophages of sarcoid patients: CCL19 interacts with CCR7 and correlates with BAL lymphocytes and T cell subsets [55], while CCL20 binds the specific receptor CCR6 expressed by DCs, favoring their migration to the lung [26]. Three lymphocyte-specific CXC chemokines, which are produced in response to IFN-␥ (i.e. CXCL10, CXCL9 and CXCL11), play an important role in the recruitment of activated T cells into the pulmonary microenvironment of sarcoidoisis [56] and tuberculosis [57] interacting with specific receptors expressed by Th1 cells (CXCR3). Alveolar macrophages and pulmonary neutrophils are the main cell sources for these molecules in sarcoidosis and tuberculosis, respectively. They release high amounts of CXCL10 and CXCL9 that allow for the accumulation of pulmonary T lymphocytes and contribute to granuloma formation. Activated bronchial epithelium is another important source of CXCL9, CXCL10, and CXCL11. CXCL8, a chemokine that favors T cell and neutrophil recruitment is actively released in the airways during sarcoidosis and hypersensitivity pneumonitis, and its release is associated with lung damage. Immunolocalization of CXCL8 demonstrated that the pulmonary fibroblasts and alveolar macrophages are the predominant cellular source of this chemokine [58].

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Recently, the new chemokine/chemokine receptor axis CXCL16/CXCR6 has been characterized in sarcoidosis. Particularly, CXCL16 induces a potent in vitro migratory activity of sarcoid CD4⫹ T cells, and it is expressed by AMs, epithelioid cells, and epithelial cells forming the granuloma [59]. T Cells The presence and accumulation of T cells is critical in granuloma formation, as the rising lesion would not mature through the accumulation of effector cells in the absence of CD4⫹ T lymphocytes. Since it is generally accepted that T cells require time for antigen presentation and for successive activation before they can respond, the early involvement of T cells in granuloma formation is still controversial. Interestingly, activated but nongranuloma antigen-specific T cells have been observed in Schistosoma mansoni-induced granulomas, suggesting that nonspecific T lymphocytes may infiltrate and participate in granuloma formation from the beginning [60]. AM production and release of cytokines and chemokines account for the T cell recruitment and activation. Pulmonary T lymphocyte characterization and definition mainly derive from the analysis of BAL cells. It is well known that BAL fluid cells indirectly reflect granulomatous events, especially in the active phase of sarcoidosis [61]. The infiltrate of CD4⫹ activated T cells represents the immunological hallmark of sarcoidosis. Although lung parenchyma normally contains only a few lymphoid elements, the lymphocyte populations are strikingly compartmentalized in sarcoidosis air spaces and interstitium. The equivalent of 25 ⫻ 106 T cells can be recovered from the BAL of patients with active pulmonary sarcoidosis (versus 5 ⫻ 103 T cells recovered from the BAL of controls). Sarcoid T cells are predominantly CD4⫹, CD45R0 T cells, coexpressing the ␣␤T cell receptor, the IL-12 receptor ␤, mainly producing IFN-␥ or IL-2, thus belonging to the Th1 cell subset. A marked accumulation of CD4⫹ lymphocytes can be observed at all tissues affected by the sarcoid immunoinflammatory process [62] where the CD4/CD8 ratio is extremely high (usually greater than 10). The association of a peripheral CD4 lymphopenia and the increase in Th1 cells in tissues where the sarcoid inflammatory process takes place [63, 64] supports the concept of a Th1 T-cell compartmentalization. It is tempting to speculate that the marked increase in Th1 CD4⫹ T cells at sites of involvement might lead to the consequent decrease in peripheral T lymphocytes. Several cytokines released by T lymphocytes are responsible for driving the development of the granulomatous

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reactions taking place in the lung. A list of these molecules can be found in the following section. Interleukin-2 Actively released by pulmonary T cells, the role of IL-2 in the pulmonary microenvironment is to expand activated T cells [65] via the binding with its receptor, constituted by three different chains: ␣ (CD25), ␤ (CD122), and ␥ (CD132). Specifically, IL-2 acts as a local growth factor for T lymphocytes infiltrating lung tissue of sarcoid patients. The addition of IL-2 to AMs increases GM-CSF expression, suggesting the hypothesis that this cytokine is involved in AM activation. The presence of binding sites for IL-2 has also been demonstrated on human lung fibroblasts, and the addition of IL-2 to fibroblasts leads to an enhanced expression of the gene coding for CCL2, also called monocyte chemoattractant protein-1, a chemokine which is involved in fibrosis through the regulation of profibrotic cytokine generation and matrix. IL-2 may thus serve to combine fibroblasts and sarcoid macrophages into a coordinated response of the connective tissue initiated by Th1 lymphocytes at sites of disease activity. Interleukin-4 Released by Th2 cells, IL-4 acts as a cofactor for proliferation of multiple cell lineages, including fibroblasts [66, 67]. Synergically with IL-2, it stimulates the growth of T cells. The production of IL-4 during pulmonary inflammation has been related to the development of pulmonary fibrosis in interstitial lung disease, including sarcoidosis [38, 67, 68]. IL-4 induces the release of chemokines from human epithelial cells, including CXCL8 (neutrophil chemoattractant) and CCL20 (DCs and CCR6⫹ T cells chemoattractant) [69]. Interleukin-10 The main pulmonary source of IL-10 is represented by Th2 cells and by CD4⫹CD25⫹ T regulatory cells [70]. IL10 has anti-inflammatory and immunoregulatory properties: it inhibits proinflammatory cytokine and chemokine production in addition to blocking T cell responses to specific antigens. It has been proposed that the local secretion of IL10 may represent a down-modulating mechanism involved in the spontaneous resolution of alveolitis in sarcoidosis. Interleukin-13 Expressed by activated Th0 and Th2 cells, IL-13 is generally considered a major inducer of fibrosis. In particular, IL-13, together with TNF-␣, induces TGF-␤1 in alveolar macrophages through a process that involves the IL-13r␣2 receptor, previously thought to act only as a decoy receptor.

The blockade of IL-13r␣2 signaling leads to a marked downregulation of TGF-␤1 production and collagen deposition in bleomycin-induced lung fibrosis [71]. Interleukin-17 The IL-17 family is composed of six members, the most active of which, in the lung, is IL-17A [72]. Produced by Th0 and Th1, but not by Th2 CD4⫹ T cells [73], IL-17A exerts its main activity on neutrophils, orchestrating their mobilization. Through neutrophil-derived compounds (in particular the serine protease neutrophil elastase), and its neutrophil-accumulating effect, IL-17A acts indirectly but deeply, in airway remodeling. IL-17 strongly induces the release of CCL20 (the potent chemoattractant for CCR6⫹ immature DCs) from human airway epithelial cells [74]. The effects of IL-17A are potentiated by other proinflammatory cytochines, such as IL-1␤ and TNF-␣.

In the BAL of patients with sarcoidosis, PMNs are found in excess only when the lungs show radiographic evidence of fibrosis, the pathologic consequence of granuloma formation. Compartmentalization of PMNs involves the interaction of homing receptors on their surface (CD62, CD11a/CD18 complex, and CD49 antigens) with molecules expressed by stimulated pulmonary endothelial cells (CD54, CD62P, and CD106). Furthermore, the migration of PMNs to the site of fibrosis can be driven by AMs, which release chemotactic factors for granulocytes, such as IL-1, TNF-␣, and CXCL8. In turn, activated neutrophils can be induced to express an array of products strongly involved in the sarcoid immuno-inflammatory response, such as IL-1, TNF-␣, IL-12, CXCR3 ligands, resulting in the amplification of the inflammatory response. At the same time, PMNs are equipped with lysosomal granules containing a variety of enzymes, including lactoferrin, elastase, myeloperoxidase, hydrolase, and bacterial permeabilityinducing proteins [78]. The oxidant and protease-mediated PMN damage to lung cells and extracellular matrix explains the lung damage in sarcoidosis, associated with a persistent neutrophilic alveolitis.

Interferon-␥ Interferon-␥ is the key factor that triggers all inflammatory Th1-mediated processes. IFN- ␥ is typically expressed by Th1 cells infiltrating the sarcoid tissue and favors the development of the typical hypersensitivity reaction and, in general terms, an inhibition of fibrogenetic processes. Through its pleiotropic effects on cytokine production IFN␥ up-regulates the expression of the co-stimulatory molecules on accessory cells, including CD80 and CD86 [75]. However, by inducing non-ERL chemokines (CXCL9, CXCL10, CXCL11, and CXCL16), IFN-␥ plays a major role in the recruitment of activated sarcoid CXCR3⫹/ CXCR6⫹ T cells into inflamed tissues. Recent data show that IFN-␥ is highly produced by pulmonary neutrophils of patients with hypersensitivity pneumonitis and this innate cell IFN-␥ production is sufficient for granuloma formation in the absence of T cells [76].

DTH granulomas are organized and dynamic structures whose composition and lifespan principally depend on the following events: (1) the macrophage-T cell interactions; (2) the recruitment of immuno-inflammatory effector cells; (3) the proliferation of cells at the site of granuloma formation, and (4) the survival of cells accumulating in the granuloma.

Polymorphonuclear Cells Polymorphonuclear neutrophils (PMNs) are among the first cells migrating into sites of infections. PMNs have been identified in human tuberculous lung granulomas [77] and recent data have demonstrated that PMNs are essential for the initial regulation of the pulmonary granuloma formation in M. tuberculosis-affected C57BL/6 mice [57]. Virtually, no granulomas have formed in PMN-depleted mice, suggesting that PMNs regulate pulmonary granuloma formation promptly after encounter with M. tuberculosis. Moreover, PMNs control tuberculous granuloma development, at least in part, via CXCR3-signalling chemokines, mainly CXCL9, amplifying T cell attraction and focusing the immune reactions at the site of infection.

Macrophage-T Cell Interactions Macrophage-T cell interactions are crucial in the formation of the DTH granuloma. The central core of the typical sarcoid granuloma is made up of a number of monocyte/macrophages in various states of activation and differentiation, as well as epithelioid cells and multinucleated giant cells. While macrophages continuously release and induce chemokines, cytokines, adhesion molecules, and activating factors for leukocytes for their recruitment from the blood to the lung, CD4⫹ T cells play a central role not only in the mobilization but also in the organization of effector cells at the site of granuloma formation. In fact, HIV patients with reduced CD4⫹ counts become susceptible to infections with intracellular pathogens which

Granuloma Formation

Accumulation and Interactions of ImmunoInflammatory Effector Cells Define the Mature Granuloma Structure

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require granulomatous inflammation for control, including M. tuberculosis and Pneumocystis carinii [79]; moreover, mice infected with S. mansoni and depleted of CD4⫹ T cells fail to form granulomas [80]. In conclusion, CD4⫹ T cells have a mandatory role in organizing the pulmonary immuno-inflammatory infiltrate into a well-structured granuloma. At the same time, macrophages and macrophagederived interdigitating professional APCs in the T cell areas express molecules, which in turn, influence the activity of CD4 lymphocytes and plasma cells surrounding the central core of the granuloma. The molecules that allow macrophages to act as professional APCs in hypersensitivity reactions related to sarcoidosis have been identified. T cell/macrophage interaction depends on the presence of a number of costimulatory molecules on APCs, including members of the B7 family (CD80 and CD86), some molecules of the TNF-receptor superfamily (CD40 and CD27) and the CD5 coligand CD72. The pattern of CD80 and CD86 expression shown by pulmonary macrophages of patients with sarcoidosis is consistent with that of conventional APCs [75, 81]. Membrane interactions occur even among different subsets of macrophages within granulomas. Epithelioid cells forming sarcoid granulomas exhibit a very high expression of CD11a and CD11c as well as the leukocyte functionassociated antigen (LFA)-1 specific ligand CD54/ICAM1 but completely lack other adhesion molecules such as the receptor for thrombospondin (CD36), the collagen/laminin receptor VLA1, and CD56/NCAM. This pattern suggests that the reciprocal recognition of CD11a/LFA1 and CD54/ ICAM1 molecules is a major mechanism involved in homotypic adhesion of inflammatory macrophages recruited from the peripheral blood and activated at sites of ongoing inflammation [82]. Epithelioid and giant cells probably arise from the aggregation and coalescence of the mononuclear phagocytes. In this regard, it is thought that GM-CSF contributes to the development of the macrophage core of the granuloma, since there is a relationship between AM proliferation and fusion and the subsequent formation of granuloma [83]. A number of CD4 lymphocytes and plasma cells surround the central core of the granuloma; in contrast, few CD8 cells are confined to the borders of the lesion. Histopathologic data also have demonstrated the presence of interdigitating HLA-DR cells in the T cell areas and that mature macrophages and epithelioid cells immunoreact with IL-1 and class II MHC determinants [84]. This type of pattern clearly indicates that CD4⫹ cells together with macrophages participate in processing a persistent unknown antigenic stimulus.

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Recruitment of Immuno-Inflammatory Effector Cells Together with cytokines, the recent identification of the chemokine family has contributed to the understanding of the signals underlying the recruitment of cells to the ongoing granuloma. Analysis of chemokine and chemokine receptor usage has revealed enhanced expression of an array of chemokines, in both Th1- and Th2-type granulomas. Particularly, Th1-type granulomas are characterized by a valence of CXCL chemokines, while Th2 granulomas present elevated CCL chemokines. The expression of cytokine and chemokine genes, which ultimately accounts for the accumulation of immunocompetent cells inside granulomas, was recently investigated in sarcoid lymph nodes. Interleukin-1␤, IFN-␥, and CXCL10 are preferentially expressed by cells inside the granuloma, whereas cells containing TNF-␣, IL-1␣, IL-6, and IL-2 mRNAs are scattered and randomly distributed. These findings emphasize the role of cells producing IL-1␤ (i.e. macrophages) and IFN-␥ (i.e. Th1 cells) to the development of the new granuloma through the local recruitment and activation of immunocompetent cells. The perpetuation of the granuloma is due to molecules with chemotactic properties and inhibitors of mobility, which cooperate to immobilize the monocytes and lymphocytes in the perivascular foci of inflammation. The in situ production of CCL2, CCL5, CXCL10, CXCL16 and IL-16 in lymph nodes and lungs presenting typical DTH lesions related to sarcoidosis [59, 85, 86] and tuberculosis [57, 87, 88] has been demonstrated. The list of chemokines actively released in sarcoid lung has been recently enriched by CCL19, which is also involved in T lymphocyte recruitment and associate with disease progression [55]. Collectively, these data outline the role of chemokines in the formation of sarcoid granuloma. Monocytes and lymphocytes can be recruited and anchored to granuloma even by matrix proteins. Specifically, osteopontin (OPN) is a noncollagenous adhesive matrix protein involved in immune response [89]. Produced by macrophages, T and NK cells, OPN expression has been described at sites of granuloma formation in tuberculosis [90], silicosis [91] and sarcoidosis [89]. In particular, OPN expression in sarcoid granuloma correlates with granuloma maturity and cellularity, with a prominent role in the initiation phase of granuloma formation. OPN binds to T cells, supports T cell adhesion (an effect enhanced by thrombin cleavage of osteopontin) and chemotaxis, and costimulates resting T cell proliferation. The latter property is shared with other matrix proteins, such as fibronectin, laminin, and hyaluronic acid, suggesting that different components

of the extracellular matrix may have specific immune modulatory effects [92, 93]. Cell Proliferation at the Site of Granuloma When macrophages aggregate into more mature components of the granuloma, they lose expression of the calgranulin Mac387 antigen and their mitotic activity. In fact, in granulomatous mononuclear cell inflammation, proliferating cells are restricted to T lymphocytes. Using double-marker analysis with mAbs recognizing cycle-related markers (Ki67 and proliferating cell nuclear antigen [PCNA]) on sarcoid lymph nodes, it is possible to demonstrate that in granuloma areas only T lymphocytes exhibiting the CD4/CD45R0 helper-memory phenotype actively proliferate [94]. Moreover, the presence of clonal expansion of T cells in schistosome-induced granulomas [60], in mycobacterium-induced granulomas [95], and in sarcoid granulomas [96, 97] points to local T cell proliferation. In addition, the in situ released cytokines, such as IL-1, IL-2, IL-15, and TNF-␣, cooperate to trigger the proliferation of activated T cells at granuloma sites [49]. Cell Survival in the Granuloma A short period of resistance towards apoptosis avoids premature death of cells participating in an immune response. Apoptosis results from the activation of an internally encoded suicide program induced by a variety of intrinsic and extrinsic signals. The delicate balance between apoptosis and survival of activated inflammatory cells is thus a crucial mechanism for the homeostasis of the immune-inflammatory reactions. To avoid tissue damage, in physiological conditions, an inflammatory response is usually resolved in a few days, generally by apoptosis of activated cell at the foci of inflammation [98]. On the contrary, in granulomatous diseases like sarcoidosis, the spontaneous resolution of the disease in a couple of years is considered a good prognosis, while the persistence of inflammation generates a massive development of granulomas, often resulting in fibrotic tissue degeneration [11]. Failure of cells to die might be one mechanism contributing to the formation of the immune granuloma, and may explain the long lifespan of cells inside the granuloma. A number of data suggests that the modulation of the cell apoptotic program is altered in subjects with progressive sarcoidosis, despite the increased expression of apoptosis signaling receptors, such as TNF receptor I and Fas (CD95), on sarcoid alveolar macrophages [99, 100]. There are data suggesting that the chronic overexpression of TNF-␣ and IFN-␥ sets the stage for the persistence and the progression of inflammatory events in patients with chronic sarcoidosis. Particularly, macrophage activation

Granuloma Formation

induced by IFN-␥ leads to the suppression of apoptosis through the expression of the cyclin-dependent kinase inhibitor p21Waf1 [101]. Noteworthy, the increased p21Waf1 expression is not a systemic effect, but a local event inside the granuloma, as circulating leukocytes from sarcoid patients did not overexpress this molecule. Cell survival is also regulated by adhesion to the components of the extracellular matrix [102]. In vitro experiments showed that the binding of macrophages to decorin inhibits apoptosis through a p21Waf1-dependent pathway [101]. Fibronectin, secreted by macrophages at the inflammatory loci in order to structure the sarcoid granuloma, indirectly favors apoptosis resistance, enhancing activation of T lymphocytes and increasing IFN-␥ production necessary for p21Waf1 induction [103]. IL-15 is another Th1 cytokine that antagonizes the clearance of T cells from sites of chronic inflammation via an inhibition of cell apoptosis due to cytokine deprivation, by the up-regulation of BCL2 expression [104]. BCL2 is an oncogene that may either be death antagonist or agonist: when growth factors like IL-2 are withdrawn, BCL2 protects cells from apoptosis. In sarcoidosis patients, BCL2 is highly expressed by T lymphocytes surrounding granulomatous lesions, and its up-regulation corresponds to a prosurvival profile [100]. Thus, the apoptosis machinery seems to be blocked in granulomatous cells: apoptosis cannot be induced neither via the receptor pathway nor via mitochondria. This is confirmed by cell apoptosis resistance shown by sarcoid T lymphocytes, despite the high levels of caspase-3 activity (a protease critical for the execution of the death signal) demonstrated in these cells [105]. Perhaps, caspase activation detected in stimulated T cells may be related to the cellular activation machinery, suggesting a correlation between T cell receptor-induced caspase activity, the activation state of the cells, and resistance to apoptosis.

Evolution of Granuloma Ends in Fibrosis

Since the granuloma structure is aimed at containing the dissemination of inciting agents in hypersensitivity reactions, it is expected that the inflammatory response spontaneously clears once the etiologic factors are isolated. This paradigm is not confirmed in the case of granulomatous disease, such as progressive sarcoidosis. In about 60% of patients with sarcoidosis the course of the disease is self-limiting with spontaneous resolution of the granuloma, whereas patients with progressive sarcoidosis show a persistent and increasing development of granulomas ending in fibrosis (fig. 2).

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In physiological conditions, fibrosis serves to wall off the granuloma contents and is part of both the wound healing response and organ damage [106]. From a pathogenic point of view, the first step in pulmonary fibrosis is represented by the invasion of pulmonary tissues by the sarcoid granuloma, which alters the permeability of type I cells causing alveolar and interstitial edema and derangement of alveolar structures. These phenomena lead to physiologic repair reactions by parenchymal cells which try to restore and re-establish normal alveolar structures [107]. The repair processes lead to an exaggerated production of collagen associated with fibroblast migration and proliferation and an abnormal increase in the extracellular matrix with derangement of alveolar structures and resultant fibrosis. Consequently, the degree of permanent alterations of the lung structure depends on the extent of tissue involved by the granulomatous reaction. With continued activity of the inflammatory cells, fibrosis becomes more widespread and involves the vasculature. While the reversible phases of initial alveolar injury in the sarcoid process are mediated by Th 1 lymphocytes, the fibrotic changes that follow the sarcoid Th1 immune response are modulated by macrophages, neutrophils, eosinophils and mast cells [108], which via the overproduction of superoxide anion, oxygen radicals and proteases can cause local injury, disruption of the epithelial basement membrane, alteration of epithelial permeability and consequent derangement of the normal architecture of lung parenchyma. The recruitment of fibroblasts and the following increased production of matrix macromolecules complete the stage of the fibrotic process. Two cytokines of the Th2-driven response have been mostly implicated in granuloma-associated fibrosis, TGF-␤ and, more recently, IL-13. TGF-␤ is secreted by granulomatous macrophages and activated lymphocytes and modulates the synthesis and the effect of several other molecules, including IL-1, IL-2, IL-3, GM-CSF, IFN-␥, and TNF-␣. This cytokine, which stimulates extracellular matrix deposition, has been found in fibrotic granuloma of tuberculosis and sarcoidosis patients [109]. IL-13, as reported above, is produced by the granulomahoming T cells, and has been implicated in the pathogenesis of a variety of diseases characterized by inflammation and tissue remodeling, including asthma and idiopathic pulmonary fibrosis, activating a broad array of downstream target genes, such as chemokines, matrix metalloproteinases, chitinases, other than TGF-␤1 [110]. Loss of Immunoregulation In late stages of infections characterized by granuloma formation, granulomas physiologically decrease in size.

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Generally, regulatory T cells (T reg) produce a complex immunoregulatory cytokine circuit dominated by IL-10 [111] and TGF-␤ [112] effects that downregulate granulomatous inflammation. This regulatory activity does not occur in chronic granulomatous disorders, where an inappropriate granuloma response takes place. The compartmentalization of different regulatory T cells (i.e. the balance between helper T cells/suppressor T cells) likely modulates the evolution of the granuloma, as suggested by studies in animal models [113]. Furthermore, CD4⫹ cells predominate in the inner area of sarcoid granulomas whereas the few CD8 cells that are present predominate in the outer margin of the lymphocyte rim. It has been hypothesized, therefore, that suppressor cells may limit the exaggerated immunologic response against the antigen causing sarcoidosis, thus exerting a suppressive effect on the formation of the sarcoid granuloma. Whether a defective recruitment of CD8 cells might lead to an ineffective control of the expansion of CD4 cells remains to be established. In fact, the possibility cannot be excluded that in a subset of patients who progress toward advanced disease, the equilibrium between helper and suppressor signals may be lost, favoring the persistence of antigenic pressure, the maintenance of the inflammatory response, and the evolution of the granulomatous process. Noteworthy, active sarcoidosis is characterized by the expansion of the innate regulatory T cell subset (CD4⫹/CD25bright T cells) both in the blood and in the involved organs, especially the lung [114]. T reg cells localized in the pulmonary microenvironment express the chemokine receptor CXCR3 (that binds CXCL10, abundantly secreted by sarcoid macrophages, [56]), which is absent in CD4⫹/CD25bright T lymphocytes circulating in the periphery. This regulatory population, accumulating at the sarcoid granuloma border, strongly inhibits the in vitro proliferation and IL-2 secretion of sarcoid CD4⫹CD25– lung T cells, while the secretion of TNF-␣ and, to a lesser extent IFN-␥, is only partially blocked [114]. The latter observation could be particularly relevant as TNF-␣ plays a key role in granuloma formation and the incomplete inhibition of TNF-␣ secretion may limit the control of granuloma evolution by T reg cells in vivo. Recent data focus the attention on a newly identified group of T cells with immunoregulatory functions, called CD1d-restricted natural killer T cells (CD1d-NKT cells) [115]. This subset of T lymphocytes, that bears surface markers of both natural killer and T cells, expresses a semi-invariant T cell receptor, composed of AV14-AJ18 and BV11 variable chains and recognizes antigen(s) only when presented by CD1d molecules (nonclassic MHC-like proteins). CD1d-NKT cells can rapidly produce large quantities of both

Th1- and Th2-biased cytokines when activated by a ligand, generally a glycolipid antigen. In mouse models, this subset prevents the progression of Th1 disorders such as diabetes mellitus [116, 117] and experimental allergic encephalitis [118]. Interestingly, patients with sarcoidosis have a loss or deficiency of CD1d-NKT cells, missing in peripheral blood, lung, and draining lymph nodes [119], while patients with sarcoidosis and Löfgren’s syndrome (known to have a good outcome) have a normal amount of these immunoregulatory cells. This finding strongly suggests that the loss of an immunoregulatory subset of T cells could contribute to lack of control of CD4⫹ T cell activity that persists for longer than appropriate, with collateral activation and maintenance of sarcoid events [120]. This is also consistent with previous studies indicating that in self-limited diseases greater effector cell activation leads to antigen elimination while defective/partial T lymphocyte activation results in an inefficient immune response and persistent disease [121]. It is noteworthy that CD1d-NKT cells are increased in tuberculosis [122]. The presence of an appropriate number of immunoregulatory cells may explain why patients with noncavitary tuberculosis, who have an immunopathology almost identical to sarcoidosis, are characterized by a localized and self-limiting granulomatous inflammation [119].

Conclusions

Granulomas are a complex and dynamic interface between host and pathogen. The enormous amount of

detailed biological information that continues to accumulate about granuloma formation and evolution has not resolved the key question dealing with the inability of the immune system to ultimately control and terminate the granulomatous diseases. It is easy to predict that the extensive understanding of the cells and the molecules involved as well as the timing of their involvement in granuloma formation will be helpful in the development of new therapies for granulomatous diseases. Above all the development of immunosuppressive approaches to inhibit the vicious and redundant network generated by cytokine and chemokine interactions will be a major challenge for clinicians dedicated to the management of granulomatous diseases. Alternative therapeutic strategies are also needed to modulate the cytokine production that causes most long-term pulmonary damages and the consequent development of lung fibrosis. At the same time, the knowledge of the role of regulatory/suppressor T cell subsets in the control of granuloma formation may allow for the manipulation of T cell functions during diseases in which granuloma formation is pathologic and the inciting agent is unknown, such as sarcoidosis. To specifically turn down granuloma enhancing T cell activity without the generalized immune suppression caused by current therapy would be a great advantage for the quality of life of patients with granulomatous diseases. We are still a long way from these goals, but it is likely that the current revolution in the areas of immunology and biology, sustained by high-throughput proteomic approaches, will develop new biologic therapies for these diseases.

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90 Koguchi Y, Kawakami K, Uezu K, Fukushima K, Kon S, Maeda M, Nakamoto A, Owan I, Kuba M, Kudeken N, Azuma M, Yara S, Shinzato T, Higa F, Tateyama M, Kadota J, Mukae H, Kohno S, Uede T, Saito A: High plasma osteopontin level and its relationship with interleukin-12-mediated type 1 T helper cell response in tuberculosis. Am J Respir Crit Care Med 2003;167:1355–1359. 91 Nau GJ, Guilfoile P, Chupp GL, Berman JS, Kim SJ, Kornfeld H, Young RA: A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis. Proc Natl Acad Sci USA 1997;94:6414–6419. 92 Shimizu Y, van Seventer GA, Horgan KJ, Shaw S: Costimulation of proliferative responses of resting CD4⫹ T cells by the interaction of VLA-4 and VLA-5 with fibronectin or VLA-6 with laminin. J Immunol 1990;145:59–67. 93 Galandrini R, Galluzzo E, Albi N, Grossi CE, Velardi A: Hyaluronate is costimulatory for human T cell effector functions and binds to CD44 on activated T cells. J Immunol 1994; 153:21–31. 94 Chilosi M, Menestrina F, Capelli P, Montagna L, Lestani M, Pizzolo G, Cipriani A, Agostini C, Trentin L, Zambello RGS: Immunohistochemical analysis of sarcoid granulomas: evaluation of Ki67⫹ and interleukin-1⫹ cells. Am J Pathol 1988;131:191–198. 95 Hogan LH, Macvilay K, Barger B, Co D, Malkovska I, Fennelly G, Sandor M: Mycobacterium bovis strain bacillus Calmette-Guerin-induced liver granulomas contain a diverse TCR repertoire, but a monoclonal T cell population is sufficient for protective granuloma formation. J Immunol 2001;166: 6367–6375. 96 Grunewald J, Janson CH, Eklund A, Ohrn M, Olerup O, Persson U, Wigzell H: Restricted V alpha 2.3 gene usage by CD4⫹ T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLADR3. Eur J Immunol 1992;22:129–135. 97 Trentin L, Zambello R, Facco M, Tassinari C, Sancetta R, Siviero M, Cerutti A, Cipriani A, Marcer G, Majori M, Pesci A, Agostini C, Semenzato G: Selection of T lymphocytes bearing limited TCR-Vbeta regions in the lung of hypersensitivity pneumonitis and sarcoidosis. Am J Respir Crit Care Med 1997;155: 587–596. 98 Savill J: Apoptosis in resolution of inflammation. J Leukoc Biol 1997;61:375–380. 99 Dai H, Guzman J, Costabel U: Increased expression of apoptosis signalling receptors by alveolar macrophages in sarcoidosis. Eur Respir J 1999;13:1451–1454. 100 Agostini C, Perin A, Semenzato G: Cell apoptosis and granulomatous lung diseases. Curr Opin Pulm Med 1998;4:261–266.

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101 Xaus J, Besalduch N, Comalada M, Marcoval J, Pujol R, Mana J, Celada A: High expression of p21 Waf1 in sarcoid granulomas: a putative role for long-lasting inflammation. J Leukoc Biol 2003;74:295–301. 102 Ruoslahti E, Reed JC: Anchorage dependence, integrins, and apoptosis. Cell 1994;77: 477–478. 103 Xaus J, Cardo M, Valledor AF, Soler C, Lloberas J, Celada A: Interferon gamma induces the expression of p21waf-1 and arrests macrophage cell cycle, preventing induction of apoptosis. Immunity 1999;11: 103–113. 104 Bulfone-Paus S, Ungureanu D, Pohl T, Lindner G, Paus R, Ruckert R, Krause H, Kunzendorf U: Interleukin-15 protects from lethal apoptosis in vivo. Nat Med 1997;3:1124–1128. 105 Stridh H, Planck A, Gigliotti D, Eklund A, Grunewald J: Apoptosis resistant bronchoalveolar lavage (BAL) fluid lymphocytes in sarcoidosis. Thorax 2002;57:897–901. 106 Sandler NG, Mentink-Kane MM, Cheever AW, Wynn TA: Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair. J Immunol 2003;171:3655–3667. 107 Agostini C, Semenzato G: Immunology of idiopathic pulmonary fibrosis. Curr Opin Pulm Med 1996;2:364–369. 108 Inoue Y, King TE Jr: Tinkle SS, Dockstader K, Newman LS. Human mast cell basic fibroblast growth factor in pulmonary fibrotic disorders. Am J Pathol 1996;149:2037–2054. 109 Marshall BG, Wangoo A, Cook HT, Shaw RJ: Increased inflammatory cytokines and new collagen formation in cutaneous tuberculosis and sarcoidosis. Thorax 1996;51: 1253–1261. 110 Chen Q, Rabach L, Noble P, Zheng T, Lee CG, Homer RJ, Elias JA. IL-11 receptor alpha in the pathogenesis of IL-13-induced inflammation and remodeling. J Immunol 2005;174: 2305–2313. 111 Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG: A CD4⫹ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737–742. 112 Weiner HL: Induction and mechanism of action of transforming growth factor-betasecreting Th3 regulatory cells. Immunol Rev 2001;182:207–214. 113 Chensue SW, Wellhausen SR, Boros DL: Modulation of granulomatous hypersensitivity. II. Participation of Ly 1⫹ and Ly 2⫹ T lymphocytes in the suppression of granuloma formation and lymphokine production in Schistosoma mansoni-infected mice. J Immunol 1981;127: 363–367.


114 Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, Kambouchner M, Valeyre D, Chapelon-Abric C, Debre P, Piette JC, Gorochov G: The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 2006;203:359–370. 115 Kronenberg M, Gapin L: The unconventional lifestyle of NKT cells. Nat Rev Immunol 2002;2:557–568. 116 Sharif S, Arreaza GA, Zucker P, Mi QS, Sondhi J, Naidenko OV, Kronenberg M, Koezuka Y, Delovitch TL, Gombert JM, Leite-De-Moraes M, Gouarin C, Zhu R, Hameg A, Nakayama T, Taniguchi M, Lepault F, Lehuen A, Bach JF, Herbelin A: Activation of natural killer T cells by alpha-galactosylceramide treatment prevents the onset and recurrence of autoimmune type 1 diabetes. Nat Med 2001;7:1057–1062. 117 Hong S, Wilson MT, Serizawa I, Wu L, Singh N, Naidenko OV, Miura T, Haba T, Scherer DC, Wei J, Kronenberg M, Koezuka Y, Van Kaer L: The natural killer T-cell ligand alphagalactosylceramide prevents autoimmune diabetes in non-obese diabetic mice. Nat Med 2001;7: 1052–1056. 118 Singh AK, Wilson MT, Hong S, OlivaresVillagomez D, Du C, Stanic AK, Joyce S, Sriram S, Koezuka Y, Van Kaer L: Natural killer T cell activation protects mice against experimental autoimmune encephalomyelitis. J Exp Med 2001;194:1801–1811. 119 Ho LP, Urban BC, Thickett DR, Davies RJ, McMichael AJ: Deficiency of a subset of T-cells with immunoregulatory properties in sarcoidosis. Lancet 2005;365:1062–1072. 120 James GD, Semenzato G: A missing link in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2005;22:163–165. 121 Kinjo Y, Wu D, Kim G, Xing GW, Poles MA, Ho DD, Tsuji M, Kawahara K, Wong CH, Kronenberg M: Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 2005;434:520–525. 122 Gansert JL, Kiessler V, Engele M, Wittke F, Rollinghoff M, Krensky AM, Porcelli SA, Modlin RL, Stenger S: Human NKT cells express granulysin and exhibit antimycobacterial activity. J Immunol 2003;170: 3154–3161.

Gianpietro Semenzato, MD Università di Padova, Dipartimento di Medicina Clinica e Sperimentale Ematologia e Immunologia Clinica Via Giustiniani 2 IT–35128 Padova (Italy) Tel. ⫹39 049 821 2298 Fax ⫹39 049 821 1970 E-Mail [email protected]


Pathogenesis of Idiopathic Pulmonary Fibrosis Paul W. Noble Yale University School of Medicine, Section of Pulmonary and Critical Care Medicine, New Haven, Conn., USA

Abstract Recent years have seen a robust influx of exciting new observations regarding the mechanisms that regulate the initiation and progression of pulmonary fibrosis. New therapeutic targets include the epithelial cell, myofibroblast as well as chronic inflammation. A schematic view of the complex biological processes that have been implicated in the pathogenesis of pulmonary fibrosis is presented. Unfortunately, it remains unknown if ‘standard’ therapy of corticosteroids and cytotoxic medications is more effective than placebo alone in the treatment of IPF. However, new insights into pathogenesis are questioning the validity of an immunosuppressive approach and generating hypotheses for new clinical trials. IPF is a complex disorder and no unifying hypothesis has been identified at present that explains all the abnormalities. However, tremendous strides are being made in elucidating novel mechanisms for pathogenesis and these targets are being tested in the clinic. Copyright © 2007 S. Karger AG, Basel

Idiopathic pulmonary fibrosis (IPF) is a progressive diffuse parenchymal lung disease of unknown etiology. The last two decades have witnessed an improvement in the specificity of the diagnosis of IPF, but the pathogenesis remains poorly understood. IPF has emerged as a distinct clinical, physiologic, radiographic, and pathologic entity, but a true ‘gold standard’ for diagnosis remains elusive [1]. The pathologic description of IPF was originally delineated by Leibow and colleagues and termed ‘usual interstitial

pneumonia (UIP)’. This description has thus far stood the test of time and concepts of pathogenesis have sought to explain this unique pattern of lung fibrosis characterized by areas of relatively uninvolved lung juxtaposed to regions of subpleural fibrosis as well as dense fibrosis (figs. 1, 2). Since the original description of the Idiopathic Interstitial Pneumonias there has been a refinement in the pathologic descriptions and the most recent classification represents a consensus of leading experts in the field [2]. Unfortunately, the prognosis of UIP/IPF remains poor and several recent studies suggest a mean survival of about 5 years [3–5]. In studies in which this description has been identified by skilled observers in lung biopsies from patients with the clinical, physiologic and radiographic findings characteristic of IPF, the majority of patients have demonstrated progressive disease and died despite treatment with high doses of corticosteroids and/or potent cytotoxic immunosuppressants such as cyclophosphamide and azathioprine. This is in contrast to patients that have distinct pathologic descriptions as well as distinguishing clinical, physiologic and radiographic features that allow for the characterization of non-specific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RBILD) or cryptogenic organizing pneumonia (COP), NSIP has been subdivided into cellular and fibrotic forms that differ in prognosis [6, 7]. This insight may also provide clues to pathogenesis. When a non-UIP pattern in recognized on surgical biopsy (whether fibrotic or cellular), it appears that patients have a much greater possibility of

inflammatory response [8–12]. This review will highlight aspects of current thoughts on pathogenesis of IFP and expand upon recent reviews [13–15].

Inflammatory Hypothesis in the Pathogenesis of IPF

Fig. 1. Light-microscopic view of a surgical lung biopsy stained with

hematoxylin and eosin demonstrating the patchy nature of fibrosis with subpleural prediliction in usual interstitial pneumonia. ⫻4.


hematoxylin and eosin demonstrating the juxtaposition of normal lung with fibrosis in usual interstitial pneumonia. ⫻10.

improving lung function by treatment with immunosuppressive therapy relative to UIP. The combination of the unique pathologic features of UIP on biopsy, the progressive clinical course and resistance to anti-inflammatory therapy constitute the cardinal manifestations of what is now termed IPF/UIP and have led to recent suggestions that new therapies should be directed at regulating fibroblast functions rather than targeting the

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Recent observations have led to new concepts in the pathogenesis of IPF. These observations are derived from clinical specimens from patients with IPF as well as from animal models of fibrosis. The preceding two decades have been dominated by what has been described as the ‘inflammatory’ concept of pulmonary fibrosis. This was largely derived from the observation that bronchoalveolar lavage fluid from patients with IPF had increased numbers of inflammatory cells (mostly neutrophils and eosinophils) relative to normal individuals [16]. The concept that emerged from these observations was that IPF resulted from a persistent inflammatory response to an exogenous insult leading to progressive fibrosis. Therapies were therefore directed at abrogating inflammation with corticosteroids. One of the clinical hallmarks of advanced IPF/UIP is the development of lower lung zone traction bronchiectasis. A revised interpretation of the inflammatory response in IPF is that the chronic inflammation is more likely explained by the structural abnormalities in lung architecture leading to altered cell trafficking. That is to say, the airway inflammation is likely a result, rather than a cause of the fibrosis. A study that contributed to the misconception that IPF is the result of unremitting inflammation found a strong correlation between severity of lung disease in IPF and levels of the CXC chemokine IL-8/CXCL8 measured in lung tissue [17]. IL-8/CXCL8 has potent chemotactic properties for neutrophils and the concept was that by targeting IL-8/CXCL8 with anti-inflammatory agents, fibrosis would be prevented. Recent observations have led to a revised hypothesis of the key elements in the pathogenesis of progressive pulmonary fibrosis. While the role of inflammation in the pathology of IPF remains unresolved, it is difficult to ignore the lack of efficacy of corticosteroids.

Role of the Alveolar Epithelial Cell in IPF Pathogenesis

An emerging body of literature has accumulated in recent years to suggest that abnormalities in alveolar type II cell injury and repair may be a critical feature in the pathogenesis of pulmonary fibrosis. Ultrastructural studies have

demonstrated alveolar type II cell injury and apoptosis in lung biopsies from IPF patients [18]. However, the nature of the injury to the alveolar epithelium remains unknown. Studies from Hara and colleagues have demonstrated increased expression of pro-apoptotic proteins in alveolar epithelial cells and in BAL from IPF patients [19–21]. More recent data have suggested that there is increased oxidative stress in alveolar epithelium in IPF patients [19, 22]. In addition, proof of principle experiments using the bleomycin model of lung injury and fibrosis in animal models have suggested that inhibiting epithelial cell apoptosis, with a variety of approaches including inhibiting the Fas-Fas ligand pathway, inhibiting production of angiotensin and blocking caspase activation all abrogate the development of experimental fibrosis [23, 24]. Uhal and colleagues [25] have suggested that IPF fibroblasts produce angiotensin peptides that promote epithelial cell apoptosis. More recently, transforming growth factor-␤ (TGF-␤) has been demonstrated to promote epithelial cell apoptosis in vitro and studies with TGF-␤ transgenic mice in vivo have suggested that lung epithelial cell apoptosis is a critical early event in the pathogenesis of pulmonary fibrosis [26, 27]. An additional mechanism proposed to explain epithelial cell apoptosis is increased production of oxidants in IPF. Several studies have shown excessive oxidant production in IPF as well as deficiencies in glutathione production [28–30]. A recently published clinical trial compared the efficacy of prednisone and azathioprine to prednisone, azathioprine and N-acetyl cysteine in patients with IPF. The results showed a modest decrease in the rate of decline in lung function in the group that received N-acetyl cysteine compared to the group that did not [31]. Collectively, these data suggest that novel approaches to alleviating oxidant stress in IPF may have clinical utility. An essential and unique element in the progressive pulmonary fibrosis of IPF appears to be the loss of the integrity of the subepithelial basement membrane [18]. This appears to be a relatively unique feature of IPF/UIP. One potential explanation for the loss of basement membrane may be that alveolar epithelial cell death leads to an absence of the protective barrier and exposure of the underlying basement membrane to oxidative injury resulting in degradation of key constituents of basement membrane. Another possibility includes the localized activation of metalloproteinases that cleave basement membrane proteins such as laminin and collagen. Hyperplastic alveolar type II cells are a common feature of the pathology of UIP [18]. ‘Frustrated’ epithelial cell generation occurs as a result of a failure of epithelial cells to attach to the underlying basement membrane and provide signals to terminate

Pathogenesis of IPF

epithelial cell proliferation. A difference in re-epithelialization has recently been demonstrated between IPF and cryptogenic organizing pneumonia (COP) [32, 33]. Although many of the same growth factors accumulate in lung tissue in IPF and COP, the intraluminal fibroblast accumulation often resolves spontaneously or with corticosteroid therapy in COP but not in IPF. The mechanisms to explain this event are unknown, but one possibility is the failure of reepithelialization in IPF results in the inability to generate a signal to stop growth factor production. The rationale for this is that a variety of growth factors accumulate following epithelial cell injury in order to promote epithelial cell proliferation. These include keratinocyte growth factor, TGF-␣, TGF-␤, insulin-like growth factor-1, platelet-derived growth factors, fibroblast growth factor-2 and hepatocyte growth factor. Many of these growth factors activate tyrosine kinase signaling pathways that promote fibroblast proliferation and matrix production. Therefore, a downstream consequence of ‘frustrated’ epithelial cell regeneration would be recruitment of fibroblasts and myofibroblasts. In essence, signals to recruit and maintain a pool of mesenchymal cells could be provided from efforts to repair damaged epithelium. Alternatively, frustrated epithelial regeneration could lead to activation of aberrant signaling pathways triggering mesenchymal transformation as suggested by the finding of evidence of Wnt/␤-catenin signaling in IPF epithelium [34]. Another potential mechanism by which the epithelium could contribute to fibrogenesis is through epithelial-mesenchymal transformation (EMT). Considerable evidence has accumulated suggesting that this may be an important mechanism for renal fibrosis [35]. Evidence has been less convincing in the lung, but a recent study provided evidence in favor TGF-␤-promoting EMT in isolated alveolar epithelial cells [36].

Aberrant Vascular Remodeling in Pulmonary Fibrosis

Abnormalities in vascular remodeling are an important component of the pathology of IPF. Pulmonary hypertension is becoming recognized as an important clinical component of progressive IPF in some patients [37]. A role for increased angiogenesis in the progression of pulmonary fibrosis has been suggested by both animal models and from clinical specimens from patients with IPF [38, 39]. This increased angiogenic activity has been attributed to an imbalance of pro-angiogenic chemokines (IL-8, ENA-78) and anti-angiogenic C-X-C chemokines (IP-10/CXCL10). IP-10/CXCL10 is induced by interferon-␥ (IFN-␥) [40].

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Several studies in both animals and humans have suggested that IFN-␥ inhibits progressive pulmonary fibrosis [41, 42]. However, other molecules that inhibit endothelial cell apoptosis such as vascular endothelial cell growth factor (VEGF) may also contribute to increased angiogenesis. Recent studies have suggested that there may be heterogeneous remodeling of lung vessels in IPF [43, 44]. In contrast to the concept that progressive IPF is associated with increased angiogenesis are the recent reports that there is decreased expression of VEGF and endothelial cell proliferation in IPF. In particular, it has been suggested that there is a paucity of of pro-angiogenic proteins in the fibroblastic foci in UIP in comparison to the granulation tissue is organizing pneumonia [45–47]. In addition, the angiostatic protein pigment epithelium-derived factor (PEDF) is increased in IPF [48]. One potential explanation to reconcile these findings is that angiogenesis may be enhanced in the earlier stages of the development of UIP, while there is a loss of blood vessels in the more advanced stages.

Matrix Remodeling

The essential hallmark of IPF is an excessive production of extracellular matrix molecules including collagens, tenascin, and proteoglycans and glysosaminoglycans. There is clearly an imbalance between the production and degradation of extracellular matrix. Data from Selman and Pardo have suggested that there is increased production of inhibitors of matrix degradation (TIMPs), accounting for the inability to degrade matrix [49]. One of the properties of TGF-␤ is promoting matrix production while inhibiting TIMP production. It is therefore unclear if the decreased production of TIMPs is an inherent defect in IPF (such as a polymorphism) or a consequence of excessive TGF-␤. It is also unclear what role matrix degradation plays in the pathogenesis of progressive fibrosis. One concept is that matrix degradation is essential for removing scar tissues. However, recent studies have suggested that matrix degradation products may stimulate inflammatory gene expression and could contribute to ongoing fibrosis [50]. An attractive hypothesis is that there is local activation of matrix degrading enzymes in the distal alveolar subepithelial regions. This could lead to basement membrane destruction and initiate the cascade of events leading to epithelial cell proliferation. Evidence for the involvement of matrix degrading enzymes in the pathogenesis of IPF was provided by gene expression analyses using a microarray approach [51]. Although this approach only represents one point in time, new insights into pathways leading to

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fibrogenesis appears possible [52]. Most of the published studies to date appear to have examined tissue from patients with advanced disease. More useful information may be gained from lung biopsy material from IPF patients without advanced honeycomb changes on chest CAT scan. Recent data have shown that microarray analysis can identify profiles of genes that distinguish IPF/UIP from chronic hypersensitivity pneumonitis [53].

Fibrogenic Cytokines

One of the rationales for corticosteroids and immunosuppressive therapy for IPF has been to target the immune system. This therapy has proven effective in autoimmune disorders such as Wegener granulomatosis and systemic vasculitides, but IPF does not appear to be in the same category. However, data have been obtained suggesting that a cytokine imbalance may exist in IPF. RT-PCR studies have suggested that there is increased production of Th2 cytokines (IL-4, IL-5 and IL-13) in lung tissue of IPF patients [54]. In addition, preliminary data suggesting that IPF may represent a relative IFN-␥ deficiency have recently been reported [41] but not verified. The link between Th2 cytokines and tissue fibrosis has been established in animal models, but the data in humans that there is a cause and effect relationship are lacking. Recently, overexpression of IL-13 in the lung using transgenic mice has been shown to result in accumulation of active TGF-␤ and increased tissue fibrosis [55]. Thus data do exist to suggest that directing therapies to restore the balance of Th1 and Th2 cytokines may be a rational approach in IPF.

Fibroblast Growth Factors in Pulmonary Fibrosis

A variety of growth factors that influence fibroblast and myofibroblast functions have been shown to be produced in the lung tissue of IPF patients and mediate the pathogenesis of experimental fibrosis [56, 57]. TGF-␤1 has been shown to be a critical mediator of lung fibrosis in animal models [58, 59]. A number of studies have shown that antagonizing TGF-␤1 prevents the development of tissue fibrosis [59]. However, concerns have been raised about potential consequences of TGF-␤1 blockade because of the finding that TGF-␤1 knockout mice die of unremitting inflammation [60]. In addition, failure to activate TGF-␤1 following fibrotic lung injury has been shown to not only prevent fibrosis, but also result in chronic lung inflammation. However, recent data in mice have shown that long-term treatment with

a TGF-␤1 antagonist did not result in significant immune disturbances [61]. Targeted overexpression of TGF-␤1 has been shown to produce progressive fibrosis [62]. Therefore, targeting growth factor signaling pathways, such as TGF-␤1, PDGF or IGF-1 with small molecules that block receptorligand interactions or inhibit tyrosine kinase signaling pathways may be important potential therapeutic strategies for IPF. While growth factors such as IGF-1, PDGF A and B and CTGF are expressed in fibrotic lung tissue, the direct contributions of these mediators to progressive fibrosis are unknown. In addition to effects on fibroblast proliferation, growth factors such as IGF-1 may promote fibroblast (and myofibroblast) survival. IGF-1 has been shown to inhibit apoptosis by activating the Akt survival pathway [63]. This may have important consequences for maintenance of a profibrotic environment. Recent experimental data in animal models of fibrosis has suggested that imatinib mysylate (Gleevec) may have a role in preventing lung fibrosis [64, 65]. There is a phase II clinical trial underway in the United States evaluating the efficacy of imatinib mesylate in IPF.

Fibroblast Homeostasis

The concept that fibroblasts from IPF patients have a unique phenotype is generally accepted although the specifics of the phenotype have been different in various studies [66–68]. Raghu et al. [68] made the observation that fibroblasts from different regions of the lung had different growth rates. Subsequent studies have shown altered production of TIMPs and other mediators suggesting that IPF fibroblasts have different properties than normal lung fibroblasts. Some discrepancies exist on whether IPF fibroblasts proliferate more or less in comparison to normal lung fibroblasts [49]. In addition, some studies have suggested increased rates of apoptosis consistent with rapidly turning over subpopulations [49]. One of the challenges of these studies is to differentiate a primary defect in the fibroblast versus altered fibroblast effector functions as a result of chronic stimulation from growth factors or other signaling molecules. More recent studies have suggested that fibroblasts isolated from IPF patients may produce chemokines and express chemokine receptors, but a distinct phenotype for UIP fibroblasts has not emerged [69].

Myofibroblast in Pulmonary Fibrosis

Recently, much attention has been focused on the role of the myofibroblast in the pathogenesis of IPF. Kuhn and

Pathogenesis of IPF


hematoxylin and eosin demonstrating a fibroblastic focus. ⫻10.

McDonald [70] described myofibroblasts in a contractile phase in fibroblastic foci from IPF lung biopsies in 1991. Recent attention was generated by the observation from two different groups that the frequency of fibroblastic foci in lung biopsies from IPF patients correlates with poor prognosis [71, 72]. The defining characteristic of the myofibroblast in the fibroblastic foci is the production of new collagen and fibronectin at the leading edge of existing scar. These foci have a unique pattern and are less common in non-UIP fibrotic lung diseases. One of the very intriguing aspects of fibroblastic foci is that they appear to be in continuum with the subepithelium (fig. 3). Myofibroblasts have contractile properties and stain positive for ␣ smooth muscle actin. In normal wound healing, myofibroblasts appear transiently but mechanisms that regulate the phenotype and maintenance of myofibroblasts are largely unknown [73, 74]. Recently it has been shown that the NH2-terminal peptide of ␣-smooth muscle actin inhibits myofibroblast contractile activity [75]. Myofibroblasts have been shown to accumulate transiently in bleomycin-induced lung fibrosis [76]. Immunohistochemical studies have suggested that they are important in the production of newly synthesized collagen [76]. However, myofibroblasts are present transiently following bleomycin-induced lung fibrosis and are largely vanished from lung tissue by day 21 [76]. The source of myofibroblasts is of great current interest. It is not known whether normal fibroblasts differentiate into myofibroblasts in vivo, but TGF-␤ has been shown to induce the expression of ␣-smooth muscle actin in normal lung fibroblasts and promote contractile activity [77, 78]. More recently, Phan and colleagues made the observation that bone marrow-derived

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precursors can contribute to the fibroblast pool following lung injury [79]. Interestingly, the bone marrow-derived precursors did not appear to be capable of acquiring the myofibroblast phenotype in response to TGF-␤. Work from Strieter and colleagues have suggested that circulating fibrocytes traffic to the lung following injury and may be a source of myofibroblasts [80]. In addition, TGF-␤ has been shown to inhibit apoptosis of myofibroblasts that is stimulated by IL-1 [81]. PDGF-A has been shown to be required for lung alveolar myofibroblast development [82]. In addition to growth factors, thrombin has been shown to differentiate normal lung fibroblasts to a myofibroblast phenotype in vitro [83]. Taken together, these studies suggest that myofibroblasts may have an important role in mediating lung fibrosis, however, in vivo studies demonstrating that targeting myofibroblast function can regulate the progression of lung fibrosis have not been obtained.

Host Responses in Pulmonary Fibrosis

One of the hallmarks of the UIP lesion is that areas of established fibrosis and tissue remodeling are intermixed with areas of normal lung architecture and transition zones where fibroblastic foci are found. This observation suggests that events are occurring at distinct points in time. This suggests that an important component of pathogenesis is to understand the host factors that limit the extent of fibrosis after lung injury and determine if they are defective in IPF patients. The concept of targeting the next ‘hit’ may be an important concept in pathogenesis and treatment. A very

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interesting observation emerged from the largest randomized placebo controlled treatment trial published in IPF [84]. 330 patients were randomized to receive either interferon-␥-1b for a minimum of 48 weeks. An effort was made to exclude patients with severe physiologic impairment. Despite this effort, 17% of the placebo-treated patients died during the trial period. This suggested that IPF patients with relatively preserved lung function might have precipitous declines. 10% of the patients who received interferon-␥-1b died during the study period. An analysis of the patients in the placebo group that died revealed that half of the deaths occurred over an acute or subacute time frame. There was no difference between the groups in the progression of disease as defined by measures of lung function. This intriguing observation must be followed up, and if confirmed suggests that augmenting host defense mechanisms may be a novel approach to therapy in IPF. Interferon-␥-1b is pleiotropic cytokine that has an important role in host defense against infection and plays a role in tumor surveillance [85]. Defects in endogenous mechanisms that limit fibrosis after acute lung injury may contribute to progressive fibrosis. The prostaglandin PGE2 is an endogenous mediator that has been shown to have antifibrotic properties [86]. Fibroblasts from IPF patients have been shown to have diminished capacity to produce PGE2 [87]. Although it is not known if this is an epiphenomena, a failure of sufficient antifibrotic responses to injury could contribute to disease progression. A recent study examined the role of the interferon-␥, IP-10/CXCL10 and CXCR3 axis in lung injury and repair [88]. In mice with a targeted deletion of CXCR3, lung injury resulted in an impaired production of interferon-␥. The transient failure to

produce this cytokine critical to host defense resulted in an exaggerated fibrotic response. An interesting report suggested that herpesvirus DNA is consistently detected in lungs of IPF patients [89]. The viral DNA was detected in alveolar epithelial cells. This observation raised the intriguing possibility that epithelial injury could occur in response to such viral infections and repeated episodes of infection or reactivation could be a source of repeated injury. The same group examined the fibrotic response to murine gamma herpesvirus in mice with a targeted deletion in the interferon-␥ receptor. The result was an augmented Th2-driven fibrotic response [90]. Collectively, these data suggest that abnormalities in host defense could be an under appreciated aspect of pathogenesis in IPF (fig. 4).

Acute Exacerbations in IPF: A Clue to Pathogenesis?

The natural history of IPF has remained elusive, but some interesting questions have been raised with the advent

of prospective, placebo-controlled randomized clinical trials in IPF. Two such studies that have recently been published have suggested that a subset of IPF patients may have a rapid decline in lung function and be at great risk for death [84, 91, 92]. Surgical lung biopsies on patients exhibiting a rapid decline in lung function have revealed a histological pattern of diffuse alveolar damage with underlying usual interstitial pneumonia [93]. Animal studies have suggested that inhibiting coagulation may have an effect of the development of lung fibrosis following acute lung injury [94]. Recently, a clinical study examined the role of anticoagulation in patients that had evidence of clinical deterioration in IPF and suggested that there may be a survival advantage in favor of anticoagulation [95]. This result needs to be followed with a prospective randomized control trial, but raises the interesting possibility that targeting acute lung injury over a long period of time may be a novel approach to the treatment of IPF. It remains unknown if IPF is the result of multiple microscopic episodes of lung injury, but this is an appealing hypothesis that is being tested in animal models.

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Paul W. Noble, MD Yale University School of Medicine, Section of Pulmonary and Critical Care Medicine 441-C CAB, 333 Cedar Street New Haven, CT 06520–8057 (USA) Tel. ⫹1 203 785 3627, Fax ⫹1 203 785 3826 E-Mail [email protected]

109


Basics of Pulmonary Vasculitis Jan Willem Cohen Tervaert Jan G.M.C. Damoiseaux Department of Clinical and Experimental Immunology, University Hospital Maastricht, Maastricht, The Netherlands

Abstract Different forms of vasculitis may induce pulmonary vasculitis. Two types of autoantibodies are clearly incriminated in the pathogenesis of this disease: ANCA and anti-GBM antibodies. For both diseases good animal models now exist. These models are important for identifying pathophysiological mechanisms and for studying new forms of therapy. Copyright © 2007 S. Karger AG, Basel

Vasculitis is a pathological process characterized by inflammation and necrosis of blood vessel walls. The vasculitic process can affect blood vessels of any type, size or location, and therefore can cause dysfunction in virtually any organ system including the lungs. Usually, pulmonary vasculitis is asymptomatic. Most frequently reported symptoms are cough, dyspnea, asthma, chest pain, inspiratory stridor and/or hemoptysis that is sometimes very severe. Chest radiographs may show nodular shadows (sometimes with central necrosis), infiltrative changes, pleural effusions, atelectasis, lymphadenopathy and/or other findings. The symptoms of pulmonary vasculitis are often observed in combination with other manifestations of vasculitis, such as arthralgias, constitutional symptoms, episcleritis, palpable purpura, cutaneous ulcers, ear-nose-throat (ENT) manifestations, microscopic hematuria and/or proteinuria. Pulmonary vasculitis may be associated with a number of clinical syndromes (secondary forms of vasculitis; table 1), whereas classification of patients suffering from

primary vasculitides is based on the predominant type and caliber of blood vessels involved (table 2) [1]. Most frequently, pulmonary vasculitis is observed in vasculitic syndromes that preferentially affect small vessels (arterioles, venules and capillaries). This group includes the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (i.e. Wegener’s granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome), anti-glomerular basement membrane (GBM) disease, cryoglobulinemic vasculitis and Henoch-Schönlein purpura (HSP). Large and/or medium-sized vessel vasculitides only occasionally affect the lungs. Therefore, this review of the basics of pulmonary vasculitis will focus on the pathogenic mechanisms of small vessel vasculitides.

Pathophysiological Mechanisms

In vasculitis, an influx of inflammatory cells from both the innate and the acquired immune system plays a pivotal role. In secondary forms of vasculitis such as caused by infections, the inflammatory response may be a result of invasion of the vessel wall by pathogens. A well-known example is invasion by rickettsial organisms that are found for instance in Rocky Mountain spotted fever. Noninfectious immunological mechanisms that may cause pulmonary vasculitis include cell-mediated inflammation, immune complex-mediated inflammation and inflammation induced by ANCA. In anti-GBM associated disease, the autoantibody itself induces the disease by a type II hypersensitivity reaction.

Table 1. Secondary forms of vasculitis

Table 3. Characteristics of ANCA-associated vasculitides

Infection-related vasculitis Immune complex mediated, e.g. hepatitis B, endocarditis Direct invasion of vessels, e.g. aspergillus, rickettsiae, mycobacteriae Vasculitis secondary to collagen vascular diseases, e.g. rheumatoid arthritis, systemic lupus erythematosus Vasculitis secondary to sarcoidosis Vasculitis in malignancies, e.g. lymphomatoid granulomatosis, hairy cell leukaemia Vasculitis due to drug reactions, e.g. hydralazine, propylthiouracil (PTU), other antithyreoid drugs Vasculitis in substance abuse, e.g. cocaine Miscellaneous secondary forms of vasculitis, e.g. transplant vasculitis Pseudovasculitis syndromes, e.g. atrial myxoma

Disease

Table 2. Classification of vasculitis

Idiopathic vasculitides Affecting predominantly large-sized blood vessels Takayasu’s arteritis Giant cell arteritis/temporal arteritis Affecting predominantly medium-sized blood vessels Polyarteritis nodosa Kawasaki’s disease Affecting predominantly small-sized blood vessels ANCA-associated vasculitis Churg-Strauss syndrome Wegener’s granulomatosis Microscopic polyangiitis Anti-GBM disease Cryoglobulinemic vasculitis Henoch-Schönlein purpura

Also in ANCA-associated vasculitis, ANCA probably induce vasculitis (see below). However, in both conditions there are indications that T cells may play an important pathophysiological role as well. In cryoglobulinemia, antibodies that precipitate under conditions of cold and solubilize on rewarming are present. Especially in type II cryoglobulinemia, i.e. cryoglobulins that contain a monoclonal IgM antibody with rheumatoid factor activity and a polyclonal IgG antibody, vasculitis may develop when immune complexes deposit in blood vessel walls and activate complement. In HSP, IgA is suggested to play a pivotal role in the pathogenesis since IgA deposition is found in inflamed blood vessels. Typically, only IgA1, but not IgA2 is found in these deposits. Aberrant glycosylation of IgA1 has been postulated to play an important role in the pathophysiology since these IgA1 molecules have the tendency to form macro-molecular complexes that can activate the alternative pathway of complement [2].

Basics of Pulmonary Vasculitis

Clinical

MPO-ANCA PR3-ANCA

Churg-Strauss asthma, eosinophilia, 30–70% of syndrome neuropathy patients Wegener’s nose bleeds, 10–30% of granulomatosis nephritis, lung patients lesions Microscopic nephritis, alveolar 30–70% of polyangiitis lung hemorrhage, patients purpura

⬍10% of patients ⬎70% of patients 10–30% of patients

In pulmonary vasculitis, most patients appear to be suffering from ANCA associated disease and/or anti-GBM associated disease. Therefore, the remainder of this review will consider the pathogenesis of these two forms of vasculitis.

ANCA-Associated Vasculitis

The ANCA-associated vasculitides consist of three different diseases: Wegener’s granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome. ANCA are frequently but not always found in these forms of vasculitis (see table 3) [3]. ANCA in these vasculitides are directed against constituents of the primary granules of neutrophils and the lysosomes of monocytes. These autoantibodies are directed against either proteinase 3 (PR3), a 29-kDa neutral serine protease, or myeloperoxidase (MPO), a 140-kDa enzyme involved in the generation of reactive oxygen species. ANCA that recognize PR3 produce a characteristic granular cytoplasmic staining pattern on ethanol fixed granulocytes when detected by a standard indirect immunofluorescence technique (C-ANCA). ANCA that react with MPO, in contrast, produce a perinuclear staining pattern (P-ANCA). In ANCA-associated pulmonary-renal syndrome either PR3-ANCA or MPO-ANCA can be found. About 30% of these patients with pulmonary-renal syndrome do not only have ANCA but also anti-GBM antibodies. In some of these patients, ANCA-associated disease may come first [4]; in other patients, however, anti-GBM disease precedes the presence of ANCA [5]. A minor subset of the patients with ANCA-associated vasculitis has only isolated necrotizing alveolar capillaritis [6, 7]. Generally, ANCA in these forms of vasculitis are of the IgG isotype. IgM ANCA may also be present. Only occasionally is IgM ANCA without IgG ANCA found [8]. Detection of PR3- and/or MPO-ANCA

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has proven to be an important diagnostic marker for ANCA-associated vasculitis. In addition, the determination of ANCA titers is of great value to predict and possibly to prevent relapses during follow-up [9]. Given the strong association of ANCA and its titers with disease activity, hypotheses have been raised about the possible origin and pathogenic role of ANCA. Furthermore, the pathogenic role of ANCA is strengthened by the observation of a case in which transfer of maternal ANCA during pregnancy resulted in pulmonary hemorrhage and abnormal renal function within 48 h after delivery [10].

Induction of ANCA

How ANCA are induced is not known. One hypothesis is that ANCA are induced when self-reactive lymphocytes escape from self-tolerance and become activated. Activating factors may be infectious agents, other environmental factors, such as silica, or drugs such as anti-thyroid drugs. These environmental triggers, in combination with genetic factors, may result in loss of self-tolerance. It may be the result of shared epitopes between pathogens and hosts (‘molecular mimicry’), activation of autoreactive lymphocytes by super-antigens or direct activation of lymphocytes by factors such as lipopolysaccharide, peptidoglycan and/or CpG motives in bacterial DNA. Furthermore, enhanced processing and presentation of autoantigens by antigen-presenting cells recruited to the inflammatory site may play a role in the priming of autoreactive lymphocytes [11]. Patients with ANCA-associated vasculitis often report prior infections and/or exposure to environmental factors such as silica. In addition, sometimes ANCA can be induced during an infectious disease and may disappear after treatment with antibiotics. Different microbial agents have been described in ANCA-associated vasculitis [12]. The most important infectious association was found in Wegener’s granulomatosis. In these patients, chronic nasal carriage of Staphylococcus aureus is found in about 60–70% of the patients. Patients that are chronically carrying S. aureus relapse nearly 8 times more frequently than noncarriers [13]. We have demonstrated that about 40–50% of these S. aureus strains are positive for staphylococcal superantigens [14]. Superantigens that are most frequently found are TSST-1, staphylococcal enterotoxin A and C, and exfoliative toxin A. Importantly, in a long-term observational study, we found that TSST-1 positive S. aureus strains but not strains that were positive for other superantigens increased the risk for relapse of Wegener’s granulomatosis.

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A clear temporal relation between the presence of superantigen positive S. aureus strains and T-cell activation, however, could not be found in our patients. Interestingly, antimicrobial agents reduce the incidence of relapses in Wegener’s granulomatosis [15]. Recently, Pendergraft et al. [16] suggested that sequences of S. aureus were complementary to portions of PR3, indicating that S. aureus may be a possible source for complementary PR3. In patients with ANCA-associated disease, it was found that the autoimmune response was not only directed to PR3 but also to complementary PR3, i.e. a peptide translated from the antisense DNA strand of PR3. Furthermore, they demonstrated that mice immunized with complementary PR3, not only developed autoantibodies to complementary PR3 but also to PR3. Based on these findings they proposed that the initial trigger for the autoimmune response may be a protein with an amino acid sequence that is complementary to PR3 and that this protein may be present in S. aureus.

Pathophysiology of ANCA-Associated Vasculitis: In Vitro Data

In vitro, ANCA can activate neutrophils primed with tumor necrosis factor (TNF)-␣ for the production of reactive oxygen intermediates (ROI), the extra cellular release of lysosomal enzymes, and the secretion of cytokines such as interleukin-1␤ [17, 18]. Furthermore, it has been demonstrated that ANCA are able to stimulate neutrophils to adhere to cultured human endothelial cells by upregulating CD116 on these neutrophils. Finally, it has been demonstrated that ANCA-stimulated primed neutrophils can lyse cytokinepretreated cultured endothelial cells [19, 20]. Apart from inducing the activation of neutrophils, ANCA also activate monocytes [21] and/or endothelial cells [22, 23]. The exact mechanisms involved in ANCA mediated neutrophil activation are not completely understood. Priming of neutrophils with proinflammatory stimuli such as TNF-␣ seems to be required. Upon priming with TNF-␣, neutrophils express PR3 and MPO on the cell surface which then become accessible for interaction with ANCA [17]. It is thought that PR3 and MPO binding to the cell membrane is both through charge interactions and receptor mediated. Binding of ANCA to primed neutrophils results in activation of neutrophils, a process that is largely dependent on engagement of ␤2-integrins and the interaction of the Fc portion of ANCA [24]. An Fc-independent mechanism, however, has also been described to be operative in vitro [17, 25]. Since the signaling cascades that are used by ANCA are different from the signaling pathways

used by Fc␥R engagement only, it is suggested that apart from Fc␥R engagement also other membrane co-factors are used by ANCA for neutrophil activation [26]. These other membrane cofactors have not been identified yet. The signals involved in neutrophil activation have been dissected and include p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) as well as phosphatidylinositol-3 kinase control systems [27].

Pathophysiology of ANCA-Associated Vasculitis: Animal Studies

Several types of pathophysiological events that may lead to vessel wall damage in vasculitis are currently recognized. These include pathogenic immune complex deposition or in situ formation, a ‘Shwartzman-like’ phenomenon in which intravascular activation and aggregation of neutrophils may be operative, antibody-dependent cell-mediated cytotoxicity, and cell-mediated immune responses [28]. Pathogenic immune complexes (ICX) deposition-mediated vasculitis is best depicted in the serum sickness animal model. In this model, rabbits are injected with bovine serum albumin and about 7–10 days later ICX are found that may induce vasculitis and/or glomerulonephritis. In ANCA-associated vasculitis, however, immune complexes are generally not found in the lesions. Therefore, the classic renal lesion in ANCA-associated glomerulonephritis is labeled ‘pauci-immune’. In kidney biopsies of patients with ANCA-associated glomerulonephritis, we found no IgA or IgG deposits and only non-specific IgM deposits in a minority of the patients [29]. Complement deposition, however, is often present (in about 50% of the cases) [29]. This may point to prior ICX deposition, but there is no proof for this hypothesis [30]. To test the hypothesis that ANCA itself may induce vasculitis [31], we immunized BN rats with human MPO, which induced antibodies to human MPO and which also crossreacted with rat MPO [32]. Furthermore, in these rats a cellular response to MPO could be detected [32]. To our surprise these rats remained completely normal and no vasculitic lesions were found at autopsy. So, the induction of ANCA appeared insufficient to induce vasculitis in rats. We hypothesized that there must first be ICX deposition at vessel walls. These ICX then attract neutrophils and these neutrophils then express MPO on their cell surface that may bind anti-MPO which results in an over-stimulation of the neutrophils resulting in vasculitis and also the rapid disappearance of ICX. To test this hypothesis, MPO-immunized rats were intravenously injected with an extract of neutrophils,


containing MPO, and hydrogen peroxide (H2O2). In this context we predicted that ICX deposition and subsequently vasculitis would occur. Indeed, we observed vasculitis of the lungs and the gut in the rats that were immunized with MPO prior to injection of the neutrophil extract, but not in the rats that only received the neutrophil extract [33]. Unfortunately, no glomerulonephritis was found. However, after unilateral perfusion of the left kidney with the neutrophil extract and H2O2 we saw a severe form of necrotizing crescentic glomerulonephritis in rats that had been immunized with MPO and no lesions in non-immunized rats [32]. More importantly, immediately after perfusion, ICX deposits were seen in the kidneys, but these were gone within a very short period and when the glomerulonephritis was at his maximum no further immune deposits were detected [32]. Using a similar approach, we demonstrated that perfusion of the pulmonary artery with a neutrophil lysosomal extract leads in MPO-immunized rats to alveolar hemorrhage and necrotizing vasculitis [34]. So, in the presence of ANCA severe vasculitis and ‘pauci-immune’ glomerulonephritis can be induced in rats when immune complexes are first deposited along the vessel wall. The next question was what would happen if ICX other than ANCA/MPO ICX are deposited along the vessel wall. To study this, Heeringa et al. [35] injected rats with an antibody to the rat GBM and compared MPO-immunized rats with non-immunized rats. For these studies, a low dose of anti-GBM antibody was used that binds to the GBM but itself is not enough to induce a glomerulonephritis. In rats with anti-MPO a severe glomerulonephritis developed whereas no lesions were found in the non-immunized rats. In mice, ANCA have been identified in MRL-lpr-/-lpr and in SCG⫺/⫺Kj mice. In these models, however, the role of ANCA is difficult to tease out from the complex backgrounds of polyclonal B cell activation. During the last several years, however, convincing evidence was obtained that ANCA are sufficient to cause systemic ‘pauci-immune’ vasculitis and glomerulonephritis in vivo [36]. Two major strategies were used to demonstrate this. In the first, MPO deficient mice were immunized with murine MPO and developed anti-MPO. Adoptive transfer of splenocytes from these mice into immune deficient RAG2⫺/⫺ mice (lacking functioning B lymphocytes and T lymphocytes) resulted in anti-MPO and the development of glomerulonephritis and capillaritis. In contrast, transfer of splenocytes from mice that were immunized with BSA into RAG2⫺/⫺ mice resulted in a mild form of immune complex glomerulonephritis without crescents. The nature of the background immune complex disease that was found in RAG2⫺/⫺ mice that received either splenocytes from mice that were

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immunized with MPO or BSA is unclear. It was hypothesized that this relatively nonspecific response may represent a form of graft versus host disease. In the second strategy, purified anti-MPO was intravenously injected into RAG2⫺/⫺ or wild-type mice. ‘Pauci-immune’ necrotizing and crescentic glomerulonephritis and systemic vasculitis, closely resembling the human disease was observed [36]. These experiments indicate that ANCA can produce vasculitis without the further participation of T and/or B lymphocytes. This suggests that ANCA indeed induce vasculitis. Recently, we demonstrated that the mild vasculitic process that is observed after transfer of MPO-ANCA, can be increased by pre-treatment with a pro-inflammatory stimulus using lipopolysaccharide [37]. Furthermore, it was shown that mice that are depleted of circulating neutrophils are completely protected from MPO-ANCA induced vasculitis [38]. Finally, Little et al. [39, 40] developed a rat model in WKY rats of MPO-ANCA induced vasculitis and showed that anti-TNF-␣ treatment in rats with established disease was a very effective treatment which reduced lung hemorrhage and renal lesions. From these experiments, we come to our current working hypothesis [41]. ANCA induce activation of neutrophils and monocytes resulting in ICX deposition in vessel walls. Other antigens, however, may also be involved in ICX formation. In the presence of ANCA this ICX deposition results in persistent activation of neutrophils and monocytes and subsequently severe glomerulonephritis or vasculitis.

diseases, there is a strong HLA association. More than 80% of the patients carry HLA DR15 and DR4 alleles, whereas the DR7 locus seems to have a protective role [43]. Several environmental factors are reported to play a role in the development of anti-GBM antibodies, especially exposure to hydrocarbon. Furthermore, different forms of glomerular pathology may cause unmasking of GBM epitopes and trigger an anti-GBM immune response. This has been clearly demonstrated in patients with ANCA-associated glomerulonephritis. Furthermore, extracorporeal shockwave lithotripsy may infrequently be complicated by the development of anti-GBM antibodies and disease. Infectious agents have also been suspected to play a causative role, e.g. influenza virus. Infectious agents may account for some of the observed clustering of cases. Finally, cigarette smoking has been reported in association with the development of disease. The development of pulmonary hemorrhage in antiGBM-mediated disease is almost exclusively seen in current smokers [44]. So, it is hypothesized that induction of anti-GBM antibodies is related to either exposure of a cryptic epitope within the alveolar basement membrane caused by factors such as infection, cigarette smoke or hydrocarbon or to exposure of a cryptic epitope within the glomerular basement membrane which may become manifest during glomerulonephritis, lithotripsy and/or a urinary infection.

Pathogenicity of Anti-GBM Antibodies Anti-GBM Disease

The spectrum of diseases associated with anti-GBM antibodies include patients with a combined pulmonary and renal vasculitic disease (i.e. Goodpasture disease), patients with isolated pulmonary hemorrhage and patients with isolated crescentic glomerulonephritis. The anti-GBM antibodies have been identified as reacting with the noncollageneous part of the ␣3 chain of type IV collagen. This antigen is only present in the glomerular and alveolar basement membrane and the cochlear membrane. Anti-GBMmediated disease is very rare with an estimated incidence of 1 patient per million population [42]. Of the patients who present with the ‘typical’ pulmonary-renal syndrome most have ANCA [3]. About 60% of the patients are ANCApositive; 20–30% of the patients have both anti-GBM antibodies and ANCA whereas 10–20% of the patients have anti-GBM antibodies only. The induction of anti-GBM antibodies seems different from the induction of ANCA. In anti-GBM mediated

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There is strong evidence that anti-GBM antibodies are directly pathogenic. The presence of these antibodies is consistently linked to the development of disease. Furthermore, antibody levels seem to correlate with disease activity. Importantly, anti-GBM disease recurs immediately in renal allografts if the recipient still has circulating antibodies. Also, antibodies eluted from kidneys from patients with anti-GBM glomerulonephritis induce glomerulonephritis in monkeys after passive transfer [45]. Another important observation is the finding that patients with Alport disease may develop anti-GBM glomerulonephritis after renal transplantation. In Alport disease, patients lack the anti-GBM antigen. After transplantation, they are exposed to this antigen for the first time and hence may develop anti-GBM antibodies [46]. The unraveling of pathogenic mechanisms in anti-GBM disease has benefited greatly from the availability of animal models. Anti-GBM antibody-mediated disease can be induced in animals actively by immunization with certain type IV collagen preparations or passively by transfer of

monoclonal and/or polyclonal anti-GBM antibodies. Mice and rats have been used most extensively in recent years. Induction of glomerulonephritis with heterologous antiGBM antibodies has two phases of injury. The first phase is a result of direct binding of the heterologous anti-GBM antibody to the GBM. The second phase is the result of autologous production of antibodies that bind to the foreign anti-GBM antibodies bound to the GBM. This model is more an immune complex disease model than a specific anti-GBM disease model. Therefore, more recent studies focused on the immunization of animals with homologous GBM antigens. Also, Meyers et al. [47] used a mouse model for anti-GBM disease that generates human autoantibodies after immunization with recombinant human GBM. While the role of antibodies to GBM is well established in the pathophysiology of anti-GBM disease, it has

been recently found that there is also a major role for cellmediated effector injury [48]. Indeed, mice that lack B cells and/or immunoglobulins can develop anti-GBM disease after immunization with the GBM antigen. The role of T cells was also implicated in studies where T cell therapy was given to animals with anti-GBM disease [42]. Cyclosporine, anti-CD4 antibodies, anti-CD8 antibodies, blockade of the B7-CD28 pathway and blockade of the CD40-CD154 pathway all reduce lesion development. Importantly, regulation of T cell responses by either the induction of mucosal tolerance or by treatment with regulatory T cells [49] also suppresses anti-GBM disease in these experimental models. However, also the autoimmune effector T cell responses are not a sine qua non, since anti-GBM antibodies can induce anti-GBM disease in mice deficient of T cells [48].

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ANCA really pathogenic? Neth J Med 2003;61: 404–407. Pusey CD: Anti-glomerular basement membrane disease. Kidney Int 2003;64:1535–1550. Fisher M, Pusey CD, Vaughan RW, Rees AJ: Susceptibility to anti-glomerular basement membrane disease is strongly associated with HLA-DRB1 genes. Kidney Int 1997;51: 222–229. Donaghy M, Rees AJ: Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane. Lancet 1983;ii:1390–1393. Lerner RA, Glassock RJ, Dixon FJ: The role of anti-glomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J Exp Med 1967;126:989–1004. Byrne MC, Budisavljevic MN, Fan Z, Self SE, Ploth DW: Renal transplant in patients with Alport’s syndrome. Am J Kidney Dis 2002;39: 769–775. Meyers KE, Allen J, Gehret J, Jacobovits A, Gallo M, Neilson EG, Hopfer H, Kalluri R, Madaio MP: Human antiglomerular basement membrane autoantibody disease in XenoMouse II. Kidney Int 2002;61:1666–1673. Dean EG, Wilson GR, Li M, Edgtton KL, O’Sullivan KM, Hudson BG, Holdsworth SR, Kitching AR: Experimental autoimmune Goodpasture’s disease: a pathogenetic role for both effector cells and antibody in injury. Kidney Int 2005;67:566–575. Wolf D, Hochegger K, Wolf AM, Rumpold HF, Gastl G, Tilg H, Mayer G, Gunsilius E, Rosenkranz AR: CD4⫹CD25⫹ regulatory T cells inhibit experimental anti-glomerular basement membrane glomerulonephritis in mice. J Am Soc Nephrol 2005;16: 1360–1370.

Prof. Dr. J.W. Cohen Tervaert Department of Clinical and Experimental Immunology, University Hospital Maastricht PO Box 5800 NL–6202 AZ Maastricht (The Netherlands) Tel. ⫹31 43 388 1433, Fax ⫹31 43 388 4164 E-Mail [email protected]


Novel Aspects of Treatment for Interstitial Lung Diseases Jürgen Behr Department of Internal Medicine I, Division of Pulmonary Disease, Klinikum der Universität München, Grosshadern, Munich, Germany

Abstract Interstitial lung diseases (ILDs) are a heterogenous group of diseases with a complex pathogenesis. Inflammation was noticed first to be a component of ILDs, but anti-inflammatory therapy proved effective only in a subgroup of disease entities with predominant inflammatory features such as nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP) or cryptogenic organizing pneumonia (COP). In fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) inflammation is more limited, whereas fibrogenesis appears to be the primary disease process. Consequently, anti-inflammatory therapy has not been proven to be effective in IPF/UIP and antifibrotic therapies are currently being developed. Treatments for IPF with an antifibrotic potential that have shown positive effects in high-quality randomized controlled trials (RCTs) are N-acetylcysteine (NAC) at a high dose of 600 mg t.i.d. which significantly decreased disease progression in terms of loss of lung function after 1 year and pirfenidone which significantly decreased the number of acute exacerbations of IPF and loss of vital capacity (VC) after 9 months. Interferon-␥ failed to meet primary and secondary endpoints in a large RCT. Based on pathogenetic considerations, a large number of treatment approaches currently under investigation are discussed. More effective therapies are urgently needed in a progressive disease such as IPF. Until more effective therapies are available, 600 mg NAC t.i.d. may be used to slow down disease progression but its efficacy has only been demonstrated when used in combination with prednisone and azathioprine. Alternative treatments are still

limited since pirfenidone is presently not available apart from in clinical trials. Combination therapy with prednisone plus azathioprine as recommended in the ATS/ERS consensus statement should be employed after critical risk-benefit assessment in the individual patient. Copyright © 2007 S. Karger AG, Basel

Introduction

Treatment approaches for interstitial lung disease (ILD) are closely linked to the underlying pathophysiologic concepts. Pathophysiologic concepts are subject to changes over time. In the field of ILDs several pathophysiologic concepts have evolved recently, that primarily relate to idiopathic pulmonary fibrosis but may also have implications for other forms of pulmonary fibrosis (IPF) such as fibrotic nonspecific interstitial pneumonia or acute interstitial pneumonia (AIP). The initial hypothesis centered on the prime event being an inflammation of the alveolar wall as the result of an unidentified insult, leading to chronic inflammation (i.e. ‘alveolitis’) and finally inducing fibrosis by a cascade of inflammatory and fibrogenic mediators. Consequently, anti-inflammatory drugs were chosen for treatment of this condition. As this approach appeared unsatisfactory with respect to treatment effect, an alternative hypothesis focusing fibrogenesis as the primary disease mechanism was generated. According to this hypothesis, a repetitive epithelial injury leads to damage of epithelial cells and basement membranes, followed by exudation of

fibrin and focal fibroblast activation and proliferation, finally resulting in fibrotic remodeling of lung parenchyma. Consequently, drugs interfering with fibrogenesis itself appeared to be potentially more logical for treatment of these diseases. Preliminary evidence from controlled clinical trials in IPF seems to provide some encouraging signals, but definitive evidence is still lacking. Additional pathophysiological aspects that may be involved in either of the two concepts involve: • Oxidant-antioxidant imbalance with a specific lack of glutathione (GSH) as a major antioxidant that also interferes with fibrogenesis itself. • Impaired fibrin degradation and formation of alveolar fibrin clots as a lead structure for fibroblast chemotactic migration and proliferation. • Exaggerated release of growth factors such as TGF-␤, IGF-1, PDGF, and CTGF may play a crucial role for expansion of connective tissue in the lungs. • Epithelial cell apoptosis, impaired epithelial regeneration and epithelial-to-mesenchymal transdifferentiation which may be closely linked to integrins and integrin signaling. • Angiogenesis and neovascularization as an integral component of fibrotic tissue remodeling. • Mesenchymal stem cells and circulating progenitor cells have been shown to modulate repair mechanisms after lung injury and may therefore be involved in the process of lung fibrosis. • Mutations of the surfactant protein-C as a cause of familial ILD has shed some light on the role of genetic predisposition and genetic control of the homeostasis and repair of the lung interstitium. A number of additional potential facets of ILD pathogenesis such as fibroblast phenotype, extracellular matrix molecules and matrix metalloproteinases, arachidonic acid metabolites, surfactant proteins, etc. can be added to this list. For each of these pathophysiologic facets involved in the pathogenesis of IPF and potentially in other forms of fibrosing lung disease, specific targets can be defined and made subject to possible therapeutic interventions (fig. 1). For some of these targets the therapeutic armamentarium is already available and experimental or clinical treatment trials are under way (table 1).

Anti-Inflammatory Therapy

Based on the so-called ‘alveolitis hypothesis’, antiinflammatory drugs have historically been recommended

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as first-line treatment in ILD. Apart from corticosteroids, a number of cytotoxic and immunosuppressant substances have been used, including azathioprine, cyclophosphamide, cyclosporine-A, mycophenolate mofetil, and methotrexate. A major shortcoming in this area is the fact that sufficiently powered controlled clinical trials to confirm or refute the efficiency of these drugs have never been performed. However, there is a strong belief and empirical knowledge that corticosteroids in combination with azathioprine or cyclophosphamide are effective treatment in nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitisassociated ILD (RB-ILD), and eosinophilic pneumonia mimicking ILD. All of these ILDs are characterized by histopathologic patterns that may occur in isolation (idiopathic) or in the context of connective tissue diseases or other precipitating triggers (e.g. hypersensitivity pneumonitis, infections, drugs). Recently, results from the scleroderma lung study have been reported. In this randomized placebo controlled clinical trial, oral cyclophosphamide at a dose of 2 mg/kg/day showed positive effects on decline of vital capacity, SF-36 vitality score, dyspnea score, and skin score as compared to placebo after one year in a total of 162 scleroderma patients with active fibrosing alveolitis (based on BAL or HRCT criteria) [1]. This finding suggests that cyclophosphamide is active in NSIP, which is the histologic pattern that is found in the majority (approximately 80%) of scleroderma patients with lung involvement. Whereas inflammation is a prominent feature of NSIP, especially in the cellular and mixed subgroups, it is scarce in IPF characterized by the usual interstitial pneumonia (UIP) pattern. Since sufficiently powered controlled clinical trials of corticosteroids or combination therapy with corticosteroids plus cytotoxic/immunosuppressive drugs (e.g. azathioprine, cyclophosphamide) are lacking, it remains unknown whether these drugs are effective or ineffective in IPF. The validity of older studies suggesting at least some effect of this approach in 20–30% of patients with IPF is doubtful, because the patient populations investigated might have included a considerable number of NSIP patients who responded, whereas UIP patients might have had no benefit from this therapy. Despite this unclear situation, but in the absence of any better options, the ATS/ERS consensus statement on the management of IPF recommended combined anti-inflammatory therapy with prednisone (initial dose 0.5 mg/kg/day) plus azathioprine (2 mg/kg/ day) or plus cyclophosphamide (2 mg/kg/day) in patients with active disease [2].

TGF-␤ Integrins

ECM

TNF-␣ ␣

␤

I -P Smad-3-P Smad-4

FAK-P

JNK-P ↑ c-jun ↑

c-junP

Fig. 1. Anti-fibrogenic treatment targets comprise among others TNF-␣, TGF-␤, integrins, Smad-3, and other cytoplasmic transcription factors. On a cellular level these activation pathway seem to be closely linked and interrelated suggesting at least partial redundancy in the respective activation mechanisms.

Nucleus Target gene Transcription of pro-inflammatory and fibrogenic genes INF-␥

Antifibrotic Therapy

Colchicine inhibits collagen secretion and fibroblast proliferation in vitro and has been studied in IPF. Retrospective and prospective nonrandomized studies and one good-quality, randomized, controlled trial did not confirm efficacy of this drug. D-Penicillamine inhibits cross-linking of collagen molecules thus inhibiting collagen maturation, turnover, synthesis, and deposition. Despite extensive use of this drug in IPF there are no RCTs available and nonrandomized uncontrolled trials failed to show any benefit of this drug in IPF. Interferon-␥1b (IFN-␥-1b) has antifibrotic properties in vitro as it inhibits fibroblast proliferation and collagen synthesis and may therefore be regarded as an antifibrotic drug. The effects of IFN-␥ are, however, much more complex as it also interferes with inflammatory mediators from phagocytes and has been shown to downregulate angiogenic biomarkers (CXCL11, epithelial neutrophil-activating protein-78). After positive signals from a randomized, prospective pilot study a pivotal RCT on 330 IPF patients was performed, which did not show a positive effect on the primary endpoint – progression-free survival [3]. However,

Treatment for ILD

ERK1, 2P

YB-1, Stat Endothelin

exploratory post hoc analysis of the data showed a significant survival benefit in a subgroup of patients with less advanced disease at baseline (FVC ⬎62%, DLco ⬎35%). This finding prompted a subsequent study (INSPIRE trial), including more than 800 patients in earlier disease states and using mortality as the primary outcome variable. This RCT was recently completed and showed that IFN-␥-1b is not effective in IPF. Pirfenidone is a pyridone compound with antifibrotic properties essentially due to inhibition of effects of TGF-␤1. Positive effects on lung function parameters (FVC, DLco) have been reported in an open label study of IPF patients suggesting a potential role in the treatment of this condition. A recent RCT using pirfenidone vs. placebo in 109 IPF patients (2:1 randomization) was stopped prematurely because of a significant accumulation of acute exacerbations in the placebo group and absence of acute exacerbations in the pirfenidone group (n ⫽ 5 vs. n ⫽ 0, p ⬍ 0.0031); it was considered ethically not justified to withhold active therapy from the placebo treated patients. The primary endpoint, difference of minimal oxygen saturation during a 6-min timed walk test at 9 months vs. baseline, showed a trend in favor of pirfenidone, but statistical significance was not met (p ⫽ 0.07), potentially due to the premature end of the study.

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Table 1. Drugs employed in recent, ongoing, and future clinical

trials in IPF Substance

Mechanism

Trial-status

Acetylcysteine

antioxidant, glutathione ↑

phase II–III completed (IFIGENIA)

Bosentan

endothelin receptor antagonist

phase II completed (BUILD-1) phase III planned (BUILD-3)

Etanercept

TNF-␣-antagonist

phase II completed

FG-3019

CTGF-antagonist

phase I–II ongoing

Heparin (inhaled)

anticoagulant

phase II ongoing

Imatinib mesylate

PDGF-receptor antagonist

phase II ongoing

Interferon-␥

fibroblast inhibition, immunomodulating

phase II completed (GIPF-001) phase III ongoing (INSPIRE)

Pirfenidone

fibroblast inhibition, TGF-␤-antagonism

phase II completed phase III starting (PIPF-003)

Rapamycin

antiproliferative, immunosuppression

phase II ongoing

SD-208

orally active TGF-␤ receptor-I-kinase inhibitor

phase I–II ongoing

Integrin-␣␯␤6-mab inhibition of integrin-mediated TGF-␤ activation

in vitro and animal models

A significant positive effect was, however, observed on the decline of FVC (p ⫽ 0.03) reconfirming a potential treatment effect [4]. Despite the premature termination of the study, pirfenidone seems to be active in IPF, but confirmation of this study in a new RCT is under way. Although pirfenidone is well tolerated when given orally, a relatively high percentage of photosensitization and gastrointestinal side effects were noted during the clinical trial [4]. Miscellaneous other compounds have been shown to have antifibrotic effects in vitro, including statins and angiotensin-converting enzyme inhibitors. Good-quality clinical trials investigating the potential effect of these substances in IPF are, however, lacking. Antioxidant Therapy

Excessive oxidative stress has been shown to occur within the lungs of IPF patients and systemically, whereas

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the major pulmonary antioxidant, GSH, is lacking in the epithelial lining fluid as well as intracellularly in BAL cells. This pro-oxidative condition has been linked to pro-inflammatory as well as fibrogenic mechanisms including fibroblast proliferation and collagen turnover. Moreover, GSH – a tripeptide consisting of ␥-glutamyl-cysteinyl-glycine – is a multi-task compound which, besides its antioxidant properties, also inhibits fibroblast and lymphocyte proliferation and differentiation, it is involved in detoxification and protein synthesis. N-acetylcysteine (NAC) at a high dose of 600 mg t.i.d. has been shown to be able to replenish GSH levels in the epithelial lining fluid as well as intracellularly in IPF patients. Potential modes of action of NAC therapy and consequent GSH replenishment are summarized in figure 2. Moreover, in one pilot study over 12 weeks, NAC 600 mg t.i.d. was reported to positively influence lung function in a mixed group of patients with IPF or fibrosing alveolitis due to systemic sclerosis [5]. Based on these and other findings a RCT, in 155 IPF patients using NAC 600 mg t.i.d., given together with prednisone and azathioprine vs. placebo together with prednisone and azathioprine, was performed showing significant beneficial effects on the decline of vital capacity (VC) and diffusing capacity (DLco) after 1 year [6]. There was an absolute difference of 180 ml of VC and 0.75 mmol/min/ kPa of DLco in favor of the NAC group as compared to placebo after 1 year, representing a relative difference between both groups of 9% for VC and 24% for DLco. A significant survival benefit was not observed in this study, which, however, was not powered nor designed to investigate survival [6]. As for the primary endpoints – change in VC and DLco after 1 year – this study was clearly positive. The clinical relevance of the findings reported is, however, still under debate. Categorical analysis of the lung function data applying the criteria given in the ATS/ERS statement [1] showed stabilization or improvement in VC (i.e. no decline of VC ⬎10% from baseline) in 61% of patients in the NAC group compared to only 49% in the placebo group; similarly stabilization or improvement of DLco (i.e. no decline of DLco ⬎15% from baseline) was observed in 57% of NAC treated patients and in 49% within the placebo group; both differences were in favor of NAC treatment but statistically not significant (p ⫽ 0.22 and p ⫽ 0.17 respectively), and were also not prespecified endpoints of the study [6]. At this time it seems fair to conclude that the available evidence supports the use of high dose NAC (i.e. 600 mg t.i.d.) together with prednisone and azathioprine in IPF patients in an attempt to slow down loss of lung function. Although the treatment effect was seen with high-dose NAC vs. placebo it remains unclear whether a similar effect could be

Oxidative stress in IPF Lack of glutathione

Excess of oxidants H2O2⫺, O2⫺, OH⫺, HOCl Proliferation Collagen expression Collagen synthesis Inflammatory cell accumulation and activation

Activation of MMPs Fibroblast

Fig. 2. Role of oxidants and antioxidants

Pro-fibrotic Cytokines PDGF ↑ FGF ↑ TGF-␤ ↑

Degradation

ECM

(e.g. glutathione) in the pathogenesis of idiopathic pulmonary fibrosis and sites of interaction with NAC therapy.

achieved with NAC alone since prednisone plus azathioprine therapy were administered equally in both groups and a combinatorial effect cannot be excluded. The absence of major side effects with this therapy also allows its broad use in IPF. Whether NAC therapy translates into a clinical benefit for the patients in terms of exercise tolerance, quality of life or survival has not yet been demonstrated and is subject to controversial discussion.

Inhibition of GSH biosynthesis

demonstrated that inhaled heparin and inhaled urokinasetype plasminogen activator are able to improve compliance and reduce fibrosis even when therapeutic intervention started 14 days after bleomycin administration [7]. A clinical phase II study is also under way, but there are no data available yet.

Antifibrogenic Therapy Anticoagulant and Fibrinolytic Therapy

Fibrinogen exudation and formation of intra-alveolar fibrin clots is described histologically in patients with ILD and pulmonary fibrosis and is interpreted as a direct consequence of an insult to lung parenchyma and/or an inflammatory reaction to lung injury. Impaired fibrinolytic activity within the lungs has been described in IPF patients and contributes to a lack of clearance of fibrin, which itself functions as a lead structure for chemotactic fibroblast migration into the alveolar wall and air spaces and allows focal fibroblast proliferation thus contributing to the fibrotic remodeling process. Moreover, formation of fibrin clots interferes with physiologic surfactant function and favours alveolar collapse and development of atelectasis. Based on these observations, a pragmatic approach is to shift coagulant/anticoagulant balance toward anticoagulation or fibrinolysis using heparin or fibrinolytic substances; both can be administered topically to the lungs via the inhaled route. In animal experiments using the bleomycin model in rabbits, it has already been

Treatment for ILD

A number of profibrogenic mediators and growth factors has been claimed to be involved in the pathogenesis of ILDs and especially IPF. An overview of cytokines and signal transduction pathways in fibrogenesis is shown in figure 1. Endothelium-derived endothelin-1 (ET-1) is not only a pulmonary vasoconstrictor but also a potent mitogen to endothelial cells, vascular smooth muscle cells, myofibroblasts, and fibroblasts. ET-1 also increases synthesis and deposition of collagen and thus may contribute significantly to pulmonary remodeling. Since elevated ET-1 levels and increased expression of ET receptors in lung tissue have been demonstrated not only in pulmonary hypertension (PH) but also in pulmonary fibrosis without PH, it is hypothesized that ET-1 is involved in the pathogenesis of ILDs and especially of IPF. Consequently, the use of the dual ET-receptor antagonist bosentan, which is already approved for treatment of pulmonary arterial hypertension, might positively influence the fibrogenic process and the course of IPF. This hypothesis is presently tested in a randomized placebo-controlled multicenter trial using

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bosentan at a dose of 125 mg b.i.d. in IPF patients. A media release by the manufacturer of bosentan on November 28th 2005 states that this study did not meet the primary endpoint, which was exercise improvement as measured by the 6-min walk test. Positive trends were, however, noted in pre-defined secondary endpoints such as the combined incidence of death or treatment failure (i.e. worsening pulmonary function tests or acute decompensation of IPF) at 12 months (36.1% in the placebo group vs. 22.5% in the bosentan group; p ⫽ 0.076; 95% CI 0.37, 1.05), representing a relative risk reduction of 38%. Since publication of these data is still pending, a more detailed interpretation is not possible at present. Tumor necrosis factor-␣ (TNF-␣) is known as a proinflammatory but also fibrogenic mediator. TNF-␣ antagonists are presently approved for the treatment of rheumatoid arthritis, psoriasis arthritis, and ankylosing spondylitis (M. Bechterew). Anecdotal reports and small case series imply that TNF-␣ antagonists may also be beneficial in cutaneous and therapy-resistant pulmonary sarcoidosis. Increased amounts of TNF-␣ have been found in the lungs of patients with IPF. On the basis of these findings, blockade of TNF-␣ using the fully human soluble TNF-␣ receptor etanercept at a dose of 25 mg s.c. twice a week over a 48week period was used in a randomized controlled trial. Eighty-seven patients with IPF were included in this trial and were randomized to receive etanercept or placebo (1:1); patients with severe disease (FVC ⬍45% predicted and/or DLco ⬍25% predicted) were excluded. Preliminary results of this study were reported during the ACCP conference in Montreal 2005 and are published as an abstract [8]. The primary endpoints – i.e. change of FVC, DLco, and P(A-a)O2 gradient vs. baseline – were not met in this study, but there was a small positive trend in favor of etanercept therapy. Moreover, post hoc analysis of disease progression or death as a combined endpoint showed an advantage for etanercept of borderline statistical significance (p ⫽ 0.052). Given these positive signals, TNF-␣ antagonism may prove effective in IPF, but additional studies are necessary. Tyrosine kinase activation is another common pathway of fibrogenesis that has been shown to be involved in bone marrow fibrosis; imatinib mesylate is an inhibitor of the tyrosine kinase and also inhibits bone marrow fibrosis. Moreover, imatinib is also an inhibitor of the plateletderived growth factor (PDGF) receptor and PDGF has been found to be one of the major fibrogenic growth factors in IPF [9]. PDGF inhibition, therefore, may be beneficial in IPF patients. A phase II randomized, placebo-controlled, study with imatinib mesylate administered orally in IPF patients is currently under way, but results are not yet

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available. Interestingly, a recent case report in a patient with progressive pulmonary arterial hypertension suggests that imatinib may be effective in this disease. In agreement with this human case report, partial reversal of vascular remodeling by imatinib has been demonstrated in two different animal models of PH [10]. Based on these positive effects, it is possible that imatinib may also be active in IPF, but studies to support this hope objectively are still pending. Another potential treatment approach is provided by the monoclonal antibody FG-3019 directed against connective tissue growth factor (CTGF), which is of crucial importance for the secretion of collagen and fibronectin. A phase I study of limited duration (1 month) in patients with IPF was initiated, and further development of this novel approach is already scheduled. Rapamycin is a macrolide molecule with profound immunosuppressive properties, which are currently exploited by use of this substance in solid organ transplantation. However, rapamycin – also known as sirolimus – also has potent antiproliferative effects especially on mesenchymal cells and may, therefore, be of potential interest for treatment of ILDs and especially IPF. There are numerous reports of positive effects of rapamycin in animal models of lung fibrosis. In Australia, an open-label randomized study has been initiated in IPF patients to receive sirolimus at a dose to achieve trough levels of 5–8 ng/ml plus prednisone 10 mg o.d. or standard therapy with the primary endpoint being absence of disease progression.

Epithelium to Mesenchyma Cross-Talk

The new hypothesis of the pathogenesis of (idiopathic) pulmonary fibrosis includes a crucial role for the interaction of epithelial and mesenchymal cells. Observations from various investigators suggest that epithelial cell apoptosis and a lack of epithelial regeneration may allow unregulated proliferation of interstitial fibroblasts. These observations from animal models resemble human UIP and AIP in histologic and ultrastructural findings. The presence of epithelial necrosis and apoptosis with denuded basement membranes in widely scattered foci that are characterized histologically by loosely aggregated interstitial fibroblasts, so called ‘fibroblast foci’, are the histologic hallmark of UIP, whereas AIP is characterized by more generalized fibroblast proliferation [11]. Based on these observations, focal or extensive acute lung injury is thought to be the cause of these changes, with an increasing number of fibroblast foci being associated with an adverse prognosis in UIP. In addition, experimental studies suggested that

Inhibition of integrin ␣v␤6-activation by monoclonal AB TGF-␤

SD-208 Oral TGF-␤ receptor I kinase inhibitor RII

RI P P

Antibody P P

Cytoplasm Smad-2/3

Smad-7 P

Smad-4 Co-Smad

R-Smad

Smad-6

P P

Monoclonal AB Nucleus P

Fibrosis related molecules

P

CTGF

Target genes

Fig. 3. Treatment approaches with respect to epithelial mesenchymal interaction and transdifferentiation aiming at inhibition of integrin and

TGF-␤ activation, and intracellular Smad signaling.

there is also the possibility that epithelial cells may under certain circumstances transform or differentiate into mesenchymal cells, i.e. fibroblasts or myofibroblasts, an observation called epithelial to mesenchymal transdifferentiation (EMT). This intriguing process can be induced by TGF-␤ and is mediated by a complex process involving the nuclear transcription factor Smad-3 [12]. In this context integrins, a family of heterodimeric transmembrane receptor proteins, may also play a crucial role as they provide cell specific binding to matrix proteins and adaption of cell phenotype to changes in matrix environment [13]. As a consequence programmed cell death (apoptosis) may even occur when appropriate signals from the environment (outsidein-signaling) are not present. Of special interest in this context is the epithelial cell specific ␣v␤6 integrin, which binds to several ligands including fibronectin, tenascin-C, and vitronectin. It has been demonstrated that activated ␣v␤6 integrin induces TGF-␤ secretion thus initiating a profibrotic signal [13]. Interestingly, integrin-␤6-deficient

Treatment for ILD

mice were resistant to bleomycin induced fibrosis but developed an exaggerated inflammatory response and blockade of various integrins – ␤2, ␣1, ␣1␤1, ␣v␤6 – has shown promising antifibrotic effects in animal experiments. Antiintegrin antibodies or pharmacologic integrin inhibitors, therefore, may provide new antifibrotic treatment options in the future. Alternative approaches to this ‘epithelium-tomesenchyma’ pathway include direct inhibition of TGF-␤ by monoclonal antibodies or inhibition of down-stream signalling, e.g. inhibition of Smad-3. All of these new potential therapeutic targets are presently under investigation, but clinical application is not yet in sight (fig. 3).

Antiangiogenic Therapy

The formation of new blood vessels is a ubiquitous, complex and fundamental process of tissue repair after injury and requires coordinated regulation of matrix proteolysis and

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endothelial cell migration. Angiogenesis and neovascularization have become an issue in the pathogenesis of pulmonary fibrosis since a net pro-angiogenesis imbalance of angiogenic and angiostatic chemokines was noted in animal models of lung fibrosis and in IPF patients [14]. Interestingly, within the fibroblast foci vascularization is diminished, whereas the surrounding areas show increased angiogenic activity. This observation prompted the interpretation that angiogenesis is part of the temporal heterogeneity in UIP and may precede the fibrotic process. Alternatively, angiogenesis may also help to conserve the lung structure by facilitating an appropriate repair [15]. A number of angiogenic mediators such as interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), epithelial neutrophil-activating protein-78 (ENA-78) and angiostatic mediators such as gamma interferon inducible protein-10 (IP-10) are involved in the process of angiogenesis. Additionally, the presence of proteolytic enzymes, e.g. matrix metalloproteinases (MMPs), is critical for local degradation of vascular basement membrane and surrounding interstitial extracellular matrix proteins to allow endothelial chemotactic migration and sprouting of new capillaries. Again this process of local proteolysis is limited and tightly regulated by tissue inhibitors of metalloproteinases (TIMP) and some MMPs also mediate angiostatic effects by converting plasminogen to angiostatin. Obviously, angiogenesis is a complex and highly regulated process and its role within the pathogenesis of pulmonary fibrosis is not yet completely defined. However, some studies in human IPF and in animal models of lung fibrosis suggest that aberrant angiogenesis contributes to an enhanced fibrotic response prompting the hypothesis that anti-angiogenic therapy may be beneficial in this condition. Indeed, interferon-␥ and the endothelin receptor antagonist bosentan may have some anti-angiogenic properties which are potentially clinical relevant. New promising targets for anti-angiogenic treatment approaches include inhibitors of angiogenic factors such as VEGF or b-FGF as well as inhibitors of specific MMPs.

Stem Cells

The origin of fibroblasts in pulmonary fibrosis is assumed to be intrapulmonary. This assumption has been challenged recently by observations that in animal models of pulmonary fibrosis mesenchymal stem cells and bonemarrow derived progenitor cells traffic to the injured lung, where they settle and differentiate into fibroblasts and myofibroblasts, thus contributing to the fibrotic response [16, 17].

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However, bone marrow-derived stem cells may also adopt an epithelium-like phenotype, which favors regeneration and ameliorates the fibrotic response [18]. The circumstances leading to differentiation into fibroblast or epithelial phenotype are, however, not yet identified. Nonetheless, these observations add a novel aspect to the traditional views of fibrotic lung disease. The potential treatment implications are speculative at present, but stem cell research is developing rapidly and it may be a reasonable vision that stem cells primed to differentiate into epithelial cells might be used to support re-epithelialization and parenchymal regeneration after lung injury thus avoiding fibrotic reactions.

Genetic Predisposition

A fast growing body of evidence supports the view that genetic predisposition plays a role in pulmonary fibrosis not only in a small percentage of familial forms of ILD but also in the context that interstitial remodeling and fibrogenesis itself may be governed by genetic factors. Mutations of the surfactant protein C gene have been found to be associated with familial idiopathic interstitial pneumonia [19, 20]. Interestingly, in the affected families there is not only a cohort of IPF patients, but other ILDs are also observed, especially in children, including non-specific interstitial pneumonia and DIP. Recently, mutations of ABCA3, an ATP binding transmembrane carrier for a wide range of substrates including proteins and lipids, have been described in association with pediatric ILD and fatal surfactant deficiency in full-term neonates [21]. These examples illustrate that specific mutations may lead to different forms of ILDs which seem to involve similar pathways of inflammation and fibrogenesis. A number of gene polymorphisms including surfactant proteins, TGF-␤, IL-1, IL-6, TNF-␣, angiotensinconverting enzyme, and complement receptor-1, have been discussed in association with the pathogenesis of ILDs [22]. Although the specific role and contribution of these genetic factors within the complex pathogenesis of pulmonary fibrosis remains to be defined, it is already obvious that genetic predispositions once identified will allow new treatment targets to be defined and, in the long run, gene therapy may even be considered to be a future treatment approach.

Conclusion

ILDs comprise a heterogeneous group of complex diseases with variable responsiveness to treatment and variable prognosis. As a rule, ILDs with predominant

inflammatory features such as cellular nonspecific ILD (NSIP), DIP, and cryptogenic (or associated) organizing pneumonia, are responsive to anti-inflammatory therapy comprising corticosteroids alone or in combination with cytotoxic agents (azathioprine or cyclophosphamide). New immunosuppressive drugs with additional antiproliferative properties such as mycophenolate mofetil or rapamycin may offer some advantages, but experience is too limited to allow recommendation of these substances outside of controlled clinical trials. In diseases with predominant fibrogenic features such as IPF (histologic pattern of UIP) and AIP (clinical presentation as Hamman-Rich syndrome) treatment is far less effective and elusive. The role of anti-inflammatory therapy employing corticosteroids and cytotoxic agents (azathioprine or cyclophosphamide) in IPF is still unknown and controlled clinical trials to settle this issue should be undertaken. However, the simultaneous presence of NSIP and UIP patterns in different biopsies from the same lung in up to 15% of patients suggests that there may be at least a limited response to anti-inflammatory therapy in some patients, which is in line with clinical experience in a small minority of IPF patients. Therefore, anti-inflammatory therapy should not be discarded completely in IPF patients until clear evidence shows that it is ineffective. It should also be noted here that there are close relations between inflammatory and fibrogenic pathogenetic pathways and available therapies are not specific in this respect but affect inflammation, fibrogenesis, and even angiogenesis to a variable extent. Recent results from well designed high-quality randomized controlled clinical trials in patients with IPF/UIP suggest that N-acetylcysteine at a dose of 600 mg t.i.d., given with prednisone and azathioprine, significantly slows down disease progression in terms of loss of lung function and pirfenidone at a dose of 600 mg t.i.d. significantly reduces the frequency of acute exacerbations and functional deterioration. However, whether these effects suffice to improve survival and change the natural course of the disease remains to be elucidated. Preliminary data on the endothelin receptor antagonist bosentan and the TNF-␣ soluble receptor etanercept in IPF

indicate interesting effects on secondary endpoints but the primary endpoints were missed. New treatment approaches targeting fibrin break down, inhibition of PDGF, TGF-␤, Integrins, transcription factors (Smad), angiogenesis are under investigation and may eventually be tested in clinical trials. Genetic predisposition, genetic control of lung parenchymal remodeling, and stem cell engraftment of injured lungs have been described and may represent a basis for the development of future treatment concepts.

Practical Recommendations

In patients with NSIP, DIP, RB-ILD, or COP either as an idiopathic disease or in association with other diseases or exposures such as collagen vascular diseases (e.g. systemic sclerosis), exposure to organic dusts (hypersensitivity pneumonitis), inhaled cigarette smoking (DIP, RB-ILD), recommended treatment after elimination of a potential causal factor are systemic corticosteroids (usually prednisone at an initial dose of 0.5 mg/kg o.d. tapered after 6–12 weeks). If resolution of the disease is not achieved despite a course corticosteroid monotherapy over 12 weeks combination with azathioprine (2 mg/kg o.d.) or cyclophosphamide (2 mg/kg o.d.) is recommended. In IPF patients (UIP pattern) N-acetylcysteine at a dose of 600 mg t.i.d. has proven effective in reducing disease progression and should be recommended for all patients who do not wish or qualify to participate in a clinical trial. Prednisone (initial dose 0.5 mg/kg o.d.) plus azathioprine (2 mg/kg o.d.) or plus cyclophosphamide (2 mg/kg o.d.) as recommended by the ATS/ERS consensus statement on IPF should be added. Pirfenidone is currently not available outside clinical trials. Since available therapies for IPF are still unsatisfactory as they usually do not restore lung function to normal or near normal it has to be emphasized that the major interest should be to include these patients in controlled clinical trials to find more effective treatment strategies; a number of promising approaches in this respect have been discussed in this chapter.

References 1 Tashkin DP, Elashoff R, Clements PJ, et al, on behalf of the Scleroderma Lung Study Research Group: Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655–2666.

Treatment for ILD

2 American Thoracic Society/European Respiratory Society: Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med 2000;161:646–664.

3 Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr: A placebo-controlled trial of interferon gamma1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125–133.

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4 Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, Taguchi Y, Nagai S, Itoh H, Ohi M, Sato A, Kudoh S: Double-blind, placebocontrolled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171:1040–1047. 5 Behr J, Maier K, Degenkolb B, Krombach F, Vogelmeier C: 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. 6 Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM, MacNee W, Thomeer M, Wallaert B, Laurent F, Nicholson A, Verbeken EK, Verschakelen J, Flower CDR, Capron F, Petruzelli S, De Vuyst P, van den Bosch JMM, Rodriguez-Becerra E, Corvasce G, Lankhorst I, Sardina M, Montanari M, the Ifigenia Study Group: High dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229–2242. 7 Günther A, Lübke N, Ermert M, Schermuly RT, Weissmann N, Breithecker A, Markart P, Ruppert C, Quanz K, Ermert L, Grimminger F, Seeger W: Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits. Am J Respir Crit Care Med 2003;168:1358–1365. 8 Raghu G, Lasky JA, Costabel U, Brown KK, Cottin V, du Bois R, Thomeer M, Utz J, McDermott L: 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. 9 Aono Y, Nishioka Y, Inayma M, Ugai M, Kishi J, Uehara H, Izumi K, Sone S: Imatinib as a

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novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 2005;171:1279–1285. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W, Grimminger F: Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811–2821. Katzenstein ALA, Myers JL: Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998;157:1301–1315. Flanders KC: Smad3 as a mediator of the fibrotic response. Int J Exp Pathol 2004;85: 47–64. Koth LL, Sheppard D: Integrins and pulmonary fibrosis; in Lynch JP III (ed): Idiopathic Pulmonary Fibrosis. New York, Marcel Decker, 2004, pp 359–378. Cosgrove GP, Brown KK, Schiemann WP, Serls AE, Parr JE, Geraci MW, Schwarz MI, Cool CD, Worthen GS: Pigment epitheliumderived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis. Am J Respir Crit Care Med 2004;170:242–251. Keane MP: Angiogenesis and pulmonary fibrosis – feast or famine? (Editorial) Am J Respir Crit Care Med 2004;170:207–208. Epperly MW, Guo H, Gretton JE, Greenberger JS: Bone marrow origin of myofibroblasts in irradiation pulmonary fibrosis. Am J Respir Cell Mol Biol 2003;29:213–224. Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH: Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest 2004;113: 243–252. Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG:

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Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effect. Proc Natl Acad Sci USA 2003;100:8407–8411. Nogee LM, Dunbar AE, Wert SE, Askin F, Hamvas A, Whitsett JA: A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 2001; 344:573–579. Thomas AQ, Lane K, Phillips J 3rd, Prince M, Markin C, Speer M, Schwartz DA, Gaddipati R, Marney A, Johnson J, Roberts R, Haines J, Stahlman M, Loyd JE: Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med 2002;165: 1322–1328. Bullard JE, Wert SE, Whitsett JA, Dean M, Nogee M: ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med 2005;172:1026–1031. Whitsett JA, et al: Genes and gene polymorphisms associated with idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 2004;31: S9–S12.

Jürgen Behr, MD Department of Internal Medicine I, Division of Pulmonary Disease, Klinikum der Universität München, Grosshadern Marchioninistrasse 15 DE–81377 Munich (Germany) Tel. ⫹49 89 7095 3071, Fax ⫹49 89 7095 8877 E-Mail [email protected]

Diseases


Sarcoidosis Lee S. Newmana Yasmine S.Wasfib a

Department of Preventive Medicine and Biometrics and Department of Medicine, Division of Allergy and Clinical Immunology, and Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colo., and bDepartment of Medicine, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, Pa., USA

Definition

Abstract Sarcoidosis is a systemic disorder that preferentially affects the lungs. Characterized by the presence of noncaseating granulomas in virtually any organ, sarcoidosis is the consequence of an antigen-specific immune response and inflammatory response to as yet unidentified triggering agents. Clinically, the presentations are variable, ranging from acute, self-limited illness to chronic, insidious disease. Most commonly, the disease clinically impacts the lungs, lymphatics, eyes, skin, heart and nervous system. Prognosis is generally good, especially in acute onset disease, however some patients develop persistent illness at multiple sites, sometimes resulting in organ failure. Although the etiologies of sarcoidosis remain elusive, recent progress has led to an improved understanding of the immunopathogenesis, genetic basis, and likely categories of environmental risk factors. Advances in imaging technologies have improved disease detection. The cornerstone of disease management involves careful baseline assessment of disease distribution and severity by organ, with emphasis on vital target organs. Because the clinical course can be unpredictable, regular monitoring for signs of disease progression is necessary, using least invasive and most sensitive tools available. Based on current understanding of pathogenic mechanisms, new therapeutic approaches have begun to emerge for treating patients with refractory disease through the use of immunomodulatory pharmaceutical agents. Copyright © 2007 S. Karger AG, Basel

The American Thoracic Society, European Respiratory Society, and World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) criteria for the diagnosis of sarcoidosis include: (1) the presence of a consistent clinical and radiographic picture; (2) the demonstration of noncaseating granulomas on biopsy; and (3) exclusion of other conditions that produce similar pathology, including infections, autoimmune diseases, and inhalational disorders [2].

Epidemiology

Sarcoidosis occurs worldwide, affecting people of all racial and ethnic backgrounds, both genders and all ages [1]. Most patients are diagnosed in adulthood, prior to the age of 40, with a slight female predominance and a peak incidence in the 20–29 age group. Estimated prevalence rates vary widely, from ⬍1 to 80 per 100,000 population. In the US, age-adjusted annual incidence rates range from 10.9 per 100,000 for whites to 35.5 per 100,000 for AfricanAmericans. Similar rates have been reported in many coutries; however, the published rates are likely underestimates, since many cases may go undiagnosed or may be misdiagnosed [1, 2].

Etiology

The cause of sarcoidosis remains unknown. However, available evidence strongly supports the hypothesis that the disease develops when a specific environmental exposure with antigenic properties occurs in a genetically susceptible individual. Spatial and temporal clustering of cases, reports of community outbreaks, as well as reports of work-related risk for health care workers, suggest either a shared environmental exposure or possibly person-to-person transmission. Clusters of disease have been found among nurses, firefighters, and military personnel. A case-control study of a sarcoidosis cluster on the Isle of Man demonstrated that a significantly greater percentage of cases than controls reported previous contact with a sarcoidosis patient. While these studies suggest the possibility of an infectious etiology, no single infectious agent or antigen has been consistently linked to sarcoidosis. Numerous studies have investigated the possibility that mycobacteria, Propionibacterium sp., Rickettsia, and viruses cause sarcoidosis. No infectious agent evaluated thus far has fulfilled Koch’s postulates. However, recent studies from two laboratories have strongly suggested a role for mycobacterial antigens in a sizable proportion of cases [3, 4] compatible with immunologic evidence of oligoclonal T cells, presumably due to antigen-driven accumulation, in sarcoidosis patients’ bronchoalveolar lavage. Evidence of an upregulated T helper 1 pattern of cytokine production (e.g. gamma interferon, interleukin-2) along with tumor necrosis factor-␣ (TNF-␣) release, suggests that whether or not the granulomatous inflammation of sarcoidosis is initiated by a microbe-related antigen, the pathologic consequence is due to an overexuberant immune response, as discussed below. A multicenter case control study of the etiology of sarcoidosis (ACCESS) examined 706 affected and unaffected pairs, but did not identify a single proximate cause of sarcoidosis by questionnaire [5]. Questionnaire results suggested a possible etiologic role for exposures in the occupational environment, including microbial bioaerosols and insecticides. A previous case-control study evaluated the rural predominance of disease, identifying exposures to wood stoves or fireplaces as potential risk factors [6]. Seasonal and geographic variation in sarcoidosis risk similarly raise questions concerning the riddle of etiology. Available lines of immunologic evidence suggest that sarcoidosis granulomas form as a result of (1) antigen exposure; (2) an antigen-specific cell-mediated immune response, and (3) inflammatory or innate immune responses that amplify and perpetuate the antigen-specific immunologic reaction.

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Substantial evidence suggests that genetic susceptibility is important to disease development, and that multiple genes comprise this genetic predisposition. Disease is two to four times more common among monozygotic than dizygotic twins. Up to 19% of affected African-American families and 5% of affected white families have more than one member with sarcoidosis [7]. An analysis of nearly 11,000 first- and over 17,000 second-degree relatives of the 706 ACCESS case-control pairs yielded an adjusted familial relative risk of developing sarcoidosis of 4.7 (95% CI ⫽ 2.3–9.7). White cases had a much higher familial relative risk than African-American cases (18.0 vs. 2.8; p ⫽ 0.098) [8]. The distribution of human leukocyte antigen (HLA) and ACE polymorphic alleles in German families suggest an excess of specific alleles among affected first-degree relatives [9–11]. Using a candidate gene approach based on our understanding of immune mechanisms, both case control studies and microsatellite linkage analysis in familial sarcoidosis strongly support the existence of a susceptibility locus for sarcoidosis on chromosome 6 in the HLA region. Specifically, sarcoidosis susceptibility or chronicity has been associated with a number of specific HLA alleles. Importantly, studies in Sweden, Holland and the United Kingdom on Löfgren’s syndrome and other acute, resolving forms of sarcoidosis have greatly elucidated the genetic basis of this clinical phenotype. HLA-DR17 (DRB1*03) was found nearly four times as often in patients with these milder forms of disease as in normal controls among Swedish subjects [12]. In a large population of British and Dutch sarcoidosis cases and controls, Sato et al. [13] showed that the HLA-DQB1*0201 was strongly associated with milder disease. These studies also identified specific genetic associations with more chronic, severe disease: with the DQB1*0602 allele in the British and Dutch and the DR14 and DR15 alleles in the Swedish population. Taken together, these data suggest that extended HLA haplotypes define a component of disease risk, especially in certain subsets of clinical phenotype. Specifically, HLA-DRB1*0301/DQB1*0201 is associated with mild disease with spontaneous resolution and HLA-DRB1*15/ DQB1*0602 is associated with more severe persistent disease [14]. Investigation of other genes in the MHC region has also yielded significant associations with antigen transporter protein TAP1 and TAP2 polymorphisms and polymorphic alleles in the TNF-␣ promoter [15]. Recently, a variant of the butyrophilin-like 2 (BTNL2) gene, which resides in the MHC class II region and probably encodes for a protein that functions as a T cell co-stimulatory molecule, has been

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associated with sarcoidosis susceptibility in both Caucasian German and US populations. Haplotypes for this gene also show a significantly weaker association with sarcoidosis risk in African-Americans [16, 17]. Other candidate gene studies have yielded negative or conflicting results, with a few notable exceptions. Various C-C chemokine receptor genes are of particular interest, as studies in three distinct populations (Japanese, Czech, and Dutch) have identified both strong positive and negative associations between specific polymorphic alleles and sarcoidosis. Most recently, a particular haplotype of the C-C chemokine receptor 2 (A at nucleotide position –6752, A at 3000, T at 3547, and T at 4385) was strongly associated with Löfgren’s syndrome, even after adjusting for other known risk factors for this sarcoidosis variant such as HLA haplotype and female sex [18].

Pathogenesis

Sarcoidosis is mediated primarily through immune effector cells, especially CD4⫹ T helper cells and cells derived from the mononuclear phagocytes. These cells accumulate within the affected tissue, where they organize into noncaseating granulomas [1, 2, 19]. The earliest manifestation of sarcoidosis is a mononuclear infiltration of the target organ, thought to be mediated primarily by CD4⫹ T lymphocytes and a host of other inflammatory cells (e.g. mast cells, fibroblasts) as well as epithelial and endothelial cells that promote the nonspecific inflammatory response leading to increased tissue permeability and cell migration. Mononuclear cell recruitment is enhanced by the production of chemokines, as well as adhesion molecules and selectins, which are chemoattractant and promote cell binding. At early stages of disease, an elevated lymphocyte count and a marked increase in the CD4/CD8 T lymphocyte ratio is observed in affected organs, such as the lungs. Effector cells such as dendritic cells and macrophages present antigen to T cells and help produce pro-inflammatory cytokines, such as interleukin-12 (IL-12) and IL-15, resulting in a so-called Th1 pattern of cytokine production including release of interferon-␥ (IFN-␥) and IL-2. IL-15 acts synergistically with IL-2 and TNF-␣ to stimulate further T cell proliferation. Naïve T lymphocytes become activated, undergo clonal expansion and differentiate into effector and memory T lymphocytes. In sarcoidosis, most T cells appear to have been previously stimulated, likely in regional lymph nodes, and to have migrated back to the affected organ. Studies of the T lymphocyte antigen receptor (TCR) repertoire in

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sarcoidosis demonstrate that the disorder is initiated by an antigen-specific immune response, based on the oligoclonal expansion of T lymphocyte subsets bearing particular, restricted alpha/beta T cell antigen receptors. Notably, in Löfgren’s syndrome and those with acute, remitting sarcoidosis there is a strong association between a lung-restricted expansion of AV2.3 CD4⫹ T cells and the expression of one of two specific antigen-presenting molecules (HLADRB3*0101, HLA-DRB3*0301) [20], suggesting that the combination of a specific T cell antigen receptor and a particular HLA antigen presentation molecule interacts with the putative sarcoidosis antigen to trigger this form of disease. The release of inflammatory cytokines serves to recruit additional peripheral blood monocytes to the affected organ, where they differentiate into exudate macrophages that show enhanced antigen-presenting capacity and release TNF-␣ and IL-1␤. Notably, from a therapeutic perspective, TNF-␣ upregulates endothelial cell adhesion molecules involved in leukocyte binding, stimulates T lymphocyte release of IFN-␥, and enhances T lymphocyte proliferation, among many other potential roles in inflammation. The net result of the cytokine cascade is an amplification of the steps in antigen-recognition, further cytokine release, cell activation, recruitment, and, ultimately, granuloma formation. Progression from granulomatous inflammation to increasing amounts of fibrosis may be a prognostically bad sign in sarcoidosis. Factors leading from granuloma to fibrosis are poorly understood, but probably involve changes in local cytokine production toward a Th2 pattern.

Pathology

The characteristic feature of sarcoidosis on biopsy of an affected organ is the noncaseating granuloma. This is classically a well-formed epithelioid cell granuloma surrounded by a rim of lymphocytes and fibroblasts, with varying degrees of peripheral collagen deposition (fig. 1). The granulomas may contain multinucleated giant cells and cytoplasmic inclusions within giant cells known as asteroid bodies or Schaumann bodies. In the lung, granulomas are found in a perilymphatic distribution, classically subpleurally and along the bronchovascular bundles. The histopathologic feature of so-called ‘necrotizing sarcoid granulomatosis’ is the presence of central necrosis within granulomas and a necrotizing granulomatous vasculitis, akin to Wegener’s granulomatosis, but with a more extensive granulomatous reaction.

Fig. 1. The noncaseating granuloma is the hallmark of sarcoidosis pathology, figures prominently in the definition of the disease, but lacks diagnostic specificity. Arrows show HE-stained typical noncaseating granuloma adjacent to a bronchiole (B) at the far left.

Clinical Assessment

The clinical presentation of sarcoidosis is diverse, ranging from asymptomatic disease captured on an incidental chest radiograph, to acute febrile illness, to chronic insidious organ failure. While disease appears typically between the ages of 20 and 50, both childhood and geriatric cases do occur. The vast majority of patients (⬎90%) have evidence of pulmonary involvement. However, sarcoidosis may affect any organ, and as such, may present with symptoms referable to any organ. Patients may also present with debilitating nonspecific systemic symptoms, including fatigue, anorexia and weight loss. A distinct subgroup of sarcoidosis patients is characterized by an acute presentation – classically with Löfgren’s syndrome, defined by acute erythema nodosum with bilateral hilar lymphadenopathy, uveitis, fever and polyarthritis. Symptoms develop abruptly and often remit spontaneously [1, 2]. Chest radiographs typically are normal or show significant hilar and mediastinal lymphadenopathy, without pulmonary infiltrates. Arrhythmias may occur due to acute granulomatous cardiac involvement. While relapse may occur, it is thought to be less common than in those patients with a more chronic presentation. Prognosis is generally good. Risk factors for chronic disease include gradual, insidious onset, presence of lupus pernio, and presence of multiorgan involvement at time of diagnosis. Chronic eye involvement includes chronic uveitis, cataracts, glaucoma, or keratoconjunctivitis sicca, which can be mistaken for

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Sjögren’s syndrome. Bone involvement is also much more common in chronic than acute cases, as are nephrocalcinosis and cor pulmonale. The lung is the most commonly involved organ in sarcoidosis, with physiologic and/or radiographic abnormalities found in more than 90% of patients. Symptoms and physical examination findings are nonspecific. Patients may present with cough, shortness of breath and/or chest pain with crackles, wheezing or often with a normal lung examination. Lung physiology is similarly nonspecific, with restriction, obstruction, a mixed disorder, and/or abnormal gas exchange. In some patients, airflow obstruction is a prominent feature due to endobronchial involvement and sometimes significant bronchostenosis. Measures of gas exchange provide greater sensitivity for sarcoidosis lung impairment and response to treatment than do lung volume and airflow measures. The radiologic patterns in sarcoidosis are classically described by chest radiographic staging, or Scadding staging, although this system is increasingly being supplanted by more sensitive and detailed imaging modalities, such as spiral/thin section computed tomography (CT). The chest X-ray stages 0–IV do not necessarily correspond to the chronologic progression of disease in all patients, but do correlate modestly with prognosis. A normal chest radiograph (stage 0) is found in 5–10% of patients at presentation. Up to half of patients with X-ray stage 0 disease have pulmonary parenchymal abnormalities on CT scan. Additionally, 20–30% have physiologic abnormalities [21]. However, this group has a low likelihood of disease progression. The most common chest radiographic presentation is stage I disease, characterized by bilateral hilar and mediastinal lymphadenopathy and normal-appearing lung parenchyma. A large majority (55–90%) of these patients will experience spontaneous disease resolution [2]. On CT scan, stage I patients may also demonstrate adenopathy at less typical sites, such as the anterior and posterior mediastinum or axilla, as well as lymph node calcification. A stage II radiograph reveals bilateral adenopathy as well as pulmonary infiltrates. Only 40–70% of these patients will remit spontaneously [2]. As illustrated in figure 2a, b, the parenchymal abnormalities may be nodular, linear or ground-glass and are typically found in the middle and upper lung zones. As shown in figure 3, on CT, the nodules often have a perilymphatic distribution around the hilar, along the bronchovascular bundles and in the subpleura. Nodules may coalesce. Stage III radiographs demonstrate parenchymal abnormalities similar to those in stage II without any lymphadenopathy. Only 10–20% of patients presenting with stage III will enjoy spontaneous resolution.

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a Fig. 2. a, b Posterolateral and Lateral chest radiographs obtained in the case of a 32-year-old female illustrates stage II sarcoidosis. Lymphadenopathy is found in both hila, as well as in the paratracheal region and aortopulmonary window, along with fine nodular infiltrates. Courtesy of David Lynch, MD.

Fig. 3. Same case as in figure 2; CT images confirmed paratracheal, aortopulmonary and subcarinal adenopathy. These lung windows showed fine parenchymal nodules, clustered around vessels and along the major fissure in the left lung. Courtesy of David Lynch, MD.

The fibrotic parenchyma that defines stage IV radiographs does not resolve. Honeycombing is seen predominantly in the mid- and upper lung zones. Stage IV radiographs may also reveal conglomerate masses, volume loss, hilar retraction, peripheral bullae and cysts [21].

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Endobronchial sarcoidosis is common. In one study, nearly half of all endobronchial biopsies from sarcoidosis patients demonstrated granulomatous inflammation, and positive endobronchial biopsies were associated with more progressive disease [22]. In another study of patients with documented endobronchial disease, up to 10% had stenoses significant enough to result in an asthma-like syndrome, with airflow limitation, localized wheezing and abnormal gas exchange [23]. Intractable cough is common in such cases. Other rare thoracic manifestations include pleural effusion, pneumothorax, chylothorax, pleural nodules and pleural thickening. The effusions typically are small to moderate in volume and unilateral, with the right side affected more often than the left. When present, pleural effusions are typically lymphocytic exudates. Careful exclusion of infection and malignancy is essential. Effusions have been reported to resolve spontaneously, as well as with steroid therapy. Pleural thickening may be the most common sarcoid-related pleural abnormality with computed tomographic (CT) studies reporting a prevalence of 11–71%. On CT, pleural nodules have been reported in 22–76%. Liebow first described the rare entity called ‘necrotizing sarcoid granulomatosis (NSG)’ in 1973. Patients may be asymptomatic, experience systemic symptoms along with cough, chest pain, and dyspnea, or have symptoms related to sites of extrathoracic involvement such as the eye or central nervous system. The typical radiographic appearance consists of solitary or multiple pulmonary nodules that

often necrose and cavitate, and are found in a distribution similar to that of sarcoidosis, subpleurally and along bronchovascular bundles. Mediastinal and hilar lymphadenopathy may also be observed. NSG is distinguished from sarcoidosis by evidence of cavitation on radiographic studies and histologic demonstration of necrosis and granulomatous vasculitis. The clinical course is generally benign and steroid responsive; however, individual cases with severe extrathoracic involvement and initial critical illness have also been reported. Bilateral hilar and/or mediastinal adenopathy in a patient who is otherwise asymptomatic or who has other features of Löfgren’s syndrome is often adequate for a presumptive diagnosis of sarcoidosis. However, biopsy evidence of noncaseating granulomas is required for a definitive diagnosis of intrathoracic involvement. In most cases, transbronchial biopsy is performed, with a diagnostic yield of 40–90%, depending in large part on the number of biopsies obtained. A minimum of six good transbronchial biopsies maximizes the yield from this procedure. Endobronchial biopsies can also be diagnostic in 40–60% of cases. Bronchoalveolar lavage (BAL) lymphocytosis and an elevated CD4/CD8 ratio in the BAL support a diagnosis of sarcoidosis but are not diagnostic. Other supportive, but nonspecific, data include an elevated serum angiotensinconverting enzyme (ACE) level, positive gallium scan or the presence of cutaneous anergy. If bronchoscopic biopsies are nondiagnostic, mediastinoscopy, video-assisted thoracoscopic lung biopsy or open lung biopsy may be considered. When isolated mediastinal adenopathy is found on CT, many clinicians consider mediastinoscopy to be the procedure of choice in order to definitively exclude lymphoma. Biopsy of more accessible sites of sarcoidosis involvement such as skin nodules, sinuses, conjunctivae, or salivary glands can sometimes obviate the need for a chest procedure.

Extrathoracic Organ Involvement

Confidence in the diagnosis of sarcoidosis rises if there is involvement in organs outside of the thorax. Key characteristics of some of the more commonly affected organs are described below. The array of extrathoracic organ manifestations is impressive and will only be touched upon in this review. A helpful set of criteria for defining organ involvement has been published by the ACCESS group [1, 2, 24]. Otorhinolaryngologic presentations include salivary gland involvement sometimes resulting in severe xerostomia, otitis media, vestibular symptoms and hearing loss.

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Nasal and paranasal sinus involvement can be difficult to properly diagnose and treat. Sometimes these cases develop lupus pernio (violaceous rash described below) accompanied by saddle nose deformity and friable hemorrhagic nasal mucosa. Lymphadenopathy is observed most commonly in the hilar and mediastinal lymph nodes (up to 90% of patients); however, a minority of patients (5–30%) has peripheral lymphadenopathy that is nontender and mobile. Cardiac sarcoidosis may occur in less than 1% to as high as 58% of patients, with prevalence estimates varying based on the population screened and case definition. The lack of a consistent case definition is in part due to the lack of sensitive and specific tests for this form of the disease. Electrocardiograms, echocardiograms, radionuclide imaging and MRI may all be abnormal in cardiac sarcoidosis, but the findings are nonspecific. Endomyocardial biopsy is highly specific when positive, but has a very poor sensitivity of 25–50%. Unfortunately, the diagnosis of cardiac sarcoidosis is commonly made when a patient presents with sudden death from ventricular arrhythmias or complete heart block. Supraventricular tachycardias, ventricular aneurysms, other conduction defects (e.g. first- and second-degree heart block, intraventricular conduction delay) and cardiomyopathy/congestive heart failure also occur with cardiac involvement. Approximately 25% of sarcoidosis patients develop skin involvement. The two most characteristic skin lesions are erythema nodosum and lupus pernio. Erythema nodosum typically presents as raised, tender, red nodules, 1–2 cm in diameter on the anterior surface of the lower legs. Lupus pernio is a rare condition, characterized by purplish plaques over the nose, cheeks, lips and ears, most commonly in African-American women. Other common skin abnormalities include red-brown to orange macules and papules, keloids and hyper- or hypopigmentation. Ocular involvement occurs in 15–54% of patients, most commonly presenting as uveitis. Anterior uveitis, which is more common in African-Americans, typically presents acutely, with pain, photophobia, lacrimation and redness, but may have a more chronic course. Posterior uveitis, which is more common in whites, is typically gradual in onset and is more likely to result in vision loss. Conjunctival nodules are common, although usually asymptomatic. While less common, lacrimal gland enlargement is characteristic of sarcoid eye disease. The posterior segment of the eye may also be affected with vitreous hemorrhage, cataracts, glaucoma and retinal ischemia with neovascularization. A higher prevalence of central nervous system involvement is observed in patients with disease of the posterior segment.

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Neurosarcoidosis is observed in less than 10% of patients, and may occur in the central or peripheral nervous system. In the central nervous system, meningeal infiltration and inflammation is most characteristic, manifesting clinically with cranial neuropathies, hydrocephalus, headaches and encephalopathy. Cranial nerve involvement most commonly presents as a unilateral seventh nerve palsy, but has been reported in every cranial nerve. Central lesions are much less common, and often present clinically when there is pituitary involvement with clinical syndromes such as diabetes insipidus and hyperprolactinemia. Peripheral neuropathy and small fiber neuropathy have also been described and may be underdiagnosed. Abnormal calcium metabolism, resulting in hypercalcemia and/or hypercalciuria, is the most common endocrine disorder in sarcoidosis. It occurs due to increased 1,25-dihydroxy vitamin D production by activated macrophages in granulomas. Left untreated, these abnormalities can lead to renal calculi, nephrocalcinosis, and sometimes renal failure. Rare forms of sarcoidosis-related renal disease include interstitial nephritis and granulomatous masses. Parotid enlargement is a classic but rare disease feature. Heerfordt’s syndrome, or uveoparotid fever, is characterized by parotid enlargement with fever, facial palsy and anterior uveitis. Liver involvement is found in 50–80% of patients. It is usually asymptomatic. Clinically apparent liver disease is rare. Although arthralgias are common in patients with Löfgren’s, other forms of sarcoidosis may also demonstrate joint involvement. Arthralgias occur in 25–39% of patients. Deforming arthritis is rare. Fewer than 5% of patients display osseous sarcoidosis, although the increasing use of MRI may increase future estimates of the frequency. The classic X-ray or MRI finding is bone cysts in the phalanges, but any bone may be involved. Clinically significant muscle involvement, characterized by intramuscular nodules, acute myositis or chronic myopathy, is rare. Hematologic abnormalities occur in 20–30% of patients, presenting as anemia, leukopenia and/or lymphopenia. Thrombocytopenia is a rare consequence of bone marrow involvement and/or splenic enlargement with enhanced platelet destruction.

Investigations

A core evaluation at time of initial presentation, as well as periodic follow-up tests are recommended [1], based on

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the expected major target organs. Additional, specialized tests may be appropriate, depending upon which organs have suspected involvement of clinical significance. Since there is no single sensitive nor specific diagnostic test, the detection of sarcoidosis hinges on establishing the compatible clinicopathological constellation while also excluding other diseases, especially infection, malignancy, occupational metal exposures, and collagen vascular disorders. An optimal evaluation provides histologic confirmation and negative cultures and special stains for organisms. In determining the extent and severity of disease, clinicians should start with the least invasive tools first. Asymptomatic organ involvement may be missed, but generally will have no consequences, with three significant exceptions. A slit-lamp examination is recommended for all sarcoidosis patients to screen for clinically silent uveitis. Subclinical hypercalciuria, even in the absence of hypercalcemia, is associated with nephrolithiasis, and thus a baseline 24-hour urine calcium measurement is advisable. Periodic electrocardiograms should also be obtained to screen for rare, but potentially life threatening, arrhythmias and conduction abnormalities. Baseline laboratory evaluation should include a CBC, to evaluate for anemia, leukopenia, and thrombocytopenia; serum calcium and liver enzymes. Serum ACE levels are frequently elevated in sarcoidosis, but are nonspecific. They are, however, sometimes useful in monitoring disease activity, including response to therapy. Tests demonstrating cutaneous anergy may also help suggest a diagnosis of sarcoidosis, but are neither sensitive nor specific. KveimSiltzbach reagent skin testing – using a sarcoidosis spleen extract that is intradermally injected – is not recommended for general use. All patients should have a thorough baseline assessment of the extent of lung disease, even when the lungs are not obviously involved. Typically, this includes pre- and postbronchodilator spirometry, body plethysmography, diffusing capacity, and one or more direct measures of gas exchange, including arterial blood gas measurements at rest and with exercise. The latter is one of the most sensitive indicators of lung impairment. Generally, patients found to have pulmonary involvement can be followed with the simplest and least-invasive testing. For example, in a patient found to have a low diffusing capacity, it is often possible to follow that test, along with spirometry and chest radiograph, rather than routinely performing more invasive studies such as exercise testing with arterial blood gases. Baseline chest X-ray should be obtained in all suspected cases. CT scanning, using spiral and thin section algorithms,

provides much greater detail of parenchymal abnormalities, but is not an essential baseline study. Gallium-67 citrate scanning adds no specificity to the diagnosis of sarcoidosis, except in the case of patients with lacrimal and salivary gland involvement. Monitoring for disease progression, regression, or response to therapy should be individualized. The clinician must remain alert for disease relapses and development of new manifestations in new or previously subclinically involved organs.

Diagnosis

Diagnosis of sarcoidosis is made in two steps: (1) identifying clinical and pathologic features consistent with the disease, and (2) excluding other conditions that have clinical overlap. Diagnostic considerations for pulmonary granulomatous inflammation include infections with mycobacteria, bacteria, fungi, spirochetes, and protozoa. Diseases caused by occupational and environmental inhaled agents must also be considered, including hypersensitivity pneumonitis due to inhaled organic and inorganic antigens, metal-induced disorders such as chronic beryllium disease [25] and silicosis. Neoplasms, including Hodgkin’s and non-Hodgkin’s lymphoma and metastatic carcinoma can simulate a sarcoidlike reaction in lymph nodes. Local sarcoidal reactions can also occur in skin, but they are not associated with systemic symptoms and lack multiorgan distribution [1, 2]. In addition, autoimmune disorders can show significant clinical and pathologic overlap with sarcoidosis.

Natural History and Prognosis

In the majority of patients with sarcoidosis, disease will resolve spontaneously. However, two sources of frustration for patients and their physicians are the highly variable natural history of sarcoidosis and uncertainty about a given individual’s prognosis. It is not known why some sarcoidosis patients recover and others progress. While general rules do apply, there are many exceptions. Acute-onset sarcoidosis is more likely to resolve spontaneously than is chronic, insidious onset disease. Presence of multiorgan involvement at time of initial presentation portends a more protracted and clinically severe illness. Even after an apparent recovery, a proportion of patients may relapse months to years later. Factors associated with worse prognosis include older age at time of diagnosis, African-American race, duration

Sarcoidosis

of illness greater than 6 months, pulmonary infiltrates, splenomegaly, lupus pernio, and number of organs involved. A more favorable prognosis has been found in patients with acute disease who expressed HLA-DR3 and HLA-DQ2, whether or not erythema nodosum was present [26].

Treatment

Because sarcoidosis can spontaneously resolve without treatment, most treatment protocols incorporate a period of observation without treatment whenever possible. A detailed summary of current pharmacotherapy in sarcoidosis has been the subject of several recent reviews [27, 28]. Oral corticosteroids remain the first line therapy in most cases, however there is no consensus as to when or how much corticosteroid should be initiated [27]. Furthermore, there is some evidence that corticosteroids may actually do more harm than good in some instances. Their use is aimed at the relief of symptoms and modulation of disease activity related to vital organs. It is debatable whether all of these goals can be achieved, especially in the light of corticosteroid side effects. In synthesizing the data from eight randomized trials of oral or inhaled corticosteroids in pulmonary sarcoidosis that included a control group, Paramothayan and Jones [27] concluded that oral corticosteroids improved chest radiographs after 6–24 months of treatment and produced a small improvement in lung function and gas exchange. They found no evidence supporting sustained improvement after withdrawal of corticosteroids. Only 2 of the 8 trials examined the efficacy of inhaled corticosteroid therapy. These demonstrated no effect on chest radiographic abnormalities, no consistent effects on lung function and only a small improvement in symptoms in one of the studies. In another review, Reich [29] has suggested that patients with recent diagnosis of stage II or III sarcoidosis might derive more long term harm than benefit from systemic steroids; that the effect on those with disease of more intermediate duration is neutral; and that patients with chronic progressive pulmonary disease respond favorably, at least in the intermediate term. The American Thoracic Society (ATS)/ European Respiratory Society (ERS)/World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) consensus statement suggests that patients with acute pulmonary sarcoidosis (stage I disease with isolated bilateral hilar adenopathy) not be treated [2]. The lack of randomized controlled clinical trials, especially for all of the various forms of sarcoidosis organ involvement, limits the conclusions that can be drawn.

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Studies examining outcome at greater than 2 years suggest no significant benefit from corticosteroid therapy in asymptomatic sarcoidosis patients with more advanced forms of pulmonary involvement [30]. In a British Thoracic Society study [31], patients not meeting the indications for immediate therapy were observed for 6 months. At that point, participants were alternatively assigned to receive either long-term corticosteroid therapy or to receive corticosteroids based on symptoms. After 2 years, the long-term therapy group showed modest improvements in pulmonary function compared to the symptom-based treatment group. Based on the available literature and a survey of clinical practice in the US and abroad, it is our general recommendation that corticosteroids should not be initiated until after a period of clinical observation, unless there is a life- or sight-threatening reason to treat, such as cardiac, neurologic or eye disease that failed topical therapy. There is no consensus regarding the optimal initial dosage of corticosteroids. The ATS/ERS/WASOG consensus statement suggests a starting dose of 20–40 mg of prednisone, or its equivalent, daily or on alternate days. The British Thoracic Society study similarly used 30 mg of prednisolone daily as a starting dose. After an initial period of treatment lasting approximately 8–18 weeks, those who objectively improve on corticosteroids can initiate a taper to as low a dose as is tolerated without return of symptoms or organ dysfunction, usually 5–10 mg daily or on alternate days. The ATS/ERS/WASOG statement recommends that for those who respond to steroids, treatment should be continued for at least 1 year [2]. If intolerable side effects occur or if the disease is not responsive to steroid therapy, patients are considered candidates for the addition of a second-line immunosuppressive agent. If patients suffer relapse on maintenance therapy, there are many potential paths, none of which have been substantiated by rigorous clinical research. In many practices, such patients are placed back on higher dose prednisone and a second line agent is considered. Patients who have evidence of a clinical response to corticosteroids are reevaluated using objective measures prior to attempts to completely withdraw immunosuppressive medication. Even patients who are believed to have entered remission should be followed up periodically, given the tendency for sarcoidosis to relapse. The use of other immunosuppressive agents in sarcoidosis should be reserved for those patients who (1) experience symptomatic disease progression despite oral corticosteroids or (2) require therapy but cannot tolerate glucocorticoid side effects. Methotrexate has emerged as one of the preferred secondline drugs, especially used as a steroid-sparing agent. There

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has only been one published randomized controlled trial of methotrexate in sarcoidosis [32]. The largest published experience comes from Lower and Baughman, who reported improvement in 33 of 50 patients treated with methotrexate for a minimum of 2 years. A follow-up report of 209 patients showed that 52% on methotrexate entered remission and 16% remained stable, with or without low dose prednisone [33]. Other reports confirm the beneficial effects of methotrexate in cutaneous and musculoskeletal sarcoidosis. In most studies, treatment doses of methotrexate range from 5 to 15 mg per week, usually taken as a single or divided oral dose taken one day per week. Methotrexate may take up to 6 months to become fully effective in sarcoidosis. Case reports on the benefits of cyclosporin A in sarcoidosis have not been supported by later larger cohort studies [34]. Azathioprine may be an effective second-line agent in a subset of sarcoidosis patients [35, 36]. It is frequently used, in titrated oral doses up to 100–150 mg daily, despite the paucity of published studies examining the drug’s efficacy in sarcoidosis [37]. It may be efficacious for some cases of extrapulmonary disease. Chloroquine has proven effective in treating cutaneous manifestations of sarcoidosis, hypercalcemia and hypercalciuria associated with sarcoidosis, and steroid-refractory neurosarcoidosis. Generally, chloroquine therapy is initiated at a dosage of 500 mg/day and may be titrated up to a maximum of 1,000 mg/day and decreased to a low of 250 mg/day. Hydroxychloroquine is often used instead, at a dosage of 200–400 mg daily, because of the lower risk of ophthalmic toxicity. In one study of chronic sarcoidosis, after an average of 19.7 months of treatment, subjects who received maintenance therapy with low dose (250 mg/day) chloroquine demonstrated a significantly slower decline in lung function and a trend toward fewer relapses compared to those who were simply observed [38]. Cyclophosphamide is employed in selected cases of corticosteroid-refractory sarcoidosis, and appears beneficial for both cardiac and neurosarcoidosis. Oral cyclophosphamide is given at a dose of 1–2 mg/kg/day to a maximum dose of 150 mg/day. Therapy is maintained for several months before tapering. Intravenous monthly pulse cyclophosphamide has been used for the treatment of neurosarcoidosis. It is logical to expect that anti-TNF-␣ therapies, such as etanercept, infliximab, adalimumab, thalidomide and pentoxifylline should prove effective in sarcoidosis. There are individual published cases and small case series data supporting the use of thalidomide in patients with cutaneous sarcoidosis, including lupus pernio [39, 40]. Pentoxifylline,

at high doses, improved lung function in a group of patients with mild pulmonary sarcoidosis [41]. A prospective, openlabel study with etanercept was terminated prior to the full planned enrollment due to excessive treatment failures [42]; however, certain design flaws limit the conclusions that can be drawn. Case reports and case series support the use of infliximab in treatment of lupus pernio, neurosarcoidosis, and progressive cutaneous sarcoidosis [43, 44]. Results of a recent major clinical trial demonstrated that at 24 weeks, patients with chronic, steroid-treated pulmonary sarcoidosis who received infliximab showed a small but statistically significant improvement in forced vital capacity compared to those who received placebo. A more sizeable improvement was seen in the subgroup of patients who entered the study with more severe pulmonary impairment. No differences in frequencies of adverse events or serious adverse events were seen between placebo-treated and infliximab-treated subjects at week 24. In light of all of these findings, infliximab has joined the armamentarium of second-line treatments for patients with refractory, debilitating, or life-threatening sarcoidosis [45]. Tuberculosis should be carefully excluded in these patients prior to and during treatment, although it is a rare complication. Combined regimens are increasingly being used to treat sarcoidosis, although there have been few trials. Most of

these regimens include corticosteroids and one or more second-line agents. Patients with severe and progressive pulmonary disease despite exhaustive medical therapy may be candidates for lung transplantation. The decision regarding timing of proceeding to transplantation is a difficult, as many patients die while awaiting a donor lung [46, 47]. There are several other issues unique to sarcoidosis patients that must be evaluated prior to proceeding to transplantation. One is the evaluation and treatment of other etiologies of pulmonary dysfunction, such as bronchiectasis, often found in patients with stage IV disease, and congestive heart failure. The presence of severe nonpulmonary sarcoidosis, especially neurologic and cardiac disease, excludes patients from consideration for lung transplantation. Heart-lung transplantation can be considered for patients with severe cardiac and pulmonary involvement. Another potential contraindication to transplantation is the occurrence of mycetomas in patients with end-stage fibrocystic sarcoidosis. In most end-stage sarcoidosis patients, single lung transplantation is considered adequate. While sarcoidosis can develop in lung allografts, several small series of patients demonstrate that survival and rates of obliterative bronchiolitis are comparable to those reported in lung transplantation for other diseases [48].

References 1 Newman LS, Rose CS, Maier LA: Sarcoidosis. N Engl J Med 1997;336:1224–1234. 2 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;160:736–755. 3 Drake WP, et al: Molecular analysis of sarcoidosis tissues for mycobacterium species DNA. Emerg Infect Dis 2002;8:1334–1341. 4 Song Z, et al: Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med 2005;201:755–767. 5 Newman LS, et al: A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med 2004;170:1324–1330. 6 Kajdasz DK, et al: A current assessment of rurally linked exposures as potential risk factors for sarcoidosis. Ann Epidemiol 2001;11:111–117. 7 Rybicki BA, et al: Genetics of sarcoidosis. Clin Chest Med 1997;18:707–717. 8 Rybicki BA, et al: Familial aggregation of sarcoidosis: a case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 2001;164:2085–2091.

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9 Schurmann M, et al: Angiotensin-converting enzyme (ACE) gene polymorphisms and familial occurrence of sarcoidosis. J Intern Med 2001;249:77–83. 10 Schurmann M, et al: Familial sarcoidosis is linked to the major histocompatibility complex region. Am J Respir Crit Care Med 2000;162 (pt 1):861–864. 11 Schurmann M, et al: HLA-DQB1 and HLADPB1 genotypes in familial sarcoidosis. Respir Med 1998;92:649–652. 12 Berlin M, et al: HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 1997;156: 1601–1605. 13 Sato H, et al: HLA-DQB1*0201: a marker for good prognosis in British and Dutch patients with sarcoidosis. Am J Respir Cell Mol Biol 2002;27:406–412. 14 Grutters JC, et al: The importance of sarcoidosis genotype to lung phenotype. Am J Respir Cell Mol Biol 2003;29(suppl):S59–S62. 15 Grutters JC, et al: Increased frequency of the uncommon tumor necrosis factor -857T allele in British and Dutch patients with sarcoidosis. Am J Respir Crit Care Med 2002;165: 1119–1124. 16 Rybicki BA, et al: The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am J Hum Genet 2005;77:491–499.

17 Valentonyte R, et al: Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet 2005;37:357–364. 18 Spagnolo P, et al: C-C chemokine receptor 2 and sarcoidosis: association with Lofgren’s syndrome. Am J Respir Crit Care Med 2003;168: 1162–1166. 19 Moller DR, Chen ES: Genetic basis of remitting sarcoidosis: triumph of the trimolecular complex? Am J Respir Cell Mol Biol 2002;27: 391–395. 20 Grunewald J, et al: Lung restricted T cell receptor AV2S3⫹ CD4⫹ T cell expansions in sarcoidosis patients with a shared HLA-DR-beta chain conformation. Thorax 2002;57:348–352. 21 Lynch DA, Newell JD, Lee JS: Imaging of Diffuse Lung Disease. Hamilton, Decker, 2000. 22 Bjermer L, et al: Endobronchial biopsy positive sarcoidosis: relation to bronchoalveolar lavage and course of disease. Respir Med 1991;85:229–234. 23 Stjernberg N, Thunell M: Pulmonary function in patients with endobronchial sarcoidosis. Acta Med Scand 1984;215:121–126. 24 Judson MA, et al: Defining organ involvement in sarcoidosis: the ACCESS proposed instrument. ACCESS Research Group. A Case Control Etiologic Study of Sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999;16: 75–86.

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25 Fireman E, et al: Misdiagnosis of sarcoidosis in patients with chronic beryllium disease. Sarcoidosis Vasc Diffuse Lung Dis 2003;20: 144–148. 26 Grunewald J, et al: Restricted V alpha 2.3 gene usage by CD4⫹ T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLA-DR3. Eur J Immunol 1992;22:129–135. 27 Paramothayan S, Jones PW: Corticosteroid therapy in pulmonary sarcoidosis: a systematic review. JAMA 2002;287:1301–1307. 28 Moller DR: Treatment of sarcoidosis – from a basic science point of view. J Intern Med 2003;253:31–40. 29 Reich JM: Adverse long-term effect of corticosteroid therapy in recent-onset sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2003;20: 227–234. 30 Zaki MH, et al: Corticosteroid therapy in sarcoidosis: a five-year, controlled follow-up study. NY State J Med 1987;87:496–499. 31 Gibson GJ, et al: British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax 1996;51:238–247. 32 Baughman RP, Winget DB, Lower EE: Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis 2000;17:60–66. 33 Baughman RP, Lower EE: Alternatives to corticosteroids in the treatment of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1997;14: 121–130.

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34 Wyser CP, et al: Treatment of progressive pulmonary sarcoidosis with cyclosporin A: a randomized controlled trial. Am J Respir Crit Care Med 1997;156:1371. 35 Lewis SJ, Ainslie GM, Bateman ED: Efficacy of azathioprine as second-line treatment in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:87–92. 36 Muller-Quernheim J, et al: Treatment of chronic sarcoidosis with an azathioprine/ prednisolone regimen. Eur Respir J 1999;14: 1117–1122. 37 Pacheco Y, et al: Azathioprine treatment of chronic pulmonary sarcoidosis. Sarcoidosis 1985;2:107–113. 38 Baltzan M, et al: Randomized trial of prolonged chloroquine therapy in advanced pulmonary sarcoidosis. Am J Respir Crit Care Med 1999;160:192–197. 39 Oliver SJ, et al: Thalidomide induces granuloma differentiation in sarcoid skin lesions associated with disease improvement. Clin Immunol 2002;102:225–236. 40 Baughman RP, et al: Thalidomide for chronic sarcoidosis. Chest 2002;122:227–232. 41 Zabel P, et al: Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med 1997;155: 1665–1669. 42 Utz JP, et al: Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 2003;124:177–185. 43 Baughman RP, Lower EE: Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001;18:70–74.

44 Mallbris L, et al: Progressive cutaneous sarcoidosis responding to anti-tumor necrosis factor-alpha therapy. J Am Acad Dermatol 2003;48:290–293. 45 Baughman RP, Drent M, Kavuru M, Judson MA, Costabel U, du Bois R, Albera C, Brutsche M, Davis G, Donohue JF, Muller-Quernheim J, Schlenker-Herceg R, Flavin S, Lo KH, Oemar B, Barnathan ES, Sarcoidosis Investigators: Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006;174: 795–802. 46 Shorr AF, Davies DB, Nathan SD: Predicting mortality in patients with sarcoidosis awaiting lung transplantation. Chest 2003;124:922–928. 47 Judson MA: Lung transplantation for pulmonary sarcoidosis. Eur Respir J 1998;11: 738–744. 48 Nunley DR, et al: Lung transplantation for end-stage pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:93–100.

Dr. Lee S. Newman Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center 4200 E. 9th Ave. Mail Stop: B164, School of Medicine Room 4608 Denver, CO 80262 (USA) Tel. ⫹1 303 315 0880, Fax ⫹1 303 315 7642 E-Mail [email protected]


Hypersensitivity Pneumonitis Claus Vogelmeier Division for Pulmonary Diseases, Department of Internal Medicine, Philipps University of Marburg, Marburg, Germany

Abstract Hypersensitivity pneumonitis (HP) is caused by inhalation of environmental antigens. The mechanisms of disease are not well understood. The clinical presentation varies from forms with acute symptoms following exposure to purely chronic forms.The natural history may be benign with recurrent acute episodes without sequelae, but the disease may also lead to the development of chronic respiratory insufficiency. Diagnosis may be difficult. The presence or absence of serum precipitins is of limited value. High-resolution CT (HRCT) scans and bronchoalveolar lavage may be informative when there is no known antigen exposure. The mainstay of treatment is cessation of exposure. Corticosteroids may be useful in acute episodes or in severe chronic and progressive disease. Copyright © 2007 S. Karger AG, Basel

majority is work-place related. The intensity of the exposure and as a consequence the prevalence of HP may vary depending on the climate, season, local customs and working conditions. For pigeon breeder’s lung, estimates range from 6 to 21% of exposed individuals [1]. Ventilation pneumonitis has been reported to develop in approximately 15% of exposed individuals [2]. In earlier studies for farmer’s lung, prevalences of up to 30 in 1,000 farmers had been reported. In a more recent study of dairy farmers, the prevalence of farmer’s lung was found to be 42 in 100,000 [3]. This reduced prevalence is probably due to changes of storage conditions for hay and increased use of silos. It was suggested that at least 1% of workers exposed to diisocyanate vapors and aerosols that report respiratory complaints suffer from HP [4]. Smoking is less prevalent in individuals who develop HP than in control populations.

Definition

Hypersensitivity pneumonitis (HP) or extrinsic allergic alveolitis is a group of diffuse parenchymal lung diseases that is mediated by the immune system and caused by repeated inhalation of a wide variety of dusts, bioaerosols and chemical compounds. Epidemiology

The agents capable of inducing HP may be encountered in an occupational, recreational or home environment. The

Etiology

The agents that may cause HP are highly diverse. Antigens can be broadly categorized as organic, high-molecularweight complete antigens and low-molecular-weight haptens. Most of the antigens belong to the thermophilic actinomycetes which have been found to be ubiquitous in soil as well as composts and other decaying vegetable matter. Other antigens are derived from fungi (e.g. Aspergillus spp.), animal proteins (e.g. from birds), amoebae, chemicals and drugs (table 1) [5].

Table 1. Types of hypersensitivity pneumonitis and their causes


Disease

Exposure

Probable antigen

Disease

Exposure

Probable antigen

Microbes Farmer’s lung

Summer-type HP moldy hay

Saccharospora rectivirgula T. vulgaris Aspergillus spp.

contaminated houses

Trichosporon spp.

Detergent lung Washing powder lung

detergents (drung processing or use)

Bacillus subtilis enzymes

Machine operator’s lung

contaminated metal working fluid

Pseudomonas spp.

Humidifier lung; air conditioner lung; misting fountain lung

contaminated humidifiers, air conditioners and misting fountains

amoebae, nematodes

Suberosis

moldy cork

Penicillium spp.

Sequoiosis

moldy redwood dust

Graphium spp. Pullularia spp.

Woodworker’s lung

contaminated wood pulp or dust

Alternaria spp.

Animal proteins Bird fancier’s disease Pigeon breeder’s disease Pituitary snuff taker’s lung

Wood trimmer’s lung contaminated wood trimmings

Rhizopus spp. Mucor spp.

Maple bark stripper’s contaminated lung maple logs

Cryptostroma corticale

Domestic allergic alveolitis

decayed wood

fungi

Sauna taker’s lung

contaminated sauna water

Aureobasidium spp.

Basement lung

contaminated basement

Cephalosporium spp. Penicillium spp.

Hot-tub lung

mold on ceiling

Cladosporium spp.

Chemicals Chemical worker’s lung

Thatched roof lung

dried grasses and leaves

Saccharomonospora viridis

Bagassosis

moldy pressed sugarcane (bagasse)

T. sacchari T. vulgaris

Mushroom worker’s lung

moldy compost and mushrooms

Saccharospora rectivirgula T. vulgaris Aspergillus spp.

parakeets, budgerigars, proteins in avian pigeons, parrots, droppings, serum chicken, turkeys, and on feathers geese, ducks bovine and porcine pituitary powder

Furrier’s lung

animal pelts

animal fur dust

Animal handler’s lung Laboratory worker’s lung

rats, gerbils

proteins from urine, serum, pelts

contaminated grain

Sitophilus granarius (i.e. wheat weevil)

polyurethane foams, spray paints, elastomers, glues

diisocyanates, trimellitic anhydride

Epoxy resin lung

heater epoxy resin

phthalic anhydride

Unknown Mummy handler’s lung

cloth wrappings of mummies

Insect proteins Miller’s lung

Coffee worker’s lung

coffee-bean dust

Tap water lung

Aspergillus clavatus

contaminated tap water

Tea grower’s lung

tea plants

Cheese washer’s lung moldy cheese or cheese casings

Peinicillium casei

Swimming pool worker’s lung

Paprika slicer’s lung

moldy paprika pods

Mucor stolonifer

endotoxin from poolwater sprays and fountains

Compost lung

compost

Aspergillus spp. T. vulgaris

Wine-maker’s lung

mold on grapes

Botrytis cinerea

Malt worker’s lung

contaminated barley

Tobacco grower’s lung mold on tobacco

Aspergillus spp.

Potato riddler’s lung

moldy hay around potatoes

thermophilic actinomycetes Aspergillus spp.

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pituitary proteins

Modified after Bertorelli et al. [5].

The most frequent form of HP is farmer’s lung. The antigen that is considered to be the most important for the induction of farmer’s lung is a bacterium now classified as Saccharospora rectivirgula. Previously, it was named Micropolyspora polyspora and Micropolyspora faeni. Bird breeder’s disease, pigeon fancier’s lung and budgerigar owner’s disease are induced by exposure to birds. The antigens appear to be glycoproteins derived from droppings, serum and the bloom from feathers from pigeons, parrots, parakeets, chicken, turkeys, geese and ducks. Free-living amoebae and nematodes in contaminated water and ventilation systems may induce humidifier pneumonitis or air conditioner lung. Recently, a new type of domestic ultrasonic humidifier (misting fountain) has been described as the cause of cases of humidifier pneumonitis [6]. In Japan, summer type HP is prevalent. It occurs from June through September, primarily affecting women living in damp, poorly ventilated dwellings. Trichosporon species may be the predominant antigens. Low-molecular-weight chemicals may react with proteins in the airways, thus forming complete antigens. Acid anhydrides including trimellitic anhydride (TMA) and phthalic anhydride (PA) have been described as causing plastic worker’s lung. Also, diisocyanates such as hexamethylene diisocyanate (HDI), toluene diisocyanate (TDI) and diphenylmethane diisocyanate (MDI) can induce HP. In addition, several drugs including procarbazine, gold, and amiodarone have been reported to cause HP. Many of these agents are components of complex mixtures. Apart from antigens a variety of potential cofactors can be found. For example, the air in agricultural settings not only contains bacteria and fungi (up to 107/m3), but also toxins from these microorganisms including endo- and mycotoxins, mites, animal epithelia, excretia and minerals. Endotoxins or lipopolysaccharides are also detectable in bird droppings. Endotoxins are constitutive components of the cell walls of gram negative bacteria. Besides ␤(1,3)-D-glucans have been identified in bird excreta. ␤(1,3)-D-Glucans are polyglucose compounds present in the cell walls of fungi and Actinomyces spp. Both endotoxins and ␤(1,3)-D-glucans are potent inducers and modulators of inflammation [7]. In addition, dusts contain inert particles. It was shown that concentrated ambient particles by themselves are capable of inducing a mild inflammation in the lower respiratory tract [8].

Pathogenesis

The pathogenesis of HP is not well understood. There is evidence for a wide range of different reactions that may be

Hypersensitivity Pneumonitis

Agents

Host factors Genetic background

Antigens

Smoking history

Nonantigenic elements

Viral infection(s)

Hypersensitivity pneumonitis

Fig. 1. Factors involved in the pathogenesis of HP (for details see text).

involved, but there is no generally accepted unifying concept. Obviously, the composition of the causative materials and host factors are of importance (fig. 1). Initially, it was hypothesized that HP is caused by a type III allergy as defined by Coombs and Gell. It was believed that HP is the consequence of an activation of the complement system by antigen-antibody complexes. This was based on the observation of precipitating antibodies against hay antigens in serum of affected individuals. Later, in addition to antibodies of the IgG class, IgM and IgA antibodies [9] and elevated levels of complement factors were found in biological samples [10]. A number of observations seem to be incompatible with this hypothesis: (a) Vasculitis is rare [11]. (b) Alveolitis and antibody levels are not correlated [12]. (c) Many individuals with antibodies do not have symptoms and patients may lack antibodies [13]. (d) In animal models with passive serum transfer no HP-like changes were observed [14]. The bronchoalveolar lavage cell differential obtained from HP patients in the first 24–48 h following antigen exposure shows a marked neutrophilia [15]. Later, lymphocytes dominate, with a decreased CD4/CD8 ratio. Histological evaluation of lung tissue from patients with HP shows granulomas and interstitial infiltrates dominated by macrophages and lymphocytes [16]. These findings lead to the hypothesis that a type IV hypersensitivity reaction is involved in the pathogenesis. This was supported by the observation of activated macrophages and T cells in samples from animals and patients [17]. Furthermore, HP could be passively transferred with sensitized lymphocytes of the Th1 type [18]. Other animal models and data from patients suggest that HP is facilitated by overproduction of IFN-␥ (a Th1 cytokine), and that IL-10 may ameliorate the severity of the disease [19]. In another study bronchoalveolar lavage cells obtained from patients with HP were IFN-␥(⫹) and CXCR3(⫹) which is the receptor for the chemokine CXCL10, suggesting that IFN-␥ mediates

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the recruitment of lymphocytes into the lung via production of CXCL10 [20]. The potential role of CXCL10 is supported by a recent gene-array study that showed that the HP gene expression signature is enriched for genes that are functionally associated with inflammation, T cell activation and immune responses including CXCL10 [21]. In addition to chemoattractants like CXCL10, selectins and their ligands mediate the migration of T cells to sites of inflammation. It could be demonstrated that L-selectin and E-selectin are upregulated during the development of HP [22]. On the other hand, many exposed but asymptomatic individuals also have a significant lymphocytosis in the bronchoalveolar lavage fluid, which may persist over years [23]. Moreover, in a mouse HP model depletion of T cells by addition of T cell antibodies did not influence the extent of inflammation [24]. These findings culminated in the hypothesis that the activated lymphocytes are merely a consequence of a local T cell-dependent immune process which is without importance for the activity of the disease. Several studies suggest that cytokines secreted by alveolar macrophages are of pivotal importance for the induction of HP [25]. Chen et al. [26] demonstrated an altered expression of tumor necrosis factor superfamily receptors by alveolar macrophages from patients with HP. Antisera against several cytokines such as TNF-␣ [25] have been shown to decrease markedly the inflammatory response in HP models. Alveolar macrophages obtained from patients with HP produce increased levels of soluble TNF receptors that may act as counterregulators of TNF-␣ [27]. Many findings suggest that mechanisms independent of antigen-driven reactions are of importance. Organic dusts contain substances that may be directly or indirectly toxic to the pulmonary epithelium. Among those are a variety of enzymes, histamine releasers, myco- and endotoxins. Endotoxins are of particular interest as they can induce clinical reactions that are comparable to an acute episode of HP. Other studies suggest that ␤(1,3)-D-glucans may have an additive effect to endotoxin. Both molecules given together to guinea pigs induced histopathological changes resembling HP [28]. In addition to the triggers that initiate HP there are likely host susceptibility factors, as only a minority of exposed individuals develop the disease. The precise nature of these factors has yet to be determined with the exception that smoking seems to be ‘protective’. Accordingly, mice exposed to nicotine showed an attenuated reaction in a HP model [29]. Viruses may act as amplifiers of the immune reaction: in an animal model of HP pretreatment of the mice with respiratory syncytial virus (RSV) augmented the reaction caused by Saccharopolyspora rectivirgula [30]. Accordingly, in

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bronchoalveolar lavage fluid samples of patients with acute episodes of HP Influenza A DNA and protein could be detected [31]. Genetic influences remain to be defined. Atopic status and HLA antigens do not appear to be important [32]. In HP and other pathologic conditions a marked change in the balance of proteolytic/antiproteolytic processes occurs, particularly in those mediated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). There is evidence that polymorphisms in the TIMP-3 promoter region may protect against the development of HP [33].

Pathology

The acute form of the disease is characterized by an interstitial and alveolar infiltrate of lymphocytes, mast cells, neutrophils and monocytes-macrophages. In the early stages this process occurs around respiratory bronchioles, while later it may affect the lung more diffusely. The majority of infiltrating cells are lymphocytes. Typically, most of the lymphocytes accumulating in the alveoli are CD8⫹ T cells. Granulomas without central necrosis and multinucleated giant cells are often present. Areas of bronchiolitis obliterans or organizing pneumonia (OP) may also be found. The subacute form is characterized by noncaseating granulomata similar to those found in sarcoidosis but less well organized [34]. Recently, open lung biopsies from a cohort of patients with chronic bird fancier’s lung were analyzed. The inflammatory and fibrotic lesions showed significant variation with changes suggestive of OP, nonspecific interstitial pneumonia (NSIP), or usual interstitial pneumonia (UIP). Patients with OP-like or cellular NSIP-like lesions tended to have presented with acute episodes, whereas patients with UIPlike lesions had an insidious onset. Patients with BOOPlike or cellular NSIP-like lesions had a more favorable outcome than those with fibrotic NSIP-like and UIP-like lesions [35].

Clinical Features

HP may present as acute, subacute or chronic disease (table 2). In the classic acute form, patients develop constitutional (fever, chills, malaise, myalgias, headache) and respiratory symptoms (nonproductive cough, dyspnea, tachypnea) associated with bibasilar rales and occasional cyanosis approximately 4–12 h following exposure to the

Table 2. Features of the different clinical presentations of hypersen-

sitivity pneumonitis Features

Acute

Subacute

Chronic

Fever, chills Dyspnea Cough Malaise, myalgia Weight loss Rales Chest film

⫹ ⫹ nonproductive ⫹ – bibasilar nodular infiltrates restrictive

– ⫹ productive ⫹ ⫹ diffuse nodular infiltrates mixed

– ⫹ productive ⫹ ⫹ diffuse fibrosis

decreased

decreased

decreased

Pulmonary function tests Transfer factor

mixed

From Grammer [36].

offending agent. The symptoms typically peak between 6 and 24 h and resolve without specific treatment in 1–3 days. Patients with very intense exposure may present with severe hypoxemia and respiratory failure. The symptoms of the chronic form are non-specific with dyspnea, malaise, fatigue, weight loss and (productive) cough. Digital clubbing may be seen. The subacute form is intermediate [36]. Both patients with recurring acute episodes and also patients with no history of acute episodes may develop interstitial pulmonary fibrosis in bird fancier’s lung. The insidious form of bird fancier’s lung may mimic idiopathic pulmonary fibrosis [37].

Investigations

Lung Function The lung function abnormalities observed in HP are neither specific nor diagnostic as they are indistinguishable from changes seen in other interstitial lung diseases. During an acute episode of HP, a transient hypoxemia in conjunction with a restrictive ventilatory defect and a reduced transfer factor are typical findings. In subacute and chronic forms of HP pulmonary function abnormalities comprise diffusion defects and restrictive dysfunction with loss of lung volumes. In addition, hypoxemia during exercise and in severe chronic disease at rest may develop [38]. Some patients exhibit obstruction of the peripheral airways, as evidenced by a decrease in the maximum to mid-lung volume flow rates or even the large airways. Additionally, a number of patients demonstrate hyperreactive airways [39].


Imaging Chest radiographic findings vary depending on the type of disease. Patients with acute and subacute forms of HP may have normal chest radiographs. In acute HP episodes the chest radiography normally reveals interstitial infiltrates and nodules. Between episodes of acute HP, chest radiographs typically revert to normal, although changes suggestive of fibrosis may be present. In chronic HP findings typical for fibrosis (often with an upper zone predilection) may be seen. Alternatively, an emphysema aspect is possible [40]. The high-resolution CT (HRCT) changes are also dependent on the type of disease. Characteristically, a mid- to upper zone predominance of centrilobular ground-glass or nodular opacities with signs of air-trapping are found [41]. In the late stages of the disease, CT scans will reveal honeycombing, bronchiectasis and emphysema, similar to findings in idiopathic pulmonary fibrosis. Nevertheless, in most cases CT can be used to distinguish HP from idiopathic pulmonary fibrosis [42]. Laboratory Tests The presence of precipitating antigen-specific antibodies – formerly considered the ‘gold standard’ for diagnosis – is now believed to merely reflect exposure. This understanding is based on studies that demonstrated antigenspecific antibodies in up to 50% or more of serum samples obtained from exposed but asymptomatic individuals. While the antibody titers tend to be higher in patients with HP there is considerable overlap [43]. The diagnostic value of antibody testing is further limited by the fact that many cases of farmer’s lung were reported where no antibodies could be found [11]. In acute episodes of HP increased leukocyte numbers in blood smears with predominance of neutrophils and elevated C-reactive protein levels are found. In chronic forms a polyclonal elevation of gammaglobulins is common. Bronchoalveolar Lavage Bronchoalveolar lavage fluid obtained in the first 24 h after exposure contains high absolute and relative numbers of lymphocytes, neutrophils, eosinophils and mast cells. When obtained 2–7 days postexposure, cell differentials show high numbers of lymphocytes, plasma cells and mast cells. In lavage samples obtained one week or more after the last exposure the distribution of all cell types shows a tendency to return to normal values, with the exception of lymphocytes [44]. Typically, in all forms of HP a significant increase in the total cell count is found. The analysis of T cell surface phenotypes in the majority of cases reveals a predominance of CD8⫹ T cells associated with a reduced

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CD4/CD8 ratio (usually ⬍1). However, the CD4/CD8 ratio may depend on the type of HP evaluated: it is typically reduced in cases of summer-type HP, whereas it may be ⬎1 in other forms. As with antibodies the diagnostic value of bronchoalveolar lavage is limited as exposed but asymptomatic individuals may also show a lymphocytic alveolitis and increased CD8⫹ T cells [45]. In patients with HP the lymphocyte numbers are generally higher, but with considerable overlap. A normal number of lymphocytes in bronchoalveolar lavage does rule out an active form of HP [46]. Cormier et al. [47] recently published a report on the long-term consequences of the detection of antigenspecific IgG antibodies and/or a lymphocytic alveolitis in asymptomatic farmers that they had followed for more than 20 years. The authors were not able to find clinically significant long-term changes in these individuals. Thus, antigenspecific IgG antibodies and increased lymphocytes in bronchoalveolar lavage fluid do not seem to predispose to the development of HP. Transbronchial Biopsies As stated above histopathologic evaluation of lung tissue is usually not necessary for the diagnosis of HP. In unclear cases where lung tissue needs to be evaluated, a video-assisted thoracoscopic or an open lung biopsy should be performed preferentially. Transbronchial biopsy specimens are of limited use [48]. Provocation Tests Specific provocations with barn dust, Saccharospora rectivirgula, bird antigens or workplace/home exposure have been used. These tests are not standardized – neither in the mode of exposure nor the criteria that are used to analyze the test result [5].

Diagnosis

In summary, there is no diagnostic test, not even lung biopsy, that is pathognomonic for HP. Recently, six significant predictors of HP were identified: (1) exposure to a known offending antigen; (2) positive precipitating antibodies to the offending antigen; (3) recurrent episodes of symptoms; (4) inspiratory crackles on physical examination; (5) symptoms occurring 4–8 h after exposure; (6) weight loss [49]. The occurrence of a diffuse parenchymal lung disease is typically demonstrated by lung function and HRCT scan (table 3). Besides, bronchoalveolar lavage is a less invasive method that may be useful in the

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Table 3. Steps to diagnose hypersensitivity pneumonitis

1. Check if the clinical history and the clinical symptoms and signs are compatible with the diagnosis 2. Identify exposure to an offending antigen 3. Demonstrate an immune response to the antigen 4. Assess the pattern and extent of lung function changes 5. Determine the pattern and extent of radiographic changes (including high-resolution CT) 6. Consider bronchoalveolar lavage 7. Evaluate the need for lung biopsy 8. Consider the usefulness of a natural or laboratory-based challenge study 9. Exclude differential diagnoses (organic dust toxic syndrome, other diffuse parenchymal lung diseases) Modified after Bourke et al. [50].

diagnostic workup. In selected cases surgically obtained lung biopsies or natural or laboratory-based challenge studies may be considered [50]. Nevertheless, a recent expert workshop came to the conclusion that strategies to improve detection and diagnosis are needed [51]. The most important differential diagnosis of acute HP is the organic dust toxic syndrome (ODTS). ODTS is a toxic reaction. The observed prevalence ranges from 1 to 50% and is correlated to the intensity of the exposure [52]. In heavily exposed groups, high attack rates for ODTS have been observed, for example in a college fraternity where more than 80% of students attending a dance in an exceedingly dusty basement covered in straw developed ODTS. Undoubtedly, many patients who are considered to have recurrent acute attacks of farmer’s lung, in reality suffer from ODTS. Patients with ODTS usually present with high fever and chills. Usually, the symptoms develop 4–6 h after exposure. Dyspnea is rare and mild. Chest radiograph and lung function are typically normal. Bronchoalveolar lavage shows an alveolitis with an isolated increase in neutrophils. ODTS in contrast to farmer’s lung does not induce structural changes of lung parenchyma. Even after many incidents there is no irreversible loss of lung function. The pathogenesis of ODTS is unclear. Initially, the term pulmonary mycotoxicosis was used as it was thought that mycotoxins are the cause. Today it is believed that endotoxins are of major pathogenetic importance. Other differential diagnoses of acute farmer’s lung are silo filler’s disease caused by inhalation of NOx and mucus irritation induced by exposure to ammonia. Chronic bronchitis is a relevant differential diagnosis in patients considered to be suffering from chronic farmer’s lung. The prevalence of chronic bronchitis is much higher in farming populations

than in nonfarmers. This chronic bronchitis is commonly obstructive. Smoking is a potentiating factor. Thus, this disease presents as chronic obstructive pulmonary disease (COPD). Asthma is also more common in farmers than in non-farmers. In particular, hog raising seems to be an important risk factor for the development of asthma with the pathogenesis mostly not being extrinsic.


Following a first acute attack of farmer’s lung, patients showed an improvement of lung function for up to 2 years after the incident. Gas exchange improved most rapidly, the improvement of forced vital capacity was slower, while the recovery of transfer factor for CO (DLco) took even longer. These improvements occurred although the majority of patients were still working on the farms [53]. In long-term follow-up studies of farmer’s lung patients, airways obstruction with or without emphysema was a common sequela [54]. Nevertheless, impairment of DLco is the most important long-term consequence of farmer’s lung. Patients with recurrent episodes had a significantly lower mean transfer factor compared to those with only a single episode [43]. There is no inevitable progression from the acute to the chronic form. It is not clear what factors determine the initial presentation and subsequent course of the disease, but the intensity and frequency of antigen exposure are believed to be important. It is thought that intermittent high grade exposure favors the development of acute attacks. In contrast, long-term low-grade exposure seems to cause a chronic form of HP preferentially. Nevertheless, farmers with acute farmer’s lung who stay on the farm may develop progressive disease. In a cohort study of individuals with farmer’s lung who continued to be exposed, 40% developed fibrotic lung disease and a decreased transfer factor [43]. In Finland the estimated mortality rate of farmer’s lung between 1980 and 1990 was 0.7%. All except one patient– had chronic disease. On average, death occurred 8 years after diagnosis. The majority of patients with a fatal outcome had suffered from symptoms of farmer’s lung for more than a year before the diagnosis was established and fibrotic changes were already visible on the chest X-ray at the time of the diagnosis. In several other studies small numbers of fatal cases were reported – all off them suffering from extensive pulmonary fibrosis [55]. Fatalities have also been reported in pigeon breeder’s lung [56]. In a recent study where open lung biopsy had been performed during the diagnostic work-up of the patients Vourlekis et al. [57] demonstrated that patients with inter-


stitial fibrosis had a by far worse long-term survival than patients with no signs of fibrosis: the median survival in the ‘fibrotic’ group was 7.1 years, in the ‘nonfibrotic’ group more than 20 years.

Management and Treatment

Continued antigen exposure is one of the identified causes of an adverse prognosis. Thus, avoidance of continued antigen exposure has been the mainstay of treatment. Avoidance of exposure may be difficult. In the case of bird keeper’s disease, high levels of bird antigen may persist for prolonged periods of time in the patient’s home, despite removal of the offending birds and a complete clean-up. This finding may account for the persistence of the disease in some patients with HP and for outbreaks in patients that moved into a new home where formerly birds had been kept [58]. Patients with bird keeper’s disease should also remove feather-containing pillows and blankets. In the chronic form of the disease subsequent avoidance of antigen by the affected individuals may fail to reverse the disease. Some patients even experience worsening despite avoiding exposure and undergoing treatment and develop end stage lung fibrosis [59]. On the other hand, studies in patients with farmer’s lung suggested that many farmers could continue farming and, if they took precautionary measures, most would not develop severe irreversible lung disease [60]. Dust masks with filters, appropriate ventilation, mechanization of the feeding process on farms, and alterations in forced air ventilatory systems may be useful precautionary measures. Nevertheless, if HP is diagnosed it remains prudent to recommend complete avoidance, until further information is available on the risks from ongoing exposure. If exposure for whatever reason cannot be completely eliminated the efficacy of the installed precautionary measures has to be monitored closely. Although most acute episodes of HP are self-limiting with the patients showing complete recovery corticosteroids are often used. In the only placebo-controlled therapy trial published so far, Kokkarinen et al. [61] have shown that therapy of patients with acute farmer’s lung using corticosteroids over a period of 2 months induced more rapid improvement in physiologic abnormalities, particularly diffusion capacity, at one month follow-up. Five years later, no functional differences were found between the treated and untreated farmers. Surprisingly, the majority of participants in both groups continued farming throughout the study period. Corticosteroid therapy is also recommended in severe chronic and progressive disease, despite the fact that longterm efficacy has not been established. Bertorelli et al. [5]

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suggest a scheme such as is employed in other interstitial lung diseases: 1 mg/kg/day of prednisone for a month, followed by gradual taper till a maintenance dose of 10–15 mg/day is reached. This dose may be continued until the patient is considered healed, or when there is no clinical and/or functional response. If pulmonary abnormalities reappear or deteriorate during the taper, the maintenance regimen may be prolonged indefinitely. Inhaled corticosteroids may be of use in patients with hyperreactive airways

as a consequence of HP. In addition, they could theoretically reduce the necessary dose of oral corticosteroids and thereby minimize side effects. However, there has been very little experience. So far, there are no studies with nonsteroidal immunosuppressants in HP. Based on the data shown above with regard to TNF-␣, there would be a rationale to test the effects of inhibitors of this cytokine, such as infliximab and etanercept. The treatment for chronic disease is supportive as in other interstitial lung diseases.

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45 Semenzato G, Bjermer L, Costabel U, Haslam PL, Olivieri D, Trentin L: Clinical role of bronchoalveolar lavage in extrinsic allergic alveolitis. Eur Respir Rev 1992;8:69–74. 46 Cormier Y, Bélanger J, Leblanc P, Laviolette M: Bronchoalveolar lavage in farmer’s lung disease: diagnosis and physiological significance. Br J Ind Med 1986;43:401–405. 47 Cormier Y, Letourneau C, Racine G: Significance of precipitins and asymptomatic lymphocytic alveolitis. Eur Respir J 2004;23: 523–525. 48 Lacasse Y, Fraser RS, Fournier M, Cormier Y: Diagnostic accuracy of transbronchial biopsy in acute farmer’s lung disease. Chest 1997;112: 1459–1465. 49 Lacasse Y, Selman S, Costabel U, Dalphin J-C, Ando M, Morell F, Erkinjuntti-Pekkanen R, Müller N, Colby TV, Schuyler M, Cormier Y, The HP study group: Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med 2003;168:952–958. 50 Bourke SJ, Dalphin JC, Boyd G, McSharry C, Baldwin CI, Calvert JE: Hypersensitivity pneumonitis: current concepts. Eur Respir J 2001;18:81S–92S. 51 Fink JN, Ortega HG, Reynolds HY, Cormier YF, Fan LF, Franks TJ, Kreiss K, Kunkel S, Lynch D, Quirce S, Rose C, Schleimer RP, Schuyler MR, Selman M, Trout D, Yoshizawa Y: Needs and opportunities for research in hypersensitivity pneumonitis. Am J Respir Crit Care Med 2005; 171:792–798. 52 Malmberg P, Raks-Andersen A, Hoglund S: Incidence of organic dust toxic syndrome and allergic alveolitis in Swedish farmers. Int Arch Allergy Immunol 1988;87:47–54. 53 Kokkarinen JI, Tukiainen HO, Terho EO: Recovery of pulmonary function in farmer’s lung: a five-year follow-up study. Am Rev Respir Dis 1993;147:793–796.


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Claus Vogelmeier, MD Division for Pulmonary Diseases Department of Internal Medicine Philipps University Marburg Baldingerstrasse DE–35043 Marburg (Germany) Tel. ⫹49 6421 2866451, Fax ⫹49 6421 2868987 E-Mail [email protected]

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Idiopathic Pulmonary Fibrosis Dominic T. K. Keating

Brian McCullagh

Jim J. Egan

Advanced Lung Disease and Irish National Lung Transplant Program, The Mater Misericordiae Hospital, St.Vincent’s University Hospital, and Our Lady’s Hospital for Sick Children, Dublin Molecular Medicine Center, University College Dublin, Dublin, Ireland

Abstract Idiopathic pulmonary fibrosis (IPF) is an increasingly common condition which poses many challenges. High resolution CT scanning offers a non-invasive technique which can secure an accurate diagnosis in the majority of patients. Lung function estimates of gas transfer allow the definition of advanced (DLco ⬍ 39% predicted) and limited disease (DLco ⬎ 40% predicted). Developments in the area of medical therapy have been slow. Based on current thinking regarding the pathophysiology of IPF, steroids are increasingly seen as having only a limited role in its treatment. Emerging studies are highlighting the importance of alternative forms of therapy including N-acetylcysteine, pirfenidone and bosentan, for example. Lung transplantation is a legitimate surgical treatment for IPF. However, in light of the high death rate on the waiting list, it is recommended that selected patients are referred early to the transplant programme. Copyright © 2007 S. Karger AG, Basel

Idiopathic pulmonary fibrosis (IPF), also known as cryptogenic fibrosing alveolitis, is one of a spectrum of idiopathic interstitial pneumonias, which share many common clinical and radiographic features (table 1). A minority of patients with confirmed IPF live beyond 5 years from the time of clinical presentation [1]. The cause remains unknown and to date no therapeutic intervention has been shown to have a major impact on disease progression [2].

Despite advances being made in the diagnosis and classification of this disease little progress has been made with regard to treatment. Traditionally, IPF was considered an inflammatory disorder of the lung. In recent years focus has changed towards IPF being a primary fibrotic disease. Current ideology would suggest that multiple sequential lung injuries take place, this in turn leads to aberrant wound healing and resultant fibrosis [3]. This has sparked interest in newer antifibrotic therapies and immune modulators [4].

Pathogenesis

The traditional concept of unchecked inflammation as the primary pathologic process in IPF has recently been challenged. One of the reasons for this reassessment was the discovery that in animal models fibrosis may occur in the absence of inflammation [5]. Some investigators now believe that inflammation is in fact an epiphenomenon of the fibrotic pathway. More recently, the epithelial cell has became the focus of attention, following the detection of a number of fibrogenic cytokines released from the epithelial cell in response to injury. Those cytokines identified include transforming growth factor-␤1 (TGF-␤1) [6], platelet-derived growth factor [7], basic fibroblastic growth factor [8], and tumour necrosis factor-␣ (TNF␣) [9]. The emerging paradigm suggests that following injury to the epithelial cell there follows a release of cytokines from the injured cell. Fibroblasts are attracted down a chemoattractant gradient to the site of injury where they begin to

Table 1. Classification and histological features of idiopathic interstitial pneumonias

Liebow and Carrington (1965)

Katzenstein and Myer (1998)

ATS/ERS international classification (2002)

Histological features

UIP

UIP

UIP

honeycomb fibrosis fibroblastic foci heterogenous involvement subpleural and paraseptal

DIP

DIP/ RBILD

DIP

lung involvement uniform alveolar macrophages prominent moderate alveolar septal thickening lymphoid aggregates (chronic inflammation) bronchiolocentric alveolar macrophages mild bronchiolar fibrosis and inflammation dusty brown cytoplasm in macrophages diffuse distribution temporally homogenous diffuse fibrosis with alveolar septal thickening hyaline membranes

RBILD

AIP

AIP

NSIP

NSIP

cellular type moderate interstitial chronic inflammation type II pneumocyte hyperplasia fibrosing type lose interstitial fibrosis without temporal heterogeneity HE lost lung architecture; relative preservation on elastic stain interstitial chronic inflammation

Bronchiolitis obliterans and interstitial pneumonia

COP

organising intraluminal pneumonia in distal air spaces patchy distribution preserved lung architecture temporally homogenous

Lymphocytic interstitial pneumonia

LIP

uniform lung involvement; prominent alveolar macrophages thickening of alveolar septa lymphoid aggregates

Giant cell interstitial pneumonia (hard metal lung)

AIP ⫽ Acute interstitial pneumonia; COP ⫽ cryptogenic organising pneumonia; DIP ⫽ desquamative interstitial pneumonia; LIP ⫽ lymphocytic interstitial pneumonia; RBILD ⫽ respiratory bronchiolitis and interstitial lung disease; UIP ⫽ usual interstitial pneumonia.

differentiate into cells that are more resistant to apoptosis and more sensitive to fibrogenic cytokines [10]. In addition to the attraction of fibroblasts there is also a phenotypic change following injury to the epithelial cell. This adaptation is termed ‘epithelial-mesenchymal transition’ and is seen by many as the initial mechanism by which fibroblasts appear following local injury [11]. Multiple recurrent injuries lead to the chronicity of the disease and ultimately to the development of ‘fibroblastic foci’, which are now regarded as the histological hallmark of the disease.

Idiopathic Pulmonary Fibrosis

Epidemiology

Males are affected more often than females with a prevalence of 1.4:1.0 and an incidence of 1.3:1.0 [12–14]. The mean age at diagnosis is 67 years, with over 60% of the patients being above 60 years of age. There is no evidence to suggest that any particular ethnic grouping has a particular predilection for the disease [15]. The precise prevalence for IPF remains uncertain to date with studies which suggest that it ranges from 14 to 42.7/

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100,000 with an incidence of 6.8–16.3/100,000 [13, 14]. Much of the data pertaining to epidemiology predates Katzenstein’s classification of the idiopathic interstitial pneumonias; therefore, these figures may be overstated. A study in Bernillo County, New Mexico, between 1988 and 1990 calculated rates for all forms of interstitial lung disease. From their data, prevalence rates were calculated as 20.2 and 13.2/100,000 of the population for men and women, respectively [13]. The incidence and prevalence rates of IPF were calculated in Moravia and Silesia (two regions in Poland and the Czech Republic with populations of around 4 million) as 0.74–1.28/100,000 and 6.5–12.1/ 100,000, respectively [16]. Recorded prevalence rates in both Finland and Norway range from 16 to 24/100,000 of the population. The incidence of IPF in Norway was calculated as 4.3/100,000 per year [17]. Prevalence rates in the United States have been reported at approximately 20/100,000 [13]. Despite varying results in the literature, broadly speaking true prevalence rates for IPF vary from 3 to 30/100,000 of the population. A UK study in 1998 estimated the median survival of incident cases of IPF to be 2.9 years. The survival reported for prevalent cases was higher at 9 years [18]. The authors concluded that for an accurate estimate of survival figures only incident cases should be taken.

Risk Factors

Reports suggest that living in an industrialised area is a risk factor compared to living in a rural setting [19]. Studies have shown that where a diagnosis of pneumoconiosis has been eliminated, environmental exposure in rural and urban areas has been found to relate to the development of IPF [20]. Metal and wood dust exposure has been associated with the development of IPF independent of cigarette smoking. In one study 75% of IPF patients had a history of smoking [21], which was associated with acceleration of the disease process [22]. While no genetic factors have been conclusively associated with IPF evidence for a genetic predisposition comes from familial cases of the disease. One such family cluster includes 16 patients from four generations [23], while other studies report familial pulmonary fibrosis most likely inherited as an autosomal-dominant trait with a variable penetrance, males and females being affected equally [24–26]. While gastroesophageal reflux has been implicated in the development of pulmonary fibrosis, its exact role in the pathogenesis is not fully clear. Approximately 90% of IPF

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patients have acid reflux and it has been suggested this results in recurrent microinjuries to the epithelium resulting in the development of a fibrotic response in the lung parenchyma [27]. Numerous viruses have been implicated in the pathogenesis of IPF [28]. A higher incidence of Epstein-Barr virus (EBV), influenza, cytomegalovirus [29], and hepatitis C [30] infections have been reported in patients with IPF. EBV in particular has been shown to be present in the lungs in patients with IPF and that they replicate in epithelial cells. EBV viral capsid antigen has been demonstrated in lung tissue analysed by immunofluorescent staining [31]. The presence of EBV (detected by PCR for LMP1) in patients with IPF has also been linked to a more progressive form of the disease [32].

Histologic Classification

The initial morphological classification of idiopathic interstitial pneumonia was described by Averill Liebow in 1975. Katzenstein and Myers revised this classification describing four specific histological subtypes of chronic disease – usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP)/respiratory bronchiolitis interstitial lung disease (RBILD), and acute interstitial pneumonia (AIP). The histological pattern presently regarded as representing clinical IPF is UIP, which also represents the commonest pattern [33]. The pattern of UIP includes temporally heterogenous features present within the same histological field, with normal and fibrotic lung juxtaposed; inflammation is usually sparse or absent. Fibrosis is in a subpleural distribution characterised by honeycombing and fibroblastic foci, which represent areas of fibroblast proliferation and collagen deposition.

Diagnosis

IPF classically presents in an insidious manner with the gradual onset of dyspnoea and cough. Dyspnoea is progressive with an incremental subjective awareness of symptoms (table 2). Another common symptom at presentation is paroxysmal coughing which is refractory to antitussive agents. The differential diagnosis for IPF is extensive and includes a heterogenous group of acute and chronic processes. On physical examination, crackles are detected on auscultation in ⬎80% of patients. These are typically dry, end-inspiratory, and ‘Velcro’ in quality, and are most prevalent

Table 2. Diagnostic criteria for IPF, ATS/ERS statement [12]1

Major criteria Exclusion of other known causes of interstitial lung diseases, such as drug toxicities, environmental exposures and connective tissue disease Abnormal pulmonary function studies including evidence of restriction (reduced VC often with increased FEV1/FVC ratio) and impaired gas exchange increased AaPO2 with rest or exercise or decreased DLCO (diffusing capacity of the lung for CO) Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scans Transbronchial lung biopsy or bronchoalveolar lavage (BAL) showing no features to support an alternative diagnosis Minor criteria Age ⬎50 years Insidious onset of otherwise unexplained dyspnoea on exertion Duration of illness ⱖ3 months Bibasilar inspiratory crackles 1

All four major and three of four minor criteria are required for diagnosis of IPF without surgical biopsy.

Traction bronchiectasis

Honeycombing

Subpleural fibrosis (basal predominance)

Fig. 1. A high resolution CT scan of a patient with IPF demonstrating, subpleural fibrosis, honeycombing and traction bronchiectatsis.

Radiology

in the lung bases. Clubbing is noted in 25–50% of patients [34]. Cyanosis, cor pulmonale, an accentuated pulmonary second sound, right ventricular heave, and peripheral oedema may be observed in the late phases of the disease. Extrapulmonary involvement does not occur, but weight loss, malaise, and fatigue may be noted. Fever is rare, and its presence suggests an alternative diagnosis. Symptoms or signs suggestive of a connective tissue disease (joint pains or swelling, musculoskeletal pain, weakness, fatigue, fever, photosensitivity, Raynaud’s phenomenon, pleuritis, dry eyes, dry mouth) should be carefully elicited.

Laboratory Investigations

IPF is confined to the lungs; as a result, the abnormalities that can be elicited by serological testing are restricted. In most circumstances the use of laboratory investigations in the workup of patients is to rule out other causes of lung fibrosis such as hypersensitivity pneumonitis. Neutrophilia may be seen, but usually it occurs in the setting of infection, while rheumatoid factor or antinuclear antibody titres can be positive in up to 40% of patients. Hypergammaglobulinaemia is also associated with IPF patients in some reports [35]. Other tests that may be useful in investigating patients include anti-neutrophil cytoplasmic antibodies and Scl 70, which would suggest Wegener’s granulomatosis or connective tissue disease.


While a normal CXR does not exclude the diagnosis of IPF, an abnormal CXR is almost universal in patients presenting with IPF [36]. The characteristic feature on the CXR of IPF patients include peripheral reticular opacities, especially at the lung bases [37]. These changes are usually bilateral, asymmetric and associated with decreased lung volumes. Asbestosis and connective tissue disease (scleroderma or rheumatoid arthritis) should be included in the radiologic differential. If other changes are present on the CXR such as alveolar space opacification, then the possibility of other disease processes such as cryptogenic organising pneumonia or malignancy should be considered. The technique of high-resolution CT (HRCT) scanning allows detailed evaluation of the lung parenchyma by using 1–2 mm thick slices, with a reconstruction algorithm that maximises spatial resolution. HRCT increases the specificity for the diagnosis of IPF, helps to narrow the differential diagnosis, and allows identification of any associated emphysema [38] (fig. 1). HRCT increases the level of diagnostic confidence compared with the chest radiograph. Trained observers in some reports have a 90% accuracy in confidently diagnosing IPF from other diseases on HRCT [39]; however, when HRCT is used in isolation for the purpose of diagnosing IPF some cases will be missed [40]. Diagnostic accuracy is excellent when the pattern of involvement on HRCT is correlated with findings on clinical examination [41]. The pattern most consistently seen in

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IPF includes bibasilar patchy, predominantly peripheral, subpleural reticular abnormalities. Ground glass changes may also be present but are not a predominant feature of the disease while areas of more severe involvement is associated with traction bronchiectasis with or without subpleural honeycombing. Connective tissue diseases (particularly scleroderma and rheumatoid arthritis) and asbestosis have similar appearances to IPF. The presence of parenchymal bands of fibrosis and pleural plaques in patients may indicate asbestosis. Patients with subacute or chronic hypersensitivity pneumonitis can have similar reticular opacity or honeycombing, but often lack the bibasilar predominance seen in IPF. IPF may also be mimicked by sarcoidosis or idiopathic BOOP on HRCT. Extensive ground glass opacity of the lung (ⱖ30% of lung is involved) should prompt consideration of another diagnosis rather than IPF, particularly desquamative interstitial pneumonitis. Similar ground glass opacification without basal or peripheral predominance may be found in patients with RBILD, hypersensitivity pneumonitis, COP, or NSIP. Close liaison between respiratory physician and radiologist resulting in correlation with clinical features should result in an accurate diagnosis in the majority of cases.

Pulmonary Function Testing

Pulmonary function tests (PFT) are the primary investigation utilized and the aim is threefold: (1) to aid diagnosis, (2) to quantify severity of disease, and (3) to measure disease progression [42]. The typical findings include a low diffusion capacity for carbon monoxide (DLCO) and low total lung capacity (TLC), with an elevated forced expiratory volume in one second over forced vital capacity of greater than 70 (FEV1/FVC ⬎70) indicating a restrictive pattern lung disease. A limitation of PFT in IPF is that there are no agreed classification systems to define disease severity and progression, such as in COPD, which outlines disease severity and progression clearly with GOLD staging [43]. Studies have shown that in patients with confirmed UIP a DLCO of ⬍39% correlates with a prognosis of 2 years or less [44, 45]. Studies have also tried to define disease progression and taking into account all the different modalities of PFTs the FVC% predicted has been shown as the best predictor of disease progression [46, 47]. Following on from this, a classification system based on ‘advanced’ and ‘limited’ disease has been proposed [48], advanced disease being defined by a DLCO ⬍39% predicted. Transplant assessment

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is deemed appropriate in this group. Limited disease is defined by a DLCO ⬎40%. Six-monthly follow-up is suggested to assess for disease progression, with a decline of 10% in FVC as the marker for progression [48].


In the early 1980s bronchoalveolar lavage (BAL) was utilised in identifying the key immune effector cells associated with inflammation associated with IPF [49]. Its use as a research tool allowed for the detection of polymorphonuclear leukocytes, neutrophil products, eosinophils, activated alveolar products, cytokines, growth factors and immune complexes in patients with IPF. The main role for BAL in the clinical setting is as a means of excluding other causes of pulmonary fibrosis such as infection, sarcoidosis, eosinophilic pneumonia and pulmonary histiocytosis X and occasionally malignancy. The profile of inflammatory cells in BAL sample may also be useful in narrowing the differential diagnosis in patients with fibrosing interstitial pneumonias. Neutrophils (level ⬎5%) are present in up to 90% of patients, with eosinophils (level ⬎5%) associated in 69%, while 20% of patients have an associated increase in lymphocytes. These findings are not pathognomonic for IPF, and if an isolated lymphocytosis is present other diagnosis should be sought including hypersensitivity pneumonitis, sarcoidosis, granulomatous infections or LIP. Some studies suggest BAL neutrophilia and/or eosinophilia is associated with worse outcomes while a lymphocytosis was associated with steroid responsiveness [50].

Surgical Lung Biopsy

HRCT can confidently secure a diagnosis in 90% of patients. Transbronchial biopsy is useful in identifying alternate diagnoses, but is limited in the size of biopsies that can be taken and as result it is not the best procedure for diagnosing IPF. Large biopsies are required in order to identify the characteristic features of IPF- fibroblastic foci, and a temporally heterogenous pattern of fibrosis. In the setting of unidentified interstitial lung disease the safest method of acquiring a sufficient tissue sample with the least risk is via an open lung biopsy performed using video-assisted thoracoscopy (VATs) [51]. VATs procedure is not without complications and patients undergoing the procedure should be carefully chosen so as not to precipitate acceleration in the disease. A mortality of up to 15% in IPF patients has been reported. When mixed patterns of disease are evident

for example both NSIP and UIP, the clinical course follows the pattern typical of patients with isolated UIP. Natural History and Prognosis

IPF patients have a mean survival of 3.2 years from the time of diagnosis [52]. Death in IPF patients has been attributed to respiratory failure, ischaemic heart disease, heart failure, infection and pulmonary emboli [53, 54]. Bronchogenic carcinoma has been recognized in up to 31% of patients with advanced stage IPF [55]. Markers of Disease Severity

Patients should be reviewed initially at two months then at three-month intervals. Review should include an assessment of spirometry, diffusion capacity, oxygenation and a 6-min walk test. A greater than 10% decline in FVC or 15% fall in diffusion capacity values from baseline would indicate a disease progression. Desaturation to less than 88% on 6-min walking distance has been shown to correlate with disease prognosis [56]. Acute Exacerbations of IPF

The specific entity of acute exacerbations of IPF are now recognized. A sudden decline in dyspnoea over a month, identification of new infiltrates on chest X-ray, worsening hypoxia, and rapid development of respiratory failure in the absence of another diagnosis indicates an acute exacerbation of IPF. This may also be referred to as ‘accelerated IPF’ [57]. One study found that acute exacerbations preceded death in 47% of cases [58]. Another study found the 2-year frequency to be 9.6%, and that most of the cases were idiopathic but that some followed intervention such as surgical lung biopsy and bronchoscopy. In addition, biopsies taken during acute exacerbation revealed diffuse alveolar damage superimposed on UIP [59]. Acute exacerbations are common in IPF and are managed using high dose corticosteroids, such as methylprednisolone 500 mg daily for 3 days, and supplemental oxygen, however, evidence for this strategy is based only on case studies. Management of the IPF Patient

To date no single treatment has been found to be effective in curing IPF. As a result the most beneficial option for


most patients is enrolment in a clinical trial if one is available to them. With increasing dyspnoea many patients abandon exercise, however the benefits of maintaining a good pulmonary rehabilitation regimen is important. In the latter stages of IPF paroxysms of coughing can prove to be extremely distressing for patients. A number of options may be attempted to ease this problematic condition; oral codeine or other antitussive agents may prove helpful in moderating the paroxysms.

Treatment of Idiopathic Pulmonary Fibrosis

Historical Pharmacologic Intervention

Corticosteroids

Corticosteroids have formed the basis of treatment for IPF. The histological reclassification of the idiopathic pneumonias has revealed the limitations of their effectiveness. More recent studies suggested that corticosteroids may be of limited value in treating the condition but also that there was a significant number of adverse effects associated with this treatment regimen [60, 61]. Despite this background most treatment algorithms continue to include corticosteroids, at least in the initial phase of treatment; the usual starting concentration being 0.5 mg/kg/day for 3 months. Reassessment of the patient is performed at the 3-month review and only those patients that have stabilized or show improvement in objective parameters are allowed to continue their use. The dose is gradually tapered to a more modest level of 0.1–0.2 mg/kg/day for those who are to remain on corticosteroids indefinitely. It is important to prophylax against steroidinduced osteoporosis by commencing calcium and bisphosphonate supplementation.

Azathioprine

Azathioprine is the most commonly used of the cytotoxic agents. It is converted into mercaptopurine, its active compound, which disrupts RNA and DNA synthesis. The precise mechanism by which azathioprine exerts its effects is unknown but cellular immunity appears to be inhibited to a greater degree than humoral immunity. One study supported its use in combination with low dose corticosteroid [62]. A Cochrane review published in 2003 identified case controlled or randomised trials looking at the effects of

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azathioprine in IPF. In one trial prednisolone and placebo was given to 13 patients in one arm with 14 patients in the other arm receiving prednisolone and azathioprine [62]. The definition of IPF used in the inclusion criteria were not identical to that used at present, but at 1 year there was no difference in clinical measures or mortality. When analysis was adjusted for age there was a significant mortality benefit in the azathioprine group. Some benefit was shown in earlier trials using azathioprine but these were performed in a more diverse group of patients [63]. In the studies to date on azathioprine the findings have been blunted by the lack of true controls. It is debatable whether a definitive conclusion can be drawn from trials without such a cohort being included. Conclusions have been drawn from the control or ‘no treatment’ arms of some of the more recent trials [60, 64, 65] and the ‘prednisolone and azathioprine’ arm of the IFIGENA study [66]. Comparison of these trials shows that the fall in FVC in the group receiving prednisolone and azathioprine in the IFIGENA trial was similar to that in the placebo group from the recent interferon gamma trial and the placebo group from the pirfenidone trial [64, 65]. In both trials [64, 65], prednisolone of 10 mg/day was allowed (77% of patients in the interferon gamma trial), so the placebo group in these trials was actually a group treated with low-dose corticosteroids. Some investigators suggest that this implies that prednisolone plus azathioprine has no advantage over placebo, or prednisolone in preserving lung function and can therefore not be recommended as a sole treatment or as a steroid sparing treatment in IPF [67].

Cyclophosphamide

Early studies with cyclophosphamide in the setting of IPF appeared to confer some advantage when used in combination with corticosteroids [68]. Cyclophosphamide is an alkylating agent and part of the nitrogen mustard group, and exerts its effects by decreasing lymphocytes and abrogating their function. Many trials have been contradictory in their findings with regard to the benefit of cyclophosphamide in IPF [69, 70]. Johnson et al. [68] performed a prospective trial in 43 patients with IPF to high-dose corticosteroids or lowdose corticosteroids and cyclophosphamide. This study was completed prior to the histological reclassification in idiopathic interstitial pneumonias. Therefore, a heterogeneous population of UIP and other idiopathic interstitial pneumonias may have been included in the study. A post hoc secondary analysis of time to death analysed as a single variable

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suggested an associated reduction in mortality with cyclophospamide. A retrospective study of 82 IPF patients treated with prednisolone and cyclophosphamide and 82 untreated matched controls showed no difference in median survival (1,431 days treated vs. 1,665 days untreated; p ⫽ 0.58). Limiting the analysis to patients who had undergone surgical biopsies, or to patients with limited disease, defined as an FVC ⬎60% predicted, failed to reach statistical significance also [71]. Due to the side effect profile and lack of significant benefit many physicians no longer use cyclophosphamide.

Warfarin

Formerly pulmonary emboli have been documented as the cause of death in 3.4% of patients with idiopathic pulmonary fibrosis [54]. A recent Japanese trial suggested that survival can be improved by the use of anticoagulation. Fifty-six patients (mean age, 69.4 years; range 47–89) admitted to 5 hospitals in the Miyagi prefecture in Japan were studied [72]. Patients were randomised to prednisolone or prednisolone and anticoagulant therapy (oral warfarin if an outpatient or low-molecular-weight heparin if admitted). Mortality as a result of acute exacerbations of IPF was significantly decreased in patients receiving anticoagulation compared to those in the anti-coagulant group (18% vs. 71%; p ⫽ 0.008). Plasma d-dimer levels in patients who died (3.3 ⫾ 2.3 ␮g/ml) were significantly higher than that in survivors (0.9 ⫾ 0.7 ␮g/ml; p ⬍ 0.0001). One limitation of this study was that there was no treatment arm where anticoagulation alone was used therefore it is difficult to attribute the benefit solely to anticoagulation.

Emerging Therapies

More recently there has been a greater emphasis on the epithelial cell and its role as the origin of the fibrotic process [73]. Present theories suggest that the continuous injury to the epithelial cell results in release of cytokines and growth factors that in turn attract fibroblasts and profibrotic mediators. In addition, some investigators suggest that the epithelial cell itself is able to alter its phenotype and function as a fibroblast in the early stage of the disease. Many of the newer research and therapeutic agents have been developed in response to the emerging knowledge.

Interferons

Interferons have a negative effect on the growth and division of human fibroblasts. In murine studies interferons have also been shown to decrease collagen production and reduce scarring formation through a reduction in collagen contraction [74, 75]. Ziesche et al. [76] first provoked interest in interferons when a pilot study of its use showed amelioration in IPF. In the group that received interferon-gamma 1b plus prednisolone, the partial pressure of arterial oxygen (SpO2) at rest increased from 64 ⫾ 9 mm Hg at baseline to 76 ⫾ 8 mm Hg at 12 months, whereas in the group that received prednisolone alone it decreased from 65 ⫾ 6 to 62 ⫾ 4 mm Hg. There was an increase in total lung capacity in the interferon group by 9% with a decrease of 4% in the group that took prednisolone alone. This prompted a large randomized placebo controlled study. The data from this study which included 330 patients was published by Raghu et al. [64] in 2004. Subjects were assigned to subcutaneous interferon-gamma 1b or placebo. The primary end point was progression-free survival measured by progression of disease or death. There was no significant difference in the duration of progression-free survival between the interferon group versus the placebo group. The median time to death or disease progression in the interferon group was calculated at 439 days as compared to 344 days for the placebo group (p ⫽ 0.5). The dyspnoea and quality of life scores were also unaltered by interferon therapy. Similarly, interferon had no effect on the mean change from baseline to week 48 in FVC and on the mean change in lung fibrosis on high resolution CT. A post hoc analysis indicated that interferon gamma might confer survival advantage to IPF patients with limited disease defined as an FVC of ⬎60%. In an effort to clarify this a large multicenter double blind placebo controlled trial was undertaken to evaluate the efficacy of interferon-gamma 1b in patients with limited disease [77]. There was no significant difference in mortality between the interferon group versus the placebo group.

Pirfenidone

The effects of pirfenidone, a pyridine molecule, have been described in animal models of IPF. Antifibrotic properties ascribed include decreased TGF-␤ and CTGF transcription, inhibition of collagen synthesis, and a diminished cellularity on BAL examination [78, 79]. The application of pirfenidone has resulted in stabilization of lung function, and radiographic scores in IPF patients [80, 81].


A more recent prospective double blind placebo controlled trial published in 2005 investigated the difference in the change in the lowest oxygen saturation by pulse oximetry (SpO2) during a 6-min exercise test from baseline to 6 and 9 months [65]. The primary endpoint in this trial was defined as the change in the lowest SpO2 during a 6-min steady-state exercise test (6MET). A 4% increase or decrease in the SpO2 reflected improvement or deterioration in the primary endpoint. At 6 and 9 months the pirfenidone group was observed to have a mean increase in baseline SpO2 of 0.64 and 0.47%, respectively, with a mean decline in baseline SpO2 in the placebo group of 0.55 and 0.94%. There was no significant difference between the pirfenidone group and the placebo group. However, there were significant improvements in some of the secondary endpoints which included changes in resting PFTs while breathing air (VC, TLC, DLCO, PaO2), disease progression by HRCT patterns, episodes of acute exacerbation of IPF, change in serum markers of pneumocyte damage, and changes in quality of life measurements. At 9 months, the difference in decline of VC between the placebo group (⫺0.13 liters) and the pirfenidone group (⫺0.03 liters) was statistically significant (p ⫽ 0.0366). Acute exacerbation of IPF was manifested in 14% of the placebo group and in 0% in the pirfenidone group during the 9 months (p ⫽ 0.0031). An international trial is presently underway to assess the response to this drug in a larger dataset of patients.

Antioxidants

It has been known since 1989 that there is glutathione deficiency present in the epithelial lining fluid of IPF patients, suggestive of an oxidant-antioxidant imbalance [82]. The reduced form of glutathione, a tripeptide thiol, is vital as an intra- and extracellular protective antioxidant against oxidative/nitrosative stresses. These play a critical role in controlling pro-inflammatory processes in the lungs [83]. Administration of N-acetylcysteine (NAC) can be used to ameliorate the levels of glutathione, and has been found to preserve DLCO better than standard therapy alone [66]. A German study published in 1997 described improvements in pulmonary function in their cohort of 18 patients who received NAC 600 mg three times daily as an adjunct to maintenance immunosuppressive therapy [84]. A limitation of this was that only 10 of their subjects fulfilled the criteria for IPF, the remainder having evidence of systemic sclerosis. They also used a centre specific marker for improvement in PFTs by cumulating three indices of

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change in vital capacity, diffusion capacity and change in exercise induced PaO2. The preliminary data from this trial prompted a large randomized study in 2005 with a cohort of 155 patients [14]. Patients in the NAC group were commenced on 600 mg three times daily along with standard therapy of prednisolone and azathioprine, compared to placebo and standard therapy alone. Eighty patients were assigned to NAC and 75 assigned to placebo, a primary endpoint of absolute changes in vital capacity and DLCO between baseline and month 12 was used. There was a slower rate of loss of vital capacity in the group receiving NAC. The trial concluded that NAC at a dose of 600 mg three times daily added to standard therapy of prednisolone and azathioprine preserves vital capacity and DLCO better than standard therapy alone. The side effect profile was not significantly different in either group and NAC was well tolerated [66]. Importantly, there were more bone marrowrelated adverse effects in the comparison group of prednisolone and azathioprine. It has been debated whether the statistical benefit observed with NAC is clinically relevant, however the magnitude of the change (9% difference for VC and 24% difference for DLCO) would appear to favour clinical relevance.

Tumour Necrosis Factor-␣

TNF␣ has been found to have a complex role in the setting of lung fibrosis; TNF␣ contributes to fibrosis in bleomycin-injured mice [85], however overexpression has been found to limit fibrosis [86]. In IPF patients there is a significant increase in TNF␣ in the hyperplastic type II pneumocytes [87], and it has been found to interact with the TGF-␤1 cascade [88]. Etanercept is a TNF␣ antagonist and a pilot study was performed in 9 IPF patents [89]. There was an improvement in FVC, DLCO and A-a gradient in these patients. Recently, etanercept was evaluated in 87 patients with UIP in a randomised double-blind, placebocontrolled, parallel group, multicenter trial. Patients received either etanercept or placebo twice a week. Three primary endpoints were assessed: FVC% predicted, DLCO% predicted, and PO2 A-a gradient. There was no statistical difference found between treatment groups as defined by primary endpoints. There was a trend towards reduced disease progression by other parameters – the frequency of patients who died or had disease progression; 15/45 (33.3%) and 22/40 (55.0%) in the etanercept and placebo groups, respectively (p ⫽ 0.052) [Raghu et al: Abstract Chest 2005]. This data does not allow the routine use of etanercept in IPF.

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Statins

Lovastatin provokes apoptosis in fibroblasts that constitutively express Myc, such as those from fibrotic lungs [90]. As IPF prognosis is linked to the prevalence of fibroblastic foci this is of potential benefit. Other studies have found that simvastatin significantly inhibited the connective tissue growth factor gene and protein expression overriding the induction of TGF-␤1 [91].

Endothelin

Endothelin-1 can originate from many sites in the lung including endothelial, smooth muscle, epithelial, platelets and macrophages [92]. Endothelin is an endothelial peptide that is present in pulmonary tissue and exercises its actions in bronchial and smooth muscle cells. In IPF patients there is a discernible increase in the quantity of endothelin-1 in the BAL [93]. It has been postulated that endothelin-1 has a role in subepithelial fibrosis in asthmatic patients [94]. As a result of the potential antifibrotic effect associated with endothelin receptor antagonists, a multicenter trial using bosentan in IPF was performed but failed to show an effect on the primary endpoint, the 6 min walk distance. A second trial in a subgroup of early IPF is underway.

Transforming Growth Factor-␤ Antagonism

In vitro and animal models used to analyse IPF treatments suggest that TGF-␤1 plays a significant and central role in the fibrotic pathway [95, 96]. In addition, it has been found that inhibition of TGF-␤1 is able to abrogate the fibrotic process in animals. Unfortunately complete inhibition of TGF-␤1 has been found to result in early death in mice due to unchecked inflammation and multiorgan failure. Studies in humans are awaited.

Imatinib

Imatinib mesylate is a derivative of phenylaminopyrimidine. It acts as a signal transduction inhibitor; in particular, it acts to inhibit signaling through the tyrosine kinase pathway that is activated by TGF-␤1. It has been shown using a mouse model of bleomycin-induced pulmonary fibrosis that fibrosis can be significantly reduced by using imatinib [97], and these findings were corroborated in radiation induced pulmonary fibrosis in mice [98]. Mesenchymal

cell proliferation is a key factor in the progression of pulmonary fibrosis and imatinib has been shown to abrogate the proliferation of these cells in the setting of bleomycininduced fibrosis suggesting that imatinib might be useful for the treatment of human IPF.

patient. IPF patients have the highest mortality on the lung transplant waiting list. This indicates that physicians should aim for early referral.

Conclusion Lung Transplantation

Despite the many potential therapeutic modalities presently being studied, the reality is that a cure for IPF remains elusive. As a result, patients without contraindications and who have significant functional impairment, defined as, a DLco ⬍39% predicted, or fall in FVC of 10% over 6 months should be listed for lung transplantation. A single lung transplant is the favoured option for the IPF

IPF presents a significant challenge to both the clinician and the biomedical research community. The disease in its purest form, UIP, is a rapidly debilitating and fatal disease. Currently, significant progress is being made in achieving improved medical therapy as a consequence of multicenter international studies. With properly designed trials some of the uncertainties about the treatment of this devastating condition may finally be defined, easing the burden for many patients.

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57 Akira M, Hamada H, Sakatani M, Kobayashi C, Nishioka M, Yamamoto S: CT findings during phase of accelerated deterioration in patients with idiopathic pulmonary fibrosis. Am J Roentgenol 1997;168:79–83. 58 Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King TE Jr, Flaherty KR, Schwartz DA, Noble PW, Raghu G, et al: The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005;142: 963–967. 59 Kim DS, Park JH, Park BK, Lee JS, Nicholson AG, Colby T: Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J 2006;27:143–150. 60 Flaherty KR, Toews GB, Lynch JP 3rd, Kazerooni EA, Gross BH, Strawderman RL, Hariharan K, Flint A, Martinez FJ: Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med 2001;110: 278–282. 61 Richeldi L, Davies HR, Ferrara G, Franco F: Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2003;CD002880. 62 Raghu G, Depaso WJ, Cain K, Hammar SP, Wetzel CE, Dreis DF, Hutchinson J, Pardee NE, Winterbauer RH: Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective doubleblind, randomized, placebo-controlled clinical trial. Am Rev Respir Dis 1991;144:291–296. 63 Winterbauer RH, Hammar SP, Hallman KO, Hays JE, Pardee NE, Morgan EH, Allen JD, Moores KD, Bush W, Walker JH: Diffuse interstitial pneumonitis. Clinicopathologic correlations in 20 patients treated with prednisone/ azathioprine. Am J Med 1978;65:661–672. 64 Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr: A placebo-controlled trial of interferon-gamma1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125–133. 65 Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, Taguchi Y, Nagai S, Itoh H, Ohi M, 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. 66 Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM, MacNee W, Thomeer M, Wallaert B, Laurent F, et al: High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353: 2229–2242. 67 Walter N, Collard HR, King TE Jr: Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc 2006;3: 330–338. 68 Johnson MA, Kwan S, Snell NJ, Nunn AJ, Darbyshire JH, Turner-Warwick M: Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis. Thorax 1989;44: 280–288. 69 Baughman RP, Lower EE: Use of intermittent, intravenous cyclophosphamide for idiopathic pulmonary fibrosis. Chest 1992;102:1090–1094.

70 Zisman DA, Lynch JP 3rd, Toews GB, Kazerooni EA, Flint A, Martinez FJ: Cyclophosphamide in the treatment of idiopathic pulmonary fibrosis: a prospective study in patients who failed to respond to corticosteroids. Chest 2000;117:1619–1626. 71 Collard HR, Ryu JH, Douglas WW, Schwarz MI, Curran-Everett D, King TE Jr, Brown KK: Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest 2004; 125:2169–2174. 72 Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe M, Sasaki H: Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005;128:1475–1482. 73 Khalil N, Greenberg AH: The role of TGF-beta in pulmonary fibrosis. Ciba Found Symp 1991;157:194–207; discussion 207–211. 74 Cornelissen AM, Von den Hoff JW, Maltha JC, Kuijpers-Jagtman AM: Effects of interferons on proliferation and collagen synthesis of rat palatal wound fibroblasts. Arch Oral Biol 1999;44:541–547. 75 Dans MJ, Isseroff R: Inhibition of collagen lattice contraction by pentoxifylline and interferon-alpha, -beta, and -gamma. J Invest Dermatol 1994;102:118–121. 76 Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH: A preliminary study of long-term treatment with interferon gamma-1b and lowdose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999;341: 1264–1269. 77 Costabel U: [INSPIRE: Multinational study on the effectivity of interferon-gamma1b in idiopathic fibrosis of the lung]. Pneumologie 2005;59:568. 78 Iyer SN, Hyde DM, Giri SN: Anti-inflammatory effect of pirfenidone in the bleomycin-hamster model of lung inflammation. Inflammation 2000;24:477–491. 79 Iyer SN, Gurujeyalakshmi G, Giri SN: Effects of pirfenidone on transforming growth factorbeta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther 1999;291: 367–373. 80 Raghu G, Johnson WC, Lockhart D, Mageto Y: Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study. Am J Respir Crit Care Med 1999;159: 1061–1069.

81 Nagai S, Hamada K, Shigematsu M, Taniyama M, Yamauchi S, Izumi T: Open-label compassionate use one year-treatment with pirfenidone to patients with chronic pulmonary fibrosis. Intern Med 2002;41:1118–1123. 82 Cantin AM, Hubbard RC, Crystal RG: Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis 1989; 139:370–372. 83 Rahman I, MacNee W: Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 2000;16:534–554. 84 Behr J, Maier K, Degenkolb B, Krombach F, Vogelmeier C: 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. 85 Ortiz LA, Lasky J, Hamilton RF Jr, Holian A, Hoyle GW, Banks W, Peschon JJ, Brody AR, Lungarella G, Friedman M: Expression of TNF and the necessity of TNF receptors in bleomycin-induced lung injury in mice. Exp Lung Res 1998;24:721–743. 86 Fujita M, Shannon JM, Morikawa O, Gauldie J, Hara N, Mason RJ: Overexpression of TNFalpha diminishes pulmonary fibrosis induced by bleomycin or TGF-beta. Am J Respir Cell Mol Biol 2003;29:669–676. 87 Piguet PF, Ribaux C, Karpuz V, Grau GE, Kapanci Y: Expression and localization of tumor necrosis factor-alpha and its mRNA in idiopathic pulmonary fibrosis. Am J Pathol 1993;143:651–655. 88 Kapanci Y, Desmouliere A, Pache JC, Redard M, Gabbiani G: Cytoskeletal protein modulation in pulmonary alveolar myofibroblasts during idiopathic pulmonary fibrosis: possible role of transforming growth factor beta and tumor necrosis factor alpha. Am J Respir Crit Care Med 1995;152:2163–2169. 89 Niden AK, Boylen CT: An open label pilot study to determine the potental efficacy of TNFR:FC (Enbrel Etenercept) in the treatment of usual interstitial pneumonitis (UIP). Am J Respir Crit Care Med 2001;163:A42. 90 Tan A, Levrey H, Dahm C, Polunovsky VA, Rubins J, Bitterman PB: Lovastatin induces fibroblast apoptosis in vitro and in vivo: a possible therapy for fibroproliferative disorders. Am J Respir Crit Care Med 1999;159: 220–227.


91 Watts KL, Sampson EM, Schultz GS, Spiteri MA: Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts. Am J Respir Cell Mol Biol 2005;32:290–300. 92 Fagan KA, McMurtry IF, Rodman DM: Role of endothelin-1 in lung disease. Respir Res 2001;2:90–101. 93 Sofia M, Mormile M, Faraone S, Alifano M, Zofra S, Romano L, Carratu L: Increased endothelin-like immunoreactive material on bronchoalveolar lavage fluid from patients with bronchial asthma and patients with interstitial lung disease. Respiration 1993;60: 89–95. 94 Sun G, Stacey MA, Bellini A, Marini M, Mattoli S: Endothelin-1 induces bronchial myofibroblast differentiation. Peptides 1997;18: 1449–1451. 95 Wang Q, Wang Y, Hyde DM, Gotwals PJ, Koteliansky VE, Ryan ST, Giri SN: Reduction of bleomycin induced lung fibrosis by transforming growth factor beta soluble receptor in hamsters. Thorax 1999;54:805–812. 96 McCormick LL, Zhang Y, Tootell E, Gilliam AC: Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatou graft-versus-host disease: a model for human scleroderma. J Immunol 1999;163: 5693–5699. 97 Daniels CE, Wilkes MC, Edens M, Kottom TJ, Murphy SJ, Limper AH, Leof EB: Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J Clin Invest 2004;114: 1308–1316. 98 Abdollahi A, Li M, Ping G, Plathow C, Domhan S, Kiessling F, Lee LB, McMahon G, Grone HJ, Lipson KE, et al: Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. J Exp Med 2005;201: 925–935.

Dr. Jim J. Egan The Mater Misericordiae University Hospital University College Dublin Eccles Street Dublin 7 (Ireland) Tel. ⫹353 1 803 2606, Fax ⫹353 1 803 2048 E-Mail [email protected]

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Nonspecific Interstitial Pneumonia Kevin R. Flaherty

Fernando J. Martinez

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan,Ann Arbor, Mich., USA

Abstract Nonspecific interstitial pneumonia (NSIP) describes a histopathologic pattern that can be seen in patients with immunodeficiency, drug or environmental exposure, or collagen vascular illnesses. NSIP is also a disease defining term in ‘idiopathic’ cases where no obvious causative factor can be identified. Patients typically manifest with cough, dyspnea, restrictive pulmonary physiology with decreased gas transfer, and ground glass infiltrates on high-resolution computed tomography (HRCT). Response to immunosuppressive therapy is often successful; however, patients with progressive disease are at increased risk of subsequent mortality and should be considered for alternative treatment strategies such as lung transplantation. Copyright © 2007 S. Karger AG, Basel

Definition

In the 1980s NSIP referred to a nonspecific histological lesion in immunocompromized patients (human immunodeficiency virus (HIV)-infected, bone marrow transplant recipients) [1–6]. In the following decade, Katzenstein and Fiorelli described NSIP as a specific pattern that did not match histopathologic criteria for other types of idiopathic interstitial pneumonias (IIP) [7]. In their series, 95 cases of surgical lung biopsies previously diagnosed as ‘chronic interstitial pneumonia, not otherwise specified or nonspecific interstitial pneumonia’ 64 cases were identified which represented similar histopathologic features, the key feature being changes of apparent similar age or ‘temporal

homogeneity’. The etiology of NSIP in this series of patients varied from connective tissue diseases, environmental exposures, and prior acute lung injury. Over time, NSIP has evolved from a term used to describe a histopathologic pattern resulting from many etiologies to a ‘provisional’ form of idiopathic interstitial pneumonia (IIP) [8]. The varied use of the term ‘NSIP’, as well as the overlap between the clinical phenotype of idiopathic NSIP and other IIPs [(the most common being idiopathic pulmonary fibrosis (IPF)], has led to consistent confusion regarding the etiology of NSIP and its relationship to other IIPs or interstitial lung diseases related to connective tissue disorders.

Epidemiology

The incidence and prevalence of NSIP are unknown. Since Katzenstein and Fiorelli’s [7] description of NSIP in 1994 several groups retrospectively evaluated cases previously classified as IPF/cryptogenic fibrosing alveolitis (IPF/CFA) to identify cases of NSIP [9–13]. These series identified NSIP in 11–43% of cases. The prevalence of IPF has been estimated at 3–20/100,000 [14–16]. Extrapolating from these data the prevalence of idiopathic NSIP could range from 1 to 9/100,000.

Etiology

The term NSIP has been used in multiple contexts. NSIP has referred to a nonspecific histopathologic lesion in

immunocompromized patients [1–6], a specific pattern in patients without and with a potential etiology [7], and most recently as a provisional type of IIP [8]. Numerous series have associated the pattern of NSIP with connective tissue disorders [7, 17–24], hypersensitivity pneumonitis [25], drugs [26, 27], infection, and immunosuppression including HIV [1–6]. Therefore it has been suggested that the identification of NSIP should ‘ . . . prompt the clinician to redouble efforts to find potentially causative exposures’ [8]. If no etiology is identified a diagnosis of idiopathic NSIP can be made.

Pathogenesis

The understanding of the pathogenesis of NSIP and other IIPs is evolving. Particularly intriguing is the potential relationship between NSIP and usual interstitial pneumonia (UIP) given the observations that similar exposures [connective tissue disease (CTD); hypersensitivity pneumonitis], inheritance, and genetic mutations can lead to NSIP or UIP and the fact that individual patients can harbor histopathologic lesions of both UIP and NSIP. Significant work accomplished over the past decade is beginning to unravel the pathobiology of NSIP and its relation to UIP. There is evidence of epithelial cell injury in the pathogenesis of UIP and NSIP. Ishii et al evaluated serum and bronchoalveolar lavage (BAL) fluid for surfactant proteins and common carbohydrate antigens such as KL-6 [28]. Serum levels of surfactant protein A (SP-A) were higher in UIP compared to NSIP or normal controls while levels of SP-D and KL-6 were elevated in both UIP and NSIP compared to controls. Interestingly, BAL levels of SP-A, SP-D, and KL-6 showed more scatter across IIPs and controls [28]. If IIPs are related to epithelial cell injury, patients that are able to repair that injury may have better outcomes. Epimorphin, a cell-surface-associated protein involved in epithelial morphogenesis in embryonic organs, has increased expression in mice following injury with bleomycin [29]. Terasaki et al. [29] observed increased epimorphin expression in NSIP biopsies compared to UIP or control biopsies. Expression was localized to mesenchymal cells and the extracellular matrix of early fibrotic lesions and further analysis revealed increased expression of MMP-2, a proteolytic factor involved in lung repair, in re-epithelialized cells overlying epimorphin positive early fibrotic lesions [29]. These data suggest that epimorphin may contribute to repair in NSIP, perhaps through induction of expression of MMP-2. Interestingly, evaluation of MMP-2 and MMP-9, two metalloproteinases that are specific for type IV collagen, showed predominantly MMP-9, which correlated with


BAL neutrophils in patients with UIP, while NSIP cases showed predominantly MMP-2, which correlated with BAL lymphocytosis [30]. Other effector molecules are also likely involved. Kakugawa et al. [31] evaluated the presence of heat shock protein (HSP) 47, a collagen-specific molecular chaperone involved in the processing of procollagens, in patients with idiopathic UIP, idiopathic NSIP, and collagen vascular disease (CVD) associated UIP. HSP 47 was expressed in type II pneumocytes in CVD-UIP and NSIP compared to idiopathic UIP while expression was seen on fibroblasts in idiopathic UIP and NSIP [31]. It is probable that numerous pathways (mechanisms of injury) can lead to UIP and NSIP. Several studies have implicated mutations in surfactant protein C (SP-C), a hydrophobic protein that requires processing and storage prior to being secreted into the alveolar space, in the development of UIP and NSIP [32–36]. It is possible that abnormal processing of this protein leads to accumulation, injury, and subsequent development of interstitial lung disease. It is interesting that adults with SP-C mutations have tended to show a pattern of UIP, while children have tended to show NSIP [32, 36]. Furthermore, a recent study of familial interstitial pneumonia, where you would expect genetics to be similar, showed that 50/111 (45%) of families had radiographic and/or histopathologic features consistent with more than one type of IIP; 35% of these families had a pattern of NSIP or IPF/UIP [37]. These data suggest that similar genetic mutations can be represented by different histopathologic manifestations. Further research is required to determine if other, yet unidentified, genetic mutations or environmental influences (such as cigarette smoking) interact to modify the immunologic response and eventual histopathologic pattern. The coagulation system may also play a role in wound repair and the pathobiology of NSIP and UIP. Mice deficient in plasminogen activator inhibitor-1 (PAI-1) are protected in a bleomycin model of pulmonary fibrosis while mice that overexpress PAI-1 show increased fibrosis [38]. Kim et al. [39] evaluated polymorphisms in the PAI-1 promoter in patients with UIP and NSIP. An insertion or deletion of a single guanine in the upstream promoter yields alleles containing either four or five consecutive guanines (4G or 5G) [40]. Subjects with 4G/4G phenotype have a higher expression of PAI-1 compared to others [41]. Kim noted that the 4G allele and 4G/4G phenotype were more common in NSIP compared to UIP and also that 4G/4G patients were younger at the time of diagnosis [39]. The immune system and its ability to influence cytokine expression also impact the pathobiology of NSIP and UIP. Intercellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin supergene family and its ligand is

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lymphocyte function-associated antigen-1. Expression of ICAM-1 is regulated by proinflammatory cytokines like IL-1, TNF-, and interferon- (INF-). ICAM-1 has been reported to play a role in the migration of leukocytes to the site of inflammation. Levels of soluble ICAM-1 are increased in patients with UIP and NSIP compared to controls [42]. ICAM-1 was localized to type I alveolar epithelial cells in controls and type II cells in patients with NSIP or UIP [42]. T helper type 2 (Th2) cytokines such as IL-4 and IL-13 are pro-fibrotic compared to Th1 cytokines such as IFN-. Jakubzick et al. [43] demonstrated that receptor subunits for IL-4 and IL-13 were present in a greater proportion of lung biopsies from patients with UIP compared to patients with NSIP. There was also a more balanced gene expression of Th1 and Th2 cytokines in patients with NSIP compared to patients with UIP (who were skewed more toward fibrosis) [43]. This same group used a conjugate protein to target Pseudomonas aeruginosa exotoxin (a protein that results in apoptosis) to the receptor for IL-13. Using this approach fibroblasts from UIP were inhibited to a much greater extent compared to fibroblasts from patients with NSIP [44]. More recent data from Keogh et al. [45] confirmed a Th1 phenotype with increased expression of interferon- (INF-) from mononuclear cells from patients with NSIP compared to UIP. These data suggest that cytokine profiles differ between patients with NSIP and UIP and may be exploitable as therapeutic targets. Chemokines are a group of proteins that bind to G protein-coupled receptors. Choi et al. [46] demonstrated that the pro-fibrotic chemokine, CCL7, was expressed more in UIP lung biopsies compared to NSIP biopsies. Furthermore, CCL5, significantly increased the synthesis of CCL7 by UIP fibroblasts suggesting that these chemokines may have an effect on the pathogenesis of UIP compared to NSIP [46]. Dendritic cells (DC) are antigen-presenting cells that play a role in the immune response. Shimizu et al. [47] evaluated the presence of S100 DCs in patients with UIP and NSIP. Few S100 DCs were noted in fibrotic areas of UIP biopsies compared to large numbers in most cases of NSIP; often in fibrosing areas [47]. CD4 and CD8 lymphocytes were always infiltrated around S-100 DCs in fibrosing areas and lymphoid follicles [47]. These data suggest that DCs and T cell-mediated immune mechanisms may play more of a role in NSIP than UIP; an interesting thought given the predominance of lymphocytes from BAL often seen in NSIP compared to UIP [13, 17, 18, 48]. Other investigators have also identified cytokines that correlate with lymphocytosis in NSIP. Ishii et al. [28] evaluated serum and BAL levels of IL-18, a proinflammatory cytokine that can induce IFN-, in

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controls and patients with UIP or NSIP. IL-18 was higher in the BAL from patient with NSIP compared to UIP or controls and correlated with the increased lymphocytes lavaged from patients with NSIP [28]. Park et al. [49] evaluated the relationship between BAL IL-6 and lymphocyte counts in patients with UIP, NSIP or controls. Lymphocyte numbers and IL-6 levels were highest in patients with NSIP compared to patients with UIP who were in turn higher than control subjects [49]. Interestingly, a subgroup of patients with UIP that had higher IL-6 levels also had more lymphocytes on BAL compared to the low IL-6 level patients with UIP [49]. In the end, fibroblasts are believed to be a key effector cell in fibrotic lung diseases [50]. Miki et al. [20] demonstrated that fibroblasts from patients with UIP had increased contractility compared to fibroblasts from patients with NSIP or controls. There was no difference in contractility between NSIP and control fibroblasts. Conditioned media from UIP fibroblasts had increased levels of transforming growth factor- (TGF-) and fibronectin compared to media from NSIP or controls. UIP conditioned media was able increase the contractility of control fibroblasts while media from NSIP fibroblasts did not. Fibroblast contractility correlated with levels of fibronectin and TGF- [20]. Wen et al. [51] also noted that TGF- increased human fetal lung fibroblast contractility. Interestingly, glucocorticoids further enhanced TGF- mediated gel contraction by inhibiting the TGF- induced release of prostaglandin E2 (PGE2). They hypothesized that the interactions between glucocorticoids and TGF- may account for the lack of a treatment effect [51]. A lack of PGE2, which inhibits fibroblast proliferation and collagen production, may also contribute to the pathobiology of fibrotic lung diseases. Keerthisingam et al. [52] demonstrated that basal and TGF induced PGE2 is decreased from fibroblasts from fibrotic lung due to an inability to up-regulate COX-2 expression. They speculate that this inability to upregulate PGE2 may result in unopposed fibroblast proliferation and collagen synthesis seen in fibrotic lung diseases. Further evaluation for this defect in fibroblasts from NSIP is needed.

Pathology

The histopathology of NSIP incorporates a broad spectrum of features with varied degrees of alveolar wall inflammation or fibrosis (table 1; fig. 1) [8, 12]. Importantly, the histopathologic features do not fit the patterns of other IIPs such as usual interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, cryptogenic organizing pneumonia, acute interstitial

Fig. 1. Histopathologic specimen from a 61-year-old male with a

6-month history of dyspnea. The biopsy displays temporally homogeneous interstitial fibrosis typical of nonspecific interstitial pneumonia.

Table 1. Histopathologic features of nonspecific interstitial pneumonia

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 Adapted from references [8, 12].

pneumonia, or lymphocytic interstitial pneumonia. Although the features of NSIP can be crisply defined the real-life separation of NSIP from other IIPs, particularly UIP/IPF, is difficult. Nicholson et al. [53] evaluated the level of agreement (kappa) between 10 expert thoracic pathologists in the United Kingdom. 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. [54] examined the agreement between general and specialty pathologists and found


discordance in 50% of cases and mis-classification of NSIP by the general pathologist in 8 of 10 subjects. The classification of NSIP if further complicated by the fact that areas of both NSIP and UIP can be located in the same patient when biopsies are taken from multiple locations. Flaherty et al. [55] evaluated 109 patients with UIP or NSIP and a surgical lung biopsy in at least two lobes. Twenty-eight patients (26%) were found to have patterns of NSIP and UIP on different biopsies (discordant UIP), 51 patients had UIP in all lobes (47%, concordant UIP) and 30 patients (27%) had NSIP in all lobes. Importantly, in a Cox proportional hazards model accounting for baseline features of age, gender, duration of symptoms, smoking history, physiology, and amount of fibrosis on HRCT there was no difference between patients with concordant UIP and discordant UIP (HR 0.97; 95% CI 0.4, 2.4; p 0.95) [55]. Similarly, Monaghan et al. [56] evaluated 64 patients with suspected UIP and a surgical lung biopsy in at least two lobes. Discordant UIP was present in 8 (13%), concordant UIP was present in 25 (39%), and NSIP was present in 31 (48%) patients. There was no difference in survival between either UIP group and each UIP group had worse survival compared to patients with NSIP. Finally, Zisman et al. [57] evaluated explants from 20 patients undergoing pulmonary transplantation for pulmonary fibrosis. Areas of NSIP were seen in 16 specimens. Together these data highlight that surgical lung biopsies should be obtained from multiple lobes and expert pulmonary pathologists are required to interpret the specimens.

Clinical Assessment

The assessment of patients with suspected NSIP requires a synthesis of clinical, radiographic and histopathologic data. This approach results in more diagnostic agreement compared to clinicians, radiologists, or pathologists working in isolation [58]. A careful evaluation is required to separate idiopathic NSIP from clinical conditions associated with a NSIP histologic pattern such as connective tissue disorders [7, 17–24], hypersensitivity pneumonitis [25], drugs [26, 27], infection, immunosuppression including HIV [1–6]. Clinical Characteristics The clinical evaluation of patients with suspected NSIP should focus on confirming that interstitial lung disease is present and looking for clues regarding a possible etiology (drug or environmental exposure, signs of connective tissue disease). Overall, the clinical characteristics of NSIP (table 2) are insufficient to distinguish NSIP from other

163

Table 2. Clinical and demographic characteristics for patients with NSIP

Series

Number of Age, years Gender patients mean SD or (range)

Collagen vascular associated cases included Katzenstein and 64 46 (9–78) Fiorelli [7]

CTD n (%)

Current or Symptom previous (%) smoking n (%)

Symptom Physical duration, examination months feature (%) mean SD or (range)

26 males 10 (6) 38 females

NA

dyspnea 8 (0.25–60) fever (22) cough wheeze (6) chest pain (8) weight loss (11)

Cottin et al. [17]

12

53


6 (50)

dyspnea (100) 31 (1–64) cough (67) fatigue (58) weight loss (42)

crackles (100)

Fujita et al. [18]

24

median 60 (44–74)


NA

cough (87) dyspnea (71)

3 (1–8)

crackles (100) clubbing (0) fever (29)

Miki et al. [20]

5

56 (42–74)

1 male 3 (60) 4 females

NA

dyspnea (100)

4 (1–9)

crackles (100)

Douglas et al. [19]

18

NA

NA

NA

NA

NA

NA

Bouros et al. [21]

74 (NSIP in 62)

46 (23–69)

13 males/ scleroderma 61 females in all

25 (33)

dyspnea (89) cough (35)

13 (0–60)

crackles (85) clubbing (3)

Yamadori et al. [23]

3

60 (50–71)

1 male/ Sjogren’s 2 females syndrome in all

NA

NA

NA

crackles (100)

Kim et al. [22]

13

45

6 males/ scleroderma 7 females in all

5 (38)

NA

6

NA

64 (52–75)

4 males all rheumatoid 3 females arthritis

NA

fever (57) cough (86) dyspnea (71) none (14)

NA

NA

Collagen vascular associated cases excluded or unknown Park et al. [48] 7 56 (43–69) 1 male NA 6 females

1 (14)

dyspnea (100) cough (57) chest pain (28)

4

fever (29) crackles (100)

Nagai et al. [13]

31

58 (40–72)

15 males excluded 16 females

18 (58)

dyspnea cough

2 (0.25–32) fever (32) clubbing (10)

Bjoraker et al. [9]

14

57 (4–73)


8 (57)


15 15


Daniil et al. [59]

15

43 (31–66)


9 (60)


18 (7–84)


Travis et al. [12]

22

50 (30–71)


15 (68)


NA

NA

Nicholson et al. [71]

28

53

20 males NA 8 females

19 (68)

dyspnea

11 median (0–180)

NA

Takehara et al. [42]

4

52 (26–75)

2 males NA 2 females

NA

NA

15 (2–29)

NA

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Yoshinouchi et al. [24] 7

polymyositis/ dermatomyositis in all


Series

Number of Age, years Gender patients mean SD or (range)

Flaherty et al. [10]

28 fibrotic 56 5 cellular 50

Riha et al. [11]

7

Vourlekis et al. [25]

Current or Symptom previous (%) smoking n (%)

Symptom Physical duration, examination months feature (%) mean SD or (range)

16 males/ excluded 12 females 3 males/ 2 females

20 (71) 2 (40)

NA

26 22

NA

49 (39–67)

2 males/ excluded 5 females

3 (43)


28 (12–36)


6

46 (21–59)

1 males/ hypersensitivity 5 females pneumonia in all

2 (33)


10 (1–24)

NA

Ishii et al. [28]

12

53 (28–71)

4 males/ excluded 8 females

3 (25)

NA

NA

NA

Jegal et al. [69]

41 NSIP fibrotic 7 NSIP cellular

54 11 59 10

12 males excluded 29 females 3 males excluded 4 females

8 (19)

NA

5.5 7

NA

4 (57)

NA

44

NA

16

58 (28–75)

5 (33)

NA

6 (1–74)

NA

Kakugawa et al. [31]

CTD n (%)


Adapted from references [72, 73].

types of IIP. The most common symptoms are cough and dyspnea; crackles are heard in the majority of patients and fever may be present in up to 1/3 of cases. In general more patients with connective tissue related NSIP are female while idiopathic NSIP is fairly balanced between males and females. Pulmonary physiology typically demonstrates a restrictive ventilatory defect with a decrease in gas transfer. Bronchoalveolar lavage is more likely to show a predominance of lymphocytes in patients with NSIP compared to UIP [13, 17, 18, 48], however, this is not always the case [59, 60] and BAL cell counts cannot be utilized to differentiate UIP from NSIP. Recently, an American Thoracic Society/European Respiratory Society (ATS/ERS) task group evaluated 305 cases from 10 international hospitals. After exclusion of connective tissue diseases, drug/environmental exposures, hypersensitivity pneumonitis, etc., 193 cases were felt to be histologically consistent with NSIP. Further clinicalradiographic-pathologic consensus review reduced this number to 67 with only 17 cases meeting definite diagnostic criteria. The age of the patients ranged from 26 to 73 years, 22 (33%) were males, and 69% were never smokers. Symptoms were cough, dyspnea, fever, and skin eruption; physiology was restrictive in 69% of cases [61].


Radiographic Characteristics The predominant HRCT feature of NSIP is ground glass opacification (GGO) which is often associated with findings of fibrosis such as volume loss, reticular pattern, and/or traction bronchiectasis (table 3; figs. 2, 3) [62]. Honeycomb change is rare and turns out to be very predictive of UIP when a predominance of GGO is absent [10, 63, 64]. Overall the HRCT features of idiopathic NSIP compared to connective tissue disease related NSIP are similar (table 3). Serial HRCT scans in patients with NSIP vary with some patients showing improvement and others showing evidence of disease progression (table 4). The ATS/ERS NSIP task group subdivided 67 patients with NSIP into three HRCT patterns. Pattern 1 was ground glass opacity and traction bronchiectasis without subpleural distribution and with lower lobe cystic changes. Pattern 2 was upper lobe emphysematous changes and lower lobe cystic changes. Pattern 3 was GGO around peribronchovascular bundles. The distribution was subpleural in 21% of the cases [61]. Unlike UIP/IPF where HRCT can at time supplant the need for a surgical lung biopsy, the ability of HRCT to make an accurate diagnosis of NSIP is more limited. Several series have evaluated the ability of HRCT to make

165

Table 3. Radiologic characteristics in patients with NSIP

Series

Katzenstein and Fiorelli [7]

n

64

CTD n (%)

10 (6)

CXR (%)

bilateral interstitial infiltrates (most)

HRCT (%) features

distribution

NA

NA

diffuse alveolar or mixed alveolar/ interstitial infiltrates (11) normal (6) Park et al. [74]

7

NA

parenchymal opacification (86)

ground glass (100) irregular lines (29) consolidation (71)

ground glass upper lobe predominant (100) lower lobe predominant (100) irregular lines upper lobe predominant (100) lower lobe predominant (100) consolidation upper lobe predominant (60) lower lobe predominant (100)

Park et al. [48]

7

NA

patchy opacification (86) normal (14)

bilateral patchy ground glass or alveolar consolidation (71) irregular lines (29) honeycombing (0)

NA

Kim et al. [75]

23

NA

ground glass opacity (100) consolidation (65) irregular lines (87) honeycombing (0)

subpleural (100)

Nagai et al. [13]

31

excluded

patchy bilateral infiltrates (77) reticular nodular shadows (22)*

honeycombing (26)* ground glass (74)*

NA

Cottin et al. [7]

12

3 (25)

diffuse infiltrate (100)

honeycombing (8) ground glass (82) septal thickening (45)

parenchymal opacities lower lobe predominant (73) diffuse (27) honeycombing subpleural (100)

Bjoraker et al. [9]

14

excluded

radiographic infiltrates (93)

NA

NA

Fujita et al. [18]

24

8 (33)

NA

interstitial, patchy parenchymal opacification** honeycombing (0)

middle/lower lobe predominance

Kim et al. [76]

13

scleroderma 1 (8)

NA

ground glass (100) interstitial opacity (100) honeycombing (8) bronchiectasis (100)

NA

Daniil et al. [59]

15

excluded

NA

typical of CFA (2)* not typical of CFA (13)*

NA

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Series

n

CTD n (%)

CXR (%)

HRCT (%) features

distribution

Johkoh et al. [77]

27

excluded

NA

ground glass (100) interstitial opacity (93) honeycombing (26)

upper lobe predominant (4) lower lobe predominant (74) random (22) peripheral (85)

Akira et al. [78]

9

NA

NA

bilateral disease (100) ground glass (100) consolidation (78) intralobular lines (78) bronchiectasis (78) honeycombing (0)

central (100) peripheral (100)

Nishiyama et al. [79]

15

7 (47)

bilateral infiltrates (100) consolidation (27) reticular density (13) consolidation reticular density (60)

ground glass (13) interstitial thickening (37) honeycombing (0) traction bronchiectasis (87)

upper lobe predominant (0) lower lobe predominant (80) peripheral (33) diffuse (60)

Hartman et al. [65]

50

NA

NA

ground glass (76) irregular linear opacities (46) honeycombing (30) consolidation (16) nodular opacities (14) emphysema (12) traction bronchiectasis (36)

ground glass upper lobe predominant (8) lower lobe predominant (59) random (14) subpleural (68) random (21) irregular linear opacities lower lobe predominant (87) random (13) subpleural (96) honeycombing upper lobe predominant (20) lower lobe predominant (67) subpleural (93)

MacDonald et al. [66]

21

excluded

NA

ground glass

basal distribution (62) subpleural distribution (60)

Riha et al. [11]

7

excluded

fine reticular markings (71) vague patchy infiltrates (43) honeycombing (14)

NA

NA


6

excluded

ground glass (67) reticular density (50) nodular density (33) honeycombing (17)

centrilobular nodule (2/2) ground glass (2/2)

reticular opacity upper lobe predominant (1/1)

Johkoh et al. [80]

55

excluded

NA

ground glass (100) air space consolidation (98) nodules (96) traction bronchiectasis (95) intralobular reticulation (87) interlobular reticulation (71) honeycombing (27)

lower lobe predominance (95)


167


Series

n

CTD n (%)

CXR (%)

HRCT (%) features

distribution

Yamadori et al. [23]

9

Sjogren’s 9 (100)

NA

ground glass (100) honeycombing (0)

NA

Kim et al. [81]

13

excluded

NA

ground glass (77) reticular opacity (54) consolidation (23)

NA

Arakawa et al. [82]

14

DM/PM 14 (100)

NA

reticular opacity (100) ground glass (93) consolidation (43) traction bronchiectasis (86) honeycombing (0)

reticular opacity peripheral (50) lower lobe (71) ground glass peripheral (39) lower lobe (85) consolidation peripheral (100) lower lobe (50) traction bronchiectasis peripheral (60) lower lobe (100)

Jegal et al. [69]

48

excluded

NA

ground glass (most patients) reticular opacity (50) consolidation (15)

*p 0.05 UIP compared to NSIP within series. **Number of patients not quantified. DM/PM Dermatomyositis/polymyositis. Adapted from references [72, 73].

Table 4. Results of serial radiographic studies in patients with NSIP


Series

n

Follow-up

Results

Series

n

Follow-up

Results

Park et al. [74]

6

13 months

3 complete resolution 3 improvement

Arakawa et al. [82]

14

3–61 months, mean 28 months

Kim et al. [76]

13

11 months

improved ground glass opacity irregular linear opacity

Nishiyama et al. [83]

15

15.6 months

3 complete resolution 9 improvement 1 persistent 1 worsened

Akira et al. [78]

9

3.1 years

4 complete resolution 1 improvement 2 persistent 2 worsened

reticular opacity – improved 11, worse 3 ground glass – improved 12, progressed 2 consolidation – improved 5, progressed 1 traction bronchiectasis – improved 4, progressed 2 honeycombing – no patient developed honeycombing

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Adapted from references [72, 73].

a

b

c Fig. 2a–c. High resolution computed tomography images from a 46-year-old female with nonspecific interstitial pneumonia. The images display mid-lobe (b) and lower lobe (c) peripheral reticular thickening with subpleural sparing. The upper lobes (a) have a mild ground glass infiltrate.

a

b

c Fig. 3a–c. High resolution computed tomography images from a 43-year-old female with nonspecific interstitial pneumonia. The images display patchy ground glass infiltrates that are worse in the mid-lobes (b) and lower lobes (c) compared to the upper lobes (a).


169

Table 5. Survival and response to treatment in patients with NSIP

Series

n

Survival

Treatment

Follow-up

Follow-up response

NA

NA

61 months 60 months

alive and well (13/22) alive with disease (9/22) dead (0/22)

group II – 24

40 months 7 months 18 months 3 months

alive and well (7/20) alive with disease (7/20) dead of disease (3/20) dead of other (3/20)

group III – 9

8 months 36 months 15 months 17 months

alive and well (1/6) alive with disease (2/6) dead of disease (2/6) dead of other (1/6)

NA

improved (10/16) remission (4/16) no change (2/16) worse (0/16) dead (0/16)

Katzenstein and Fiorelli [7] group I – 31

Nagai et al. [13]

cellular NSIP – 16

NA

fibrotic NSIP – 15

none (8/16) CS (6/16) CS IS (2/16)

none (4/15) CS (5/15) CS IS (6/15)

improved (8/15) remission (1/15) no change (1/156) worse (3/156) dead (2/15)

Cottin et al. [17]

12

NA

CS (5/12) CS IS (7/12)

50 months

improved (10/12) worse (2/12) dead (0/12)

Bjoraker et al. [9]

14

median 13 years

NA

NA

NA

Douglas et al. [19]

70

median 7 years

CS (67/70)

NA

NA

Daniil et al. [59]

15

median 7 years

none (2/14) CS (1/14) CS IS (11/14)

NA

improved (2/12) stable (4/12) worse (3/12) dead (1/12)

Nicholson et al. [71]

28

median 52 months

CS (12/28) CS IS (9/28)

NA

NA

Bouros et al. [21]

62

median 10 years 5 years – 91%

NA

NA

dead (16/62)

Fujita et al. [18]

24

NA

CS (21/24) CS IS (3/24)

NA

improved (17/24) worse (1/24) dead of disease (4/24) dead of other (2/24)

Travis et al. [12]

cellular NSIP – 7 fibrotic NSIP – 22

10 years – 100% 10 years – 35%

NA

NA

NA

Flaherty et al. [10]

33

median 9 years

none (2/33) CS (18/33) CS IS (4/33) Other (9/33)

NA

improved (4/10)* stable (4/10) worse (1/10)

Riha et al. [11]

7

median 178 months

None (2/7) CS (2/7) CS IS (2/7) Other (1/7)

NA

NA

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Series

n

Survival

Treatment

Follow-up

Follow-up response


6 with hypersensitivity pneumonitis

NA

CS (3/6) CS IS (3/6)

5.5 years

NA

Shimizu et al. [47]

cellular NSIP – 13 fibrotic NSIP – 2

NA

NA

NA

improved (9/15) stable (5/15) died (1/15)

Kim et al. [81]

13

NA

CS (1/12) CS IS (11/12)

34.5 months

improved (5/8) stable (3/8) died (1/8)

Kondoh et al. [84]

12

median 12 years

CS IS

mean 92 months range (60–148)

improved (5/12) stable (4/12) worse (3/12)

CS Corticosteroids; IS immunosuppressive therapy. *After a 3-month trial of high-dose steroids in a subset of NSIP patients. Adapted from references [72, 73].

a diagnosis of NSIP (as confirmed by surgical lung biopsy). Hartman et al. [65] evaluated 50 patients with NSIP. The HRCTs from 11 (22%) patients were felt to be compatible with NSIP, 16 (32%) with UIP, and 23 (46%) either nondiagnostic or compatible with other diseases [65]. MacDonald et al. [66] evaluated 21 patients with NSIP and 32 patients with UIP. The ability of HRCT to identify NSIP was fair with a sensitivity of 70%, specificity of 63%, and accuracy of 66%. These results were similar to Flaherty et al. [64] where the ability of HRCT to separate 23 patients with NSIP from 73 patients with UIP displayed a sensitivity of 78%, specificity of 64%, and accuracy of 68%. Similar to pathology, the interpretation of HRCT is complicated and significant inter-rater variability exists [67]. Aziz et al. [67] evaluated inter-rater agreement for the interpretation of a series of HRCTs from patients with interstitial lung disease. The kappa for agreement of a NSIP pattern was moderate at 0.51; NSIP was involved in 55% of the cases with disagreement [67]. Given the prognostic and treatment implications of NSIP versus UIP these data highlight that although HRCT can suggest a diagnosis of NSIP a surgical lung biopsy is required for confirmation.

Diagnosis

The diagnosis of NSIP requires a collaborative integrative approach between the clinician, radiologist, and pathologist [8, 58]. A careful clinical assessment must be made to look for potential etiologies (see ‘Clinical Assessment’ above) which could explain the disease and be removed as


part of treatment. Although HRCT features can suggest the diagnosis of NSIP (see ‘Clinical Assessment’ above) the test characteristics are too unreliable to rely solely on HRCT without a confirmatory surgical lung biopsy [64–67]. Once the clinical history and HRCT suggest the possibility of NSIP a surgical lung biopsy (see ‘Pathology’ above) should be obtained if medically feasible. Unfortunately transbronchial lung biopsy specimens are inadequate to make the diagnosis of most IIPs, including NSIP [8].


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 stems from retrospective analysis of patients previously classified as IPF/CFA and the vast majority of these patients were treated with immunosuppressive agents. At baseline, compared to IPF/CFA, the overall prognosis and response to therapy for NSIP is favorable [9–13]. Over time an individual’s physiologic course may become as important or more important that the baseline histopathology [68–70]. Latsi et al. [70] evaluated patients with UIP (n 61) and NSIP (n 43). Patients with NSIP had a more favorable prognosis (median survival 56 vs. 33 months); however, survival differences did not appear until after 2 years of follow-up. Histopathology (UIP vs. NSIP) predicted prognosis as a baseline factor and when 6-month changes in pulmonary physiology were examined. After 12

171

months of follow-up, physiology [change in forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLCO) and a composite physiology index] predicted subsequent mortality while histopathology was no longer predictive [70]. At 12 months change in DLCO was the strongest determinant of mortality [70]. In a similar study, Jegal et al. [69] found that at baseline a lower DLCO, older age, and diagnosis of UIP were risk factors for subsequent mortality while gender, FVC, and PaO2 were not. After 6 months of follow-up initial DLCO, change in FVC, and gender were predictors of mortality while age, histopathology, baseline FVC, and PaO2 were not [69]. Together these data suggest that histopathology is a good baseline predictor of subsequent mortality, however, over time, changes in physiology become more important than histopathology. Patients with NSIP that show signs of progression despite treatment should be considered for lung transplantation, similar to a patient with IPF/UIP.


Patients with NSIP often have a favorable response to immunosuppressive therapy (table 5), although not all patients respond to treatment and patients with progressive disease are at risk for increased mortality [69, 70]. Multiple series suggest that most patients with NSIP warrant a trial of immunosuppressive therapy (table 5). These series suggest that many, but not all patients with NSIP will respond to treatment with immunosuppressive agents. Following an initial response some patients will relapse following the cessation of immunosuppressive treatment suggesting that long-term treatment may be required in some patients [17]. Acknowledgements This work was supported in part by National Institutes of Health Grants 5P50HL56402, 2 K24 HL04212, 1 K23 HL68713, and U10HL080371.

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8

9

10

11

12

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Kevin R. Flaherty, MD, MS Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center 3916 Taubman Center, Box 0360 Ann Arbor, MI 48109–0360 (USA) Tel. 1 734 936 5201, Fax 1 734 936 5048 E-Mail [email protected]


Diseases: Other Entities of the Idiopathic Interstitial Pneumonias Harold R. Collard Department of Medicine, University of California San Francisco, San Francisco, Calif., USA

Abstract Beyond idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia, the idiopathic interstitial pneumonias represent a collection of rare but well-described conditions. They include respiratory-bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia, and acute interstitial pneumonia.These five conditions make up approximately 16% of cases of idiopathic interstitial pneumonia. This chapter provides an overview of the epidemiology, etiology, pathology, and clinical management of these disorders. Copyright © 2007 S. Karger AG, Basel

Respiratory Bronchiolitis-Associated Interstitial Lung Disease

Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) is a distinct form of idiopathic interstitial pneumonia (fig. 1). It was first described by Myers et al. [1] in 6 patients with otherwise unexplained interstitial lung disease. Previously categorized as DIP, RB-ILD has a more focused epidemiology and better prognosis than DIP. Epidemiology RB-ILD is almost exclusively a disease of cigarette smokers. Of the 81 cases of RB-ILD reported in the literature, 80 were documented as current or former smokers [1–5, 8, 93]. The mean age at presentation is 42 years; men and women appear equally affected.

Etiology In 1974, Niewoehner et al. [6] described brownpigmented macrophages in the respiratory bronchioles of 19 smokers at autopsy. This histopathologic pattern was termed respiratory bronchiolitis. Respiratory bronchiolitis was seen in the lungs of all 83 current smokers reviewed by Fraig et al. [7] and can persist in the lungs of ex-smokers for many years. Based on its near universal association with cigarette smoking, RB-ILD is considered to be caused in part by exposure to cigarette smoke. There have been a handful of cases reported with no identifiable association to cigarette smoking, and the possibility of alternative exposures causing RB-ILD remains. In support of this possibility is the observation of respiratory bronchiolitis in the lungs of 7 nonsmokers [6, 7]. Of these cases, one was a stoker in a foundry, another had severe ‘hay fever,’ and a third had significant exposure to diesel smoke. A nonsmoker with exposure to solder flux fumes has also been reported [8].

Pathology The histopathologic pattern seen in RB-ILD is that of respiratory bronchiolitis (table 1). This pattern is characterized by the accumulation of ‘… clusters of brown pigmented macrophages in the first order and second order respiratory bronchioles …’ [6]. Macrophage accumulation can extend into the peribronchiolar airspaces. There is often a mild associated submucosal infiltrate of lymphocytes and histiocytes and alveolar septal fibrosis [1, 9].

COP 2%

LIP 1%

ruling out alternative etiologies such as infection, malignancy, and evaluating for other forms of interstitial lung disease such as eosinophilic pneumonia, sarcoidosis and hypersensitivity pneumonitis. The bronchoalveolar lavage may demonstrate pigmented macrophages and neutrophilia.

AIP 3%

DIP/RBILD 10%

IPF 60%

NSIP 24%

Fig. 1. Relative frequency of idiopathic interstitial pneumonia.

Modified from Collard HR, King TE Jr: Diffuse lung disease: a practical approach. Baughman, Lynch and DuBois (eds).

Clinical Assessment The clinical assessment of patients with suspected ILD is described in the chapter by Yang and Raghu [this vol]. Although the onset of symptoms in RB-ILD is generally chronic (i.e. months), a more rapidly progressive course may be seen [9]. Close attention should be paid to symptoms of dyspnea and cough, and any history of cigarette smoking. Physical examination may reveal inspiratory crackles. Clubbing is rare but has been reported [4]. Pulmonary function testing is usually abnormal in RB-ILD. An equal number of patients demonstrate obstructive and restrictive physiology; many only manifest a decrease in diffusing capacity [3, 4]. Investigations High-Resolution Computed Tomography (HRCT). The HRCT appearance in RB-ILD has been well described (table 1) [3, 10]. A review of 21 HRCT found the most common abnormalities to be bronchial wall thickening (90%), centrilobular nodules (71%), and ground glass opacity (67%) [3]. There was no clear anatomic predilection. Emphysema was reported in the upper lobes of 57% of the cases. Less common findings included reticular and septal lines (33%) and irregular calcified nodules (19%). One patient had mild honeycombing of the lower lung zones. Bronchoscopy. There is generally little role for bronchoscopy in the diagnosis of RB-ILD. Its main utility is for

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Diagnosis A clinical presentation consistent with idiopathic interstitial pneumonia is critical to the diagnosis of RB-ILD, as the histopathologic pattern of respiratory bronchiolitis can be seen in asymptomatic smokers. A careful review of the surgical lung biopsy to rule out alternative histopathological patterns is essential. Transbronchial biopsy is insufficient as there is inadequate sampling and preservation of the lung parenchyma for proper evaluation. A detailed approach to the diagnosis of idiopathic interstitial pneumonia is presented in the chapter by Lynch [this vol]. Natural History and Prognosis The initial report by Myers et al. [1] of RB-ILD suggested a benign clinical course, with 5 of 6 patients asymptomatic several years after diagnosis, despite all but one continuing to smoke cigarettes. Three of these patients received corticosteroids. Yousem et al. [5] reported that of 18 cases, all 15 who quit smoking had resolution of symptoms. It is unclear how many of these patients received corticosteroids. Of the nine patients with follow-up data available, Park et al. [3] reported universal improvement with smoking cessation and corticosteroids. Recently, two reports have suggested a less benign course, with the majority of patients requiring therapy [4, 93]. Of the 5 patients who successfully quit smoking, 2 improved and 2 remained stable. No deaths from progressive lung disease have been reported. Management and Treatment Despite early contention that smoking cessation alone may be adequate treatment for RB-ILD, most patients have received corticosteroids [1–5, 93]. The combination of smoking cessation and corticosteroids has led to improvement in many cases. In mild cases, a trial of smoking cessation alone with careful clinical follow-up may be justified; in all other cases, combining smoking cessation with at least 3 months of corticosteroid therapy is recommended, with careful assessment of respiratory symptoms and function (e.g. pulmonary function and gas exchange) before and after therapy. Progressive disease may require the addition of immunomodulatory agents (e.g. cyclophosphamide, azathioprine) but should first prompt careful reassessment of the diagnosis.

Table 1. Summary of clinical, radiological and histopathological presentation of selected IIPs

Condition

Demographics

Clinical history

Radiology

Histopathology

RB-ILD

age: 42 years gender: equal smoking: 98%

chronic dyspnea, cough crackles PFT variable

bronchial wall thickening (90%) centrilobular nodules (71%) ground glass (67%)

RB pattern: bronchiolocentric macrophage accumulation

DIP

age: 44 years gender: M ⬎ F smoking: 78%

chronic dyspnea, cough crackles, clubbing (25–50%) PFT restriction

ground glass (100%) irregular lines/distortion (50%) cysts (32%) traction bronchiectasis (25%)

DIP pattern: diffuse macrophage accumulation, variable inflammation and fibrosis

COP

age: 56 years gender: equal smoking: 21%

acute/subacute dyspnea, cough, fever crackles PFT restriction

consolidation (79%) ground glass (63–90%) small nodules (common) ‘reverse halo sign’

organizing pneumonia: patchy intra-alveolar myofibroblast accumulation

LIP

age: 50 years gender: F ⬎ M smoking: unclear

chronic dyspnea, cough, chest pain, fever crackles PFT restriction

ground glass (100%) centrilobular nodules (100%) bronchovascular thickening (86%) cysts (68%) mediastinal/hilar adenopathy (68%)

LIP pattern: diffuse interstitial lymphocytic infiltration, lymphoid follicles

AIP

age: 56 years gender: equal smoking: unclear

viral prodrome acute dyspnea, cough crackles

ground glass (100%) traction bronchiectasis (100%) consolidation (92%) interlobular septal thickening (89%) bronchovascular thickening (86%) nodular opacities (86%)

DAD pattern: hyaline membranes, interstitial edema, fibroblast proliferation

AIP ⫽Acute interstitial pneumonia; COP ⫽ cryptogenic interstitial pneumonia; DAD ⫽ diffuse alveolar damage; DIP ⫽ desquamative interstitial pneumonia; LIP ⫽ lymphocytic interstitial pneumonia; PFT ⫽ pulmonary function test; RB ⫽ respiratory bronchiolitis; RB-ILD ⫽ respiratory bronchiolitis-associated interstitial lung disease.

Desquamative Interstitial Pneumonia

Desquamative interstitial pneumonia (DIP) was first described by Liebow et al. [11] in 1965, when they reported eighteen patients sharing a histopathologic pattern ‘ . . . characterized by massive proliferation and desquamation of large alveolar cells . . .’. Relatively quickly it was realized that the ‘desquamating’ alveolar cells were instead predominantly macrophages [12, 13]. Some have recommended the more appropriately descriptive name ‘alveolar macrophage pneumonia’, but the name DIP has remained. Epidemiology Desquamative interstitial pneumonia occurs in all age groups, and is the most common form of idiopathic interstitial pneumonia in children [14]. Whether the pediatric and adult diseases are distinct clinical entities is unknown. Several centers have published retrospective analyses of

Other Idiopathic Interstitial Pneumonias

patients with DIP [2, 4, 5, 11, 15–17]. The average age is 44 years and men are more commonly affected than women. While early reports of DIP do not comment on the prevalence of cigarette use [11, 17, 18], the majority of patients appear to have a history of smoking. Of the approximately 80 cases of DIP reported in the 4 more recent case series, 62 (78%) were known to be active or former cigarette smokers [2, 4, 5, 15]. Etiology Several observations suggest DIP may develop due to both host and environmental factors. The association of DIP with cigarette smoking has prompted many to label DIP a smokingrelated interstitial lung disease [19, 20]. Supporting this hypothesis is the fact that DIP is histopathologically similar in appearance to respiratory bronchiolitis, a pattern seen primarily in cigarette smokers [7]. A number of additional exposures have been associated with DIP including nitrofurantoin [21],

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asbestos, tungsten carbide and other inorganic particulates [22–25]. Host factors may also be important. DIP occurs in nonsmoking adults and children, and has been reported in families [26, 27]. It has been described in patients with viral infections [28, 29], autoimmune disease [15] and leukemia [30, 31]. A combination of genetic, acquired, and environmental factors may contribute to the development of DIP. Pathology The histopathologic pattern of DIP remains largely unchanged since its description 40 years ago. The pattern is predominantly that of widespread accumulation of pigmented, granular-appearing macrophages in the alveolar spaces (table 1). Mild focal interstitial thickening is common [11, 32]. The abnormality is anatomically and temporally uniform and generally involves the majority of the biopsy specimen. There are occasional lymphoid follicles and eosinophils seen [2]. Importantly, a ‘DIP-like’ reaction, characterized by focal collections of intra-alveolar macrophages, can be seen superimposed on other patterns of fibrotic lung disease such as usual interstitial pneumonia pattern and nonspecific interstitial pneumonia pattern [33]. These biopsies should generally be classified based on their underlying histopathologic pattern. Clinical Assessment The clinical assessment of patients with suspected DIP is similar to that of all forms of interstitial lung disease, as described in the chapter by Yang and Raghu [this vol]. The presentation is generally that of chronic progressive dyspnea and cough. Close attention should be paid to any history of cigarette smoking, occupational exposures, or autoimmune disease. Physical examination usually reveals inspiratory crackles, and clubbing is reported in a quarter to a half of the patients [4, 5]. Pulmonary function testing usually reveals evidence of restriction. Investigations High-Resolution Computed Tomography. The HRCT appearance in DIP has been well described (table 1) [34, 35]. The largest series by Hartman et al. [34] described the HRCT appearance in 22 patients with DIP and found that all had ground glass attenuation in the middle and lower lung zones. The majority (82%) had upper lung zone involvement as well. There was generally a lower lung zone predominance; only 3 patients had the majority of ground glass in the upper lung zones. Irregular lines and architectural distortion were seen in 50%, and traction bronchiectasis was seen in a quarter of the cases. Cystic changes, generally scattered with a peripheral lower lung zone

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predominance, were present in 32%. Diffuse centrilobular nodules were noted in 2 patients. These findings were corroborated by Heyneman et al. [35]. Bronchoscopy. Brown-pigmented macrophages and lymphocytosis may be seen on bronchoalveolar lavage. As with RB-ILD, findings on bronchoscopy in DIP are nonspecific and its main utility is in ruling out alternative etiologies. Lymphocytes and neutrophils are commonly increased in the lavage returns, with or without eosinophilia. Diagnosis The diagnosis of DIP requires a clinical presentation consistent with idiopathic interstitial pneumonia and a surgical lung biopsy demonstrating DIP pattern. Transbronchial biopsy is insufficient as there is inadequate sampling and preservation of the lung parenchyma for proper evaluation. A detailed approach to the diagnosis of idiopathic interstitial pneumonia is presented in the chapter by Lynch [this vol]. Natural History and Prognosis Historically, DIP was considered a histopathological manifestations of early idiopathic pulmonary fibrosis (IPF), and its relationship to the more typical ‘usual interstitial pneumonia’ pattern was unclear [17]. It was hypothesized that a DIP pattern evolved over time into a UIP pattern, but this has proven incorrect. Unlike patients with UIP pattern on surgical biopsy, most patients with DIP stabilize or improve with corticosteroid therapy [2, 4, 5, 11, 15–17]. A minority of patients with DIP will progress to end-stage fibrosis despite therapy. The two largest recent case series report discordant survival estimates with 14 of 19 (74%) alive at a mean follow-up of 3 years in one and 20 of 20 (100%) alive at a mean follow-up of over 7 years in the other [2, 4]. The largest historical cohort of welldescribed DIP patients reported a survival of 68% at a mean follow-up of 9 years, although 11 subjects (30%) were lost to follow-up [15]. There have been reports of spontaneous resolution of DIP, but it is likely that many if not all of these cases were misclassified RB-ILD [15]. Management and Treatment Because of the likely contribution of cigarette smoke to disease activity, smoking cessation is paramount. Corticosteroid therapy is the mainstay of treatment, but it appears that at best half of the patients will improve on therapy. Of the 23 patients with DIP reported by the Mayo Clinic, only one had objective improvement in respiratory function or gas exchange on corticosteroids therapy at 9 months [4]. The majority of patients stabilized (63%). Because there are no placebo-controlled trials of corticosteroids in

DIP, it is unclear whether stabilization or improvement is a result of corticosteroid therapy, smoking cessation, or represents the natural history of the disease. However, observational data on subjects with DIP before and after treatment suggest that most patients worsen without therapy (63%) [15]. It is generally recommended that all patients with DIP receive a trial of corticosteroid therapy for at least 3 months with careful assessment of respiratory symptoms and function (e.g. pulmonary function and gas exchange) before and after therapy. Corticosteroids should be stopped in patients who worsen; those who stabilize may warrant continued therapy. Single lung transplantation should be considered in progressive disease; recurrence of DIP in the transplanted lung has been described [36]. Relationship of DIP to RB-ILD Several reviews have suggested that RB-ILD and DIP may represent a continuum of the same disease process, with the more focal and bronchiolocentric respiratory bronchiolitis pattern developing into the more diffuse DIP pattern over time [5, 35, 37]. Others have argued that there remain enough differences in the epidemiology and behavior of the two diseases to warrant maintaining distinct clinical definitions [2, 38]. It may be that RB-ILD and DIP share a common pathobiological response to lung injury (i.e. accumulation of macrophages), but have different underlying etiologies. RB-ILD seems to represent an exuberant response to smoking-related lung injury, while DIP may be a more complex interaction of genetic or acquired immunologic abnormality and environmental exposure, of which cigarette smoking is the most common. Until there is a clearer understanding of the pathophysiology of these diseases, RB-ILD and DIP should remain separate entities.

Cryptogenic Organizing Pneumonia

In 1983, eight patients with histopathologic intra-alveolar organization of unknown cause were reported by Davison and colleagues at the Brompton Hospital [39]. They termed the condition cryptogenic organizing pneumonia (COP). Two years later, Epler et al. [40] in Boston reported a much larger cohort of 50 patients with a similar condition and named it bronchiolitis obliterans organizing pneumonia (BOOP). As occurred with the synonymous terms ‘cryptogenic fibrosing alveolitis’ and ‘idiopathic pulmonary fibrosis’, COP and BOOP were used interchangeably for many years. In 2002, the American Thoracic Society and European Respiratory Society issued a joint statement agreeing that COP was the preferred term ‘… because it


conveys the essential features of the syndrome . . . and avoids confusion with airway diseases such as constrictive bronchiolitis obliterans . . .’ [41]. Epidemiology Cryptogenic organizing pneumonia occurs at all ages; the average age at diagnosis is 56 years [39, 40, 42, 43]. Men and women appear equally affected. Of the 131 patients reported in the four largest case series, 28 (21%) were active smokers; approximately half were never smokers [39, 40, 42, 43]. A protective effect of smoking is hypothesized but remains unproven. Etiology Organizing pneumonia, the histopathologic pattern seen in COP, was originally described as a postinfectious complication of pneumonia, and has been associated with infection [39, 44], drug toxicity [45–47], graft vs. host disease [42, 48], thoracic radiation [49, 50], malignancy [51, 52] and autoimmunity [40, 53–55]. In the absence of any of the above identifiable causes, COP is diagnosed. Whether COP represents a pathophysiologically distinct condition is unknown. A comparison of 74 cases of both COP and secondary organizing pneumonia found no difference in the symptoms, signs, laboratory findings, pulmonary function test results, radiology or histopathology between groups [56]. Resolution of symptoms and survival were better in COP. Pathology The histopathological pattern seen in COP is that of organizing pneumonia (table 1). The predominant abnormality is that of well-formed plugs of granulation tissue involving the alveolar space [40]. This process can extend into the respiratory and terminal airways. A mild lymphoplasmacytic infiltrate may be present but there is generally preservation of the underlying pulmonary parenchyma. Organizing pneumonia can be seen accompanying other forms of idiopathic interstitial pneumonia; alternative histopathologic patterns must be carefully excluded before a biopsy is consistent with COP. Clinical Assessment The clinical assessment of patients with suspected COP is similar to that of all forms of interstitial lung disease, as described in the chapter by Yang and Raghu [this vol]. The presentation is generally subacute (i.e. weeks), although more rapid progression can be seen [57]. Cough dyspnea and fever are common findings [42]. Close attention should be paid to antecedent infection, drug exposure, radiation, or autoimmune disease. Patients often have inspiratory crackles.

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Clubbing is rare but has been reported [39]. Pulmonary function testing usually reveals evidence of restriction. Investigations High-Resolution Computed Tomography. The HRCT findings in COP have been well described (table 1) [42, 58, 59]. A review of 43 cases found the most common pattern to be consolidation (79%), generally in a patchy subpleural and bronchocentric distribution [58]. Ground glass attenuation is also seen in the majority of cases (63–90%) [58, 60]. Small nodules (⬍1 cm) are commonly seen and likely represent areas of focal organizing pneumonia [61]. Irregular linear densities suggesting fibrosis are uncommonly reported [59]. A relatively specific radiographic finding for COP has been termed the ‘reverse halo sign’: a rounded central area of ground glass surrounded by a crescent-shaped rim of consolidation. In a series of 31 patients with COP, the reverse halo sign was seen in 6 (19%) [59]. It was not observed in a control population of 30 patients with Wegener’s granulomatosis, bronchoalveolar cell carcinoma, chronic eosinophilic pneumonia and Churg-Strauss syndrome. Bronchoscopy. Bronchoalveolar lavage typically shows marked increases in lymphocytes and mild increases in neutrophils and eosinophils [62]. The majority of lymphocytes are CD8-positive. The accuracy of BAL for the diagnosis of COP is only moderate [62]. Transbronchial biopsy is generally inadequate for the diagnosis of COP, as organizing pneumonia can be seen as a secondary finding in many forms of diffuse lung disease. It has been argued that in the right clinical and radiographic setting, transbronchial biopsy may be sufficient [42, 62]. In one series highly enriched for COP (27 of 35 patients), the positive predictive value of transbronchial biopsy was 94% [62]. This is reduced significantly with more moderate prevalence estimates. Diagnosis The diagnosis of COP requires a clinical presentation consistent with idiopathic interstitial pneumonia and a surgical lung biopsy demonstrating organizing pneumonia in the absence of other histopathologic patterns. A detailed approach to the diagnosis of idiopathic interstitial pneumonia is presented in the chapter by Lynch [this vol]. Natural History and Prognosis Initial reports of COP suggested a universally benign clinical course, with nearly all patients improving and recovering lung function with therapy [39, 40]. More recent data suggest a small subset of patients with more aggressive disease [42, 63]. In a comparative study of treatment responsive and treatment unresponsive patients, only fibrosis

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and architectural remodeling on surgical lung biopsy were significantly different (10 vs. 89%, respectively) [63]. It may be that these cases are misdiagnosed cases of other forms of idiopathic interstitial pneumonia, particularly idiopathic pulmonary fibrosis. Acute exacerbations of idiopathic pulmonary fibrosis with widespread organizing pneumonia overlying chronic fibrosis have been described [64]. Relapse occurs in a significant number of cases of COP [39, 40, 42, 43]. A large study of relapse in COP found that one or more relapses occurred in 58% of patients [43]. The majority of these relapses occurred during the initial taper of corticosteroid therapy. Importantly, relapses do not appear to adversely affect outcome, with no difference seen in follow up pulmonary function or chest radiography. No deaths were attributable to COP in either group. Management and Treatment Corticosteroids are the mainstay of treatment for COP [39, 40, 42, 43]. Most patients will have a brisk response to treatment, with improvement in symptoms, lung function and radiology. Therapy is generally continued for at least 3 months before tapering. Relapse is common in the first year of treatment, but generally responds to retreatment [43]. A retrospective comparison of low-dose (ⱕ20 mg/ day) vs. high-dose (⬎20 mg/day) prednisone for relapse showed no difference in response rates, with a higher incidence of side effects with high doses [43]. In patients that cannot tolerate corticosteroids, azathioprine has had anecdotal success [65]. Lymphocytic Interstitial Pneumonia

Lymphocytic interstitial pneumonia (LIP) was first described in 1969 by Liebow and Carrington [66] as a form of idiopathic interstitial pneumonia. They reported 13 patients with ‘ . . . widespread focally massive lymphoid infiltration of the lung, often exceedingly difficult to distinguish from lymphoma’. They went on to distinguish it from lymphoma by its confinement to the lungs and its chronic clinical course. Although this distinction was debated over the next several decades – in fact, LIP was removed from the classification schema for a period of time [32], it is generally accepted as a rare form of idiopathic interstitial pneumonia [41]. Epidemiology LIP is commonly seen in the setting of underlying autoimmune disease, most often Sjogren syndrome [67–69]. It has also been described with immunodeficiency states such as HIV infection [70, 71] and hypogammaglobulinemia [68, 69]. For the purposes of classification as a form of

idiopathic interstitial pneumonia, only idiopathic cases of LIP should be included. No review comments explicitly on idiopathic cases. Extrapolating from general case series of LIP, the average age at diagnosis is around 50 years and women comprise the majority (68%) of patients [66–69]. Etiology Lymphocyte dysregulation appears central to the development of LIP [72]. A study of 14 patients with LIP found evidence of EBV infection in 9 (64%) compared to 20% of controls [73]. Other studies have shown this association [74, 75]. The etiology of LIP is likely multifactorial, with all causes leading to a common pathway of immune dysregulation. Pathology The histopathological appearance of LIP has much in common with a number of other clinical conditions such as hypersensitivity pneumonitis, non-specific interstitial pneumonitis, and lymphoma [72]. The lesion in LIP is characterized by interstitial infiltration of lymphocytes, plasma cells and histiocytes, with germinal centers commonly observed (table 1). There may be infiltration and obstruction of the small airways, but the larger bronchi and pleura are generally spared [66, 68]. Interstitial fibrosis with histopathologic honeycombing has been well described in a subset of patients with LIP [66, 68, 69]. Clinical Assessment The clinical assessment of patients with suspected LIP is similar to that of all forms of interstitial lung disease, as described in the chapter by Yang and Raghu [this vol]. The presentation is generally chronic, with cough and dyspnea being common; chest pain and fever may be reported [68, 69]. Patients almost always have inspiratory crackles. Clubbing is rare but has been reported [66, 68, 69]. Pulmonary function testing usually reveals evidence of restriction. Careful attention to signs and symptoms of autoimmune disease is warranted. Investigations High-Resolution Computed Tomography. A review of 22 HRCT found ground glass abnormality (100%) and poorly-defined centrilobular nodules present in all 22 cases (table 1) [67]. The ground glass was diffusely distributed in the majority of cases (64%). Other findings included thickened bronchovascular bundles (86%), interlobular septal thickening (82%), small cystic airspaces (68%), and lymphadenopathy (68%). Both hilar and mediastinal lymph nodes were generally involved. Honeycombing was seen in only one patient.


Bronchoscopy. Bronchoscopy is generally nondiagnostic in LIP. Its main utility is in ruling out alternative etiologies. The bronchoalveolar lavage may reveal a lymphocytosis and polyclonal CD-20 B cells [72]. Diagnosis The diagnosis of LIP requires a clinical presentation consistent with idiopathic interstitial pneumonia and a surgical lung biopsy demonstrating LIP pattern. A detailed approach to the diagnosis of idiopathic interstitial pneumonia is presented in the chapter by Lynch [this vol]. Natural History and Prognosis The natural history of LIP has been debated over the years. Today, it is generally accepted that LIP represents a distinct idiopathic forms of chronic interstitial pneumonia. Its clinical course is widely variable based on the largest case series published to date: 17 of 27 patients (63%) with follow-up information remained stable or improved over an average of 3–4 years [68, 69]. Management and Treatment Treatment of LIP generally consists of corticosteroids at doses similar to those employed for other forms of idiopathic interstitial pneumonia. There are occasional cases that received no therapy or received therapy aimed at the presumed etiology (e.g. gammaglobulin for hypogammaglobulinemia) [68, 69]. Successful treatment of pediatric LIP with chloroquine has been reported [76]. Acute Interstitial Pneumonia

Acute interstitial pneumonia (AIP) was first described by Hamman and Rich [77, 78] in a case series of 4 patients with rapidly progressive interstitial lung disease. The name ‘AIP’ was coined by Katzenstein et al. [79] to distinguish its rapid course from the more chronic idiopathic interstitial pneumonias. The histopathologic corollary of AIP is diffuse alveolar damage, the pattern of lung injury seen in the acute respiratory distress syndrome (ARDS) [80]. While many feel that AIP is synonymous with idiopathic ARDS, described differences in the clinical characteristic and prognosis of AIP and ARDS remain [81]. Epidemiology Several case series of AIP have been published to date [79, 82–86]. The mean age at presentation is approximately 56 years, with an equal number of men and women affected. Little data inform the relationship of AIP to smoking status or other demographic factors.

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Etiology It remains unclear if AIP is pathobiologically distinct from ARDS. It may be that AIP is the result of lung injury from clinically occult infection, aspiration, drugs or another of the common causes of ARDS. Diffuse alveolar damage (DAD) pattern has been seen on surgical lung biopsies from patients with autoimmune disease [84] and acute exacerbations of idiopathic pulmonary fibrosis [87, 88]; some cases of AIP may in fact be index presentations of these more chronic interstitial pneumonias. Pathology The histopathological pattern seen in AIP is DAD (table 1) [80]. Two histopathological stages of DAD are described: the acute or exudative stage and the organizing or fibroproliferative stage. The exudative stage is characterized by interstitial edema and hyaline membranes. The fibroproliferative stage is characterized by alveolar repair, resolution of hyaline membranes and fibroblast proliferation. Significant overlap often occurs within a single surgical lung biopsy. Olsen et al. [84] reviewed the histopathological features of 29 patients with AIP and reported the majority had histopathologic features of the fibroproliferative stage of DAD. Clinical Assessment The clinical assessment of patients with suspected AIP is similar to that of all forms of interstitial lung disease, as described in the chapter by Yang and Raghu [this vol]. The presentation is usually quite rapid, with cough and progressive dyspnea developing over days to weeks [81, 84, 86]. A viral prodrome of cough and fever is common. Patients almost always have inspiratory crackles. Clubbing is not reported. Because of the acute nature and rapid progression of AIP, pulmonary function data at presentation do not exist. Attention must be paid to ruling out identifiable causes of ARDS, underlying autoimmune disease, or preexisting idiopathic pulmonary fibrosis. Investigations High-Resolution Computed Tomography. The HRCT findings in AIP have been well described (table 1) [82, 83, 85, 89–91]. A review of 36 cases found ground glass abnormality, traction bronchiectasis and architectural distortion in all cases [83]. Consolidation (92%), interlobular septal thickening (89%), thickened bronchovascular bundles (86%), and nodular opacities (86%) were also quite common. Honeycombing (14%) and lymphadenopathy (8%) were rarely seen. The presence of traction bronchiectasis, interlobular septal thickening, and honeycombing

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appears to distinguish AIP from radiographically similar conditions such as ARDS and COP [90, 91]. The extent of ground glass abnormality or consolidation associated with traction bronchiectasis also predicts worse survival [82]. Bronchoscopy. Bronchoalveolar lavage typically shows neutrophilia with occasional atypical type II pneumocytes and extracellular amorphous material thought to represent fragments of hyaline membranes [92]. These findings are nonspecific for AIP. As with the other idiopathic interstitial pneumonias, transbronchial biopsy is not sufficient for the tissue diagnosis of AIP. Diagnosis The confident diagnosis of AIP requires a clinical presentation consistent with ARDS, the absence of any identifiable precipitating cause, and a surgical lung biopsy demonstrating DAD pattern. A detailed approach to the diagnosis of idiopathic interstitial pneumonia is presented in the chapter by Lynch [this vol]. Natural History and Prognosis Because the typical presentation of AIP is respiratory failure, improvement in respiratory function and survival are tightly linked. Survival rates of 11–50% have been published in retrospective case series [82, 83, 85, 89–91]. With modern advances in the care of mechanically ventilated patients, it is likely that the survival rate is now improved. An analysis of the clinical data from 13 cases of AIP revealed serum creatinine and hematocrit to be predictive of survival [81]. Whether these associations are biological or the result of multiple comparisons is unclear. Of those that survive their acute presentation, one quarter have normal lung function, one quarter have stable but diminished lung function, and half have slowly progressive pulmonary fibrosis [81–83, 85, 89–91]. Vourlekis et al. [86] reported recurrent acute respiratory failure in 3 of 7 patients with previous AIP. Whether these cases represent a variant natural history of AIP or are misclassified (e.g. acute exacerbations of idiopathic pulmonary fibrosis, aspiration pneumonitis) is unknown. Management and Treatment The management of AIP generally involves high-dose corticosteroids, although there are little data to suggest efficacy. In a review of 29 cases of AIP, there was no difference in survival between the 20 patients who received corticosteroids and the 9 patients who did not [84].

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64 Dallari R, Foglia M, Paci M, Cavazza A: Acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir J 2004;23:792. 65 Laszlo A, Espolio Y, Auckenthaler A, Michel JP, Janssens JP: Azathioprine and low-dose corticosteroids for the treatment of cryptogenic organizing pneumonia in an older patient. J Am Geriatr Soc 2003;51:433–434. 66 Liebow AA, Carrington DB: The interstitial pneumonias; in Simon M, Potchen EJ, LeMay M (eds): Frontiers of Pulmonary Radiology. New York, Grune & Stratton, 1969, pp 102–141. 67 Johkoh T, Müller NL, Pickford HA, Hartman TE, Ichikado K, Akira M, et al: Lymphocytic interstitial pneumonia: thin-section CT findings in 22 patients. Radiology 1999;212: 567–572. 68 Koss MN, Hochholzer L, Langloss JM, Wehunt WD, Lazarus AA: Lymphoid interstitial pneumonia: clinicopathological and immunopathologic findings in 18 cases. Pathology 1987;19:178–185. 69 Strimlan CV, Rosenow EC III, Weiland LH, Brown LR: Lymphocytic interstitial pneumonitis: a review of 13 cases. Ann Intern Med 1978;68:616–621. 70 Grieco MH, Chinoy-Acharya P: Lymphocytic interstitial pneumonia associated with the acquired immunodeficiency syndrome. Am Rev Respir Dis 1985;131:952–955. 71 Oldham SA, Castillo M, Jacobson FL, Mones JM, Saldana MJ: HIV-associated lymphocytic interstitial pneumonia: radiologic manifestations and pathologic correlation. Radiology 1989;170:83–87. 72 Nicholson AG: Lymphocytic interstitial pneumonia and other lymphoproliferative disorders in the lung. Semin Respir Crit Care Med 2001;22:409–422. 73 Barbera JA, Hayashi S, Hegele RG, Hogg JC: Detection of Epstein-Barr virus in lymphocytic interstitial pneumonia by in situ hybridization. Am Rev Respir Dis 1992;145: 940–946. 74 Kaan PM, Hegele RG, Hayashi S, Hogg JC: Expression of bcl-2 and Epstein-Barr virus LMP1 in lymphocytic interstitial pneumonia. Thorax 1997;52:12–16. 75 Kramer MR, Saldana MJ, Ramos M, Pitchenik AE: High titers of Epstein-Barr virus antibodies in adult patients with lymphocytic interstitial pneumonitis associated with AIDS. Respir Med 1992;86:49–52. 76 Waters KA, Bale P, Isaacs D, Mellis C: Successful chloroquine therapy in a child with lymphoid interstitial pneumonitis. J Pediatr 1991;119:989–991. 77 Hamman L, Rich AR: Fulminating diffuse interstitial fibrosis of the lungs. Trans Am Clin Climatol Assoc 1935;51:154–163. 78 Hamman L, Rich AR: Acute diffuse interstitial fibrosis of the lungs. Bull Johns Hopkins Hosp 1944;74:177–212. 79 Katzenstein ALA, Myers JL, Mazur MT: Acute interstitial pneumonia: a clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol 1986;10:256–267. 80 Katzenstein AL: Idiopathic interstitial pneumonia: classification and diagnosis; in Katzenstein AL, Askin FB (eds): Surgical Pathology of Non-Neoplastic Lung Disease. Philadelphia, Saunders,1997, pp 1–31.

81 Vourlekis JS, Brown KK, Schwarz MI: Acute interstitial pneumonitis: current understanding regarding diagnosis, pathogenesis, and natural history. Semin Respir Crit Care Med 2001;22: 399–408. 82 Ichikado K, Suga M, Muller NL, Taniguchi H, Kondoh Y, Akira M, et al: Acute interstitial pneumonia: comparison of high-resolution computed tomography findings between survivors and nonsurvivors. Am J Respir Crit Care Med 2002;165:1551–1556. 83 Johkoh T, Muller NL, Taniguchi H, Kondoh Y, Akira M, Ichikado K, et al: Acute interstitial pneumonia: thin-section CT findings in 36 patients. Radiology 1999;211:859–863. 84 Olson J, Colby TV, Elliott CG: Hamman-Rich syndrome revisited. Mayo Clin Proc 1990;65: 1538–1548. 85 Primack SL, Hartman TE, Ikezoe J, Akira M, Sakatani M, Muller NL: Acute interstitial pneumonia: radiographic and CT findings in nine patients. Radiology 1993;188:817–820. 86 Vourlekis JS, Brown KK, Cool CD, Young DA, Cherniack RM, King TE Jr, et al: Acute interstitial pneumonitis: case series and review of the literature. Medicine 2000;79:369–378. 87 Ambrosini V, Cancellieri A, Chilosi M, Zompatori M, Trisolini R, Saragoni L, et al: Acute exacerbation of idiopathic pulmonary fibrosis: report of a series. Eur Respir J 2003; 22:821–826. 88 Kondoh Y, Taniguchi H, Kawabata Y, Yokoi T, Suzuki K, Takagi K: Acute exacerbation in idiopathic pulmonary fibrosis: analysis of clinical and pathologic findings in three cases. Chest 1993;103:1808–1812. 89 Ichikado K, Johkoh T, Ikezoe J, Takeuchi N, Kohno N, Arisawa J, et al: Acute interstitial pneumonia: high-resolution CT findings correlated with pathology. AJR Am J Roentgenol 1997;168:333–338. 90 Mihara N, Johkoh T, Ichikado K, Honda O, Higashi M, Tomiyama N, et al: Can acute interstitial pneumonia be differentiated from bronchiolitis obliterans organizing pneumonia by high-resolution CT? Radiat Med 2000;18: 299–304. 91 Tomiyama N, Muller NL, Johkoh T, Cleverley JR, Ellis SJ, Akira M, et al: Acute respiratory distress syndrome and acute interstitial pneumonia: comparison of thin-section CT findings. J Comput Assist Tomogr 2001;25:28–33. 92 Bonaccorsi A, Cancellieri A, Chilosi M, Trisolini R, Boaron M, Crimi N, et al: Acute interstitial pneumonia: report of a series. Eur Respir J 2003;21:187–191. 93 Portnoy J, Veraldi KL, Schwarz MI, Cool CD, Curran-Everett D, Cherniack RM, King TE Jr, Brown KK: Respiratory bronchiolitis-interstitial lung disease: long-term outcome. Chest 2007; 131:664–671.

Harold R. Collard, MD Department of Medicine, University of California San Francisco 1001 Potrero Avenue, 5K1 San Francisco, CA 94110 (USA) Tel. ⫹1 415 206 8314, Fax ⫹1 415 695 1551 E-Mail [email protected]


Pulmonary Fibrosis in Collagen Vascular Disease Rachel K. Hoyles

Athol U. Wells

Interstitial Lung Disease Unit, Royal Brompton Hospital, Sydney Street, London, UK

Abstract Lung parenchymal involvement is common in the collagen vascular diseases (CVDs) and is associated with significant associated morbidity and mortality. Improved management of systemic disease has led to increasing numbers of patients surviving to develop clinically significant pulmonary fibrosis.This provides a difficult challenge for respiratory physicians, particularly in view of the lack of randomised controlled trials of therapy in these diseases. Screening for pulmonary fibrosis causes additional difficulties, because of the high frequency of sub-clinical involvement. Importantly, significant heterogeneity of disease patterns can be seen within the interstitium of patients with CVDs, often admixed with other non-parenchymal pulmonary pathology, and complicating the interpretation of investigations such as high resolution computerised tomography and pulmonary function tests. In this chapter, the features of the most commonly encountered CVDs, namely systemic sclerosis, rheumatoid arthritis, polymyositis/dermatomyositis, Sjögren’s syndrome, systemic lupus erythematosus and ankylosing spondylitis, will be summarised and key clinical issues will be briefly reviewed. Copyright © 2007 S. Karger AG, Basel

Prevalence

Pulmonary disease is the most common cause of death in many of the collagen vascular diseases (CVDs), especially systemic sclerosis (SSc) and polymyositis/dermatomyositis (PM/DM). However, estimates of prevalence vary widely in

reported studies, largely depending on the method of detection. Respiratory symptoms are notoriously unreliable in this regard. Dyspnoea is common, particularly in SSc and PM/DM, but is not consistently indicative of parenchymal disease; the increased work of locomotion due to arthritis or myositis may produce exertional breathlessness. Conversely, patients with severe extra-pulmonary disease may be unable to exercise sufficiently to provoke respiratory symptoms, providing false reassurance. Chest radiography is also insensitive. This is particularly true in rheumatoid arthritis (RA), where large studies have suggested a disease prevalence of 1–5%, at odds with high resolution computerised tomography (HRCT) data which indicate a prevalence of interstitial abnormalities in excess of 20% [1]. HRCT studies have highlighted the difficulties of defining clinically significant disease. HRCT is arguably the most sensitive detection modality, identifying parenchymal involvement in 20–50% of patients in many CVDs; however the detection of trivial, sub-clinical disease, which in many cases does not progress, often creates management difficulties. Biopsy and autopsy studies are fraught with selection bias, often overestimating disease prevalence by reflecting tertiary centre patient populations, or patients with atypical or severe internal organ disease. However, despite these difficulties, a reasonably accurate estimate of the prevalence of parenchymal involvement can now be made in the CVDs. Pulmonary fibrosis is most prevalent in SSc (SSc-PF), forming part of the American Rheumatism Association minor diagnostic criteria for SSc [2]; together with pulmonary hypertension, SSc-PF is the most common cause of

death. Up to 70% of patients with SSc have pulmonary fibrosis in autopsy studies [3], and up to 90% have abnormalities in lung function, often consisting of minor reductions in gas transfer (DLCO), reflecting sub-clinical parenchymal or pulmonary vascular pathology. Chest radiographic and HRCT studies suggest a prevalence of pulmonary fibrosis of up to 65%, the highest amongst the CVD, with HRCT identifying many patients with sub-clinical disease [4]. Estimates of clinically significant SSc-PF approximate 30%, with many patients experiencing disabling breathlessness. Clinically important pulmonary fibrosis is not common in RA. However, DLCO measurements are reduced in 20–40% of unselected patients [1], and, in one study, pulmonary fibrosis was found in 60% of volunteers with RA undergoing open lung biopsy, highlighting the difficulties in assessing prevalence when clinically insignificant disease is included [5]. Amongst other CVDs, pulmonary fibrosis is most frequent in PM/DM, with at least 30% of patients having clinically overt disease [6]. Inconsistent reports of prevalence are found in systemic lupus erythematosus (SLE), with limited pulmonary fibrosis at autopsy seen frequently but likely to reflect episodes of self-limited interstitial inflammation. In one HRCT study, interstitial abnormalities were present in 30% [7], but less than 5% of SLE patients have clinical or chest radiographic evidence of interstitial disease at presentation, and a further 5% develop progressive pulmonary fibrosis during follow-up. Studies of Sjögren’s syndrome (SS) have been confounded by the inclusion of both patients with primary SS and those with SS secondary to other CVDs. Clinically overt interstitial lung disease approximates 10% in primary SS [8], although 35% have HRCT abnormalities [9], 50% have a lymphocytosis on bronchoalveolar lavage (BAL) [10], and there is a high prevalence of respiratory symptoms. Lastly, ankylosing spondylitis (AS) is frequently associated with limited non-specific HRCT abnormalities, but clinically significant upper zone fibrobullous disease is relatively uncommon [11]. In summary, clinically significant pulmonary fibrosis occurs in approximately 30% of patients with SSc and PM/DM, 10% with SS, and in less than 5% with SLE or RA [12], with studies of lung function and HRCT suggesting a much higher prevalence of sub-clinical disease in all of these disorders.

Systemic Sclerosis

Predisposing Factors and Pathogenesis Although it is likely that major organ involvement tends to cluster in CVD, no consistent relationship has been

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documented between the severity of systemic and pulmonary disease. However, in SSc, genetic, autoimmune and environmental predisposing factors have been identified. Genetic associations with class II MHC status (HLADR3, 52a) in UK Caucasians have been described as markers of pulmonary disease within SSc [13]. Serological markers in SSc have provided further insights. The autoantibody status appears to drive the pattern of phenotypic expression, especially internal organ involvement and is highly associated with specific genotype; the anti-topoisomerase antibody (ATA) has a close association with the development of SSc-PF [14]. The anti-RNA polymerase antibody (ARA) is linked with diffuse cutaneous disease and renal pathology, whereas the anti-centromere antibody (ACA) is linked with limited cutaneous disease and pulmonary vascular disease; both have a dichotomous relationship with SSc-PF, potentially suggesting that a second insult may be required for disease expression in the lung. These serological markers are mutually exclusive. SSc-PF has been associated with several environmental or occupational exposures, including d-penicillamine, tryptophan, bleomycin, pentazocine, vinyl chloride, benzene, toluene, trichloroethylene, and rapeseed cooking oil denatured with aniline (the ‘toxic oil syndrome’). The pathogenesis of pulmonary fibrosis has been most extensively studied in SSc, although pathogenetic mechanisms are likely to be similar in other CVDs. Although the pathogenesis of SSc-PF is incompletely defined, it is believed that chronic inflammation leads to progressive lung injury and incremental fibrosis. A widely accepted model is that the accumulation of connective tissue in the lung in SSc-PF is autoimmune, with environmental factors triggering initial injury and a subsequent amplification of the immune response in genetically susceptible individuals [15]. Mediators involved in promoting lung injury and fibrosis include transforming growth factor-␤ (TGF␤), tumour necrosis factor-␣ (TNF␣), connective tissue growth factor (CTGF) and a T helper cell 1 (TH1) to TH2 cytokine shift, promoting a pro-fibrotic micro-environment. Several cytokines identified in BAL fluid in SSc amplify injury, including interleukin-8 (IL-8), and macrophage inflammatory protein (MIP-1). There are restricted T cell responses to epitopes of deoxyribonucleic acid (DNA) topoisomerase I in SSc and, thus, the ATA antibody may have an immunopathogenetic role, although it may also reflect an immune response to a separate key immunopathological process [16]. The pathogenetic mechanisms in SSc-PF appear to reflect complex interactions between alveolar epithelial cell injury, inflammatory cell recruitment and activation, and fibroblast activation and differentiation into

the myofibrolast phenotype, with subsequent accumulation of matrix proteins in the interstitium. Pathology Historically, the interstitial lung disease in SSc and other CVDs was thought to have histological features similar to idiopathic lung fibrosis (IPF), despite considerable differences in outcome. The reclassification of interstitial lung disease by the ATS/ERS Consensus Committee [17] has allowed more precise recognition of the true diversity of histological patterns. In a large series of SSc-PF, the fibrosing non-specific interstitial pneumonia (NSIP) pattern of disease was seen to predominate, with cellular NSIP occurring in a small sub-group with potentially more ‘reversible’ disease; moreover, the small proportion (⬍10%) with the usual interstitial pneumonia (UIP) pattern of disease had a similar survival after 8 years to the NSIP cohort, in marked contrast to outcome differences between UIP and NSIP in patients with idiopathic interstitial pneumonia [18]. Other pathological processes occur in SSc-PF, including a picture of accelerated decline which is usually inflammatory in nature, organising pneumonia (rare and usually in association with penicillamine therapy), superadded bacterial infection, and a small increase in the risk of pulmonary malignancy. Clinical Features Exertional dyspnoea is the common presentation of clinically significant SSc-PF. However, many SSc patients with dyspnoea do not have significant parenchymal disease; systemic disease, an increased work of locomotion due to myopathy or arthropathy, and co-existent pulmonary vascular disease may all result in dyspnoea. If a persistent cough is present, secondary SS and reflux should be considered. The clinical findings of SSc-PF are similar to those in IPF, with a lower-zone predominance of fine end-inspiratory crackles, and in severe disease, tachypnoea, cyanosis and right heart failure. Clubbing is usually absent. Importantly, lung involvement may precede the systemic manifestations, and ‘systemic sclerosis sine scleroderma’, the presence of internal organ involvement together with an auto-antibody profile compatible with SSc, is probably under-recognised [19]. Investigations As in many forms of interstitial lung disease, lung function tests are typically reduced in a restrictive pattern, with a proportionally greater reduction in gas transfer. DLco is highly sensitive for the presence of pulmonary fibrosis and correlates well with disease extent on HRCT, although its interpretation is confounded by co-existent, often subclinical pulmonary vascular disease which also lowers

Pulmonary Fibrosis in CVD

DLco, particularly in patients carrying ACA serology. An isolated reduction in DLco is often seen in sub-clinical disease. A significant reduction in lung volumes is more reliably indicative of clinically significant pulmonary fibrosis. However, mild reductions in volumes are often difficult to interpret, in view of the wide range of normal predicted values. Plain chest radiography often under-estimates the severity of SSc-PF, often showing limited lower zone reticulo-nodular changes. An apparently normal chest radiograph should not inhibit the further investigation of patients with respiratory symptoms. HRCT has revolutionised the approach to pulmonary fibrosis in the CVDs, owing to its high sensitivity and good correlation with the underlying histological appearance. In most cases of SScPF, lower zone ground glass attenuation is associated with reticulation and traction bronchiectasis, indicating fine intralobular fibrosis equating with the histological pattern of fibrotic NSIP [20]. In a minority of patients with cellular NSIP, ground-glass attenuation without traction bronchiectasis may predominate although HRCT features are often intermediate between these two poles. BAL has been widely advocated, both to detect sub-clinical disease and to predict outcome, but the value added by BAL, following HRCT evaluation and measurement of pulmonary function tests, is uncertain. A BAL neutrophilia [21] and eosinophilia [18] have both been linked to a poor outcome. However, both BAL profiles are associated with more extensive HRCT abnormalities, suggesting that BAL abnormalities may merely denote severe disease, which is intrinsically more likely to progress [22]. Rapid clearance of 99mTc diethylene triamine penta-acetate (DTPA), as a marker of alveolar epithelial injury and permeability, has been linked with the risk of subsequent decline, whereas a normal clearance usually predicts non-progressive disease [23]. Prognosis and Natural History The prognosis in SSc-PF, as in all CVDs, is linked to the severity of pulmonary disease. Survival studies are sometimes misleading, owing to the inclusion of patients with sub-clinical disease and non-homogeneous patient groups pre-dating the histological reclassification. Despite this, the 10-year survival from presentation with SSc-PF approximates 70% [24], and is substantially better than IPF, when matched for disease severity [25]. Diffusing capacity for carbon monoxide (DLco) levels have been consistently linked to mortality; a reduction to less than 40% of predicted has been associated with a 5-year survival of less than 10% [26]. An important caveat is that DLco reduction may be indicative of underlying pulmonary vascular disease in SSc. Predictors of poor outcome include early

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systemic disease (within 5 years of diagnosis), severe disease (HRCT or PFT), or deteriorating disease as judged by serial lung function trends (both forced vital capacity (FVC) and DLco [27]). Markers of epithelial injury including DTPA clearance, and serum markers including surfactant protein D (SPD) and Krebs-von-Lungen-6 (KL-6) have postulated roles in prognostic determination.

Rheumatoid Arthritis

Predisposing Factors and Pathogenesis Factors that potentially contribute to the pathogenesis of pulmonary fibrosis in RA include genetic susceptibility, development of an altered immunologic response, and aberrant host repair processes [28]. As in SSc, it is likely that host susceptibility and environmental triggers interact to initiate the development of pulmonary disease. Genetic studies have shown that pulmonary fibrosis is associated with HLA-B8 and HLA-Dw3 positivity [29]. The risk of developing pulmonary fibrosis increases with high titres of rheumatoid factor and the presence of rheumatoid pulmonary nodules. Smoking has been identified as a risk factor in the development of both sub-clinical and clinically significant pulmonary fibrosis [30], although it is possible that co-existent smoking-related lung pathology may skew measures of lung function. Secondary causes of interstitial disease in RA include atypical pulmonary infections (mycobacterial species, cytomegalovirus, Pneumocystis carinii), particularly in conjunction with immunosuppressive agents, and drug-induced interstitial lung disease, including that caused by methotrexate and gold therapy. At a cellular level, the pathogenesis of pulmonary fibrosis in RA is similar to many of the CVD, with the accumulation of inflammatory cells, particularly T lymphocytes and macrophages with immune-dysregulation, proteaseantiprotease imbalance, the generation of a pro-fibrotic cytokine milieu, and recruitment of matrix-secreting cells together with altered repair mechanisms. Pathology The histology of pulmonary fibrosis in RA is characterised by an early lymphocytic interstitial infiltrate with prominent associated peribronchial follicles which, in later disease, evolves to a predominantly fibrotic appearance. In contrast to many of the other CVDs, a UIP pattern of disease is present, with a subpleural fine reticular pattern which evolves to a microcystic, or honeycomb appearance, with fibroblastic foci adjacent to established disease. However, interstitial abnormalities in RA are highly variable,

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with recent data suggesting that NSIP and UIP are similar in prevalence [31]. Organising pneumonia (OP) with multi-focal consolidation and lymphocytic interstitial pneumonia (LIP) are both found in a subset of patients. Pulmonary rheumatoid nodules, which often cavitate, are an occasional finding. Obliterative bronchiolitis (OB) is often clinically silent until advanced, where it is associated with a poor prognosis, whereas follicular bronchiolitis, due to external compression of bronchioles by hyperplastic lymphoid follicles is often more responsive to therapy [32]. Occasionally, patients with underlying fibrotic disease may develop an accelerated decline, characterised by diffuse alveolar damage (DAD); this carries a poor prognosis. Other pulmonary manifestations of RA include pleural disease (effusions and thickening), rheumatoid pulmonary nodules (usually associated with extrapulmonary nodules), drug-induced pulmonary fibrosis (methotrexate, gold, sulphasalazine, penicillamine), bronchiectasis (often clinically silent, and may predate systemic disease), pulmonary infections, Caplan’s syndrome (cavitating pulmonary rheumatoid nodules in association with coal-miner’s pneumoconiosis), and rarely pulmonary vasculitis. Clinical Features The onset of clinically significant pulmonary fibrosis in RA is usually between the ages of 50 and 70. The clinical features of RA are similar to those in many other fibrotic lung diseases, with insidious dyspnoea the most frequent presenting symptom. Pleural disease is associated with pleuritic chest pain and occasional fever, whereas a nonproductive cough may reflect airways-centred pathology. There is a high incidence of sub-clinical disease. Examination often reveals fine end-inspiratory crepitations, and clubbing is often present in advanced rheumatoid lung, in contrast to lung disease in the other CVDs. Approximately 10–20% of patients develop pulmonary symptoms before the onset of systemic features of RA [33]. Investigations Spirometry is characteristically restrictive, with reduced lung volumes and DLco in established lung fibrosis; an isolated reduction in DLco is often seen in sub-clinical disease. Super-added airflow obstruction should lower the threshold for investigation of OB, bronchiectasis, or smoking-related pathology. Occasionally, extra-pulmonary restriction is seen in severe pleural disease. Chest radiographic features are variable and include patchy alveolar opacities, reticulo-nodular densities, and end-stage honeycombing. The co-existence of pleural abnormalities and,

less frequently, cavitating rheumatoid nodules provide supportive evidence for rheumatoid lung. HRCT, the more sensitive imaging modality, most commonly reveals a UIP pattern of disease, with peripheral reticulation and microcystic change, indistinguishable from IPF, although an NSIP pattern with patchy ground glass opacification together with traction bronchiectasis is also seen [34]. Multi-focal consolidation with florid ground glass is seen in OP. OB is characterised by areas of mosaic attenuation, due to both severe bronchiolitis and regional hypoxic vasoconstriction, whereas follicular bronchiolitis has the appearance of micronodular opacities and tree-in-bud opacities due to small airways exudates. Often these pathologies coexist on HRCT, and the determination of the dominant pathology poses a considerable challenge in RA. The reported BAL findings in RA have been highly variable and nonspecific, and do not usually form part of the routine work-up. Prognosis and Natural History The clinical course of pulmonary fibrosis in RA is heterogeneous, and is usually linked to disease severity. Although more severe disease is generally insidious, chronic and progressive, no overall consensus has been reached on the prognosis of less extensive disease. Infective complications are the leading cause of mortality in RA, accounting for approximately 20% of deaths. Many patients with sub-clinical pulmonary fibrosis remain relatively stable under follow-up, although limited HRCT abnormalities were associated with an increased risk of subsequent deterioration in pulmonary function in one study [35].

Polymyositis/Dermatomyositis

Predisposing Factors and Pathogenesis The combination of diffuse lung disease with myositis and arthritis (the anti-synthetase syndrome) is associated with antibodies to aminoacyl tRNA synthetases; antihistidyl tRNA sythetase (Jo-1) is present in up to 30% of patients with inflammatory myopathy and in over 50% of patients with inflammatory myopathy associated with diffuse lung disease [36]. Other less prevalent anti-tRNA synthetase antibodies (PL12, PL7, EJ, OJ) have also been linked to interstitial lung disease in PM/DM. No consistent genetic associations have been identified. Pathology Pulmonary disease in PM/DM is characterised by pulmonary fibrosis, usually of the NSIP type [37, 38], sometimes


associated with or preceded by OP, often in a bronchocentric distribution; the co-existence of OP and NSIP carries a worse prognosis. Potential complications include superadded respiratory muscle weakness, due to active myositis, leading to extra-pulmonary restriction, and infection secondary to pharyngeal muscle weakness and aspiration pneumonia, or related to immunosuppressive therapy. There is an increased risk of malignancy in PM/DM, although the risk is significantly over-stated in many early reports. Clinical Features The clinical manifestations of pulmonary fibrosis in PM/DM vary from the absence of symptoms to severe, rapidly progressive dyspnoea which is often a feature of an accelerated decline characterised by OP, fibrosing NSIP and occasionally a picture suggestive of diffuse alveolar damage [39]. In 30% of cases, symptoms of pulmonary fibrosis predate the systemic manifestations [40]. An active myositis impacts greatly on dyspnoea, both secondary to respiratory muscle involvement, with the potential risk of ventilatory failure, and due to increased difficulties with locomotion; this requires urgent management. The presence of significant cough suggests the possibility of aspiration pneumonia which is common, occurring in up to 20% of cases, especially in advanced systemic disease. The respiratory examination is similar to that in other CVDs. Investigations Lung function tests in patients with pulmonary fibrosis typically show a restrictive pattern with decreased lung volumes and DLco, although restriction may also result from significant respiratory muscle weakness. In the presence of OP, consolidation is often detectable on a chest radiograph. In early disease, HRCT findings are often those of multifocal consolidation and ground glass attenuation, variably in a sub-pleural and bronchocentric distribution [41], with, occasionally, a co-existent basal NSIP pattern of disease. Later in disease, evolution to a predominantly fibrosing NSIP pattern, with fine fibrosis and traction bronchiectasis occurs in a subset of patients [42], with honeycomb change present in a minority of cases. BAL is particularly useful in excluding infection as a cause of pulmonary consolidation in the event of a clinical decline, but at present its role in guiding the management of patients with PM/DM remains controversial; the presence of a marked neutrophilia suggests established fibrosis, but its added value to other measures of disease severity is unclear.

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Prognosis Recent reports have suggested a 5-year survival of 60–85% in patients with PM/DM and interstitial lung disease [37, 43]. The clinical course of patients with PM/DM and lung fibrosis tends to be dominated by pulmonary disease. Negative prognostic factors for survival include a Hamman-Rich-like syndrome (with DAD), and severe disease (DLco less than 45% of predicted). Organising pneumonia associated with PM/DM does not always respond as strikingly to treatment as is usual in idiopathic OP and in a minority of patients the outcome is fatal despite intense treatment. Pulmonary disease has a worse treated outcome when muscle enzyme levels are normal or only mildly increased, and this picture was associated with a one-year survival rate of only 31% in a recent report [44]. Elevated levels of serum KL-6 have been linked positively to more severe disease, but the prognostic significance of this observation is not yet clear [45].

Systemic Lupus Erythematosus

Predisposing Factors and Pathogenesis Interstitial lung disease is an uncommon complication of SLE and tends to be more prevalent with increased SLE duration, although acute lupus pneumonitis has been linked with early systemic disease and a younger age group [46]. Immunopathological findings suggest that the deposition of immune complexes and activation of the complement cascade may play a role in the pathogenesis of acute pneumonitis [47]. An association between acute lupus pneumonitis and anti-Ro/SSa antibodies has been described [48]. Pulmonary fibrosis may represent post-inflammatory damage, due to alveolar haemorrhage, infection or acute lupus pneumonitis, but is occasionally a primary pathological process. Infection is the most common cause of pulmonary infiltrates in SLE, due to the inherent immunological dysfunction of the disease and to the widespread use of immunosuppressive treatments. Pathology Acute lupus pneumonitis, an accelerated interstitial lung disease occurring with a prevalence of less than 2%, is characterised by a picture of DAD similar to the Hamman-Rich syndrome, although the pathological features are not pathognomonic. It can be difficult to differentiate from fluid overload or an infective process, and is believed by some to be initiated by infection or aspiration. Diffuse interstitial fibrosis is relatively uncommon in SLE, compared to other CVDs, and is poorly characterised, although NSIP appears

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to be more prevalent than UIP, based on early reports. Pleuritis is common in SLE. Other pulmonary manifestations of SLE include airway abnormalities (bronchiectasis and constrictive bronchiolitis), diaphragmatic muscle weakness, pulmonary thromboembolism and pulmonary hypertension. Pulmonary haemorrhage, a rare but life-threatening complication, is thought to be caused by a necrotising angiitis related to immune complex deposition [49]. Clinical Features Pleuritic chest pain, dyspnoea and a non-productive cough are the most common presenting symptoms. Acute lupus pneumonitis often develops during a multi-system generalised flare of SLE, and presents with the additional symptoms of fever and haemoptysis; the differential diagnoses include opportunistic infection, alveolar haemorrhage, pulmonary embolism, and aspiration. Lung manifestations of SLE may present prior to the development of systemic symptoms. Investigations Restrictive spirometric volumes in SLE do not discriminate between pulmonary fibrosis, pleural disease and respiratory muscle weakness; however, marked reduction in the total gas transfer (DLco) level and widening of the alveolararterial oxygen gradient are both compatible with pulmonary fibrosis but not with extra-pulmonic restriction. Striking increases in DLco levels, measured using the single breath methodology, are pathognomonic of pulmonary haemorrhage, but this requires gas transfer measurement to be performed with 36 h of haemorrhage. HRCT in SLE often reveals pleural thickening and small effusions, and may demonstrate inter- and intra-lobular septal thickening, reticulo-nodular changes and predominantly lower zone architectural distortion in the presence of interstitial disease [7]. Non-specific HRCT changes are common in patients with normal lung function, and in most cases are unlikely to represent significant disease. More florid alveolar interstitial infiltrates and consolidation are found in acute lupus pneumonitis. The rare ‘shrinking lung’ syndrome, characterised by elevation of the hemi-diaphragms and basal atelectasis, occurs secondary to diaphragmatic dysfunction [50], and does not denote parenchymal disease. BAL is invaluable in the exclusion of infection in acute lupus pneumonitis, but BAL cell differential percentages are not routinely useful in the investigation of pulmonary fibrosis in SLE. Prognosis and Natural History Most patients with sub-clinical pulmonary fibrosis remain relatively stable under follow-up. Acute lupus pneumonitis

has a mortality of greater than 50%; factors contributing to poor outcome include intercurrent infection, aspiration, diaphragmatic dysfunction, cardiac and renal failure, and drug toxicity.

Sjögren’s Syndrome

Predisposing Factors and Pathogenesis Primary SS should be differentiated from SS secondary to other CVDs, where the lung abnormalities are ascribable to the associated CVD. Patients carrying the anti-Ro antibody often develop more aggressive systemic manifestations, including pulmonary disease [51]. Pathology Lung pathology in SS includes interstitial lung disease indistinguishable from other CVDs and a spectrum of benign to malignant lymphoproliferation including benign lymphocytic infiltration, lymphocytic interstitial pneumonia (LIP), pseudolymphoma and lymphoma. A sub-clinical lymphocytic bronchiolitis with bronchial wall thickening is common, and of uncertain clinical significance, whereas a follicular bronchiolitis, with external compression of bronchioles by hyperplastic lymphoid follicles, and variable lymphocytic infiltration of the bronchiolar wall often provokes respiratory symptoms. LIP is characterised by a benign diffuse lymphocytic infiltration most prominent around bronchioles, causing both tracheo-bronchial and interstitial disease. Patients with SS have a 40-fold risk of developing pulmonary lymphoma. NSIP is the predominant form of fibrotic lung disease [52], being much more prevalent than LIP in a recent biopsy series [53]. Inflammation and atrophy of tracheo-bronchial submucosal glands leads to dessication of the trachea and large bronchi (‘xerotrachea’) in 25–50%, chronic bronchitis, and small airways disease with associated airway hyperresponsiveness. Secondary amyloidosis is a rare complication. Clinical Features Cough secondary to tracheo-bronchial involvement is the most common presenting symptom but does not discriminate between dryness of airways with viscidity of secretions and a lymphocytic bronchiolitis. Patients with impaction of viscid secretions are at increased risk of developing recurrent respiratory tract infections. Investigations LIP is often characterised by a mixed ventilatory defect with a reduced DLco. The restrictive component usually


predominates, with the obstructive component representing either a bronchocentric element or, in occasional cases, the development of prominent cystic disease. Small airways disease and linear opacities are frequent findings on HRCT [9], and diffuse ground glass shadowing and irregular thinwalled cysts, which co-exist with airway-centred abnormalities, are typically seen in LIP [54]. Follicular bronchiolitis appears as small centrilobular nodules, bronchial wall thickening, and focal air-space consolidation. A sub-clinical BAL lymphocytosis is common, but has not consistently been shown to predict the development of parenchymal disease. Prognosis and Natural History Although there is a high prevalence of airway-centred symptoms in SS, most patients with primary SS do not develop progressive interstitial lung disease, with stable lung function over prolonged follow-up [55]. LIP is often steroid responsive, and carries a better outcome than interstitial pathology associated with other CVDs. However, a poor outcome is seen in a minority with non-responsive disease.

Ankylosing Spondylitis

Predisposing Factors and Pathogenesis Ankylosing spondylitis carries a strong association with the presence of HLA-B27 and the male sex, and is present in nearly 1% of the population; commonly, patients develop a sacroiliitis and a spondylitis of the axial skeleton. Chest wall restriction and pleuro-parenchymal involvement are the most important forms of thoracic involvement. Pathology Limitation of chest wall expansion due to costovertebral joint ankylosis is the most frequent clinically significant thoracic manifestation [56]. Clinically significant pleuroparenchymal involvement is an uncommon extra-skeletal manifestation of AS. Until recent years, the most recognised pathology has been upper lobe fibro-bullous disease; a slowly progressive fibrosis of the upper lobes with lymphocytic infiltration, which is usually bilateral and leads to superior retraction of the hila. This rare complication of AS appears on average two decades after the onset of AS, and is clinically significant in less than 2% of patients, judging from chest radiographic findings in a large consecutive cohort [57]. The distorted apical tissue often cavitates, with the potential for secondary colonisation by mycobacteria and fungi in the late stages of disease; aspergillus fumigatus is found in 60% of cases. A recent HRCT study has

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highlighted the high prevalence of sub-clinical abnormalities (bronchial wall thickening, bronchiectasis, pleural thickening/effusions) [11]. Clinical Features Pulmonary complications of AS are usually asymptomatic. Chest wall deformity is the most common complaint, with the potential risk of hypoventilation and respiratory failure. Late onset fibro-bullous disease is often asymptomatic, probably because the upper lung zones make little contribution to pulmonary function in health. Complications of fibrobullous disease include pneumothorax secondary to the degeneration of sub-pleural bullae, and haemoptysis that may require embolisation, which is preferable to surgical intervention in view of the risk of empyema and the development of broncho-pleural fistulae [58]. Investigations Immobilisation of the chest wall leading to extra-pulmonary restriction may exaggerate or mimic the restrictive defect of upper lobe interstitial disease, and is not always associated with elevated Kco levels. Small airways obstruction is common, with gas trapping and reduction in MEF25–75; co-existent restrictive and obstructive defects are common. HRCT is more sensitive than chest radiography in detecting early parenchymal changes; the most common abnormalities are linear opacities, parenchymal bands, bronchial wall thickening, small airways disease with mosaic attenuation, and pleural thickening, most of which are not associated with clinically significant disease [11]. Overall, there is a poor correlation between pulmonary function and the extent of radiographic abnormalities. A BAL lymphocytosis is common but has uncertain clinical significance. Prognosis and Natural History Most patients with AS and pulmonary abnormalities will not develop clinically significant disease. Rarely, progressive upper lobe fibro-bullous disease will lead to significant morbidity. Extra-pulmonary restriction may lead to the development of hypercapnoeic respiratory failure requiring the use of non-invasive ventilatory strategies.

Key Clinical Issues

Which Patients Should Be Screened to Identify Pulmonary Fibrosis? Because lung involvement is now a major cause of death in CVD, there is an increasing focus on the early identification of pulmonary fibrosis. HRCT is the most accurate

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diagnostic modality for pulmonary fibrosis, with a very low prevalence of false positive results, provided that prone sections are performed when abnormalities are limited. In diseases with a particularly high prevalence of pulmonary fibrosis (SSc and PM/DM), a routine baseline respiratory evaluation can be justified, when systemic disease is first diagnosed. The optimal screening strategy during baseline evaluation has yet to be validated but baseline chest radiography and pulmonary function tests are warranted, with routine HRCT evaluation when abnormalities are evident or respiratory symptoms are present. It is not yet clear that a screening baseline HRCT is justified in unselected patients with SSc or PM/DM, and it is more difficult to justify low yield screening procedures associated with even a low radiation burden in the remaining CVDs, in which clinically significant pulmonary fibrosis is much less prevalent. Baseline chest radiography should be performed in all CVDs and a careful respiratory history elicited. However, in SLE, SS and AS, HRCT and detailed PFT evaluation should probably be reserved for symptomatic patients and for patients with chest radiographic abnormalities. The initial evaluation of RA is more contentious. However, routine baseline PFT are justifiable because functional impairment in RA is common and many therapeutic agents, including methotrexate, penicillamine, gold and salazopyrine, cause lung toxicity, which may be difficult to substantiate or to distinguish from rheumatoid lung without baseline evaluation (and, thus, the ability to detect functional deterioration during follow-up). Patients with functional impairment should undergo routine HRCT evaluation in view of the multiplicity of intra-thoracic disease processes encountered in RA. Which Patients Should Be Treated? Histological distinctions between fibrotic disorders are less useful prognostically in CVD than in IIP. In SSc, outcome differs little between UIP and NSIP [18] and in general, UIP in CVD has a better outcome than UIP in IPF [59]. RA may be an exception, with UIP associated with a worse outcome than NSIP in a recent series [60]. However, HRCT features are predictive of a UIP histologic pattern in RA [31, 60]. Thus, a routine surgical biopsy is difficult to justify for prognostic purposes in lung disease in CVD. Similarly, distinctions between fibrotic HRCT patterns are less useful in CTD than in idiopathic disease. In SSc, the HRCT picture closely resembles idiopathic NSIP [20] and as NSIP predominates in other CVDs, it appears unlikely that the HRCT sub-classification of fibrotic disease will prove to have major prognostic significance, except, possibly, in RA. HRCT has much greater clinical

usefulness in the identification of reversible disease (i.e. organizing pneumonia or prominent ground-glass attenuation without associated fibrotic abnormalities). Thus, although histological or HRCT appearances may guide treatment decisions in a small minority of cases, decisions on the institution of therapy are more commonly based on traditional clinical evaluation. The principles applied to SSc-PF, the most widely studied disorder, are largely applicable to pulmonary fibrotic processes in other CVD. In SSc-PF, the threshold for introducing treatment is reduced when: (1) The duration of systemic disease is less than 5 years, indicating a higher risk of clinically significant progression of lung disease [61]. (2) Disease is severe, judging from pulmonary function tests and HRCT findings. DLco levels provide a stronger prediction of mortality than other variables [18, 62]. Although there is no agreed cut-off level, most clinicians view a DLco level of less than 65% as indicative of moderate (as opposed to mild) functional impairment. (3) There is evidence of recent deterioration (symptomatic, radiographic or functional worsening). In SSc-PF patients, deterioration despite treatment is more predictive of mortality than any clinical feature at presentation [18]. In summary, decisions on which patients to treat are more dependent upon disease severity and likely future progression (based upon observed change and the duration of systemic disease) than upon histological and HRCT observations. What Treatment Should Be Used? There has been a paucity of controlled treatment data in this field, with treatment decisions largely based upon retrospective clinical series and case reports. The treatment of SSc-PF has been most widely evaluated. High doses of corticosteroids are not efficacious in SSc-PF and are associated with a major increase in the risk of scleroderma renal crisis [63, 64]. The most widespread regimen is low dose corticosteroid therapy (e.g. prednisolone 10 mg daily) in combination with an immunosuppressive agent, most commonly oral cyclophosphamide at a dose of 1.0–1.5 mg/kg [21, 65]. More recently, intravenous cyclophosphamide has been increasingly used, with evidence of partial regression of lung disease, as judged by serial PFT [66, 67] or serial HRCT [66, 68]; intravenous cyclophosphamide is well tolerated, at dosages of 500–750 mg at 4-weekly intervals. Placebo-controlled trials of oral and intravenous cyclophosphamide in SSc-PF have recently been reported.


Daily treatment with oral cyclophosphamide for one year, at a maximum dose of 2 mg/kg/day, was associated with a small but statistically significant benefit in forced vital capacity levels, compared to inactive treatment (with parallel benefits in several secondary end-points) [69]. In a smaller study, intravenous cyclophosphamide for 6 months, at a monthly dose of 600 mg/m2, followed by oral azathioprine at 2.5 mg/kg/day, in combination with low dose prednisolone throughout, also conferred FVC benefits at 1 year, although the statistical significance was marginal [70]. Taken together, the two studies provide support for the widespread use of immunosuppressive therapy in clinically significant SSc-PF, despite the relatively small effect on FVC levels. The amplitude of treatment benefits in placebocontrolled evaluation is sometimes difficult to interpret, as participation is often more likely to be accepted by patients with relatively indolent disease, especially when open treatment is readily available for overtly progressive disease. These data are consistent with anecdotal use of oral azathioprine given in combination with low dose prednisolone, which has been shown to be clinically beneficial, albeit in an uncontrolled retrospective analysis [71]. The treatment effects in this report were similar to uncontrolled benefits reported with oral cyclophosphamide in other studies, and this supports the increasing use of oral azathioprine in combination with low dose prednisolone, except in very severe or progressive disease, as azathioprine is less toxic than oral cyclophosphamide. The treatment of rheumatoid lung suffers from an extreme paucity of outcome data. Historically, high doses of oral corticosteroids have been used, with the addition of an immunosuppressive agent as steroid therapy is reduced in selected patients, based upon disease severity and progressiveness. Cyclosporine A, azathioprine, and anti-TNF␣ therapy have all been useful anecdotally as steroid sparing agents when disease has progressed despite initial treatment. As in other CVDs, the treatment of lung disease in PM/DM has suffered from the lack of randomised, controlled trials. However, based on uncontrolled reports, high dose corticosteroid therapy has been more efficacious than in other CVDs, with initial responses seen in 80–90% of cases [72, 73], reflecting the relatively greater prevalence of a component of organizing pneumonia in PM/DM, even when fibrotic disease is present. However, disease is fulminant in a minority of cases and high-dose IV methyl-prednisolone (1.0 g daily for 3 days) [74, 75] may be required, with variable efficacy. Second line treatments are introduced as steroid-sparing agents or when disease progresses despite

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steroid therapy, with anecdotal responsiveness to cyclophosphamide, azathioprine, methotrexate, or cyclosporine A in individual cases. In other CVDs, there is little useful guidance on treatment in the medical literature and therapeutic decisions in patients with pulmonary fibrosis tend to be informed by accumulated clinical experience in SSc, RA and PM/DM. In a minority of patients with predominant inflammatory

disorders across all CVDs, initial treatment as for cryptogenic disease is appropriate. High dose corticosteroid therapy is usual in organizing pneumonia, cellular NSIP and drug-induced lung disease. However, especially in patients with organizing pneumonia, supervening fibrotic disease is more frequent than in idiopathic disease, with second line agents more frequently required to prevent disease progression.

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41 Ikezoe J, Johkoh T, Kohno N, Takeuchi N, Ichikado K, Nakamura H: High-resolution CT findings of lung disease in patients with polymyositis and dermatomyositis. J Thorax Imaging 1996;11:250–259. 42 Saito Y, Terada M, Takada T, et al: Pulmonary involvement in mixed connective tissue disease: comparison with other collagen vascular diseases using high resolution CT. J Comput Assist Tomogr 2002;26:349–357. 43 Marie I, Hachulla E, Cherin P, et al: Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum 2003;47:614–622. 44 Nawata Y, Kurasawa K, Takabayashi K, et al: Corticosteroid resistant interstitial pneumonitis in dermatomyositis/polymyositis: prediction and treatment with cyclosporine. J Rheumatol 1999;26:1527–1533. 45 Kubo M, Ihn H, Yamane K, et al: Serum KL-6 in adult patients with polymyositis and dermatomyositis. Rheumatology 2000;39:632–636. 46 Cheema GS, Quismorio FP: Interstitial lung disease in systemic lupus erythematosus. Curr Opin Pulmon Med 2000;6:424–429. 47 Quismorio FP: Clinical and pathologic features of lung involvement in systemic lupus erythematosus. Semin Respir Dis 1988;9:297–304. 48 Mochizuki T, Aotsuka S, Satoh T: Clinical and laboratory features of lupus patients with complicating pulmonary disease. Respir Med 1999;93:95–101. 49 Zamora MR, Warner ML, Tuder R, et al: Diffuse alveolar haemorrhage and systemic lupus erythematosus: clinical presentation, histology, survival and outcome. Medicine 1997;76:192–202. 50 Gibson CJ, Edmonds JP, Hughes GRV: Diaphragm function and lung involvement in systemic lupus erythematosus. Am J Med 1977;63:926–932. 51 Kelly CA, Foster H, Pal B, et al: Primary Sjogren’s syndrome in north east England: a longitudinal study. Br J Rheumatol 1991;30: 437–442. 52 Yamadori I, Fujita J, Bandoh S, et al: Nonspecific interstitial pneumonia as pulmonary involvement of primary Sjogren’s syndrome. Rheumatol Int 2002;22:89–92. 53 Ito I, Nagai S, Kitaichi M, et al: Pulmonary manifestations of primary Sjogren’s syndrome: a clinical, radiologic, and pathologic study. Am J Respir Crit Care Med 2005;171:632–638. 54 Jeong YJ, Lee KS, Chung MP, et al: Amyloidosis and lymphoproliferative disease in Sjogren syndrome: thin-section computed tomography findings and histopathologic

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comparisons. J Comput Assist Tomogr 2004;28: 776–781. Davidson BK, Kelly CA, Griffiths ID: Ten year follow up of pulmonary function in patients with primary Sjogren’s syndrome. Ann Rheum Dis 2000;59:709–712. Fournie B, Boutes A, Dromer C, et al: Prospective study of anterior chest wall involvement in ankylosing spondylitis and psoriatic arthritis. Rev Rhum Engl Ed 1997;64:22–25. Rosenow E, Strimlan CV, Muhm JR, Ferguson RH: Pleuropulmonary manifestations of ankylosing spondylitis. Mayo Clin Proc 1997;52: 641–649. Jewkes J, Kay PH, Paneth M, Citron KM: Pulmonary aspergilloma: analysis of prognosis in relation to haemoptysis and survey of treatment. Thorax 1983;38:572–578. Flaherty KR, Colby TV, Travis WD, et al: Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med 2003;167:1410–1415. Lee HK, Kim DS, Yoo B, et al: Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest 2005;127:2019–2027. Steen VD, Conte C, Owens GR, Medsger TA Jr: Severe restrictive disease in systemic sclerosis. Arthritis Rheum 1994;37:1283–1289. Scussel-Lonzetti L, Joyal F, Raynauld J-P, et al: Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis and survival. Medicine 2002;81:154–167. Steen VD, Medsger TA Jr: Case-control study of corticosteroids and other drugs that could precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 1998;41:1613–1619. DeMarco PJ, Weisman MH, Seibold JR, et al: Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum 2002;46:2983–2989. Behr J, Vogelmeier C, Beinert T, et al: Bronchoalveolar lavage for evaluation and management of scleroderma disease of the lung. Am J Respir Crit Care Med 1996;154:400–406. Pakas I, Ioannidis JP, Malagari K, et al: Cyclophosphamide with low or high dose prednisolone for systemic sclerosis lung disease. J Rheumatol 2002;29:298–304. Giacomelli R, Valentini G, Salsano F, et al: Cyclophosphamide pulse regimen in the treatment of alveolitis in systemic sclerosis. J Rheumatol 2002;29:731–736.


68 Griffiths B, Miles S, Moss H, et al: Systemic sclerosis and interstitial lung disease: a pilot study using pulse intravenous methylprednisolone and cyclophosphamide to assess the effect on high resolution computed tomography scan and lung function. J Rheumatol 2002;29:2371–2378. 69 Tashkin DP, Elashoff R, Clements PJ, et al, on behalf of the Scleroderma Lung Study Research Group: Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655–2666. 70 Hoyles RK, Ellis RW, Wellsbury J, et al: A multicenter, prospective, randomised, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 2006;54:3962–3970. 71 Dheda K, Lalloo UG, Cassim B, Mody GM: Experience with azathioprine in systemic sclerosis associated with interstitial lung disease. Clin Rheumatol 2004;23:306–309. 72 Arakawa H, Yamada H, Kurihara Y, et al: Nonspecific interstitial pneumonia associated with polymyositis and dermatomyositis: serial high-resolution CT findings and functional correlation. Chest 2003;123:1096–1103. 73 Mino M, Noma S, Taguchi Y, et al: Pulmonary involvement in polymyositis and dermatomyositis: sequential evaluation with CT. AJR Am J Roentgenol 1997;169:83–87. 74 Nawata Y, Kurasawa K, Takabayashi K, et al: Corticosteroid resistant interstitial pneumonitis in dermatomyositis/polymyositis: prediction and treatment with cyclosporine. J Rheumatol 1999;26:1527–1533. 75 Hirakata M, Nagai S: Interstitial lung disease in polymyositis and dermatomyositis. Curr Opin Rheumatol 2000;12:501–508.

Prof. Athol U. Wells Interstitial Lung Disease Unit Royal Brompton Hospital, Sydney Street London SW3 6NP (UK) Tel. ⫹44 207 351 8327 Fax ⫹44 207 351 8336 E-Mail [email protected]

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Pulmonary Vasculitis Joseph P. Lynch IIIa Michael C. Fishbeinb

Eric S.Whitec

a

Division of Pulmonary, Critical Care Medicine and Hospitalists, Department of Internal Medicine, Department of Pathology and Laboratory Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, Calif., cDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Mich., USA b

Abstract Pulmonary vasculitis is an uncommon but potentially lethal disorder which may cause complications in diverse systemic vasculitis disorders. The most common pulmonary vasculitides, which include Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, are discussed in detail here. These three vasculitic disorders are associated with circulating antibodies directed against the cytoplasmic components of neutrophils and monocytes (ANCA). Treatment with corticosteroids and immunosuppressive or cytotoxic agents is highly effective against each of these entities, with response rates of 70–95%. We briefly discuss other rare disorders that may involve pulmonary vessels including bronchocentric granulomatosis, necrotizing sarcoid angiitis, lymphomatoid granulomatosis, Behcet disease, and Takayasu’s arteritis. Copyright © 2007 S. Karger AG, Basel

Systemic necrotizing vasculitis involves the lung primarily in the context of the small vessel vasculitides [e.g. Wegener’s granulomatosis (WG), Churg-Strauss syndrome (CSS), and microscopic polyangiitis (MPA)], in all of which pulmonary capillaritis may be a component. Each of these disorders may be associated with circulating antibodies against cytoplasmic components of neutrophils and monocytes (i.e. ANCA) (discussed in detail below). Pulmonary hemorrhage (usually due to capillaritis) and glomerulonephritis (GN) may occur in ANCA-associated vasculitides whereas these findings are not present in classical polyarteritis nodosa (PAN). Lymphomatoid granulomatosis,

bronchocentric granulomatosis, and necrotizing sarcoid angiitis display histological features of vascular inflammation, but should not be considered true vasculitides. Finally, pulmonary involvement (principally pulmonary arterial aneurysms) may complicate Takayasu’s arteritis and Bechet’s disease.

Antineutrophil Cytoplasmic Antibodies

Circulating ANCAs are frequently found in necrotizing small vessel vasculitis, associated with glomerulonephritis or pulmonary capillaritis [manifesting as diffuse alveolar hemorrhage (DAH)] [1–5]. ANCAs with differing antigenic specificities display differing prognostic and clinical significance [2, 4, 6]. Antibodies with antigenic specificity for proteinase 3 (PR3) exhibit a cytoplasmic pattern on immunofluorescence (c-ANCA); antibodies with antigenic specificity for myeloperoxidase (MPO) exhibit a perinuclear pattern (p-ANCA) [2]. Antibodies with distinct antigenic determinants are observed in different types of vasculitis. c-ANCA (PR3-ANCA) are detected in 70–93% of patients with untreated WG [1, 2, 7] and 10–20% of patients with MPA or CSS [5, 8–10] (table 1). Circulating p-ANCA (MPO-ANCA) is found in ⬎50% of patients with MPA or CSS whereas p-ANCA is uncommon (⬍10%) in WG [7–9]. c-ANCA is ⬎90% specific for small vessel vasculitis [1, 2] but p-ANCA may be observed in myriad inflammatory disorders in which vasculitis is lacking (e.g. collagen vascular disease, inflammatory bowel disease) [10]. Importantly, c-ANCA is associated with a more aggressive course (e.g.

Table 1. Pulmonary vasculitides: histopathology, clinical features, and serology

Histopathology

Wegener granulomatosis Polyarteritis nodosa Microscopic polyangiitis Churg-Strauss syndrome

Serology

histopathology

granulomatous

eosinophils

renal involvement

capillaries, venules, arterioles medium-sized vessels capillaries, venules, arterioles capillaritis

prominent

rare

pauci-immune GN 70–85%

no no

rare no

renal artery aneurysms common pauci-immune GN ⬎90%

yes

prominent

GN uncommon (⬍10%)

ANCA (70–93%) PR-3 ⬎⬎ MPO Negative ANCA ANCA (50–90%) (MPO ⬎ PR-3) ANCA (40–73%) (MPO ⬎ PR-3)

ANCA ⫽ Anti-neutrophil cytoplasmic antibody; GN ⫽ glomerulonephritis; MPO ⫽ myeloperoxidase; PR-3 ⫽ proteinase-3.

rapidly progressive GN, pulmonary capillaritis) and increased mortality compared to p-ANCA [6]. Epidemiology and Prevalence The annual incidence rates of ANCA-associated vasculitides are variable among different studies and different geographic regions. Estimated annual incidence rates are as follows: WG, 4–23 cases per million; MPA, 3–25 cases per million; CSS; 2–9 cases per million [3, 5, 7, 11, 12]. The peak incidence for all 3 disorders is in the third through fifth decades of life [7, 11, 12]. There is no gender predominance in WG or CSS; MPA is slightly more common in males [3, 5].

Pulmonary Capillaritis

Diffuse alveolar hemorrhage (DAH) is due to pulmonary capillaritis that may occur in the context of WG, MPA and CSS and is a potentially fatal complication of ANCAassociated vasculitides [3, 10, 13, 14]. Classical findings include hemoptysis, diffuse alveolar infiltrates, hypoxemia, renal failure, and iron-deficiency anemia [13]. However, the clinical spectrum is wide, and some of these features may be subtle or absent. In the vast majority (⬎90%) of ANCA-associated DAH, necrotizing GN is present [3, 13]. Prompt diagnosis and institution of therapy is vital to avert early mortality from DAH and late sequelae from end-stage renal disease. The role of surgical lung biopsy (SLBx) in the diagnosis of DAH is controversial. We believe the risk of SLBx in patients with severe DAH and respiratory failure outweighs benefit. However, SLBx may be considered for patients with isolated alveolar hemorrhage who are not in respiratory failure. Further, histological features of DAH are nonspecific. Predominant findings are extensive intra-alveolar

Pulmonary Vasculitis

hemorrhage and necrotizing pulmonary capillaritis [13]. Capillaritis is characterized by neutrophilic infiltration of capillaries, fragmented neutrophils (leukocytoclasis), and necrosis of the capillary walls [13] (fig. 1). Hemosiderinladen macrophages (siderophages) accumulate within the alveolar spaces and interstitium; their presence is a clue to prior episodes of DAH (fig. 2). Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is usually adequate to exclude infectious etiologies and support the diagnosis of DAH. Bloody or serosanguinous BAL fluid (with progressively more blood with serial aliquots) and large numbers of hemosiderin-laden macrophages may be sufficient to justify initiation of therapy provided clinical and serological features are present. Ancillary studies such as serologies, renal function tests, and urinalysis may support the diagnosis. If microscopic hematuria or renal insufficiency is evident, percutaneous renal biopsy should be performed. Pauci-immune necrotizing GN is a cardinal (albeit nonspecific) feature of immune-mediated or ANCA-associated DAH (fig. 3) [13]. The histological spectrum is varied, ranging from mild mesangial thickening to severe crescentic GN. Vasculitis of renal arteries is rarely found, even in granulomatous vasculitides. In summary, a presumptive diagnosis of DAH can be made by the constellation of severe anemia, rapidly progressive glomerulonephritis (RPGN), diffuse pulmonary infiltrates on chest radiographs (fig. 4), high-titer circulating ANCA, and characteristic findings on (BAL) [15]. Severe DAH is a medical emergency. For immune-mediated or ANCA-associated DAH, prompt and aggressive treatment with pulse intravenous (i.v.) methylprednisolone (1 g daily for 3 days) is advised [1, 13]. Corticosteroids (CS) are continued, and gradually tapered over the next several months. For ANCA-associated DAH, cyclophosphamide

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Fig. 2. Photomicrograph. Hemosiderin-laden macrophages (sidero-

phages) are prominent in the alveolar interstitium in a patient with recurrent alveolar hemorrhage (hematoxylin-eosin). Courtesy of Joseph Fantone, MD, University of Michigan Medical Center, Ann Arbor, Mich., USA. Reprinted with permission from Lynch and Leatherman [13].

Wegener’s Granulomatosis

Fig. 1. Photomicrograph. Capillaritis and pulmonary hemorrhage in Wegener granulomatosus. Upper left: Numerous neutrophils hug alveolar capillaries associated with recent alveolar hemorrhage. Upper right: Early fibrinoid necrosis of alveolar wall associated with capillaritis. Lower left: Pulmonary hemorrhage with capillaritis. Lower right: Linear band of degenerating neutrophils from zone of necrotizing capillaritis. Reprinted with permission from Lynch et al. [7].

(CYC) is administered concomitantly (i.v. or oral) [16]. A minimum of 12–18 months of therapy is recommended. However, immunosuppressive agents with lower toxicity [e.g. azathioprine (AZA), methotrexate (MTX), or mycophenolate mofetil (MMF)] can be substituted for CYC by 3–6 months (provided complete remissions have been achieved) [14, 17]. Adjunctive treatment with plasma exchange is recommended for DAH and severe renal failure (serum creatinine ⬎4 mg%) or patients refractory to CS and cytotoxic agents [14, 16].

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Lynch/Fishbein/White

Wegener’s granulomatosis (WG), the most common of the pulmonary granulomatous vasculitides, typically involves the upper respiratory tract (e.g. sinuses, ears, nasopharynx, oropharynx, trachea), lower respiratory tract (bronchi and lung), and kidney, with varying degrees of disseminated vasculitis [7]. Clinical manifestations of WG are protean, and virtually any organ can be involved. Upper airway symptoms are present in ⬎90% of patients with WG, and are often the predominant manifestations [7]. Pulmonary involvement occurs in more than two thirds of the patients; GN, in 55–85% [7]. Although WG usually involves multiple organs, limited variants exist, involving only one or two organs. This subset of patients has a more favorable prognosis [7]. Many classical features lacking in the early phases of the disease may evolve months or even years after the initial presentation. Histological Features The cardinal histopathological features of WG include: a necrotizing vasculitis affecting arterioles, venules, and capillaries; granulomatous inflammation; geographic parenchymal necrosis [7] (fig. 5a–d). Multinucleated giant cells, epithelioid cells, and collections of histiocytes are usually evident in involved organs, but well-formed sarcoid-like granulomas are uncommon (fig. 5a–c). Fibrinoid necrosis and thrombosis within vascular lumens are early findings (fig. 4d). Later, fibrosis of vascular walls may result in stenosis or

a Fig. 4. Alveolar hemorrhage due to WG. Posteroanterior chest radiograph from a 67-year-old man demonstrates extensive bilateral alveolar infiltrates. Complete recovery was achieved with cyclophosphamide and corticosteroid therapy. Reproduced with permission from Lynch et al. [7].

and inflammation and necrosis of the alveolar capillaries importantly, granulomatous vasculitis or extensive parenchymal necrosis characteristic of WG are lacking [7] (fig. 5e–f). Similarly, the characteristic renal lesion of WG is a pauci-immune segmental focal GN [7]. With more fulminant forms, necrotizing, RPGN is observed. Granulomatous vasculitis is observed in only 6–15% of renal biopsies from patients with WG [7].

b Fig. 3. Kidney from patient with microscopic polyangiitis: (a) renal glomerulus with crescentric glomerulonephritis; note cellular proliferation and collagen deposition in glomerulus, and (b) small artery in kidney with vasculitis; note destruction of vessel wall and fibrin deposition (arrow). HE. ⫻200.

obliteration of the lumens. Classical histological features may be lacking if small or nonrepresentative biopsies are obtained. Since infections (particularly mycobacterial or fungal etiologies) may evoke granulomatous, vasculitic responses, special stains for acid-fast bacilli (AFB) and fungi should be performed in any granulomatous or necrotic lesion. Histological features of capillaritis complicating WG are nonspecific. The predominant features include DAH


Clinical Features Upper Respiratory Tract The upper respiratory tract is involved in ⬎90% of patients with WG, and is often the presenting feature [7]. Sinus X-rays or thin-section computed tomographic (CT) scans are abnormal in ⬎80% of patients with WG; erosion or destruction of sinus bones may occur [7, 18]. Otologic involvement (e.g. otitis media, otalgia, mastoiditis, hearing loss), occurs in 30–50% of patients [7]. The nasopharynx is involved in 60–80% of the patients. Clinical manifestations include: epistaxis; nasal septal perforation; persistent nasal congestion or pain; mucosal ulcers; saddle nose deformity [7]. Despite the frequent involvement of the upper respiratory tract, histological confirmation is difficult. Biopsies of upper airway lesions often demonstrate nonspecific findings of necrosis and chronic inflammation [7]. Generous biopsies of involved sites or biopsies of additional sites are critical to substantiate the diagnosis.

199

10 8 NG

6 4

a

b Flow (liters/s)

2

A

c

d

0 1

2

3

4

5

6

7

8

9

⫺2 ⫺4 ⫺6 ⫺8

e

f

Fig. 5. Histopathology of WG. a Necrotizing granuloma (NG) with

⫺10

giant cell present (arrow). HE. ⫻100. b Granulomatous arteritis with large multinucleated giant cell in the wall of a pulmonary artery (arrow). HE. c Arteritis with numerous inflammatory cells in and around a small pulmonary artery (A). HE. ⫻100. d Fibrinoid necrosis of artery with rare eosinophils present (arrow). HE. e Acute hemorrhage and capillaritis, with numerous neutrophils in alveolar septal capillaries (arrow). HE. ⫻200. f Capillaritis with necrosis of alveolar septae which are no longer intact. HE. ⫻200.

Fig. 6. Flow-volume loop demonstrating truncation of both inspiration and expiratory limbs, consistent with fixed anatomic narrowing of the proximal trachea (subglottic stenosis) in a 28-year-old male with WG. Cyclophosphamide had been discontinued 4 months earlier after he had been in continuous remission for nearly 18 months. Dyspnea, due to subglottic stenosis, was the initial manifestation of recrudescent WG. Reproduced with permission from Lynch and Quint [53].

Ocular Involvement Ocular involvement occurs in 20–50% of patients with WG [7]. Manifestations may be superficial (e.g. conjunctivitis, scleritis) but uveitis, vasculitis, or compression of the optic nerve may lead to blindness in 2–9% of the patients [7]. Proptosis from a retro-orbital granulomatous inflammatory process may compromise the blood supply to the optic nerve [7]. In this context, surgical decompression may be required for patients failing medical therapy.

With tracheal stenosis, both inspiratory and expiratory limbs of the flow-volume loop are truncated [7] (fig. 6). Spiral CT scans more objectively quantitate the degree of airway stenosis (fig. 7). Endobronchial biopsies usually demonstrate nonspecific changes (e.g. necrosis or inflammation) [7]. The diagnosis of tracheal or endobronchial involvement in patients with known WG must be presumed, provided the clinical context is consistent, even when biopsies are not definitive. Importantly, progressive subglottic or bronchial stenosis can develop even when the disease is quiescent at other sites. Severe stenosis of large airways may necessitate treatment with Nd:YAG laser, dilatation, intratracheal corticosteroid injections, or placement of silastic airway stents [7]. Severe UAO may mandate tracheostomy.

Involvement of Trachea and Bronchi Granulomatous involvement of the trachea or major bronchi leads to stenosis in 10–30% of patients with WG [7]. Symptoms include dyspnea, wheezing or stridor. Tracheal or bronchial involvement is invariably associated with involvement of the nasopharynx or sinuses. Tracheal stenosis is usually localized, extending only 3 to 5 cm below the glottis, but more extensive involvement of the distal trachea or main stem bronchi may occur [7]. Spirometry may detect upper airway obstruction (UAO).

200


Lung Involvement Abnormalities on chest radiographs are noted in more than 70% of patients with WG during the course of the disease [7]. Single or multiple nodules or nodular infiltrates

Fig. 8. Posteroanterior chest radiograph from a patient with WG.

White arrows point to small parenchymal nodules. The black arrow points to the right middle lobe infiltrate.

Fig. 7. WG. 3-dimensional shaded surface display created from helical CT data shows severe stenosis of the left main stem bronchus (arrows) in a patient with WG. Reproduced with permission from Lynch and Quint [53].

(with or without cavitation) are characteristic (figs. 8, 9). Other features include: focal pneumonic infiltrates, mass lesions, pleural effusions, stenosis of trachea or bronchi, or atelectasis. Extensive alveolar or mixed interstitial alveolar infiltrates may be seen with pulmonary capillaritis and DAH [13] (figs. 4, 10). Chest CT scans typically reveal nodules, masses, cavitary lesions, or focal infiltrates in the context of active disease (fig. 11); septal bands, parenchymal scarring, irregular pleural thickening, or stenosis of large airways may reflect chronic or irreversible disease [19]. Surgical (thoracoscopic) lung biopsy is usually required to establish the diagnosis of pulmonary WG as the yield of endobronchial or transbronchial lung biopsies is low (3–18%) [7]. In contrast, SLBx in the setting of DAH is usually not helpful, as biopsies demonstrate nonspecific findings of capillaritis [7, 13] (fig. 5e, f). More than 90% of


Fig. 9. Posteroanterior chest radiograph from a patient with WG. Note the right upper lobe infiltrate with accompanying cavity (see white bars). An air-fluid level can be seen within the cavity (see black arrow).

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patients with pulmonary capillaritis in WG have RPGN [13]. Thus, if microscopic hematuria or renal insufficiency is evident, percutaneous renal biopsy should be performed. Pauci-immune RPGN is characteristic of WG in the context of DAH [7, 13]. As with other ANCA syndromes, a presumptive diagnosis of DAH can be made on the basis of clinical and radiographic features, circulating c-ANCA, and bronchoscopy with BAL. Renal Involvement Glomerulonephritis (pauci-immune) occurs in 70–85% of patients with WG during the course of the disease, but severe renal failure is present in only 11–17% of patients at presentation [7]. Microscopic hematuria or proteinuria precede abnormalities of renal function. Renal failure may progress rapidly (within a few days) or indolently, over months or even years. Unfortunately, 11 to 32% of patients with WG eventually develop end-stage renal disease (ESRD) requiring chronic dialysis [6, 7]. Renal transplantation is an option for patients with ESRD provided WG is in complete remission. Fig. 10. WG. Posteroanterior chest radiograph from a 70-year-old

woman demonstrates extensive airspace consolidation, particularly involving the right lung. Sinus and lung biopsies demonstrated areas of necrosis and granulomatous vasculitis. Although she initially improved with medical therapy, she died 8 weeks later of opportunistic infection. Reproduced with permission from Lynch et al. [7].

Fig. 11. WG. CT scan from a patient with WG demonstrates thickwalled cavitary nodules. Thoracoscopic lung biopsy demonstrated WG. Reproduced with permission from Lynch and Keane [54].

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Central or Peripheral Nervous System Involvement Central or peripheral nervous system involvement occurs in fewer than than 4% of patients with WG at initial presentation, but eventually develops in 10 to 34% [7]. Mononeuritis multiplex or polyneuritis is the predominant feature but other manifestations include: cerebral infarction or hemorrhage; cranial nerve palsies; focal deficits or seizures from cerebral mass lesions; diabetes insipidus; quadriparesis or paraparesis; visual loss (from compression of the optic nerve or vasculitis of the vasculature) [7]. Vasculitis of the CNS is rarely confirmed histologically, because of inaccessibility or risks associated with biopsies. The diagnosis is usually affirmed by noninvasive studies [e.g. electromyography (EMG), magnetic resonance imaging (MRI) or CT scans of the brain] in patients with neurological symptoms and documentation of WG at extraneural sites. Other Organ Involvement Constitutional features (e.g. malaise, fatigue, fever, weight loss) occur in 30–50% of patients with WG [7]. Nondeforming polyarthritis occurs in two-thirds of patients, and parallels activity of the systemic disease [7]. Cutaneous lesions develop in 20–50% of patients during the course of the disease [7]. Manifestations include palpable purpura, subcutaneous nodules, papules, petechiae, ulcers, nonspecific erythematous or maculopapular rashes. Skin biopsies may reveal granulomatous vasculitis with

necrosis, but usually show nonspecific changes of leukocytoclastic vasculitis. Cardiac involvement is rarely diagnosed ante mortem, but coronary arteritis, pericarditis, cardiomyopathy, conduction defects, and fatal arrhythmias may occur [7]. Gastrointestinal manifestations are diagnosed in fewer than 10% of patients [7]. Laboratory Features Striking increases in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are characteristic of active, generalized disease [7]. However, ESR or CRP can be normal with active disease, particularly when only a single site is involved. Serial measurements of ESR or CRP are useful to monitor the disease, but elevations may also reflect intercurrent infections. Autoantibodies directed against c-ANCA are present in more than 90% of patients with active generalized WG, and in 40–70% of patients with active regional WG [7]. Changes in c-ANCA usually correlate with disease activity, and are unaffected by infections. However, c-ANCA titers may persist in 30 to 40% of patients in complete remission [7]. Further, increases in c-ANCA titers do not consistently predict clinical relapse. Serial determinations of c-ANCA provide useful adjunctive information to the clinical data, but treatment decisions should not rely exclusively on c-ANCA titers. In contrast to CSS, peripheral blood eosinophilia is not a feature of WG [4, 5, 7]. Therapy Oral CYC (1–2 mg/kg/day) combined with corticosteroids (CS) [i.e. prednisone 1 mg/kg/day or equivalent, with gradual taper] is the initial treatment of choice for WG [7, 17, 20]. With this regimen, remissions are achieved in 70–93% of patients; early mortality rates are less than 15% [7, 17]. Optimal CS dosing and rates of tapering have not been studied in randomized trials. The dose and duration should be individualized, based on acuity and intensity of illness, clinical response, and presence of absence of CS side effects. For nonfulminant cases, we attempt to taper prednisone to 30 mg/daily (or equivalent) by 6–8 weeks, and to 10 mg/day by 4–6 months. Thereafter, low dose prednisone (e.g. 10–20 mg alternate days) may be used, with cessation of CS by 9 months. Relapses occur in 30–50% of patients, but usually respond to reinstitution of therapy [7, 20]. A minimum of 12–18 months of therapy is advised [20]. Intermittent i.v. pulse CYC is less toxic than daily oral CYC, but is less effective in maintaining durable remissions [7]. Sequelae of vasculitis (e.g. cerebrovascular accidents, myocardial infarction, renal failure, hypertension) or complications of CYC


(e.g. opportunistic infections, neoplasms) contribute to late mortality and morbidity [6, 21]. Because prolonged therapy with CYC is associated with myriad complications (including malignancies) [20], recent treatment strategies advocate initial treatment with CYC and CS for 3–6 months (until remissions are achieved), followed by maintenance therapy with less toxic agents (e.g. MTX or AZA) [17, 20]. Further, oral or i.v. methotrexate, administered once weekly, may be used as initial therapy for patients for non-life-threatening WG, as maintenance therapy following induction of remission with CYC, or for patients with serious adverse effects from CYC [7, 20]. Since MTX is eliminated via the kidneys, toxicity is increased in the presence of renal insufficiency. Anecdotal successes have been noted with other immunosuppressive or cytotoxic agents (e.g. AZA [20], cyclosporin A [7], MMF [22, 23], leflunamide [20, 24], and 15-deoxyspergualin [25]) but data are limited to small series and nonrandomized trials. Azathioprine is less effective than CYC in inducing remissions but is as effective as CYC in maintaining remissions following induction with CYC and CS [17, 20]. Other Therapeutic Options Anecdotal responses have been cited with diverse monoclonal antibodies, even in patients failing conventional therapy with CYC and CS. These include: rituximab (a chimeric monoclonal antibody directed against CD20) [26, 27], antithymocyte globulin [28]; monoclonal antibodies targeted against CD4 cells; Campath-1H (a monoclonal antibody directed against CD52), and inhibitors of tumor necrosis factor-␣ (TNF-␣) (e.g. infliximab and etanercept) [20, 29, 30]. However, a recent randomized, double-blind, placebo-controlled trial found that the addition of etanercept to conventional therapy (CYC or MTX plus CS) had no effect on the rate of sustained remissions, severity of disease flares, or quality of life [31]. Nonetheless, anecdotal responses to infliximab have been cited among patients failing conventional therapy [29, 30]. Trimethoprim/Sulfamethoxazole Trimethoprim/sulfamethoxazole (T/S) is of doubtful value as initial therapy for WG, but may have value as adjunctive therapy. In a randomized, placebo-controlled trial, the addition of one double strength tablet of T/S (i.e. 160 mg/800 mg) twice daily reduced relapse rates in patients with WG treated with CYC/prednisone [32]. In view of its low toxicity, T/S may be considered as adjunctive therapy for persistent, indolent (‘grumbling’) disease despite CYC and CS [7].

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Polyarteritis Nodosa

Classical (macroscopic) polyarteritis nodosa (PAN) is a necrotizing vasculitis involving small and medium-sized muscular arteries [1]. Microscopic vessels (e.g. small arterioles, venules, capillaries) are spared in PAN [1]. Most cases of PAN are primary or idiopathic, but secondary forms (e.g. due to hepatitis B virus or tumor antigens) occur [1]. Clinical manifestations predominantly affect the GI tract, kidneys, CNS, skin, heart, and viscera [1, 15]. Macroscopic aneurysms involving the renal, mesenteric, or hepatic arteries are present in more than two thirds of patients [1]. Clinically significant lung involvement is rare in PAN (⬍2%) [1, 15]. Most previous reports of PAN with lung involvement probably represented either CSS or MPA (discussed below) [2]. Circulating ANCA are not found in classical PAN [1, 15]. Treatment Patients with PAN and hepatitis B antigenemia are usually treated with antiviral therapies combined with immunosuppressive agents or plasmapheresis [1]. For PAN without hepatitis B antigenemia, CS plus CYC (oral or i.v. pulse) is the mainstay of therapy [1, 15]. Plasmapheresis is reserved for fulminant PAN refractory to conventional therapy [8]. Since classic PAN does not involve the lung, PAN will not be further discussed here.

Microscopic Polyangiitis

Microscopic polyangiitis (previously termed overlap polyangiitis syndrome) (MPA) has clinical and histopathological features that overlap with classical PAN and CSS [1, 2, 14–16]. As its name implies, MPA involves small vessels (i.e. arterioles, venules, and capillaries) whereas PAN spares small vessels [2]. Medium-sized or small arteries can be affected in either MPA or PAN [1, 2]. Granulomata are absent in both disorders [1, 2]. The predominant feature is pauci-immune GN, present in ⬎90% of patients; pulmonary capillaritis occurs in 15–40% of patients, and is an important cause of morbidity and mortality [3, 14–16]. Histopathology As with other ANCA-associated vasculitides, MPA principally affects small arterioles, venules, and capillaries [1, 15]. In contrast to WG and CSS, a granulomatous component is lacking and eosinophils are rare or absent [1, 15] (fig. 12a–c). The pulmonary lesion of MPA is nonspecific, revealing capillaritis and DAH (fig. 12b, c). The renal

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lesion in MPA reveals a focal and segmental GN with fibrinoid necrosis of the glomerular capillary wall, leading to crescents [3]. More chronic changes of interstitial fibrosis, tubular atrophy, and glomerulosclerosis may be observed in some patients (particularly those with MPO-ANCA) [3]. Immune complexes are non-detectable or present in only small amounts in involved tissue (pauci-immune) [1, 15]. Clinical Features Glomerulonephritis is present in ⬎90% of patients with MPA; pulmonary capillaritis, in 15–40% [3, 15, 16]. Additional manifestations of MPA include: arthralgias (30–60%); myalgias (40%); weight loss (35–60%); fever (40–50%); skin lesions (typically leukocytoclastic vasculitis) (30%); peripheral neuropathy, especially mononeuritis multiplex (40–60%) [1–3, 15, 16]. A prodromal respiratory illness precedes the onset of vasculitis in one-third of patients [1, 3, 15, 16]. Renal infarcts, renal vasculitis, and visceral aneursyms, cardinal features of PAN, are rarely observed in MPA [3, 15, 16]. In contrast to WG, sinus or upper airway involvement are rarely prominent or presenting features [1, 15, 16]. Ocular involvement is rare in MPA (⬍5%) [15]. Circulating ANCAs (principally p-ANCA) are present in 50–90% of patients with MPA [2, 15, 16]. Serial measurement of ANCA may be useful in patients with MPA. Asthma or eosinophilia (in blood or tissue), characteristic features of CSS [8, 9, 33] are not found in MPA [3]. Treatment Treatment regimens for MPA are generally similar to those adopted for WG (i.e., CS combined with CYC) [3, 6, 16, 34]. Rapidly progressive GN mandates prompt and aggressive treatment to avert end stage renal disease [6]. Plasmapheresis is reserved for severe rapidly progressive glomerulonephritis or fulminant or refractory cases [6, 35]. Remissions are achieved with CS and CYC in approximately 80% of patients [2, 3, 34, 36]. After remissions have been achieved, AZA, MTX, or MMF may be substituted for CYC after 3–6 months [17, 34]. As with WG, treatment should be continued for a minimum of 1 year after complete clinical and laboratory remission has been achieved [34]. Relapses occur in 20–54% of patients, usually as the immunosuppressive therapy is tapered or discontinued [15, 16, 34, 36]. Treatment of relapses is similar to initial induction therapy. With therapy, 10-year survival exceeds 70% [3, 36]. In a study of 342 patients with MPA (n ⫽ 260) or CSS (n ⫽ 82), 5 factors were associated with

H

a Fig. 12. Histopathology

of microscopic polyangiitis. a Low-power view showing acute hemorrhage (H), hemosiderin-pigment deposition indicative of prior hemorrhage (arrow), organizing hemorrhagic fibrinous alveolar exudate resembling organizing pneumonia (asterisks), and capillaritis (arrowheads). HE. ⫻100. b Capillaritis and acute hemorrhage (H). HE. ⫻200. c Arteritis with inflammation in the wall of a small artery (A). HE.

H A

b

worse survival: (1) proteinuria (⬎1 g/day); (2) renal insufficiency (serum creatinine ⬎1.58 mg%); (3) cardiomyopathy; (4) CNS involvement, and (5) severe GI tract involvement [36].

Churg-Strauss Angiitis (Allergic Angiitis and Granulomatosis)

Churg-Strauss syndrome (CSS), also termed allergic angiitis and granulomatosis [5, 8, 9], is associated with asthma, necrotizing vaculitis, extravascular granulomata, and tissue eosinophilia. In 1984, Lanham et al. [33] proposed the following criteria for the diagnosis of CSS: evidence for a systemic vasculitis involving two or more extrapulmonary organs; asthma; peripheral blood eosinophilia (⬎1.5 ⫻ 109/l or ⬎10% of total leukocyte count). In 1990, the American College of Rheumatology proposed specific diagnostic criteria for the syndrome [37]. A diagnosis of CSS is affirmed if there is biopsy evidence for vasculitis and at least 4 of the 6 following criteria are met: (1) moderate-to-severe asthma; (2)


c

peripheral blood eosinophilia (⬎10%); (3) mononeuropathy or polyneuropathy; (4) nonfixed pulmonary infiltrates; (5) paranasal sinus abnormality; (6) biopsy containing a blood vessel with extravascular eosinophils. Histopathology The salient histological features of CSS include a necrotizing vasculitis involving small arteries and veins, with eosinophilic and granulomatous components [5, 8, 33] (fig. 13a–f). Vascular walls and extravascular tissues are infiltrated by eosinophils but mononuclear cells, neutrophils, multinucleated giant cells, and palisading histiocytes are also present [3, 15, 16]. The pronounced eosinophilic and granulomatous character distinguishes CSS from other pulmonary vasculitides [3, 15, 16]. The diagnosis of CSS can be assumed even when histological features are not definitive, provided the clinical and laboratory features are characteristic [33]. Pathogenesis of CSS The pathogenesis of CSS is not known, but ANCA likely plays an important role in at least some cases [2, 4, 9].

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A

Fig. 13. Pathology of Churg-Strauss syndrome. a Arteritis, with eosinophils infiltrating the wall of a small artery (A). HE. ⫻200. b Capillaritis, with alveolar septal capillaries distended by neutrophils and eosinophils (arrow). HE. ⫻200. c Granulomatous inflammation with numerous multinucleated giant cells present. HE. ⫻200. d Eosinophilic pneumonia. HE. ⫻200: inset shows red macrophage that has phagocytized eosinophil granules. HE. ⫻400. e Eosinophilic pleuritis, with numerous eosinophils in pleura (P), as well as adjacent alveoli (asterisk). HE. ⫻200. f Eosinophilic bronchitis, as seen in asthma. HE. ⫻200.

a

b

c

d

P

e

Repeated antigenic stimulation may play a role [8, 9]. A link between leukotriene receptor antagonists (LTRA) (e.g. zafirlukast, montelukast, and pranlukast) use and CSS was initially suspected, but most experts now believe that CSS was related to unmasking underlying vasculitis as systemic CS were withdrawn, rather than a direct effect of LTRA [4]. Clinical Features Asthma precedes the diagnosis of CSS in ⬎90% of patients, and is usually the presenting feature [4, 8, 9, 33, 38]. Atopy and asthma typically precedes vasculitis by months or even years [9, 33, 38]. More than two thirds of patients with CSS have a history of hay fever, nasal polyposis, allergic rhinitis, or sinusitis [4, 9, 33, 38]. Peripheral blood and tissue eosinophilia develops later [8, 33]. Vasculitis develops years after these earlier phases [4, 8, 9,

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f

33, 38]. Increasingly severe and more frequent exacerbations of asthma precede the development of vasculitis [33]. Asthma is present in virtually all patients [4, 8, 9, 33, 38]. Abnormalities on chest radiographs (typically focal alveolar infiltrates) are present in 30–70% of patients with CSS during the course of the disease; pleural effusions are noted in up to 30% of the patients [9, 33]. Diffuse alveolar hemorrhage is a rare complication (⬍5%) of CSS [8]. Chest CT scans may reveal focal parenchymal infiltrates, often with consolidation, in a peripheral distribution. Other features include: ground glass opacities; cavitary pulmonary nodules; bronchial wall thickening; centrilobular nodules; thickened interlobular septae; pleural and pericardial effusions; enlarged hilar or mediastinal lymph nodes [39]. Additional features of CSS include: constitutional symptoms (⬎90%); arthralgias or myalgias (30–50%);

neurological involvement (principally peripheral neuropathy or mononeuritis multiplex) (40–78%); cutaneous manifestations (e.g. subcutaneous nodules, purpura, or petechiae; leukocytoclastic vasculitis) (60–70%); cardiac involvement (15–59%); abdominal viscera (30–62%) [2, 4, 8, 9, 33]. In contrast to WG or MPA, renal failure is uncommon (⬍5%) in CSS. Ocular involvement occurs in fewer than 5% of patients [8, 33]. Elevations in ESR and blood eosinophil counts are present in more than 80% of patients during acute exacerbations and usually correlate with disease activity [3, 15, 16]. Elevations in serum IgE are common (⬎50%) [3, 15, 16]. Circulating ANCAs (primarily p-ANCAs) are present in 40–73% patients with CSS, and correlate with disease activity [4, 40]. Therapy In the 1980s and 1990s, French investigators performed several prospective randomized trials that compared diverse therapeutic regimens in patients with PAN or CSS [5, 8, 36]. Regimens included: CS alone; CS plus oral CYC; CS plus i.v. ‘pulse’ CYC; CS plus plasma exchange (PE); the combination of CS, CYC, and PE [8]. Survival rates were similar with the various regimens (3-year survival rates, 80–90%; 10-year survival, 72–78%). Five factors were associated with worse survival: (1) proteinuria (⬎1 g/day); (2) serum creatinine ⬎1.58 mg%; (3) cardiomyopathy; (4) CNS involvement; (5) severe GI tract involvement [36]. In addition, age ⬎65 years was associated with higher mortality rates [1, 38]. Treatment of CSS should be individualized, depending upon the acuity and severity of the disease. Mild-to-moderate cases with no adverse factors can be treated with CS alone [4, 38]. Immunosuppressive agents (principally oral or i.v. pulse CYC) are added for more severe cases, when unfavorable prognostic features are present, or to achieve a steroid-sparing effect [4, 5, 8, 33]. For fulminant cases, pulse methylprednisolone (1 g i.v. daily for 3 days) combined with CYC is advised. Relapses occur in 20–50% of patients, often as the dose of CS or cytotoxic drug is reduced [5, 8, 33]. Thus, prolonged maintenance therapy may be required. As with WG and MPA, AZA, MTX, or MMF may be substituted for CYC either as initial induction therapy or as maintenance therapy after 3 to 6 months once remissions have been achieved with CYC [9, 17]. Occasional patients with CSS fail treatment with CS and cytotoxic agents. In this context, anecodotal responses were cited with plasma exchange, ␥-interferon, antithymocyte globulin, or pooled i.v. immunoglobulin, but data are sparse [5].


Bronchocentric Granulomatosis

Bronchocentric granulomatosis (BCG), initially described in 1973, represents a striking granulomatous response centered within bronchi and bronchioles, resulting in destruction and obliteration of affected airways [10]. Mild perivascular involvement within pulmonary vessels contiguous to the granulomatous process may be present, but true vasculitis is absent [10]. Most cases of BCG are due to a hypersensitivity response to fungal hyphae (most commonly aspergillus) within bronchial lumens. BCG has also been described as an unusual host response to infections and autoimmune diseases [10]. BCG is not a true vasculitis and will not be further discussed.

Necrotizing Sarcoid Angiitis and Granulomatosis

Necrotizing sarcoid angiitis and granulomatosis (NSG) is a small vessel granulomatous vasculitis involving pulmonary vessels, associated with large masses of confluent, non-necrotizing granulomata involving bronchi, bronchioles, and lung parenchyma [10] (fig. 14a–d). Extrapulmonary involvement is rare, and systemic vasculitis is absent. Most patients with NSC are asymptomatic, and the prognosis (with or without therapy) is generally excellent [10]. We believe that NSG is a variant of sarcoidosis, resembling ‘nodular sarcoid’.

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis (LYG), initially described in 1972, is a necrotizing vasculitic disorder with features that overlap with WG and atypical lymphoma [10]. The lung is nearly invariably involved [10]. Chest radiographs typically reveal multiple or single nodules, alveolar infiltrates, cavitary lesions, or pleural effusions [10]. Most common sites of extrapulmonary involvement include CNS (30%) and skin (30%) but virtually any organ can be involved [10]. Histological features reveal atypical lymphohistiocytic infiltrates surrounding small and medium-sized arteries and veins, a granulomatous component, and necrosis of involved organs [10]. Molecular biological and immunohistochemical techniques (e.g. T cell gene rearrangements, monoclonal stains) have shown that LYG represents diverse lymphoreticular disorders including malignant lymphomas and angioimmunoblastic lymphadenopathy [10]. Lymphomatoid granulomatosis should not be classified as a true vasculitis, but rather a stereotypic response to diverse

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LN

LN

LN

a

cm

1

2

3

4

5

b Fig. 14. Necrotizing sarcoid angiitis and

granulomatosis. Pathology of sarcoidosis. a Gross photograph of lung showing marked subpleural fibrosis (asterisks) and numerous enlarged hilar lymph nodes (LN). HE. b Bronchial wall with non-necrotizing granulomas. HE. ⫻200. c Low power of intrapulmonary vessel with granulomatous inflammation in the wall of the vessel (oval). HE. ⫻40. d Granulomatous vasculitis with numerous giant cells in the wall of the vessel (arrows; L ⫽ lumen). HE.

c

lymphoreticular disorders. The term angioimmunoproliferative lesion/angiocentric lymphoma (AIL) has been suggested in lieu of LYG. Behçet Disease

Behçet disease (BD) is a systemic vasculitis of unknown cause characterized by recurrent oral apthous ulcers (100%), genital ulcers (65–90%) uveitis (35–70%), arthritis (50%), and skin lesions (30–50%) [41–43]. Lung involvement (principally pulmonary artery aneurysms) occurs in 1–8% of patients with BD, and may be life-threatening [41–43].

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L

L

d

Additional features include: deep venous thrombosis (20–40%), arterial aneurysms and/or occlusions (7–38%); CNS involvement (10–20%) [41–44]. Less common sites of involvement include: GI tract; kidneys; heart; epididymitis [41–43]. BD is not a chronic persistent inflammatory disorder, but is characterized by recurrent attacks of acute inflammation, followed by remissions (spontaneous or induced) [42, 43]. Although many symptoms spontaneously remit, recurrent attacks of uveitis lead to blindness in nearly one-quarter of the patients [41–43]. Further, involvement of large vessels, CNS, or lungs may be life-threatening [42, 45].

The prognosis of BD is worse in males and young age at onset [44, 45]. Epidemiology and Prevalence BD is worldwide in distribution, but it is far more common in the Eastern Mediterranean Basin, along the ancient Silk Road [42]. The highest prevalence is in Turkey, ranging from 80 to 370 per 100,000 [42, 43]. Prevalence is lower (2–30 cases per 100,000) in other Asian countries, with lower figures (⬍1 per 100,000) in Europe and the USA [42, 43]. There is no gender predominance [43], but the disease is more severe in males [45]. Susceptibility to BD is associated with the HLA-B51 allele (positive in 50–70%) [42, 43]. Both genetic and environmental factors (possibly infectious agents) are likely important in the pathogenesis [42, 43]. Histological Features Histological features of BD are nonspecific. The central finding is a necrotizing vasculitis involving arteries, veins, and capillaries [43]. Inflammatory infiltrates are composed of lymphocytes, plasma cells, and polymorphonuclear leukocytes. Varying degrees of fibrosis, thrombosis, and necrosis are evident but fibrinoid necrosis is not found [43]. Destruction of arterial walls may lead to aneuryms or pseudoaneurysms [45]. Pulmonary artery aneurysms display perivascular infiltrates, marked intimal thickening, destruction of the elastic lamina, thrombotic occlusion, and recanalization [43]. Clinical Features of Pulmonary Involvement in BD Pulmonary artery aneurysms (PAAs) are the most common pulmonary lesions in BD; male gender is a risk factor for PAA [45]. When PAAs are present, multiple branches of the pulmonary artery are usually involved; 60% are bilateral [45]. In a recent review, large extrapulmonary vascular lesions (venous thrombi or arterial aneurysms and/or occlusions) were present in 78% of patients with BD and PAA; 93% had hemoptysis [45]. Pulmonary thromboembolism is rare in BD, because the thrombi within inflamed veins are strongly adherent [43]. Sudden hilar enlargement or polylobular rounded opacities on chest radiographs suggest PAAs [43]. Helical CT scans or MRI/angiography are the preferred methods to diagnose PAAs [43, 45]. Fatal hemorrhage due to rupture or erosion of PAAs may occur [44, 45]. The present of PAAs augurs a poor prognosis (60% fatality rate within 5 years) [43–45]. Therapy Because BD is rare, few controlled therapeutic trials have been done. Therapy depends upon the site(s) and severity of disease. Topical CS, colchicine, or thalidomide may be


adequate for oral and genital ulcers or mild uveitis [41–43]. Thalidomide is more effective than colchicine, but has numerous toxicities (including teratogenicity), and should never be used in women of child-bearing age. More severe cases warrant treatment with systemic CS and immunosuppressive or cytotoxic agents [41–43]. Anecdotal responses have been noted with interferon-␣ (IFN-␣) and infliximab for BD resistant to immunosuppressive agents, but data are limited [42, 46]. Anticoagulants and antiplatelet agents may be used to treat deep venous thrombosis [41–43], but are contraindicated if pulmonary vessels are involved [42]. Embolization of PAAs, with or without immunosuppressive therapy, has been successful in some cases [45]. Aneurysms involving large vessels (e.g. pulmonary artery, aorta, subclavian, innominate arteries) require resection [44, 47] but graft occlusions or new aneurysms may develop [44, 47]. Corticosteroids and immunosuppressive agents may reduce post-operative recurrences or graft occlusions [44, 47].

Takayasu Arteritis

Takayasu arteritis (TA) is an idiopathic granulomatous vasculitis primarily affecting large vessels (e.g. aorta and its branches), which may cause arterial stenoses, aneurysms, and distal arterial insufficiency [48–52]. Diffuse involvement of the aorta is typical [49]. The subclavian arteries (particularly the left) are most often involved, near their junction with the aorta [48, 49, 52]. The inflammatory process eventually involves the entire vessel wall, leading to occlusions or stenosis in ⬎95% of patients; aneurysms in 10–47% [48, 49, 51]. Major criteria for the diagnosis include: age of disease onset ⬍40 years; claudication of extremities; decrease of brachial artery pulse; blood pressure difference ⬎10 mm Hg; bruit over subclavian arteries or aorta; abnormal arteriogram. The diagnosis of TA is established if 3 or more of these criteria are met [49]. Epidemiology and Prevalence Most series of TA have been reported from Japan, Southeast Asia, and Mexico [52]. Takayasu’s arteritis is rare in the United States and Europe (estimated incidence 2–3 cases per million per year) [49–51]. Most patients present between ages 20 and 40 [49]. There is a striking female predominance (9:1 ratio) [49, 50]. Histopathological Features Histopathological features of TA reveal a granulomatous, sclerosing arteritis indistinguishable from giant cell

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(temporal) arteritis [51]. Intimal hyperplasia is a constant finding in TA [51]. Inflammation and subsequent neointimal proliferation results in stenotic or occlusive lesions whereas destruction of the elastic and muscularis causes vascular dilatation or aneurysms [51]. Clinical Features Fever, night sweats, myalgias, and arthalgias, and anemia may be presenting symptoms [48–50]. Marked elevation in the ESR is typical, and may be a surrogate marker of disease activity [48]. Antinuclear antibodies and rheumatoid factor are negative. After a lag time of months to years, symptoms of organ ischemia develop [49, 50]. Clinical manifestations include: claudication of arms or legs; transient ischemic attack (TIA), stroke, or dizziness (reflecting occlusion of the carotid or vertebrobasilar arteries); angina; visual loss; back pain (reflecting aortic aneurysms); renovascular hypertension [48–50]. Vascular bruits or absent or reduced pulses (particularly in the arms) are characteristic findings on physical examination (hence, the term ‘pulseless disease’ [52]. Conventional angiography, MRI or CT scans may detect occlusions, stenosis, luminal irregularities, tortuosity, or aneurysms [48–50]. The course of TA is variable. A progressive or relapsing/remitting course is typical but the disease is self-limited in 20% of cases [51]. Pulmonary Manifestations Pulmonary vasculitis is rarely recognized ante mortem, but pulmonary artery aneurysms or stenoses have been doc-

umented in up to 50% of patients by pulmonary angiography or necropsy [48, 49]. The severity of the pulmonary arterial involvement does not necessarily parallel the lesions in the aorta or its main branches [51]. Series from Japan and Mexico detected pulmonary arterial hypertension (PAH) in 27 to 73% of patients, but PAH has been uncommon (⬍10%) in most series from Europe and the USA [49–51]. Therapy Corticosteroids (alone or combined with immunosuppressive agents) are the cornerstone of therapy for TA [48, 49, 51]. Immunosuppressive or cytotoxic agents are used for severe cases or patients failing or experiencing adverse effects from CS [48, 49, 51]. Responses have been noted with anti-TNF agents (e.g. infliximab or etanercept) among patients refractory to CS and immunosuppressive agents, but data are limited [51]. With aggressive medical therapy, survival exceeds 90% and severe sequelae can be averted [51]. Far-advanced stenoses or sclerotic lesions will not be influenced by immunosuppressive therapy. In this context, angioplasty, surgical reconstruction, or bypass grafts should be done when symptoms of vascular insufficiency are evident [48, 49]. Main indications for surgery include: renovascular hypertension; cerebral hypoperfusion; limb claudication; aneurysms; severe dilatation of the aortic root, aortic insufficiency [49, 51]. Bypass grafts are usually successful, but re-stenosis or occlusion has been noted in 20–30% of patients on long-term follow-up [49, 51]. Serial MRI or CT angiograms are useful to assess disease activity or progression [51].

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43 Erkan F, Gul A, Tasali E: Pulmonary manifestations of Behcet’s disease. Thorax 2001;56: 572–578. 44 Calamia KT, Schirmer M, Melikoglu M: Major vessel involvement in Behcet disease. Curr Opin Rheumatol 2005;17:1–8. 45 Uzun O, Akpolat T, Erkan L: Pulmonary vasculitis in behcet disease: a cumulative analysis. Chest 2005;127:2243–2253. 46 Tugal-Tutkun I, Mudun A, Urgancioglu M, Kamali S, Kasapoglu E, Inanc M, Gul A: Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in Behcet’s disease: an open-label trial. Arthritis Rheum 2005;52:2478–2484. 47 Kalko Y, Basaran M, Aydin U, Kafa U, Basaranoglu G, Yasar T: The surgical treatment of arterial aneurysms in Behcet disease: a report of 16 patients. J Vasc Surg 2005;42: 673–677. 48 Mwipatayi BP, Jeffery PC, Beningfield SJ, Matley PJ, Naidoo NG, Kalla AA, Kahn D: Takayasu arteritis: clinical features and management: report of 272 cases. Aust N Z J Surg 2005;75:110–117. 49 Vanoli M, Daina E, Salvarani C, Sabbadini MG, Rossi C, Bacchiani G, Schieppati A, Baldissera E, Bertolini G: Takayasu’s arteritis: a study of 104 Italian patients. Arthritis Rheum 2005;53:100–107. 50 Ringleb PA, Strittmatter EI, Loewer M, Hartmann M, Fiebach JB, Lichy C, Weber R, Jacobi C, Amendt K, Schwaninger M: Cerebrovascular manifestations of Takayasu arteritis in Europe. Rheumatology (Oxford) 2005;44:1012–1015. 51 Liang P, Hoffman GS: Advances in the medical and surgical treatment of Takayasu arteritis. Curr Opin Rheumatol 2005;17:16–24. 52 Weyand CM, Goronzy JJ: Medium- and largevessel vasculitis. N Engl J Med 2003;349: 160–169. 53 Lynch JP III, Quint LE: Tracheobronchial and esophageal manifestations of systemic diseases; in Cummings CE (ed): Otolaryngology Head and Neck Surgery, ed 3. St Louis, Mosby-Year Book, 1998, pp 2343–2367. 54 Lynch JP III, Keane M: Current approaches to the treatment of parenchymal lung diseases; in Spina D, Pagge CP, Metzger WJ, O’Connor BJ (eds): Drugs for the Treatment of Respiratory Diseases. London, Cambridge University Press, 2003, pp 247–335.

Joseph P. Lynch III, MD Division of Pulmonary, Critical Care Medicine, and Hospitalists The David Geffen School of Medicine at UCLA 10833 Le Conte Avenue, Room CHS 37–131 Los Angeles, CA 90095 (USA) Tel. ⫹1 310 825 8599, Fax ⫹1 310 206 8622 E-Mail [email protected]

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Drug-Induced and Iatrogenic Infiltrative Lung Disease Philippe Camus Department of Pulmonary Medicine and Intensive Care, University Medical Center Le Bocage and Medical School, Université de Bourgogne, Dijon, France

Abstract An ever increasing number of therapy drugs, abused substances and chest/breast radiation therapy can produce varied patterns of infiltrative lung disease, closely mimicking naturally-occurring forms of theses diseases. A few drugs can produce more than one distinct pattern of infiltrative lung disease. The diagnosis of iatrogenic infiltrative lung disease is by exclusion, and requires careful exclusion of other causes and conditions, coherent temporal association with exposure to the drug and, ideally, abatement of symptoms following drug therapy withdrawal. Histopathological features sometimes enable instant recognition of the drug etiology. Rechallenge is not recommended. Pneumotox® (www.pneumotox.com) provides free and updated information on drug-induced respiratory disease. Copyright © 2007 S. Karger AG, Basel

Many drugs belonging to different therapeutic classes can cause injury of the respiratory system [1–7]. Most of the knowledge in the area was gained in the past 40 years, as an increasing number of therapy drugs were made available [1]. In addition to precription drugs, over-the-counter medications, herbal therapy (neutraceuticals) and abused substances also can cause sometimes severe lung or liver injury [8, 9]. Drug-induced infiltrative lung disease (InLD) has long been a trendy topic, and is likely to remain so in the foreseeable future. Firstly, because such agents as amiodarone, nitrofurantoin, antineoplastic chemotherapy and radiation therapy

are responsible for a persistent background of InLD, which is not well reflected in the current literature, as few more cases of InLD from these classic agents are being published. Secondly, the number of drugs capable of causing lung injury and the resulting patterns of involvement are expanding, as novel therapy drugs and biologicals are made available. For instance, such novel drugs as tyrosine-kinase inhibitors (gefitinib, erlotinib), rapamycin derivatives (sirolimus, everolimus, temserolimus), imatinib, interferon (IFN)-alpha and -beta, rituximab, and anti-tumor necrosis factor (TNF)-alpha antibody (adalimumab, etanercept, infliximab) have been shown to cause pulmonary toxicity [1]. Accordingly, patients with rheumatoid arthritis, lung cancer, or hematologic malignancies, and recipients of solid organ transplant exposed to the above agents have emerged as novel groups at risk [10]. The situation is complex in patients exposed to several drugs or agents capable of causing lung damage, in whom drug-induced lung disease sometimes is referred to as ‘chemotherapy lung’, or ‘idiopathic pulmonary syndrome’ to denote our inability do discern which drug, agent or association thereof injured the lung. Drug-induced InLD is not a trivial problem, because in some groups of patients, the incidence rate may be as high as 40%, raising complex management issues particularly when the background disease responded favorably to the specific drug and because outcome of patients with certain drug-induced complications (adult respiratory distress syndrome (ARDS), pulmonary fibrosis) is poor. Drugs can directly damage almost any part of the respiratory system, including the upper and lower airways,

lung parenchyma, pleural surfaces, pulmonary circulation, mediastinum, muscles and nerves, and respiratory centers, producing manifold possibilities and patterns of respiratory involvement [2, 7, 11–25]. Drugs can also cause indirect lung damage, via myocardial injury, with consequent pulmonary edema, or cause a generalized bleeding diathesis which manifests with diffuse alveolar hemorrhage [7]. The group of InLD, the topic of the present chapter, is the commonest pattern of drug-induced involvement, accounting for about three quarters of all reports on druginduced adverse respiratory effects. Infiltrative lung disease is a broader and preferred term as opposed to interstitial lung disease, as this encompasses varying interstitial diseases and alveolar reactions such as pulmonary edema and diffuse alveolar hemorrhage. Drugs can produce virtually any known pattern of the current classification of InLD [26, 27] including, by approximate order of decreasing frequency, cellular- and fibrotic nonspecific interstitial pneumonia (NSIP), eosinophilic pneumonia/pulmonary infiltrates and eosinophila (PIE), organizing pneumonia (OP), granulomatous interstitial pneumonia, pulmonary fibrosis with a usual interstitial pneumonia (UIP) pattern, pulmonary edema, diffuse alveolar hemorrhage (DAH) with or without demonstrable capillaritis, diffuse alveolar damage (DAD), a mimic of lipid storage disease and pulmonary vasculitis [28]. Less often, drugs produce a desquamative interstitial pneumonia (DIP) pattern, pulmonary alveolar proteinosis, or diffuse pulmonary calcification [28]. Respiratory bronchiolitis-interstitial lung disease, and pulmonary amyloid deposits are not recognized patterns of reaction to drugs. All of these patterns can produce pulmonary infiltrates on imaging, and it is generally difficult to infer the histopathologic background of drug-induced lung disease from appearances on imaging [29] (table 1). The bronchoalveolar lavage (BAL) may not enable the distinction between InLD due to drugs vs. other causes [30]. It is also difficult to secure the diagnosis of drug-induced InLD by examination of lung tissue without knowledge of exposure to drugs, except for a few agents which produce a suggestive pattern of pulmonary involvement. Examples include amiodarone and a pattern of pulmonary dyslipidosis, nitrofurantoin and DIP, and kayexalate with pleated foreign-body material in the distal airways [28]. The severity of drug-induced InLD varies with the specific drug and with the clinico-radiographic-pathologic syndrome. Dense pulmonary infiltrates, diffuse alveolar damage, pulmonary edema, diffuse alveolar hemorrhage and accelerated pulmonary fibrosis have the greatest impact on lung volumes and gas exchange. It is in these

Drug-Induced and Iatrogenic Infiltrative Lung Disease

cases that acute respiratory failure or an ARDS picture can develop. It may take only a few days for patients to progress from barely visible infiltrates on the chest radiograph or high-resolution computed tomography (HRCT), to dense diffuse and life-threatening pulmonary involvement particularly, but not exclusively so, when the causal drug is inappropriately continued. The outcomes of drug-induced InLD and InLD of other causes look similar, with cellular pulmonary reactions having a better prognosis than a fibrotic pattern of involvement [26]. Drugs generally involve the lung in isolation. Occasionally, there is concomitant involvement of the liver and lung, for instance with the use of amiodarone, dantrolene, nilutamide and nitrofurantoin. Rarely, drugs cause a systemic illness which may involve several internal organs including the lung (e.g. in the drug-induced lupus syndrome, vasculitis, or drug rash and eosinophilia and systemic symptoms) [31]. Patients with drug-induced InLD may be admitted to the department where the causal drug was originally prescribed, for instance in oncology or hemato-oncology with antineoplastic chemotherapy, cardiology with amiodarone, rheumatology with disease-modifying antirheumatic drugs, dermatology with minocycline for acne vulgaris, or gastroenterology with sulfasalazine for inflammatory bowel disease. Severe cases such as acute pulmonary edema, acute interstitial or eosinophilic pneumonia are admitted to intensive care units, while milder cases are diagnosed in family practice. Thus, any health professional should be cognizant of drug-induced lung injury. Drugs account for approximately 3% of all InLD cases. However, recognition of the drug etiology is crucial, since drug therapy withdrawal may lead to abatement of all symptoms and improvement of imaging and physiology. There is no classification of drug-induced InLD that is ideal. We rely herein on a classification based on the clinical-pathologic syndrome. A classification based on drugs is available at www.pneumotox.com and in specific review articles [2, 14, 20], where the particulars for each drug can be found.

Risk Factors

Risk factors for drug-induced InLD have been identified only for a few drugs, and prediction of drug-induced InLD is difficult. Current smoking, an abnormal baseline imaging or physiology, a history of lung disease or of pneumonectomy may increase the risk of developing drug-induced InLD. It is unclear whether the above factors

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Table 1. Drug-induced infiltrative lung disease: appearances on imaging and corresponding drugs and histopathologic patterns of involvement

Discrete pattern on imaging Chest radiograph Bilateral ground-glass or haze

Diffuse micronodules, miliary pattern Bilateral alveolar opacities with or without the batwing pattern Peripheral, subpleural opacities, the photographic negative of pulmonary edema, or reversed batwing Alveolar opacities with a recognizable lobar or segmental distribution ⫾ volume loss Lone consolidation or mass

Migratory opacities Biapical opacities Multiple nodules HRCT Ground-glass

Smooth mosaic lung attenuation

Sharply-demarcated mosaic

Patchy or diffuse pulmonary shadows with increased attenuation numbers Multiple patchy opacities along the bronchovascular bundles Multiple shaggy nodules Lone mass or consolidation

Localized honeycombing ⫾ traction bronchiectasis Bilateral, basilar honeycombing Spontaneous angiogram Tree in bud

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Prototypical drugs (see Pneumotox®)

Histopathological correlate(s)

drugs which produce cellular NSIP chemo agents radiation therapy (total body) BCG therapy, methotrexate, sirolimus drugs which produce pulmonary edema drugs which produce DAH drugs which produce DAD drugs which produce PIE drugs which produce OP

alveolitis early diffuse pulmonary edema or DAD early radiation pneumonitis granulomas pulmonary edema alveolar hemorrhage ⫾ capillaritis DAD eosinophilic pneumonia organizing pneumonia

amiodarone paraffin

amiodarone pulmonary toxicity exogenous lipoid pneumonia

drugs which produce OP or PIE amiodarone paraffin drugs which produce OP or PIE breast radiation therapy mesalazine bone marrow transplantation amiodarone bleomycin

organizing- or eosinophilic pneumonia amiodarone pulmonary toxicity exogenous lipoid pneumonia, paraffinoma organizing or eosinophilic pneumonia organizing or, less often, eosinophilic pneumonia organizing pneumonia, eosinophilic pneumonia pulmonary graft versus host disease amiodarone pulmonary toxicity organizing pneumonia, nodular fibrosis

drugs which cause cellular NSIP drugs which cause pulmonary edema or DAD drugs which cause cellular NSIP drugs which cause pulmonary edema drugs which produce diffuse alveolar hemorrhage nitofurantoin mineral oil (paraffin) busulfan, imatinib? amiodarone

cellular NSIP, alveolitis early pulmonary edema or DAD

desquamative interstitial pneumonia exogenous lipoid pneumonia pulmonary alveolar proteinosis, secondary amiodarone pulmonary toxicity

nitrofurantoin

patchy organizing pneumonia

amiodarone bleomycin drugs that produce organizing pneumonia or eosinophilic pneumonia amiodarone paraffin radiation therapy

amiodarone pneumonitis focal organizing pneumonia localized organizing and/or eosinophilic pneumonia

chemotherapeutic agents amiodarone paraffin kayexalate

pulmonary fibrosis (UIP), honeycombing pulmonary fibrosis (UIP), honeycombing unknown bronchiolitis, aspiration pneumonia

cellular NSIP pulmonary edema alveolar hemorrhage with or without capillaritis

amiodarone pulmonary toxicity paraffinoma pulmonary fibrosis (UIP pattern), honeycombing

merely increase the impact of any drug-induced involvement or make the lung more susceptible to injury from drugs. Coexisting or incidental infection with Pneumocystis or viral agents may play a crucial role [32]. In rheumatoid arthritis, preexisting interstitial abnormalities corresponding to the ‘rheumatoid lung’ increase the risk of methotrexate pulmonary toxicity eight- to tenfold [33]. Prior interstitial rheumatoid involvement may also increase the risk of diffuse alveolar damage from antiTNF-alpha antibody therapy (i.e. adalimumab, etanercept, infliximab) [34]. Prior adverse reactions to diseasemodifying antirheumatic drugs other than methotrexate may increase the risk of methotrexate pulmonary toxicity. Patients with the above characteristics require careful monitoring during long-term therapy with methotrexate [33]. Renal failure occurring, for instance, as a complication of chemotherapy with cisplatin, increases bleomycin blood levels and, consequently, may increase the risk of bleomycin pulmonary toxicity [20]. Asthma and atopy may predispose to drug- or radiation-induced eosinophilic pneumonia or the Churg-Strauss syndrome. The risk of developing nitrofurantoin pulmonary toxicity is increased in patients with prior reactions to sulfamides. Drug dosage may influence the likelihood of developing adverse lung reactions. Pulmonary infiltrates, pulmonary edema or ARDS may develop after an overdose with amitryptiline, aspirin, carbamazepine, cocaine, diltiazem, epineprine, haloperidol, heroin, isosorbide, nifedipine, quinine, tricyclic antidepressants and verapamil [35]. Doserelated toxicity also has been evidenced with conventional, i.e. therapeutic, doses of such drugs or agents such as amiodarone, aspirin, bleomycin, cyclophosphamide, nitrosoureas (e.g. BCNU, CCNU), paclitaxel, sirolimus, and radiation therapy [3, 36–38]. Corresponding threshold values are ⱖ500 units for bleomycin, ⱖ1,000–1,200 mg/m2 for bischloroethyl-nitrosourea (BCNU or carmustine), ⱖ20 ng/ml for sirolimus and ⱖ70 Gy for radiation therapy (although newer three-dimensional stereotactic body conformal radiation techniques are likely to increase the threshold values for radiation therapy further). Some correlation exists between the degree of exposure (a composite of dose and duration of treatment) to amiodarone and the incidence of amiodarone pulmonary toxicity [14]. However, no definite threshold dose has been identified. The relationship of amiodarone dosing and likelihood of amiodarone pulmonary toxicity is loose, and this condition can occur following a wide range of amiodarone doses and treatment schedules. Even though elevated drug dosages increase the incidence rate of lung disease from the above


drugs, severe InLD can occur following treatments with conventional or low dosages of these agents [39]. The combination of chemotherapy with radiation therapy and/or oxygen, or with hematopoietic colony-stimulating factors, or concurrent exposure to amiodarone and oxygen lowers the threshold at which pulmonary toxicity from each drug or agent occurs, and increases both the likelihood and severity of pulmonary toxicity. Similarly, radiation therapy delivered to the chest in patients with a history of exposure to chemotherapeutic agents may produce a ‘recall’ reaction for a threshold dose of radiation that would be considered safe in the absence of such history. The recall reaction involves the lung and/or skin precisely in the previously irradiated area. The risk of recall also can be observed in patients with a history of radiation therapy to the chest, who later are exposed to chemotherapeutic agents [40]. Doserelated pulmonary toxicity and the interplay between chemotherapy and radiation therapy is of considerable medical and legal relevance. Care should be taken in every patient to stay below identified threshold values, and to not unduly combine several pneumotoxic agents with radiation therapy, concomitantly or in sequence. In recipients of bone marrow or stem cell transplant, T cell depletion of the infused marrow reduces the risk of acute lung injury, whereas the presence of graft-vs.-host disease is associated with an increased risk [41]. Acetylator phenotype, certain HLA haplotypes and genes coding for TNF-alpha 2 may modulate the risk of developing chemotherapy-induced pulmonary fibrosis. The combined effect of all of the above factors with different genetic backgrounds may explain the wide range of individual susceptibility to the adverse effects of drugs.

Drugs Causing Infiltrative Lung Disease

The epidemiology of drug-induced InLD has changed with time. Severe OP from the early antihypertensive agents hexamethonium and mecamylamine fell into oblivion with the disuse of these drugs [1]. The eosinophilia myalgia syndrome due to a specific contaminant in ltryptophan has almost disappeared following l-tryptophan recall. Nitrofurantoin lung and amiodarone pulmonary toxicity were in fashion in the 1960s and 1980s, respectively. The number of reports peaked in those years and declined thereafter as it does for most drugs, a phenomenon known as the ‘␤ effect’. These agents are still being widely prescribed and cause significant pulmonary toxicity. Methotrexate and anti-TNF-alpha antibody therapy have revolutionized the management of rheumatoid arthritis, and

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have almost supplanted penicillamine and gold. Logically, the number of reports of toxicity from the two latter drugs has decreased, while cases of InLD due to methotrexate and anti-TNF agents have burgeoned. Recently-developed chemotherapeutic and immunosuppressive drugs (fludarabine, gemcitabine, gefitinib, gemcitabine, imatinib, irinotecan, rituximab, sirolimus, trastuzumab and taxanes) also can cause InLD [1]. It is the changing nature of druginduced InLD that makes this field so attractive. The incidence rate of drug-induced InLD varies with the specific drug and among studies between 1/100,000 and 1/5,000 treatment courses for nitrofurantoin, to 1–5% of patients exposed to regular doses of amiodarone long term, 17–36% of patients treated with rapamycin and congeners [42], and ⬎30% in patients exposed to high-dose amiodarone (ⱖ1,200 mg/day) [14] or in breast cancer patients receiving a high-dose nitrosourea-based chemotherapy regimen [43]. Drugs and drug classes which more often cause InLD include amiodarone, chemo agents (bleomycin, busulfan, chlorambucil, cyclophosphamide, gemcitabine, imatinib, methotrexate, mitomycin C, nitrosoureas (BCNU, CCNU and newer nitrosoureas), rituximab, trastuzumab and taxanes), disease-modifying anti-rheumatic drugs (methotrexate, anti-TNF-alpha antibody therapy), IFN, minocycline, nitrofurantoin, nonsteroidal antiinflammatory drugs (NSAIDs), and rapamycin [1]. Drugs given by almost any route of administration (oral, parenteral, inhaled, topical (ophthalmic, dermal, intranasal), intrathecal, intracavitary, and intra-arterial) can cause InLD. However, the vast majority of cases results from oral or parenteral administration of drugs. Drug-induced pulmonary toxicity generally occurs unexpectedly as an idiosyncratic reaction in a few individuals receiving long-term treatments with regular doses of the causal drug. This makes early detection and prevention difficult. Less often, pulmonary toxicity is diagnosed very early, even after the first administration of the drug or later, up to several years, after termination of treatment. Some drugs cause a stereotypical clinico-radiographicpathologic pattern of pulmonary involvement. For instance, minocycline and NSAIDs produce eosinophilic pneumonia, whereas methotrexate occasions an acute granulomatous InLD, which may mimic miliary tuberculosis or an opportunistic infection. Several drugs in a therapeutic class may produce the same pattern of pulmonary involvement, suggesting a common cytopathic mechanism linked to the molecular structure and/or mechanism of pharmacological action of the drug. For instance, several NSAIDs produce eosinophilic pneumonia, glitazones collectively increase capillary permeability and can induce pulmonary edema,

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and most alkylating agents can produce diffuse alveolar damage, vascular leak and pulmonary edema or pulmonary fibrosis. Therefore, resuming treatment with a drug belonging to the same therapeutic class may equate to rechallenge and produce a cross-reaction. In contrast, other drugs (e.g. amiodarone, bleomycin) can produce a multitude of patterns of pulmonary involvement, including asymptomatic pulmonary infiltrates, nonspecific cellular interstitial pneumonia, pulmonary infiltrates and eosinophilia, OP, pulmonary fibrosis, diffuse alveolar damage or an ARDS picture.

Diagnosis of Drug-Induced Infiltrative Lung Disease

The diagnosis of drug-induced lung disease is challenging. No universal test is available, rather an aggregate of criteria is discussed. Establishing the diagnosis of drug-induced InLD requires the conjunction of (1) a high level of awareness, (2) access to updated information on drugs that may injure the lung and the corresponding patterns of involvement, (3) meticulous discussion of all diagnostic criteria, (4) exclusion of other causes for the InLD (mainly an infection, left ventricular dysfunction, or pulmonary involvement from the background disease for which the drug was exactly given), and (5) abatement of signs and symptoms following drug therapy withdrawal. Rechallenge with the suspected drug followed by relapse of symptoms is the most definitive test in favor of drug-induced disease. However, rechallenge can be life-threatening and is reserved for specific cases. Rechallenge may have been performed unintentionally by the patient prior to the first evaluation, and this may have led to relapsing symptoms. Patients should be asked specifically about that at history taking. A set of criteria to diagnose drug-induced InLD follows [28, 44]: 1 A high index of suspicion is required at all times in patients exposed to drug(s) capable of causing lung disease, in whom develop otherwise unexplained respiratory signs or symptoms, or changes occur on chest imaging. 2 Correct identification of the drug: History-taking should include current and remote exposure to drugs, including each type of prescription drug, dosage and duration of treatment, route of administration, exposure to over-the-counter medications, dietary and health supplements, herbals/neutraceuticals, illicitly, abused, oddly or homemade substances, chemicals such as paraquat, and radiation therapy to the chest [11, 24, 45, 46]. 3 Drug singularity: Diagnosis of drug-induced InLD is easier in patients exposed to a single drug and is increasingly difficult in patients concomitantly exposed to

several potentially pneumotoxic drugs. The respective likelihood of lung damage to each specific drug is evaluated against the respective incidence rate and pattern of lung reaction of each drug considered separately, and an order of decreasing likelihood is tabulated. This helps selectively withdraw the drug(s) most likely to have caused the reaction, and reintroduce the drugs less likely to be involved. 4 No evidence for InLD should be present prior to onset of treatment with the drug under suspicion. Therefore, earlier available chest films and HRCT should be reviewed for evidence of InLD. This is why chest imaging and pulmonary physiology are recommended to avoid confusion in patients considered for treatments with drugs that often injure the lung such as amiodarone, antineoplastic chemotherapy and disease modifying antirheumatic drugs including methotrexate, as well in patients with a background condition which often involves the lung, such as connective tissue disease (e.g. rheumatoid arthritis), inflammatory bowel disease and in recipients of bone marrow or stem cell transplant. Any change in symptoms, pulmonary imaging and/or physiology which might occur during treatment would then be compared to the evaluation at baseline. 5 Temporal eligibility: Onset of respiratory symptoms should be temporally related to drug administration, and follow, not predate the onset of treatment with the suspected drug. Recognition of the drug etiology is easier when drugs produce InLD in close temporal association (e.g. hours or days) with exposure, than when acute InLD develops years after uneventful therapy with the drug. Determining the exact time when symptoms developed relative to onset of treatment with the drug may be difficult in retrospect, particularly when lung reactions develop insidiously. The time it takes into treatment with the causal drug before InLD develops ranges from a few minutes or hours, for instance, when hydrochlorothiazide produces pulmonary edema, to days when nitrofurantoin produces an acute ‘allergic’ pneumonitis, weeks when minoycline produces eosinophilic pneumonia, or years when amiodarone pulmonary toxicity, chemotherapy or radiation-induced lung injury develops. Inexplicably, acute InLD may develop after years of treatment with methotrexate, without any detectable triggering factor. 6 Characteristic pattern of lung reaction to the specific drug: Drugs or drug classes may at times produce a distinct clinico-radiographic-bronchoalveolar lavage (BAL)-pathologic syndrome. Sometimes, the pattern of involvement is so distinctive, it enables confident


recognition of the drug etiology. Examples include (1) radiation pneumonitis, which tends to localize in the irradiated area and is sharply demarcated from the neighboring unexposed lung along the boundaries of the radiation beam, (2) nitrofurantoin, which can produce a perfect mimic of desquamative interstitial pneumonia, (3) methotrexate or bacillus Calmette-Guérin, which induce an acute granulomatous pneumonitis, (4) bleomycin, which produces patchy bibasilar pulmonary infiltrates or lung nodules corresponding histopathologically to OP, and (5) mitomycin C or gemcitabine which produce the hemolytic and uremic syndrome, a systemic disorder with renal, neurologic, hemodynamic and pulmonary involvement. Similarly, histopathologic findings in amiodarone pulmonary toxicity (APT) include foamy lipid deposits in alveolar macrophages and in resident lung cells, interstitial inflammation, OP and fibrosis, a combination of findings almost diagnostic of APT. Exogenous lipoid pneumonia due to chronic ingestion of paraffin produces low attenuation densities in the basilar regions of the lung on HRCT, along with a distinctive accumulation of the stainable mineral lipid in alveolar cells, sputum or BAL. Chronic aspiration of kayexalate is diagnosed by the presence of basophilic, amorphous foreign material in distal airways. In most other cases, however, the clinical, radiographic and histopathologic manifestations of drug-induced InLD are nonspecific and cannot be reliably distinguished from those of InLD of other causes, or which occur idiopathically [26]. Accordingly, an open lung biopsy is seldom justified to diagnose drug-induced InLD. 7 Exclusion of other causes for the InLD is the most difficult part of the exercise. Since the clinical, radiographic and histopathologic manifestations of drug-induced InLD often are nonspecific [29], drug-induced InLD cannot reliably be distinguished from InLD of other causes. Thus, the diagnosis of drug-induced InLD is by exclusion. It is particularly important to exclude an infection, because several of the drugs which cause lung injury (e.g. alkylating agents, methotrexate, anti-TNF antibody therapy) are immunosuppressives, and carry the risk of exposure to opportunistic infections [23, 47, 48]. However, precise identification of the infectious agent may not translate into better outcomes [49]. Competing diagnoses other than an infection include cardiac and noncardiac pulmonary edema (NCPE), diffuse alveolar hemorrhage, pulmonary involvement from the basic disease and other incidental lung diseases. Diagnostic tools used to separate these conditions include history taking, cardiac ultrasound and forced

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diuresis to diagnose cardiac pulmonary edema, microbiological examination of blood, sputum and BAL using special stains, cultures, and molecular techniques to evidence bacteria, protozoae, parasites, or viral agents and in some patients, an open lung biopsy is required to rule out specific non-drug-induced conditions. 8 Effect of drug therapy withdrawal: Signs and symptoms of InLD tend to improve upon discontinuation of the culprit drug. The results of drug therapy withdrawal are definite in cases with drug-induced cellular InLD (e.g. methotrexate lung, hydrochlorothiazide-induced pulmonary edema), and less so in those with fibrotic lung reactions (e.g. amiodarone- or chemotherapy-induced pulmonary fibrosis). Drug therapy withdrawal may be without an effect in acute drug-induced InLD, such as acute methotrexate pneumonitis or minocycline-induced acute eosinophilic pneumonia because, once initiated, severe drug-induced reactions may progress at their own pace until a peak is reached. Corticosteroid therapy, in addition to drug therapy withdrawal, is reserved for cases with severe involvement and/or acute respiratory failure. Corticosteroid therapy complicates the assessment of drug causality. 9 In vitro tests may support the diagnosis of drug-induced InLD: • Lymphocytes, neutrophils or eosinophils may be selectively increased in the BAL, compared to normal, depending on which drug caused the reaction (for review, see [30]). • Stimulation of peripheral or BAL lymphocytes, lymphoblastic transformation test, stimulation of CD4⫹ and CD8⫹ cells and inhibition of leukocyte migration have been studied in the presence of the causal drug or metabolite with variable results. There is no current consensus on the utility of these tests in the diagnosis of drug-induced InLD. • Antinuclear antibodies are detected in patients with drug-induced lupus, and perinuclear antineutrophil cytoplasmic antibodies in patients with certain types of drug-induced vasculitis. Antibody levels tend to diminish with time, following drug therapy withdrawal [50]. • Determination of the acetylator phenotype, measurement of KL-6 and of TGF-␤1 in drug-induced or radiation pneumonitis have not demonstrated sufficient diagnotic reliability to be recommended as routine at this time. Recurrence with rechallenge is central to the diagnosis of any drug-induced condition. However, this test carries a significant risk of severe pulmonary reaction and death, even though the original lung reaction was mild [51]. Only in

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patients with mild InLD in whom no alternate therapy is available to treat the basic disease, can rechallenge be contemplated. In patients with presumed drug-induced InLD who were on multiple drugs and in whom all medications are discontinued, sequential rechallenge can be attempted, starting with the drug least likely to have caused the reaction. Clinico-Radiographic-Pathologic Syndromes of Drug-Induced Infiltrative Lung Disease

Diagnostic and management issues differ in acute, as opposed to chronic, and in mild as opposed to severe druginduced InLD. Acute drug-induced InLD may cause acute respiratory failure, requiring emergent management [7]. Although some patients present with mild drug-induced InLD, the clinical and imaging status may accelerate swiftly, particularly if the drug etiology is not recognized, and the drug is not discontinued in time. Acute Drug-Induced Infiltrative Lung Disease Acute InLD induced by drugs is a relatively common illness. Patients present with the progressive or rapid onset of cough, usually nonproductive, fever and breathlessness, in the context of widespread pulmonary opacities, hypoxemia, respiratory failure and, sometimes, an ARDS picture requiring immediate ventilatory support. Figures 1–4 illustrate four examples of acute infiltrative lung disease. On chest radiography and HRCT, early stages show a groundglass appearance, linear shadows, inter- and intralobular thickening or, less often, a miliary pattern [29, 52, 53]. When the disease progresses or accelerates, diffuse alveolar shadowing with air bronchograms and volume loss may develop. Pleural effusion is an occasional finding in acute methotrexate pneumonitis and in acute drug-induced eosinophilic pneumonia [17]. Acute drug-induced InLD may correspond to several clinical-histopathologic syndromes and causal drugs: • Acute cellular interstitial pneumonia, which is now called nonspecific interstitial cellular pneumonia, can occur with the use of chrysotherapy, ␤-blockers, methotrexate and nitrofurantoin. • Granulomatous infiltrative lung disease, which can occur with intracavitary BCG therapy, IFN-alpha/beta, methotrexate, sirolimus and anti-TNF-alpha antibody therapy. • Acute eosinophilic pneumonia can occur during treatments with angiotensin-converting enzyme inhibitors (ACEI), minocycline, NSAID, quinine and sulfamides.

Fig. 1. Acute nitrofurantoin lung after a

a

b

few days on the drugs. The disease is characterized by acute onset and diffuse pulmonary infiltrates on chest radiograph (a) and HRCT (b). Acute methotrexate or gold lung would have a similar presentation. Pathologically, there is diffuse cellular infiltration of the lung. This particular patient, an elderly lady, improved in a few days after withdrawal of drug therapy and corticosteroid therapy.

Fig. 2. Transfusion-related acute lung injury (TRALI) occurred a few hours after blood transfusion in a middle-aged woman. TRALI is a form of pulmonary edema which complicates transfusion of blood or blood products. TRALI can be linked to an antibody present in one donor, which should be identified.

Fig. 3. Amiodarone pulmonary toxicity

a

b

may present acutely with respiratory failure, as in this 84-year-old man. The disease often responds to corticosteroid therapy (b was taken 2 weeks after a). Fig.

a

b


4. Acute chemotherapy lung or ‘chemoradiotherapy lung’ can complicate treatments with chemo agents, radiation therapy or multimodality treatments combining chemotherapy and radiation therapy. On imaging, there is diffuse haze or a groundglass pattern early in the disease, followed by diffuse alveolar opacities as the disease progresses. Pathologically, diffuse alveolar damage is present. The disease may not respond to drug therapy withdrawal and corticosteroid therapy, and outcome often is grim.

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• Diffuse alveolar damage, a form of chemotherapy lung, which occurs as a complication of antineoplastic therapy. • Dyslipidosis, a hallmark of amiodarone pulmonary toxicity (APT). • Pulmonary edema with or without and ARDS picture, which can complicate treatments with aracytine, aspirin, ␤2-agonists, hydrochlorothiazide, and blood transfusions. • Diffuse alveolar hemorrhage, an elective complication of oral anticoagulants, superwarfarins, fibrinolytic agents and platelet receptor inhibitors. • OP and acute fibrinous OP have been temporally associated with amiodarone, IFN, nitrofurantoin and, possibly, statins. Patients with acute severe drug-induced InLD may be very ill, and their respiratory condition may not leave much space for any invasive procedure such as an open lung biopsy. Patients who require mechanical ventilation or who are immunosuppressed have an increased risk of death following surgical lung biopsy [54]. Most patients can undergo a BAL, an essential tool to rule out an infection and to support the drug etiology, when there is an increase in lymphocytes, eosinophils, or dysplastic type II cells [30]. In diffuse alveolar hemorrhage, the BAL is stained with blood, and there is increased staining in successive aliquots [21]. It is often difficult to infer the histopathologic background of any acute drug-induced InLD from the pattern on imaging or BAL [29]. It is also difficult in patients with acute InLD to separate the drug condition from an opportunistic infection [23], as both conditions can produce an indistinguishable pattern of involvement on imaging. In selected cases, an open lung biopsy can be performed and is required to rule out non-drug-induced conditions and to support the drug etiology, when a pattern consistent with the specific drug is found [28]. However, it is unclear whether determination of the exact histopathological pattern of involvement in drug-induced InLD translates into better outcomes. Acute Methotrexate Pneumonitis Acute methotrexate lung typifies acute drug-induced cellular interstitial pneumonia [55, 56]. The condition develops after variable times into treatment with the drug in ⬍1 to 12% of patients who receive the drug for hematologic malignancies or, mainly nowadays, rheumatoid arthritis. Risk factors include a background of rheumatoid lung involvement, advanced age, diabetes mellitus and a low serum albumin. The use of anti-TNF agents in conjunction with methotrexate may trigger the onset of

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methotrexate lung. Onset of methotrexate lung is heralded by dry cough, fever and shortness of breath, contrasted with a near-normal chest radiograph at onset. After a few days or 1–2 weeks, methotrexate lung rapidly accelerates, producing acute InLD with patchy dense or diffuse interstitial, ground-glass or alveolar shadowing with volume loss on the chest radiograph, and septal lines and widespread or patchy areas of alveolar shadowing on HRCT [57]. The BAL can be performed in the majority of patients suspect of having methotrexate pneumonitis, and is best done close to an ICU, where provision is made to correct the hypoxemia which almost invariably occurs during the procedure. Some patients will deteriorate during or shortly after the BAL, requiring mechanical ventilation for a few days. The BAL shows elevated CD4⫹ or CD8⫹ lymphocyte counts. Part of the variability in terms of lymphocyte percentage and/or subtypes in BAL may stem from when into the disease the BAL is performed, and whether corticosteroid drugs have been used to control the disease before BAL is done [58]. Infection with Pneumocystis jiroveci, Cytomegalovirus, Cryptococcus, herpes zoster and Nocardia have been described as a complication of chronic treatments with methotrexate [23], especially if blood CD4⫹ lymphocyte counts are below 150/␮l or cumulated doses of methotrexate are above 700 mg. Therefore, when a diagnosis of methotrexate pulmonary toxicity is entertained, it is crucially important to rule out an opportunistic infection using the BAL, since opportunistic pneumonias are similar in presentation to methotrexate lung, with no real clinical or radiological discriminators. Pneumocystis pneumonia with low microorganism counts can be particularly difficult to distinguish from methotrexate lung, and a lung biopsy may be needed to separate these two entities. In a review of 123 methotrexate pneumonitis cases, histological findings were available in 49 [55]. Cellular interstitial inflammation, fibrosis, ill-defined granulomas, and tissue eosinophilia were present in 71, 59, 35 and 18% of cases, respectively. Blood and tissue eosinophilia in methotrexate pneumonitis, when present, are mild and this condition is not an eosinophilic pneumonia. In the predominantly granulomatous form of methotrexate lung, involvement is usually patchy with intervening areas of normal tissue, or tissue showing moderate cellular interstitial pneumonia [55]. Hyperplasia of type II pneumocytes is a notable feature of methotrexate lung, but is less prominent than in ‘chemotherapy lung’, a classic complication of alkylating agents (see below). Frank pulmonary edema, diffuse alveolar damage and diffuse alveolar hemorrhage characterize those cases with severe hyperacute disease.

Classic diagnostic criteria [51] include otherwise unexplained breathlessness of recent onset, fever ⬎38⬚C, tachypnea (⬎28/min), diffuse pulmonary opacities, a PaO2 ⬍50 mmHg breathing room air, white blood cells ⬎1,000/␮l, lack of evidence for an infection in samples from blood, sputum, BAL for lung tissue, low lung volumes and diffusing capacity of carbon monoxide, and evidence for InLD on a lung biopsy specimen. The disease is deemed possible, probable or certain if 4, 5 or 6 criteria are fulfilled, respectively. Drug therapy withdrawal and high-dose intravenous corticosteroid therapy (e.g. methyl-prednisolone 60–240 mg b.i.d.) are recommended and are usually quickly followed by improvement. In the majority of patients, there is improvement of clinical symptoms and gas exchange in a few days, progressive clearing of pulmonary infiltrates [57] and amelioration of lung function over a few weeks, and normalization of lung volumes and the diffusing capacity in a few months. Long-term residual impairment of pulmonary function often is insubstantial. Methotrexate lung does not relapse in the absence of rechallenge [56]. Even though, in some patients, the disease did not recur following rechallenge with the drug, re-exposure is associated with relapse and death [51] and is therefore contraindicated. A mortality rate of 15% underscores the need for careful management of acute methotrexate lung [51]. How long corticosteroids should be given after an episode of methotrexate pneumonitis is an unresolved issue. Duration of corticosteroid therapy is guided by the clinical response, improvement on imaging, and requirements for controlling any basic condition for which methotrexate was prescribed, for instance rheumatoid arthritis. Our own experience indicates that 2–3 months with a slow taper should suffice in most cases. Pulmonary fibrosis following an episode of methotrexate pneumonitis is a possibility, although this is rare. Pretherapy chest radiograph and pulmonary physiology are indicated, particularly in rheumatoid arthritis patients [59]. Contrary to amiodarone, monitoring chest imaging and pulmonary function during therapy with methotrexate offers no protection and is unrewarding, since the disease often develops acutely and unexpectedly. Many of the features that characterize acute methotrexate pneumonitis, except granulomas, are also found in gold lung [60]. However, the incidence of gold lung has sharply decreased in the recent past, as the drug almost disappeared from the armamentarium of drugs used to treat rheumatoid arthritis. Gold lung also has an acute course, produces diffuse infiltrates with respiratory failure, cellular interstitial pneumonia on histology, and responds well to drug discontinuance


and corticosteroid therapy. There is lymphocytosis in the BAL, and gold lung may be a mimic of diffuse pulmonary infection. Overall, however, gold lung seems to have less severe a course than has methotrexate lung. Rechallenge with gold produces relapse of the condition. Other drugs capable of producing acute cellular interstitial pneumonia with acute respiratory failure similar to methotrexate or gold lung include fludarabine, imatinib, IFN-alpha, nilutamide, rituximab, sirolimus, trastuzumab, and venlafaxine (for a complete list, see [1]). Management of InLD occurring with the use of these drugs is similar to methotrexate lung. Acute Eosinophilic Pneumonia The major difference between acute drug-induced eosinophilic pneumonia and the above pattern resides in the presence of eosinophils in peripheral blood, BAL and/or lung tissue in eosinophilic pneumonia, as opposed to cellular interstitial pneumonia. Drugs causing eosinophilic pneumonia also are different and include amitryptiline, chloroquine, minocycline, sertraline, troleandomycin and venlafaxine, in addition to abused drugs (crack, cocaine, heroin, mephenidate and, possibly, marijuana) and acute exposure to tobacco smoke (for a complete list, see [1]). Drugs that produce eosinophilic pneumonia do not generally produce cellular nonspecific interstitial pneumonia and vice versa. On imaging in acute eosinophilic pneumonia, there is dense bilateral shadowing with, sometimes a peripheral subpleural distribution. Pleural effusion and mediastinal lymph node enlargement are occasional findings. The BAL can reliably establish the diagnosis of eosinophilic pneumonia, when it shows increased numbers and percentage of eosinophils, which can be as high as 80%. As in any case of eosinophilic pneumonia, parasitic infections must be excluded, as these require specific management and therapy. An open lung biopsy rarely is needed for the diagnosis of acute eosinophilic pneumonia. On histopathologic examination, there is tissue eosinophilia and a dense mononuclear cell infiltrate. Sometimes, the histopathologic features overlap with those of OP or, less commonly, eosinophilic vasculitis of Churg-Strauss syndrome. Patients with drug-induced acute eosinophilic pneumonia usually do well following drug discontinuance and corticosteroid therapy. The condition generally relapses if rechallenge is attempted. Severe cases of acute eosinophilic pneumonia may exhibit the features of drug rash and eosinophilia with systemic symptoms (DRESS), a generalized, life-threatening drug-induced condition with diffuse involvement of skin and internal organs, causing severe organ dysfunction (see below).

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Diffuse Alveolar Damage – ‘Chemotherapy Lung’ The chemotherapy lung is a subacute or acute lung reaction which complicates treatments with chemotherapeutic agents used as solo agents or, more often, as part of a multiagent chemotherapy regimen [20]. Drugs causing this condition include antineoplastic antibiotics (bleomycin, mitomycin C), alkylating agents (busulfan, cyclophosphamide, chlorambucil, melphalan), antimetabolites (azathioprine, aracytine, gemcitabine, fludarabine, 6-mercaptopurine, methotrexate), nitrosamines (bischloroethyl nitrosourea BCNU, chloroethyl-cyclohexyl nitrosourea CCNU and novel nitrosoureas), podophyllotoxins (etoposide, the taxanes paclitaxel and docetaxel), gefitinib, imatinib, irinotecan, granulocyte-stimulating/granulocyte monocyte colony-stimulating factors and all-transretinoic acid (ATRA) [1, 20, 61]. The condition occurs more frequently and tends to be more severe following exposure to multi-agent chemotherapy, as opposed to therapy with a single agent, if high doses of drugs are utilized, or if oxygen- and/or radiation therapy is given in conjunction with chemotherapy. Patients treated for solid tumors or hematologic malignancies, and recipients of bone marrow or stem cell transplant are at risk. It is unusual for this condition to follow exposure to noncytotoxic agents such as aspirin, methotrexate, nitrofurantoin, IFN-gamma, IL-2 or TNFalpha antibody therapy [1]. Pretreatment with corticosteroids may quench some forms of chemotherapy lung [61, 62]. Chemotherapy lung manifests with dyspnea, dry cough, diffuse pulmonary infiltrates with, generally, volume loss on imaging and hypoxemia. The density of pulmonary infiltrates ranges from discrete and diffuse haze or ground-glass in early cases, to widespread opacification in more advanced cases [29, 52, 53, 63]. On HRCT, there are ground-glass or linear opacities, inter- or intralobular thickening and, later, develops alveolar shadowing. The chemotherapy lung must be differentiated from cardiogenic edema, overload pulmonary edema, transfusion-related lung injury, alveolar hemorrhage and opportunistic pulmonary infections, to which the chemotherapy lung resembles [20]. Tools used to segregate these entities include forced diuresis and BAL, complemented with appropriate microbiological techniques on BAL fluid. A confirmatory lung biopsy is often not requested due to the lack of specific histopathological features in chemotherapy lung, or is not feasible due to the severity of the underlying illness, or because acute respiratory failure is present. On histology, there is the combination of cellular inflammation, interstitial and alveolar edema, diffuse alveolar damage and hyaline membranes, alveolar fibrin or OP, reactive or dysplastic type II cells and

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early interstitial fibrosis. These changes are suggestive but not specific for the drug etiology. Response of the chemotherapy lung to corticosteroid therapy is unpredictable. However, a trial with corticosteroids is indicated, once chemotherapy lung is diagnosed. In early cases, corticosteroid therapy may result in significant improvement, whereas in later or severe cases, the response is poor or transient, with accelerated pulmonary fibrosis or an ARDS picture as a terminal event [20]. Occurrence of chemotherapy lung negatively impacts on the management of the basic disease if a change in therapy is required towards less efficacious drugs. Acute Amiodarone Pulmonary Toxicity [14, 64] Early acute APT can occur after a few days on high-dose intravenous amiodarone particularly, but not exclusively so, after thoracic or cardiac surgery [65]. Patients with a recent history of lung resection for lung cancer are at risk. A study in such patients in whom amiodarone was used prophylactically to prevent arrhythmias showed that the incidence of ARDS increased 6-fold, compared to unexposed controls [66]. Thus, routine use of amiodarone in this setting is discouraged. Acute APT manifests with dyspnea, diffuse alveolar shadowing, volume loss, hypoxemia, respiratory failure and/or an ARDS picture. Pulmonary edema, coincidental infection, postoperative atelectasis, thromboembolic disease and lung cancer must be ruled out carefully by means of diuresis, cardiac ultrasound, BAL and, if needed, measurement of pulmonary capillary wedge pressure. The BAL in acute APT may exhibit lipid-laden macrophages, a hallmark of APT, even in patients recently exposed to the drug. The finding of dyslipidotic cells in BAL may help inititate corticosteroid therapy, which can be used as a diagnostic tests, since the clinical and imaging manifestations of APT may quickly reverse under this form of therapy. In selected cases, an open lung biopsy is indicated. Histological findings include resolving diffuse alveolar damage, fibrinous OP, interstitial edema and fibrosis, superimposed on the background of dyslipidotic changes typical of APT. Mortality in acute APT is substantial (up to 40–50%), despite amiodarone therapy withdrawal and high-dose corticosteroid therapy. Classic APT can present acutely, after months or years into treatment with the drug. Symptoms include dyspnea, fever, diffuse fluffy opacities, and hypoxemia. Amiodarone pneumonitis with an acute presentation is characterized by lymphocytosis in the BAL and consistent response to corticosteroid therapy [14]. Acute Pulmonary Edema [1, 19] Drug-induced pulmonary edema generally is closely related to drug administration. Frank pulmonary edema

may be preceded by several episodes of dyspnea or flu-like symptoms during previous courses with the drug, that resolved spontaneously after cessation of exposure or with corticosteroid therapy. These may be interpreted as mild undiagnosed bouts of drug-induced pulmonary edema, and should be looked for at history taking. Drug-induced pulmonary edema can develop within minutes after the first administration of the causal drug or later into treatment, especially with aspirin. Aspirin produces a form of pulmonary edema related to blood levels of the drug. Druginduced pulmonary edema manifests with dyspnea, diffuse interstitial infiltrates and, in advanced cases, alveolar shadowing. Acute respiratory failure or an ARDS picture characterize those cases with severe pulmonary edema. Rarely, an abundant foamy exudate with a high fluid:plasma protein ratio is present at the mouth or in ventilator tubings, or alveolar hemorrhage is present as an associated feature. Significant weight gain suggests generalized capillary leak. Drug-induced pulmonary edema is generally noncardiogenic (NCPE), and results from an increase in capillary permeability elicited by the drug, in lung and sometimes in other organs. The noncardiac nature of pulmonary edema is confirmed by the normalcy of heart size on imaging, ultrasound evaluation, and pulmonary capillary (wedge) pressure. Histopathologic appearances include interstitial edema or fibrinous OP in early cases, and bland edema with proteinaceous fluid filling most alveolar spaces in severe cases. Several types of drug-induced pulmonary edema are recognized: • Drug-induced NCPE is a classic complication of drug overdoses (e.g. of nifedipine, heroin (the ‘heroin lung’), and tricyclic antidepressants). This form of edema may quickly improve following withdrawal of drug therapy, gastric lavages and mechanical ventilation, cause sudden death as in the heroin lung, or evolve toward an ARDS picture. • NCPE can occur as a complication of treatments with therapeutic doses of narcotic analgesics, aspirin, intravenous ␤-2 agonists, colchicine, cyclophosphamide, adrenalin/epinephrine, intrathecal methotrexate, nitrofurantoin, noramidopyrine, NSAIDs, opiates, quinine, radiographic contrast media, thiazolidinediones (glitazones), vasopressin and vinorelbine. Rarely, NCPE occurs in association with hyperacute methotrexate-, gold- or nitrofurantoin-induced acute cellular interstitial pneumonia [1, 19]. • NCPE and generalized capillary leak may develop following treatments with all-trans retinoic acid, cytarabine, gemcitabine, interleukin-2 and taxanes [1, 19, 67].


• NCPE has been described in patients with pulmonary hypertension receiving nifedipine, prostacyclin or nitric oxide [1]. • A peculiar form of pulmonary edema follows transfusion of whole blood or blood products, including packed red blood cells, platelets, fresh frozen plasma, plasmaderived coagulation factors, immunogobulins, and allogeneic stem cells [68–70]. Transfusion-related acute pulmonary reactions typically develop within hours or less of transfusion, in the form of chills, fever, low blood pressure, dyspnea, bilateral alveolar opacities, hypoxemia, leukopenia and mild eosinophilia. Some patients develop an ARDS picture. Based on the severity of pulmonary involvement, oxygen therapy and mechanical ventilation may be required. Post-transfusion pulmonary edema results either from circulatory overload and is coined ‘TACO’ for transfusion-associated circulatory overload, or from transfusion-related lung injury (TRALI) [18, 69, 71]. TACO and TRALI can occur independently or in association. TRALI can be further subdivided into immune and nonimmune TRALI [72]. In immune TRALI, granulocyte-binding alloantibodies (complement-activating HLA class I or II granulocytespecific, or lymphocytotoxic antibodies) are passively transferred from one donor in the pool of donors to the recipient, whose leukocytes express the cognate antigens. This results in antibody:antigen interaction, complement-mediated activation of neutrophils, loss of integrity of the endothelial barrier and pulmonary capillary leak. Nonimmune TRALI results from the transfer of biologically active lipids or CD40 ligand present in stored blood. These substances also have neutrophilpriming activity and this also results in endothelial cell damage and capillary leak. Immune TRALI occurs mainly after the transfusion of fresh-frozen plasma and platelet concentrates, is less common (incidence about one per 5,000 transfusions) and is more severe (mechanical ventilation required in about 70% of cases; fatality rate 6–10%) than nonimmune TRALI. In contrast, nonimmune TRALI occurs mainly after the transfusion of stored platelet and erythrocyte concentrates. Management of posttransfusional pulmonary edema rests on oxygen therapy, ventilatory support and supportive care. In TACO, fluid restriction and diuresis are indicated. In TRALI, the exaggerated capillary permeability may have caused fluid loss. Therefore, diuretics are not indicated, as they may cause further fluid loss with consequent hemodynamic compromise. TRALI has the reputation for being poorly known and for being diagnosed suboptimally [73]. However,

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diagnosing immune TRALI is critically important and has far-reaching consequences. Since the condition results from the transfer of antibodies, the specific donor should be identified and blood products from that donor should be quarantined until the diagnosis of TACO vs. nonimmune or immune TRALI is clarified. When identified, the donor (generally a woman with a history of two or more pregnancies) is permanently deferred form blood donation [74]. • There are a few convincing cases of cardiac pulmonary edema following drug-induced myocardial injury [75]. The condition has been described after exposure to cyclophosphamide, doxorubicin, fluorouracil, interleukin-2, propranolol and abused thyroid hormone. Improvement may follow drug therapy withdrawal. Acute Alveolar Hemorrhage [21] Drug-induced diffuse alveolar hemorrhage (DAH) consists of diffuse bleeding from the pulmonary microcirculation to the alveolar spaces, with or without histologically demonstrable pulmonary capillaritis. Drug-induced alveolar hemorrhage occurs either in isolation (bland alveolar hemorrhage), as a complication of drug-induced thrombocytopenia, or in association with involvement of the kidney or other internal organs suggesting drug-induced pneumorenal syndrome and/or micropolyangiitis. Drugs causing bland alveolar hemorrhage include abciximab, oral anticoagulants, allopurinol, aspirin, ATRA, azathioprine, clopidogrel, fibrinolytic agents, methotrexate, nitrofurantoin, phenytoin, propyl-thiouracil, retinoic acid, abused silicone, sirolimus or tirofiban. DAH also occurs as a complication of bone marrow grafting (for a complete list, see [1]). Accidental, deliberate or surreptitious poisoning with superwarfarins also causes DAH. Hydralazine, penicillamine or propylthiouracil produce alveolar hemorrhage in association with renal involvement and/or systemic symptoms mimicking naturally-occurring Goodpasture’s or Wegener’s disease [31, 76]. Patients may present with positive ANCA testing and a perinuclear (p-ANCA) staining pattern with myeloperoxidase, lactoferrin, or elastase specificity, contrasted with the cytoplasmic c-ANCA staining pattern and proteinase 3 specificity of idiopathic Wegener’s. In contrast, antiglomerular basement membrane antibodies are a rare finding in drug-induced alveolar hemorrhage, and characterize naturally-occurring Goodpasture’s. Rarely, DAH occurs as a complication of hyperacute gold, methotrexate or nitrofurantoin pneumonitis, or in the context of severe drug-induced pulmonary edema [1]. Diffuse alveolar hemorrhage is diagnosed by BAL, which demonstrates increased bleeding in serial aliquots.

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Microscopically, the BAL shows red cells. Hemosiderin-laden macrophages in the BAL characterize those cases with subacute or chronic bleeding prior to full-blown DAH [21]. A lung biopsy seldom is indicated to diagnose DAH, as this may show the predictable changes of alveolar hemorrhage, and evidencing capillaritis may not radically change the treatment approach. Drug-induced DAH manifests with dyspnea, profound anemia and alveolar infiltrates, which may assume a batwing pattern. Hemoptysis is not a constant finding, even though significant alveolar bleeding has occurred. An increase in the diffusing capacity suggesting free hemoglobin in airspaces may be present in patients with active alveolar bleeding; however, this is not a consistent or reliable finding. Diffuse alveolar hemorrhage with systemic involvement may manifest with fever and arthralgias, in addition to the above findings. Diffuse alveolar hemorrhage requires expeditious management, as the disease can be rapidly progressive. Pulmonary complications include clotting in the airspaces, causing the ‘stone lung’, or clotting in the large airways causing life-threatening large or upper airway obstruction. Drug therapy withdrawal and supportive care may suffice in patients with moderate DAH. Patients with alveolar hemorrhage and persistent bleeding despite drug therapy discontinuance, or those with evidence for multiorgan involvement are considered for treatment with vitamin K infusions, fresh frozen plasma, activated factor VIIa, corticosteroids, immunosuppressive drugs, plasma exchange and mechanical ventilation. Acute Organizing Pneumonia Circumstantial evidence relates exposure to amiodarone, nitrofurantoin, d-penicillamine, and HMG-CoAreductase inhibitors (statins) to acute OP or acute fibrinous OP [1]. Acute OP is unusual and characterized by dyspnea and dense pulmonary infiltrates with air bronchograms. Since there is no distinctive BAL pattern associated with drug-induced acute OP, a confirmatory lung biopsy may be required, patient status permitting. Evaluation of drug causality is difficult, since acute OP can occur sporadically with no identifiable cause, or occurs unexpectedly in connective tissue diseases. Response to drug therapy withdrawal and corticosteroid therapy is unpredictable. Transient Pulmonary Infiltrates Drug-induced ‘transient pulmonary infiltrates’, as coined in the literature, are difficult to classify. These appear as discrete, fleeting pulmonary opacities during or shortly after exposure to antithymocyte globulin, bleomycin, chemotherapeutic agents, crack cocaine, intravenous

immune globulins, hydrochlorothiazide or nitrofurantoin [1]. Transient pulmonary infiltrates can also occur shortly after liposuction [77] or vertebroplasty with methacrylatebased cement [78]. Dyspnea and chest pain can be disproportional to the changes on imaging, which may be minimal. The histopathological background of transient pulmonary infiltrates is generally unknown, with edema, angiitis, cellular pneumonia, fibrinous or vague OP documented in a few cases. Withdrawal of the causal agent is usually followed by rapid resolution of all manifestations of the disease, which will relapse upon rechallenge, often with greater severity leading to NCPE or ARDS [79].

Subacute and Chronic Drug-Induced Infiltrative Lung Disease All of the above patterns of drug-induced InLD can occur in a diminutive form (1) if the drug etiology is suspected in time and the drug is discontinued early, (2) if the reaction is quenched by corticosteroid therapy, or (3) because some drugs intrinsically produce a mild pulmonary reaction [1]. Cellular Interstitial Pneumonia – Cellular Nonspecific Interstitial Pneumonia Many cases of drug-induced cellular-interstitial pneumonia, which is also called cellular nonspecific interstitial pneumonia (NSIP) have a benign course characterized by moderate dyspnea, cough, fever, diffuse pulmonary infiltrates and hypoxemia. Drugs causing this condition include ␤-blockers, chlorambucil, flecainide, fludarabine, fluoxetine, gold, maprotiline, mesalazine, nilutamide, nitrofurantoin, procainamide, simvastatin, sirolimus and sulfasalazine (for a complete list, see [1]). Although methotrexate pneumonitis generally has an acute presentation, some patients with methotrexate lung present with an attenuated pattern of reaction, and a mild clinical course [57]. Imaging studies indicate bilateral, roughly symmetrical linear or, less often, micronodular interstitial opacities, diffuse haze or alveolar infiltrates. The opacities may localize in the caudal, mid- or upper zones of the lung, or they can be diffuse. Radiographic attenuation can be discrete haze or ground-glass, patchy or dense disseminated areas of consolidation. Pleural effusion and mediastinal lymphadenopathy are occasional findings. On HRCT, there is intra- or interlobular septal thickening, a crazy-paving appearance, or zonal increases in attenuation with a groundglass or mosaic pattern [52, 53, 63]. Restricted lung volumes, low carbon monoxide diffusion and hypoxemia


generally are proportional to the changes on imaging. The BAL is indicated to exclude an infection and supports the drug etiology, when it shows a lymphocyte predominance and an increase in either CD4⫹ or CD8⫹ lymphocyte subsets [30]. An increase in neutrophils in the BAL, or a mixed increase in lymphocytes, neutrophils and/or eosinophils can sometimes be found [30]. Most cases of mild drug-induced nonspecific interstitial pneumonia have a benign course and respond well to drug therapy withdrawal with or without corticosteroid therapy. Histopathologic appearances include cellular interstitial inflammation and edema and, sometimes, areas of OP or moderate fibrosis. A risk-benefit evaluation of lung biopsy vs. conservative or ‘lean’ management in drug-induced InLD is not available. However, the absence of really specific findings on histopathologic examination of the lung in this setting does not justify the routine use of lung biopsy to diagnose this condition. Outcomes of patients with mild drug-induced cellular interstitial pneumonia is good, provided the causal drug is discontinued early, otherwise the disease may accelerate unexpectedly, producing acute respiratory failure or an ARDS picture. Corticosteroid therapy is indicated if extensive opacities or significant hypoxemia are present, and in patients in whom drug discontinuation does not unequivocally translate into betterment in a few days. Rechallenge with the drug may lead to relapse with an increase in severity. Therefore, patients should be instructed to avoid inadvertent exposure to the drug. The development of pulmonary fibrosis following recognition and treatment of this condition is unusual except, perhaps, following methotrexate pneumonitis superimposed on a background of rheumatoid lung injury. Pulmonary Infiltrates and Eosinophilia Drug-induced pulmonary infiltrates and eosinophilia (PIE) also known as eosinophilic pneumonia can be caused by a multitude of drugs or agents including ACEIs, antibiotics (minocycline, sulfamides), aspirin, tricyclic antidepressants (amitriptylline, clomipramine), carbamazepine, chloroquine, IFN, iodinated radiographic contrast material, maprotiline, mesalazine, minocycline, inhaled or parenteral pentamidine, phenytoin, pyrimethamine, radiation therapy, sertraline, trazodone, venlafaxine, the sulfamides sulfasalazine and sulfamethoxazole [1, 12]. In the 1990s, ltryptophan produced a systemic condition called the eosinophilia myalgia sydrome or EMS. More than one drug in a therapeutic class (e.g. several antibiotics, tricyclic antidepressants, ACEIs, NSAIDs, sulfamides) may cause the PIE syndrome [1]. Leukotriene receptor antagonists may produce Churg-Strauss vasculitis. Minocycline and anticonvulsants may induce PIE with systemic symptoms, a

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generalized condition known as the DRESS syndrome (see below) [80]. Patients who develop drug-induced PIE do so after a few weeks to a few months, rarely several years into treatment. There may be a history of repeated exposure to the drug followed by relapsing symptoms of intolerance, forcing patients to stop the drug temporarily before full-blown PIE develops. Patients with PIE present with malaise, dyspnea, dry cough, low-grade fever, chest discomfort, pulmonary infiltrates and, sometimes, a skin rash is present. Involvement of organs other than the lung (e.g. heart or nervous system) can be present, particularly in patients with marked blood eosinophilia, or in those with ChurgStrauss vasculitis or DRESS. Opacities in PIE can localize in the apices, mid-lung zones, bases, or they can be diffuse. The classic pattern of biapical subpleural opacities known as the photographic negative of pulmonary edema certainly is a distinctive appearance on imaging in PIE. However, this pattern is not seen in every patient. Occasionally, the opacities of PIE wander from one area of the lung to another, or appear as discrete non-migratory shadowing with a ground-glass appearance, or as bibasilar Kerley ‘B’ lines. PIE may be scaled down to barely visible haze and BAL eosinophilia. An eosinophilic pleural exudate or enlargement of the mediastinal lymph nodes are occasional findings. On HRCT, opacities of PIE range from a discrete haze to patchy subpleural crescentic shadowing, or multifocal areas of consolidation with air brochograms. Pulmonary infiltrates and eosinophilia may be at times difficult to separate clinically and on imaging from OP, cellular interstitial pneumonia or interstitial cardiac edema. Pulmonary infiltrates and eosinophila are diagnosed by the presence of peripheral eosinophilia, which can be as high as 80%, along with an increase in eosinophils or in eosinophils and lymphocytes in BAL [30, 81], and/or eosinophilia in lung tissue. Sometimes, peripheral and/or BAL eosinophilia is insignificant, and the diagnosis is made on BAL and/or histopathological examination of lung tissue, which shows an interstitial infiltrate of eosinophils admixed with mononuclear cells. Clusters of eosinophils may be noted around small pulmonary arteries, but active vasculitis is unusual and raises the suspicion of ChurgStrauss syndrome. OP is a common incidental finding in PIE and separating PIE from OP may be problematic if patients present with overlapping features of the two conditions [28]. Relating PIE to drug exposure is straightforward in patients exposed to one eligible drug and/or if drug therapy withdrawal is rapidly followed by improvement of symptoms, imaging and eosinophilia. If needed, corticosteroid therapy will accelerate the resolution of all manifestations

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of PIE, at the expense of drug causality assessment, as PIE responds to this form of therapy almost regardless of its cause. Rechallenge with the causative medicine leads to recurrence of systemic symptoms, blood and BAL eosinophilia and pulmonary infiltrates. Apparently, rechallenge carries little risk, as malaise, fever and blood eosinophilia can easily be monitored and act as early markers of relapse. However, the diagnostic contribution of rechallenge is unclear, especially if drug therapy withdrawal without corticosteroid therapy was followed by improvement, and if an alternate drug is available to treat the basic disease. In some patients who developed PIE as a result of exposure to bowel-disease-modifying drugs (mesalazine, sulfasalazine), rechallenge with the purpose of inducing tolerance was attempted using incremental doses of the drug up to the full therapeutic dose, with no relapse of PIE and maintained control of the background bowel disease [82]. Amiodarone Pulmonary Toxicity – Amiodarone Pneumonitis [14, 36] Pulmonary toxicity from the antiarrhytmic drug amiodarone was first described in 1980. During long-term treatments, amiodarone accumulates in many organs including the lung, achieving tissue concentrations above cytotoxic thresholds. The main metabolite of amiodarone, desethylamiodarone, also accumulates in lung and does so to a greater extent than the parent compound. Desethylamiodarone is equitoxic to amiodarone. Two iodines on each molecule of both amiodarone and desethylamiodarone account for the high attenuation numbers found in the liver and in the areas of amiodarone pneumonitis in some patients, a suggestive feature of amiodarone exposure and pulmonary toxicity, respectively. Amiodarone and metabolite cause a progressive disturbance of endogenous phospholipid catabolism. Consequently, phospholipids and phospholipid-drug complexes accumulate in lung, causing a form of lipid storage disease. Amiodarone and metabolites efflux very slowly from lung and other tissues after drug withdrawal. Significant levels of both compounds can be found in lung and other tissues several months after drug discontinuation. All of the above features account for several distinctive characteristics of APT, such as its insidious onset, target organs corresponding to tissues where amiodarone accumulates most, high attenuation numbers on HRCT, evidence of dyslipidosis in BAL cells or lung tissue, sluggish improvement following drug discontinuation, possible relapse when steroids are tapered too swiftly, even though the drug has been withdrawn months earlier, and possible development after termination of treatment with

the drug. The beneficial effect of corticosteroid therapy in the majority of patients indicates that APT probably is also an inflammatory condition. Corticosteroid therapy may serve as a diagnostic test to differentiate APT from other non-steroid-sensitive conditions (e.g. pulmonary edema), without recourse to the lung biopsy. The main risks of APT are a presentation with acute respiratory failure or an ARDS picture, lack of response to drug therapy withdrawal plus corticosteroid therapy, the development of pulmonary fibrosis, complications of long-term corticosteroid therapy including opportunistic infections, and the risk of arrhythmic death following amiodarone therapy withdrawal. The incidence rate of amiodarone pneumonitis is a function of both daily dose and duration of treatment, and ranges from 0.1% in patients on low doses (100–200 mg/day) to 50% in patients exposed to high doses (⬎1,200 mg/day) of amiodarone. Onset of APT is after a few weeks and up to several years into treatment (18–24 months on average). Due to patient- and physician-related factors, APT is generally diagnosed 2 months on average after the onset of clinical symptoms. Early onset of APT after a few days on amiodarone is unusual, except if large loading doses of amiodarone are utilized. Clinically, APT manifests insidiously, with gradual weight loss, malaise, dyspnea, dry cough, slight fever and, sometimes, pleuritic chest pain. Crackles or moist rales are a common finding at auscultation, and a friction rub may be present. Leukocytosis, an increased blood LDH level and a raised erythrocyte sedimentation rate are common. The two latter findings can predate the clinical onset of APT. The role of serum brain natriuretic peptide levels in distinguishing APT from pulmonary edema is imprecise, inasmuch as patients may present with an association of both conditions [83]. Adverse effects of amiodarone in the liver or thyroid are occasionally present in association with the pulmonary toxicity and appropriate tests are required to detect these complications. A hyperthyroid state may increase the perception of dyspnea in APT and may also deteriorate left ventricular function, with consequent pulmonary edema superimposed on APT. Amiodarone pulmonary toxicity is a disease of the alveolar and interstitial compartment, and may therefore exhibit interstitial, alveolar or mixed opacities on imaging. It is easy to be misled in cases with subtle or unilateral involvement, when the disease develops on a background of prior infiltrative lung disease, pulmonary edema or emphysema, or when APT develops after amiodarone therapy withdrawal. Amiodarone pulmonary toxicity manifests with distinctive changes on imaging, and each patient seems to have a distinct pattern of involvement. Radiographic appearances in


APT include dense uni- or bilateral, often asymmetrical interstitial or alveolar infiltrates, which may involve any area of one or both lungs, including the apices. Areas of involvement in APT often abut the pleura, which can be thickened en face in the involved area. A loss of volume is generally present in the areas of greatest involvement. Opacities in APT sometimes assume a recognizable lobar or segmental distribution with partial atelectasis simulating pneumonia, OP, primary lung cancer, bronchoalveolar carcinoma, or primary pulmonary lymphoma. There is an impression that the right lung (mainly the right-upper lobe) is more frequently involved than the left lung. Patients may present with unilateral involvement on the chest radiograph, however, involvement of the opposite lung generally is detectable on HRCT. Less common patterns of APT include a coin lesion, a lone mass, multiple masses with a center of decreased attenuation on CT simulating pulmonary infarction, pneumonia or lung cancer. Uncommonly, APT presents in the form of multiple shaggy nodules with the halo sign, corresponding to attenuated amiodarone pneumonitis peripherally. On HRCT, the involvement often is patchy, scattered and asymmetrical, with areas of haze, ground glass, alveolar shadowing, crazy paving, inter- or intralobular linear opacities or dense consolidation or mass(es) with high attenuation numbers. Pleural thickening is confirmed en face the areas of parenchymal involvement. In a study of 20 patients with moderate APT [84], ground-glass opacities were present in all 20 patients, areas of consolidation were found in 4, and intralobular reticulations in 5. A subpleural distribution of the opacities was more common than a central distribution (in 18 vs. 2 patients). High density in the area of APT was present in 8 of the 20 patients. In advanced disease, increased attenuation seems a more consistent finding [85]. An exudative pleural effusion is occasionally present in association with parenchymal disease, but rarely occurs in isolation. Logically, the expression of APT on imaging is attenuated and the impact on gas exchange is greater in patients with a background of pulmonary emphysema, presumably because less tissue is available for expression of the disease. Patients on amiodarone may present with subclinical pulmonary infiltrates. Although such pulmonary infiltrates may correspond to scattered areas of early APT, their significance often remains unclear, and amiodarone therapy withdrawal is not a requisite. A positive 67Ga scan or definite cellular changes in BAL may help suspect early APT. Serial follow-up with continued exposure to the drug is required, to monitor whether the infiltrates will progress to overt APT or disappear with time. Interpretation of pulmonary function tests in APT is often against a background of airway obstruction from

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prior smoking, or restrictive lung dysfunction from left ventricular failure, two common conditions in patients on amiodarone [83]. Restrictive lung disease, decreased diffusing capacity for carbon monoxide (CO) and hypoxemia are present in clinically significant APT, and these changes are more in patients with extensive disease. The earliest functional abnormality in APT is a precipitous and consistent decrease in the diffusing capacity for CO. Left ventricular failure, pulmonary edema and simple exposure to amiodarone alter this measurement to a lesser extent than does APT. Conversely, an isolated decrease of the diffusing capacity does not necessarily indicate disease, as overt APT will develop in a third of such patients. A wide range of abnormalities can be found in the BAL in APT [30, 86]. The most consistent finding is the presence of numerous foam cells, which contain osmiophilic lamellar inclusions on electron microscopy. Foam cells are a routine finding during treatments with amiodarone and indicate chronic exposure to the drug, not necessarily toxicity [87]. However, the absence of foam cells in the BAL is against the diagnosis of APT. Shifts in other cell types in APT include an increase in neutrophils, lymphocytes or in both cell types. A normal distribution can be found in authentic APT. Lymphocytosis in BAL suggests inflammation and denotes a shorter time to onset, correlates with diffuse fluffy opacities on imaging and predicts response of APT to corticosteroid therapy. Lone eosinophilia and alveolar hemorrhage are rare findings in APT. Like most drug-induced InLD, APT is a diagnosis of exclusion. An open lung biopsy is rarely deemed necessary, since patients may deteriorate after the procedure and risk may outweigh benefits [83]. A lung biopsy is indicated, however, to confirm or exclude APT in patients with severe ventricular arrhythmia in whom develop pulmonary opacities and there is no substitute for amiodarone, or in patients considered for valvular replacement or heart transplantation, in whom the diagnosis of pulmonary infiltrates must be secured before surgery is planned. Histopathological appearances of APT include septal thickening by interstitial edema, nonspecific inflammation, interstitial fibrosis, and lipids in interstitial, endothelial and alveolar cells, and lying free in alveolar spaces [64, 88]. A large number of free foamy macrophages in alveolar lumens supports the diagnosis of APT. These cells may be so numerous as to mimic desquamative interstitial pneumonia. Other findings include organizing or fibrinous OP, reactive changes in type II cells and mutilating interstitial fibrosis. Active or resolving diffuse alveolar damage and hyaline membranes characterize those cases with acute presentation or an ARDS picture (see above). In most patients it is reasonable to narrow down the

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diagnostic possibilities by such noninvasive tests as forced diuresis, BAL and cardiac evaluation and then to proceed with withdrawal of drug therapy (underlying arrhythmia permitting), using corticosteroid therapy as a diagnostic test if indicated. Since amiodarone withdrawal alone is often not followed by improvement, and because persistent APT may lead to irreversible pulmonary fibrosis in a few weeks, corticosteroid therapy is indicated in most cases with ‘significant’ APT. When indicated, corticosteroid therapy should be given for several months (although there is no study to support this, our group usually advises a 6- to 12-month duration of treatment with tapered dosage). A slow taper is essential, otherwise APT may relapse once or several times owing to the persistence of elevated amiodarone levels in the lung after amiodarone therapy withdrawal. Relapse of APT following steroid tapering is a classic feature of APT and the relapse may be more difficult to control. Mortality in APT is about 10% in ambulatory patients. The attrition rate is substantially higher (20–33%) in patients who are diagnosed late, or in those who require admission to the hospital for the treatment of their condition. Should regular chest radiographs be taken and pulmonary physiology be measured in patients receiving amiodarone long term? [89]. No guidelines exist and practices vary widely. A chest radiograph should be taken prior to the commencement of treatment with amiodarone, to detect prior abnormalities to which any change occurring later can be compared. During treatment, the chest radiograph can be monitored at regular intervals, e.g. every 4–12 months depending on drug dosage, and/or whenever develop unexplained changes in symptoms. Two to three sets of pulmonary function tests (lung volumes and diffusing capacity) at the time and shortly after amiodarone is instituted will serve as reference baseline to which any further change can be compared. Routine follow-up of pulmonary physiology is unrewarding, as APT may develop rapidly between two sets of measurements, and modest decrements in lung function and diffusing capacity are common during long-term treatments with amiodarone and do not equate clinical toxicity. An isolated reduction of the diffusing capacity should not prompt discontinuation of amiodarone, unless there is clinical or imaging evidence for APT, because amiodarone withdrawal carries a risk of recurrence of arrhythmia. Instead, an isolated reduction of the diffusing capacity commands repeated measurement of this parameter over a shorter period of time. A stable diffusing capacity and imaging with time will indicate lack of clinically meaningful APT. In practice, pulmonary function and diffusing capacity should be reevaluated only if otherwise unexplained symptoms or pulmonary infiltrates

develop. Self-reporting of symptoms, serial clinical evaluation and occasional chest imaging are indicated in any patient receiving amiodarone longterm. This is an easy and meaningful way to detect APT early. Drug-Induced Organizing Pneumonia [15] The diagnosis of OP, formerly known as bronchiolitis obliterans OP or BOOP, rests on the finding of ductal and/or alveolar fibrosis in conjunction with interstitial inflammation as the dominant histopathological features. OP has many recognized causes and contexts other than drugs or radiation therapy [90], making evaluation of causality difficult. Drug-related OP was recognized in the 1950s during treatments with the early antihypertensive drugs hexamethonium and mecamylamine, which have long been recalled. Later, nodular OP simulating pulmonary metastases on HRCT was described following treatments with bleomycin in children as well as in adults [91]. Eventually, amiodarone, ␤-blocking agents, carbamazepine, ergolines, gold, IFN-alpha and -beta, methotrexate, minocycline, nitrofurantoin, penicillamine, sulindac and breast radiation therapies were implicated. Circumstantial evidence relates OP with ACEI, NSAIDs, inhibitors of 3-hydroxy-3-methyl glutaryl-coenzyme-A reductase (statins), and a few other drugs [1]. Clinically, OP manifests with malaise, dyspnea, lowgrade fever and, sometimes, pleuritic chest pain. Typically, the disease is suspected when migratory opacities are seen on serial chest films taken over a few weeks or months. There may be intervening periods with a perfectly normal chest radiograph, despite continued exposure to the causal drug. In other cases, opacities are in the form of a lone mass or masses, which sometimes assume a recognizable segmental or lobar distribution. Patchy shadowing with air bronchograms along the bronchovascular bundles suggest nitrofurantoin-induced OP [52, 92]. Other imaging patterns include multiple shaggy nodules with the use of bleomycin, carbamazepine, minocycline, or statins, elongated dense biapical subpleural masses containing air bronchograms with the use of mesalazine or sulfasalazine in inflammatory bowel disease [82], and dense diffuse pulmonary infiltrates with the use of IFN, nitrofurantoin or d-penicillamine [93]. Although lymphocytes and sometimes neutrophils and/or eosinophils can be increased in the BAL, no distinctive BAL pattern is described in association with drug-induced OP. If a lung biopsy is deemed necessary to confirm the diagnosis, the open approach is preferred to the transbronchial route, since alveolar or ductal fibrosis is an incidental finding in numerous other conditions, including infectious pneumonia, eosinophilic pneumonia, aspiration,


and atelectasis distal to airway obstruction [90]. Histology in OP reveals the dominant background of alveolar and ductal fibrosis, superimposed on widespread interstitial inflammation. Dyslipidosis suggestive of amiodarone pulmonary toxicity can be present in conjunction with the classic features of OP in amiodarone-induced OP. In a fraction of patients with drug-induced OP, tissue eosinophilia is present, making the recognition of organizing from eosinophilic pneumonia difficult. Acute fibrinous OP (AFOP) is a recently recognized entity, which shares several features with classic OP, including exposure to drugs [94]. On histology in AFOP, there is intra-alveolar fibrin and OP associated with varying amounts of type II cell hyperplasia, interstitial edema and acute or chronic inflammation [94]. There is the impression that the course of AFOP is more severe than that of OP. Distinguishing OP due to drugs from cryptogenic OP, or OP associated with a background connective tissue disease can be problematic. Indeed, OP has been described in association with, sometimes as an early manifestation of rheumatoid arthritis, systemic lupus erythematosus, polymyositis, polymyalgia rheumatica and inflammatory bowel disease [82, 95]. Also, the histopathological features of OP are similar regardless of its cause, except in amiodarone-induced OP, where dyslipidotic changes can still be present at the time of biopsy. In patients with moderate symptoms, drug discontinuance is justified and follow-up will indicate whether signs and symptoms of OP abate, supporting the drug etiology. Patients with OP improve with corticosteroid therapy regardless of its etiology. Therefore, corticosteroid therapy cannot be used as a diagnostic test to separate druginduced OP, from OP due to other causes. Not all patients with migratory pulmonary opacities and a background of compatible exposure to drugs have OP, as the same imaging pattern can be seen in the pulmonary infiltrates and eosinophila syndrome, and BAL may not separate the two conditions well. In patients with migrating opacities and mild symptoms, the lung biopsy may not be justified and the patient may be observed after drug therapy withdrawal, which serves as a diagnostic test. Disappearance of symptoms and pulmonary opacities will support the drug etiology, even though the histopathologic background remains unclear. Should drug discontinuation not be followed by improvement within a few weeks, then a trial of corticosteroid therapy or a lung biopsy are indicated. Multiple relapses of pulmonary infiltrates can occur when the drug etiology is not recognized, even though significant dosages of corticosteroid drugs are given, requiring repeated courses or augmented dosage of corticosteroids. Due to the

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persistence of amiodarone in lung, OP due to therapy with that drug may relapse after steroids are tapered, even though the amiodarone was withdrawn weeks or months earlier. Prolonged use, augmented dosage or reinstatement of corticosteroid therapy is indicated, until amiodarone has washed out of the lung. Desquamative Interstitial Pneumonia Desquamative interstitial pneumonia is a rare pattern of lung response to amiodarone, nitrofurantoin or IFN. The condition is diagnosed on histopathology [1, 96]. Pulmonary Fibrosis • Paraquat is a herbicide chemical that may be ingested accidentally or deliberately in a suicide attempt. In survivors, paraquat produces acute lung injury followed by pulmonary fibrosis in a few weeks [97]. Very few drugs, aside from amiodarone, produce a similar pattern of lung reaction. • Pulmonary fibrosis is a complication of treatments with chemotherapeutic agents (bleomycin, busulfan, chlorambucil, cyclophosphamide, BCNU, CCNU), amiodarone and chest radiation therapy. Chrysotherapy, methotrexate and sulfasalazine have rarely been cited [1]. Ascribing pulmonary fibrosis to drugs is difficult, due to the confounding background incidence of idiopathic pulmonary fibrosis or rheumatoid fibrotic lung involvement. Drug-induced pulmonary fibrosis may develop during or later, up to several years after treatment with the causal drug or radiation therapy [20, 98, 99]. Drug-induced pulmonary fibrosis manifests with cough, dyspnea, basilar crackles and weight loss. Skin discoloration is associated with busulfan toxicity. Clubbing of the digits is an unusual finding. On chest radiography, there are predominantly basilar or diffuse linear or streaky shadows. Volume loss predominates in the involved regions. On HRCT, coarse reticular perilobular and/or subpleural thickening and traction bronchiectases often predominate in the lung bases. Honeycombing is a late and inconsistent finding. Patients with drug-induced fibrosis may suffer repeated episodes of pneumothorax which are difficult to treat, since the underlying fibrotic lung reexpands poorly. Drug therapy withdrawal is indicated in all cases. However, this is rarely followed by significant improvement. Response to corticosteroid drugs is often limited and/or transient. Lung transplantation has been an option for a few patients. • Amiodarone-induced pulmonary fibrosis can develop after an episode of nonresolving APT, especially if

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corticosteroids were not given, or occurs as a de novo process [14]. Criteria for diagnosis of amiodaroneinduced fibrosis include a normal chest radiograph prior to institution of treatment with the drug, definite temporal association between exposure to the drug and the development of pulmonary fibrosis, compatible imaging and, when lung tissue is available, the presence of compatible histopathological features. Histopathological features are those of interstitial fibrosis or usual interstitial pneumonia (UIP), with fibrotic alveolar septae, type II cell hyperplasia and honeycombing. Dyslipidotic changes (see above, under ‘Amiodarone pulmonary toxicity’) may be present, depending on time from discontinuation of the drug to the lung biopsy. The outcomes of patients with amiodarone-induced fibrosis is poor. However, some patients stabilize on long-term corticosteroid therapy. • A peculiar pattern of pleuropulmonary fibrosis can occur in adolescents or in adults after treatments with carmustine, cyclophosphamide or multiagent chemotherapy for hematologic malignancies in childhood [98, 100]. The clinical-radiographic features of these conditions are a pattern of fibrosis of the upper lobes and the corresponding pleural surfaces. As fibrosis of the upper lobes and pleura is more advanced, progressive sagittal narrowing of the chest develops, which contributes to the restrictive physiology. Clinically, there is dyspnea and, often, significant pleuritic chest pain and a friction rub. Chest pain may improve on NSAIDs. Outcomes of the few cases available for review was poor, with progression of the disease despite corticosteroid therapy, debilitating pneumothorax and a 50% mortality rate. • Pulmonary infiltrates and, more often, subpleural comet-and-tail-shaped areas of consolidation can develop in patients with ergoline-induced pleural thickening. Most ergolines (bromocriptine, cabergoline, ergotamine, methysergide, nicergoline) can produce this condition [1, 101]. Although ergoline-induced pleural thickening is often referred to as ‘pleuropneumonitis’ in the literature, the parenchymal involvement may simply represent areas of atelactasis or ‘folded lung’ in the vicinity of pleural thickening. • Pulmonary and pleural fibrosis are classic complications of radiation therapy to the chest [11] (see separate section below). This condition is characterized by its sharp limits along the radiation beam and is recognized at history taking. The expression of radiation-induced involvement may change as newer three-dimensional techniques are made available [102].

Exogenous Lipoid Pneumonia [103–105] Exogenous lipoid pneumonia is a classic complication of paraffin given orally to combat constipation. Risk factors include ageing, chronic aspiration and achalasia. In achalasia, the upper paraffin layer in the dilated esophagus may spill over, down into the bronchial tree and lung. Other contexts for exogenous lipoid pneumonia include inhalation of amphotericin B and cyclosporin, since these drugs are dissolved in a lipidic vehicle, nasal or laryngeal application of mineral oil, compulsive use of lipsticks, application of oil-containing eye drops, facial ointments containing petrolatum, application of oil-containing gauze on a chest wound and smoking cannabis oil-coated cigarettes. The spreading of nondigestible and difficult-to-clear mineral oil leads to alveolar filling and to an interstitial reaction followed by pulmonary fibrosis. Exogenous lipoid pneumonia manifests with right-sided, basilar or diffuse shadowing. Paraffinoma denotes a solitary mass of exogenous lipoid pneumonia, which can be mistaken for lung cancer. On HRCT, alveolar filling causes a ground-glass pattern or crazy paving appearance which stay at some distance of the pleura and exhibit low attenuation numbers. On contrast unenhanced HRCT, pulmonary vessels may spontaneously be visible within the areas of parenchymal filling, a sign known as the ‘spontaneous angiogram’ [103–105]. The BAL typically has an oily or greasy appearance and contains increased numbers of lymphocytes and/or neutrophils, in addition to lipid-laden vacuolated macrophages. Diagnosis of exogenous lipoid pneumonia is suggested at history taking, and is confirmed by examination of sputum or BAL, which show lipidladen cells and free-floating oil. Mineral oil stains positive with oil-red-0 and Sudan black. Organic extracts of BAL supernatant and lung tissue can be chromatographed or submitted to mass spectrometry to evidence paraffin [103–105]. Although a lung biopsy is not indicated for the diagnosis of this condition, unfortunately, about half the patients are diagnosed retrospectively after the lung biopsy shows suggestive changes, indicating failure to recognize this condition at history taking [103]. Histopathologic features and staining patterns differentiate this condition from amiodarone pneumonitis and from naturally-occurring lipid storage diseases. Not every patient with exogenous lipoid pneumonia will improve after withdrawal of lipid-containing material and corticosteroid therapy. Complications include recurrent bronchopneumonia, superinfection with atypical mycobacteria or Aspergillus sp., pulmonary fibrosis and lung cancer [106]. Drug-Induced Granulomatosis and Sarcoidosis • More or less well-formed granulomas, not the real clinical entity of sarcoidosis, have been described following


treatments with bleomycin, etanercept, methotrexate, phenylbutazone, phenytoin, sirolimus and antineoplastic chemotherapy [1]. • There are two distinct patterns of granulomatous pulmonary reaction to intracavitary BCG therapy [107]. One is widespread BCG-induced sterile granulomas, which can be dense and occasion acute respiratory failure. BCG-related granulomas can also be found in liver and/or in other organs. The condition is improved on corticosteroids. The other is diffuse BCG-induced granulomatous infection. The condition is diagnosed on direct stains, cultures and molecular techniques applied to BAL and/or lung tissue. BCG-induced infection needs to be separated from BCG-induced granulomas, because in the former, antituberculous agents are required in addition to corticosteroids [108]. • Drug-induced sarcoidosis, not just granulomas, can complicate treatments with IFN-alpha and -beta in patients with viral hepatitis C infection, multiple sclerosis, hematologic malignancies, or solid tumors [109, 110]. Both the pegylated and unpegylated forms of IFN can produce sarcoidosis, or reactivate sarcoidosis that was diagnosed earlier and was quiescent until treatment with IFN was given. Generally, IFN-induced sarcoidosis develops after a few months into treatment, with malaise, fever, dyspnea and cough, and may mimic the flu-like symptoms often associated with the first weeks of treatment with IFN. IFN-induced sarcoidosis reproduces most clinical, imaging and histopathologic features of naturally-occurring sarcoidosis, including lung involvement, BAL lymphocytosis, mediastinal lymph node enlargement, dermatological involvement including erythema nodosum and Löfgren syndrome, involvement of liver, central nervous system or kidney, and hypercalcemia. Noncaseating granulomas can be found in bronchial mucosa, lung, mediastinal lymph nodes, skin and other organs. IFN-induced sarcoidosis is improved in a few months with reduction in drug dosage, drug therapy withdrawal, and/or corticosteroids.

Infiltrative Lung Disease and Drug-Induced Vascular Involvement [1] Treatments with leukotriene receptor antagonists used as corticosteroid-sparing agents in asthma have been temporally associated with Churg-Strauss syndrome, but the strength of this association is disputed [1]. The condition manifests with blood eosinophilia, pulmonary infiltrates and extrapulmonary involvement including cardiomyopathy,

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muscle pain, mononeuritis and, sometimes, digestive or dermatological involvement. Onset of the disease is after a few weeks or months into treatment, particularly, but exclusively so, when corticosteroids used to treat the asthma are tapered or discontinued. Circumstantial evidence relates treatments with macrolides, aspirin, hepatitis B vaccination and immunotherapy with Churg-Strauss syndrome [1]. No description of pulmonary pathology is available in druginduced Churg-Strauss syndrome. Limited evidence indicates that drugs may induce Wegener’s vasculitis [76, 111]. Drug-induced veno-occlusive disease is a rare complication of bleomycin, carmustine, gemcitabine, mitomycin, vinca alkaloids, radiation therapy and bone marrow transplantation [112]. The condition refers to widespread lumenal obliteration of pulmonary venules by fibrous tissue. Veno-occlusive disease can also develop in the course of solid or hematologic malignancies prior to any form of treatment. Patients present with dyspnea, ill-defined linear opacities, Kerley B lines and post-capillary pulmonary hypertension. Right heart failure eventually develops. The contribution of drugs vs. radiation therapy, the underlying basic malignancy or a chance association needs to be evaluated in each case. Endogenous fat embolism can develop a few hours following liposuction. Symptoms include dyspnea, chest pain and pulmonary infiltrates. The disease is often self-limited [113]. The infusion of propofol and total parenteral nutrition with intralipid can cause pulmonary infiltrates and deterioration of gas exchange, corresponding to exogenous fat embolism [1].

Infiltrative Lung Disease in Other Drug-Induced Systemic Conditions [31] The hemolytic and uremic syndrome is a severe complication of treatments with mitomycin C and gemcitabine [1]. The condition manifests with systemic and pulmonary hypertension, rapidly progressive renal failure, anemia hemolysis and schizocytosis, during or after discontinuation of therapy (up to several months) with the above drugs. Monitoring of kidney function before each drug administration and for a few months thereafter should help recognize early manageable forms of this condition. The drug rash with eosinophilia and systemic symptoms (DRESS) or drug hypersensitivity syndrome [1, 80], also known as the anticonvulsant, carbamazepine or sulfone (hypersensitivity) syndrome, is an idiosyncratic reaction

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occurring in a subset of predisposed individuals. There is the clinical triad of fever, rash and internal organ involvement (hepatitis, myocarditis, nephritis, neurologic disturbances) with or without pulmonary infiltrates. The syndrome develops after a few weeks into treatment with anticonvulsants, with an attack rate of 1 of 5,000 to 10,000 patients, abacavir, allopurinol, aromatic anticonvulsants, atenolol, azathioprine, bupropion, captopril, chrysotherapy, clopidogrel, diltiazem, lamotrigine, leflunomide, minocycline, nevirapine, oxicams, spironolactone, streptomycin, sulfasalazine, sulfonamides or trimethoprim. Onset is gradual, with fever and papulopustular erythematous skin reactions as the first indicators. Other presentations of DRESS include dermatological, neurologic (agitation, confusion), hematologic (anemia, thrombopenia, leukemic reactions) and lymphatic involvement, or internal organ involvement, which can mimic a systemic illness or an infection. The severity or extent of the skin-related changes do not correlate well with the severity of internal organ involvement, which may range from the asymptomatic state to life-threatening organ failure. Eosinophilia and atypical lymphocytosis occur in up to a third of cases. Thoracic manifestations of DRESS occur in about 10% of patients, and include a lymphoid interstitial infiltrate, nonspecific cellular interstitial pneumonia, eosinophilic pneumonia, OP, pleural effusion and lymph node enlargement which may progress to malignant lymphoma or Hodgkin’s disease. Treatment consists of immediate withdrawal of the suspected drug (this may not translate into improvement before a few week time), supportive care and high-dose corticosteroid therapy. Mortality is about 10%, despite optimal management. Patients must avoid re-exposure to the causal drug and related aromatic compounds (phenytoin, carbamazepine, phenobarbitone). Because genetic factors are suspected in the pathogenesis of DRESS, relatives of the patient should be instructed as regards their enhanced risk of developing DRESS-like reactions, should they take the same or chemically-related medications [31]. The pleura and lung can be involved in drug-induced lupus, a complication of treatments with about 60 chemicallyunrelated drugs (amiodarone, ACEI, anti-TNF agents, novel biologicals, ␤-blockers, carbamazepine, chlorpromazine, oral contraceptives, dihydralazine, ethosuximide, IFN, mesalazine, methyldopa, minocycline, nitrofurantoin, phenytoin, primidone, propylthiouracil, trimethadone, valproate, statins, sulfasalazine and ticlopidine) [1, 50]. Drugs may cause 5–30% of all cases of lupus. The prevalence of pleuropulmonary involvement in drug-induced SLE is between 15 and 60%, depending on the causative drug [114]. Clinical manifestations of the drug lupus include chest pain, cough, dyspnea, arthralgias, skin changes, fever,

malaise, pleuritis, pericarditis and pleural or pericardial effusion. Pulmonary infiltrates without the pleural manifestations of the disease occur in a small minority of patients. The lupus anticoagulant and antiphospholipid antibodies may produce thromboembolic phenomena or the hypercoagulable state. The scarcity of drug-induced lupus cases with renal impairment, neurological involvement and alveolar hemorrhage separate the drug condition from naturally-occurring lupus. Diagnostic criteria for drug induced lupus include (1) treatment with an SLE-inducing drug, (2) a suggestive clinical picture, and (3) a positive antinuclear antibody or antihistone test without, generally, the presence of anti-double-strand DNA antibodies. Management of drug-induced SLE consists of drug therapy withdrawal, with corticosteroid therapy, immunosuppressives and plasma exchange reserved for severe cases. Clinical manifestations reverse more rapidly than do ANA levels, which decrease slowly over months after drug therapy withdrawal.

Thoracic Complications of Radiation Therapy

Irradiation causes dose-related changes in tissues, including the lung, and the therapeutic ratio for radiation is narrow [11]. Radiation lung injury can manifest during or weeks, months or years after radiation therapy for lung cancer, breast carcinoma, Hodgkin’s or non-Hodgkin’s lymphomas, or following total body irradiation in recipients of bone marrow or stem cell transplant. Radiationinduced changes may involve the pleura, heart, pulmonary veins, mediastinum, lymphatic vessels and nerves in addition to the lung, creating manifold possibilities and patterns of involvement. Patient with a history of head and neck radiation therapy may develop chronic debilitating aspiration pneumonia. Although not directly related to radiation-induced lung injury, esophageal involvement can be particularly worrisome and life-threatening. The pattern of radiation pneumonitis has changed with time, as radiation sources and delivery techniques were improved. Radiation therapy for lung cancer tends to produce essentially unilateral changes, while mantle-field irradiation for Hodgkin’s disease or lymphoma produces changes in the upper chest, mediastinum and supraclavicular areas, and breast radiation therapy produce ipislateral apical changes or bilateral OP. The expression of radiation-induced lung injury depends upon (1) the nature of ionizing radiation, (2) the dose and direction of the radiation beam, with recent conformal techniques being developed to maximize the dose delivered to the tumor field and reduce the dose to normal tissues, and (3) coexisting factors such as


chemotherapy or oxygen that may potentiate radiationinduced lung injury. Other risk factors include an advanced age, low baseline pulmonary function or baseline PaO2. Current smoking may have a protective effect. Recent ablative pulmonary surgery and pneumonectomy are risk factors, as pulmonary reserve is compromised and more remaining lung is exposed to radiation, as postpneumonectomy hemithorax contracts. Changes induced by radiation therapy in lung are usually self-limiting, and reverse in a few weeks or months in most patients. Radiation therapy can produce changes in areas of the lung that are remote from the radiation beam. This is supported by the following findings: (1) there is an increase in BAL lymphocytes and 67Gallium or 18F-deoxyglucose uptake in the irradiated and in the contralateral nonirradiated lung, (2) radiation injury may spread out of the irradiated field to involve the remaining or opposite lung diffusely in the form of acute radiation pneumonitis with, sometimes, an ARDS picture, and (3) organizing or eosinophilic pneumonia may develop at a distance from the irradiated lung, following breast radiation therapy. • Classic radiation pneumonitis, also called sporadic radiation pneumonia [11], is a common pattern of radiationinduced lung injury, with approximately 10% of patients who receive radiation therapy to the chest developing some radiographic changes consistent with radiation pneumonitis. When present, symptoms include dry cough, moderate fever, dyspnea and dysphagia and range from minimal to severe. Early symptoms indicate more severe disease. On imaging, changes related to lung injury typically develop 1–2 months after the beginning of treatment, in the form of a discrete haze, ill-defined patchy nodules, or an area of condensation with air bronchogram(s) and volume loss. Changes predominate in the irradiated area and along the radiation beam, to involve the opposite lung where changes are generally milder. Changes may reverse within 6 months leaving a discrete scar, or progress towards fibrosis which, with time, becomes sharply-demarcated along the radiation beam and may exhibit traction bronchiectasis. Mild restrictive lung function develops early in the course of sporadic radiation pneumonitis. Lung volumes generally normalize in 18–24 months. A lung biopsy is rarely needed to establish the diagnosis. Histopathological features include interstitial edema, hemorrhage, a fibrinous exudate and reactive type II cells in early stages of the disease with, later, distortion, fibrosis, and dysplasia of type II cells. Symptomatic patients with sporadic radiation pneumonitis respond well to the administration of corticosteroids. However, this form of treatment is not

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required in all cases, and indication for treatment is guided by time to onset, with cases with an early onset more likely to require corticosteroid therapy, severity of symptoms, and the presence of hypoxemia. Late complications of chronic radiation pneumonitis include bronchiectasis in the fibrotic area, pneumothorax, and colonization by Aspergillus sp. Late radiation-induced myocardial or valvular dysfunction may produce pulmonary congestion and pulmonary edema on their own. With the current use of multiple three-dimensional sterotactic radiation portals, infiltrates from radiation therapy may not result in the traditional straight-edged infiltrate, and assume a mass-like or whorled appearance, which may be more difficult to distinguish from progression or relapse of lung cancer, or from other entities [115]. • Rapid extension of infiltrates shortly after radiation therapy to the chest or in candidates for bone marrow or stem cell transplantation who received conditioning chemotherapy and total body irradiation suggests acute radiation pneumonia [11, 116]. In addition to radiation dose and portal size, a history of recent exposure to chemotherapeutic drugs or oxygen, or withdrawal of corticosteroids are risk factors. Acute radiation pneumonia is associated with significant symptoms and, some patients develop respiratory failure or an ARDS picture. Patients may respond satisfactorily to the administration of corticosteroids. • OP following radiation therapy typically develops a few months after radiation therapy to the breast [117]. No known risk factor has been identified for this condition, which is diagnosed when migratory opacities develop a few weeks to a few months after termination of breast radiation therapy, in the context of mild respiratory and constitutional symptoms and BAL lymphocytosis with a high CD4⫹/CD8⫹ ratio. Virtually no case or radiationinduced OP has been reported after chest irradiation for lung cancer or malignant lymphoma. Radiation-induced OP is controlled by corticosteroids in a manner similar to OP of other causes.

• Eosinophilic pneumonia is a rare occurrence that has been described in 5 women after radiation therapy for breast carcinoma. All 5 patients had a history of asthma and/or atopy, a finding in history similar to patients with drug-induced eosinophilic pneumonia. Patients developed the condition an average of 3.5 months after completion of radiation therapy [118]. Radiographic appearances included pulmonary infiltrates in the irradiated lung in 3 women, and bilateral infiltrates in the remaining 2. In 1 patient, pulmonary opacities were shown to migrate from one to another area of the lung, a feature common to both OP and eosinophilic pneumonia. Eosinophilia was present in blood, and all 5 patients had ⬎40% eosinophils in the BAL. Corticosteroid therapy was associated with prompt recovery, although symptoms and pulmonary opacities relapsed after corticosteroid withdrawal in two cases, as they may do in OP. • Therapeutic doses of 131I or 90Y infused via the intravenous or hepatic arterial route to treat thyroid or hepatocellular carcinoma may spill into the pulmonary circulation. A sizable fraction of the isotope may lodge in pulmonary arterioles, causing considerable tissue irradiation and damage. Irreversible changes develop in 5–10% of patients after one or more treatment courses. Early disease is in the form of alveolar infiltrates and respiratory failure, or an ARDS picture. Later changes are in the form of distinctive, presumably fibrotic, opacities which stay at a distance of both the pleural surface and the hilum on the chest radiograph and CT [119].

Acknowledgements and Dedication The author’s coworkers O. Reybet-Degat, F. Massin, N. Baudouin, M. Merati, A. Fanton, C. Rabec, N. Favrolt, C. Beynat and A. Pavon. P. Foucher and B. Martha, who maintain Pneumotox®. Geneviève Jolimoy and Clio Camus, our Pharmacovigilance consultants. Physicians who notified Pneumotox® with cases of drug-induced lung disease. Patients with drug-induced and iatrogenic conditions. Isabelle de Kaenel and coworkers, Medical Library, CHUV, Lausanne, Switzerland.

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Prof. Philippe Camus Department of Pulmonary Medicine and Intensive Care University Medical Center Le Bocage and Medical School, Université de Bourgogne FR–21079 Dijon (France) Tel. ⫹33 38 029 3772, Fax ⫹33 38 029 3625 E-Mail [email protected] www.pneumotox.com®

Appendix

Space constraints limited the number of references. Further literature can be found at www.pneumotox.com or on request to the author. For further details, see text and consult Pneumotox®.


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Idiopathic Eosinophilic Pneumonias Romain Lazora,b Jean-François Cordiera a

Reference Center for Orphan Pulmonary Diseases, Louis Pradel Hospital, Claude Bernard University, Lyon, France; bPulmonary Division, University Hospital, Bern, Switzerland; and Swiss Registries for Interstitial and Orphan Lung Diseases

Abstract Eosinophilic lung diseases constitute a broad array of disorders of various origin. Beside infectious, drug-induced, and allergic diseases, 4 idiopathic eosinophilic disorders have been identified. Idiopathic chronic eosinophilic pneumonia is characterized by progressive cough, dyspnea, fever and weight loss, with moderate blood eosinophilia, multiple alveolar opacities at imaging, and eosinophilic alveolitis. It responds well to corticosteroids, but relapses are frequent and may require prolonged therapy. Idiopathic acute eosinophilic pneumonia presents as respiratory failure and diffuse pulmonary infiltrates at imaging in previously healthy young adults. Marked alveolar eosinophilia contrasts with an initially normal blood eosinophil count. Short-term corticosteroids provide a rapid and complete recovery. Churg-Strauss syndrome presents with asthma, marked blood eosinophilia, occasional pulmonary infiltrates on imaging, and further a small-vessel vasculitis affecting the heart, digestive tract, and peripheral nervous system. Long-term corticosteroids, with or without further immunosuppressive agents, are needed to control the disease. Hypereosinophilic syndrome is a hematological disorder resulting from either the production of eosinophilopoietic chemokines by clonal lymphocytes, or from a clonal proliferation of eosinophils. It is characterized by severe and prolonged blood eosinophilia leading to endomyocardial fibrosis and life-threatening heart failure. Lung involvement mainly consists of isolated chronic cough, sometimes associated with bronchospasm or pulmonary infiltrates. Copyright © 2007 S. Karger AG, Basel

Eosinophilic lung diseases are a heterogeneous group of disorders characterized by the predominance of eosinophils at histopathological examination. They have many possible causes, and can be broadly separated into disorders of determined and undetermined origin (table 1). Eosinophilic lung diseases of determined origin are due to infection (especially parasitic or fungal), drugs, and allergic bronchopulmonary mycoses. Idiopathic eosinophilic lung diseases include idiopathic chronic eosinophilic pneumonia (ICEP), idiopathic acute eosinophilic pneumonia (IAEP), Churg-Strauss syndrome (CSS) and hypereosinophilic syndrome (HES). Eosinophils may also be found as an ancillary feature in other pulmonary disorders such as histiocytosis X, idiopathic pulmonary fibrosis, or organizing pneumonia. A comprehensive review of all eosinophilic lung diseases is beyond the scope of this chapter, which will focus on the four above-mentioned idiopathic eosinophilic disorders. Review of other eosinophilic lung diseases can be found elsewhere [1].

Diagnostic Approach to Eosinophilic Pneumonias

The clinical diagnosis of eosinophilic pneumonia (EP) is usually made by the combination of pulmonary infiltrates on imaging and increased levels of eosinophils in blood and/or bronchoalveolar lavage (BAL). Peripheral blood eosinophilia may provide an important clue to diagnosis of EP. However, blood eosinophilia does not prove the eosinophilic nature of the pulmonary opacities. The threshold to

Table 1. Clinical classification and etiology of eosinophilic lung diseases

Infectious eosinophilic pneumonias Parasites: Ascaris lumbricoides, Ascaris suum, Toxocara canis, Toxocara cati, Strongyloides stercoralis, Ancylostoma duodenale, Necator americanum, Necator brasiliense, Wuchereria bancrofti, Brugia malayi, Dirofilaria immitis, Schistosomia mansoni, Schistosomia haematobium, Schistosomia japonicum, Paragonimus westermani, Trichomonas tenax, Angiostrongylus, Loa loa, Capillaria aerophila, Clonorchis sinensis, Trichinella spiralis, Opisthorchiasis, Echinococcus granulosus, Echinococcus multilocularis, Entamoeba histolytica Fungi: Coccidioides immitis, Bipolaris australiensis, Bipolaris spicifera, Pneumocystis jiroveci Bacteria: Corynebacterium pseudotuberculosis, Mycobacterium simiae Drug-, chemical-, and radiation therapy-induced eosinophilic pneumonias Common cause of eosinophilia: acetylsalicylic acid, captopril, diclofenac, ethambutol, fenbufen, granulocyte macrophage colony-stimulating factor, ibuprofen, L-tryptophan, minocycline, naproxen, p-(4)-aminosalicylic acid, penicillins, phenylbutazone, piroxicam, pyrimethamine, sulindac, sulphamides, sulfonamides, tolfenamic acid, trimethoprim-sulfamethoxazole Occasional cause of eosinophilia: bleomycin, carbamazepine, chlorpromazine, cocaine, desipramine, dapsone, febarbamate, gold salts, heroin, imipramine, isoniazid, loxoprofen, mephenesin, methotrexate, methylphenidate, nitrofurantoin, nomifensine, pentamidine, perindopril, phenytoin, propranolol, sulfasalazine, trimipramine Exceptional cause of eosinophilia: amiodarone, aminogluthetimide, ampicillin, beclomethasone, bicalutamide, cephalosporins, chloroquine, chlorpropamide, clofibrate, cromoglycate, diflunisal, erythromycin, furazolidone, glafenine, indomethacin, iodinated contrast medium, levofloxacin, maloprim, maprotiline, mesalazine (5-aminosalicylic acid), metronidazole, nalidixic acid, nilutamide, paracetamol, penicillamine, procarbazine, propylthiouracil, ranitidine, scotchguard, streptomycin, tenidap, tetracycline, tolazamide, tosufloxacin tosilate, trazodone, troleandomycin, venlafaxine Radiation therapy for breast cancer Allergic bronchopulmonary mycoses Allergic bronchopulmonary aspergillosis (Aspergillus fumigatus) Other allergic bronchopulmonary syndromes associated with fungi or yeasts (Pseudallescheria boydii, Cladosporium herbarum, Candida albicans, Stemphilum species, Torulopsis species, Curvularia lunata, Bipolaris species, Trichosporon terrestre, Rhizopus species, Fusarium vasinfectum, Helminthosporium species). Idiopathic eosinophilic pneumonias Idiopathic chronic eosinophilic pneumonia Idiopathic acute eosinophilic pneumonia Churg-Strauss syndrome Hypereosinophilic syndrome Myeloproliferative variant Lymphoproliferative variant Other syndromes with possible pulmonary eosinophilia Asthma, eosinophilic bronchitis, organizing pneumonia, idiopathic pulmonary fibrosis and other idiopathic interstitial pneumonias, histiocytosis X, lymphomas, other malignancies

define significant blood eosinophilia is also imprecise. Blood eosinophil count ranges from 0 to 0.65 G/L in normal subjects [2], and has been considered as a pathologic condition above 1.5 G/L [3]. In a series of unselected blood samples, eosinophil counts above 1 G/L were found in only 0.6% of cases, and eosinophil counts 2.0 G/L in only 0.1% [2]. A threshold of 2 G/L was found to discriminate best between diseases associated with hypereosinophilia (including malignancies) and atopic diseases with minor eosinophilia [2]. Thus, in the absence of BAL, a confident diagnosis of EP based on the sole presence of blood eosinophilia and pulmonary infiltrates requires a significant elevation of blood eosinophils (1.5 G/L) and typical clinico-radiological features.

Idiopathic Eosinophilic Pneumonias

BAL is now a widely accepted and minimally invasive technique to establish the diagnosis of EP and should be performed whenever possible. BAL eosinophil count is normally lower than 1% in nonsmokers, with slightly higher values in former smokers and smokers. BAL eosinophil count is usually considered elevated above 3–5% [4, 5]. However, the diagnostic value of mild BAL eosinophilia is limited. In one analysis of 1084 consecutive BALs, BAL eosinophil count between 3 and 9% was found in various disorders such as asthma, infection, sarcoidosis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, interstitial lung disease associated with connective tissue disease, radiation pneumonitis, and pneumoconiosis [4]. BAL with 40% eosinophils was mainly found in ICEP. In another series of 1,059 BALs using

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a threshold of 5% eosinophils, an elevated BAL eosinophil count was found in only 5% and was associated with interstitial lung disease, Pneumocystis jiroveci pneumonia, ICEP, and drug-induced lung disease [5]. A threshold value of 25% eosinophils has been proposed to define IAEP [6], and we used a cut-off of 40% to define ICEP in our studies [7, 8]. In clinical practice, we consider that a diagnosis of EP is supported by BAL findings when eosinophils exceed 25% (and preferably 40%) of the differential cell count. Pathological examination of surgical lung biopsy might be considered as the gold standard to identify EP, but lung biopsy is only rarely performed because EP is recognized with less invasive procedures. Transbronchial lung biopsy (TBB) may also show characteristic features, but the small size of the specimens makes it difficult to state that the eosinophilic infiltrate is the main pathological finding, and not just an ancillary feature in the frame of another diagnosis. Once the diagnosis of EP has been made, a thorough work-up is necessary to make a correct etiological diagnosis. A comprehensive search for the cause of EP is an essential step, since identifying and treating (or removing) the causal agent is usually curative and unnecessary treatments and procedures can be avoided. This search is made by a combination of clinical and laboratory investigations. Past medical history should especially search for asthma, rhinitis, sinusitis, allergy, atopy, travels to countries with endemic parasitic diseases, smoking, and environmental exposures at home and workplace. Beside the lungs, the history and physical examination should carefully search for any minor sign suggesting involvement of the heart, kidney, digestive tract, joint, muscle, peripheral nervous system and skin. Search for drug-induced lung disease requires a comprehensive history of all drugs currently taken or recently discontinued, and a systematic comparison with available electronic databases such as www.pneumotox.com. Chest high-resolution computed tomography (HRCT) may provide important clues to the diagnosis. Laboratory investigations include a search for parasites using appropriate blood serology, and stool and urine examination. The biological markers include complete blood count and biochemistry, total and specific IgE, Aspergillus precipitins, and antineutrophil cytoplasmic autoantibodies (ANCA). Specific cellular and molecular biology markers are needed to diagnose HES (see below). BAL differential count and microbiological analyses for bacteria, fungi, and viruses are needed in virtually all cases. Ear-nose-throat status, imaging of paranasal cavities, smear of nasal secretions, and/or biopsy of nasal mucosa may provide useful diagnostic information. If neuromuscular symptoms are present, electroneuromyography

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should be performed in search of neuropathic or myopathic changes, and these findings may further lead to peripheral nerve and/or muscle biopsy in search of vasculitis. Skin lesions must be carefully examined and biopsied if vasculitis is suspected. Corticosteroids constitute the cornerstone of treatment for idiopathic EP. Because of their effectiveness, the clinician might be tempted to initiate such a treatment as a ‘therapeutic trial’ before having collected all the information allowing complete characterization of the disease. Although this may appear rewarding in the short term, the great disadvantage is to remove rapidly all the features which would allow a secure diagnosis being made. Once corticosteroid therapy has been instituted, the clinician must decide which doses should be given and for how long, and whether other drugs (especially immunosupressors) are necessary. Several EP may recur when steroids are tapered or stopped, and this may challenge the initial diagnosis. Diagnostic and therapeutic uncertainty may thus lead either to insufficient disease control with possible organ damage, or to overtreatment with unnecessary side effects. Therefore, every effort should be made to achieve a confident and rapid diagnosis before instituting therapy.

Idiopathic Chronic Eosinophilic Pneumonia

Definition and Epidemiology Idiopathic chronic eosinophilic pneumonia (ICEP) is an EP of undetermined origin [7, 9–12] first individualized by Carrington et al. [13]. It is characterized by multiple alveolar opacities of subacute onset with alveolar and blood eosinophilia. By definition, the diagnosis of ICEP requires compatible clinical, imaging, and BAL features as described below, and the exclusion of all known causes of EP. The incidence and prevalence of ICEP is not known. Etiology and Pathogenesis Various changes have been reported in BAL fluid of patients with ICEP, including activation of eosinophils, overexpression of CD44 on eosinophils, accumulation of CD4 lymphocytes, increased concentration of eosinophil cationic protein, eosinophil derived neurotoxin, immunoglobulins, prostaglandin E2, prostaglandin F2, RANTES, eotaxin, IL-5, thymus-regulated chemokine and activation-regulated chemokine, macrophage-derived chemokine, and macrophage inflammatory protein 1. However, the cause and mechanisms leading to the development of ICEP remain unknown.

Pathology ICEP was initially described in open lung biopsy specimens [13] and its histological features are usually considered as being common to most EP whatever the cause. At low magnification, the distribution of lesions in ICEP appears usually diffuse, although a more focal involvement or a bronchocentric or angiocentric distribution may be found in some cases. The architecture of the lung parenchyma is usually preserved, without distortion or interstitial fibrosis. At high magnification, the most prominent feature is filling of alveolar spaces by eosinophils, with associated macrophages and scattered multinucleated giant cells, both of which sometimes containing eosinophilic granules or Charcot-Leyden crystals. Intra-alveolar foci of necrotic eosinophils surrounded by macrophages or palisading epithelioid cells may be found and constitute the so-called eosinophilic microabcess. The inflammatory cells are usually accompanied by an extracellular proteino-fibrinous exudates. The alveolar interstitium also contains inflammatory cells including eosinophils, lymphocytes, plasma cells, and histiocytes. Mucus plugs obstructing the small airways may be present. Intraluminal organization of the distal airspaces is usually mild and not a major feature, in contrast with organizing pneumonia (although overlaps between both conditions may exist). A mild non-necrotizing vasculitis involving small arteries and venules is common, and usually appears as perivascular inflammation with only minimal vascular wall infiltration. These features may be undistinguishable from those seen in CSS during the prevasculitic phase (see below). Clinical Assessment ICEP occurs mainly in adults during their fourth decade and is twice as frequent in females as in men [7, 10]. The vast majority of patients are non-smokers [7, 10, 12]. A prior history of asthma is found in up to two thirds of cases [7, 10–12, 14]. Asthma may also appear simultaneously to ICEP in 15% of cases, or develop subsequently in another 13% [8]. A prior history of atopy is found in about half of cases. Allergic rhinitis has been reported in up to 24%, chronic sinusitis in around 20%, nasal polyps in 13%, drug allergy and urticaria in 10%, and eczema in 5% [7]. The clinical presentation of ICEP is similar in asthmatic and nonasthmatic subjects, except for higher total IgE levels in the formers [8]. ICEP usually presents in a chronic or subacute fashion with cough, dyspnea, and chest pain, often associated with prominent systemic symptoms such as fever, weight loss, malaise, fatigue, anorexia and night sweats. Wheezing and crackles at chest auscultation are each found in about one


third of cases [7, 10]. Extrathoracic manifestations have occasionally been reported in ICEP, including pericarditis, repolarization abnormalities on the electrocardiogram, eosinophilic enteritis, diarrhea, altered liver enzymes, mononeuritis multiplex, arthralgias, cutaneous immune complex vasculitis, and skin nodules [7, 13, 15]. Such cases probably represent an overlap between ICEP and other eosinophilic disorders, especially a ‘limited form’ of CSS (see below).

Investigations and Diagnosis Peripheral blood eosinophil count exceeding 6% has been reported in 88% of 111 cases of ICEP in one review [10], with a mean eosinophil count of 26%. In another large series of 62 cases, the mean blood eosinophil count was 5.5 G/L [7]. Blood inflammatory markers are usually elevated in ICEP, with increased erythrocyte sedimentation rate and C-reactive protein. Total serum IgE levels are increased in about half of the cases, and exceed 1,000 kU/l in 15% [7]. At chest imaging, ICEP is characterized by multiple peripheral, frequently bilateral opacities predominating in the upper lung fields, with ill-defined margins and a density varying from ground-glass to consolidation (fig. 1a, b). A migratory character is found in one fourth of cases. Additional HRCT features include septal lines [16] and band-like opacities parallel to the chest wall [17]. Mediastinal lymph node enlargement has been reported in 17% of cases and small pleural effusions were found in only 10% [7]. Of note, the classical chest X-ray pattern of ‘photographic negative of cardiogenic pulmonary edema’ [18] is seen in only one fourth of cases [10]. BAL eosinophilia is a characteristic feature of ICEP, although the level of alveolar eosinophilia may vary with the definitions used. In a series of 62 cases in which BAL eosinophil count 40% or blood eosinophil count 1 G/L were used as criteria to define ICEP, the mean BAL eosinophil count reached 58% [7]. Other BAL cell population may also be increased, including neutrophils, mast cells and lymphocytes. Pulmonary function tests in ICEP disclose an obstructive ventilatory defect in about half of cases, and a restrictive pattern in the other half [7]. Hypoxemia has been reported in 64% [7], and an increased alveolo-arterial oxygen difference in up to 90% [10]. Reduced carbon monoxide transfer factor has been found in more than half of patients [7]. Although pulmonary function test usually normalize under therapy, development of permanent airflow obstruction has been reported in some patients [7, 19].

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respond well to increase of steroid dose. The frequency of relapses appears reduced in patients with prior asthma, possibly because they remain on inhaled corticosteroids after weaning of oral prednisone [7, 8]. Inhaled corticosteroids may therefore allow a reduction in the maintenance dose of systemic steroids in relapsing ICEP. Idiopathic Acute Eosinophilic Pneumonia

Definition and Epidemiology Idiopathic acute eosinophilic pneumonia (IAEP) is a form of EP of unknown cause, which has been recently individualized from the other EPs [6, 11, 20–24]. It differs from ICEP by a more acute onset, more severe gas exchange impairment, lack of blood eosinophilia at presentation contrasting with marked alveolar eosinophilia, and absence of relapses. Epidemiological data on IAEP are scarce. An incidence of 9.1 per 100,000 has been found in one recent study of military personnel but this may be an overestimation of the incidence [25].

a

b Fig. 1. Chest high-resolution computed tomography in idiopathic chronic eosinophilic pneumonia. a Multifocal patchy condensation with peripheral predominance. b Bilateral ground-glass opacities, with band-like subpleural location on the left lung.

Natural History, Management and Prognosis Spontaneous resolution has been reported in ICEP [7, 10], and death appears to be rare, but the natural course without treatment is not well described. One characteristic feature of ICEP is its very high sensitivity to corticosteroid therapy. In one series with a mean initial prednisone dose of 1 mg/kg/day, symptoms improved within days after treatment onset and pulmonary opacities cleared within 1 week in up to two thirds of cases [7]. Normalization of chest Xray was achieved in the vast majority of cases. The optimal dose of prednisone for treatment onset is not well established. Our current practice is to start with prednisone 0.5 mg/kg/day and taper over a period of 3 months. Relapses have been reported in more than half of cases [7, 10] when corticosteroids are reduced or stopped, but they

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Etiology and Pathogenesis Several reports have suggested a relationship between IAEP and smoking, especially smoking of recent onset [24, 25]. Other IAEP cases have been associated with various exposures to dust [6, 24]. Among 18 cases of IAEP occurring in US military personnel in Iraq, 100% were smokers and 94% were exposed to fine airborne sand or dust [25]. New-onset smokers were at significantly increased risk, although toxicological analyses of the inhaled tobacco products did not disclose any unusual components, such as toxins or pesticide residues [25]. Given the high prevalence of smoking in the general population, it seems unlikely that tobacco alone is necessary or sufficient for the development of IAEP, but it may be a co-factor. Environmental dust may play a role, as it could trigger inflammation and activation of cytokines such as IL-5, a potent recruiter of eosinophils. Increased BAL fluid levels of IL-5, IL-18, and macrophagederived cytokines have been found in IAEP [26–29]. Pathology When performed lung biopsy in IAEP disclosed acute and organizing diffuse alveolar damage with interstitial, alveolar, bronchial, and bronchiolar infiltration by eosinophils, as well as alveolar edema [6, 21]. Clinical Assessment The mean age at presentation is 30 years but IAEP can occur in patients 20 or 80 years of age [24]. In contrast

to ICEP, the disease is more common in men and there is no history of prior asthma. IAEP usually presents in previously healthy individuals with acute onset of severe dyspnea, tachypnea, cough, chest pain, fever, crackles, diffuse pulmonary opacities, and refractory hypoxemia [6, 11, 20–24]. This non-specific clinical picture may be misdiagnosed as severe community-acquired pneumonia. The respiratory distress may be life-threatening, and many patients fit the criteria of acute lung injury or acute respiratory distress syndrome (ARDS). Abdominal symptoms and myalgias have also been reported. Investigations and Diagnosis Leukocytosis with increased polymorphonuclear neutrophils is usually present, whereas eosinophils are only rarely elevated initially [6, 24]. Blood eosinophilia usually develops subsequently during the following days, and may reach high values. This particular course of blood eosinophilia constitutes a remarkable feature of IAEP. Chest X-ray shows bilateral alveolar and/or interstitial infiltrates, Kerley B lines, and bilateral pleural effusions [6], thereby often mimicking cardiogenic pulmonary edema (fig. 2a). At HRCT, the pulmonary infiltrates appear as ground-glass opacities (fig. 2b) or parenchymal consolidations. The majority of cases also present with interlobular septal thickening and ill-defined nodules [6]. Pleural effusion, usually bilateral, has been reported in up to two thirds of cases in some series [6, 24], in contrast with ICEP where it is absent. Since blood eosinophilia is usually absent initially, a BAL with differential cell count is critical for diagnosis of IAEP. Mean BAL eosinophil counts of 37–54% have been reported in IAEP [6, 24]. A mild elevation of lymphocytes and neutrophils is also observed [6]. Pleural fluid differential cell count shows eosinophilia ranging from 10 to 50%. When done, pulmonary function tests showed a mild restrictive ventilatory defect, normal FEV1/FVC ratio, and reduced carbon monoxide transfer factor. The following criteria have been proposed to define IAEP [6]: (1) acute onset within 7 days; (2) fever; (3) bilateral infiltrates on chest X-ray; (4) severe hypoxemia on room air (PaO2 60 mm Hg, or SaO2 90%, or AaDO2 40 mmHg); (5) pulmonary eosinophilia (25% BAL eosinophil count or predominance of eosinophils at open lung biopsy), and (6) absence of identified cause (including no history of drug hypersensitivity, and no evidence of infection). Since blood eosinophilia is usually absent initially, it does not constitute a useful diagnostic criterion. Regarding the criterion of the duration of disease onset, a study by our group found no differences between patients


a

b Fig. 2. Chest X-ray (a) and chest high-resolution computed tomogra-

phy (b) in idiopathic acute eosinophilic pneumonia. Diffuse groundglass opacities are visible throughout both lung fields.

with disease onset of, respectively, 7 days and 7–30 days [24]. We therefore consider that IAEP may be diagnosed in patients developing the disease in a time frame of more than 7 days, i.e. up to 30 days [24]. Complete response to steroid therapy has also been proposed as a diagnostic criterion of IAEP [21], but it may not be reliable since spontaneous improvement without steroids can also occur [24]. Lung biopsy appears unnecessary in typical cases of IAEP. However, a determined cause of EP must be carefully ruled out, with a special attention to infection and drug toxicity. Natural History, Management and Prognosis Although milder forms have been reported [25], patients with IAEP often present as acute lung injury or ARDS, with

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severe hypoxemia requiring intensive care and mechanical ventilation [20, 24]. Multiple organ failure and shock are not features of IAEP, but the mortality nevertheless reached 11% in one series [25]. Spontaneous recovery of IAEP has been reported [24, 25], but this cannot be predicted at the time of initial presentation. Intravenous corticosteroids have been used in most published cases and were associated with rapid clinical improvement and weaning from mechanical ventilation. Intravenous steroids are usually switched to oral prednisolone within days, and corticosteroids are tapered down to zero over 2–4 weeks [6]. The optimal dose and treatment duration are not known. Clinical recovery is usually complete without significant sequels at imaging. Lung function usually normalizes, although a restrictive ventilatory defect may persist in some patients. Relapses do not occur in IAEP, in contrast to ICEP [25].

Churg-Strauss Syndrome

Definition and Epidemiology Churg and Strauss described the eponymous syndrome in 1951 as ‘allergic granulomatosis and angiitis’, mainly based on autopsy findings [30]. In the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis [31], Churg-Strauss syndrome (CSS) was included in the group of small vessel vasculitis, and defined as an eosinophil-rich and granulomatous inflammation involving the respiratory tract, and a necrotizing vasculitis affecting small- to medium-sized vessels associated with asthma and eosinophilia. The incidence of CSS is approximately 1 case/million [32], and the prevalence around 10 cases/ million [33]. Among asthmatic patients, the incidence may reach 67 cases/million [34, 35]. Etiology and Pathogenesis CSS is considered as an autoimmune process involving T cells, endothelial cells, and eosinophils. Allergy could play a role, in view of the frequency of allergic rhinitis and family history of atopy in many patients with CSS. Various triggering or adjuvant factors have been suspected such as vaccines, desensitization, Aspergillus, allergic bronchopulmonary candidiasis, Ascaris, bird exposure or cocaine. Drug-induced eosinophilic vasculitis with pulmonary involvement has been reported with diphenylhydantoin, diflunisal, and macrolides. More recently, the leukotrienereceptor antagonists montelukast, zafirkukast, and pranlukast have been suspected to favor the development of CSS [36, 37]. However, it remains unclear whether these drugs really play a role in the pathogenesis of the vasculitis,

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whether some cases of incipient CSS flare because corticosteroids are reduced when leukotriene-receptor antagonists are added for asthma control, or whether the association is purely coincidental. In practice, we currently consider that leukotriene-receptor antagonists should be avoided in patients with asthma and eosinophilia, or with extrapulmonary manifestations compatible with incipient CSS. Pathology The characteristic pathologic lesions of CSS include: (1) vasculitis mainly involving the medium-sized arteries with or without necrosis, and (2) granulomatous eosinophilic tissue infiltration [38, 39]. The extravascular granuloma consists of palisading histiocytes and giant cells. However, all of these features are seldom found on a single biopsy, possibly because they reflect different disease phenotypes [40, 41]. In the early pre-vasculitic phase, CSS is characterized by eosinophilic infiltration and accumulation of perivascular eosinophils without vasculitis. When present, the eosinophilic pneumonia of CSS is similar to ICEP. Clinical Assessment Onset of CSS vasculitis usually occurs during the fourth decade [36, 42], but it has also been reported in children and adolescents. There is no gender predominance. Asthma occurs at a mean age of about 35 years and generally becomes severe, requiring oral corticosteroids [42]. Asthma usually precedes the onset of vasculitis by 3–9 years, but this interval may be much longer, or both may develop simultaneously [36, 42–44]. The severity of asthma usually increases progressively until vasculitis develops, but it may attenuate when the vasculitis becomes present and increase again when vasculitis recedes [42, 44]. Allergic rhinitis is present in three fourths of cases [42] and is often accompanied by relapsing sinusitis and/or nasal polyps. Paranasal sinusitis has been reported in 61% of patients [43]. Crusty rhinitis may be present, but is much less severe than in Wegener’s granulomatosis, and septal perforation or nasal saddling are exceptional. Asthenia, weight loss, fever, arthralgias, and myalgias often announce the development of extrathoracic manifestations of vasculitis. These features are unusual in simple asthma and must raise the suspicion of CSS in an asthmatic patient. Involvement of the peripheral nervous system is present in three fourth of cases [43] and mainly consists of mononeuritis multiplex or asymmetrical polyneuropathy, whereas cranial nerve palsies and central nervous system involvement are less common. Phrenic nerve palsy has been reported. Heart damage resulting from eosinophilic myocarditis and/or coronary arteritis may be severe and

lead to death [36, 42–45]. A thorough cardiac evaluation is therefore mandatory in any patient with suspected CSS. Cardiac involvement is often insidious and asymptomatic, and thus may be recognized only when left ventricular failure and dilated cardiomyopathy have developed. Symptoms of left heart failure may be confounded with asthma. Heart failure may require heart transplantation and recurrence of eosinophilic vasculitis is possible in the transplanted heart. However, myocardial impairment as well as coronary arteritis may markedly improve with corticosteroid treatment. Pericarditis with limited effusion is common in CSS. Occasionally, pericardial effusion may be more important and lead to tamponade. Digestive tract involvement is present in 31% of cases with CSS [43]. It usually manifests as isolated abdominal pain, but may also manifest as cholecystitis or vasculitis of any part of the digestive tract with diarrhea, hemorrhage, ulceration, and perforations. Cutaneous lesions are present in about half of patients [43] and mainly consist of erythematous rashes, urticaria, palpable purpura, and subcutaneous nodules typically developing on the lower extremities and progressing proximally. Skin biopsy provides evidence of a leukocytoclastic vasculitis, with or without prominent eosinophilic infiltration. Renal involvement, present in 26% of cases, is usually mild [43]. Investigations and Diagnosis Blood eosinophilia is a major feature of CSS and usually parallels disease activity. Blood eosinophils are generally between 5 and 20 G/L, but they may reach higher values [42–44]. Blood eosinophilia often disappears dramatically after the initiation of corticosteroid treatment. CSS is one of the pulmonary antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides, together with Wegener’s granulomatosis and microscopic polyangiitis. ANCA have been reported in around 40% of patients with CSS [40, 41, 43]. ANCA are mainly p-ANCA with myeloperoxidase specificity, and much less often c-ANCA with proteinase 3 specificity [40, 41, 43]. Recent data suggest that ANCA-positive and ANCA-negative CSS might differ in clinical expression, ANCA positivity being associated with renal involvement, peripheral neuropathy, and biopsy-proven vasculitis, whereas negative ANCA status was correlated with heart involvement [40, 41]. A possible pathogenic role of circulating ANCA is suggested by the higher frequency of vasculitis in ANCA-positive CSS patients [40, 41]. IgE levels are usually markedly increased in CSS. On chest X-ray, pulmonary infiltrates have been reported with a frequency of 37 to 72% [42, 43]. Infiltrates are usually noted at presentation, but may also develop later


Fig. 3. Chest high-resolution computed tomography in Churg-

Strauss syndrome. Multifocal patchy opacities with density varying from ground-glass to consolidation.

during follow-up. Alternatively, the chest X-ray may remain normal throughout disease course. The pulmonary infiltrates usually consist of ill-defined opacities of varying density, and a transient and migratory character [42, 44]. Small pleural effusions may be observed. On HRCT, the pulmonary opacities appear as ground-glass attenuation or airspace consolidation, with peripheral predominance or random distribution (fig. 3). Less common features include centrilobular nodules, bronchial wall thickening or dilatation, interlobular septal thickening, hilar or mediastinal lymphadenopathy, and pleural or pericardial effusion [46]. Eosinophilia is found on BAL differential cell count (sometimes 60%) [47], and in the pleural effusions (generally 60%) [48]. Pleural effusions may also reflect heart failure due to cardiomyopathy. The natural history of CSS classically follows three phases: (1) asthma and rhinitis; (2) tissular eosinophilia, with pulmonary disease resembling ICEP, and (3) extrapulmonary eosinophilic disease with vasculitis [42]. However, these phases do not necessarily follow one another consecutively. The diagnosis of CSS is usually considered when patients present with mild signs partially suppressed by corticosteroid treatment for asthma (the so-called ‘limited forms’ or ‘formes frustes’ of CSS). At this stage, the lack of overt features of CSS often makes a clear diagnosis difficult. On the other hand, it is extremely important to make the diagnosis before occurrence of the vasculitic phase with severe organ involvement. Lanham et al. [42] have

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proposed three diagnostic criteria including (1) asthma; (2) eosinophilia exceeding 1.5 G/L, and (3) systemic vasculitis of two or more extrapulmonary organs. ANCA were not available when the latter criteria were established, and ANCA positivity may likely be considered now as a diagnostic criterion when present. A histological diagnosis of CSS is desirable, but not mandatory in most cases. The skin, nerve, and muscle are the most common sites where a pathological diagnosis of vasculitis may be obtained [43]. Surgical lung biopsy is rarely useful. Transbronchial biopsy usually does not show vasculitis or granulomata, and is not a useful procedure. The borders separating CSS from the other ANCA-associated vasculitides and the other eosinophilic syndromes are occasionally difficult to establish. An eosinophilic variant of Wegener’s granulomatosis has been described [49]. Distinguishing between mild CSS and ICEP with minor extrathoracic symptoms may also be difficult, as mild nonnecrotizing vasculitis is common in ICEP [13], and ICEP may further progress to CSS [50]. In addition, ‘limited forms’ or ‘formes frustes’ of CSS have been reported [51, 52] including those involving solely the lung or the heart. These often consist of cases where the disease has been somewhat controlled by corticosteroids given for asthma. Some cases of CSS may be difficult to distinguish from HES. Natural History, Management and Prognosis Corticosteroids are the first-line treatment of CSS, and suffice in the majority of cases [42, 53]. An initial methylprednisolone intravenous bolus may be useful in severe cases, usually followed by oral prednisone 1 mg/kg/day. The use of immunosuppressive agents depends on the presence of factors of poor prognosis. In a retrospective study of patients with polyarteritis nodosa or CSS [53], parameters associated with increased mortality were proteinuria 1 g/day (relative risk RR 3.6), renal insufficiency with serum creatinine 15.8 mG/L (RR 1.9), and gastrointestinal tract involvement (RR 2.8). Although not reaching statistical significance in this study, cardiomyopathy (RR 2.2) and central nervous system involvement (RR 1.8) may be also considered as factors of poor prognosis. In patients with one or more of these factors at onset, immunosuppressive treatment (such as cyclophosphamide or azathioprine) is warranted in addition to corticosteroids. The addition of immunosuppressive agents improves disease control, but may predispose to more infections. This may be reduced by using bolus intravenous cyclophosphamide rather than oral cyclophosphamide [54, 55]. Once instituted, treatment is maintained for several months with progressive dose

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reduction. Relapses are common, and asthma often persists or reappears during prednisone tapering. Relapse or recurrence of asthma must be distinguished from relapse or persistence of vasculitis. In asthma without relapse of vasculitis, blood eosinophilia is expected to remain below 1 G/L. Immunosuppressive agents are considered in patients with relapses of vasculitis despite 20 mg/day of prednisone. Subcutaneous interferon- has been successfully used mainly in CSS patients with severe disease [56]. High dose intravenous immunoglobulins and cyclosporin have been occasionally used successfully. The 5-year survival in CSS is currently estimated to 79% [53].

Hypereosinophilic Syndrome

Definition A definition of the ‘idiopathic’ hypereosinophilic syndrome (HES) was proposed in 1975 as follows [3]: (1) persistent eosinophilia 1.5 G/L for longer than 6 months, or death before 6 months associated with the signs and symptoms of hypereosinophilic disease; (2) no evidence of parasitic, allergic, or other known causes of eosinophilia, and (3) signs and symptoms of organ involvement, including hepatosplenomegaly, organic heart murmur, congestive heart failure, diffuse or focal central nervous system abnormalities, pulmonary fibrosis, fever, weight loss, or anemia. It later appeared that idiopathic HES in fact represents a heterogeneous population. Recent advances in molecular biology have identified distinct underlying hematological disorders, which affect, respectively, the myeloid and lymphoid cell populations [57]. Pathogenesis In contrast to most other causes of hypereosinophilia, which usually represents a reactive non-clonal process, HES may result from either (1) a clonal proliferation of eosinophils (myeloproliferative variant, m-HES) or (2) a clonal proliferation of lymphocytes producing eosinophilopoietic chemokines (lymphoproliferative variant, l-HES) [58–61]. In one third to one half of patients, the m-HES variant results from the fusion of the FIP-like 1 gene with the plateletderived growth factor receptor alpha gene (FIP1L1-PDGFR) as a consequence of a chromosomal deletion [62]. The fusion gene encodes for a protein with constitutive tyrosine kinase activity, which is inhibited by imatinib mesylate. This drug now constitutes an effective treatment in patients with m-HES bearing the FIP1L1-PDGFR fusion protein [62]. Some patients responding to imatinib do not exhibit the fusion

protein, suggesting the involvement of other, as yet unidentified, imatinib-sensitive tyrosine-kinases. Other patients do not respond to imatinib, which probably reflects the existence of other molecular pathways of eosinophil clonal expansion [57]. The l-HES variant results from the clonal proliferation of nonmalignant T lymphocytes bearing an aberrant immunologic surface phenotype (CD3, CD4), and producing eosinophilopoietic cytokines (especially IL-5), which leads to accumulation of eosinophils [57]. The primary event leading to clonal T cell expansion may differ among patients with lHES. Most patients have papules or urticarial plaques infiltrated by lymphocytes and eosinophils, and some of them ultimately present with a cutaneous T cell lymphoma or the Sezary syndrome. In such cases the HES may be considered as a premalignant T cell disorder [63, 64]. Organ damage in HES results from the local release of toxic molecules by the infiltrating eosinophils, including cationic proteins, reactive oxygen species, enzymes, proinflammatory cytokines and lipid mediators. However, there is no clear correlation between blood eosinophil levels and severity of organ damage [57]. Clinical Features The HES occurs between 20 and 50 years of age and 90% of patients are men [65]. The onset is generally insidious. The main presenting symptoms are weakness and fatigue (26%), cough (24%), and dyspnea (16%) [66]. Cardiovascular involvement, present in 58% of cases, is a major cause of morbidity and mortality [65]. Cardiac manifestations include congestive heart failure, mitral regurgitation and cardiomegaly [66, 67]. Fibrotic thickening of the endocardium by collagen-rich connective tissue (endomyocardial fibrosis) is characteristic of HES [66, 68] and clearly differs from the cardiac involvement seen in CSS which is mainly myocardial. The pulmonary involvement in patients with HES has not been described in detail particularly in the context of the distinction of the m-HES and l-HES variants. Pulmonary involvement has been reported in 40% of patients with HES in older series [66, 69]. The most frequent feature is chronic dry cough, usually occurring in the absence of abnormalities at chest imaging and lung function tests, or associated with bronchospasm or pulmonary infiltrates [67, 69]. Other features include pleural effusion, pulmonary emboli, and interstitial infiltrates [3, 66]. HES may also present with neurological and cutaneous manifestations [65, 70]. Investigations and Diagnosis The mean blood eosinophil count at presentation reached 20.1 G/L in one series of HES [69], but values


above 100 G/L are found in some patients [3]. Eosinophilia is discovered incidentally in 12% of cases [66]. Distinction between m-HES and l-HES variants is now a critical step for optimal therapy and follow-up, and requires specific analyses [57]. Between one third and one half of patients with HES bear the FIP1L1-PDGFR fusion protein detected by fluorescence in situ hybridization or reverse transcription polymerase chain reaction [57]. Patients with m-HES also present with anemia, thrombocytopenia, increase serum vitamin B12, increased serum tryptase, circulating immature myeloid precursors, dysplastic eosinophils, splenomegaly, and significant organ damage (especially the heart) [57]. Patients with l-HES are characterized by phenotypically aberrant T cell population subsets (especially CD3CD4 and CD3CD4CD8) at flow cytometry, clonal TCR gene rearrangement, and increased production of eosinophilopoietic cytokines by T cells. They also have increased IgE, polyclonal hypergammaglobulinemia, and predominant cutaneous manifestations [57]. Chest imaging findings in HES are not well defined. In a small series, chest CT identified small nodules with or without a halo of ground-glass attenuation, and focal areas of ground-glass attenuation mainly in the lung periphery [71]. In some cases, chest CT abnormalities may reflect pulmonary edema due to heart failure, rather than eosinophilic involvement of the lung. Echocardiography may show mural thrombus, ventricular apical obliteration and involvement of the posterior mitral leaflet [72]. Only mild eosinophilia at BAL contrasting with high blood eosinophilia has been reported in patients with HES [73]. Treatment and Prognosis In the past decades, therapeutic strategies for HES mainly relied on corticosteroids, hydroxyurea, interferon- and chemotherapeutic agents such as vincristine and etoposide. Therapeutic perspectives have now radically changed with the description of the FIP1L1-PDGFR fusion protein with tyrosine-kinase activity in a significant number of patients with m-HES. The tyrosine-kinase inhibitor imatinib mesylate has proven highly effective in these patients, and now constitute the first-line treatment. A subgroup not bearing the fusion protein also responds to imatinib. Response to therapy is rapid but endomyocardial fibrosis appears usually irreversible. Relapses can occur due to mutations conferring resistance to imatinib [62]. Institution of imatinib therapy in HES with heart involvement may be associated with severe congestive heart failure related to local destruction of eosinophils by imatinib and release of toxic molecules. This event is preceded by a raise of troponin levels and can be managed by early administration of corticosteroids

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[57]. In l-HES, the therapeutic objectives are to decrease eosinophil levels through suppression of eosinophilopoietic cytokines, and to prevent malignant transformation of aberrant T cells [57]. Corticosteroids are usually effective in decreasing eosinophil levels in l-HES, but their effect on clonal T cells is variable. Monoclonal anti-IL-5 antibodies have been recently developed as a targeted therapy for HES [74] and promising results have been reported in 2 small

series of HES with the anti-IL-5 antibody mepolizumab [75, 76]. Whereas the 3-year survival was only 12% in the first published series [3], a 10-year survival of 70% has been reported more recently [66], probably as the result of improved prevention and management of end-organ damage. Malignant transformation of m-HES to eosinophilic leukemia, and of l-HES to T-cell lymphoma may, however, occur [57].

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Jean-François Cordier, MD Reference Center for Orphan Pulmonary Diseases, Louis Pradel University Hospital FR–69677 Lyon (Bron) (France) Tel. 33 4 72 35 76 69, Fax 33 4 72 35 76 53 E-Mail [email protected]

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Diffuse Alveolar Hemorrhage Amy L. Olson

Marvin I. Schwarz

University of Colorado Health Sciences Center, Division of Pulmonary Sciences and Critical Care Medicine, Denver, Colo., USA

Abstract

Table 1. Causes of diffuse alveolar hemorrhage categorized accord-

ing to underlying histopathologic findings

Diffuse alveolar hemorrhage (DAH) refers to a clinical syndrome resulting from injury to the alveolar capillaries, arterioles, and venules leading to red blood cell accumulation in the distal air spaces. It is defined by the clinical triad of hemoptysis, anemia, and progressive hypoxemia. Chest radiographs reveal non-specific patchy or diffuse, bilateral pulmonary infiltrates.The diagnosis requires confirmation of the alveolar hemorrhage by bronchoscopy in which serial bronchoalveolar lavage samples reveal persistently hemorrhagic fluid. A number of conditions are associated with DAH, and underlying disease determines the prognosis and the treatment regimen. While there is no uniformly accepted classification of DAH, it is generally categorized according to the underlying histology. Copyright © 2007 S. Karger AG, Basel

Etiology

A number of conditions have been associated with the clinical syndrome of DAH (table 1). In one study of biopsyconfirmed DAH, Wegener’s granulomatosis (WG) was the most frequent underlying condition, followed by Goodpasture’s syndrome, idiopathic pulmonary hemosiderosis, and collagen vascular diseases. Overall, vasculitis (either WG or microscopic polyangiitis [MAP]) was the most frequent, representing 41% of cases [1].

With pulmonary capillaritis: Wegener’s granulomatosis Microscopic polyangiitis Isolated pulmonary capillaritis Systemic lupus erythematosusa Connective tissue diseasesa Pimary antiphospholipid syndrome Mixed cryoglobulinemia Behçet’s syndrome Henoch-Schönlein purpura Goodpasture’s syndromea Puci-immune glomerulonephritis Immune-complex-associated glomerulonephritis

With bland pulmonary hemorrhage: Idiopathic pulmonary hemosiderosis Goodpasture’s syndromea Mitral stenosis Acid anhydrides, isocyanates Penicillamine, amiodarone, nitrofurantoin Pulmonary veno-occlusive disease Pulmonary capillary hemangiomatosis Lymphangioleiomyomatosis Tuberous sclerosis Coagulation disorders Systemic lupus erythematosusa Diffuse alveolar damage (Including inhalational cocaine use)b

Drug-induced Acute lung allograft rejection a

These diseases may be associated with either pulmonary capillaritis or bland pulmonary hemorrhage (see text). bDiffuse alveolar damage is a unique histopathologic pattern of lung injury which is the result of a variety of toxic insults (see text).

a Fig. 2. Photomicrograph of bland alveolar hemorrhage. The alveolar

septa appear intact with hemorrhage into the alveolar spaces. Type II alveolar epithelial cell hyperplasia can also be seen. Original magnification ⫻40.

b Fig. 1. a Photomicrograph of pulmonary capillaritis revealing infiltration of the alveolar septum (lung interstitium) with fragmented and pyknotic neutrophils. The alveolar walls are edematous, and red blood cells that have escaped from the capillaries into the interstitium and alveolar spaces can be seen. Original magnification ⫻40. b Photomicrograph of pulmonary capillaritis with fibrinoid necrosis of the capillary wall and interstitium as injured capillaries have released fibrin. Original magnification ⫻40.

Pathology

The histologic patterns described in the presence of DAH include pulmonary capillaritis, bland alveolar hemorrhage, and diffuse alveolar damage. Pulmonary capillaritis, first described by Spencer [2] in 1957, is the most common histologic pattern in DAH [1] and is characterized by infiltration of alveolar septa (lung interstitium) with neutrophils (fig. 1a). It is likely that these cells, through the release of oxygen radicals and cytoplasmic enzymes, damage alveolar capillaries, alveolar capillary basement membranes, and alveolar walls. With necrosis, the integrity of these structures is lost and red blood cells escape from the capillaries

Diffuse Alveolar Hemorrhage

into the interstitium and alveolar spaces. Fibrin may also be released from the injured capillaries, and true fibrinoid necrosis of the capillary wall and interstitium may be seen (fig. 1b). As neutrophils undergo destruction (leukocytoclasis) they become fragmented and pyknotic, and nuclear debris accumulates in the interstitium and alveolar spaces. Other histologic features include alveolar capillary thrombosis, type II alveolar epithelial cell hyperplasia, intraalveolar organizing pneumonia, and mononuclear cell infiltration of the alveolar interstitium [1, 3]. During the resolution phase of DAH, hemosiderin deposits appear in the interstitium and in alveolar macrophages [4]. Other histologic patterns in DAH include bland pulmonary hemorrhage (fig. 2) and diffuse alveolar damage (fig. 3). Bland pulmonary hemorrhage is characterized by hemorrhage in to the alveolar spaces without inflammation or necrosis of the alveolar structures present in pulmonary capillaritis. Histopathologic features include alveoli filled with red blood cells and type II alveolar epithelial cell hyperplasia [5]. After repeated episodes of DAH, interstitial fibrosis may evolve [6]. Diffuse alveolar damage can also result in DAH and is characterized by interstitial and alveolar edema and alveolar hyaline membrane formation [7, 8].

Clinical Assessment and Investigations

The onset is typically abrupt. Most affected individuals seek medical attention within one week from the onset of

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Fig. 3. Photomicrograph of diffuse alveolar damage. Interstitial and

alveolar edema is evident, as is hyaline membrane formation. Original magnification ⫻40.

Fig. 5. Physical exam finding of palpable purpura in a gentleman

with diffuse alveolar hemorrhage.

Fig. 4. Serial aliquots (from left to right) of bronchoalveolar lavage

fluids demonstrating persistently hemorrhagic fluid supporting the diagnosis of diffuse alveolar hemorrhage.

symptoms, which include dyspnea, hemoptysis, and cough. Less commonly, fever and nonspecific chest pain are reported. Importantly, up to 33% of patients with DAH do not report hemoptysis even though extensive intra-alveolar hemorrhage may have occurred [9]. In the absence of hemoptysis, diffuse alveolar infiltrates on the chest radiograph (CXR), a low or declining hematocrit, and hemorrhagic fluid on sequential bronchoalveolar lavage support the diagnosis of DAH (fig. 4) [10]. If additional symptoms are present, these may highlight an accompanying systemic disease (table 1). The physical examination may also be supportive of a systemic disease such as palpable purpura, synovitis, or eye involvement (fig. 5). Although nonspecific,

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Olson/Schwarz

Fig. 6. Chest radiograph of diffuse alveolar hemorrhage with nonspecific, diffuse, bilateral alveolar infiltrates.

the pulmonary examination may reveal inspiratory crackles and signs of pulmonary consolidation [11]. Chest radiographs show nonspecific patchy or diffuse, bilateral alveolar infiltrates (fig. 6). These are, on occasion,

Fig. 7. Computed tomography of the lung parenchyma in a diffuse alveolar hemorrhage resulting from post-capillary pulmonary hypertension (pulmonary veno-occlusive disease). Kerley B lines are evident in the periphery.

symmetric or unilateral. In cases where DAH is recurrent, an interstitial pattern (representing pulmonary fibrosis) may be present [6]. Kerley B lines can be present in DAH associated with post-capillary pulmonary hypertension as seen in mitral stenosis and pulmonary veno-occlusive disease (fig. 7) [12]. Computed tomography is nonspecific, revealing ground-glass attenuation and patchy consolidation (fig. 8) [13]. Magnetic resonance imaging has been used in idiopathic pulmonary hemosiderosis to detect recurrent pulmonary hemorrhage, which demonstrates a diminished T2 relaxation time [14]. Routine laboratory studies reveal an anemia, due to acute blood loss and/or iron deficiency anemia. Because several causes of DAH also result in renal disease (see below), routine investigations may reveal an elevated creatinine and urinalysis may show an active urine sediment with red blood cells, crenated red blood cells, or red blood cell casts [6]. Hypoxemia is almost always present and in many cases acute respiratory failure requiring mechanical ventilation


Fig. 8. Computed tomography of the lung parenchyma in a diffuse alveolar hemorrhage with area of consolidation as well as ground glass attenuation.

supervenes [6]. In subacute DAH the diffusing capacity for carbon monoxide is typically elevated, reflecting the high affinity of carbon monoxide for hemoglobin [15]. Recurrent and chronic DAH has been associated with restrictive physiology [16].

Diagnosis

If DAH is suspected, the diagnosis must first be confirmed, and then, identification of an underlying etiology should be sought. Bronchoscopy usually secures the diagnosis; sequential bronchoalveolar lavage samples (from the same location) with an increasing red blood cell count is regarded as diagnostic of DAH (fig. 4) [11]. Surgical lung biopsy confirms the presence of DAH, but usually not the underlying systemic disease [1]. Surgical lung biopsy should be strongly considered in younger patients who have isolated pulmonary hemorrhage without clinical or serological evidence of a systemic disease (table 1). The diagnoses

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Table 2. Laboratory findings and potential sites of systemic involvement typically associated with the specific dis-

eases resulting in DAH ANCA

ANA

RF

Complement levels

ABMA

Sites of systemic involvement

Wegener’s granulomatosis

⫹CANCA

⫹Ⲑ⫺

⫹Ⲑ⫺

normal

no

renal skin joints

Microscopic polyangiitis

⫹PANCA

⫹Ⲑ⫺

⫹Ⲑ⫺

normal

no

renal skin joints

Isolated pulmonary capillaritis

no

no

no

normal

no

none

Systemic lupus erythematosus

no

yes

yes

low

no

renal skin joints

HenochSchönlein purpura

⫹Ⲑ⫺

no

no

normal

no

renal skin joints

Goodpasture’s syndrome (ABMA)

no

no

no

normal

yes

renal

Idiopathic pulmonary hemosiderosis

no

no

no

normal

no

none

ABMA ⫽ Anti-basement membrane antibody; ANA ⫽ anti-nuclear antibody; ANCA ⫽ anti-neutrophil cytoplasmic antibody; RF ⫽ rheumatoid factor.

of specific diseases associated with DAH are discussed below (table 2).

Natural History, Management, and Prognosis of Specific Diseases Associated with Diffuse Alveolar Hemorrhage and Pulmonary Capillaritis

Wegener’s Granulomatosis WG is a systemic small and medium vessel vasculitis which typically affects the upper and lower respiratory tracts and kidneys. Other organ systems (eyes, skin, central nervous system, and gastrointestinal system) may also be involved. The characteristic lung histopathology is a necrotizing granulomatous vasculitis, and kidney biopsy reveals a focal, segmental necrotizing glomerulonephritis (FSNG) (fig. 9). In patients with classic symptoms, the diagnosis is often confirmed serologically by the presence of antineutrophil cytoplasmic antibodies (c-ANCAs), and further confirmation of the diagnosis requires tissue biopsy in selected cases [17]. DAH due to pulmonary capillaritis in WG may occur after an established diagnosis, but can be the initial manifestation

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Fig. 9. Photomicrograph of a renal biopsy with a focal segmental

necrotizing glomerulonephritis. Original magnification ⫻40.

of WG in as many as 10% of patients. In most patients with WG and DAH, lung histology reveals both necrotizing granulomatous vasculitis and pulmonary capillaritis, and renal histology reveals a FSNG [6, 18, 19]. WG with DAH

may be clinically indistinguishable from microscopic polyangiitis (MAP) if the lung biopsy reveals only pulmonary capillaritis [10]. In this scenario, the presence of serum c-ANCA positivity supports the diagnosis of WG while serum p-ANCA positivity (see next pharagraph) suggests a diagnosis of MAP. However, there are reports of serum p-ANCA positive WG, and serum c-ANCA positive MAP [20, 21]. In this situation, the diagnosis of WG may be delayed months or years until more typical clinical manifestations of WG develop [22]. On immunofluorescence staining of ethanol-fixed neutrophils, c-ANCA positivity is determined by a pattern of diffuse staining of the cytoplasm whereas p-ANCA positivity is defined by a pattern of perinuclear staining. The cytoplasmic antibodies are most often directed against proteinase 3 (PR3), and the perinuclear antibodies are often directed against myeloperoxidase (MPO) antibodies. These specific antibodies to PR3 and MPO may be tested by enzyme-linked immunoassays (ELISAs) [23]. Recommended therapy for DAH associated with WG includes high-dose corticosteroids and cyclophosphamide. In patients who require mechanical ventilation, intravenous methylprednisolone (250–1,000 mg/day for 3–5 days) and intravenous cyclophosphamide is recommended (1 g/m2). For those patients who do not require mechanical ventilation, oral prednisone (1 mg/kg/day) and cyclophosphamide (2 mg/ kg/day) is the mainstay of treatment. Once a therapeutic response is achieved (clinical improvement, normalization of gas exchange abnormalities, and clearing of radiographic infiltrates), coricosteroids are tapered over the following 2–6 months, while cyclophosphamide is continued for 6–12 months. Due to the high incidence of Pneumocystis jiroveci with this regimen, trimethoprim-sulfamethoxazole prophylaxis is also recommended [24]. Although data are limited, azathioprine and methotrexate have be used in patients who do not tolerate cyclophosphamide therapy [24–26]. In persistent disease, intravenous immunoglobulin has been shown to be of benefit [27]. Because recurrences are common, disease monitoring by erythrocyte sedimentation rates, ANCA levels, urinalysis, and diffusing capacities are recommended [15]. With an early mortality of 37%, the prognosis of WG with DAH is worse than in WG alone [10]. Microscopic Polyangiitis The small-vessel vasculitis variant of polyarteritis nodosa (PAN) is termed microscopic polyangiitis (MAP), previously referred to as microscopic polyarteritis. Manifestations almost always include FSNG, and pulmonary capillaritis with DAH is reported to occur in approximately 30% of patients. Additional extra-renal signs and


symptoms include fever, weight loss, arthralgias, arthritis, myalgias, skin involvement (raised purpura), epistaxis, episcleritis, peripheral neuropathy, hypertension, and gastrointestinal bleeding [28, 29]. Reported mean ages of patients with MAP range from 40 to 50 years [29], but those with DAH tend to be older with a mean age of 56 years [28]. Laboratory studies reveal non-specific elevations in the erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and antinuclear antibodies, which normalize after treatment. Circulating immune complexes have been reported in approximately half of the cases, but are rarely detected in tissue [28, 29]. Classic PAN, in which DAH does not occur, is associated with hepatitis B [30]. Antineutrophil cytoplasmic antibodies (ANCAs) are present in approximately 75% of patients with MAP. These antibodies are directed against myeloperoxidase (p-ANCA) in 85% of patients and against proteinase-3 (c-ANCA) in 10–15% of patients, implying that the ANCA pattern alone can not be relied upon to distinguish MAP from WG [21]. As with WG, treatment is initiated with corticosteroids and cyclophosphamide, and substitution of cyclophosphamide with azathioprine is appropriate once the disease is in remission [25]. Additionally, intravenous immunoglobulin has shown some benefit in persistent disease [25]. In one case, life-threatening DAH was successfully treated with recombinant factor VIIa [31]. In patients with MAP and DAH, the early mortality reaches 30% [29]. Recurrences are common, may be lethal, and have been associated with the development of both obstructive lung disease and pulmonary fibrosis [28, 32, 33]. The 5-year survival is approximately 65% [28, 29]. Isolated Pulmonary Capillaritis Isolated pulmonary capillaritis is a lung-limited small vessel vasculitis in which there is no evidence of an accompanying systemic disease. Although most patients diagnosed with isolated pulmonary capillaritis have negative serologies, there are reports of patients with isolated pulmonary capillaritis with positivity of serum p-ANCA [34, 35], suggesting that at least some cases may represent a lung-limited form of microscopic polyangiitis [10, 36]. Since isolated pulmonary capillaritis is a lung specific disease, it must be distinguished from idiopathic pulmonary hemosiderosis, and therefore, a lung biopsy is required. In retrospective review of 8 patients with isolated pulmonary capillaritis, the clinical presentation included symptoms of dyspnea, cough, pleuritic chest pain, fever, and hemoptysis [36]. Over half the patients had symptoms suggestive of an upper respiratory tract infection prior to

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the onset of DAH, and none had evidence of a systemic disease at a median follow-up of 43 months. Lung histology demonstrated the typical features of pulmonary capillaritis, and direct immunofluorescence for IgA, IgE, IgG, IgM, albumin, and complement was negative. Of the 5 patients treated with intravenous corticosteroids and/or cyclophosphamide, 4 survived and 1 died of septic complications related to immunosuppressive therapy. Two patients survived without immunosuppressive treatment. Recurrences occurred in 2 patients, although both were reportedly noncompliant with cyclophosphamide therapy. Overall, 7 of the 8 patients survived. Treatment recommendations are similar to those for other forms of pulmonary vasculitis (see ‘Wegener’s Granulomatosis’) [23]. Connective Tissue Disease (Systemic Lupus Erythematosus) There are a number of pleuropulmonary complications that may occur in patients with systemic lupus erythematosus (SLE). DAH is uncommon, occurring in less than 4% of tertiary hospital admissions for SLE complications. DAH is more likely to occur in patients with an established diagnosis of SLE than as the initial presentation. Typically, patients with SLE and DAH have extrapulmonary manifestations of SLE. The most common of these is active lupus nephritis. While hemoptysis may not be evident at presentation, DAH with resultant severe gas exchange disturbances often necessitates mechanical ventilation. Zamora et al. [37] recently highlighted that pulmonary capillaritis is the predominant histologic pattern in SLE associated DAH, although bland pulmonary hemorrhage and diffuse alveolar damage have been described [6, 38]. Myers and Katzenstein [39] described microangiitis (small-vessel vasculitis of the capillaries, arterioles, and small muscular arteries) in addition to pulmonary capillaritis in 3 of 4 patients with SLE and DAH. In DAH-associated SLE, immunofluorescence and electron microscopy frequently reveal immune complex deposition with the granular accumulation of IgG and C3 along the alveolar septae and occasionally within blood vessel walls [6, 37, 39]. In patients with SLE and hemoptysis, conditions such as pneumonia, acute lupus pneumonitis, and pulmonary embolism must also be considered. Infectious pneumonia is the most common cause of pulmonary infiltrates in patients with SLE. Acute lupus pneumonitis (ALP), typically characterized by the acute or subacute onset of dyspnea with diffuse or patchy opacities on chest radiographs, is more likely than DAH to be an initial manifestation of SLE.

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Hemoptysis may occur in ALP, in addition to more common symptoms of dyspnea, tachycardia, cough, and fever. Pleural effusions are present in 50% of patients with ALP as opposed to patients with SLE and DAH. Diffuse alveolar damage is the most frequently described histologic pattern of injury, and significant decreases in hemoglobin concentrations are not expected [40]. Pulmonary embolism and infarction have been reported in patients with SLE, and may occur in association with DAH [41, 42]. DAH with SLE-associated antiphospholipid syndrome has been reported to occur [43]. Management of DAH in SLE includes corticosteroids and immunosuppressive agents (including cyclophosphamide and azathioprine). While mortality rates in most series have been quite high [6, 37, 44], a recent series has reported a 100% survival [45]. High mortality rates are most likely influenced by a number of factors including the need for mechanical ventilation and concurrent infection. Plasmapheresis has not been shown to improve survival [37].

Other Connective Tissue Diseases Although more commonly seen in SLE, DAH has been described in association with other connective tissue diseases. DAH with pulmonary capillaritis has rarely been reported to complicate rheumatoid arthritis, mixed connective tissue disease, and polymyositis [46, 47]. DAH with pulmonary capillaritis and rapidly progressive renal failure has been reported to occur in patients with scleroderma [48]. Patients with primary APS may also present with DAH. Treatment with corticosteroids typically results in rapid improvement [49].

Behçet’s Syndrome Behçet’s syndrome is a chronic systemic vasculitis defined by the clinical triad of relapsing iritis and oral and genital ulcers. The syndrome typically appears in the third decade. Pulmonary involvement occurs in 10% of patients, is frequent in men, tends to occur several years after the onset of disease, and is associated with hemoptysis in over 75% of cases. Additional manifestations include skin lesions (erythema nodosum-like lesions and skin reactivity to needle pricks), arthritis, thrombophlebitis, and neurologic involvement (of both the central and peripheral nervous systems) [50] Renal disease may be more frequent than previously recognized and includes amyloidosis and a wide spectrum of glomerulonephritides including rapidly progressive glomerulonephritis [51].

involvement is rare and tends to occur in older children and adults; 75% of patients with pulmonary involvement are over 10 years of age. The majority of patients with pulmonary involvement present with diffuse alveolar hemorrhage. Additional pulmonary manifestations reported include hemoptysis due to bronchial petechial lesions and interstitial lung disease [58]. Diffuse alveolar hemorrhage with pulmonary capillaritis is the predominant histopathologic finding [58]. Immunohistochemistry reveals deposition of IgA along the alveolar septa, similar to findings seen in the kidneys and skin lesions [59]. While there are no controlled trials of corticosteroids, they have been found effective in preventing the HSP associated nephritis and have been recommended for use in HSP-associated DAH [60]. Fig. 10. Computed tomography of the chest in a patient with Behçets

disease and an aneurysm of the pulmonary left pulmonary artery.

Pulmonary involvement is usually the result of vasculitis. In the small vessels, a transmural and lymphocytic predominant infiltrate results in venulitis, capillaritis, and arteriolitis leading to DAH. In larger vessels, the inflammatory infiltrate appears within the subintimal layer and results in destruction of the arterial wall with aneurysm formation. Aneurysms of the pulmonary and bronchial arteries, in the presence of a persistent inflammatory process, may erode into adjacent bronchi causing massive pulmonary hemorrhage (fig. 10). Additionally, pulmonary artery aneurysms may become thrombosed, resulting in infarction and occasionally hemoptysis [52]. Immunohistochemical studies indicate that IgG, C3, and C4 are deposited in the walls of small veins and capillaries in lung tissue, as well as in the subendothelium of the kidneys [53]. Circulating immune complexes are present in higher concentrations in patients with more severe disease than in those with mild disease [54]. Pulmonary involvement with hemoptysis, regardless of underlying cause, is a poor prognostic sign associated with death in 30% of patients [52]. Corticosteroids and immunosuppressive agents are the mainstay of therapy [55, 56], and anti-tumor necrosis factor therapy has been reported to be of benefit in case reports. [57]. Henoch-Schönlein Purpura Henoch-Schönlein purpura (HSP) is another small-vessel vasculitis. While HSP more commonly occurs in children, it can occasionally affect adults. It is characterized by palpable purpura, hematuria (due to a FSGS), abdominal pain, gastrointestinal bleeding, and arthralgias. Pulmonary


Drug-Induced Capillaritis A number of medications have been reported to cause diffuse alveolar hemorrhage with bland alveolar hemorrhage (see below). However, DAH with associated capillaritis has been reported following the administration of propylthiouracil [61, 62], hydralazine [63] and All-trans-retinoic acid (ATRA) [64]. Other drugs including, gemtuzumab ozogamicin [65] and infliximab [66], have reportedly led to DAH although the mechanisms remain unknown. Mixed Cryoglobulinemia Mixed cryoglobulinemia is an immune complex-mediated vasculitis, in which antigen-antibody complexes are deposited in small and, less frequently, medium-sized arteries. Clinical manifestations include palpable purpura, arthralgias, asthenias, hepatomegaly, and peripheral neuropathy. A proliferative glomerulonephritis may be present. Studies have strongly suggested an etiologic role for hepatitis C and less commonly, hepatitis B and HIV [67]. While pulmonary symptoms are typically not severe, pulmonary function testing and chest radiographs frequently reveal abnormalities [68]. Although very rare, mixed cryoglobulinemia associated with DAH and pulmonary capillaritis has been reported [69].

Specific Diseases Associated with Diffuse Alveolar Hemorrhage and Bland Alveolar Hemorrhage

Goodpasture’s Syndrome – Anti-Basement Membrane Antibody Disease Goodpasture’s syndrome is characterized by DAH and glomerulonephritis in which anti-basement membrane antibodies (ABMA) are found in the serum, lung, and/or kidney (fig. 11) [70]. These antibodies are directed against type IV

257

Fig. 11. Immunofluorescence study revealing a linear pattern of

staining with immunoglobulin G in Goodpasture’s syndrome.

collagen (specifically the NC1 domain of the ␣-3 chain), which is a major component of glomerular and alveolar basement membranes [71]. Because not all patients with these pathologic antibodies develop both DAH and glomerulonephritis [72], the term ABMA disease is now used to describe the clinical spectrum of disease [10]. In Goodpasture’s syndrome, serum ABMA are present in up to 90% of patients, and antibody levels correlate with the severity of renal (but not pulmonary) involvement [73]. Concurrent pulmonary and renal involvement occurs in up to 80% of cases [72]. Isolated glomerulonephritis occurs in most of the remaining cases, while sole DAH occurs in less than 10% of cases [6, 72]. Goodpasture’s syndrome occurs more frequently in men. Most patients are between 20 and 30 years of age, although any age group may be affected [74, 75]. Histocompatibility human leukocyte antigen (HLA-DRw2) is seen in a majority of patients with Goodpasture’s syndrome, suggesting a genetic susceptibility [76, 77]. Cigarette smoking has been associated with Goodpasture’s syndrome. In one study of 51 patients with ABMA disease and glomerulonephritis, all 37 of the smokers developed DAH, while only 20% of nonsmokers developed DAH [78]. Restarting smoking has been associated with recurrent DAH [78]. Hydrocarbon fume exposure and re-exposure have also been linked to DAH and DAH exacerbations [7, 78, 80]. Histopathologically, both bland pulmonary hemorrhage and pulmonary capillaritis have been reported, bland pulmonary hemorrhage being more common [7]. Renal biopsy reveals a FSGS with crescent formation, even in patients without clinical evidence of renal disease [81]. Immuno-

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fluorescence to IgG antibody demonstrates a linear pattern along the basement membranes of glomerular tufts and alveolar walls (fig. 11) [8, 82]. Treatment depends on the extent of involvement. In patients with DAH and without renal involvement, the disease typically responds to corticosteroids alone [83]. Renal involvement is treated with a combination of corticosteroids, cytotoxic drugs (cyclophosphamide), and plasmapheresis [84]. The mortality or renal transplant rate was as high as 90% prior to the introduction of this regimen [10]. Levy et al. [84] found improved recovery of renal function and better longterm outcomes since the introduction of this regimen, which included oral prednisolone (approximately 1 mg/kg of body weight per day to a maximum of 60 mg), oral cyclophosphamide (2–3 mg/kg/day), and plasma exchange (50 ml/kg to a maximum of 4 liters daily for at least 14 days or until antibodies were undetectable). However, anuric patients do not appear to respond to this regimen and may require persistent renal replacement therapy or transplant [85]. Of all the etiologies of DAH, Goodpasture’s syndrome has the poorest response to therapy and poorest survival; this is likely related to early and undetected renal disease [10]. The 2-year survival rate in treated patients is approximately 50%. Death is more likely to occur within the first year and is more commonly the result of complications of DAH including unremitting pulmonary hemorrhage and refractory respiratory failure [75]. Progressive renal disease is a poor prognostic factor [85]. In cases without renal involvement, spontaneous remissions have been reported to occur [83]. Idiopathic Pulmonary Hemosiderosis Idiopathic pulmonary hemosiderosis (IPH) describes a diffuse alveolar hemorrhage syndrome without an associated systemic disease, in which other causes of pulmonary hemorrhage have been excluded-including isolated pulmonary capillaritis [86]. The clinical course of this disease is characterized by recurrent episodes of DAH. IPH is primarily a disease of children; however, 20% of cases present in adulthood. In adults, IPH is more common in men, and most patients are between 20 and 40 years of age. There may be a genetic predisposition in some cases of IPH, as familial clustering has been reported [87]. Typically, the hemoptysis in IPH is episodic and recurrent, and the presentation ranges from mild dyspnea to frank respiratory failure. Chronic, recurrent DAH may result in pulmonary fibrosis and clubbing of the digits (fig. 12). Low-grade fever may be present, and iron deficiency anemia is common [86]. Patients usually have an abnormal chest radiograph. Pulmonary function tests reveal a restrictive pattern

recurrent episodes of massive pulmonary hemorrhage with early death [86, 98].

Fig. 12. Photomicrograph of pulmonary fibrosis resulting from chronic, recurrent diffuse alveolar hemorrhage in idiopathic pulmonary hemosiderosis. Original magnification ⫻40.

(resulting from DAH-included fibrosis) and a decreased diffusing capacity [88] or, less commonly, an obstructive pattern (resulting from DAH-induced emphysema) [89, 90]. Bronchoalveolar lavage demonstrates pulmonary hemorrhage with hemosiderin-laden macrophages. A lung biopsy revealing bland pulmonary hemorrhage is necessary for a definitive diagnosis [36]. In addition to bland pulmonary hemorrhage, histology demonstrates type II epithelial cell hyperplasia, capillary dilatation and tortuosity, and hemosiderin-laden macrophages within the interstitium and alveolar spaces. Immune complexes are not present. Electron microscopy has revealed type I epithelial cell damage with exposure of the alveolar capillary membrane. The alveolar capillary membrane is also abnormal with duplication, separation, and focal ruptures of the membrane and collagen deposition within the membrane [91]. While the pathogenesis of IPH is unknown, there is evidence suggesting an autoimmune process. Observations supporting this include the following findings: elevated serum IgA levels have been reported to occur in as many as 50% of cases [92]; there is an association of IPH with celiac disease [89, 90]; and recurrences have been described after lung transplantation [93]. Treatment options include anti-inflammatory drugs, cytotoxic agents, and possibly plasmapheresis [86, 94, 95]. Adults have a better prognosis than children [96, 97]. Onequarter of patients remain disease free after the initial episode of DAH, one-quarter of patients are free of active disease but have persistent symptoms including dyspnea and anemia, one-quarter of patients have active disease that leads to pulmonary fibrosis, and the remaining quarter have


Acid Anhydrides (Trimellitic Anhydride and Pyromellitic Dianhydride) and Isocyanates Acid anhydrides, including trimellitic anhydride (TMA) and pyromellitic dianhydride (PMDA), are low-molecularweight, reactive organic chemicals. TMA and PMDA are components of epoxy resins employed in the manufacture of paints and plastics. After the inhalation of these acid anhydrides, diffuse alveolar hemorrhage has been reported [99, 100]. The mechanism by which these acid anhydrides lead to DAH is not known, but may include direct toxic injury and immune-mediated damage [101]. Isocyanate exposure, including hexamethylene diisocyanate and toluene diisocyanate, has also been associated with DAH [102]. After occupational exposure to trimellitic anhydride, acute symptoms include cough, chest discomfort, dyspnea, epistaxis, and mild hemoptysis. With persistent exposure (often months), DAH may occur. At this point, patients are typically hospitalized with severe respiratory distress, significant hemoptysis, and fever. Systemic involvement has not been reported. Laboratory findings reveal anemia thought to be related to the lung hemorrhage. Some patients have evidence of a hemolytic anemia. Anti-basement membrane antibodies are absent and complement levels are normal. Serum antibodies directed against TMA-human serum albumin complexes and PDMA have been reported, and are believed to be involved in the pathogenesis of the syndrome [100, 101]. Additionally, hemolytic antibodies (directed against TMA-haptenized erythrocytes) and hemagglutination antibodies (directed against TMA-erythrocyte complexes) have been found. While these antibodies may be involved in the hemolytic anemia reported in some patients, Coombs’ testing has been negative [101]. Bilateral pulmonary opacities are typically found on chest radiographs, and transbronchial lung biopsy reveals bland alveolar hemorrhage with type II alveolar cell hyperplasia and interstitial edema. Immunofluorescent studies have been negative for immunoglobulin or complement deposition [101, 102]. Treatment consists of removing the patient from the anhydride exposure and supportive care, which has resulted in complete clinical recovery [103, 104]. Drug-Induced – Penicillamine, Amiodarone, and Nitrofurantoin Penicillamine (typically used in the treatment of Wilson’s disease and rheumatoid arthritis) has been associated with DAH and glomerulonephritis producing a

259

‘pseudo-Goodpasture’s syndrome’ [105]. It is rare, and appears to occur with high-dose D-penicillamine (average maximum daily dose of 1.3 g) and a prolonged course of therapy (average duration of 37 months prior to the onset of symptoms). Pulmonary symptoms include dyspnea, cough, and hemoptysis, while renal symptoms include hematuria. The glomerulonephritis leads to renal failure, which typically necessitates hemodialysis. Chest radiographs reveal bilateral basilar infiltrates, diffuse interstitial infiltrates, bilateral alveolar infiltrates, and diffuse alveolar infiltrates [106]. Renal biopsy exposes a crescentic glomerulonephritis and may reveal a granular (not linear) pattern of antibodies (IgG and IgM) or complement (C3) on immunofluorescent staining [106, 107]. Granular fibrinogen deposits have also been reported [106]. Unlike Goodpasture’s syndrome, the majority of these patients lack anti-basement membrane antibodies [106]. However, circulating antibodies have been reported in some patients [108]. Lung biopsy reveals bland pulmonary hemorrhage with intra-alveolar hemorrhage with hemosiderin-laden macrophages, and fibrosis may be present. Immunohistochemical staining of the alveolar capillary basement membrane does not reveal antibody deposition. The development of this Goodpasture-like syndrome has resulted in death in nearly 50% of the cases reported. In survivors, the most commonly used therapeutic regimen has included a combination of corticosteroids, immunosuppressive agents, and plasmapheresis [106, 109]. This regimen is similar to that used in Goodpasture’s syndrome (see above). Amiodarone is a class III anti-arrhythmic well known for its pulmonary toxicity [110]. Cases of DAH have been reported to occur after both intravenous and oral administration of amiodarone [111–114]. The clinical presentation is similar to that of patients with DAH resulting from other conditions, but may include orthodeoxia (a fall in oxygen saturation in the upright position) [112]. Lung biopsy reveals findings consistent with amiodarone toxicity, namely large numbers of foamy, intra-alveolar macrophages, in addition to either diffuse alveolar damage with intra-alveolar hemorrhage or bland pulmonary hemorrhage [112, 114]. The DAH is thought to be due to the direct toxic effect of amiodarone or, alternatively, an immune-mediated injury [110]. The DAH has responded both to withdrawal of amiodarone and corticosteroid therapy [112, 115]. Nitrofurantoin has been associated with fatal and nonfatal diffuse alveolar hemorrhage, and lung biopsy has revealed bland pulmonary hemorrhage [116, 117]. In the nonfatal case, nitrofurantoin was discontinued, and the patient was treated with corticosteroids, cyclophosphamide, and plasmapheresis [117].

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Fig. 13. Photomicrograph of a small pulmonary arteriole with the infiltration and proliferation of capillary networks within the arteriole wall in pulmonary capillary hemangiomatosis. Original magnification ⫻100.

Drug-Induced – Antiplatelet and Anticoagulation Drugs Abciximab, a monoclonal antibody against platelet glycoprotein IIb/IIIa receptors, has been associated with diffuse alveolar hemorrhage. While the histopathologic changes are unknown, reversal of the antiplatelet effects with blood product transfusions is the recommended therapy [118]. Anticoagulation therapy with warfarin has been associated with DAH, and was successfully treated with vitamin K and fresh-frozen plasma [119]. Pulmonary Capillary Hemangiomatosis Pulmonary capillary hemangiomatosis (PCH) is a rare disorder in which capillaries proliferate within the alveolar interstitium and walls of pulmonary veins. This abnormal proliferative process occludes the pulmonary arterioles and venules, causing post-capillary pulmonary hypertension, which may in turn result in DAH. The mean age of onset is 29, but cases have been reported to occur from 2 to 71 years of age. The most common presenting symptom is dyspnea, followed by hemoptysis. With progression, severe pulmonary hypertension and cor pulmonale occurs in 50% of patients [120]. DAH may be intermittent and life-threatening [121]. Familial occurrences have been reported [122]. PCH has been reported to occur after bilateral lung transplantation for ␣1-antitrypsin deficiency emphysema, though the donor lung had no evidence of PCH at the time of retrieval [123]. The histopathologic features of PCH include proliferation of capillaries within the interstitium and infiltration of these capillary networks into the walls of small arterioles and venules (fig. 13). The venous infiltration has been associated with intimal fibrosis, which may mimic and must be

distinguished from veno-occlusive disease [124]. Alveolar hemorrhage with hemosiderin-laden macrophages is seen in areas of involvement [121]. The median survival is 3 years from the onset of symptoms [120], and death results from cor pulmonale,

pulmonary hemorrhage, or both [125]. Therapy has been directed at inhibiting the proliferation of endothelial cells with interferon-alpha-2a, and case reports have reported a clinical benefit [120, 125]. Successful lung transplantation has been reported [125].

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103 Herbert FA, Orford R: Pulmonary hemorrhage and edema due to inhalation of resins containing tri-mellitic anhydride. Chest 1979; 76:546–551. 104 Ahmad D, Morgan WK, Patterson R, Williams T, Zeiss CR: Pulmonary haemorrhage and haemolytic anemia due to trimellitic anhydride. Lancet 1979;2:328–330. 105 Israel-Biet D, Labrune S, Huchon GJ: Druginduced lung disease: 1990 review. Eur Respir J 1991;4:465–478. 106 Derk CT, Jimenez SA: Goodpasture-like syndrome induced by D-penicillamine in a patient with systemic sclerosis: report and review of the literature. J Rheumatol 2003;30: 1616–1620. 107 Gavaghan TE, McNaught PJ, Ralston M, Hayes JM: Penicillamine-induced ‘Goodpasture’s syndrome’: successful treatment of a fulminant case. Aust NZ Med 1981;11: 261–265. 108 Louie S, Gamble CN, Cross CE: Penicillamine associated pulmonary hemorrhage. J Rheumatol 1986;13:963–966. 109 Swainson CP, Thomson D, Short AI, Winney RJ: Plasma exchange in the successful treatment of drug-induced renal disease. Nephron 1982;30: 244–249. 110 Olson AL, Heard K: Class III antidysrhythmic agents; in Dart RC (ed): Medical Toxicology, ed 3. Philadelphia, Lippincott, Williams, & Wilkins, 2004, pp 689–699. 111 Vizioli LD, Cho S: Amiodarone-associated hemoptysis. Chest 1994;105:305–306. 112 Iskander S, Raible DG, Brozena SC, Gaitanaru DM, Ayala G, Isakndrian AE: Acute alveolar hemorrhage and orthodeoxia induced by intravenous amiodarone. Cathet Cardiovasc Interv 1999;47:61–63. 113 Goldstein I, Topilsky M, Segev D, Isakov A, Heller I: Very early onset of acute amiodarone pulmonary toxicity presenting with hemoptysis. Chest 1997;111:1446–1447. 114 Ravishankar R, Samuels LE, Kaufman MS, Samuels FL, Thomas MP, Galindo L, Morris RJ, Brockman SK: Amiodarone-associated hemoptysis. Am J Med Sci 1998;316: 390–392. 115 Dean PJ, Groshart KD, Porterfield JG, Iansmith DH, Golden EB Jr: Amiodaroneassociated pulmonary toxicity: a clinical and pathologic study of eleven cases. Am J Clin Pathol 1987;87:7–13. 116 Averbuch SD, Yungbluth P: Fatal pulmonary haemorrhage due to nitrofurantoin. Arch Intern Med 1980;140:271–273.


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Amy L. Olson, MD Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center Division of Pulmonary Sciences and Critical Care Medicine 4200 East Ninth Avenue, C272 Denver, CO 80262 (USA) Tel. ⫹1 303 398 1621, Fax ⫹1 303 270 2740 E-Mail [email protected]

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Pulmonary Langerhans’ Cell Histiocytosis Sergio Harari

Antonella Caminati

U.O. di Pneumologia e Terapia Semi-Intensiva Respiratoria, Servizio di Fisiopatologia Respiratoria ed Emodinamica Polmonare, Ospedale San Giuseppe AFAR, Milano, Italy

Abstract Pulmonary Langerhans’ cell histiocytosis (PLCH) is a diffuse, smoking-related lung disease characterized pathologically by bronchiolocentric inflammation, cyst formation, widespread vascular abnormalities, and physiologically by exercise limitation. It is part of a heterogeneous group of conditions of unknown etiology characterized by an abnormal proliferation of antigen presenting cells of bone marrow derivation known as Langerhans’ cells. Pulmonary involvement is not unusual in systemic forms of Langerhans’ cell histiocytosis, but symptoms are rarely prominent. Localized pulmonary involvement is a rare pulmonary disease that occurs predominantly in young adults. It has several unique clinical and epidemiological features that justify its classification as a distinct clinical-pathological entity. The precise incidence and prevalence of PLCH are unknown, although studies of lung-biopsy specimens from patients with interstitial lung disease identified PLCH in only 5% of cases. Light microscopy of lung biopsy shows scattered stellate nodules that are frequently bronchiolocentric. The nodules are formed of focal collections of Langerhans’ cells characterized by their morphology (nuclei with fine chromatin and grooves or folds), immunophenotype (S100 and CD1 positive) and ultrastructure (cytoplasmic Birbeck granules), interspersed with eosinophils and small lymphocytes.The infiltrate leads to progressive destruction of lung parenchyma and to the development of widespread cystic change.The pathogenesis of PLCH is not well understood but its bronchiolocentricity and tendency to regress following cessation of cigarette smoking suggests a reactive immune

response in the bronchioles mediated by the Langerhans’ cell, possibly through cytokine production. The outcome is highly variable, ranging from rapid spontaneous resolution to irreversible respiratory failure. Stop smoking leads to stabilization of symptoms in most patients. No treatment has been confirmed to be useful and no double-blind therapeutic trials have been reported. Lung transplantation has also been performed for treatment of PLCH but the disease may recur in the transplanted lung in up to 25% of patients. Copyright © 2007 S. Karger AG, Basel

Definition

Pulmonary Langerhans’ cell histiocytosis (PLCH) is a smoking-related interstitial lung disease histologically characterized by a proliferation of Langerhans’ cell (LC) infiltrates which form multiple, bilateral, interstitial, peribronchiolar nodules [1]. The nodular lesions frequently cavitate and form thick and thin-walled cysts. LCs are differentiated cells of monocyte-macrophage lineage that function as antigen-presenting cells. The normal LC is a dendritic cell that occurs in epithelial surfaces, particularly the skin. Abnormal proliferation of LCs is linked to a heterogeneous group of disorders and clinical syndromes currently known as LC histiocytosis (LCH) [2–4]. PLCH affects the lung either in isolation or in addition to other organ systems [2, 5]. The concept of histiocytosis X was proposed by Lichtenstein in 1953 [6] to embrace three major localized and generalized patterns of histiocytosis including eosinophilic granuloma,

Hand-Schüller-Christian disease, and Letterer-Siwe disease. These different forms of disease are united by a common histopathological finding – the LC granuloma – but the clinical spectrum of these disorders is extremely large, extending from an acute, disseminated form with a poor prognosis to the presence of lesions localized to a single organ which follows a more benign clinical course [3, 7]. The eosinophilic granuloma is the unifocal variant and commonly involves bone, lymph nodes, or lungs as a primary target. HandSchüller-Christian disease is a multifocal disease of early childhood that commonly affects the lungs and bones; a classic triad of bone defects, exophthalmos, and diabetes insipidus can be seen. This multisystem disease is treated with systemic chemotherapy. Letterer-Siwe disease is a potentially fatal systemic disease in infants and children. It is characterized by involvement of the skin, lymph nodes, bone, liver and spleen. Pneumothorax is a common pulmonary complication. Pulmonary symptoms are rarely prominent, although the presence or absence of lung involvement does appear to have a bearing on the outcome [3]. However, this concept of histiocytosis X is no longer used due to the imprecise definitions of these terms, the recognition that the proliferating cells are LCs, and the growing recognition that there are profound differences in organ involvement, clinical course, and therapeutic response [1, 2]. LCH replace the many previous terms for this disorder [2]. PLCH occurs most commonly in young adults and has several unique clinical and epidemiological features that justify its classification as a distinct clinicopathological entity [2, 3, 7, 8].

Epidemiology

PLCH in adults is a rare disease but the precise incidence and prevalence are unknown. In a large series of patients undergoing open lung biopsy for the diagnosis of diffuse lung disease, PLCH was observed in less than 5% of cases [9]. In the period from May 2001 to January 2005, the RIPID (Italian Register for Diffuse Infiltrative lung Disorders) registered 3,152 cases of rare interstitial pulmonary diseases; the related prevalence of PLCH was 2.8% [10]. However, because the disease may be asymptomatic, undergoes spontaneous remission in a substantial proportion of patients and may be difficult to identify on the basis of lung biopsy in patients with advanced disease, it is probably underdiagnosed. There are no known genetic factors that predispose persons to PLCH and the disease is essentially sporadic [2]. PLCH occurs predominantly in young adults with a peak

Pulmonary Langerhans’ Cell Histiocytosis

frequency between 20 and 40 years of age [2, 3, 7, 8]. A strong male predominance was initially reported [11, 12], but in other studies, a similar proportion of males and females or a predominance of females were observed [13, 14]. This discrepancy probably reflects differences in smoking habits of patients in the populations evaluated. Indeed, the principal epidemiological factor associated with PLCH is smoking: 90–100% of patients have been current smokers in almost all series [11–13]. These patients are often heavy smokers (⬎1 pack per day), but because of their relatively young age, total lifetime cigarette consumption is not necessarily striking. No other environmental factors have been associated with PLCH. For unknown reasons, the disease is rarely observed in African-American or Asian people [2]. An association has been reported between PLCH and lymphoma [3, 15]. Focal LCH lesions have been identified in lymph node biopsy specimens from areas adjacent to lymphomatous involvement [3], but clinically apparent PLCH is more likely to be observed in the follow-up of patients previously treated with chemotherapy and/or radiation therapy, usually for Hodgkin’s disease [16, 17].

Pathogenesis and Etiology

The pathogenesis and etiology of LCH are not well understood. Despite histological similarities in the lesions in diffuse and localized forms of the disease, it remains unclear whether the mechanisms are similar in these different clinical forms. A major and persistent question is whether the disease is a malignancy or reactive disorder. The widespread infiltration of tissues by LC in diffuse forms of LCH is certainly suggestive of malignancy. Furthermore, some studies have shown that LC in both diffuse LCH and localized forms of the disease, including PLCH, are clonal in origin [18, 19], whereas a more recent study suggests polyclonal expansion of LCs in most patients with adult PLCH [19a]. Clonal populations are not necessarily malignant, however, and several observations argue strongly against the idea that LC in PLCH are neoplastic. These arguments include the high proportion of patients that show spontaneous regression, the isolated involvement of lung in most cases, the strong bronchocentric distribution of the nodular lesions, the virtual absence of LC in end-stage lesions, the rarity of cellular atypia, and the low rate of replication of LC in LCH granulomas [8, 11–13, 20]. PLCH is generally believed to be a reactive rather than a neoplastic process. Because the proliferation rate of LC in LCH granulomas is low [20], it is likely that recruitment is the major force driving the accumulation of LC in early lesions. Normal pulmonary LCs are present only within the bronchial

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and bronchiolar epithelia [21]. Similarly, the granulomatous lesions in PLCH are highly bronchiolocentric, suggesting that an epithelial microenvironment remains an important determinant for the accumulation of LCs in this disease [3, 8, 11]. Because of the prominent effects of heavy smoking on the bronchiolar epithelium and the strong association between PLCH and smoking, the possibility that smoking induced changes in the epithelium promote accumulation of LCs is attractive. Epithelial cells are able to produce a variety of cytokines, including factors that influence the proliferation, survival, and differentiation of LCs [21, 22]. In this regard, bronchiolar epithelial cells overlying early LCH granulomas produce greater amounts of GM-CSF than epithelial cells in adjacent uninvolved bronchioles, compatible with the idea that focal abnormalities influence the initiation of the pathological lesions [23]. Mediators produced by other airway cells may also be important. Neuroendocrine cells, a source of bombesin-like peptides, are substantially increased in the bronchioles of patients with PLCH [24]. Cigarette smoke induces secretion of these peptides that may have an important role in mediating lung injury by promoting the secretion of cytokines by lung macrophages and stimulating the growth of lung fibroblasts, which may eventually proceed to lung fibrosis [2]. The importance of these and other changes in the airway epithelium in the pathogenesis of PLCH, however, remains to be established. Other components of cigarette smoke, such as tobacco glycoprotein, have also been implicated in the pathogenesis of PLCH [2]. Tobacco glycoprotein is an immunostimulant that induces lymphocyte differentiation and lymphokine production [2]. Whatever the role of smoking induced epithelial modifications in the initiation of the process, only a very small proportion of smokers develops PLCH, indicating that other factors must also be required. Recent evidence strongly supports the idea that intrinsic abnormalities in LCs are also important for their massive accumulation in early lesions. A consistent feature of PLCH is the destruction of the bronchioles and adjacent structures by the granulomatous lesions [3]. LCs in LCH granulomas, unlike those present in the normal lung or in other pathological conditions, exhibit a number of phenotypic features characteristic of ‘mature’ LCs [25–27]. It is possible that these cells express activities that directly result in local tissue damage. It appears more likely, however, that these ‘mature’ LCs express enhanced lymphostimulatory activity and initiate an uncontrolled immune response that damages the airways and adjacent lung parenchyma [3]. This hypothesis presupposes the presence of an antigenic trigger, but such putative antigen remain to be identified. The possibility of a viral etiology has been raised and a role for a herpes virus (HSV6) has been suggested [28]. The bronchiolocentric

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distribution of the lesions and the strong association with cigarette smoking has raised the possibility that an immune reaction against a component of cigarette smoke is involved [3]. Abnormal bronchiolar epithelial cells could be a target [29]. According to this scenario, hyperplastic or dysplastic epithelial lesions would participate in two step of the process – the production of mediators necessary for the recruitment and/or differentiation of abnormal LCs and the expression of neoantigens that are a trigger for the ensuing granulomatous response. The targeting of epithelial cells would account for the bronchocentric nature of the lesions and the early destruction of the epithelium, and would also explain why cigarette smoking, a common cause of epithelial abnormalities, is frequently associated with PLCH. Nevertheless, no direct evidence for this possibility has been presented [3].

Pathology

The characteristic lesion of PLCH is composed of activated LCs organized into a loose granuloma and associated with lymphocytes and inflammatory cells, particularly eosinophils and macrophages [1, 3, 8, 29]. Both the appearance of the granulomas and the number of LCs can vary considerably depending on the stage of evolution of the lesions [1–3, 8]. At the light microscopic level, LC have highly irregular and folded nuclei and pale weakly eosinophilic cytoplasm. Cell borders are poorly defined because of numerous dendritic processes on the cell surface. The identity of these cells as LC must be confirmed by immunohistochemical staining with anti-CD1a monoclonal antibodies or by the identification of Birbeck granules using electron microscopy. In the future, it should be replaced by the use of anti-Langerin antibodies that specifically identify LC [30]. Although these cells also express cytoplasmic S-100 protein, this marker is present at the surface of other cell types and is therefore less specific. PLCH has a distinctive low-power appearance consisting of multiple nodular infiltrates with a stellate border extending into the surrounding interstitium [1]. The lesions are centered around distal bronchioles and infiltrate and destroy the airway walls. A recent study demonstrated that LC granulomas are found to be systematically centered on small airways, extending without interruption down to and including alveolar ducts. The granulomatous reaction appears to progress along the bronchiolar axis over time and is capable of extending the abnormalities in both the proximal and distal directions [31]. In view of this characteristic feature, PLCH should be considered to be a bronchiolitis rather than a diffuse interstitial lung disease.

of eosinophils is highly variable and they may be difficult to find in some cases. The fibrotic scars often maintain the stellate shape of the cellular lesions. This may provide a clue to the diagnosis in cases where only fibrotic lesions are sampled in an open biopsy. The number of LC diminishes in these advanced lesions. Severe cases may progress to honeycomb fibrosis, but this is uncommon.

Clinical Assessment

a

b

Fig. 1. a Low-magnification view of PLCH demonstrating the char-

acteristic stellate shape and the typical peribronchiolar location of the lesion (kindly provided by Prof. A. Pesci). b Low-magnification view of PLCH showing characteristic nodular cellular infiltrates that are separated by large areas of normal parenchyma. Increased numbers of macrophages are present in the alveolar spaces (kindly provided by Prof. A. Pesci).

Because of their close anatomic association with the bronchioles, vascular structures are also involved, although the disease is not primarily a vasculitis. The lesions are focal and are separated by apparently normal lung parenchyma [1–3, 8]. The granulomas in PLCH are poorly defined and extend into adjacent alveolar structures (fig. 1). Organizing pneumonia may be seen at the edge of the nodular infiltrates. The surrounding alveoli can contain large numbers of macrophages (a DIP-like reaction) associated with LCs. Nonspecific lesions associated with cigarette smoking (respiratory bronchiolitis, small lymphoid aggregates in the alveolar walls) are commonly present in these patients. Respiratory bronchiolitis (RB) is a histologic lesion reported to occur in virtually all smokers [32]. Since DIP is also etiologically linked to smoking, it is not unexpected that RB/DIP-like reactions frequently coexist in histologic specimens of PLCH [1–3, 32]. Emphysematous changes are also common [2, 33]. PLCH lesions progress from a cellular process to fibrotic scars, which may be nondiagnostic. Central cavitation is common. The cavities present in PLCH lesions represent the often highly distorted bronchiolar lumen remaining after destruction of the airway walls, and can evolve into thick- or thin-walled cysts [31]. Often, a spectrum of cellular, intermediate, and fibrotic lesions is seen in the same biopsy specimen. The cellular lesions consist of varying numbers of LCs mixed with macrophages, lymphocytes, and eosinophils. The number


Patients with PLCH present in a variety of ways. Up to 25% of patients are asymptomatic at presentation and the disease is diagnosed because of incidentally discovered radiographic abnormalities [2, 3, 13, 15]. Nevertheless, approximately two thirds of patients present with respiratory symptoms, usually a dry cough (50–70% of cases) and dyspnea (35–87% of cases). Less common presenting symptoms include fatigue (16–30%), weight loss (9–30%), chest pain that is frequently pleuritic (9–18%) and fever (15%) [8, 33, 34]. The presence of constitutional symptoms may lead to a search for an occult cancer unless the diagnosis of PLCH is suspected [2]. In a few cases chest pain is caused by rib involvement, but more frequently pain is a sign of a pneumothorax resulting from rupture of a subpleural cystic lesion, a complication seen in approximately 10–20% of patients [7, 8, 12–14, 34]. Pneumothorax can occur at any time throughout the evolution of the disease and can be recurrent and bilateral, but appears to be particularly frequent in younger men [8, 12–14, 34] (figs. 2, 3). More unusual presentations of PLCH include wheezing and hemoptysis (less than 5% of patients) [11–13, 34]. The occurrence of hemoptysis in an adult with PLCH should not be attributed to the underlying disease until other causes, such as bronchogenic carcinoma, have been excluded [2]. Other symptoms due to the involvement of other organs occur in 5–15% of patients [2, 13, 34]. The symptoms include pain due to involvement of bone; polyuria and polydipsia with diabetes insipidus related to hypothalamic involvement; rush secondary to cutaneous LCH; adenopathy due to superficial lymph-node involvement; and abdominal discomfort due to infiltration of the liver and spleen [2, 15, 34]. Physical examination of the chest is often normal except in patients with pneumothorax, rib lesions or those presenting with advanced disease in whom signs of cor pulmonale are frequently present. Clubbing is an exceptional finding. Rarely the patients can present atypically with predominant severe pulmonary hypertension, and the symptoms and hemodynamic features are similar in those seen in primary pulmonary hypertension [35–37].

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Fig. 4. Chest radiograph in a case of PLCH. A bilateral, reticular pattern Fig. 2. Chest radiograph shows right pneumothorax in a case of PLCH.

predominantly involving the middle and upper lung zones is present.

Fig. 3. HRCT of the chest in a case of bilateral pneumothorax.

Investigations

Fig. 5. Coronal reconstruction of a case of PLCH. HRCT of the chest

The chest radiograph is abnormal in most patients [11, 13, 34]. The radiographic findings of PLCH include reticular, nodular and reticulonodular patterns, often in combination [11, 34]. Abnormalities are usually bilateral, predominantly involving the middle and upper lung zones, with relative sparing of the costophrenic angles [2, 11, 13, 15] (fig. 4). Lung volumes are characteristically normal or increased.

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confirms the predominant upper lung involvement with relative sparing of the lung bases.

High-resolution computed tomography (HRCT) of the chest is a useful and sensitive tool in the diagnosis of PLCH and should be performed in all patients in which the diagnosis is suspected [38, 39] (fig. 5). HRCT findings mirror

a

b

Fig. 6. a Gross findings in a case of PLCH. Multiple cystic spaces are present. Although many cysts appear round, they can also have bizarre shapes. b HRCT findings mirror the gross pathologic appearances of this disease; there are cystic airspaces with thin but welldefined walls. Some cysts are confluent or appear irregular in shape.

Fig. 8. HRCT of the chest shows large cysts and bullae in a case of

PLCH.

Fig. 7. HRCT of the chest shows multiple, bilateral cystic airspaces.

a

b

Fig. 9. a, b CT of the chest in a case of PLCH shows nodules. Some

the gross pathologic appearances of this disease (fig. 6). In almost all patients, HRCT demonstrates cystic airspaces, which are of variable size, usually less 10 mm in diameter (fig. 7). Although many cysts appear round, they can also have bizarre shapes, being bilobed, cloverleaf shaped, or branching in appearance [40]. These unusual shapes are postulated to occur because of fusion of several cysts, or perhaps because the cysts sometimes represent ectatic and thick-walled bronchi [40]. Large cysts or bullae are also seen in more than half of cases [39] (fig. 8). In some patients, cysts are the only abnormality visible on HRCT, but in the majority of cases, small nodules (usually smaller than 5 mm in diameter) are also present [39, 40] (fig. 9).


are solid, others are cavitated; some have smooth margins, others have irregular or poorly defined margins.

Nodules can vary considerably in number in individual cases, probably depending on the activity of the disease; nodules can be few in number or myriad [39, 40]. The margins of nodules are often irregular. Many nodules can be seen to be peribronchial or peribronchiolar and therefore centrilobular in location. Some of the nodules may be cavitary. In the early stages, the most common finding is nodular change, whereas in the later stages, cystic change and fibrosis predominate [2, 3]. Serial study of individual

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patients indicates that the lesions evolve as follows: nodules, cavitary nodules, thick-walled cysts, thin-walled cysts [41, 42]. These studies also demonstrate that whereas some lesions can regress (nodules, cavitary nodules), cystic lesions tend to remain stable or increase in size [41]. The combination of diffuse, irregularly shaped cystic spaces with small peribronchiolar nodular opacities, predominantly in the middle and upper lobe, is highly suggestive of PLCH [39, 40]. The presence of typical features on HRCT frequently allows the clinician to make a diagnosis of PLCH without lung biopsy. HRCT reveals the nature of the parenchymal lesions more clearly than routine chest radiographs. HRCT scans often show that ‘reticular’ abnormalities on chest radiographs represent the confluence of shadows produced by multiple cystic lesions [39]. HRCT also permits the demonstration of parenchymal abnormalities in patients whose chest radiographs are interpreted as normal (5% of cases). In patients who require a lung biopsy HRCT scanning is indispensable for choosing an appropriate site. Although highly suggestive of PLCH, the typical pattern is not always present, and nonspecific patterns may be encountered. Ground-glass attenuation is an uncommon finding in PLCH but some patients can have a marked component of RB/DIP-like changes, which may be associated with diffuse ground-glass attenuation on HRCT; this radiographic finding can cause diagnostic difficulty [32]. Evidence of mosaic perfusion on inspiratory scans and airtrapping on expiratory scans may be seen in patients who have LCH and show nodular opacities or lung cysts [43]. This may reflect the presence of bronchiolar obstruction or air-trapping in cystic lung regions. HRCT has proved to be of considerable value in the follow-up of the disease. A nodular pattern on HRCT clearly reflects a histopathological activity of the disease, but caution must be used in evaluating patients with a cystic pattern, since HRCT does not permit to differentiate between fibrous cysts and cavitary granulomas. Thus, although it is usually considered to correspond to an end-stage disease, a cystic pattern does not exclude a still active pathological process [44]. The degree and extent of abnormalities on pulmonary function testing depend on the extent of pulmonary involvement and the stage of disease. Respiratory function at rest is normal in 10–15% of patients despite the presence of radiographic abnormalities [11, 14, 15]. The most frequently observed abnormality is a reduction in diffusing capacity (DLCO), seen in 70–90% of patients [8, 11, 12, 14]. This alteration is attributed to the thickening of the alveolo-capillary membrane, to the vascular involvement

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Fig. 10. Bronchoalveolar lavage in a case of PLCH: CD1a-stained cells are greater than 5%.

and to the subsequent alteration of the ventilation-perfusion ratio rather than to the destruction of the alveolo-capillary membrane [14]. A restrictive, obstructive or a mixed pattern have been described [8, 11, 34]. The presence of predominantly obstructive abnormalities in pulmonary function, rarely observed in most diffuse interstitial lung disease, is a useful indicator for a diagnosis of PLCH [3]. Resting blood gas tensions are typically normal or show moderate hypoxemia, but exercise limitation is often observed [13–15]. Morphological confirmation of the diagnosis may be obtained by bronchoalveolar lavage (BAL), transbronchoscopic lung biopsy, or surgical lung biopsy. The number of cells recovered by BAL is usually increased and is almost entirely due to an increase in alveolar macrophages resulting from cigarette smoking. The percentage of neutrophils is often somewhat higher than that of otherwise healthy smokers, and moderate eosinophilia (⬍10%) is not infrequent. The presence of increased numbers of LCs in the BAL fluid (identified by staining with antibodies against CD1a) is strongly suggestive of PLCH [3, 45] (fig. 10). When the proportion of CD1a-stained cells in the BAL fluid is greater than 5%, the diagnosis of PLCH is very likely [3]. An indeterminate elevation in the percentage of CD1a-positive cells (2–5%) is found on BAL in many cases. Increases in CD1a cells in this range may be present in heavy smokers and in persons with other interstitial lung diseases, rendering low-level elevations of CD1a cells difficult to interpret with certainty. If the threshold of 5% LC is used for the diagnosis of PLCH in adults, the specificity of the test is good, but the sensitivity appears to be quite

low (⬍25%). Transbronchoscopic lung biopsy has a low diagnostic yield, ranging from 10–40% [2, 3, 8], because of the patchy nature of the disease and the small amounts of tissue obtained. Surgical lung biopsy has the highest diagnostic yield [2, 3, 8, 34]. This high rate is principally due to the relatively large amount of tissue obtained during the procedure, which results in a greater likelihood that involved lung tissue will be sampled. Although it is the gold standard, surgical lung biopsy may also be subject to sampling error, since the lesions of PLCH are focal and of varying ages.

Diagnosis

PLCH should be suspected in any adult smoker with upper-lobe infiltrates especially if pulmonary function studies reveal mild impairment in diffusing capacity. The definitive diagnosis of PLCH generally requires evaluation of appropriate tissue biopsies. Although the diagnosis can sometimes be obtained by transbronchial lung biopsy [3, 8, 15], surgical biopsy (generally by videothoracoscopy) is generally preferable to obtain adequate tissue specimens. The results of HRCT are very useful in choosing appropriate sites for biopsy. In view of the focal nature of the granulomas in PLCH, several other precautions should be respected to optimize the diagnostic yield: sample of sufficient size; through evaluation of all samples, including the use of immunohistochemical techniques to facilitate the identification of LC. DIP-like reaction and RB are often observed in biopsies from patients with PLCH [2]. The presence of these findings should not discourage a meticulous search for pathological changes specific of PLCH. In many cases, however, a presumptive diagnosis can be established without tissue confirmation, and the decision to proceed to open lung biopsy must be made on a case by case basis. Open lung biopsies are not usually necessary in patients whose HRCT scan shows nodular lesions and cavitary nodules in association with thin and thick walled cysts, especially in smokers with mild or no symptoms who are to be followed without treatment. In the appropriate clinical context, the presence of typical changes on HRCT scan renders the diagnosis almost certain and may obviate the need for further testing [2, 38, 39]. The finding of elevated levels of CD1a-positive cells (⬎5% of cells) in the BAL fluid strongly supports the diagnosis [2]. In patients with extensive lung destruction a biopsy may not be warranted because of the excessive surgical risk. Open lung biopsies are generally performed in patients with pneumothorax who require surgical intervention, in women with


diffuse cystic lesions (to distinguish PLCH from lymphangioleiomyomatosis), in symptomatic patients with predominantly nodular lesions who are likely to be treated with corticosteroids, and in patients with atypical presentations [2, 3, 46]. In patients with extrathoracic involvement such as bone lesions, biopsy specimens from these sites can be used to support the diagnosis in cases with otherwise typical clinical and radiological features of PLCH. The differential diagnosis depend on the stage of the disease. In patients who show nodules as the only HRCT abnormality, the differential diagnosis is extensive; differentiation from sarcoidosis, silicosis, metastatic disease, and tuberculosis may be impossible, although the typical distribution of the nodules (centrilobular in PLCH and septal, subpleural and peribronchovascular in sarcoidosis, silicosis and lymphangitic carcinomatosis) can be valuable [47]. In women, cystic lesions identical to those seen in PLCH can be seen in lymphangioleiomyomatosis or tuberous sclerosis [48]. In patients who have lymphangioleiomyomatosis, the lower one-third of the lungs is usually involved, and nodules are rarely seen. Centrilobular emphysema typically has an upper lobe predominance similar to that seen in PLCH. However, in many patients who have centrilobular emphysema, focal areas of lung destruction lack visible walls, distinguishing them from the lung cysts typical of this disease. Cystic airspaces are also common in a variety of fibrotic interstitial lung diseases, particularly end-stage IPF [49], lymphocytic interstitial pneumonia [50] and a rare autosomal-dominant inherited disorder, the Birt-HoggDubè syndrome [51].


The natural history and long-term prognosis of PLCH in adults are variable and unpredictable [2, 3, 15]. A number of retrospective studies suggest that most of patients have a favorable clinical course, either spontaneously or while receiving corticosteroids with partial or complete resolution of radiographic abnormalities [2, 3, 15]. In approximately 10–20% of patients, the disease course becomes rapidly progressive, marked either by recurrent pneumothoraces or progressive respiratory failure leading to cor pulmonale. Patients are generally followed using clinical parameters, chest radiography (including HRCT scanning when changes on routine chest radiograph are noted), and assessment of pulmonary function, initially at intervals of at least every 6 months. Long-term follow-up of these patients is required because, even after years of apparent quiescence, lung function can deteriorate and new nodular lesions can occur,

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suggesting a recrudescence of disease activity [52, 53]. Several factors are associated with a poor prognosis – namely, onset of disease at a very young or old age, persistence of systemic symptoms, recurrent pneumothoraces, the presence of extrathoracic lesions (except for bone lesions which do not appear to modify the prognosis), the presence of diffuse cystic lesions on the chest radiographs, prolonged corticosteroid therapy, and major abnormalities in pulmonary function at initial assessment (especially markedly reduced DLCO, reductions in FEV1, FEV1/VC and, to a lesser extent, increases in the RV/TLC ratio) [7, 11, 12, 29, 46, 54, 55]. None of these criteria is sufficiently reliable to be used to establish a firm prognosis in individual patients. Patients with severe pulmonary hypertension follow a poor prognosis [5–37, 54]. Pregnancy does not appear to influence the evolution of PLCH in most cases, although the exacerbation of diabetes insipidus has been reported [56]. Thus, in the absence of accompanying respiratory insufficiency and/or pulmonary hypertension, PLCH is not a contraindication to pregnancy. In addition to the association with lymphomas, a high incidence of neoplasms in patients with PLCH has been reported, including both bronchogenic carcinoma (likely to be due at least in part to the heavy smoking history of most patients), as well as a variety of other malignant tumors which are possibly coincidental [57]. LCH and lymphoma may involve the same lymph node, or nodal lymphoma may be associated with extranodal histiocytosis, in with case either condition may follow the other by a period of up to several years. When the association is limited to one group of nodes, a wide variety of lymphomas may be involved, and here the LC infiltration may merely reflect the immunodeficiency commonly encountered in lymphoproliferative states. When LCH is followed by lymphoma, the latter is usually Hodgkin’s disease or malignant histiocytosis, and it has been suggested that this may represent a transformation from a hyperplastic to a neoplastic process within the histiocyte-reticulum cell system [58]. Cigarette smoking, prior treatment with chemotherapeutic agents, and chromosomal or genetic abnormalities are factors that may confer a

predisposition to the development of malignant neoplasms in patients with PLCH [54].


The variable natural history of PLCH and the lack of prognostic indicators complicate the management of this disorder. An essential part of treatment is smoking cessation [2, 59], which leads to stabilization of symptoms in most patients and should be aggressively encouraged in all patients. Indeed, in a substantial proportion of patients, smoking cessation is the only intervention required. A few reports also document objective radiographic and physiologic improvement in lung function after smoking cessation [59, 60]. Currently, no treatment has been clearly shown to be beneficial in this disease, and no randomized therapeutic trials have been reported. Corticosteroids have been used frequently in symptomatic patients with disease of recent onset, e.g. prednisone or prednisolone at an initial dose of 0.5–1 mg/kg body weight/day, followed by gradual tapering over 6–12 months. Although corticosteroid treatment was reported to be associated with an improvement in clinical status and radiological findings, no significant change in pulmonary function was seen [13]. Corticosteroid therapy is generally reserved for symptomatic patients with nodular lesions on HRCT, in the hope of accelerating the resolution of the inflammatory process. Chemotherapeutic agents such as vinblastine, methotrexate, cyclophosphamide, etoposide and cladribine have been used in patients with progressive disease who are unresponsive to corticosteroids or in those with multiorgan involvement [2, 7]. Lung transplantation has been performed with success in patients with advanced respiratory failure and in a few patients with severe arterial hypertension [61, 62]. Recurrence of PLCH in the transplanted lung appears to occur in a significant proportion of patients [63–65]. This complication can be associated with a clinically important deterioration in lung function, but the effect on overall survival remains to be established.

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Dr. Sergio Harari Ospedale San Giuseppe, Via San Vittore, 12 IT–20123 Milano (Italy) Tel. ⫹39 (0) 2 85994580 Fax ⫹39 (0) 2 85994400 E-Mail [email protected]


Lymphangioleiomyomatosis Simon R. Johnson Division of Therapeutics and Molecular Medicine, University Hospital, Queens Medical Centre, Nottingham, UK

Definition

Abstract Lymphangioleiomyomatosis (LAM) is a progressive lung disease of unknown cause which affects women. The disease occurs in isolation (sporadic LAM) with a prevalence of 1–2 per million and in approximately 40% of adult women with tuberous sclerosis complex (TSC). LAM is characterised by invasion of the lungs and axial lymphatics by smooth muscle like cells termed LAM cells which have mutations in TSC1 or more commonly TSC2 resulting in activation of mTOR, abnormal cellular growth and migration. LAM commonly presents with dyspnoea and pneumothorax. Diagnosis is generally made by the finding of thin walled cysts on CT scanning or ␣-smooth muscle actin and HMB45 positive cells on lung biopsy. LAM is characterised by progressive airflow obstruction and impaired gas transfer. Patients develop progressive dyspnoea,most have recurrent pneumothorax and some chylous effusions: survival is 76–90% at 10 years. Forty percent of patients have renal angiomyolipomas, benign tumours which should be screened for. LAM patients should receive influenza and pneumococcal vaccination, pulmonary rehabilitation and avoid oestrogen containing medications. Treatment is predominantly supportive with oxygen, bronchodilators and sometimes lung transplantation. Pleural complications are frequently recurrent and may need surgical treatment at an early stage. Although antioestrogen therapies are commonly used, there is no evidence base to support their efficacy. Progesterone therapy should only be considered in patients with poor or rapidly declining lung function. Currently, inhibitors of mTOR show promise in laboratory models and are in clinical trials. Copyright © 2007 S. Karger AG, Basel

Lymphangioleiomyomatosis (LAM) is a progressive lung disease of unknown cause which affects women. The disease occurs in isolation (sporadic LAM) and in patients with tuberous sclerosis complex (TSC-LAM). LAM is characterised by invasion of the lungs and axial lymphatics by smooth muscle like cells and is associated with a tendency to develop the tumour angiomyolipoma.

Epidemiology

Sporadic LAM is a rare disease, registries in several countries including the UK, France and United States suggest that LAM occurs in 1–2 per million of the population [1, 2]. Although identified in most populations prevalence data is not currently available for non-Western countries. LAM is much more common in patients with TSC: three recent studies have screened tuberous sclerosis patients with high resolution CT scanning and found lung cysts compatible with LAM in approximately 40% in adult women [3–5]. The majority of TSC-LAM patients identified by screening have normal lung function, no respiratory symptoms and few cysts [5]. Only a minority of TSC-LAM patients have symptoms with retrospective series estimating this at 2–5% of patients with TSC [6]. Sporadic LAM only occurs in women. Reports of sporadic LAM in men have not been substantiated following critical review [7]. Although tuberous sclerosis has an

equal sex distribution, the great majority of TSC-LAM occurs in women. A small number of men with TSC have been described as having LAM [8]. LAM most commonly presents between the menarche and menopause: although some patients present after the menopause (especially after starting oestrogen replacement therapy [9]), it is likely that the disease was present sub-clinically prior to this. TSCLAM that becomes symptomatic also tends to present in the 30s similar to sporadic LAM [5, 10]. The first case of LAM was described in 1918 [11] and since then there has been an increasing number of cases reported in the world literature. It is likely that in recent years an apparent rise in prevalence has been the result of identification of milder and in some cases, asymptomatic patients by high-resolution CT scanning (HRCT). The advent of CT scanning has also identified LAM in an increasing number of older patients and has broadened the clinical description of the disease [10, 12].

Mitogens

PDK1

PI3K

The cause of LAM is unknown; however, the association between LAM and TSC has been a key pointer to the molecular mechanisms underlying the disease. TSC occurs as the result of a mutation in one of two genes, TSC1 and TSC2 (named hamartin and tuberin, respectively). Tuberin/hamartin form a heterodimer which represses the kinase mammalian target of rapamycin (mTOR). The hetrodimer acts as a GTPase-accelerating protein (GAP) for rheb, another small GTPase which normally activates mTOR [13, 14]. In cells lacking tuberin, mTOR and its targets, S6K1, ribosomal S6 and E4BP1 are inappropriately activated [15–20] (fig. 1). mTOR is a central regulator of processes contributing to cell growth, including initiation of mRNA translation, ribosome synthesis, expression of metabolism associated genes and cytoskeletal reorganisation [21]. mTOR is controlled by at least two pathways: firstly, by growth factors including insulin-dependent growth factor-1 (IGF-1) via phosphoinositide 3-OH kinase (PI3K), and, secondly, by mitogens. mTOR is also influenced by cellular nutrient status with reduced amino acid levels, mitochondrial function [22] and cell stress resulting in inhibition of mTOR via its partner regulatory associated protein of TOR, Raptor [23]. Activation of mTOR can occur when tuberin is phosphorylated by Akt resulting in dissociation of tuberin/hamartin and degradation of tuberin by the proteosome [24]. Phosphorylation of tuberin by P90 ribosomal S6kinase (RSK1) via Ras, MEK1/2 and ERK1/2 has also been shown to enhance

Johnson

AMP

IRS

ras PTEN

AMPK raf akt

MEK ERK Tuberin

Amino acids

RSK

Hamartin

B-raf rheb rho

P42/44 MAPK

mTOR S6K1

Protein synthesis

Pathogenesis

276

Growth factors

Migration

raptor 4EBP1

Cell cycle

Fig. 1. Role of tuberin and hamartin in integrating cell signalling via

PI3K and ras pathways.

the activation of mTOR indicating that tuberin may be a major integrator of mitogenic signalling [25]. Recently, evidence has emerged that tuberin activity is also responsive to cellular energy status. Under of energy depletion, adenosine monophosphate kinase (AMPK) is activated by rising AMP levels and phosphorylates tuberin (discreet from the Akt [17] and MAPK [26] phosphorylation sites) to enhance tuberinmediated repression of mTOR. AMPK-dependent phosphorylation is also required for regulation of translation and cell size control in response to energy deprivation and protects cells from energy deprivation-induced apoptosis [27]. These data emphasise that tuberin may be a central controller of mitogenic signalling, only allowing growth and progression through the cell cycle when adequate nutrient levels are present. In addition to the interaction with mTOR, the tuberin/ hamartin complex has other effects on the cytoskeleton [28], cellular adhesion [29] and other downstream pathways [30]. In tuberous sclerosis with germ line mutation of TSC1 or TSC2 hamartomas develop at multiple sites when the second normal allele is inactivated by a further somatic mutation (second hit) [31, 32]. In sporadic LAM biallelic inactivation of TSC2 or rarely TSC1 results in the same disease [33–35].

Fig. 2. Histological appearance of LAM stained with ␣-smooth muscle actin which stains LAM cells.

Pathology

LAM is categorised by the invasion of the lungs and axial lymphatics by an abnormal type of smooth muscle cell termed the LAM cell which has the abnormalities described in TSC1 or TSC2. In the lungs, LAM cells invade the lung parenchyma and line the air spaces, pulmonary vessels and lymphatics [36]. Initially, LAM cells are sparse and difficult to detect but as the disease progresses they form nodular clumps lining air spaces which progressively enlarge (fig. 2). Cystic spaces develop, probably by the release of proteolytic enzymes, including urokinase-type plasminogen activator [37] and matrix metalloproteinases [38, 39]. Pulmonary vessel occlusion can result in venous congestion, pulmonary haemorrhage and haemosiderosis. Pulmonary, pleural and also the axial lymphatics of the thorax, abdomen and pelvis are infiltrated by LAM cells and become occluded and thickened. Occlusion of the pleural lymphatics and thoracic duct can cause lymph leakage resulting in chylous pleural and rarely pericardial effusions. Invasion of the abdominal and pelvic lymphatics by LAM cells results in lymphadenopathy in a significant number of patients and occasionally large cystic masses containing chyle termed lymphangioleiomyomas [40]. In advanced disease chylous ascites may result [41]. Approximately half of patients with LAM have a benign renal tumour known as an angiomyolipoma. These occur chiefly in the kidneys and are a hamartomatous proliferation of LAM cells, adipocytes and both reactive and neoplastic


blood vessels of varying types [42–44]. In LAM angiomyolipomas are generally small but may enlarge or be multiple [41, 45]. LAM cells have a specific and unusual immunophenotype and can be identified in histological sections by the monoclonal antibody HMB45 [46]. HMB45 recognises a melanoma-associated glycoprotein termed GP100, a normal constituent of pre-melanosomes [47]. The significance of this in LAM is unknown. However, the presence of HMB45 in the lung is a useful diagnostic marker for the disease [48]. In most cases LAM cells also express oestrogen and progesterone receptor [49, 50]. LAM nodules are complex structures often with a central lymphatic channel surrounded by heterogeneous collection of LAM cells. At the centre of nodules are predominantly spindle-shaped LAM cells with a high proliferative capacity which strongly express proliferating cell nuclear antigen (PCNA). The periphery is composed of epithelioid-type cells with lower PCNA expression but a greater reactivity to HMB45 [47], oestrogen and progesterone receptors [50, 51]. LAM lesions are lined by type II pneumocytes and associated with LAM in the small airways, bronchiolitis is frequently seen [52, 53].

Clinical Assessment

Patients with LAM most frequently present with dyspnoea or pneumothorax. Less common presentations include haemoptysis, cough, chyloptysis and extra pulmonary manifestations including angiomyolipoma and symptomatic abdominal lymphatic masses (table 1) [1, 2, 12, 41]. Increasingly cystic lung disease consistent with LAM is being observed on HRCTs performed for other purposes. Clinical examination of patients with sporadic LAM is often normal: however cyanosis, hyperinflation, wheezing and occasionally crackles are present. Rarely abdominal manifestations of LAM including large angiomyolipomas may be palpable. In all patients, a thorough search for signs of tuberous sclerosis should be made as a significant number of patients have been identified as having tuberous sclerosis once LAM has been diagnosed. Cutaneous signs of tuberous sclerosis include ungual fibromas, facial angiofibromas, hypomelanotic macules and ash leaf macules [54] (table 2). A history of learning difficulties, epilepsy and a family history of tuberous sclerosis or its manifestations is important but two thirds of cases of tuberous sclerosis occur sporadically. Recent reports have suggested an increased prevalence of meningioma in LAM with a small number of patients

277

Table 1. Clinical characteristics and investigations

At presentation % (n) Clinical Features [1, 2, 36, 38, 40, 41, 57, 87, 88] Dyspnoea 42 (256) Cough 20 (221) Chest pain 14 (152) Haemoptysis 14 (138) Pneumothorax 43 (256) Chylous effusion 12 (256) Lung function [36, 38, 41, 71, 89] Normala Obstructiveb Restrictivec Combined obstructive/ restrictive Low gas transferd Hypoxaemiae Chest radiograph [2, 38, 57] Normal Reticulo-nodular infiltrate Cysts/bullae Pleural effusion Pneumothorax Hyperinflation

Table 2. Revised diagnostic criteria for tuberous sclerosis complex

During disease course % (n)

87 (164) 51 (164) 34 (32) 22 (164) 65 (213) 28 (213)

10 (42) 29 (42) 26 (42) 36 (42)

4 (97) 63 (97) 10 (97) 15 (97)

96 (31) 83 (42)

91 (89) 76 (81)

5 (147) 68 (147)

0 (32) 94 (32)

47 (147) 5 (78) 35 (78) 27 (147)

41 (32) 28 (32) 81 (32) 25 (32)

Minor features 1. Multiple randomly distributed pits in dental enamel 2. Hamartomatous rectal polypsc 3. Bone cystsd 4. Cerebral white matter migration linesa,d 5. Gingival fibromas 6. Non-renal hamartomac 7. Retinal achromic patch 8. ‘Confetti’ skin lesions 9. Multiple renal cystsc Definite TSC: Either 2 major features or 1 major feature and 2 minor features. Probable TSC: One major feature and one minor feature. Possible TSC: Either 1 major feature or 2 or more minor features. a

Thoracic CT [2, 38, 41] Cysts Ground glass opacities Nodular densities Pneumothorax Pleural effusion Hilar/mediastinal adenopathy Dilated thoracic duct Pericardial effusion

100 (104) 29 (104) 9 (104) 16 (38) 13 (38) 6 (104)

100 (35) – – 6 (35) 14 (35) –

– –

11 (35) 6 (35)

Co-existent cerebral cortical dysplasia and cerebral white matter migration tracts count as one feature; bCo-existent LAM and renal angiomyolipomas count as one feature; cHistologic confirmation suggested; dRadiographic diagnosis sufficient. Adapted from Roach et al. [54].

Investigations

Abdominal CT [40, 87, 88] Normal Renal angiomyolipoma Lymphadenopathy Lymphangioleiomyoma Ascites Hepatic angiomyolipoma

5 (80) 53 (111) 39 (80) 16 (80) 9 (80) 3 (80)

All values ⬎80% predicted; bFEV1 ⬍80%, FEV1/FVC ⬍70% predicted; cFVC ⬍80%, FEV1/FVC ⬎70% predicted; d⬍80% predicted. e Pa02 ⬍ 10.6 kPa. a

requiring surgical treatment [55]. It has been suggested that patients should be screened for meningioma [55]. As progesterone is a mitogen for meningiomas, it would certainly be appropriate to do this if progesterone treatment was being considered [55, 56].

278

Major features 1. Facial angiofibromas or forehead plaque 2. Non-traumatic ungual or periungual fibroma 3. Hypomelanotic macules (more than three) 4. Shagreen patch (connective tissue nevus) 5. Multiple retinal nodular hamartomas 6. Cortical tubera 7. Subependymal nodule 8. Subependymal giant cell astrocytoma 9. Cardiac rhabdomyoma, single or multiple 10. Lymphangiomyomatosis or renal angiomyolipomab

Johnson

The plain chest radiograph is generally normal in early LAM. As the disease progresses, reticular changes are apparent and unlike most interstitial diseases, the lung volumes are preserved. Pneumothorax or chylous pleural effusions may also be visible [57] (table 1; fig. 3). The key investigation in LAM is HRCT of the thorax. HRCT demonstrates multiple thin walled cysts distributed evenly throughout the lung fields with normal intervening lung parenchyma (table 1; fig. 3). Occasional areas of ground glass change are visible which probably represent localised areas of pulmonary haemorrhage [58]. Occasionally, an enlarged thoracic duct may be visible. In patients with suspected LAM an abdominal CT scan should also be performed to document abdominal disease and determine if angiomyolipomas are present [40] (table 1; fig. 4). This is important both for diagnostic purposes and for avoiding potential complications from large angiomyolipoma. Pulmonary function tests generally show airflow

a

b

c

d

Fig. 3. Chest X-ray and CT appearances in

LAM. a Right chylo-pneumothorax in patient with early disease and no interstitial changes. b Bilateral reticular changes with increased lung volumes in patient with advanced disease. c High resolution CT scan of patient with moderate disease. d HRCT in patient with advanced disease, little normal lung remains and the cysts have amalgamated to form irregular shapes.

obstruction with preserved lung volumes and impaired gas transfer [1, 12], restrictive changes may be the result of pleural complications (table 1). In early disease, lung function tests may be normal [12]. In cases where tuberous sclerosis is suspected a full dermatological examination should be performed (including the use of Woods light to demonstrate hypomelanotic patches), MRI scan of the brain and if the diagnosis remains unclear a formal examination by a clinical geneticist is advised. Lung biopsy combined with staining for smooth muscle actin and HMB45 is the gold standard for the diagnosis of LAM. However, in patients with a classical clinical history and typical CT scan, in the presence of other features supportive of LAM including angiomyolipoma, chylous pleural collection or tuberous sclerosis, a tissue biopsy is not required. In patients where cystic lung disease is seen on CT scan without other evidence of LAM, a tissue biopsy is generally advisable if the patient’s lung function is adequate particularly if treatment for LAM is contemplated [59]. Lung biopsy is best performed by video assisted thorascopic surgery and tissue stained for smooth muscle actin and HMB45. One series has reported that transbronchial lung biopsy can be adequate to diagnose LAM when combined with HMB45 staining [60]. In cases where abdominal disease is detected, a biopsy of the extra-pulmonary


disease may be diagnostic and may be a safer alternative in patients with advanced lung disease (fig. 5). The differential diagnosis of LAM is broad. The nonspecific nature of the symptoms of LAM including breathlessness and wheeze often result in the label of asthma or emphysema. When pneumothorax is the presenting feature it may be attributed to primary spontaneous pneumothorax especially in early disease when the chest X-ray does not show parenchymal abnormalities. Thus a significant diagnostic delay can result and in previous series the mean time to diagnosis was 3–4 years [9, 10]. In patients with cystic lung disease visible on high resolution CT scan, Langerhans cell histiocytosis (LCH) is an important differential. In contrast to LAM, the cysts in LCH tend to be more irregular, have thicker walls and predominate in the upper and mid zones with relative sparing of the bases. In LCH, the cysts are interspersed with nodules although in advanced LCH nodules are less predominant and consequently the disease is more difficult to distinguish from LAM [61]. Emphysema may have a similar radiological appearance to LAM as not all LAM patients have obvious walls to their pulmonary cysts on HRCT. However, emphysema is a relatively unusual diagnosis in younger women especially those with normal ␣1-antitrypsin levels and no history of heavy smoking. BirtHogg-Dubé syndrome is an autosomal-dominant disease

279

Classical history and HRCT

a Y

LAM or other diagnosis

Y

N

N

Biopsy appropriate

Probable LAM* (consider biopsy)

Y

LAM

N

Search for supportive features**

*Consider/exclude other diseases **Supportive features Angiomyolipoma Lymphangioleiomyoma Chylous collection

b

Supportive features**

Y

Probable LAM*

N Possible LAM*

Fig. 5. Suggested diagnostic approach to patients with suspected LAM.

c Fig. 4. Angiomyoliopmas in LAM. a Small angiomyolipoma visible as typical echo-dense lesion on renal ultrasound. b The same angiomyolipoma as (a) shown as lesion of fat density on the outer border of the right kidney. c Larger angiomyolipoma visible as lesion of mixed CT density replacing most of the right kidney.

categorised by multiple skin tumours, lung cysts and malignant renal tumours due to mutations in the folliculin gene and although rare is an important mimic of LAM [62]. Occasional patients with metastatic endometrial sarcoma will develop cystic pulmonary lesions which progress over a period of years [63]. Occasionally, hypersensitivity pneumonitis can cause cysts; however, the intervening lung parenchyma is abnormal and the cysts are relatively sparse.


Early reports of the disease based on case reports and post-mortem series suggested that survival in LAM was between 4 and 7 years from the onset of symptoms [36, 64]. These gloomy figures represent only a small minority of

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Johnson

patients with LAM. Although patients with LAM have an uncertain prognosis several retrospective studies estimate a 10-year survival of 71–90% with a significant number of patients surviving 20–30 years [2, 38, 57, 65, 66]. At present there are no reliable methods of predicting the rate of decline in individual patients. However, a young age at onset and a low initial DLCO may be associated with a more rapid decline in lung function [67]. Greater profusion of cystic and nodular lesions in lung biopsy is associated with shorter survival [66]. Preliminary evidence is emerging that patients presenting with pneumothorax rather than dyspnoea may have a more benign clinical course however this is not entirely certain as it may merely reflect an earlier diagnosis in those presenting with pneumothorax [10]. The natural history of LAM is of gradually progressive airflow obstruction, recurrent pneumothorax and chylous effusions [68, 69]. Several retrospective series estimate the rate of decline of FEV1 in LAM at 75–120 ml/year which is similar to that seen in patients with severe ␣1-anti-trypsin deficiency [2, 9, 70]. Pneumothorax occurs in about two thirds of patients at some point in their disease. Of these, approximately two thirds will have recurrent pneumothorax with an average of 3–4 episodes per patient [1, 12]. Chylous pleural effusions occur in 10–20% of patients. Those with more advanced disease tend to suffer frequent lower respiratory infections. Angiomyolipoma are often asymptomatic however a small minority of patients will

develop larger tumours which may cause pain and occasionally renal haemorrhage necessitating intervention [40].

expensive a low-fat diet is often recommended as an alternative. Patients with symptomatic recurrent effusion despite non-invasive methods may require pleurectomy and occasionally ligation of the thoracic duct [1, 72].


At present there is no proven therapy for LAM and treatment comprises supportive management of complications, hormone therapy in some cases and emerging treatment studies. Supportive Therapy Dyspnoea Dyspnoea due to airflow obstruction and lung cystic change occurs in almost all patients. Dyspnoea generally progresses at a variable rate and at 10 years from the onset of symptoms 55% of patients have limited exercise tolerance on level ground and 10% are too breathless to leave the house [65]. Up to 20% of patients have a significant response and a greater number feel a subjective improvement to inhaled bronchodilators: particularly those with a low FEV1 [1, 53]. Hypoxaemia should be treated with oxygen; in addition an assessment of exertional hypoxaemia and consideration of ambulatory oxygen should be made as LAM patients often desaturate markedly during exercise. As in other obstructive lung diseases, pulmonary rehabilitation is probably useful in LAM. Pneumothorax Pneumothorax is a cause of significant morbidity with a high rate of recurrence. In one study conservative treatment was associated with recurrence of pneumothorax in two thirds of cases. In contrast, surgical pleurodesis or pleurectomy was more effective in preventing recurrence [1]. Patients who have had pleurectomy are at greater risk of complications from peri-operative bleeding if treated by lung transplantation [71] and for this reason some will avoid radical pleural procedures. However, previous pleural surgery, although associated with peri-operative bleeding, does not appear to effect overall outcome following transplantation [McCormack FX Jr, pers. commun.]. Chylous Effusion Small pleural effusions that do not cause worsening dyspnoea can merely be observed. Symptomatic effusions should be treated by aspiration or chest tube drainage depending on their size although after aspiration alone recurrence is common [72]. Attempts to reduce chyle formation include substituting dietary fat with medium chain triglycerides (MCT) which are carried in blood rather than lymphatics. However, as an MCT diet is unpalatable and


Lung Transplantation Lung transplantation is an option for patients with advanced LAM. As LAM is a rare disease referral criteria for transplantation are not specific to LAM. The majority of patients referred for transplant have an FEV1 in the range of 20–30% predicted and resting hypoxaemia is almost universal [71, 73]. Prior to referral, extra-pulmonary disease should be screened for as large angiomyolipomas and osteoporosis are common [74]. Patients with TSC-LAM have also undergone lung transplantation although learning difficulties, difficult epilepsy and renal disease may be relative contraindications to transplantation. Angiomyolipoma The majority of angiomyolipomas in patients with LAM occur in the kidneys but can rarely be found at other sites including the liver, uterus and lung. Most angiomyolipomas in sporadic LAM are asymptomatic and have a mean diameter of less than 1.5 cm [45]. In patients with TSC-LAM, tumours are larger and more prevalent [75]. Tumours may enlarge and cause symptoms [76]. A cohort study suggests that tumours larger than 4 cm are more prone to aneurysm formation and bleeding [76]. A number of case reports describe rupture of angiomyolipoma during pregnancy [77, 78]. Although the overall risk of rupture in pregnancy is not high, the possibility should be considered in pregnant patients with abdominal pain [79]. No prospective studies have been performed to determine the optimal management of angiomyolipoma. It is thought that asymptomatic tumours less than 4 cm should be monitored by ultrasound every 2 years. Those greater than 4 cm should be evaluated, once to twice yearly. Large symptomatic or bleeding tumours require treatment. The decision to act on intermediate size asymptomatic tumours is unclear and depends upon patient specific factors including renal reserve, lifestyle and pregnancy plans [75]. Elective surgery is aimed at preventing renal haemorrhage and nephrectomy. Conservation of renal tissue is important as angiomyolipoma may develop or progress in the contralateral kidney and compromise renal function. Embolisation may be the treatment of choice allowing good tumour shrinkage, reduction of both long-term and perioperative bleeding [75, 80–82]. Complications of embolisation include post-embolisation syndrome, which can be reduced using corticosteroids [83], and abscess formation

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which may require percutaneous drainage [75]. Partial nephrectomy may be indicated if a lesion is atypical on CT or a histological diagnosis is required. General Advice As LAM is hormone dependent, patients are advised to avoid oestrogen-containing medication including the combined oral contraceptive pill and oestrogen-containing hormone replacement therapy. Women with LAM are at increased risk of pneumothorax and should be educated regarding symptoms and advised to seek medical advice promptly. Similarly, they should be warned that haematuria and flank pain may be caused by bleeding from an angiomyolipoma. Pregnancy is associated with an increased risk of pneumothorax and chylous effusion [1]: whilst some women with LAM have uncomplicated pregnancies, ideally patients should discuss pregnancy with their physician before conception. Patients with rare diseases often have limited information and patients groups can be a good source of support and information. Patients groups for LAM exist in many countries and can be accessed via the internet. As in other chronic respiratory diseases LAM patients should receive prophylactic vaccination against influenza, Pneumococcus and given be assistance to quit smoking if necessary. Hormone Therapy As LAM only occurs in women, appears to progress in high oestrogen states and LAM cells have hormone receptors: various anti-oestrogen therapies have been used since the initial case report of progesterone use 25 years ago [84]. Progesterone is still used in up to half of the patients [12] although there is no convincing evidence it is effective. One retrospective study suggested that progesterone may slow the rate of decline of DLCO and possibly FEV1; however,

the effect was variable and short lived [9], a larger retrospective study showed no effect of progesterone although the patients in this study had better preserved lung function [70]. Side effects of progesterone include flushing, nausea, oedema, abdominal bloating and osteoporosis. Recently, concern over the association of between progesterone and meningioma in LAM has further curtailed its use [55]. Gonadotrophin-releasing hormone agonists such as goserelin suppress oestrogen levels to a similar level as oophorectomy and are occasionally used in LAM either alone or in combination with progesterone but evidence of their efficacy is mixed and limited to case reports [85]. Other anti-oestrogen measures including tamoxifen, selective oestrogen receptor modulators and oophorectomy have all been tried but lack evidence of efficacy [68]. Hormone treatment of any sort is not of proven efficacy and therefore not indicated in patients with well preserved lung function. In those with poor or rapidly declining lung function who cannot be enrolled in a treatment study progesterone may be tried. No specific consensus exists regarding dose but medroxyprogesterone 400 mg i.m. monthly or 10–20 mg orally per day are generally used. Treatment Studies The recent findings of dysregulation of mTOR signalling in LAM has suggested that specific inhibitors of mTOR such as rapamycin (Sirolimus) may be potential therapies for LAM [15, 86]. At the time of writing trials of rapamycin in LAM and angiomyolipoma are underway in the United States and UK. Further international trials of mTOR inhibitors are being planned by various groups and inclusion in a treatment study is likely to form part of the management of many patients with sporadic and TSCLAM in the coming years.

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Dr. Simon R. Johnson Division of Therapeutics and Molecular Medicine, D Floor, South Block University Hospital, Queens Medical Centre Nottingham NG7 2UH (UK) Fax ⫹44 115 823 1059 E-Mail [email protected]


Acquired Idiopathic Pulmonary Alveolar Proteinosis Ulrich Costabela Peter C. Bauera Josune Guzmanb a

Medical Faculty, University of Duisburg-Essen, and Department of Pneumology/Allergy, Ruhrlandklinik, Essen, bGeneral and Experimental Pathology, Ruhr-University, Bochum, Germany

Abstract Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by abundant deposition of surfactant-like material in the aveoli. In this article we focus the discussion on the primary acquired (idiopathic) PAP. We report the studies that developed the concept that this disorder is an autoimmune disease caused by auto-antibodies against GM-CSF. The clinical management of the patients is also described, with a specific focus on the fact that the treatment with whole lung lavage is still the standard treatment, which is very effective, and that treatment with GM-CSF should be considered experimental. Copyright © 2007 S. Karger AG, Basel

Definition

Pulmonary alveolar proteinosis (PAP) is a rare diffuse parenchymal lung disease characterized by excess accumulation of surfactant-derived phospholipids and protein components within the alveoli [1–5]. Congenital PAP occurs in full-term newborns caused by hereditary surfactant protein B deficiency associated with different mutations in the SPB gene [6, 7], or by mutation in the gene encoding the GMCSF receptor [8], as well as by mutations in the SLC7A7 gene resulting in lysinuric protein intolerance [9]. Conventional medical therapy is ineffective, and lung transplantation is the only treatment option for the congenital

forms. A secondary form of PAP may develop in association with malignancies, particularly lymphoma and leukemia, infections such as nocardiosis, cryptococcosis, mucormycosis, histoplasmosis, mycobacterial disease, pneumocystosis (in both HIV-positive and non-HIVimmunosuppressed patients) and HIV disease, and finally with inhalation exposure to silica, metal dust and chemicals [2–5]. Secondary PAP is much rarer than the primary (idiopathic) PAP which constitutes over 90% of all reported cases. Only the acquired primary form is associated with the presence of antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), indicating that this is an autoimmune disorder. PAP was first reported by Rosen et al. [1] in 1958 who described that the abundant eosinophilic material consists of lipids, proteins and carbohydrates. The first treatment with whole lung lavage was done by Ramirez et al. [10] in 1965. In 1968, Larson and Gordinier [11] postulated that the material is lung surfactant, which would either be produced in excess, not cleared normally or be structurally abnormal. In 1980, the first diagnosis by segmental lavage was achieved by Martin et al. [12]. The breakthrough in the pathogenesis was a chance finding in 1994 by hematologists that an alveolar proteinosis-like disorder developed in GM-CSF-deficient knock-out mice [13]. Finally, in 1999 Kitamura et al. [14] discovered a neutralizing antibody against GM-CSF in serum and BAL fluid of patients with acquired disease which was the evidence for an autoimmune disease.

Epidemiology

The true prevalence is unknown, with current understanding based on fewer than 500 reported cases. In Israel, the prevalence of human alveolar proteinosis has been estimated to be 0.37 per 100,000 [15]. It is primary (idiopathic) in more than 90% of cases. The median age at onset is 39 years, the male to female ration is 3:1 [4], and smokers are predominantly affected. 72% of patients have a smoking history [3], 82% were smokers in our own series of 39 patients. The historical smoking habits may explain the male predominance.

Etiology and Pathogenesis

Based on the evidence that surfactant and surfactant-like substances are abundantly accumulating, a disturbance in the normal pathway of surfactant production, metabolism, recycling or degradation has long been postulated. Recently, abnormal GM-CSF activity has been considered pathogenic in acquired idiopathic PAP. In the normal human lung, surfactants lipids and proteins are synthesized, stored and released in the form of lamellar bodies by alveolar type II epithelial cells. In the alveolar lumen, the lamellar bodies are converted into surfactant structures known as tubular myelin as well as into large aggregates composed of extracellular lamellar bodies. Both have surface-active properties. The surfactant is inactivated by mechanical and biological processes and converted into small aggregates which are surfaceinactive. About 70–80% of the small aggregates are taken up by the type II cells and recycled for surfactant synthesis [4, 16, 17]. The rest of the small aggregates is catabolized through phagocytosis and degradation by alveolar macrophages. This process is critically dependent on GMCSF which is essential for normal surfactant clearance by activating the alveolar macrophages and increasing their rate of surfactant clearance [18, 19]. In vivo and in vitro data showed that GM-CSF binding to specific receptors on alveolar macrophages stimulates the terminal differentiation of the macrophages through the nuclear transcription factor PU.1 [20]. This GM-CSF signaling is the critical process for the catabolism of surfactant by alveolar macrophages. In idiopathic PAP, surfactant homeostasis is disrupted. Overwhelming data of ultrastructural, biochemical and functional investigations, including results of studies in genetically modified mice, strongly support the concept that the accumulation of surfactant material in alveolar

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proteinosis is due to reduced clearance rather than to overproduction. An important clue emerged in 1994 when hematologists discovered that knock-out mice lacking the GM-CSF gene presented with impaired surfactant clearance leading to murine alveolar proteinosis which resembled human disease [13]. The development of alveolar proteinosis in these mice could be corrected by several interventions such as lung-specific delivery of the GM-CSF gene [21], by inhalation of aerosolized GM-CSF [22], and by bone marrow transplantation for hematopoetic reconstitution [23]. In these animal models it was shown that the abnormal accumulation of surfactant phospholipids and proteins is due to an interruption of GM-CSF signaling in the alveolar macrophage which impairs the catabolism of the surfactant by alveolar macrophages without impairing its uptake. Studies in adult human alveolar proteinosis showed that at least 2 nuclear transcription factors, PU.1 and PPAR-␥, which are regulated by GM-CSF, are deficiently expressed by alveolar macrophages [20, 24]. The defective clearance of surfactant by alveolar macrophages leads to progressive expansion of the extracellular surfactant pool and the accumulation of cellular debris eventually causing the alveolar filling syndrome. In addition, the alveolar macrophages are overfed with surfactant inclusions which are not degradable. As a result, the alveolar macrophages show several secondary functional defects such as reduced mobility [25], impaired adherence and chemotaxis [26], reduced phagocytosis [27, 28] and decreased ability to kill ingested micro-organisms [26]. All these secondary defects can be explained by the lack of GM-CSF stimulation of alveolar macrophages. The functional impairment of macrophages contributes to the increased risk of pulmonary infections associated with alveolar proteinosis. Ultimately, the discovery of autoantibodies against GM-CSF was able to explain the GM-CSF deficiency in the acquired form of human alveolar proteinosis. In 1999, Nakata and co-workers identified a GM-CSF-neutralizing autoantibody in the serum and BAL fluid of patients with acquired alveolar proteinosis that was not found in patients with congenital or secondary form of disease, in those with several other lung disorders, or normal controls [14, 29]. These findings have been confirmed by other authors [30–33]. It is likely that the anti-GM-CSF antibody is pathogenic in the development of the disease through its ability to inhibit the activity of endogenous GM-CSF, leading to a state of functional GM-CSF deficiency [34]. In summary, current evidence suggests that adult idiopathic PAP is an autoimmune disease caused by decreased availability of functional GM-CSF due to CM-CSF blocking activity of a neutralizing autoantibody.

Pathology

On histopathology, the alveolar spaces are filled with a characteristic acellular, finely granular material that stains with periodic acid-Schiff (PAS) stain and is diastase-negative. The interstitial structures are free of inflammatory infiltrates. Type II pneumocytes may be hyperplastic [1]. In this regard, alveolar proteinosis is a classical alveolar filling syndrome. On electron microscopy, the abnormal material consists predominantly of unusual tubular, myelin-like, multilamellated structures, which are similar to the tubular myelin found in normal lungs but without the intersecting membranes of normal tubular myelin. Structures that relate to cell debris are also present. Lamellar bodies of normal lungs are only minor components [3–5]. Biochemical analysis of the material, mainly obtained from bronchoalveolar lavage (BAL) fluid demonstrated that total phospholipids are increased, with a relative decrease in phosphatidylcholine and phosphatidyIglycerol, and a relative increase in sphingomyelin and phosphatidylinositol. Surfactant proteins A, B and D are also increased. The relative abundance of surfactant protein A isoforms varies markedly from patient to patient and is different from normals [3–5, 16]. Clinical Assessment

The majority of patients suffer from slowly increasing dyspnea on exertion (80%) and cough (60%). Less frequently, fever, weight loss, fatigue, chest pain and hemoptysis are reported, especially if secondary infection develops. The physical examination is inconclusive and may reveal inspiratory crackles in 40–80%, clubbing in 30–50%, cyanosis in 25%, and sometimes evidence of cor pulmonale [2–4, 35, 36].

Fig. 1. Chest radiograph of pulmonary alveolar proteinosis: bilateral symmetrical alveolar opacities creating a ‘butterfly’ appearance.

Table 1. CT features of pulmonary alveolar proteinosis (n ⫽ 27):

adapted from Holbert et al. [39] Pattern Ground grass Air space Fibrosis Interlobular Intralobular

100% 78% 30% 85% 7%

Distribution Geographic Diffuse

77% 8%

• ground-glass opacities sharply demarcated from normal lung, creating a ‘geographical’ pattern

Investigations

• intra- and interlobular septal thickening, often in polygThe chest radiograph may be distinctive showing diffuse bilateral symmetrical alveolar infiltrates with air bronchograms. The shadowing may be cloudy and butterfly- or batwing-like, as a result of the more prominent involvement of the perihilar regions (fig. 1). Less commonly, unilateral infiltrates or a reticulonodular pattern may by seen. Lymphadenopathy and pleural lesions are rare. Kerley B lines are absent initially but may develop later. Cavitation has not been reported in noninfectious alveolar proteinosis [36, 37]. The HRCT shows airspace filling in variable and patchy distribution (table 1). The distinctive features are:

Alveolar Proteinosis

onal shapes, called ‘crazy-paving’ • areas of consolidation with air bronchograms, surrounded by ground-glass opacification. These features are virtually pathognomonic for the disease (fig. 2) [37–39]. The crazy-paving pattern is not specific for PAP, however. Less frequently, other conditions may also show crazy-paving [40] (table 2). Lung function tests usually show restriction and a reduced diffusing capacity. Hypoxemia at rest is seen in about one-third and during exercise in more than one-half of patients [35, 36]. An increase in the shunt fraction while breathing 100% oxygen occurs in almost all patients [41].

287

Fig. 2. HR-CT of pulmonary alveolar proteinosis: characteristic

Fig. 3. BAL cytology with the characteristic aspect of alveolar

‘crazy-paving’ pattern in a ‘geographic’ distribution.

proteinosis.

Diagnosis Table 2. Crazy-paving pattern in various disorders: adapted from

Johkoh et al. [40] Prevalence of crazy-paving

%

Alveolar proteinosis Diffuse alveolar damage superimposed on UIP Acute interstitial pneumomia ARDS Cardiogenic edema Drug-induced pneumonia

100 67 31 21 14 12

Laboratory blood tests frequently show an increase of serum lactate dehydrogenase (LDH) which is nonspecific and declines after therapeutic lavage or spontaneous resolution. The LDH isoenzyme pattern is normal [41]. Elevation of serum carcinoembryonic antigen (CEA) and other tumor markers can be observed and has been proposed as marker of disease activity. Serum levels of surfactant protein A and D can be increased but this is also not specific for the disease, since high levels have also been reported in patients with idiopathic pulmonary fibrosis [16]. Serum levels of KL-6, a mucin-like glycoprotein, are extremely high in PAP, higher than in patients with other interstitial lung disease [42]. Serological diagnosis of primary PAP by demonstration of autoantibodies against GM-CSF is not yet a routine procedure, but a promising test for the future. The test has an excellent sensitivity and specificity for primary PAP, and is negative in the congenital and secondary form of disease.

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The diagnosis of PAP should be suspected in a patient with slowly developing dyspnea, a ‘butterfly’ pattern of acinar shadowing on the chest radiograph and characteristic findings on HRCT (geographical distribution of a ‘crazy-paving’ pattern) along with elevated serum LDH and an increased shunt fraction. The diagnosis can usually established by BAL, obviating the need for transbronchial or open biopsy in many instances [5, 12, 43–46]. In our own center which has a large experience with BAL, the diagnosis was made by BAL in 64% of the total 39 patients with acquired PAP. This was reported in only 4% of 410 patients in a large cumulated literature series. In our own centre, in only 13% of patients the diagnosis was made by surgical biopsy, compared to 71% in the literature series [3]. On gross examination, the BAL fluid has a characteristic milky appearance. On light microscopy the striking features are (fig. 3): • acellular globules that are basophilic on May-GrünwaldGiemsa and positive with PAS staining • few and foamy macrophages • large amounts of cell debris showing weak PAS staining. Electron microscopy is not usually required to establish the diagnosis but if performed shows that the BAL sediment consists of characteristic myelin-like multilamellated structures and lamellar bodies.

Management

Spontaneous remission occurs rarely and was documented in only 24 of 303 patients (8%) analyzed in large

0.9% Saline

Ventilator

Ventilated lung

Whole-lung lavage The patient is intubated with a Carlen’s tube. One lung is lavaged with repeated volumes of 1 litre of saline while the other lung is ventilated.

Lavaged lung

Modified from Rogers et al 1972

Lavage effluent

Fig. 4. Technique of whole lung lavage.

literature review [3]. Treatment is indicated when respiratory symptoms impair the quality of life or when lung function deteriorates. The treatment of choice is wholelung lavage, which is almost always effective [2–5, 35, 36, 47–53]. Treatment with GM-CSF has still to be considered experimental. Two prospective, open-label, uncontrolled trials of GM-CSF therapy for acquired alveolar proteinosis have been undertaken. The first, conducted from 1995 to 1998, evaluated subcutaneous GM-CSF at a dose of 5 ␮g/kg daily for 6–12 weeks in 14 patients. 5 patients improved at this dose, 4 patients only responded to a higher dose of 20 ␮g/kg, and the remaining 5 patients did not respond to the higher dose [54]. A second trial, the largest reported to date, evaluated the response to daily subcutaneous injections of GM-CSF in escalating doses of up to 18 ␮g/kg daily. The dose at which a clinical response was seen was continued for a total duration of treatment of 12 months. Only 12 of 25 patients responded [55]. In addition, there are several anecdotal reports on this form of treatment. Taken together, daily subcutaneous administration of recombinant human GM-CSF is effective in only 50% of patients with alveolar proteinosis. It is unclear, whether the pretreatment blood levels of anti-GM-CSF antibodies are


able to predict a response to such treatment since two groups reported conflicting data [32, 55, 56]. Whether administration of aerosolized GM-CSF by inhalation is more effective, as recently demonstrated in a small study [57] and in a retrospective case series [58], should be further tested in a controlled prospective trial. A recent case study suggested that plasmapheresis is associated with clinical improvement and a reduction in the titer of anti-GMCSF antibodies [59]. Whole-lung lavage is the standard of care [5, 60]. It is safe when performed by an experienced team and under continuous monitoring of oxygen saturation, blood pressure, electrocardiography and lavage fluid balance. The more severely affected lung is lavaged first. The severity of respiratory impairment may be estimated by CT scan or by lung perfusion scanning. The second lung may be lavaged 3–7 days later. The procedure is performed under general anesthesia. The patient is intubated with a double-lumen endotracheal tube (e.g. Carlens tube). After 15 min ventilation of both lungs with 100% oxygen to wash out the nitrogen, one lung is lavaged with isotonic saline at 37⬚C. The volume used for each filling is 500–1,000 ml. The lung is then allowed to drain by gravity. This filling and drainage is repeated until the effluent is virtually clear which may require 10–40 l (fig. 4).

289

Prognosis

The prognosis has improved considerably with the introduction of whole lung lavage. Previously, one-third of the patients died but death is now extremely rare. In 7 series totaling 137 patients there were no deaths related to alveolar proteinosis after 10–15 years’ experience with wholelung lavage [35, 36, 47, 49, 50, 53, own data]. Improvement may be long-lasting: 25–50% of patients achieve permanent remission after one lavage. In the others the procedure has to be repeated at intervals of 6–24 months. Based on a retrospective analysis of 231 cases, clinically significant improvement in radiologic appearance, PaO2, lung volumes and DLCO is seen in 84% of patients following the first therapeutic lavage [3]. The median duration of clinical benefit from lavage has been reported to be 15 months, with less than 20% of those patients followed beyond 3 years remaining free of recurrent PAP [3]. Such therapy also improved the survival: the rate of survival at 5 years was 94 ⫾ 2% in a group of 146 patients with lavage, as compared with 85 ⫾ 5% in 85 patients without lavage [3]. Interestingly, therapeutic whole lung lavage improves the defects in the migration and phagocytosis of alveolar macrophages [25, 51]. The interval between the diagnosis of alveolar proteinosis and the first application of therapeutic lavage ranged from 0 (immediate lavage) to 210 months,

with a median of 2 months [3]. The majority of patients who underwent lavage did so within 12 months of diagnosis (79%), but there was a steady increase in the proportion of patients having received such therapy over time. The likelihood of a patient to remain free from therapeutic lavage was only 37% at 5 years [3]. Comparing the demographic and disease-related features of patients who did or did not respond to therapeutic lavage, there were no differences seen in gender, region of origin, duration of symptoms, smoking status, and time from diagnosis to lavage [3]. The current authors feel, however, that smoking cessation is important in alveolar proteinosis. In our own series, the 7 nonsmokers needed an average number of 1.3 lavages per patient, the 12 exsmokers an average number of 1.5, and the 16 smokers required 3.0 lavages per patient to achieve long lasting remission. Alveolar proteinosis may be complicated by infections such as nocardiosis, cryptococcosis, mucormycosis and others. In the era of therapeutic lavage these complications are rare. There have been single reports of progressive interstitial pulmonary fibrosis developing in patients previously affected by alveolar proteinosis. Lung transplantation may be an option for these patients, although recurrence of disease has been reported in one patient following doublelung transplantation [61].

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Ulrich Costabel, MD Department of Pneumology/Allergy, Ruhrlandklinik Tueschener Weg 40 DE–45239 Essen (Germany) Tel. ⫹49 201 433 4020, Fax ⫹49 201 433 4029 E-Mail [email protected]

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Bronchiolitis Venerino Polettia,b Gianluca Casonia Maurizio Zompatoric Marco Chilosid a

Department of Diseases of the Thorax, GB Morgagni Hospital, Forlì, bPostgraduate School of Respiratory Medicine, University of Parma, and cDepartment of Radiology, University Hospital of Parma, Parma, and dDepartment of Pathology, University of Verona,Verona, Italy

Abstract Bronchiolitis may be defined as a process centered in and around membranous and/or respiratory bronchioles with sparing of a considerable portion of the other parenchymal structures in which inflammatory cells and mesenchymal tissue are both present. Bronchiolar abnormalities occur in a variety of clinical settings, including infections, connective tissue diseases, and other immunologic disorders, cystic fibrosis, inhalational injuries, drug reactions, allograft transplantations, and many others. A clinical definition of bronchiolitis is still elusive. Signs and symptoms are nonspecific and polymorphous. The course is usually chronic but it may be acute or subacute. Actually the high-resolution CT scan (HRCT) allows to identify more specific patterns that correlate with the involvement of small airways and it is clinically useful in order to confirm a suspected bronchiolar lesion. The advent of macrolide therapy has improved the prognosis and clinical outcome of the disease. Copyright © 2007 S. Karger AG, Basel

Bronchiolar abnormalities occur in a variety of clinical settings, including infections, connective tissue diseases, and other immunologic disorders, cystic fibrosis, inhalational injuries, drug reactions, allograft transplantations, and many others. Bronchiolar diseases have emerged as a distinctive entities in the 19th century when Reynaud (1835) reported a morphological description on obstruction of bronchi. Wilhelm Lange first used the term ‘bronchiolitis obliterans’ at the beginning of the 20th century [1]. The

histopathology of bronchiolitis obliterans due to nitrogen oxides was described soon after by Fraenkel in 1902 [1]. However, an explosion of reports and interest around this topic started about 70 years later when bronchiolar diseases associated with collagen-vascular diseases and transplantation were described. More recently, the development of high-resolution CT scan (HRCT) has greatly contributed to establishing bronchiolar disorders as an important aspect of pulmonary medicine. Bronchiolitis results from damage to the bronchiolar epithelium. The repair process leads to excessive proliferation of granulation tissue in the airway walls, the lumen, or both. The alveoli adjacent to the small airways are often involved. These diseases are rare and the level of evidence, as derived from well-conducted cohort studies, is limited. As a result, many uncertainties remain regarding the epidemiology, pathophysiology, and therapy.

Anatomy and Definition

Bronchioles are small airways without cartilage in their wall. Their diameter is less than 2–3 mm. The final purely conducting bronchiole is the terminal bronchiole. Distal to terminal bronchioles is the gas-exchanging unit of the lung known as acinus, comprising respiratory bronchioles (that have both alveolated and nonalveolated walls), alveolar ducts and alveoli. Bronchiolitis may be defined as a process centered in and around membranous and/or respiratory bronchioles with sparing of a considerable portion of the other parenchymal

structures in which inflammatory cells and mesenchymal tissue are both present [1, 2]. The distribution and amounts of the cellular and mesenchymal components vary from case to case and are at the basis of the variety of histopathological, radiographic and clinical aspects of bronchiolitis. The symptoms and signs of bronchiolitis are nonspecific [2]. The course is usually chronic but it may be acute or subacute. Pulmonary function tests most frequently demonstrate an obstructive pattern but may also be characterized by a restrictive profile or may be normal in the early phases of disease. Specific laboratory markers for bronchiolitis are not yet identified. HRCT scans have allowed more specific patterns to be identified which correlate with disease involvement of the small airways.

Classification

Two classification schemes are most frequently used in defining cases of bronchiolitis. A clinical classification divides cases into several groups according to the associated primary disease (table 1). Although this etiologic classification is useful for reminding the physician when to suspect the presence of bronchiolitis, a more functional classification scheme is based on histological characteristics. A classification based on histological patterns allows a better correlation with radiologic manifestations, the natural history of disease and the response to therapy.

Table 1. Clinical classification of bronchiolitis

Inhalation bronchiolitis Toxic fume inhalation Irritant gases and mineral dusts Organic dusts Infectious and postinfectious bronchiolitis Drug-induced bronchiolitis Collagen-vascular disease-associated bronchiolitis Inflammatory bowel disease associated bronchiolitis Posttransplant bronchiolitis Paraneoplastic pemphigus-associated bronchiolitis Neuroendocrine cell hyperplasia with bronchiolar fibrosis Diffuse panbronchiolitis Cryptogenic bronchiolitis Miscellaneaous Familial forms of follicular bronchiolitis Immunodeficiency Lysinuric protein intolerance Ataxia-telangiectasia IgA nephropathy

Bronchiolitis

Table 2. Histopathological classification of bronchiolitis

Cellular bronchiolitis Follicular bronchiolitis Diffuse panbronchiolitis Respiratory bronchiolitis Bronchiolitis with inflammatory polyps or bronchiolitis with intraluminal polyps Constrictive (cicatricial) bronchiolitis Neuroendocrine hyperplasia and bronchiolar fibrosis Bronchiolar loss Peribronchiolar fibrosis and bronchiolar metaplasia

The broad spectrum of inflammatory and fibrotic lesions of bronchiolitis may be stratified in four main histologic patterns (table 2). Cellular Bronchiolitis The bronchiole’s structures show an increased number of inflammatory cells. Depending on the cell type present the lesion is termed acute (neutrophils) or chronic (lymphocytes, plasma cells, macrophages) (fig. 1a). Necrosis of epithelial and inflammatory cells (bronchiolar mucosal necrosis), submucosal edema or necrosis, neutrophilic microabscesses, germinal center hyperplasia (follicular bronchiolitis) are part of the wide spectrum of pathologic changes observed in cellular bronchiolitis (fig. 1b). Diffuse panbronchiolitis [3] is a specific morphologic form of cellular bronchiolitis. Severe chronic inflammation is centered first on respiratory bronchioles and only in the advanced stage also on distal membranous bronchioles. There is a mural infiltrate of lymphocytes, plasma cells and histiocytes, and intraluminal aggregates of neutrophils (fig. 1c). Most characteristic is the accumulation of foamy macrophages in the interalveolar walls. Polyps of granulation tissue may partially occlude adjacent bronchiolar or alveolar lumina. Germinal center hyperplasia can be prominent. Bronchiolitis with Inflammatory Polyps or Bronchiolitis with Intraluminal Polyps Inflammatory polyps project into the lumen of membranous and respiratory bronchioles (fig. 2). These polyps can have a myxoid or pale staining matrix (rich in acid mucopolysaccharides) in which elongated fibroblast are embedded or they can be richer in collagen fibers. Adjacent airspaces can be obliterated by these fibroblastic plugs. However, when the lesion is mostly centered on alveolar spaces the term organizing pneumonia is more precise. In this situation any reference to bronchiolar involvement should be avoided, e.g. bronchiolitis obliterans and organizing pneumonias leads to confusion.

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a Fig. 1. Cellular bronchiolitis. a A membranous bronchiole presents a thickened wall infiltrated by lymphocytes. The lumen is almost completely occluded by inflammatory cells and the anatomic structure may be recognized only for the presence of muscle cells. Patient with graft-vs.-host disease-related bronchiolitis obliterans. b Inflammation consisting mainly of mononuclear cells thickens the bronchiolar wall. The lumen contains neutrophils. Patient with rheumatoid arthritis. c Diffuse panbronchiolitis. A respiratory bronchiole has the wall infiltrated by lymphocytes and the lumen filled by neutrophils. Foamy macrophages accumulate in the peribronchiolar septa (as clearly shown in the inset).

c

Fig. 2. Bronchiolitis with inflammatory polyp. The lumen of a

membranous bronchiole is almost completely occluded by granulation tissue in which inflammatory cells are embedded (inflammatory polyp).

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b

Poletti/Casoni/Zompatori/Chilosi

Constrictive or Cicatricial Bronchiolitis Mural thickening of membranous bronchioles caused by submucosal collagenization is the morphological hallmark. Progressive concentric narrowing is associated with distortion of the lumen, mucostasis and patchy chronic inflammation (fig. 3). Bronchioloectasis with mucus stasis and bronchiolar smooth muscle hypertrophy may complete the pattern. In some cases, subtle changes or completely distorted and scarred bronchioles can be best appreciated in slides stained with an elastic tissue stain or by immunohistochemistry using monoclonal antibodies against bronchiolar smooth muscle or epithelium. A unique form of constrictive bronchiolitis includes neuroendocrine cell hyperplasia with bronchiolar fibrosis which has been reported by Aguayo et al. [4] in 1992. The mildest lesion consists of linear zones of neuroendocrine cell hyperplasia in the bronchiolar mucosa with focal subepithelial fibrosis (fig. 4). In more obvious lesions, a plaque of eccentric fibrous tissue partially occlude the lumen. In the most severe stage there is a total occlusion of the lumen by fibrous tissue with few visible neuroendocrine cells.

Fig. 5. Peribronchiolar fibrosis and bronchiolar metaplasia. A bronchi-

ole is evident in the upper left corner. The lumen is slightly reduced, and bronchiolar epithelium extends into the surrounding airspaces. Fig. 3. Constrictive or cicatricial bronchiolitis. A membranous bronchiole has the lumen partially occluded by eccentric mural noncellular fibrosis.

the adjacent fibrotic alveolar walls. Inflammatory cells are scanty and usually in the bronchiolar lumen [1] (fig. 5). In some cases the pattern consists of respiratory bronchioles that end in multiple fibrous-walled channels covered by cuboidal epithelium, rather than opening into thin-walled alveolar ducts.

Pathogenesis

Fig. 4. Neuroendocrine cell hyperplasia. The bronchiolar epithelium is substituted by cromogranin-positive (neuroendocrine) cells.

Bronchiolar loss or vanishing bronchiolar pattern is the abnormality, that can that results from cicatricial bronchiolitis which progresses to total fibrous obliteration of bronchioles and to their loss and disappearance. This may be documented by quantitative methods [5]. Peribronchial Fibrosis and Bronchiolar Metaplasia Bronchiolar and peribronchiolar scarring is associated with metaplastic bronchiolar epithelium that extends onto

Bronchiolitis

Injury to distal airway epithelial cells leads to discrete types of cellular and molecular responses including: cell damage and death, reparative regeneration of epithelial tissue, triggering of cascades of mediators which are able to recruit and activate various inflammatory cells (B and T lymphocytes, macrophages, neutrophils, eosinophils, mast cells, dendritic cells). In addition, the injury leads to perturbation of the functions of mesenchymal cells such as fibroblasts, myofibroblasts and endothelial cells, with eventual deregulated production of extracellular matrix molecules and fibrogenesis [2]. Depending on the etiology, localization and intensity of the injury, all these factors variably contribute to the remodeling of the bronchiolar microenvironment with eventual airflow limitation. Epithelial Cell Injury and Regeneration Cell injury can be caused by a variety of etiological factors including irritants, viral infection, drugs, as well as by endogenous mediators produced by inflammatory cells in autoimmune diseases and transplanted patients.

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The injury can be either limited to distal airways, or can also affect variable amounts of alveolar spaces. The epithelial cell loss is followed by reparative reactions of bronchiolar and alveolar cells, triggered by proliferative and differentiative signals on multipotent cells such as basal and/or Clara cells in distal airways and type II pneumocytes in alveoli. Proliferation, differentiation and turnover of epithelial and mesenchymal cells are tightly regulated so that an equilibrated remodelling of the lung can occur limited injury. On the other hand, in a severely altered microenvironment the proliferation and differentiation of epithelial cells can be so deregulated, that abnormal repertoires of signal molecules can be produced with eventual growth of an untidy reparative tissue. Epithelial regeneration following cell death can be either compensatory, with reconstitution of pulmonary functions, or excessive with production of epithelial overgrowth, metaplasia and fibrosis, or deficient, with eventual bronchiolar loss. Progression through the cell-cycle in eukaryotic cells is mediated by positive regulators of cell proliferation such as cyclins and cyclin-dependent kinases (cdks), and negative regulators such as those encoded by tumor suppressor genes including p53 and retinoblastoma, as well as different cdk inhibitors such as p21WAF1, p27KIP-1, p16MTS1 [6]. All these molecules act in concert in order to regulate cell proliferation, differentiation and programmed cell death. In fact, the p53 pathway induces growth arrest and apoptosis following DNA damage and cell distress triggering the expression of p21WAF1, a potent inhibitor of cell cycle progression. Further complexity of the fine tuning of reparative processes is given by other regulatory molecules which positively or negatively modulate the action of p53. Among these, the tumor suppressor p14ARF that acts as an oncogene checkpoint upstream of p53, as well as two other recently described molecules belonging to the p53 family: p73 and p63 [2]. P63 is mainly represented in normal tissues by the truncated delta N-isotype which is able to block p53-mediated transactivation [6, 7], and is expressed at high levels in the basal cells of bronchial and bronchiolar mucosa. These cells have important functions in the attachment of bronchiolar mucosa to the basal lamina and also as the main stem cells from which secretory and ciliated cells derive. Exaggerated and/or untidy epithelial regeneration following prolonged injury further allows the production of inflammatory and fibrogenic mediators such as TGF-␤1 and interleukin (IL)-4, potent cytokines that are involved in the pathogenesis of obstructive bronchiolitis and idiopathic pulmonary fibrosis [8].

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Inflammatory Reactions The type and distribution of inflammatory cells provide relevant information on the pathogenesis of different types of bronchiolitis. However, the precise role of lymphocytes, macrophages, granulocytes and other inflammatory cells is not fully understood. In follicular bronchiolitis, a marked infiltration of B-lymphocytes is observed, forming follicles with well developed germinal centers. In fact, in other types of immunomediated bronchiolitis, including transplanted patients and GVHD, an immunological and pathological response is centered on T lymphocytes. Accordingly, the lymphocytes intruding the bronchiolar epithelium in most types of bronchiolitis, cellular, with inflammatory polyps or constrictive, are in fact T cells with a prevalence of cytotoxic (CD8⫹) cells. The local immune deregulation, either due to autoimmune injury or secondary to epithelial cell injury, can be varied and complex, involving discrete T-cell clonal expansions, deregulated T cell subsets (e.g.TH1/TH2), abnormal production of cytokines and chemokines. Altered cytokine profiles (e.g. excessive IL-4 production) can interfere with epithelial cell differentiation and fibroblast growth, activation and apoptosis. Other types of inflammatory and antigen-presenting cells can also have a role in this complex scenario. It has demonstrated that the CXC chemokines (monokines induced by IFN-␥ (MIG)/CXC chemokine ligand (CXCL)9, IP-10/ CXCL10, and IFN-inducible T cell ␣-chemoattractant (ITAC)/CXCL11) through their interaction with their shared receptor, CXCR3, play a pivotal role in mediating the persistent recruitment of peribronchiolar mononuclear cells that lead to obliterative brochiolitis [9]. In addition, these chemokine interactions, with their shared receptor CXCR2, are important inducers of angiogenic activity in obliterative bronchiolitis following lung transplantation [10]. Proof-of-concept studies using a murine model of obliterative bronchiolitis has demonstrated that these ELR⫹ CXC chemokines have a bimodal function. Acutely, they are responsible for intragraft neutrophil infiltration during ischemia/reperfusion injury, and chronically, they are responsible for the vascular remodeling needed to support the fibroproliferative phase of the disease independent of neutrophil infiltration. The findings of this study may ultimately result in novel therapies designed to attenuate the CXCR2/CXCR2 ligand biological axis and lead to better intervention in the prevention and treatment of obliterative bronchiolitis A significant influx of antigen-presenting dendritic cells has also been demonstrated in airway inflammation, and a pathologic role for CD1⫹, CD83⫹ mature dendritic cells has been suggested in diffuse panbronchiolitis [3].

Macrophages are also relevant in the pathogenesis of bronchiolar lesions, since they are able to produce a large array of cytokines, which contribute to the deranged inflammatory network. In addition, the presence of increased numbers of macrophages with foamy morphology are considered a morphological expression of obstruction. Foamy macrophages are especially numerous in diffuse panbronchiolitis, but the significance of this finding is still unclear since they appear predominantly interstitial [3]. Local recruitment of neutrophils can exacerbate the inflammatory process with the production of toxic molecules which further trigger fibrotics response as observed in diffuse panbronchiolitis. Different neutrophil chemoattractants including IL-8 are produced at elevated levels in different types of bronchiolitis. Recent data analyzing bronchoalveolar lavage (BAL) have demonstrated that neutrophilia may be a marker of obliterative bronchiolitis. Finally, a study has evaluated the levels of eosinophil cationic protein (ECP) and IL-8 in BAL fluid from patients with acute asthma and acute bronchiolitis [11]. ECP levels in BAL fluids were significantly higher in the asthma group compared to the bronchiolitis group. In contrast, IL-8 levels were significantly higher in the bronchiolitis group than in the asthma group suggesting that the nature of the inflammatory process within the lower respiratory tract is different in these two airways diseases.

Radiographic Findings Radiographic manifestations of diseases affecting the small airways are variable. The chest radiograph can often be normal in patients with documented bronchiolitis and its sensitivity to detect small airways disease is exceedingly low. HRCT is currently the best imaging technique for the evaluation of patients suspected of having bronchiolitis. Muller and Miller [12] proposed a new classification of bronchiolar disorders based on HRCT findings present in bronchiolar diseases (table 3). Centrilobular tubular branching or nodular opacities usually represent abnormal bronchioles filled with cells fluid, mucus or pus. This pattern is also known as ‘tree in bud

Table 3. Classification of HRCT findings in bronchiolar diseases

Centrilobular nodules and branching lines (tree in bud) Ground glass attenuation and/or alveolar consolidation Low attenuation (mosaic perfusion) and expiratory air trapping Mixed or different pictures

Bronchiolitis

Fig. 6. HRCT. Small centrilobular nodules, rosettes, and tubular

branchings in the left lower lobe (‘tree in bud’ pattern). Patient with Klebsiella infection.

opacity’. Poorly defined centrilobular nodular opacities resulting from peribronchiolar inflammation or fibrosis can occur (fig. 6). Particularly in cases with an infectious origin, the linear branching and nodules are often accompanied by scattered areas of ground glass attenuation or consolidation (which reflect the involvement of the adjacent alveolar structures and therefore progression to pneumonia). A mosaic perfusion pattern reflects decreased vascular perfusion in areas with bronchiolar obstruction and flow redistribution to normal areas. Partial airways obstruction or collateral air drift to alveoli beyond the obstructed bronchiole typically lead to air trapping, which is best seen on expiratory scans (dynamic HRCT) (fig. 7). Dynamic CT has been shown to be more sensitive in detecting regional abnormalities and air trapping. The variation in attenuation of individual lobules, accentuated when images are obtained after the patient exhales to residual volume is thought to be caused by heterogeneity of airway involvement resulting in patchy airway closure. A mixed pattern (for example, association of tree in bud with mosaic perfusion and expiratory air trapping) can be seen in a variety of entities, such as: bronchiectasis, acute bronchopulmonary infections (in particular Mycoplasma pneumoniae pneumonia, chronic aspiration).

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Fig. 7. Graft-vs.-host disease. Dynamic HRCT. In expiratory phase an

air trapping is evident mostly in the left lower lobe. Bronchiectasis and bronchial wall thickening are also evident.

and may allow earlier identification of bronchiolar inflammation or dysfunction. The single-breath washout appears particularly well suited as a screening test because it takes only a few minutes to be measured, does not necessitate special operator expertise or patient aptitude, requires only simple equipment, and is totally noninvasive [2]. However, it is not an appropriate test for patients with single-lung transplantation [2]. Increased alveolar-arterial O2 gradient and/or hypoxemia at rest or during effort are evident in cases in which inflammation/fibrosis is located mainly in the alveolar structures. Recently, it has been evaluated whether exhaled nitric oxide (eNO) measurements provide useful information for monitoring patients with obliterative bronchiolitis. Early data suggest that changes in eNO measurements following lung transplant may indicate some form of graft dysfunction [15].

Clinicopathologic Bronchiolitis

Abnormalities of large airways are a variable feature on HRCT in patients with documented bronchiolitis. This is not unexpected given the anatomic continuity of bronchi with the small airways. It appears that bronchial dilatation and bronchial wall thickening are relatively late features of constrictive bronchiolitis. These findings are more frequent in immunologically mediated disease, such as rheumatoid arthritis or post transplantation. Ventilation-perfusion scans may be helpful since a markedly abnormal pattern of patchy, matched ventilation and perfusion defects is often seen, even when the plain film in unremarkable. Magnetic resonance imaging with hyperpolarized 3 He has made the noninvasive reproducible measurement of structure-function relationship in small airways possible.

Pulmonary Function

Pulmonary function tests help to identify where the inflammatory/fibrosing process is mainly located. When membranous bronchioles are involved, an obstructive ventilatory impairment may be evident, being the involvement of the ‘inner area’ (between basement membrane and smooth muscle) of the bronchioles probably more correlated with functional impairment [13, 14]. Diffusing capacity is usually normal [2]. More sophisticated measurements of small airways function have been developed. Frequency dependent compliance, density dependent gas flow studies, measurements of ventilation distribution and measurements of closing volumes offer more sensitive assessment

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Bronchiolitis Obliterans Secondary to Irritants Inhalation Inhaled gases and fumes can produce severe bronchiolitis with acute ulceration and inflammation followed by occlusion of the airways by loose connective tissue and finally complete stenosis. Functionally significant bronchiolitis has been reported after exposure to ammonia, oxides of nitrogen, fire smoke, hydrogen selenide, phosgene, hydrogen bromide, manganese sulfate sulfur dioxide, chlorine gas, thionyl chloride, grain dust, flavoring agents in popcorn production workers, free base cocaine. A unique form of lymphocytic bronchiolitis and peribronchiolitis with lymphoid hyperplasia was reported in workers at nylon flock facilities [31]. Symptoms of obstructive lung function and bronchiolitis are experienced by workers in the poultry and swine confinement industries. It is likely that many more agents can produce this condition. The distribution and extent of the lung injury depends on the concentration of the agent, duration of exposure, route and pattern of breathing, solubility and biologic reactivity of the agent and biologic individual susceptibility. The typical clinical course following toxic fume exposure consists of three phases: an acute onset, with upper respiratory symptoms and, sometimes, pulmonary edema, a latent period and finally an irreversible obstructive, physiological picture with dyspnea and cough. Physical examination reveals dry crackles over the lower lobes, particularly in inspiration, and a mid-expiratory squeak. Chest radiographs are normal or show hyperinflation and air trapping. Bronchiectasis may coexist. In a series of Iranian war victims exposed to

mustard gas HRCT scans have also documented tracheobronchomalacia [16]. Histologically, there is a pure constrictive bronchiolitis. The prognosis is poor as steroids seem to have no beneficial effects. Infectious and Postinfectious Bronchiolitis in Adults Bronchiolitis as a manifestation of an acute infection in adults may be due to viruses, most frequently in immunocompromised hosts and elderly people. Cases due to adenovirus, Herpes simplex, respiratory syncitial virus, cytomegalovirus, Mycoplasma pneumoniae, acid-fast Mycobacteria, Bordetella pertussis and Bordetella influenza have been described. Uncommon causes of infectious bronchiolitis are: Legionella pneumophila, Haemophilus influenzae, Klebsiella pneumoniae, Serratia marcescens, Aspergillus or Mucor, Nocardia asteroides, rubeola, measles, Enteroviruses, human immunodeficiency virus, malaria, Cryptosporidium species, Microsporidia (Encephalitozoon hellem) (table 4). Typical viral inclusions or the identification of the offending microorganism with more sophisticated techniques in serum, throat swabs, tracheal aspirates, bronchoalveolar lavage fluid, or lung biopsies can help to address a definitive diagnosis. Histologically, nonspecific, acute or chronic, or granulomatous cellular bronchiolitis, is observed in the majority of cases. Follicular bronchiolitis is reported especially in HIV

Table 4. Causes of infectious bronchiolitis

Common causes Mycoplasma pneumoniae Respiratory syncitial virus Adenovirus Herpes simplex Cytomegalovirus Acid-fast Mycobacteria Bordetella pertussis Influenza Uncommon causes Legionella pneumophila Haemophilus influenzae Klebsiella pneumoniae Serratia marcescens Aspergillus or Mucor Nocardia asteroids Rubeola Measles Enteroviruses Human immunodeficiency virus Malaria Cryptosporidium species, Microsporidia (Encephalitozoon hellem)

Bronchiolitis

patients. Centrilobular and peribronchial nodules, ‘tree in bud’ pattern and areas of ground glass opacity or consolidation are the findings in HRCT scans. Sometimes, mosaic oligemia and expiratory air trapping can be found. Sporadic cases of fixed airflow obstruction with mosaic oligemia and expiratory air trapping secondary to infections have been reported in adults. The agents that have been associated with bronchiolitis include adenovirus types 3, 7 and 21, rubeola, measles, influenza, parainfluenza, cytomegalovirus and Mycoplasma pneumoniae. Constrictive bronchiolitis is the most common histopathologic pattern found following infection. Bronchiolitis with inflammatory polyps has been more rarely reported. Sawyer-James syndrome (also termed MacLeod’s syndrome, unilateral or lobar emphysema, and unilateral hyperlucent lung) is a peculiar variant of postinfectious bronchiolitis. It usually develops as a sequel of viral pulmonary infection in infancy or early childhood and leads to alveolar destruction and obliterative bronchiolitis. Drug-Induced Bronchiolitis Obliterans Gold compounds, penicillamine and tiopronin have been associated with bronchiolitis obliterans. In the cases in which an open lung biopsy was performed a concentric constricitive bronchiolitis was identified. Most of the patients reported were women. Dyspnea, cough and wheezing, a high pitched inspiratory squeak were the symptoms and signs more frequently described. Pulmonary function tests showed a fixed obstruction on expiration. Chest X-ray films were normal or showed a mild hyperinflation. Many of the described patients suffer with rheumatoid arthritis so that a strict association between these drugs and constrictive bronchiolitis is lacking. An outbreak of rapidly progressive respiratory distress associated with consumption of uncooked Sauropus androgynus, a vegetable, has been recently reported in Taiwan. S. androgynus is claimed to be effective in weight control [17]. Most of the patients were young or middle-aged women. Respiratory symptoms (cough and dyspnea) occurred about 10 weeks after ingesting the vegetable juice. Other symptoms included dizziness, insomnia, and palpitations. Laboratory tests were normal. Although chest radiographs were essentially normal, HRCT of lung revealed bilateral bronchiolar wall thickening and dilatation and low attenuation areas with air trapping. Pulmonary function tests disclosed severe obstructive impairment with no response to bronchodilators. A moderate-to-severe reduction in diffusion capacity was also observed. Histopathologic changes ranged from bronchiolar inflammation and fibrosis to severe constrictive bronchiolitis. Areas of bronchiolitis obliterans with organizing pneumonia were also reported. Segmental ischemic necrosis of the small

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Fig. 8. Ulcerative colitis-related bronchiolitis. Dynamic HRCT. In the inspiratory phase cylindrical bronchiectasis are evident in the lower lobes (a). In the expiratory phase areas of air trapping appear (b). Case studied in collaboration with Dr. A. Carloni, Terni (Italy).

a

bronchi has also been reported. Neutrophils and, to a lesser extent, eosinophils were increased in the lavage fluid. Lung transplantation is the only effective treatment reported. Connective Vascular Diseases and Bronchiolitis Obliterans Diseases involving the conducting small airways have been reported in rheumatoid arthritis and, less frequently, in lupus erythematosus, polymyositis-dermatomyositis, ankylosing spondylitis, Sjogren’s syndrome and scleroderma. Dyspnea and cough (in some cases with sputum production) often associated with inspiratory rales and mid-inspiratory squeak are observed in middle-aged women with seropositive rheumatoid arthritis (or less frequently in patients with juvenile rheumatoid arthritis, SLE, scleroderma, Bechet’s disease) and/or evidence of Sjogren’s syndrome. Pulmonary function tests show fixed airflow obstruction with normal or near normal diffusing capacity. HRCT shows bilateral patchy areas of low attenuation or centrilobular nodules and branching lines. Bronchiectasis can also be documented. Histology findings in these patients are heterogeneous: follicular bronchitis and bronchiolitis, centrilobular clusters of foamy macrophages (diffuse panbronchiolitis like pattern), constrictive bronchiolitis, and acute epithelial injury often coexist in the same specimen. BAL cell analysis reveals a marked increase in the percentage of neutrophils. In cases where the dominant histolologic pattern is characterized by lymphoid hyperplasia (follicular bronchiolitis) a response to corticosteroids or to erythromycin is frequently observed. Oral prednisone and intravenous cyclophosphamide have been suggested to be effective in some cases. Improvement of refractory rheumatoid-arthritis associated constrictive bronchiolitis with etanercept has been reported [18]. Bronchiectasis detected by HRCT is found in about 30% of patients with rheumatoid arthritis and less frequently in patients with other collagenvascular diseases.

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b

Inflammatory Bowel Disease (IBD) Associated with Bronchiolitis Obliterans Pulmonary complications occur in an estimated 0.21% of patients with IBD. Ulcerative colitis is most frequently associated with pulmonary complications. The most common presentation is large airway disease, such as tracheobronchitis, chronic bronchitis or bronchiectasis [33]. Cellular bronchiolitis with intraluminal accumulation of neutrophils and chronic inflammation, cicatricial bronchiolitis, and epithelial ulceration, findings comparable with diffuse panbronchiolitis have been described. Chronologically, small airways involvement can develop at any time during the course of IBD. In about 80% of the cases, however, the onset of pulmonary symptoms follows the diagnosis of IBD by months to years. The spectrum of HRCT changes is broad (fig. 8): bronchiectasis, thickening of the bronchioles walls, mosaic perfusion and air trapping centrilobular nodules and branching linear opacities (‘tree in bud’ appearance) have been reported. Patients may have cough, dyspnea or systemic symptoms such as fever or asthenia. Inhaled or oral steroids are the recommended treatment. Bronchiolitis Obliterans in Transplanted Patients Posttransplant obstructive lung disease occurs exclusively after allogenic bone marrow or stem cell transplantation (BMT) and in lung transplant recipients (LTR). Histologically, this is characterized by obliterative bronchiolitis. The clinical, imaging, and functional features are similar in both settings. The prevalence of obliterative bronchiolitis has been reported by different centers to have an incidence of between 1.2 and 11% for BMT and 20–50% in LTR. Risk factors for BMT-associated obliterative bronchiolitis include older age, recurrent sinusitis, chronic GVHD, methotrexate prophylaxis for GVHD, and acquired hypogammaglobulinemia [2]. In LTR, the development of obliterative bronchiolitis is frequently preceded by acute graft

rejection. More frequent, more severe, and longer episodes of acute cellular rejection confer an increased risk for bronchiolitis obliterans syndrome. Nonimmunological inflammatory conditions, such as viral infection and ischemic injury, may also trigger obliterative bronchiolitis LTR. The peak incidence is between 7 and 12 months. Dyspnea with exertion, nonproductive cough and nasal congestion are the symptoms at presentation. Cough becomes progressively productive earlier in LT patients. The presentation may be acute and may imitate a respiratory infection. At physical examination scattered wheezes and expiratory squeaks are more frequently noted. Airway colonization by bacteria including Pseudomonas and Staphylococcus and fungi often develops later. Low levels of Clara cell secretory protein (CC16) are associated with obliterative bronchiolitis after allogeneic stem cells transplant and its monitoring in serum may have potential as an early marker [19]. Pulmonary function tests show irreversible airflow obstruction, the total lung capacity being lower in LTR the DLCO may be moderately depressed. Because of the difficulty in securing a histological diagnosis by transbronchial biopsy, a clinical classification has been derived. Consequently, graft dysfunction is referred to as bronchiolitis obliterans syndrome (BOS) (table 5). The aim of this classification is to standardize nomenclature and define disease progression. Dynamic HRCT has been used to aid the diagnosis of BOS particularly when pulmonary function tests are normal. A mosaic oligemia pattern and expiratory air trapping may be seen. However, a recent study suggested that the sensitivity of CT-depicted air trapping before the clinical appearance of BOS is lower than has been reported previously [20]. Bronchoalveolar lavage in BOS is characterized by an increased total cell count with a substantial neutrophilia,

Table 5. Bronchiolitis obliterans syndrome classification system

(2002 Classification) FEV1 ⬎ 90% of baseline and FEF25⫺75 ⬎ 75% of baseline FEV1 81–90% of baseline and FEF25⫺75 ⱕ 75% of baseline FEV1 66–80% of baseline FEV1 51–65% of baseline FEV1 ⱕ50% of baseline

BOS 0 BOS 0p* BOS 1 BOS 2 BOS 3

*BOS 0p ⫽ Potential-BOS stage; FEV1 ⫽ forced expiratory volume in 1 s. From Estenne et al. [30].

Bronchiolitis

increased levels of granulocyte activation markers (IL-8, myeloperoxidase, eosinophil cationic protein). CD8⫹ lymphocytes may be observed in bone marrow or stem cells transplanted patients. Pathologic findings include a moderate to severe peribronchial and peribronchiolar mononuclear cell inflammatory infiltrate accompanied by exocytosis into the bronchiolar epithelium (lymphocytic bronchitis/bronchiolitis). A lymphocytic infiltrate may be present in the interstitium adjacent to the affected bronchioles. Constrictive bronchiolitis account for the lumen narrowing and for bronchioloectasis in the vast majority of cases but bronchiolitis with intraluminal polyps can be also present in a patchy distribution. An alveolar component of lung rejection or pulmonary GVHD is more typical of the active phase. A leading hypothesis relating to pathogenesis is that the immunologic reaction is due to upregulation of class II major histocompatibility complex (MHC) antigens on airway epithelium and vascular endothelium. CD4⫹ and CD8⫹ lymphocytes are mostly involved but NK cells, Langerhans cells and L26 (a pre-plasma cell B marker)positive cells contribute to the inflammatory infiltrate. Infections with immunomodulant viruses (CMV, HHV-6, Epstein-Barr virus) are also important to up-regulate HLA expression and cytokine production in LTR. Elevated levels of IL-8 and transforming growth factor-␤ (TGF-␤) in BAL fluid have been reported. IL-8, TGF-␤ and tumor necrosis factor-␣ may act as key mediators for airway inflammation and fibroproliferation in the pathogenesis of BOS, with bronchial epithelial cells serving as a relevant source of IL-8. Aspiration of duodenogastroesophageal refluxate is prevalent after lung transplantation and is associated with the development of BOS. Elevated BALF bile acids may promote early BOS development via an inflammatory process, possibly mediated by IL-8 and alveolar neutrophilia. Insulin growth factor-1 and -3 (IGF-1 and -3) could have a role in the fibrotic process underlying obliterative bronchiolitis and could be considered early markers of this complication. Ischemic injury to the graft patients is also relevant because it is associated with acute inflammation of the airways. Recent pilot studies indicate a potential benefit for azithromycin in not only halting, but reversing the declining lung function seen in obliterative bronchiolitis. Lowdose macrolides with their anti-inflammatory effects offer a new and exciting therapeutic strategy for the treatment of progressive BOS [21, 22]. It has hypothesized that the inhalation of an aerosol cyclosporine would provide high pulmonary concentrations of the drug with minimal systemic toxicity, resulting in less acute and chronic rejection

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after lung transplantation. Evidence suggests that the number of respiratory infections and the aggressiveness with which these infections are treated influences air flow obstruction progression. Lung transplantation or retransplantation are the last resort in well-selected patients.

immunostaining for bombesin, a neuropeptide with growth factor-like properties, has been demonstrated within neuroendocrine cells. Lung transplantation is the only effective treatment in cases with severe irreversible airflow obstruction.

Paraneoplastic Pemphigus and Constrictive Bronchiolitis Paraneoplastic pemphigus is an autoimmune disease that frequently accompanies an overt or occult malignant non-Hodgkin lymphoma. It has also been reported in patients with other neoplasms including chronic lymphocytic leukemia, Castleman’s disease, thymoma, retroperitonel sarcoma, and Waldenström macroglobulinemia. It is characterized by the presence of IgG autoantibodies that react against desmosomal and hemidesmosomal plakin proteins, desmosomal transmembrane proteins and an unidentified 170-kDa antigen. A recently recognized complication in about 30% of patients is respiratory failure with clinical features of bronchiolitis obliterans. The large airways appear to be involved early in the course of the disease. Acantholysis of differentiated ciliary epithelium from the underlying basilar cells is evident in endobronchial biopsy specimens. Later involvement of small airways leads to respiratory failure and death. Evidence to date indicates that autoantibodies directed against plakin proteins may be responsible for acantholytic changes in the bronchial/bronchiolar epithelium observed in these cases.

Diffuse Panbronchiolitis (DPB) DPB is a distinctive form of small airway disease. DPB is largely restricted to Japan. It has also been reported from China and Korea. A familial predisposition with a significant increase in HLA-Bw 54 has been described in Japan. In Korea the most represented haplotype is A11 [25]. Environmental factors appear to be important since the disorder is very uncommon in persons of Asian ancestry living abroad. Sporadic case reports and a few short series describing DPB in western populations have been published [3]. Diagnostic criteria [3] include: (1) symptoms of chronic cough, sputum, and dyspnea on exertion; (2) physical signs of rales and ronchi; (3) a chest radiograph showing diffusely disseminated fine nodular shadows, mainly in the lower lung fields with hyperinflation; (4) lung function studies showing at least three of the four abnormalities: forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) less than 70%, vital capacity (VC) less than 80% of the predicted value, residual volume (RV) greater than 150% of the predicted value, or PO2 less than 80 mm Hg. Additional clinical and laboratory findings include chronic paranasal sinusitis (present in 75–100% of cases), increased cold hemagglutinin titers, increased immunoglobulin A and increased serum Ca 19–9. It is more prevalent in males (M/F ⫽ 2/1) and the peak incidence occurs between the fourth and seventh decades of life. Sinus symptoms often precede chest symptoms by years or decades. Early in the disease course, sputum cultures are unrevealing. Infection and/or colonization of the airways with H. influenzae, and occasionally with Streptococcus pneumoniae, Klebsiella pneumoniae, or Staphilococcus aureus follows. Ultimately, these are replaced by chronic infection with Pseudomonas aeruginosa or other Pseudomonas species. Histologically, all layers of the walls of the respiratory bronchioles are involved (pan-bronchiolitis). The most distinctive feature of DPB is an accumulation of foam cells in the walls of the respiratory bronchioles, adjacent alveolar ducts, and alveoli. An intense T lymphocytic infiltrate is evident around the bronchiolar lumen and neutrophils accumulated within the lumen (fig. 9). Hyperplastic lymphoid follicles and granulation tissue tufts are also present around the bronchioles. A marked increase of Langerhans cells in the bronchiolar submucosa associated with a marked expression of GM-CSF protein in the bronchiolar epithelium

Neuroendocrine Cell Hyperplasia with Bronchiolar Fibrosis In 1992, Aguayo et al. [4] reported 6 patients, all nonsmokers, with moderate chronic airflow obstruction, 3 of whom had peripheral carcinoid tumors and 3 progressive dyspnea. All the patients had foci of neuroendocrine hyperplasia around the bronchioles, and this was associated with partial or total occlusion of their lumen by fibrous tissue. In a study of 25 patients with peripheral carcinoid tumors Miller and Muller [23] found that 19 (76%) had neuroendocrine cell hyperplasia in airways, mostly bronchioles. Eight patients (32%) were also found to have constrictive bronchiolitis. All 8 patients were women as were the 3 patients with carcinoids reported by Aguayo. Pulmonary function tests were normal or showed a mild or severe airflow obstruction. The HRCT findings were quite characteristic with peripheral nodules and mosaic oligemia and/or expiratory air trapping. The hypothesis is that bronchiolar fibrosis is related to one or more peptides secreted by neuroendocrine cells and that these cells are more effective in stimulating fibrosis in women [24]. Specific

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Fig. 9. Diffuse panbronchiolitis. a Neutrophilic accumulation in the lumen of respiratory bronchioles (slide stained using CD15 monoclonal antibodies). b Foamy macrophages in the surrounding alveolar walls (slide stained using CD68 monoclonal antibodies).

a

has been described. Advanced disease is manifested by secondary ectasia of the proximal small bronchi. HRCT findings are quite characteristic but not specifically pathognomonic. Nodular shadows are distributed in a centrilobular fashion, often extending to small, branching linear areas of attenuation (‘tree in bud’ pattern). Peripheral air trapping is usually confirmed in expiratory films. In addition, dilatation of airways and bronchial wall thickening are present. BAL fluid analysis reveals a marked neutrophilia, a decreased CD4/CD8 ratio, an increase in absolute number of the CD8⫹HLA-DR⫹ cells and CD3⫹gammadelta⫹ cells. IL-8, leukotriene B4 and defensins have been reported to be present in elevated concentrations in lavage fluid. Low-dose erythromycin (200–600 mg/day) is the therapy of choice [3]. Macrolides impair neutrophil chemotaxis, neutrophil superoxide production and neutrophilderived elastolytic activity. Furthermore they significantly reduce neutrophil count and defensin concentrations, leukotriene B4 and IL-8 in BAL fluid and also reduce the circulating pool of T lymphocytes bearing HLA-DR. In addition, erythromycin may cause a reduction in mucus production by decreasing glycoconjugate secretion. After at least 3 months of therapy, a reduction in the extent of small nodular opacities, of the severity of ‘periairways’ thickening, and in the extent of mucus plugging can be seen on HRCT scanning, with a corresponding significant improvement in lung function. Nonsteroidal inflammatory drugs may have a role in controlling the bronchorrhea associated with this disease by altering airway epithelial ion and water transport. Routine use of ␤2-agonists or oxitropium bromide can help to promote mucociliary clearance and bronchodilatation in patients with a component of reversible airway disease. Chronic pulmonary infection due to diffuse panbronchiolitis may be associated with p-ANCA polyangiitis.

Bronchiolitis

b

Cryptogenic Bronchiolitis The existence of cases of cryptogenic bronchiolitis obliterans was first considered by Turton et al. [26]. Kindt and coworkers in the late 1980s described 16 patients who presented with evidence of airflow limitation and hyperinflation [32]. The majority of the patients were current or former smokers. The pathologic findings have been briefly reported as bronchiolar inflammation, often with an acute component, ‘bronchiolar obliteration’ and excess ‘mucus’ cells in the bronchioles. Bronchoalveolar lavage profile was characterized by a substantial accumulation of neutrophils and neutrophil products. Steroid treatment has been beneficial. Kraft et al. [27] have described a cohort of patients with cryptogenic bronchiolitis. They reported 4 female patients 36–59 years old with mild nonspecific symptoms (coryza, cough, dyspnea) in whom there was no associated systemic disease. Two patients had crackles on auscultation. The chest roentgenogram was normal in 1 patient, and it revealed increased bronchial wall thickening in 3 patients. HRCT demonstrated abnormal interstitium in 1 patient, airway dilatation in another, and minimal upper lobe centrilobular thickening in the third. Pulmonary function testing yielded a variety of results: 2 patients presented with increased volumes and airflow limitation, 1 patient had a mixed disorder, and the remaining patient exhibited normal pulmonary function. Diffusing capacity was reduced in 3 patients. These patients showed constrictive bronchiolitis described as concentric fibrotic narrowing of the lumen of membranous bronchioles accompanied by muscle hyperplasia and ‘mucus stasis’ (fig. 10). A series of patients with chronic bronchiolitis with intraluminal accumulation of acute inflammatory cells, scattered foamy cells and HRCT findings suggesting a diagnosis of

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a

Fig. 10. Cryptogenic bronchiolitis. Dense fibrosis around a membranous bronchiole whose lumen appears to be distorted. In this area inflammation is scanty (a). Focal accumulation of B lymphocytes (slide stained using CD20 monoclonal antibodies) (b) and T lymphocytes (slide stained using CD3 monoclonal antibodies) (c) is present in the bronchiolar wall.

b

diffuse panbronchiolitis has been reported [3]. In these patients serum Ca 19–9 was increased. Peribronchiolar fibrosis and bronchiolar metaplasia has recently been described. This may be a unique histological lesion with clinical features mimicking idiopathic pulmonary fibrosis or chronic hypersensitivity pneumonitis. These patients are more frequently females and may have a poor prognosis in spite of immunosuppressive treatment [28]. Respiratory Bronchiolitis-ILD Respiratory bronchiolitis is a distinct histopathologic entity defined in 1974 [1]. In surgical and autopsy specimens, respiratory bronchiolitis is usually considered an incidental finding and a proof of cigarette smoke inhalation. Myers et al. [29] in 1987, however, reported a syndrome of diffuse interstitial lung disease in which the only pathologic lesion in surgical specimens was respiratory bronchiolitis. The authors referred to this entity as respiratory bronchiolitis-associated interstitial lung disease (RB-ILD). It occurs mainly in cigarette smokers in their fourth or fifth decade of life. Symptoms reported in the two larger series include mild dyspnea on exertion (70.8%); nonproductive cough (58.3%); chest pain (8.3%). A small minority are asymptomatic at the time of diagnosis (8.3%). Rales (inspiratory and expiratory coarse and prolonged crackles) on auscultation were detected in 33.3%. Clubbing or systemic complains

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c

have not been reported. An association between spontaneous pneumothorax and RB has recently been suggested [2]. Mild-to-moderate reduction in diffusing capacity is the most consistent abnormality of pulmonary function tests (92%). In 50% of patients, a mild desaturation after exercise has been reported. Chest radiograph reveals diffuse reticular or reticulonodular shadows in a bibasilar distribution and less frequently bronchial wall thickening, small irregular opacities, prominent peribronchiolar interstitial markings and peripheral ring shadows are observed. A small number of patients have bibasilar atelectasis or even normal chest radiographs. On HRCT, the abnormalities consist of diffuse or patchy areas of ground glass attenuation with or without fine reticular or poorly defined nodular opacities. Emphysema is often present but is not usually conspicuous on HRCT (fig. 11). Bronchoalveolar lavage yields increased cellularity compared to control subjects who smoke. The increased cellularity is due to an increase of macrophages and (to a lesser degree) of lymphocytes. The diagnosis is usually secured by a surgical biopsy which demonstrates characteristic pigmented macrophages. There is an overlap between RB-ILD and desquamative interstitial pneumonitis (DIP). Some authors suggest that RB-ILD is a precursor of DIP or a less severe form of the same fundamental lesion. RB-ILD usually has a good prognosis and it can improve after smoke cessation alone or after steroid treatment.

Wheezing, inspiratory squeaks, crackles, obstructive impairment; ↑↑ ESR, ↑↑ Ca 19–9, ↓↓ CC-16 Clinical settings

TBB and BAL

Surgical lung biopsy

HRCT findings • Tree in bud • Alveolar ground-glass opacities • Mixed pattern • Mosaic oligemia/exp air trapping 1 With unusual clinical context 2 With a definite clinical setting such as allogenic transplantation

Fig. 11. HRCT. Respiratory bronchiolitis-ILD. Patchy, mostly centrilobular ground glass opacities are evident. Areas of centrilobular emphysema are also evident. Bronchiolitis Definitive diagnosis

Miscellaneous A variety of miscellaneous conditions have been associated with bronchiolitis obliterans, including gastroesophageal reflux, activated charcoal used for management of parasuicide, Stevens-Johnson syndrome, and primary biliary cirrhosis. Follicular bronchiolitis has been reported in families and in patients with common acquired hypogammaglobulinemia or other forms of immunodeficiency. In patients with common variable immunodeficiency syndrome and follicular bronchiolitis, there is a higher incidence of lymphoproliferative disease. The cardinal features of follicular bronchiolitis on HRCT consist of centrilobular nodules measuring 3–12 mm in diameter, which are variably associated with peribronchial nodules and patchy areas of ground-glass opacity. The nodules and groundglass opacities are generally bilateral and diffuse in distribution. Mild bronchial dilatation with wall thickening is seen in some cases. These patients have generally been treated with bronchodilators and corticosteroids. More recently, erythromycin therapy has been reported to be of benefit. Adult patients with lysinuric protein intolerance can also present with reversible respiratory insufficiency and signs of bronchiolitis obliterans. Interestingly, 4 patients with ataxia-telangiectasia who had died of respiratory failure had features of bronchiolitis obliterans in all lobes examined at autopsy.

Bronchiolitis

Fig. 12. Practical approach to bronchiolitis.

Diagnostic Approach

The clinical spectrum of bronchiolar inflammatory disorders in adults is wide. A detailed history may indicate a source of bronchiolar injury. The auscultatory findings of wheeze, inspiratory squeaks or crackles and pulmonary function tests indicating an airflow obstruction may point to bronchiolar disease. Laboratory markers associated with bronchiolar disease are an increased serum Ca 19–9, an increased ESR or the presence of autoantibodies. The critical diagnostic step is a HRCT study with dynamic (inspiratory and expiratory) scans. The pattern of mosaic oligemia and expiratory air trapping can be considered sufficient per se for a definitive diagnosis in specific clinical settings (post-transplanted patients, bronchiolitis due to toxic gases and fumes, metabolic disorders). BAL is part of the armamentarium to exclude infections, to confirm a neutrophilic or mixed (neutrophils and lymphocytes) profile. Histological documentation is, however, deemed useful in the other cases. Surgical lung biopsy is warranted in cases of mosaic oligemia and expiratory air trapping when small transbronchial lung biopsies do not allow pathological characterization. In cases of HRCT ‘tree in bud pattern’, alveolar/ground glass attenuation, or mixed pattern, transbronchial lung biopsy and BAL are usually adequate for diagnosis (fig. 12).

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References 1 Colby TV: Bronchiolitis: pathologic considerations. Am J Clin Pathol 1998;109:101. 2 Poletti V, Chilosi M, Zompatori M: Bronchiolitis; in Gibson GJ, Geddes DM, Costabel U, Sterk PJ, Corrin B (eds): Respiratory Medicine. Philadelphia, Saunders, 2003, vol 2, pp 1526–1539. 3 Poletti V, Casoni G, Chilosi M, Zompatori M: Diffuse panbronchiolitis. Eur Respir J 2006;28: 862–871. 4 Aguayo SM, Miller YE, Waldron JA, et al: Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med 1992;327:1285. 5 Thurlbeck WM, Write JL: Chronic airflow obstruction; in: Thurlbeck’s Chronic Airflow Obstruction, ed 2. New York, Decker, 1999. 6 Chen X: The p53 family: same response, different signals? Mol Med Today 1999;5:387. 7 Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V, Andrews NC, Caput D, McKeon F: p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 1998;2:305. 8 Elssner A, Jaumann F, Dobmann S, Behr J, Schwaiblmair M, Reichenspurner H, Furst H, Briegel J, Vogelmeier C: Elevated levels of interleukin-8 and transforming growth factorbeta in bronchoalveolar lavage fluid from patients with bronchiolitis obliterans syndrome: proinflammatory role of bronchial epithelial cells. Transplantation 2000;70:362. 9 Belperio JA, Keane P, Burdick MD, Lynch JP, Xue Y, Li K, Ross DJ, Strieter RM: Critical role for CXCR3 chemokine biology in the pathogenesis of bronchiolitis obliterans syndrome. J Immunol 2002;169:1037–1049. 10 Belperio JA, Keane MP, Burdick MD, Gomperts B, Xue Y, Hong K, Mestas J, Ardehali A, Mehrad B, Saggar R, Lynch JP, Ross DJ, Strieter RM: Role of CXCR2/ CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome. J Clin Invest 2005;115:1150–1162. 11 Kim CK, Kim SW, Kim YK, Kang H, Yu J, Yoo Y, Koh YY: Bronchoalveolar lavage eosinophil cationic protein and interleukin-8 levels in acute asthma and acute bronchiolitis. Clin Exp Allergy 2005;35:591–597. 12 Pipavath SJ, Lynch DA, Cool C, Brown KK, Newell JD: Radiologic and pathologic features of bronchiolitis. Am J Roentgenol 2005;185: 354–363. 13 Ward C, De Soyza A, Fisher AJ, Pritchard G, Forrest I, Corris P: A descriptive study of small airway reticular basement membrane thickening in clinically stable lung transplant recipients. J Heart Lung Transplant 2005;24: 533–537.

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14 Siddiqui MT, Garrity ER, Martinez R, Husain AN: Bronchiolar basement membrane changes associated with bronchiolitis obliterans in lung allografts: a retrospective study of serial transbronchial biopsies with immunohistochemistry. Mod Pathol 1996;9: 320–328. 15 Brugiere O, Thabut G, Mal H, Marceau A, Dauriat G, Marrash-Chahla R, Castier Y, Leseche G, Colombat M, Fournier M: Exhaled NO may predict the decline in lung function in bronchiolitis obliterans syndrome. Eur Respir J 2005;25:813–819. 16 Ghanei M, Moqadam FA, Mohammad MM, Alani J: Tracheobronchomalacia and air trapping after mustard gas exposure. Am J Respir Crit Care Med 2006;173:304–309. 17 Oonakahara K, Matsuyama W, Higashimoto I, Machida K, Kawabata M, Arimura K, Osame M, Hayashi M, Ogura T, Imaizumi K, Hasegawa Y: Outbreak of Bronchiolitis obliterans associated with consumption of Sauropus androgynus in Japan: alert of food-associated pulmonary disorders from Japan. Respiration 2005;72:221. 18 Cortot AB, Cottin V, Miossec P, Fauchon E, Thivolet-Bejui F, Cordier JF: Improvement of refractory rheumatoid arthritis-associated constrictive bronchiolitis with etanercept. Respir Med 2005;99:511–514. 19 Mattsson J, Remberger M, Andersson O, Sundberg B, Nord M: Decreased serum levels of clara cell secretory protein (CC16) are associated with bronchiolitis obliterans and may permit early diagnosis in patients after allogeneic stem-cell transplantation. Transplantation 2005;79:1411–1416. 20 Konen E, Gutierrez C, Chaparro C, Murray CP, Chung T, Crossin J, Hutcheon MA, Paul NS, Weisbrod GL: Bronchiolitis obliterans syndrome in lung transplant recipients: can thinsection CT findings predict disease before its clinical appearance? Radiology 2004;231: 467–473. 21 Yates B, Murphy DM, Forrest IA, Ward C, Rutherford RM, Fisher AM, Lordan JL, Dark JH, Corris PA: Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2005;2: 772–775. 22 Khalid M, Al Saghir A, Saleemi S, Al Dammas S, Zeitouni M, Al Mobeireek A, Chaudhry N, Sahovic E: Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study. Eur Respir J 2005;25: 490–493. 23 Miller RR, Muller NL: Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumors. Am J Surg Pathol 1995;19:653.


24 Cohen AJ, King TE, Gilman LB, Magill-Solc C, Miller YE: High expression of neutral endopeptidase in idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells. Am J Respir Crit Care Med 1998;158:1593–1599. 25 Keicho N, Totunaga K,Nakata K, et al: Contribution of HLA genes to genetic predisposition in diffuse panbronchiolitis. Am J Respir Crit Care Med 1998;158:846. 26 Turton CW, Williams G, Green M: Cryptogenic obliterative bronchiolitis in adults. Thorax 1981;36:805. 27 Kraft M, Mortensen RL, Colby TV, Newman L, Waldron JA, King TE: Cryptogenic constrictive bronchiolitis: a clinicopathologic study. Am Rev Respir Dis 1992;148:1093. 28 Fukuoka J, Franks T, Colby TV, Flaherty KR, Galvin JR, Hayden DD, Gochuico BR, Kazerooni EA, Martinez F, Travis WD: 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. 29 Myers JL, Veal CF, Shin MS, Katzenstein AL: Respiratory bronchiolitis causing interstitial lung disease. Am Rev Respir Dis 1987; 135:880. 30 Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz MI, Mallory GB, Snell GI, Yousem S: Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21:297–310. 31 Eschenbacher WL, Kreiss K, Lougheed MD, Pransky GS, Day B, Castellan RM: Nylon flock-associated interstitial lung disease. Am J Respir Crit Care Med 1999;159:2003–2008. 32 Kindt GC, Weiland JE, Davis WB, Gadek JE, Dorinsky PM: Bronchiolitis in adults. A reversible cause of airway obstruction associated with airway neutrophils and neutrophil products. Am Rev Respir Dis 1989;140: 483–492. 33 Colby TV, Camus P: Pathology of pulmonary involvement in inflammatory bowel disease. Eur Respir Mon 2007;39:199–207.

Venerino Poletti, MD Dipartimento Toracico Ospedale GB Morgagni via C. Forlanini 34 IT–47100 Forlì (Italy) Tel. ⫹39 0543 735830, Fax ⫹39 0543 735882 E-Mail [email protected]; [email protected]


Lymphoproliferative Lung Disorders Venerino Polettia,b Pier Luigi Zinzanic Sara Tomassettia Marco Chilosid a

Department of Diseases of the Thorax, G.B. Morgagni Hospital, Forlì; bPostgraduate School of Respiratory Medicine, University of Parma, Parma; cInstitute of Hematology and Medical Oncology ‘L. & A. Seràgnoli’, University of Bologna, Bologna, and dDepartment of Pathology, University of Verona, Verona, Italy

Abstract The aim of this review is to describe the pathophysiological, diagnostic, prognostic and therapeutic aspects of benign and malignant lymphoproliferative lung disorders including reactive pulmonary lymphoproliferative disease, primary and secondary pulmonary lymphomas. The lung parenchyma is frequently involved by disseminated lymphomas (secondary pulmonary lymphomas), it is rarely involved by extranodal malignant lymphoproliferative disorders arising primary in the lung without evidence of extrapulmonary involvement (primary pulmonary lymphomas). Malignant lymphoproliferative disorders are sometimes difficult to differentiate from reactive pulmonary lymphoproliferative disease, or from other benign infiltrative parenchymal lung disease or common malignant tumours. Lymphoproliferative lung disorders may be asymptomatic, or present with cough, dyspnea, pain, fever, recurrent infections, hemoptypsis. Radiological features include pulmonary consolidations, nodules, pulmonary opacities, pleural effusion, mediastinal adenopathy. The diagnosis and characterization of pulmonary lesions can be difficult and requires histological analysis, assessment of clonality using immunochemistry and molecular biology. Treatment and prognosis vary with the different histology.

Reactive pulmonary lymphoproliferative diseases may cause enlargement of intrapulmonary lymph nodes, manifest as reactive lymphoid hyperplasia which includes four different clinicopathological patterns: lymphocytic interstitial pneumonia (LIP), follicular bronchiolitis/bronchitis, nodular lymphoid hyperplasia (pseudolymphoma), angiofollicular lymphoid hyperplasia (Castelman’s disease). Primary pulmonary presentation of lymphoproliferative diseases is rare, on the other hand secondary pulmonary lymphomas occur relatively more often. Malignant lymphoproliferative diseases include Hodgkin’s and non-Hodgkin’s lymphomas (HL and NHL), affecting B or T cells. Malignant lymphoproliferative disorders may arise as primary pulmonary lymphomas (PPL) within the lung parenchyma without evidence of extrapulmonary involvement or as secondary pulmonary lymphomas spreading from systemic lymph nodes or neighboring sites (e.g. from mediastinal lymph nodes or thymus). Malignant proliferative diseases occur more frequently in immunocompromized hosts. Post-transplant patients and HIV-positive patients demonstrate a different clinical and pathological profile in contrast to patients with autoimmune disorders or immunocompetent hosts.


Reactive Pulmonary Lymphoproliferative Disease

Reactive pulmonary lymphoid hyperplasia and malignant lymphoproliferative disorders are sometimes difficult to differentiate, and may mimic other benign infiltrative parenchymal lung disease or common malignant tumors. A schematic classification is shown in figure 1.

Hyperplasia of lymphoid elements, such as intrapulmonary lymph nodes, mucosa-associated lymphoid tissue (MALT) and lymphoreticular aggregates in the terminal bronchioles, may be seen in a variety of lung disease.

Pulmonary lymphoproliferative disorders

Reactive pulmonary lymphoproliferative disease

Intrapulmonary lymph nodes

Primary pulmonary lymphomas

Reactive pulmonary lymphoid hyperplasia

Secondary pulmonary lymphoma

B cell non-Hodgkin’s lymphomas

Lymphocytic interstitial pneumonia (LIP)

MALT lymphoma

Follicular bronchitis/bronchiolitis

Follicular lymphoma

Nodular lymphoid hyperplasia, ‘pseudolymphoma’

High-grade large B cell lymphoma

Angiofollicular lymph node hyperplasia (Castelman’s disease)

Pulmonary plasmacytoma

T cell-rich B cell lymphoma (lymphomatoid granulomatosis)

T cell non-Hodgkin’s lymphomas

Extranodal NK/T cell lymphoma, nasal type

Anaplastic large T cell lymphoma

Mycosis fungoides/ sézary syndrome

Peripheral T cell lymphoma, unspecified

Hodgkin’s lymphoma

Post-transplant lymphoroliferative disorders (PTLD)

Fig. 1. Classification of lymphoproliferative lung disorders.

Intrapulmonary lymph nodes are distributed at the hilum and are occasionally found in the vicinity of the pleura. Hyperplasia of intrapulmonary lymph nodes may be due to a wide spectrum of causes ranging from common

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Poletti/Zinzani/Tomassetti/Chilosi

hyperplastic and reactive processes to malignant changes. To evaluate the nature of intrapulmonary lymph nodes high-resolution computed tomography (HRCT), positron emission computed tomography (PET-CT) are useful tools,

Fig. 2. Castleman’s disease in a HIV-positive

patient. Prone HRCT images show bilateral poorly defined, more often centrilobular nodules and thickening of the interlobular septae.

but surgery is usually necessary to obtain a definitive diagnosis. Reactive pulmonary lymphoid hyperplasia include angiofollicular lymph node hyperplasia, nodular lymphoid hyperplasia and diffuse lymphoid hyperplasia. Angiofollicular lymph node hyperplasia (Castleman’s disease) is a disorder classified according to the histopathologic findings as hyaline-vascular, plasma-cell type, or a mixed type variant of the two, and according to the clinical profile, as localized or multicentric [1]. Multicentric Castleman’s disease (MCD) is often associated with human immunodeficiency virus (HIV) infection and with human herpesvirus 8 (HHV8, or Kaposi’s sarcoma herpesvirus KSHV) and Epstein-Barr virus (EBV) infections. Pathogenesis remain largely unknown, but HHV8 and EBV may encode for a homologue of interleukin-6 (vIL-6) which may mediate some systemic features of MCD. MCD in HIVpositive patients has a higher prevalence of pulmonary symptoms and usually present with generalized lymphadenopathy characterized by perifollicular vascular proliferation and germinal center angiosclerosis, polyclonal hypergammaglobulinemia, hepatosplenomegaly and constitutional symptoms. In the immunocompetent host, the more common histopathologic pattern of hyaline-vascular change usually manifests as a localized asymptomatic mediastinal mass in most cases curable by surgery. The plasma-cell variant is more often associated with the multicentric disease characterized by lymphadenopathy, hepatosplenomegaly, skin rashes, sweating, fatigue, anemia, elevated erythrocyte sedimentation rate (ESR), polyclonal hypergammaglobulinemia and bone-marrow plasmacytosis. It may be associated with the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-proteins and skin changes). In MCD the chest radiographs may show reticular and/or nodular interstitial patterns often associated with

Lymphoproliferative Lung Disorders

mediastinal lymphadenopathy and in some cases accompanied by bilateral pleural effusions. Common CT findings are poorly defined centrilobular nodules, thickening of the bronchovascular bundles and interlobular septae, and thinwalled cysts (fig. 2), mostly related to diffuse interstitial, interalveolar, infiltration of small lymphocytes (LIP pattern). Less common findings include subpleural nodules, areas of ground glass attenuation, air-space consolidation and bronchiectasis. Microbiological investigations on BAL fluid permit to exclude common infectious etiologies, and genotyping analysis allows detecting HHV-8 DNA. A definite diagnosis is secured histologically, most cases being diagnosed by peripheral lymphnode biopsy. Specimens of pulmonary lesions may be obtained by trans-bronchial biopsy or by surgical biopsy. First line treatment of MCD in non-HIV patients consist of single chemotherapeutic agent, high doses of steroid and/or anti-CD-20 monoclonal antibodies. Recent studies show that humanized anti-human IL-6 receptor monoclonal antibody significantly alleviates chronic inflammatory symptoms and wasting [2]. However, the prognosis remains poor, patients die after relapsing of disease, progression to lymphoma or for bacterial sepsis, median survival time being 5 years [3]. The median survival in HIV-positive patients is 14 months. Patients die from infections, transformation to NHL or chemotherapy toxicity. Recent reports suggest that there may be some benefit using chemotherapy and highly active antiretroviral therapy (HAART), or HAART therapy alone. Nodular lymphoid hyperplasia, also known as ‘pseudolymphoma’, is a localized mass characterized by a lymphoid infiltrate with the absence of clonality despite immunohistochemical and genetic studies. The most common clinico-radiological feature is a localized and asymptomatic mass, although few patients present fever and elevated ESR. The single lesion is usually curable by

309

a

b

c

d

Fig. 3. LIP. Lung biopsy showing a dense interstitial lymphoid infiltrate and centrolobular nodules (a). HE. b Cytokeratin: the epithelial component is evidenced by low-molecular-weight cytokeratin showing discrete pneumocyte-II hyperplasia. c CD20: immunostaining demonstrates the B nature of lymphoid follicle. The diffuse interstitial lymphoid component is on the other hand mainly composed of CD3⫹ T cells (d).

surgical excision. Diffuse lymphoid hyperplasia encompasses two histological patterns of lymphocytic interstitial pneumonia (LIP) and follicular bronchitis/bronchiolitis. Lymphocytic interstitial pneumonia (LIP) [3] is a rare interstitial lung disease characterized by the presence of aggregates of B and T polyclonal lymphocytes within the lung interstitium (fig. 3). LIP is associated with serum protein abnormality (monoclonal gammopathy, polyclonal dysproteinemia, hypogammaglobulinemia). A variety of immunological disorders, such as Sjogren syndrome (25% of cases), primary biliary cirrhosis, myasthenia gravis, Hashimoto thyroiditis, pernicious anemia/agammaglobulinemia, autoimmune hemolytic anemia, systemic lupus erythematosus, celiac disease, HIV infection, EBV infection, chronic active hepatitis, other infections (e.g. pneumocystis, tuberculosis), drug injury, allogeneic bone marrow transplantation (GVHD; graft-vs.-host disease), extrinsic allergic alveolitis are associated with LIP. LIP occurs most commonly in women at a mean age of 55 years. Presenting symptoms are progressive cough and dyspnea, weight loss, fever, arthralgias. Common physical

310


findings are bibasilar crackles and finger clubbing (reported in about 50% of the cases). Pulmonary function tests show reduction of lung volume, reduction of DLco, hypoxemia and usually hypocapnia. The chest radiograph characteristically shows bibasilar reticulonodular infiltrates, a mixed alveolar-interstitial pattern can occur when infiltrates coalesce and cause compression of the alveoli. Typical HRCT abnormalities consist of areas of ground-glass attenuation and poorly defined centrolobular nodules and subpleural small nodules, mostly bilateral (⬎90%) and with a diffuse distribution (⬎60%). Other common findings are thickening of bronchovascular bundles, interlobular septal thickening (82%), cystic lesions (68%) (fig. 4), and lymph node enlargement (68%). Less common findings include nodules 1–2 cm in diameter (41%), airspace consolidation (41%), emphysema (23%), bronchiectasis (18%), pleural thickening (18%), and honeycombing (5%) [4]. Honeycombing and pulmonary hypertension appears in advanced disease. Pleural effusion are infrequent, except in HIV-related LIP. Usually the presence of pleurisy, large nodules and mediastinal adenopathy is suggestive for pulmonary lymphoma. Histologically, LIP is

important to assess air trapping. BAL usually documents a slight increase of polyclonal B lymphocytes. Surgical lung biopsy is often performed to obtain a definite histological diagnosis. Therapy with steroids and also with macrolides at low dose may have some benefit.

Primary Pulmonary Lymphomas

Fig. 4. LIP in a patient with Sjogren syndrome. HRCT showing bilateral bibasilar ground glass opacities, septal thickening and cystic lesions.

characterized by a heavy interstitial lymphoid infiltrate with minor peribronchiolar involvement. Granuloma formation is sometimes noted. Intra-alveolar accumulation of small lymphocytes, scanty granulation tissue tufts, and proteinaceous material along with type II cell hyperplasia are ancillary findings. Immunohistochemestry using CD-20 shows that B cells are mainly limited to germinal centers. The interstitial, interalveolar, lymphocytes are prominently T cells, plasma cells, histiocytes. Amplification of the immunoglobulin heavy chain gene or the T cell receptor gene using the polymerase chain reaction shows a polyclonal pattern. EBV has been identified in lung biopsy specimens from both HIVinfected and noninfected patients. Treatment with corticosteroid and immunosuppressive drugs may lead to resolution. Median survival is 11.5 years. The outcome is unpredictable and may vary from resolution to death due to progression to fibrosis, cor pulmonale and respiratory failure, to superimposed infection, or to development of a complicating lymphoma. Follicular bronchitis/bronchiolitis is a term introduced to describe the predominant peribronchial lymphocytic infiltrate with abundant germinal centers, associated with a variety of allergic diseases, immunodeficiency disorders (HIV infection, common immunodeficiency syndromes), and collagen vascular diseases. Patients usually present with dyspnea, occasionally fever and cough, hypoxemia, hypocapnia; either obstructive or restrictive spirometric patterns have been reported. The chest film shows bilateral reticular or nodular opacity. Common high-resolution CT findings are centrolobular nodules, bronchiolar dilatation, tree in bud and mosaic perfusion patterns. Expiratory dynamic HRCT scans are


A lymphoma can be defined as primary when it affects one or both lungs without any evidence of extrapulmonary involvement for up to 3 months following the diagnosis. Nevertheless, exceptions to these criteria are represented by cases where the lung is the principal site of involvement (cases with satellite nodes or multifocal MALT are cases which can be considered as primary). Primary pulmonary involvement by malignant lymphoma is rare representing 0.5–1% of all pulmonary neoplasms and 3.6% of all lymphomas. B Cell Non-Hodgkin Lymphomas The most common primary pulmonary lymphomas are B cell non-Hodgkin’s lymphomas, particularly the MALT type, followed by the less common B cell high-grade primary pulmonary lymphoma. Other types of primary pulmonary B cell non-Hodgkin’s lymphomas such as follicular lymphoma, diffuse large B cell lymphoma, intravascular large B cell lymphoma, pulmonary plasmocytoma, lymphomatoid granulomatosis, are extremely rare. MALT lymphoma (WHO classification ICD-O code 9699/3) is a low-grade B cell non-Hodgkin’s lymphoma arising from bronchus-associated lymphoid tissue (BALT). Lowgrade B cell lymphomas represent 50–90% of all primary lung lymphomas. Among non-gastrointestinal MALT lymphomas pulmonary lymphomas are the most frequent [5]. Pulmonary MALT lymphomas seem to arise in preexisting inflammatory lymphoid tissue (lymphoid follicles of the bronchus-associated lymphoid tissue – BALT). BALT is inconspicuous in adults, but the tissue undergoes hyperplasia in patients with chronic immune-mediated diseases such as chronic infections, connective tissue diseases, rheumatoid arthritis, and Sjogren’s syndrome. The cause of these inflammatory processes is likely related to chronic antigen stimulation, as in other extranodal lymphomas. Accordingly, the occurrence of intraclonal sequence variations (ongoing mutations) is a common finding in both gastric and pulmonary lymphomas, indicating the role of antigen stimulations in their pathogenesis [6, 7]. In a proportion of pulmonary lymphomas there appears to be a link with conditions where the immune system is abnormally

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Fig. 5. MALT lymphoma primary in the lung. HRCT scan shows a well-delineated mass in the middle lobe (a) and a pulmonary consolidation with air bronchogram in the dorsal segment of the upper right lobe (b). Patient with CT scan imaging showing a typical single mass with air bronchogram localized in the middle lobe (c).

stimulated or deregulated, such as in autoimmune diseases (Sjogren’s syndrome, Hashimoto thyroiditis, systemic lupus erythematosus – SLE, rheumatoid arthritis), or immunodeficiency (primary or acquired). These lymphomas are indolent, remain confined to the lung for long periods and appear to have a favorable prognosis. Although in a proportion of cases occurs a multiorgan disease [6–8]. This slow progression has resulted in cases of pulmonary MALT lymphoma being defined as ‘pseudolymphoma’. At the time of diagnosis a half of patients are asymptomatic, the lesions being discovered by routine chest radiography. Other patients present with nonspecific respiratory symptoms such as cough, dyspnea on effort, rarely hemoptysis and/or chest pain or even less frequently systemic symptoms (fever, weight loss). Laboratory findings are nonspecific and usually normal. A few patients have increased levels of lactate dehydrogenase (LDH) and/or ␤2-microglobulin in the serum and also less frequently a monoclonal band in serum immunoelectrophoresis is found. Radiologic feature of MALT lymphoma are solitary, well-delineated soft-tissue masses with air bronchogram (fig. 5). Although hilar and mediastinal lymphadenopathy is not a prominent radiologic finding, nodal involvement is documented at pathologic analysis in about the 30% of cases. HRCT findings include: areas of aveolar consolidation more frequently centered on dilated bronchi, ground glass attenuation, the presence of the ‘halo sign’, peribronchovascular nodules, ‘tree in bud pattern’, peribronchovascular thickening and septal lines [9]. The lesions are multiple in more then 70% of cases. The so-called ‘angiogram sign’, previously considered typical of low-grade lymphoma in the lung, has now been observed in other numerous alveolar filling disorders. Cases of endotracheobronchial

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MALT lymphoma with polypoid features have been reported. MALT lymphomas have generally been reported not to show increased fluorine 18-fluorodeoxyglucose (18FDG) accumulation on positron emission tomography (PET) [10]. High-grade primary large pulmonary B cell lymphomas represent a minority of cases of primary pulmonary lymphoma (11–19%). They often occur in patients with underlying immunological disorders such as after solid organ transplant, HIV infection and Sjogren syndrome [11]. Patients are usually symptomatic with respiratory symptoms (cough, dyspnea, hemoptysis), fever and weight loss. Common radiological and CT findings include single pulmonary mass, not infrequently excavated, and atelectasis; pleural effusion may be present. In HIV patients or in other immunosuppressed hosts, multiple excavated opacities are frequently found. Median survival time is 8–10 years, but relapse and progression occur early and survival is dramatically poorer in patients with underlying immunologic disorders such as AIDS and transplantation. Follicular lymphoma (WHO classification ICD-O code 9690/3) is a neoplasm of follicle center B cells with a partially follicular pattern (fig. 6). It affects adults (median age 59 years) and it is more frequent in females (male/female ratio 1/1.7) [1]. Follicular lymphoma predominantly involves lymph nodes, and only rarely extra-nodal sites, such as gastrointestinal tract, lung, skin and other sites. Primary lung involvement is usually asymptomatic. HRTC scan shows ground glass opacities sometimes with a ‘crazy paving’ pattern or nodules (fig. 7). Histological grades correlate with prognosis: grades 1 and 2 are indolent and usually not curable, whether grade 3 is more aggressive but potentially curable with aggressive therapy.

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Fig. 6. Primitive follicular lymphoma of the lung. a A large nodular area of infiltration formed by lymphoid follicules. HE. The differential diagnosis of this lesion is either nodular follicular hyperplasia or follicular lymphoma. b CD10 immunostaining defines the centrofollicular nature of follicular lymphocytes. c bcl-2 cytoplasmic expression in most centrofollicular lymphocytes defines their abnormal nature. d Irregular expression of CD23 in follicular dendritic cell.

Fig. 7. Follicular lymphoma primary in the lung. Chest CT scan shows bilateral nodular ground glass opacities.


Intravascular large B cell lymphoma (WHO classification ICD-O code 9680/3) is a rare subtype of B cell lymphoma characterized by the presence of lymphoma cells, with a peculiar endothelial localization in the lumen of small vessels and capillaries. It occurs in adults, but due to its rarity epidemiological features are not well characterized. It is usually disseminated to extranodal sites. Central nervous system, lung, kidneys and skin are the most common sites affected. Lung involvement is usually indicated by shortness of breath and fever, or fever of unknown origin [12]. LDH, soluble IL-2 receptor (sIL-2R) and ESR are usually elevated. Pulmonary function tests show a diffusing capacity which is decreased. Chest X-ray may be normal or show reticulonodular infiltrates or pleural effusion. CT findings may include bilateral reticular shadow, reticulonodular shadow, ground glass opacity, wedge-shaped subpleural opacities and pleural effusion. 18F-fluorodeoxyglucose positron emission tomography (18-FDG-PET) shows increased FDG uptake [10]. A ventilation/perfusion (V/Q) scan may document a mismatched segmental defect identical to that observed in pulmonary thromboembolism. An ante mortem diagnosis is

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difficult. Transbronchial biopsies can assist with the diagnosis, as can cytological analysis of pulmonary capillary blood cells. The prognosis is usually very poor despite combination chemotherapy. Pulmonary plasmacytoma (WHO classification ICD-O code 9731/3) is an extremely rare tumor. Less than 50 cases are reported in literature and in fact represent only the 6% of all extramedullary plasmacytomas. About 7% of patients affected by multiple myeloma have intrathoracic disease. The less-differentiated pulmonary plasmacytoma (plasmablastic lymphoma) occurs mainly in patients with advanced HIV infection. Phenotypically, the malignant cells appear most like plasmablasts. The prognosis in HIVpositive patients is poor (5,5 months) although this may improve with the advent of HAART therapy. In immunocompetent patients pulmonary plasmacytoma is more frequently observed in the upper respiratory tract. Common clinical findings are cough, dyspnea and hemoptysis. Laboratory features include paraproteinemia and urinary Bence-Jones. CT images show solitary nodule or lung masses; lobar consolidation has also been described. Lymphomatoid granulomatosis (LYG; WHO classification ICD-O code 9766/1) is an extranodal angiocentric and angiodestructive lymphoproliferative disorder, composed of a polymorphous infiltrate of atypical appearing EBV virus-infected B cells and numerically more abundant and mixed reactive T cells [1, 13]. This condition usually affect adults (average age 50) with a predilection for men (male to female ratio 2:1) and for patients with underlying immunodeficiency (HIV-positive patients, Wiskott-Aldrich syndrome). In LYG, the lung is the most frequently involved site. Although the upper respiratory tract is less commonly involved, ulceration of the upper airways have been described in 10–30% of cases. Other sites of involvement are brain, kidney, liver, skin, soft tissues, bladder and gastrointestinal tract. Few subjects are asymptomatic. Nearly 90% of patients report chronic respiratory symptoms, mainly cough, chest pain and dyspnea accompanied by B symptoms such as fever, weight loss and sweating. Laboratory findings are characterized by increased ESR and, in a minority of cases by lymphopenia, leukocytopenia and low CD4⫹ lymphocyte count. Lung nodules are the most common feature in chest X-ray films occurring in perhaps 80% of cases, and cavitation may be noted in a 20% of cases. Pulmonary nodules are the most common findings also on CT scanning [14]. The

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margins of the nodules are usually irregular, but welldefined and distributed along the bronchovascular bundles or interlobular septa. This distribution can be explained by the angiocentric distribution of lymphomatoid granulomatosis. Small thin-walled cystic lesions as well as masses growing through the lumen of the pulmonary artery with vascular occlusion may also be present. Thirty percent of patients have a pleural effusion. Hilar adenopathy is found in less than 25% of cases. Uncommon radiologic features reported in literature are: single nodules, alveolar opacities and reticulonodular diffuse lesions [14]. The differential diagnosis in patients with LYG is a real challenge and includes: Wegener’s granulomatosis, other necrotizing vasculitides, necrotizing nodular sarcoidosis, infections, bronchogenic carcinoma and metastatic tumors. The clinical course is highly variable. Patients may show waxing and waning of their disease; in grade 1 and when the lesions are localized to the lungs spontaneous resolving may be observed in up to 27% of cases [13]. One-third of patients with grade 1 lesions progress to malignant lymphoma, whereas two-thirds of patients with grade 2 lesions develop lymphoma. The aggressive form of disease may lead to death within 2 years. T Cell Primary Pulmonary Lymphomas Different types of extranodal T cell lymphomas can occur as a primary in the lungs. These include nasal-type T/NK lymphoma, anaplastic large T cell lymphoma, mycosis fungoides, and peripheral T cell lymphoma unspecified [1, 10, 13]. Due to their rarity only anectodal descriptions of their features are available. Recent reports have shown T cell lymphomas occurring at a grater rate in HIV-infected individuals than in HIV-negative subjects [13]. Nasal-type T/NK lymphomas (WHO classification ICDO code 9719/3) in the lung present with clinico-radiologial features similar to LYG. CD4⫹ lymphopenia and systemic symptoms such as fever, malaise and weight loss are more frequent. Lung involvement may show nodules or excavated masses. Pleural effusion may also be present. Anaplastic large T cell lymphoma (WHO classification ICD-O code 9714/3) has rarely been described as the primary pulmonary presentation; masses or single nodules are the features observed at CT, the patient presents with B symptoms. Mycosis fungoides (WHO classification ICD-O code 9700/3) in its rare granulomatous variant may involve primarily the lungs. Clinically, patients present with fever, lymphopenia, eosinophilia and increased ESR and LDH. CT features include nodules with halo signs, peripheral

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Fig. 8. Primary pulmonary Hodgkin’s lymphoma. CT images in this patient show multiple bilateral nodular or pseudonodular parenchymal consolidation, some with air bronchogram (a) distributed on the mid-lower lobes, with a concomitant parenchymal mass with air bronchogram on the upper left lobe (b).

consolidation and a crazy-paving pattern [15]. Due to its rarity and lack of clinico-radiological specificity the diagnosis is always difficult and require accurate histopathological analysis.

Primary Pulmonary Hodgkin’s Disease Primary pulmonary Hodgkin’s disease is extremely rare [16]. In the few cases reported the median age is 50 years with a bimodal distribution (younger than 35 years and older than 60 years), female outnumber men (2:1). Cases of primary diffuse infiltrative lung disease due to an EBV-associated lymphoproliferative disorder with features simulating Hodgkin’s disease superimposed on a honeycomb lung background have been reported in patients receiving long-term low-dose Methotrexate therapy for rheumatoid arthritis [1, 13]. Hodgkin’s lymphoma is linked to HIV infection with a relative risk of 11.5%. HIV-positive patients often show two unfavorable subtypes: lymphocyte depletion and mixed cellularity. In immunocompetent hosts, the nodular sclerosis variant is more common. Patients affected by primary pulmonary Hodgkin’s disease are rarely asymptomatic. Symptoms reported are productive or dry cough, fever and weight loss (B symptoms). Endobronchial disease is rare [17]. All cases described have roentgenographic signs of disease, the most common findings are pulmonary nodules either multiple or solitary. Other radiologic findings include cavitary nodules, reticulonodular infiltrates, pneumonic consolidation and pleural effusion (fig. 8). Nodules or infiltrates may wax and wane.


The diagnosis usually requires a surgical biopsy. Morphological differential diagnosis may be difficult including: other non-Hodgkin’s lymphomas, organizing pneumonia, Wegener’s granulomatosis, necrotizing infections, eosinophilic granuloma, extrinsic allergic alveolitis, angioimmunoblastic lymphadenopathy, and carcinomas with prominent lymphoid stroma. The prognosis is poor. Treated patients relapse within 2 years and clinical relapse result in a high mortality. Patients older than 60 years with B symptoms, multiple and bilateral lesions and HIV infection have a particularly poor prognosis.

Post-Transplant Lymphoproliferative Disorders Post-transplant lymphoproliferative disorders (PTLD) develop in solid organ or bone marrow transplant recipients and range from benign lymphoid hyperplasia to frank malignant lymphoma [1, 3]. The spectrum of disease includes: ‘Benign plasmacytic hyperplasia and infectious-mononucleosis-like PTLD’ arise in oropharynx or lymph nodes and is polyclonal; ‘Polymorphic lymphoproliferative disorder’ may be nodal or extranodal and is usually monoclonal; ‘Monomorphic PTLD’ classified according to lymphoma classification is predominantly a B cell neoplasm. The incidence varies depending on type of organ transplant recipient (⬍1% renal recipients; hepatic and cardiac allografts 1–2%; heart-lung or liver-bowel allografts 5%). Marrow allograft recipients in general have a low risk of PTLD (1%) but those who receive HLA-mismatched or T cell-depleted bone marrow and those who receive immunosuppressive therapy for GVHD are at the highest risk for development of lymphoma (up to 20%). EBV primary mismatching (donor-positive and recipient-negative) and HLA matching are key risk factors for the development of post lung transplant lymphoproliferative disease. Also, a high dose of immunosuppression is significantly associated with PTLD development. The median time interval from transplantation to diagnosis is about 8 months (with a range of 1–97 months). Common symptoms in high-grade lesions are fever, weight loss, high values of ESR and C-reactive protein (CRP), whereas plasmacytic hyperplasia and polymorphic lymphoproliferative disorder are usually asymptomatic and generally regress spontaneously following reduction in immunosuppression. Typical radiological findings are single or multiple nodules with hilar or mediastinal adenopathy. Nodules with peripheral ground glass attenuation (halo sign) may mimic invasive mycoses.

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Diagnosis and Staging The diagnosis and characterization of lymphomas can be difficult if based solely on histological analysis. Therefore the use of more sensitive and specific techniques including immunophenotypic analysis by immunohistochemistry and/or flow cytometry, and molecular biology is recommended. Surgically acquired tissue is the gold standard, however endoscopic bronchial or transbronchial biopsy is the most frequently used technique. When the lesion appears in the central airways large biopsies obtained by rigid bronchoscope are generally sufficient for a precise diagnosis [17]. The diagnostic yield of transbronchial biopsy is higher when it targets visible radiographic abnormalities and when CT imaging is used to address the bronchoscopist to the appropriate biopsy site. Open-lung biopsy or video-assisted thoracoscopic surgery can be chosen if tissue from endoscopy biopsy is not sufficient. Bronchoalveolar lavage does not allow making a complete morphologic analysis for an accurate diagnosis of lymphoma [18, 19]. Almost all patients with suspected pulmonary lymphomas receive a bronchoscopic examination and undergo a transbronchial biopsy, but only in less than half cases (30–50%) is possible to reach an histological diagnosis without a surgical lung biopsy. Broncho-alveolar lavage (BAL) is an essential tool for differential diagnosis of subacute or chronic alveolar opacities, and seems to be valuable for the positive diagnosis of PPL. The differential diagnosis is primary based on clinico-radiological and histological findings; however, BAL is particularly valuable in excluding an alternative diagnosis. In about two-third of patients with MALT lymphoma associated with CT scan findings of alveolar and/or ground glass opacities the BAL may show lymphocytic alveolitis (lymphocytes ⬎20% total cells), and a high percentage of cells expressing a B phenotype. In some cases cytological features consistent with low-grade malignant lymphoma (medium-sized lymphoid cells with lymphoplasmocytoid differentiation and irregular nuclear borders) may be seen. Flow cytometry and immunocytochemical analysis of BAL fluid may document a monotypic expression of surface light chains (indicating a clonal B cell proliferation) [18]. Recent studies report that genotyping investigation on BAL fluid can contribute to the diagnosis of MALT lymphoma with a greater sensitivity and sensibility than flow cytometry or immunocytochemistry. In particular immunoglobulin heavy chain gene rearrangement analysis by PCR of alveolar lymphocytes is highly sensitive and specific (97% specificity, 95% negative predictive value) allowing the detection of clonal alveolar lymphocytes population in patients with B cell pulmonary NHL. Therefore, when a

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Fig. 9. BAL of pulmonary Hodgkin’s lymphoma. Relapse of HL with lung involvement. BAL shows scattered Reed-Sternberg/Hodgkin’s cells, neutrophils and eosinophils.

dominant B cell clone is not documented on BAL fluid more invasive investigation can dismissed [19]. In other lymphomas, BAL is less sensitive and specific. Rarely, ReedSternberg/ Hodgkin’s cells may be observed in BAL fluid (fig. 9). Morphologic and flow cytometry analysis of transcutaneous fine-needle aspiration/biopsy samples obtained under fluoroscopic or CT scan may be diagnostic in a minority of cases. This procedure is of value in the diagnosis of posttransplant lymphoproliferative disorders and can exclude invasive fungal disease. When a pleural effusion is present medical thoracoscopy may be also diagnostic [20]. When these less-invasive procedures fail, a definitive diagnosis relies on histological examination of surgical samples (video-assisted thoracoscopy or open lung thoracotomy). Immunohistochemical analysis is mandatory in characterizing all types of pulmonary lymphomas. The neoplastic lymphocytes have distinct molecular profiles that can be easily demonstrated on routine paraffin sections. This allows pulmonary MALT lymphoma to be distinguished from reactive processes and also other lymphomas. The analysis of immunoglobulin light chains (kappa and lambda) can occasionally provide evidence of clonal expansion, especially in cases with increased secretory differentiation. Neoplastic marginal-zone cells can be characterized by either positive markers (e.g. the abnormally expressed CD43 antigen), or by the absence of a variety of markers, including those expressed by follicular lymphoma, mantle

Fig. 10. Relapse of Hodgkin’s lymphoma with pulmonary involvement. PET-CT images show PET-positive intraparenchymal nodules.

cell lymphoma or chronic lymphocytic leukemia, such as bcl-6, CD10, CD5, CD23, cyclin-D1, TCL-1 [21]. Flow cytometry can provide relevant information by revealing the presence of clonal B cell populations characterized by immunoglobulin light chain restriction, as well as illustrating an antigenic profile compatible with the diagnosis. PCR molecular genetic analysis can provide information regarding the presence of clonal lymphocyte population by investigating rearrangements of either immunoglobulin or T cell receptor genes. This analysis can be performed, due to its extraordinary sensitivity, on very small amount of tissue. However, the occurrence of false-negative and false-positive results must be taken into account. Staging procedures to evaluate the extent of the disease includes a complete physical examination of the patient, laboratory tests such as ␤2 microglobulinemia, LDH, lymphocytic total count, lymphocyte subsets analysis, serology for HIV, Cytomegalovirus, and Epstein-Barr viruses infection, thoracic, abdominal/pelvic CT scan, and bone marrow biopsy [22]. CT-PET provides morphologic and metabolic information increasing the diagnostic accuracy (fig. 10). Histology and Molecular Biology Characteristics Pulmonary MALT B Cell Lymphoma Cytogenetic Features and Molecular Pathogenesis. As in other extranodal MALT lymphomas, a heterogeneous pattern of cytogenetic abnormalities has been demonstrated in pulmonary lymphomas, including aneuploidy (observed in nearly 40% of cases, with trisomy 3 and 18 being the most common), and specific chromosomal translocations. Translocation t(11;18)(q21;q21) which characterizes about one-third of extranodal marginal MALT lymphomas is the most frequent chromosome translocation occurring in pulmonary MALT lymphomas (38.3–41%). This translocation


involves the API2 and MALT1 genes, and can be directly correlated to the pathogenesis of this lymphoma [23]. Accordingly, API2 is a member of the IAP (inhibitor of apoptosis) gene family, whereas MALT1, a paracaspase of unknown functions, is able to interact with bcl-10 inducing NF-k␤ (nuclear factor -kapp beta) activation. The abnormal fusion of MALT1 with API2 produces chimeric transcripts which inhibit apoptosis. Data relating to the occurrence and frequency of other genetic abnormality involved in the pathogenesis of MALT lymphomas such as t(1;14)(p22;q32) are scanty. Morpho-Molecular Features. Histological analysis shows the pulmonary structures being effaced by abnormal lymphocyte infiltration, predominantly localized along bronchovascular bundles, interlobular septa and visceral pleura [24]. MALT lymphoma emerges as an accumulation of clonal lymphoid cells characterized by the morphological and biological features of marginal-zone B cells. Marginal-zone cells are post-germinal center lymphocytes with memory functions, particularly abundant in the spleen. They migrate from lymphoid tissues to extranodal sites where they can rapidly become antibody producing plasma cells upon stimulation. Morphologically, lymphoma cells are similar to normal marginal-zone cells, exhibiting a spectrum of cytological features (small round cells, centrocyte-like cells, monocytoid cells), characterized by small and irregular nuclei, inconspicuous nucleoli, and abundant clear cytoplasm (fig. 11). Neoplastic lymphocytes typically accumulate around non-neoplastic lymphoid follicles, forming poorly defined sheets of cells at the periphery of the mantle zones, extending into the lung parenchyma. The presence of reactive follicles, can be particularly abundant and can pose diagnostic problems at morphological and also immunophenotypical analysis. The presence of lympho-epithelial lesions (neoplastic lymphoid cells infiltrating bronchiolar epithelium) is frequent and involves

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Fig. 11. Pulmonary marginal-zone B cell lymphoma. a, b Heavy parenchymal infiltration of lymphoid cells is shown, characterized by medium-sized nuclei and large cytoplasms, surrounding reactive follicles. HE. c, d CD20 immunostaining defines the B cell nature of neoplastic lymphocytes (note bronchiolar infiltration by CD20⫹ cells). e TCL1 immunostaining shows that the reactive follicles are positive, whereas neoplastic marginal B cells around them are unreactive. f Stathmin (a proliferation-related markers) is expressed at low levels in nonproliferating neoplastic B cells, whereas reactive germinal center cells are mostly positive.

bronchiolar and bronchial epithelial structures. Histologically, the differential diagnosis includes any pulmonary diseases characterized by accumulation of lymphoid follicles: in particular, the spectrum of follicular hyperplasia, follicular bronchiolitis, and lymphocytic interstitial pneumonia, as well as, more rarely, hypersensitivity pneumonitis, inflammatory pseudotumor, intraparenchymal thymoma, and Castleman’s disease. For these reasons, the use of immunophenotypical and molecular techniques is recommended to secure the histological diagnosis of

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pulmonary MALT lymphoma, especially when the tissue samples are small [25]. In a consistent proportion of cases it is possible to demonstrate lymphoplasmacytic differentiation, with a significant plasma cell component exhibiting immunoglobulin light chain restriction. It is possible that at least some cases of primary plasmacytoma of the lung (a rare low-grade tumor of unclear etiopathogenesis presenting as isolated nodules or diffuse) can in fact be included within the spectrum of MALT lymphomas.

Other B Cell Primary Lymphomas Lymphoma cells in these cases are formed by large cells with round nuclei, prominent nucleoli, dispersed chromatin, and high mitotic count [24]. Morphologically these lymphomas are heterogeneous, with centroblastic, immunoblastic, or anaplastic features. EBV is often demonstrated in these high-grade lymphomas by immunohistochemistry and/or molecular studies.

distinguished, histologically from other diseases characterized by polymorphous lymphoid infiltration. For example, T cell lymphoma, infection due to EBV, inflammatory sarcomatoid carcinoma, Wegner’s granulomatosis, other malignant lymphomas in particular enteropathy-associated T cell lymphoma and acute T cell lymphoblastic leukemia), with or without zonal coagulative necrosis and prominent angioinvasion. [1, 13].

Lymphomatoid Granulomatosis (LYG). The term LYG includes a group of related lesions characterized by the infiltration of pulmonary parenchyma by a heterogeneous cell population composed of a large number of T lymphocytes, and a variable proportion of large EBV-infected B cells, expressing B-cell related antigens CD20 and CD79a. EBV infection is defined as the expression of markers such as latent membrane protein-1 (LMP-1) and EBV-encoded RNA (EBER) [26]. The lymphoid infiltrate often surrounds muscular pulmonary arteries and veins and typically invades the walls of these vessels. Necrosis is frequent, although not a universal, feature of the disease. LYG lesions are heterogeneous, and have been graded according to the proportion of neoplastic B cells and surrounding reactive T cells, the degree of lymphocytic atypia, and the heterogeneity of the infiltrates. These features distinguish three grades characterized by varying proliferation index and prognostic differences. Grade 1 lesions contain few or no EBV-infected cells (less than 5 per high-power field), usually lack necrosis, and are polymorphous. Monoclonality is usually difficult to demonstrate. Grade 2 lesions have scattered EBV-infected cells (5–20 per high-power field) and foci of necrosis, but remain polymorphous. The grade 3 forms shows features of T cell-rich B cell lymphomas (WHO classification ICD-O code 9680/3); foci of necrosis are evident and sheets of markedly atypical B cells (resembling immunoblasts or with double nuclei resembling ReedSternberg cells) infiltrate the lung parenchyma in an angiocentric fashion. The T cell component is non-neoplastic by definition, exhibits an activated cytotoxic phenotype, and can be considered as a reactive response to infected/ neoplastic B cells. Similarities exist between PTLD and LYG. Grade 1 cases may be EBV driven polyclonal lymphoproliferations, and grade 2 cases may be similar to polymorphous, monoclonal PTLD, in which some degree of immunodeficiency allows proliferation of clonal EBVpositive cells. Grade 3 LYG is a true monomorphous diffuse large B cell lymphomas. Chemokines such as IP-10 and Mig, which are elaborated as the result of the EBV infection, may be responsible for vascular damage by promoting T cell adhesion to endothelial cells. LYG need to be

Intravascular Large B Cell Lymphoma [1, 13]. Histology shows subtle changes and is characterized by small pulmonary vessels and dilated capillaries showing intraluminal infiltration of medium-sized cells with ovoid hyperchromatic nuclei. The neoplastic cells are immunoreactive for leukocyte common antigen (LCA) and B cell markers. Compared with non-neoplastic leukocytes, large malignant lymphocytes appear either negative or only weakly positive for the leukocyte surface glycoprotein CD18. CD18 is the beta-chain of the CDIIa/CD18 complex (lymphocyte function-associated antigen-I, LFA-I), which mediates cell-to-cell adhesion of lymphocytes. Furthermore, the malignant lymphoid cells stain positively with Hermes3 antibody, which recognizes a common structure of the CD44 class of molecules involved in lymphocyte homing.


T Cell Lymphomas Nasal-type T/NK lymphomas when occurring in the lung has many similarities with LYG, including angioinvasion, expression of markers of EBV infection, necrosis, immune disturbances and a rich T-cell infiltrate exhibiting cytotoxic immunophenotype, defined by the expression of CD8, TIA-1, granzyme-B, and perforin [1, 11]. The occurrence of EBV marker expression is heterogenous in pulmonary T cell lymphomas. Anaplastic large cell lymphoma, T cell type (ALCL, WHO ICD-O code 9714/3), was previously recognized as Ki-1 lymphoma because of the marked expression of the activation antigen CD30/Ki-1 (fig. 12). Hodgkin’s Lymphoma (HL) Neoplastic nodules are formed by an heterogeneous cell population, including many inflammatory cells (macrophages, T lymphocytes, granulocytes) and isolated atypical cells characterized by the cytological features of Reed-Sternberg cells (as defined in the WHO classification, ICD-0 code 9650/3). Immunophenotypic analysis can be highly useful in characterizing Reed-Sternberg/ Hodgkin’s cells. Recent studies have precisely defined the molecular profile of these cells, which are in fact B cells with defects in the mechanisms of immunoglobulin

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Fig. 12. Primary pulmonary anaplastic-large-cell lymphoma, T cell type. a, b A large neoplastic nodule is shown, formed by neoplastic cells

characterized by heterogeneous morphology. HE. The immunophenotypic profile of neoplastic cells includes the expression of CD30 (c), and CD3 (d).

production, and are recognized by the absence or very low expression of B cell-related markers (Bob-1, Oct-2, CD79a), as well as by the strong expression of activation markers (CD30, CD15, MDC, fascin) [27, 28]. Various modifications can be observed in the parenchyma adjacent to the neoplastic nodules of Hodgkin’s lymphoma, including focal organizing pneumonia, endoalveolar accumulations of foamy macrophages and interstitial lymphoid infiltration. Post-Transplant Lymphoproliferative Disorders (PTLD) [13]. In plasmacytic hyperplasia and in infectious-mononucleosis-like lesions there is a mixture of polyclonal B cells, plasma cells, and T cells. There is evidence of EBV infection and no evidence of oncogene or tumor-suppressor gene alterations. Pleomorphic PTLD are composed of immunoblasts, plasma cells, and intermediate-sized lymphoid cells that form destructive masses in the lung parenchyma. There may be areas of necrosis and numerous mitoses may be present. Molecular genetic studies virtually always show clonal rearrangement of immunoglobulin genes and/or EBV genomes, but cytogenetic analysis and studies of oncogenes such as myc, ras, and TP53 typically show no mutation. These

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lesions display variable clinical behavior, their progression correlating with bcl-6 gene mutations [1]. Monomorphic PTLD consist of areas of necrosis surrounded by a dense monomorphic lymphoid infiltrate (angioinvasive and destructive infiltrate). The cells appear to be characterized by large, blastic cells with prominent nucleoli and basophilic cytoplasm. A plasmoblastic differentiation may be prominent. They show clonal Ig gene rearrangement or, less frequently, clonal T-cell receptor gene rearrangement. B cells have evidence of latent EBV infection, characterized by LMP, and EBER expression. About a quarter of monomorphic T-PTLDs have evidence of latent EBV infection. Treatment The initial treatment for pulmonary lymphoma has commonly been surgical resection. However, given current less invasive alternatives to achieve a secure diagnosis, there is little data that resection contributes to the outcome. Lowgrade lymphoma may be treated with chemotherapy, usually of a single alkylating or nonanthracycline-combination type. These lesions are commonly chemoresponsive and are

also radioresponsive, although tolerance issues limit the applicability of radiotherapy. There is no indication that such treatments are curative, although prolonged survival has been reported. BALT/MALT Lymphoma. While pulmonary MALT lymphoma is a highly indolent disease, no standard approach for the management of such patients has been defined [29–31], while resection or, when surgery is high risk, radiotherapy are still indicated for localized lesions. Relapses appear to be common following localized treatment, indicating that systemic therapy may be beneficial. A variety of chemotherapeutic agents have been tested, including alkylating agents such as cyclophosphamide or chlorambucil, the nucleoside analogs cladribine (2CdA) or fludarabine, the latter in combination with mitoxantrone. Other combination regimens include cyclophosphamide, vincristine, and prednisone, or mitoxantrone, chlorambucil, and prednisone. Oxaliplatin (L-OHP) seems to be another highly active agent. Low-dose thalidomide has been reported to be associated with a very good partial response. Long-term outcomes, however, have to be interpreted with caution in view of the relatively short follow-up time in these series and the tendency of MALT lymphomas to recur, sometimes even after decades. Recent reports have suggested that Rituximab as single agent is safe and effectively in untreated or relapsed BALT lymphomas [32]. Treatment with the anti-CD20 antibody Rituximab has been reported also to transform the MALT lymphoma in a pure plasma cell tumor. Another potentially active class of anti-cancer agent drugs are those targeted to the inhibition of the NF-␬␤ pathway, the common target of the recurrence translocations. An example of this class is bortezomib which is currently being tested in clinical trials specifically designed for patients with MALT lymphoma. LYG; Aggressive B Cell and T Cell Type Lymphomas. LYG grade 1 and 2 are often treated with interferon-␣2b; LYG cases in which steroids and/or cyclophosphamide were beneficial have been reported. The use of Rituximab has been shown to be efficacious in LYG grade 3, in PTLD monomorphic disorders and is promising in other forms of large B cell lymphomas. The B cell lymphomas require chemotherapy or combined-modality therapy [33]. Despite such different therapies, however, systemic progression is still common, and relapse-free rates of approximately 40–50% are expected. T cell lymphomas have a poorer prognosis with 50% mortality at 2 years even with combined modality treatment. In HIV patients, highly active antiretroviral therapy is useful. In transplanted recipients, a reduction of immunosuppression is the first step with or without Rituximab.


Secondary Lymphomas

Secondary disease in the lung from lymphomas is identified relatively frequently at autopsy (up to 20.5%). There are different patterns of infiltration: peribronchial/perivascular, nodular, alveolar, interstitial, pleural, endobronchial. A lymphangiitic infiltrative pattern is frequent in B cell lymphomas and leukemia, whereas the nodular and interstitial patterns are mainly observed in Hodgkin’s lymphoma and T cell lymphomas, respectively [34]. The lungs are the most common site of visceral involvement in patients with mycosis fungoides. Radiographic manifestations can simulate pneumonia and herald a poor prognosis. Mycosis fungoides is an extranodal CD4⫹ T cell lymphoma primarily affecting the epidermis, and it is not clear why the lungs represent a preferential target of secondary involvement, although it is possible to speculate that homing signals shared by epidermal and pulmonary microenvironments can attract the same subset of T lymphocytes (similar to Langerhan’s cell localization in bronchiolar epithelium). Radiological evidence of lung involvement can occur in 12% of patients with Hodgkin’s lymphoma at diagnosis. Radiological abnormalities can be caused by either secondary HL involvement or infective diseases. When a lymphoma develops in neighboring sites (e.g. mediastinal lymph nodes and thymus) the lungs can be directly infiltrated by neoplastic cells. Complications can be minimal or severe, depending on the type and amount of involvement. The lymphomas that more frequently invade the lungs from the mediastinum are Hodgkin’s lymphoma classic type, mediastinal large B cell lymphoma, and T cell precursor lymphoma. Mediastinal large B cell lymphoma (WHO ICD-O code 9679/3) is characterized by peculiar clinical and biological features, and needs to be distinguished by other DLBCL involving the lungs [30]. Light chain deposition disease (LCDD) is a rare occurrence that very uncommonly affects the lung [35]. Cases of severe LCCD leading to lung transplantation have been reported [36].

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References 1 Jaffe ES, Harris NL, Stein H, Vardiman JW: Pathology and Genetics of Tumours of Haematopietic and Lymphoid Tissues. World Health Organization Classification of Tumors. Lyon, IARC Press, 2001. 2 Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, Nakano N, Ikeda Y, Sasaki T, Nishioka K, Hara M, Taguchi H, Kimura Y, Kato Y, Asaoku H, Kumagai S, Kodama F, Nakahara H, Hagihara K, Yoshizaki K, Kishimoto T: Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 2005;106: 2627–2632. 3 Nicholson AG, Poletti V, Semenzato G: Lymphoproliferative disease; in Gibson GJ, Geddes DM, Costabel U, Sterk PJ, Corrin B (eds): Respiratory Medicine, ed 3. London, Saunders, 2003. 4 Jonkoh T, Muller NL, Pickford HA, Hartman TE, Ichikado K, Akira M, Honda O, Nakamura H: Lymphocytic interstitial pneumonia: thinsection CT findings in 22 patients. Radiology 1999;212:567–572. 5 Cordier J, Chailleux E, Lauque D, et al: Primary pulmonary lymphomas. A clinical study of 70 cases in non-immunocompromised patients. Chest 1993;103:201–208. 6 Bertoni F, Zucca E: Delving deeper into MALT lymphoma biology. J Clin Invest 2006; 116: 22–26. 7 Isaacson PG, Du MQ: MALT lymphoma: from morphology to molecules. Nat Rev Cancer 2004;4:644–653. 8 Thieblemont C, Berger F, Dumontet C, et al: Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed. Blood 2000;95:802–806. 9 King LJ, Padley SP, Wotherspoon AC, Nicholson AG: Pulmonary MALT lymphoma: imaging findings in 24 cases. Eur Radiol 2000;10:1932–1938. 10 Alinari L, Castellucci P, Elstrom R, Ambrosini V, Stefoni V, Nanni C, Berkowitz A, Tani M, Farsad M, Franchi R, Fanti S, Zinzani PL: 18FFDG PET in mucosa associated limphoid tissue (MALT) lymphoma. Leuk Lymphoma 2006;47:2008–2010. 11 Li G, Hansmann ML, Zwingers T, Lennert K: Primary lymphomas of the lung: morphological, immunohistochemical and clinical features. Histopathology 1990;16:519–531. 12 Yamagata T, Okamoto Y, Ota K, Katayama N, Tsuda T, Yukawa S: A case of pulmonary intravascular lymphomatosis diagnosed by thoracoscopic lung biopsy. Respiration 2003;70: 414–418. 13 Travis WD, Brambilla E, Müller-Hermelink, Harris CC: Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. World Health Organization Classification of Tumors. Lyon, IARC Press, 2004.

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14 Lee JS, Tuder R, Lynch DA: Lymphomatoid granulomatosis: radiologic features and pathologic correlations. Am J Roentgenol 2000;175: 1335–1339. 15 Sverzellati N, Poletti V, Chilosi M, Casoni GL, Hansell DM, Zompatori M: The crazy-paving pattern in granulomatous mycosis fungoides: HRTC-pathologic correlation. J Comput Ass Tom 2006;30:843–845. 16 Yousmen SA, Weiss LM, Colby TV: Primary pulmonary Hodgkin’s disease. Cancer 1986;57: 1217–1224. 17 Kiani B, Magro CM, Ross P: Endobronchial presentation of Hodgkin lymphoma: a review of the literature. Ann Thorac Surg 2003;76: 967–972. 18 Poletti V, Romagna M, Gasponi A, Baruzzi G, Allen KA: Bronchoalveolar lavage in the diagnosis of low-grade, MALT type, B-cell lymphoma in the lung. Arch Chest Dis 1995;50: 191–194. 19 Zompi S, Couderc LJ, Cadranel J, Antoine MA, Epardeau B, Fleury-Feith J, Popa N, Santoli F, Farcet JP, Delfau-Larue MH: Clonality analysis of alveolar B lymphocytes contributes to the diagnostic strategy in clinical suspicion of pulmonary lymphoma. Blood 2004;103:3208–3215. 20 Poletti V, Chilosi M, Olivieri D: Diagnostic invasive procedures in diffuse infiltrative lung diseases. Respiration 2004;71:107–119. 21 Begueret H, Vergier B, Parrens M, et al: Primary lung small B-cell lymphoma versus lymphoid hyperplasia: evaluation of diagnostic criteria in 26 cases. Am J Surg Pathol 2002;26: 76–81. 22 Raderer M, Vorbrck F, Formanck M, et al: Importance of extensive staging in patients with mucosa associated lymphoid tissue (MALT)type lymphoma. Br J Cancer 2000;83: 454–457. 23 Yonezumi M, Suzuki R, Suzuki H, et al: Detection of AP12-MALT1 chimaeric gene in extranodal and nodal marginal zone B-cell lymphoma by reverse transcription polymerase chain reaction (PCR) and genomic long and accurate PCR analyses. Br J Haematol 2001;115: 588–594. 24 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. 25 Nicholson AG, Wotherspoon AC, Diss TC, et al: Pulmonary B-cell non-Hodgkin’s lymphomas: the value of immunohistochemistry and gene analysis in diagnosis. Histopathology 1995;26:395–403. 26 Bolaman Z, Kadikoylu G, Polatli M, Barutca S, Culhaci N, Senturk T: Migratory nodules in the lung: lymphomatoid granulomatosis. Leuk Lymphoma 2003;44:197–200.


27 Chilosi M, Pizzolo G: Biopathologic features of Hodgkin’s disease. Leuk Lymphoma 1995;16: 385–395. 28 Stein H, Marafioti T, Foss HD, et al: Downregulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood 2001;97: 496–501. 29 Zinzani PL, Stefoni V, Musuraca G, et al: Fludarabine-containing chemotherapy as frontline treatment of nongastrointestinal mucosa associated lymphoid tissue lymphoma. Cancer 2004;100:2190–2194. 30 Raderer M, Wührer S, Bartsch R, et al: Phase II study of oxaliplatinum for treatment of patients with mucosa associated lymphoid tissue lymphoma. J Clin Oncol 2005;33: 8442–8446. 31 Vanden EF, Fadel E, de Perrot M, de Montpreville V, Mussot S, Dartevelle P: Role of surgery in the treatment of primary pulmonary B-cell lymphoma. Ann Thorac Surg 2007;83:236–240. 32 Conconi A, Martinelli G, Thieblemont C, et al: Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood 2003;102:2741–2745. 33 Zinzani PL, Martelli M, Bertini M, et al: International Extranodal Lymphoma Study Group (IELSG). Induction chemotherapy strategies for primary mediastinal large B-cell lymphoma with sclerosis: a retrospective multinational study on 426 previously untreated patients. Haematologica 2002;87:1258–1264. 34 Costa MB, Siqueira SA, Saldiva PH, Rabe KF, Mauad T: Histologic patterns of lung infiltration of B-cell, T-cell, and Hodgkin lymphomas. Am J Clin Pathol 2004;121:718–726. 35 Bhargava P, Rushin JM, Rusnock EJ, Hefter LG, Franks TJ, Sabnis SG, Travis WD: Pulmonary light chain deposition disease: report of five cases and review of the literature. Am J Surg Pathol 2007;31:267–276. 36 Colombat M, Stern M, Groussard O, Droz D, Brauner M, Valeyre D, Mal H, Taille C, Monnet I, Fournier M, Herson S, Danel C: Pulmonary cystic disorder related to light chain deposition disease. Am J Respir Crit Care Med 2006;173:777–780.

Venerino Poletti, MD Dipartimento Toracico Ospedale GB Morgagni via C. Forlanini 34 IT–47100 Forlì (Italy) Tel. ⫹39 0543 735830, Fax ⫹39 0543 735882 E-Mail [email protected]; [email protected]

Special Considerations


Interstitial Lung Diseases in Children Annick Clement

Brigitte Fauroux

AP-HP, Hôpital Trousseau, Pediatric Pulmonary Department, Paris; Inserm, UMRS U719, Paris; Université Pierre et Marie Curie, Paris, France

Abstract Interstitial lung disease (ILD) in infants and children represents a heterogeneous group of respiratory disorders that are mostly chronic and associated with high morbidity and mortality. The definition and diagnosis of ILD in children remain difficult due to the large diversity of clinical presentation and entities. The disease occurs more frequently in very young patients. The presenting clinical manifestations are nonspecific and variable, with tachypnea being observed in most cases. There is now compelling evidence that some forms of ILD are observed more frequently in infants, while others are more specific to older children. Consequently, the stage of lung development and maturation should be taken into account in order to provide a more appropriate approach to the diagnosis of pediatric ILD. The main therapeutic strategy employs the use of corticosteroids administered orally and/or intravenously, with a favorable response reported in 40–65% of the cases. In the future, there is a strong need for international collaboration which will result in the collection of sufficiently large cohorts of patients allowing appropriate therapeutic trials. Copyright © 2007 S. Karger AG, Basel

Interstitial lung disease (ILD) in infants and children represents a heterogeneous group of respiratory disorders that are mostly chronic and associated with high morbidity and mortality [1, 2]. They are characterized by the presence of diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with evidence of a restrictive

ventilatory defect and/or impaired gas exchange [3]. The occurrence of ILD is much lower in children than in adults. A prevalence of 0.36/100,000 was suggested in a national survey in the United Kingdom and Ireland [1]. However, it is important to point out that the definition and diagnosis of ILD in children remain difficult due to the large diversity of clinical presentation and entities [4]. Consequently, no reliable data on pediatric ILD epidemiology are currently available.

Current Concepts of the Pathogenesis of ILD in Children

ILD in children comprises a broader spectrum of disorders than in adults. This is certainly linked to the fact that the disease occurs in the context of lung growth at the various stages of alveolar development and maturation. Each of these stages being regulated by specific cascades of events. In children, ILD is most frequently diagnosed in the first year of life with predominance of specific pediatric entities. These include pulmonary interstitial glycogenosis, the neuro-endocrine cell hyperplasia of infancy, and genetic disorders of surfactant metabolism [1, 2]. In older children, the spectrum ILD shares similarities with that observed in adults, and the pathological changes are characterized by derangement of the alveolar septum with the presence of focal zones of fibroblast proliferation called fibroblastic foci. These patchy fibrotic lesions appear to occur at sites of recent alveolar injury, and their number seems to correlate with worsening lung function and poor prognosis.

Epithelial-Mesenchymal Cross-Talk as Pathogenic Pathway The current understanding of the mechanisms involved in the pathogenesis of ILD reinforces the concept that alveolar damage is pivotal to the development of subsequent fibrosis [5–8]. The initial event is linked to injury of the alveolar surface with marked disruption in the integrity of the epithelium [9–11]. ILD develops following epithelial damage; this induces the accumulation and activation of immuno-inflammatory cells, with subsequent migration and proliferation of fibroblasts and deposition of extracellular matrix. Foci of fibroblasts/myofibroblasts within the alveolar interstitium can be identified in lung tissue biopsies. This pathological pattern is now thought to be the result of abnormal repair of the lung. Under physiological conditions, the alveolar epithelium responds to injury by an adequate process of wound healing to restore lung surface integrity. A key step in this process is the capacity of alveolar epithelial type 2 cells to initiate re-epithelialization rapidly. Indeed, these cells represent the stem cells of the alveolar epithelium due to their ability to proliferate and to undergo transition into the terminally differentiated type 1 cells. In situations of extensive damage to the lung surface, there will be a delay in the initiation and progression of the re-epithelialization process [12, 13]. Consequently, prolonged denudation of the basement membrane will contribute to altered interactions and cross-talk between alveolar epithelial cells and mesenchymal cells, resulting in profound modifications of cell functions with imbalanced production of polypeptide mediators including cytokines, growth factors, oxidants, and proteases [6, 14]. The local population of fibroblasts and myofibroblasts will progressively increase due to stimulation of proliferation by mitogenic factors and reduction of apoptosis [15, 16]. This leads to progressive aberrant tissue remodeling by disorganization of extracellular matrix component deposition, including fibrillar collagen, elastic fibers, fibronectin and proteoglycans. In addition, the abnormal lung architecture observed in pulmonary fibrosis appears to be associated with the formation of new blood vessels. This process requires the secretion of angiogenic molecules to promote endothelial cell migration and revascularization. A cascade of mediators produced locally by epithelial, mesenchymal and inflammatory cells play a critical role in the progression of the fibrotic changes. Among them, an important molecule acting at various stages of the disease is transforming growth factor-␤ (TGF-␤). TGF-␤ regulates a number of cell functions including cell proliferation, cell differentiation, apoptosis, cell adhesion/motility, and matrix production. In vivo studies have demonstrated

Interstitial Lung Diseases in Children

increased TGF-␤ gene expression and protein secretion in the lung of animals and humans with fibrotic disease [17, 18]. Several findings support the critical role TGF-␤ plays such as: tissue damage increases TGF-␤ production before initiation of extracellular matrix accumulation; TGF-␤ is a potent stimulator of the production and deposition of extracellular matrix; TGF-␤ induces fibrosis independently of tissue damage; inhibitors of TGF-␤ receptor binding reduce or abolish fibrosis. In addition, overexpression of active TGF-␤ in rat lung has been shown to result in severe interstitial fibrosis and the emergence of cells with a myofibroblast phenotype. Recently, it has been reported that exposure of alveolar epithelial cells to TGF-␤ resulted in increased expression of mesenchymal markers including ␣-smooth muscle actin, type 1 collagen and vimentin, and decreased expression of epithelial markers [19]. Pathogenesis of ILD in the Context of Lung Growth The frequency of ILD and fibrotic disorders is much lower in children than in adults. Certainly, some clinical situations have features unique to children, but many overlap with their adult equivalent. The overall outcome and prognosis of the disease in children are thought to be less severe than in adult patients, and pediatric ILD is more responsive to therapeutic strategies than adult ILD. These differences may be the result of heterogeneous injuries, or different host characteristics. Another explanation is the modification of the process of wound healing with age [20]. The process of healing involves the coordinated regulation of cell proliferation and migration and tissue remodeling, predominantly by polypeptide growth factors. The slowing of wound healing that occurs in the elderly may be related to changes in the activity of these various regulatory factors. In a study on the role of aging in the development of cardiac fibrosis in a rabbit model, differences in the cascade of events leading to myocardial remodeling were observed. This was characterized mainly by the presence of more myofibroblasts synthesizing collagen and expressing high levels of TGF-␤ in the older animals [21]. A study of skin wound healing in young and older mice also showed age-dependent changes. Expression of all the fibroblast growth factors was diminished in older mice, even in healthy skin [22]. In addition, the post-wound regulation of fibroblastic factors and of TGF-␤ are less pronounced and slower than in the young mice. These findings are in agreement with data observed in muscle that indicated significant alterations in the TGF␤ production with age [23]. Muscle cells from older animals exhibited major alterations in the expression level of many genes directly or indirectly involved with the TGF-␤

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signaling pathway. In ILD, an essential step for the restoration of alveolar integrity is the rapid re-epithelialization of the altered surface, mainly through epithelial proliferation and migration processes. These are dependent on a balanced availability of growth factors, with TGF-␤ being an important component of this balance. In young patients, one can suggest that the programmed increased production of mitogenic factors together with a more adapted regulation of TGF-␤ expression may favor the process of reepithelialization and may help to counteract the altered secretion of mediators involved in migration and proliferation of fibroblasts as well as in differentiation into myofibroblasts. Genetic Factors Epidemiologic studies have confirmed the occurrence of familial ILD cases, with an estimated prevalence ranging from 1.3 to 5.9 per million [24]. The familial form of ILD is probably transmitted as an autosomal-dominant trait with reduced penetrance. Among the recent genetic findings is the identification of causal mutations in the surfactant protein (SP) genes, mainly in SP-B and SP-C genes [25]. SP-B and SP-C are hydrophobic proteins that interact with surfactant lipids to facilitate adsorption to the air-liquid interface. Defects in SP-B, when homozygous for the most common mutations (121ins2), are highly lethal in the first months of life. Reported patients with partial SP-B deficiency had mutations leading to production of small amounts of SP-B or to pro-SP-B which was not further processed to mature SP-B. For SP-C, several mutations have been described, the first being a guanine (G) to adenine (A) substitution on the first base of intron 4 (IVS4 ⫹ 1G⬎A) causing skipping of exon 4 with the deletion of 37 amino acids. Abnormal expression of SP-C is associated with variable phenotypes. Patients with SP-C mutations can present with severe manifestations early in life or may develop symptoms in adulthood [26]. Mutations in other genes involved in the surfactant metabolism have also been reported. Among them are the mutations in the ABCA3 gene [27]. ABCA3 is a member of the ATP binding cassette protein family. It is highly expressed in alveolar epithelial cells at the limiting membrane of lamellar bodies, and may play a role in lipid homeostasis of lamellar bodies. The precise phenotypes of ABCA3 mutations need further evaluation. In most cases of adult and childhood ILD, no family history can be documented. Therefore it is likely that multiple genetic factors may contribute to a modest effect on predisposition to the disease, in combination with appropriate environment. Recently, several case-control association

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studies have been reported. Although many candidate genes can be proposed, only limited numbers have been evaluated and have confirmed associations. Among them are polymorphisms in TGF-␤1, tumor necrosis factor-␣ (TNF-␣), interleukin-1 cluster, chemokine-related genes, angiotensinconverting enzyme gene, and interferon-␥ gene. These reports are from adult studies. No information is currently available in the pediatric population.

Diagnosis of ILD

Patient Presentation and Clinical Evaluation Pediatric ILD occurs more frequently in the youngest subset of patients. This as been well illustrated by the results of the European Respiratory Society (ERS) Task Force on chronic ILD in immunocompetent children [28]. Review of the medical records indicated that almost one third of the patients with ILD were diagnosed before the age of 2 years. The onset of symptoms is, in most cases, insidious and many children may have had symptoms for years before the diagnosis of ILD is confirmed. The presenting clinical manifestations are often subtle and nonspecific. They include respiratory symptoms such as cough, tachypnea, dyspnea, effort intolerance, tiring during feeding, wheezing, respiratory infection, and failure to thrive [4, 29, 30]. Tachypnea is present in 80% of patients and is usually the earliest and most common respiratory sign. It is associated with subcostal or intercostal retractions. The clinical findings are of inspiratory crackles, tachypnea and retraction. In a child with a normal birth history, these findings are strongly suggestive of ILD. Rarer findings associated with an advanced stage of the disease include finger clubbing and cyanosis during exercise or at rest. During the physical examination it is essential to look for the presence of associated nonrespiratory conditions such as joint disease, cutaneous rashes, or recurrent fever typical of collagen-vascular disorders. Chest Imaging High-resolution computed tomography (HRCT) is the key chest imaging tool for diagnosis. It can visualize the parenchymal structure to the level of the secondary pulmonary lobule. Recent pediatric literature confirms that HRCT increases the level of diagnostic confidence for infiltrative lung disease [31–33]. HRCT has also been proven to be useful for patient management including help to select the lung area to be biopsied.

In many forms of ILD, the most common HRCT feature is widespread ground-glass attenuation. Intralobular lines and irregular interlobular septal thickening are also reported. Large subpleural air cysts in the upper lobes adjacent to areas of ground-glass opacities seem to be unique to childhood ILD. These cysts are interpreted as paraseptal or irregular emphysema. In rare situations honeycomb pattern could be observed. Some groups of ILD have more specific HRCT features [33]. In Langerhans cell histiocytosis, HRCT detects peribronchial or peribronchiolar granulomas, which appear as micronodules mainly found in the upper and middle lung zones. These lesions seem to progress from nodules to cavitary nodules, to thick-walled cysts and finally to thin-walled cysts. In sarcoidosis, HRCT shows granulomas distributed along the lymphatics in the bronchovascular sheath and in the interlobar septa and pleural. Large parenchymal nodules represent coalesced granulomas, and ground-glass opacities seem to be due to the presence of numerous sarcoid granulomas below the resolution of HRCT.

Pulmonary Function Tests Generally, in ILD, pulmonary function abnormalities reflect a restrictive ventilatory defect with reduced lung compliance and decreased lung volume [28, 34]. Vital capacity (VC) is variably diminished. The decrease in total lung capacity (TLC) in general is relatively less than in VC. Functional residual capacity (FRC) is also reduced but relatively less than VC and TLC, and residual volume (RV) is generally preserved; thus, the ratios of FRC/TLC and RV/TLC are often increased. Airway involvement occurs only in a minority of patients [35]. Diffusion of carbon monoxide (DCO) is often markedly reduced and may be abnormal before any other radiologic or physiologic findings. However, DCO corrected for lung volume may also be normal in many children. Patients with mild forms of ILD are often normoxic in resting conditions. However, in those patients, reduced arterial oxygen saturation (SaO2) can be documented during exercise. Thus, gas exchange during exercise might be a valuable and sensitive indicator of early disease. In more advanced forms of ILD, hypoxemia at rest is frequently observed. Hypercapnia occurs only late in the course of the disease. The pulmonary function tests which can be performed in children with ILD clearly depend on the age of the patient. In all patients, these tests are part of the diagnostic work-up, as well as of the follow-up to evaluate the response to therapy.


Bronchoalveolar Lavage The technique of bronchoalveolar lavage (BAL) in children has been recently reviewed, and recommendations for sampling cellular and biochemical components have been reported together with information on reference values for pediatric BAL [36]. As for adult ILD, BAL may be of importance for the diagnosis of specific forms of ILD [28]. Indeed, in cases of infections especially in immunocompromised children, BAL can provide specimens for cytological examination, microbial cultures, and molecular analysis. BAL is also essential for the diagnosis of pulmonary alveolar proteinosis, which is characterized by milky appearance fluid, abundant extracellular and intra-macrophage proteinaceous periodic acid-Schiff-positive material, and presence of foamy alveolar macrophages [37]. The detection of pulmonary alveolar hemorrhage relies on the macroscopic appearance of the BAL fluid return or the presence of red blood cells in alveolar macrophages or hemosiderin-laden cells. BAL provides materials for the diagnosis of Langerhans cell histiocytosis with the use of the monoclonal antibodies revealing the presence of CD1a positive cells (in more than 5% of the BAL cells). Lipid disorders with lung involvement represent another indication of BAL. This includes congenital lipid-storage diseases (Gaucher’s disease and Niemann-Pick disease) or chronic lipid pneumonia due to chronic aspiration [28]. Sarcoidosis has a BAL lymphocytosis characterized by an increase in T helper cells and a high CD4/CD8 ratio [38]. Hypersensitivity pneumonitis has a marked T lymphocytosis, especially the suppressor subset CD8. Also, an increase in BAL eosinophils suggests pulmonary infiltrates associated with eosinophilia syndromes. Finally, BAL may help identifying lung involvement in children with nonprimary lung disorders, for example collagen vascular diseases, inflammatory bowel diseases, or liver diseases. Importantly, several reports indicate available in the pediatric literature, that BAL may be an aid to diagnosis but it has no utility as a prognostic indicator or as a guide to therapy [28]. Lung Biopsy Compared with HRCT and clinical data, histological information has the greatest impact on the final diagnosis. However, despite its importance, lung biopsy continues to be underused in pediatric ILD. This is mainly explained by the fact that the findings on lung biopsy do not alter the proposed treatment plan in most situations. Consequently, many pediatricians remain reluctant to subject their patients to lung biopsy. In the recent ERS Task Force on ILD in children, only 55% of the children with a final diagnosis of

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idiopathic ILD had a lung biopsy. This attitude needs to be changed, as histopathologic information is important to progress in the classification of ILD. The risk of the procedure lies not in the surgical procedure itself, but mainly in the underlying overall condition of the patient. The techniques of choice for lung biopsy in children are open lung biopsy and video assisted thoracoscopy biopsy [28, 39]. Open lung biopsy can provide a specific diagnosis in a high proportion of patients, and only very few complications related directly to the procedure have been reported. Other methods such as transbronchial lung biopsy or percutaneous needle lung biopsy are rarely used. In clinical situations with involvement of several organs, sites for tissue biopsy other than lung should be considered. These sites include mainly visible skin lesions, salivary gland, superficial lymph nodes and liver. Other Tests Depending on the history and clinical presentation, noninvasive diagnostic tests can be required. They include serologic studies (immunologic studies, hypersensitivity panel tests, infectious disease titers), microbiological studies, pH studies and barium swallow, echocardiography, and ventilation-perfusion scans [28]. Classification ILD is difficult to diagnose in children, consequently no unifying classification has emerged. Recently, it has been suggested that pediatric ILD is classified as either primary pulmonary disorders or as systemic disorders with pulmonary involvement [4]. There is now evidence that some pediatric ILD are observed more frequently in infants, while others are more specific to older children. In infants, specific forms of ILD should be considered initially such as neuroendocrine cell hyperplasia, pulmonary glycogenosis, genetic defects of surfactant function, and disorders of lung growth/development. In older patients, hypersensitivity pneumonitis, druginduced lung disease, histiocytosis, and sarcoidosis are more often observed. Consequently, the stage of lung development and maturation should be taken into consideration when approaching a diagnosis of ILD. Therefore, and in agreement with recent proposals derived from international consensus statements from the American Thoracic Society (ATS)/ERS classification of adult ILD, the following diagnostic grouping could be proposed: (1) primary forms of ILD; (2) ILD associated with systemic conditions, and (3) ILD unique to infancy (table 1) [1, 28, 40]. Some of the primary forms of ILD and forms unique to infancy will be discussed here.

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Table 1. Classification of pediatric ILD

Primary forms of ILD Known causes Infectious causes Drug or irradiation induced lung disease Hypersensitivity pneumonitis (and other environmental exposures) Surfactant deficiency Aspiration syndrome Unknown causes Usual interstitial pneumonia Desquamative interstitial pneumonia Nonspecific interstitial pneumonia Lymphoid interstitial pneumonia Idiopathic pulmonary hemosiderosis Pulmonary alveolar proteinosis Pulmonary microlithiasis Pulmonary infiltrates with eosinophilia Bronchiolitis obliterans organizing pneumonia Pulmonary vascular disorders Pulmonary lymphatic disorders ILD with other organ involvement Histiocytosis Sarcoidosis Connective tissue diseases Vascular disorders Lymphatic disorders Metabolic disorders Neurocutaneous syndromes Liver/bowel diseases Malignancies ILD unique to infancy Neuroendocrine cell hyperplasia Pulmonary interstitial glycogenosis Chronic pneumonitis of infancy Lung growth and development disorders

The terms of usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), and lymphocytic interstitial pneumonia (LIP) refer to characteristic pathologic processes with histopathological criteria initially described in adults. Through the ERS task force, data on 185 cases of ILD in immunocompetent children have been collected and reviewed [28]. A diagnosis of UIP was made in 7 patients, DIP in 13 patients, and of LIP in 1 patient. These results are in agreement with previous reports in the literature indicating that UIP, DIP and LIP remain quite rare in children. In 67 children, the reported diagnosis was idiopathic pulmonary fibrosis. The term of idiopathic pulmonary fibrosis should be taken with caution as it does not exclude the possibility that some of the cases may represent nonspecific interstitial pneumonitis (NSIP). The diagnosis of NSIP was not listed in the 185 cases and it is uncertain whether NSIP is a specific separate entity in children.

Several forms of ILD appears unique to infancy [1]. Among them is the descriptive term of neuroendocrine cell hyperplasia associated with persistent tachypnea of infancy. It is characterized by the presence of neuroendocrine bodies in the lung parenchyma. Longitudinal studies will be required to determine the impact of this disorder on lung function during childhood. Pulmonary interstitial glycogenosis has recently been described in neonates [41]. It may represent a maturation defect of interstitial cells that leads them accumulating glycogen within their cytoplasm. Most cases have had a favorable prognosis. Its relationship to histologic patterns such as cellular interstitial pneumonia remains uncertain. Chronic pneumonitis of infancy is characterized by a specific histological pattern showing florid type 2 cell hyperplasia and diffuse expansion of the interstitium by fibroblastic tissue with comparatively little inflammation [42, 43]. Acellular intra-alveolar material resembling that seen in alveolar proteinosis is a frequent finding. The etiology is unknown.

Treatment

To provide guidelines for treatment of ILD in children is extremely difficult for several reasons [1, 28]. The major one is the very limited number of patients available for an adequate clinical trial. To overcome this difficulty, only multiple center trials should be considered. However, these studies are not easy to organize, especially in children, due to the lack of consensus regarding the criteria and outcome variables, and the large differential diagnosis. Controlled trials with a placebo arm are unacceptable because of the poor prognosis of untreated cases and the reported efficacy of anti-inflammatory therapies in cohort studies. Few children require no treatment and recover spontaneously. Most, however, need oxygen therapy based on day and nocturnal SaO2 levels. In all situations, maintenance of nutrition with an adequate energy intake is extremely important in the management of children with ILD. Immunization with influenza vaccine on an annual basis is recommended along with other routine immunizations against major respiratory pathogens. The main therapeutic strategy is based on the concept that suppressing inflammation most likely may prevent progression to fibrosis. Among the anti-inflammatory agents used in pediatric ILD, steroids are the preferred choice, administered orally and/or intravenously. This has been well illustrated by the results of the ERS Task Force. Oral prednisolone is most commonly administered at a dose of 1–2 mg/kg/day [28]. Children with significant disease are best treated with pulsed methylprednisolone at least initially


[45, 46]. This is usually given at a dose of 10–30 mg/kg/day for 3 days consecutively at monthly intervals. The minimum number of cycles recommended is 3 but treatment may need to be continued for a longer period of 6 months or more depending on response. When the disease is under control, the dosage of methylprednisolone can be reduced or the time between cycles can be spaced out. The disease may then be controlled with oral prednisolone preferably given as an alternate-day regime. In few cases oral prednisolone is used from the beginning simultaneously with intravenous methylprednisolone but this should only be required in those with very severe disease. Methylprednisolone sometimes works even when other forms of steroids administration fail [47]. An alternative to steroids is hydroxychloroquine with a recommended dose of 6–10 mg/kg/day. Individual case reports have described a response to chloroquine even in the presence of steroid resistance [48]. Some groups have proposed that the decision as to which agent is used should be based on the lung biopsy findings. For example steroids in cases with large amount of desquamation and inflammation and hydroxychloroquine if increased amounts of collagen representing pre-fibrotic change are found. However, as documented in the ERS Task Force report, the preferred choice of treatment is highly dependent on the expertise of the center in charge of the patient, and does not seem to be directed by the histopathological pattern [28]. In case of severe disease, steroids and hydroxychloroquine may used in combination. Other treatments include immunosuppressive agents such as azathioprine (2–3 mg/kg/day), cyclosphosphamide (1–1.5 mg/kg/day), cyclosporin (6 mg/kg/day), or methotrexate (2.5–7.5 mg/kg/week). In pulmonary alveolar proteinosis, whole lung lavage can be effective by removing the material from the alveolar space [28]. Treatment with GM-CSF has also been used [28]. To date, there are no reports on the use of novel therapies such as interferon-␥, pirfenidone, or inhibitors of TNF-␣ in pediatric ILD. Lung transplantation has emerged as a viable option for end-stage ILD in children with various forms of the disease [1]. The outcome and survival do not seem to be different from those reported in other conditions, although comparisons are difficult to establish due to the very few number of reported cases on lung transplantation in pediatric ILD [49].

Outcome

Response to treatment and outcome can be judged along similar lines to those quoted for adult disease [1, 28].

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Improvement is judged by decreased breathlessness or cough, increase in SaO2 at rest, and changes in pulmonary function tests. Improvements on chest X-ray and HRCT scan may also be seen, but these tend to occur over a much longer period of time. Reports in children with ILD have not shown a good correlation between histological findings and outcome. Some children with relatively severe fibrosis on lung biopsy make good progress, whereas others with mild desquamation have a poor outcome. This is probably due to the variable severity of the disease in different parts of the lung especially in relation to the particular area biopsied. Overall, a favorable response to corticosteroid therapy can be expected in 40–65% of cases. Reported mortality rates are around 15%. The outcome for infants is more variable [50]. Although patients in this age group can have a significant mortality, others have reported a relatively good outcome.

Conclusion

Pediatric ILD comprises a large spectrum of disorders. However, there is now compelling evidence that some of these disorders are observed more frequently in infants, while others are more specific to older children. Consequently, the stage of lung development and maturation should be taken into account in order to provide a more appropriate approach to the diagnosis of pediatric ILD. In the future, there is a need for international collaboration which will allow the collection of sufficiently large cohorts of patients with specific entities in order to perform proper therapeutic trials. As a prerequisite, however, a clear and standardized classification of the histopathology of the underlying conditions has to be developed. Such multicenter trials will help reduce the considerable morbidity and mortality in children with ILD.

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12 Kasper M, Haroske G: Alterations in the alveolar epithelium after injury leading to pulmonary fibrosis. Histol Histopathol 1996;11: 463–483. 13 Barbas-Filho JV, Ferreira MA, Sesso A, Kairalla RA, Carvalho CR, Capelozzi VL: Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)/usual interstitial pneumonia (UIP). J Clin Pathol 2001;54:132–138. 14 Kinnula VL, Fattman CL, Tan RJ, Oury TD: Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy. Am J Respir Crit Care Med 2005;172:417–422. 15 Phan S: Fibroblast phenotype in pulmonary fibrosis. Am J Respir Cell Mol Biol 2003;29: S87-S93. 16 Henson PM: Possible roles for apoptosis and apoptotic cell recognition in inflammation and fibrosis. Am J Respir Cell Mol Biol 2003;29: S70-S76. 17 Kaminsli N: Microarray analysis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 2003;29:S32-S37. 18 Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, et al: Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol 2005;166: 1321–1332. 19 Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z: TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res 2005;6:56. 20 Massaro D, Massaro GD: Critical period for alveologenesis and early determinants of adult pulmonary disease. Am J Physiol 2004;287: L715–L717.

21 Orlandi A, Francesconi A, Marcellini M, Ferlosio A, Spagnoli LG: Role of ageing and coronary atherosclerosis in the development of cardiac fibrosis in the rabbit. Cardiovasc Res 2004;64:544–552. 22 Komi-Kuramochi A, Kawano M, Oda Y, Asada M, Suzuki M, Oki J, et al: Expression of fibroblast growth factors and their receptors during full-thickness skin wound healing in young and aged mice. J Endocrinol 2005;186: 273–289. 23 Beggs ML, Nagarajan R, Taylor-Jones JM, Nolen G, Macnicol M, Peterson CA: Alterations in the TGFbeta signaling pathway in myogenic progenitors with age. Aging Cell 2004;3:353–361. 24 Grutters JC, du Bois RM: Genetics of fibrosing lung diseases. Eur Respir J 2005;25: 915–927. 25 Hartl D, Griese M: Interstitial lung disease in children–genetic background and associated phenotypes. Respir Res 2005;6:32. 26 Cameron HS, Somaschini M, Carrera P, Hamvas A, Whitsett JA, Wert SE, et al: A common mutation in the surfactant protein C gene associated with lung disease. J Pediatr 2005;146: 370–375. 27 Bullard JE, Wert SE, Whitsett JA, Dean M, Nogee LM. ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med 2005;172:1026–1031. 28 Clement A: Task force on chronic interstitial lung disease in immunocompetent children. Eur Respir J 2004;24:686–697. 29 Fan LL: Pediatric interstitial lung disease; in Schwartz KT Jr (ed): Interstitial Lung Disease. Hamilton, Decker, 1998, pp 103–188. 30 Hilman BC: Diagnosis and treatment of ILD. Pediatr Pulmonol 1997;23:1–7.

31 Lynch DA, Hay T, Newell JD Jr, Divgi VD, Fan LL: Pediatric diffuse lung disease: diagnosis and classification using high-resolution CT. Am J Roentgenol 1999;173:713–718. 32 Lucaya J, Piqueras J, Garcia-Pena P, Enriquez G, Garcia-Macias M, Sotil J: Low-dose highresolution CT of the chest in children and young adults: dose, cooperation, artifact incidence, and image quality. Am J Roentgenol 2000;175:985–992. 33 Koh DM, Hansell DM: Computed tomography of diffuse interstitial lung disease in children. Clin Radiol 2000;55:659–667. 34 Erbes R, Schaberg T, Loddenkemper R: Lung function tests in patients with idiopathic pulmonary fibrosis. Are they helpful for predicting outcome? Chest 1997;111:51–57. 35 Sharief N, Crawford OF, Dinwiddie R: Fibrosing alveolitis and desquamative interstitial pneumonitis. Pediatr Pulmonol 1994;17: 359–365. 36 de Blic J, Midulla F, Barbato A, Clement A, Dab I, Eber E, et al: Bronchoalveolar lavage in children. ERS Task Force on Bronchoalveolar Lavage in Children. European Respiratory Society. Eur Respir J 2000;15:217–231. 37 Tredano M, De Blic J, Griese M, Fournet JC, Elion J, Bahuau M: Clinical biological and genetic heterogeneity of the inborn errors of pulmonary surfactant metabolism. Clin Chem Lab Med 2001;39:90–108. 38 Baculard A, Blanc N, Boule M, Fauroux B, Chadelat K, Boccon-Gibod L, et al: Pulmonary sarcoidosis in children: a follow-up study. Eur Respir J 2001;17:628–635. 39 Fan LL, Kozinetz CA, Wojtczak HA, Chatfield BA, Cohen AH, Rothenberg SS: Diagnostic

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value of transbronchial, thoracoscopic, and open lung biopsy in immunocompetent children with chronic interstitial lung disease. J Pediatr 1997;131:565–569. 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. Canakis AM, Cutz E, Manson D, O’Brodovich H: Pulmonary interstitial glycogenosis: a new variant of neonatal interstitial lung disease. Am J Respir Crit Care Med 2002;165: 1557–1565. Katzenstein AL, Gordon LP, Oliphant M, Swender PT: Chronic pneumonitis of infancy: a unique form of interstitial lung disease occurring in early childhood. Am J Surg Pathol 1995;19:439–447. Katzenstein AL, Myers JL: Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998;157:1301–1315. Thomas AQ, Lane K, Phillips J 3rd, Prince M, Markin C, Speer M, et al: Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med 2002;165: 1322–1328. Desmarquest P, Tamalet A, Fauroux B, Boule M, Boccon-Gibod L, Tournier G, et al: Chronic interstitial lung disease in children: response to high-dose intravenous methylprednisolone pulses. Pediatr Pulmonol 1998;26: 332–338.


46 Osika E, Muller MH, Boccon-Gibod L, Fauroux B, Sardet A, Grosskopf C, et al: Idiopathic pulmonary fibrosis in infants. Pediatr Pulmonol 1997;23:49–54. 47 Paul K, Klettke U, Moldenhauer J, Muller KM, Kleinau I, Magdorf K, et al: Increasing dose of methylprednisolone pulse therapy treats desquamative interstitial pneumonia in a child. Eur Respir J 1999;14:1429–1432. 48 Balasubramanyan N, Murphy A, O’Sullivan J, O’Connell EJ: Familial interstitial lung disease in children: response to chloroquine treatment in one sibling with desquamative interstitial pneumonitis. Pediatr Pulmonol 1997;23: 55–61. 49 Balfour-Lynn IM, Martin I, Whitehead BF, Rees PG, Elliott MJ, de Leval MR: Heartlung transplantation for patients under 10 with cystic fibrosis. Arch Dis Child 1997;76: 38–40. 50 Hacking D, Smyth R, Shaw N, Kokia G, Carty H, Heaf D: Idiopathic pulmonary fibrosis in infants: good prognosis with conservative management. Arch Dis Child 2000;83: 152–157.

Annick Clement, MD Pediatric Pulmonary Department and Research Unit Inserm U719 Hopital d’enfants Armand Trousseau Assistance Publique-Hopitaux de Paris Université Pierre et Marie Curie-Paris 6 26, avenue du Dr. Arnold-Netter F–75571 Paris cedex 12 (France) Tel. ⫹33 1 4473 6668, Fax ⫹33 1 4473 6718 E-Mail [email protected]

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Lung Transplantation for Diffuse Parenchymal Lung Disease Sarosh Irani

Annette Boehler*

Clinic of Pulmonary Medicine and Lung Transplant Program, University Hospital Zurich, Zurich, Switzerland

Abstract Since the first successful lung transplantation was performed two decades ago, this procedure has emerged to a mainstay of therapy for patients suffering from end-stage lung diseases. Diffuse parenchymal lung diseases (DPLD) represent a broad range of entities, which show substantial differences in terms of natural history, recommended referral practice, waiting list mortality, and short- and long-term survival. Due to shortage of donor organs, time on the waiting list is increasing in most transplant programs and, therefore, timing of referral and listing is crucial. The aim of this chapter is to discuss different aspects to be considered when advising potential lung transplant recipients suffering from DPLD. Particularly, appropriate time of referral, disease specific comorbidities, and posttransplant prognosis are focused on. Copyright © 2007 S. Karger AG, Basel

Since the first successful lung transplantation was carried out in Toronto in the early 1980s, this procedure has emerged to a mainstay of therapy for patients suffering from end-stage lung diseases, and lung transplant programs nowadays exist in many countries. Internationally, more than 1,400 transplants are performed per year. In the last decade there has been a dramatic reduction in the incidence

*A. Boehler holds a professorship position from the Swiss National Science Foundation.

of perioperative complications. In particular, bronchial anastomotic disruption and necrosis rarely occurs in experienced centers. The shortage of donor organs and chronic allograft rejection causing bronchiolitis obliterans syndrome are the two major problems in contemporary lung transplantation medicine. Whilst the latter remains the leading cause of morbidity and mortality affecting up to 50% of long-term survivors after transplantation, the first causes the loss of many candidates on the waiting list. The selection of patients who potentially profit from favorable long-term outcomes represents an elementary issue in transplantation medicine. In addition to considering absolute and relative contraindications in patients with endstage lung diseases, timing of referral and listing of appropriate candidates is crucial. While the remaining life span should surpass the expected waiting time on the list, ideally after transplantation the patients should benefit with regard to both life expectancy and quality of life (QoL). Due to the sum of variables to be considered, this process is a matter of ongoing evaluation. In May 2005, in the United States a new lung allocation system was introduced. This system ranks candidates for lung transplantation based on a Lung Allocation Score, incorporating waiting list and posttransplant survival probabilities [1]. Lung transplantation is indicated in selected patients with chronic end stage lung disease who are receiving optimal medical therapy but nonetheless have limited survival. For lung transplant candidates there should be no alternative medical or surgical therapies available. Furthermore, their disease is usually associated with a significantly diminished

Table 1. General eligibility for lung transplantation

Table 2. Contraindications for lung transplantation

Disease related Chronic progressive end-stage lung disease Under optimal alternative therapy Substantially diminished quality of life Poor prognosis, expected mean survival ⬍2–3 years Expected survival ⬎6 months

Significant dysfunction of other organ systems Creatinine clearance ⬍50 ml/min Bilirubin ⬎35 ␮mol/l, factor V ⬍50% Left-ventricular ejection fraction ⬍30% Untreatable coronary artery disease Progressive neurologic disorders

Host related Stable psychosocial background Free of substance addiction ⬎6 months Age ⬍65(⫺70) years Ability to absorb and assimilate complex information Lacking contraindication

Diagnosis of malignancy within last 2 years Less than 5 years disease-free interval after Extracapsular renal cell carcinoma Breast cancer (ⱖ stage II) Colon cancer (⬎ Dukes A) Melanoma (ⱖ level III Clark) Documented noncompliance Incompletely treatable psychopathological conditions

QoL and a poor prognosis (table 1). Guidelines for the selection of lung transplant candidates were published in 1998 [2], and a multi-authored update written by internationally renowned experts was published recently [3]. Ideally, potential transplant recipients are suffering from single organ failure with no additional medical disease, with a stable social background and absent of psychopathological conditions. However, the transplant team will frequently be faced with a patient who has one or more comorbidities rather than an isolated organ dysfunction. It must be stressed that the referral of potential lung transplant candidates to the transplant center should not be delayed due to treatment of associated conditions. The time span between referral and listing should be properly calculated and the treatment therapies of accompanying diseases such as osteoporosis, diabetes mellitus, psychological impairments, nutritional issues, chronic infections, systemic hypertension should occur concurrently. Since time on the waiting list varies substantially among different transplant centers, the best possible time schedule for listing should be established by the local multidisciplinary transplantation team. Therefore, patients who are appropriately referred before the actual need for listing can be seen at regular intervals by the transplant center, while continuing care is provided by the referring physician. Providing counseling to candidates about the risks and benefits of the procedure is of critical importance, and patients should be given a significant amount of information to absorb and assimilate. The age limit for lung transplant recipients has been extended during the last years. Although older patients have slightly poorer survival than younger patients following transplantation, there is no evidence that this group has less to gain from transplantation. Irreversible significant dysfunction of another major organ system is generally regarded as contraindication for

Lung Transplantation for DPLD

lung transplantation (table 2). This includes significant renal impairment (creatinine clearance ⬍ 50 ml/min), severe liver diseases (bilirubin ⬎ 35 ␮m/l, factor V ⬍ 50%) or heart disease (left-ventricular ejection fraction ⬍ 30% and/or untreatable coronary artery disease) or progressive neurological disorders. In selected patients, the option of a simultaneous renal, liver or heart transplantation can be discussed. Additionally, generalized, atherosclerosis is a contraindication for transplantation. With the exception of basal cell and squamous cell carcinoma of the skin, diagnosis of malignancy within last 2 years is a contraindication for transplantation. At least a five year disease-free interval is required for breast cancer (ⱖstage II), extracapsular renal cell carcinoma, and colon cancer (⬎Dukes A) and melanoma (ⱖlevel III Clark). Since rigorous compliance with medical care and treatment plans has a vital impact on survival, incompletely treatable and unstable psychiatric or psychopathological conditions are contraindications for the procedure. Transplantation medicine is continuously developing and disease specific experiences may vary between different programs, therefore many relative contraindications such as concomitant infectious diseases, nutritional issues or anatomical abnormalities should be discussed with the local transplant centre on the basis of an individual patient.

General Aspect of Patients with Diffuse Parenchymal Lung Diseases

It is important to emphasize that the decision to refer a particular patient to the transplant center should be based

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Table 3. Indications for referral for lung transplantation in DPLD

Idiopathic pulmonary fibrosis Consider referral at time of diagnosis Symptomatic patients Pulse oximetry below 89% while 6-min walk test Diffusing capacity for carbon monoxide below 45% predicted Nonspecific intersitital pneumonia Fibrotic NSIP with forced vital capacity (FVC) below 60% Pulse oximetry below 89% while 6-min walk test Diffusing capacity for carbon monoxide below 45% predicted More than 10% decrease in forced vital capacity (FVC) in 6 months Progressive disease under drug treatment Lymphangioleiomyomatosis (LAM) Forced expiratory volume in one second (FEV1) ⬍30% predicted Severe restrictive lung function due to treatment of recurrent pneumothorax Pulmonary Langerhans cell histocytosis (LCH) Progressive disease despite of sustained smoking cessation Severe functional limitation due to parenchymal disease Severe functional limitation due to pulmonary hypertension Sarcoidosis Hypoxemia (PaO2 of ⬍8 kPa while breathing room air) Low cardiac index (⬍2 l/min/m2) associated with pulmonary hypertension Elevated right atrial pressure (⬎15 mm Hg) Collagen vascular disease (CVD) associated lung disease Severe functional limitation due to parenchymal disease Severe functional limitation due to pulmonary hypertension Progressive disease

on cumulative findings rather than relying on single functional parameters. According to the latest data from the International Society for Heart and Lung Transplantation (ISHLT) [4], idiopathic pulmonary fibrosis (IPF), the most common form of diffuse parenchymal lung diseases (DPLD), represents 17% of all lung transplantations performed in the adult population. Only 3.9% of all lung transplant recipients are patients suffering from sarcoidosis, lymphangioleiomyomatosis (LAM) or histiocytosis X. Therefore, scientific data on disease specific predictors of survival and mortality with and without transplantation in DPLD other than IPF are scarce and, therefore, the decision regarding who to list and when to transplant is complex. In the following overview, unique problems and specific considerations of the particular diseases will be focused on with regard to lung transplantation. Table 3 indicates the functional findings when referral to a lung transplant center is indicated in patients with DPLD.

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Disease-Specific Considerations

Idiopathic Pulmonary Fibrosis IPF typically shows rapid progression and, in the main, treatment trials are ineffective. Historically, response rates to immunosuppressive therapy trials are as high as 30%. However, these data come from studies performed prior to the current case definition of IPF. Recent data suggest an even worse response to therapy of maximum 10% [5]. On the transplant waiting list IPF patients have the highest mortality, which emphasize that referral is often too late. On the other hand, for these patients lung transplantation provides not only an improvement in QoL but also a clear survival benefit. The authors believe that referral of potential transplant candidates with IPF should be considered at the time of diagnosis. Different parameters have been related to the prognosis of IPF, including age, serial changes in lung function parameters, smoking status, high resolution computed tomography fibrosis scores, and responses to therapy trials. Recent data suggest that a decrease in pulse oximetry below 89% during the 6-min walk test with the patient breathing room air [6], a diffusion capacity below 39% predicted [7], or a decrease of forced vital capacity (FVC) during six months of follow-up [8] indicate poor prognosis. These criteria justify referral for transplantatiom. However, it must be stressed that patients who maintain FVC within 10% of their baseline values are also at risk of dying from their disease. Hence, spirometry is not a robust tool to prove stability of disease in IPF patients. Response to therapy is another potential pitfall in the treatment of patients suffering from IPF. The outcome of a therapy trial should not be awaited before referring a patient. The schedule of these patients can easily be adapted during the evaluation for transplantation in case of improvement during a therapy trial. Recent data suggest a higher prevalence of malignancy and cardiovascular comorbidities [9] in IPF patients compared to non fibrotic lung diseases. Successful lung transplantation can be performed after coronary artery revascularization and hence, only the presence of untreatable coronary artery disease is considered an absolute contraindication for lung transplantation [2]. Single lung transplantation is a less complex procedure compared to bilateral lung transplantation this method potentially offers lower surgical risks to patients of older age or associated comorbidities. Therefore, many transplant programs perform single lung transplantation in patients with IPF. Recurrence of IPF after transplantation has not yet been reported. There is increasing evidence that gastroesophageal

Fig. 1. CT scan of an IPF patient with known gastroesophagael reflux disease two years after bilateral lung transplantation. The fibrotic changes in the left lower lobe are thought to be the consequence of ongoing pulmonary aspiration.

reflux disease is frequent in fibrotic lung disorders and might be a relevant factor to be considered. Whilst before transplantation gastroesophageal reflux may possibly accelerate disease progression [10], after transplantation persistent aspiration is increasingly recognized as a factor leading to progressive graft dysfunction (fig. 1). Nonspecific Interstitial Pneumonia The prognosis of nonspecific interstitial pneumonia (NSIP) is better than the prognosis of usual interstitial pneumonia (UIP). However, particularly in patients with fibrotic NSIP and functional deterioration mortality is high [7]. There is a significant individual overlap in outcome. Many fibrotic NSIP patients have a prognosis as poor as UIP patients. Treatment strategies in NSIP are not standardized and in most survival studies heterogeneous treatment regimens were used. Therefore, for NSIP only limited data are available concerning respond to therapy trials and timing of referral to a lung transplant center. Consequently, it seems prudent not to wait for patients to respond to therapy, particularly in fibrotic NSIP with severe functional impairment (FVC less than 60%) at presentation. Furthermore, it is not justified to delay referral to await the response of a second drug regimen when an initial therapy trial failed.


Lymphangioleiomyomatosis Lung transplantation has become an accepted option for patients with end-stage lung disease due to LAM [11]. Airflow limitation is the most important functional feature in these patients and is also the primary determinant of exercise limitation. Rarely, patients present with a restrictive or combined restrictive-obstructive pattern, which in most cases is the consequence of treatment of recurrent pneumothoraces or chylothoraces. Though impaired gas transfer with moderate hypoxemia is typical, development of pulmonary hypertension is uncommon in LAM. LAM is a progressive disease. In earlier studies the 10-year survival has been as low as 23% [12], whereas more recent studies have shown a 10-year survival up to 79% [13]. Since the awareness of the disease has increased, this in part might be the result of a lead time bias. In an international survey of 34 LAM patients undergoing lung transplantation [11] the interval between the onset of symptoms and transplantation was 11 ⫾ 6 years and at the time of evaluation for transplantation the forced expiratory volume in 1 s (FEV1) was 24 ⫾ 12% predicted. The authors recommended lung transplantation in patients with FEV1 below 30% predicted and hypoxemia, and also patients with recurrent pneumothorax in whom treatment leads to severe restrictive impairment of the lung function. It has to be kept in mind that median waiting time spent on the waiting list for transplantation varies among different countries and might influence referral criteria. In the most recent report of the international registry [4], 40% of the 138 registered LAM patients received single lung and 60% a bilateral transplantation. The most important intraoperative complication in LAM patients is bleeding due to multiple pleural adhesions because of LAM or previous pleurectomy. The recent registry data indicates that survival of LAM is similar or better compared to patients transplanted for other diseases [14]. Recurrent pneumothorax in the native lung is a common problem after transplantation. Conservative treatment may be successful, but pleurectomy is often required. Figure 2 shows the follow up CT scan eleven years after single lung transplantation of a patient from the authors’ center. The natural history of the remaining native LAM lung with increasing hyperinflation can be seen in this asymptomatic patient. She suffered recurrent oligosymptomatic pneumothoraces that have been successfully treated by conservative measures. Chylothorax may occur in LAM patients after single, bilateral and heart-lung transplantation. Therapy consists of drainage, progesterone treatment, diet containing mediumchain triglycerides, thoracic duct ligation, pleurodesis, and pleurectomy. Recurrence despite treatment is frequent.

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Fig. 2. CT scan two (a) and thirteen (b) years after right single lung transplantation in LAM. The natural history of the remaining LAM lung with increasing hyperinflation can be seen in this asymptomatic patient. Recurrent oligosymptomatic left sided pneumothoraces have been successfully treated by conservative measures.

a

Renal angiomyolipomas have rarely caused bleeding after lung transplantation. In accordance with the generally recommended management of angiomyolipomas [15], patients with asymptomatic lesions smaller than 4 cm in diameter may be followed annually by ultrasound or CT. If the diameter extends 4 cm the lesion should be followed every 6 months. In patients with tuberous sclerosis complex and angiomyolipoma an increased risk in renal cell cancer has been described [16]. In case of bleeding after transplantation, conservation of the kidney should be attempted with selective embolization whenever possible. Recent data suggest that the loss of function mutation in the tumor suppressor gene tuberous sclerosis complex 2 (TSC2) is associated with pulmonary LAM [17]. TSC2 leads to a suppression of the mammalian target of rapamycin (mTOR)/ribosomal protein S6 pathway [18]. Rapamycin, therefore, might be a promising future therapeutic strategy in these patients that currently is evaluated in clinical trials. In LAM patients immunosuppressive therapy with this drug can be considered after transplantation, though data supporting this practice are lacking. Recurrence of pulmonary LAM after transplantation has been described in several cases. In recent studies [19, 20] it has been shown with the aid of genetic analyses that the recurrent LAM lesions of the allograft lung originated from the recipient. These data suggest that metastatic spread of LAM cells or migration of progenitor cells may play an important role in the pathogenesis of LAM. Symptomatic recurrence of LAM in a lung transplant recipient has not yet been reported. However, as a consequence of long term survival, clinicians might be faced with functionally relevant reappearance of pulmonary LAM in the future. Pulmonary Langerhans Cell Histiocytosis Lung transplantation is an established option for therapy in advanced progressive lung disease due to Langerhans cell histiocytosis (LCH). Internationally, pulmonary

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b

manifestations of LCH accounts for 0.3% of all lung transplants performed [4]. The natural history of pulmonary LCH is highly variable. In addition to obstructive, restrictive or mixed lung function impairment, these patients frequently develop a significant pulmonary hypertension. The extent of the pulmonary hypertension is often out of proportion to that associated with other restrictive or obstructive lung disorders and seems to be an independent feature of the disease rather than a consequence of hypoxia. In most cases, pulmonary LHC is associated with former or current cigarette consumption and smoking cessation is highly recommended. Several factors have been described that are associated with a higher risk of disease progression (older age, reduced FEV1 and FEV1/FVC ratio, higher residual volume/total lung capacity (TLC) ratio, [21]). Even so, predicting the prognosis of an individual patient remains difficult. Indications for lung transplantation include limitations due to severe parenchymal disease and limitations due to progressive pulmonary hypertension. When evaluation for transplantation occurs, nonpulmonary manifestations should be considered. Hypothalamopituitary abnormalities in adult patients are common [22]. Diabetes insipidus is the earliest hormonal deficiency and tends to predate the development of anterior pituitary involvement by 2 years. Serum levels of thyroid-stimulating hormone, growth hormone, and adrenocorticotropic hormone should be assessed. An observed reduction of nasal desmopression substitution therapy after lung transplantation has been reported [23]. This is thought to be the result of immunosuppressive therapy. After transplantation, recurrence of the disease in the allograft has been described in several patients [23–25]. Most of these patients resumed smoking after transplantation. Posttransplant recurrence occurred following the reduction in immunosuppressive therapy. Bronchiolar injuries due to cigarette smoking play a major role in

recruiting large numbers of Langerhans cells. Therefore, recurrence of the disease in the transplanted lung is likely to be the result of both the repopulation with recipient’s Langerhans cells and the stimulation by cigarette smoke. Disease recurrence is established by high resolution CT and/or transbronchial biopsy (including immunostaining with CD1 or S100). In 2 patients, therapy with cyclophosphamide has led to stabilization of lung function [23], whereas another patient did not tolerate chemotherapy [25]. Sarcoidosis In adults, 2.5% of lung transplantations have occurred for sarcoidosis [4]. Pulmonary sarcoidosis has a variable natural history. Two-thirds of patients show spontaneous remission of disease, whereas in 10–30% of the affected patients a chronic course develops. Although sarcoidosis is regularly diagnosed many years before severe functional limitation occurs, recent studies revealed high mortality rates of up to 53% in sarcoid patients on a lung transplant waiting list [26]. This indicates that listing may occur too late in the course of disease and that the definition of prognostic factors is limited. In retrospective studies [26, 27], clinical variables associated with less favorable outcome in sarcoid patients on the lung transplant waiting list included black race, elevated right atrial pressure, pulmonary hypertension with low cardiac index, and the presence of hypoxemia. Shorr et al. [27] retrospectively fitted a mortality prediction model which included the amount of supplemental oxygen required, race, and mean pulmonary artery pressure from a cohort of 300 sarcoid patients on the lung transplant waiting list. Based on the validation cohort of 100 patients, the concordance of the model for death within two years of listing was 0.61 (confidence interval 0.47–0.76), indicating only modest predictive power. Hence, early referral of these patients to a transplant center seems to be prudent. Patients with end-stage pulmonary sarcoidosis are predisposed to mycetoma development. Such patients are at risk of disseminated aspergillus infection after transplantation, mycetomas are considered a relative contraindication for lung transplantation. However, it has been shown recently [28], that aggressive antifungal therapies before and after lung transplantation may lead to improved outcomes in patients with mycetomas. Extrapulmonary manifestations of sarcoidosis have to be considered in the context of lung transplantation. In the presence of neurosarcoidosis, cranial nerve involvement seems to have a good prognosis, whereas central nervous system lesions other than cranial nerves and peripheral nerve involvement seem to be progressive in 50% [29]. Cardiac involvement may lead to cardiomyopathy, arrhyth-


mia, and sudden death. Patients with both heart and lung involvement are potential candidates for combined heartlung transplantation. Hepatic manifestations are most often characterized by elevation of liver enzymes without clinical symptoms. This is not a contraindication to lung transplantation, and postoperative therapy with immunosuppressive drugs is usually well tolerated. In contrast, poor protein synthesis function or portal hypertension rarely occurs in sarcoid patients. In these cases, combined liver-lung transplantation might be an option. Recurrence of sarcoidosis in the allograft is common and occurs in 30–50% of patients [30] as early as 21 days after transplantation [31]. As has been shown recently by fluorescence in situ hybridization [30] and DNA analysis [32], recurrent sarcoid granulomas derive from recipient immune calls. Despite the high frequency of histological recurrence, this is usually not of clinical significance. It might well be that after transplantation immunosuppressive drugs may modify the natural course of sarcoidosis. These drugs do not prevent the occurrence of sarcoid lesions; however, they might decrease and mitigate the amount of inflammatory reactions. Nevertheless, it remains to be seen, whether with increasing overall survival, recurrent sarcoid lesions remain clinically insignificant over a longer time period. In a retrospective study Shorr et al. [33] reviewed the registry of The United Network for Organ sharing (UNOS) and identified persons who underwent lung transplantation between 1995 and 2000. Of 4,721 transplantations 133 were performed for sarcoidosis. Survival was similar in the two groups after correcting for factors known to affect survival after lung transplantation (health insurance status, race of donor and recipient, donor age, etc.). Collagen Vascular Disease Diffuse parenchymal lung disease associated with collagen vascular disease (CVD) was a reported indication for lung TX in 65 of 13,007 (0.5%) adult lung transplants reported to the ISHLT registry between January 1995 and June 2004 [2]. Therefore only limited data exist regarding the prognostic factors in patients suffering from pulmonary involvement of CVD. In patients with scleroderma age [34] and FVC [35] at diagnosis seem to be independent poor prognostic factors. Although histological and radiological features of CVD associated DPLD are similar to those of idiopathic interstitial pneumonia (IIP), the former usually have a more indolent course. Additionally, favorable responses with immunosuppressive therapy have been cited in DPLD associated with scleroderma [36] or rheumatoid arthritis [37]. However, since the course of pulmonary disease is highly variable in these patients, the criteria for

337

100

Zurich IPF (n⫽21)

ISHLT IPF (n⫽ 2,058)

Zurich ALL (n⫽172)

ISHLT ALL (n ⫽13,462)

80 Survival (%)

timing of selection for transplant as listed for IPF should be followed. The degree of systemic involvement and non-pulmonary organ damage has to be considered on an individual basis. In general, inactive systemic disease is required for transplant consideration. In scleroderma patients associated renal dysfunction and the risk of aspiration because of esophageal involvement should be evaluated carefully. The most extensive experience with lung transplantation in CVD associated lung disease is in scleroderma, where similar results have been shown in survival, lung function, and posttransplant kidney function when compared with patients receiving lung transplants for other indications [38].

60

40

20

2

4

6

8

10

Survival time (years)

Outcome after Lung Transplantation

Considering lung transplantation in a particular patient, weighting up outcome with and without the procedure is essential. Long-term survival rates from lung transplant recipients are lower than those observed in kidney, liver, and heart recipients. Lung transplant recipients have a higher incidence of infection, and acute and chronic rejection than recipients of other solid organs. Since the lung is in direct contact with the outside environment, pollution and infectious agents can easily enter into the graft. The impaired mucociliary clearance of transplanted lungs is an additional factor, which predisposes this organ to non alloimmune injuries. Although chronic allograft rejection is thought to be mediated by alloimmunological inflammatory reaction, also non-alloimmunological injuries caused by infection or aspiration might be important pathogenetic factors. Ultimately, these inflammatory injuries result in obliteration of the small airways causing a progressive airflow obstruction. Internationally, survival rates have significantly improved in the last years. The overall one-year survival rate published in the ISHLT report 2004 (77%) was 15% higher than it was for recipients in the 1988 to 1992 era (67%) (fig. 3) [39]. However, after the first year, further improvements have yet to be seen, which is at least in part the consequence of the persistently high prevalence of bronchiolitis obliterans syndrome, the clinical correlate of chronic graft rejection. Kaplan-Meier survival curves of the ISHLT registry of more than 14,000 lung transplant recipients separated according to age groups currently show a 5-year survival of patients 18–34, 35–49, 50–64 and over 65 years of age of 50, 51, 44, and 35%, respectively. Beside better survival, improving of QoL is the major aim of lung transplantation. Many transplant related

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Fig. 3. Actuarial survival for adult lung transplantations for patients with idiopathic pulmonary dibrosis (IPF) compared to all transplantations performed between January 1994 and June 2003 according to the Registry of the International Society of Heart and Lung Transplantations and at the Lung Transplantation Program of the University of Zurich. (Reprinted in part from Trulock EP et al. [4], with permission fron the Journal of Heart and Long Transplantation).

aspects disadvantageously impact on QoL after transplantation. Chronic allograft dysfunction is associated with significant decline in QoL [40] due to reappearance of shortness of breath, increased risk of infection, and psychological stress related to an intensified therapeutic regimen. Drug related morbidity is of major importance when considering QoL of long-term survivors [41]. In addition to an increased risk of infection and malignancy, from immunosuppression, typical side effects of calcineurin inhibitors (including renal dysfunction, hypertrichosis, neurotoxicity) and corticosteroids frequently result in osteoporosis, weight gain and diabetes. Nevertheless, significant and durable improvements of QoL following lung transplantation have been shown in both longitudinal and cross-sectional studies [41–43]. Lung transplantation is performed in a wide variety of diseases. As shown in table 4 the underlying disease has a considerable impact on long-term survival. Patients with chronic obstructive pulmonary disease enjoy the best shortterm survival. Since the prognosis of patients with IPF is extremely poor in most cases, the survival benefit after lung transplantation is most significant but still lags behind other patient groups. This can be explained with the older age of this group.

Table 4. Kaplan-Meier survival by diagnosis (January 1900 to June

Outlook

2002) Year

PPH (n ⫽ 737)

CF (n ⫽ 1,923)

COPD (n ⫽ 4,955)

IPF (n ⫽ 2,119)

1 3 5 10 t cond.

64.8 54.4 45.2 20.3 8.2

78.6 63 52.9 34.1 8.4

79.9 62.4 46.8 18.2 5.9

67.5 51.6 40 17.5 6.2

Adapted from the registry of the International Society for Heart and Lung Transplantation (www.ishlt.org/registries), in %. t cond. ⫽ Conditional half-life; the conditional half-life (years) is the estimated time point at which 50% of the recipients who survive to at least 12 months have died.

The risk of disease recurrence in the allograft is a well known event that, however, seldom has clinical implications: sarcoidosis, lymphangioleiomyomatosis, histiocytosis, and pulmonary alveolar proteinosis are diseases that have been pathologically proven to recur in the allograft.

Though still the leading cause of morbidity and mortality in long-term survivors, encouraging management options to treat bronchiolitis obliterans syndrome (BOS) patients are becoming available in recent times. In lung transplant recipients with established BOS low-dose azithromycin was shown to stabilize or even improve lung function [44]. Although the mechanism of action of this drug in BOS is not completely understood, it is thought to be the result of anti-inflammatory properties rather than direct microbiological action. Recently, most promising results were also reported after fundoplication in lung transplant recipients [45]. The hypothesis is supported by these results that gastroesophageal reflux is an important non-alloimmune dependent mechanism leading to BOS, which, under ideal circumstances, may be partly or completely reversible. The negative impact of bronchiolitis obliterans syndrome on both QoL and survival is well known. Furthermore, the economic consequences of chronic allograft rejection are considerable [46] even though data on this topic are still scarce. Measures to decrease the incidence of BOS are highly warranted also from an economic point of view.

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27 Shorr AF, Davies DB, Nathan SD: Predicting mortality in patients with sarcoidosis awaiting lung transplantation. Chest 2003;124: 922–928. 28 Hadjiliadis D, Sporn TA, Perfect JR, Tapson VF, Davis RD, Palmer SM: Outcome of lung transplantation in patients with mycetomas. Chest 2002;121:128–134. 29 Judson MA: Lung transplantation for pulmonary sarcoidosis. Eur Respir J 1998;11: 738–744. 30 Milman N, Andersen CB, Burton CM, Iversen M: Recurrent sarcoid granulomas in a transplanted lung derive from recipient immune cells. Eur Respir J 2005;26:549–552. 31 Johnson BA, Duncan SR, Ohori NP, Paradis IL, Yousem SA, Grgurich WF, et al: Recurrence of sarcoidosis in pulmonary allograft recipients. Am Rev Respir Dis 1993;148:1373–1377. 32 Ionescu DN, Hunt JL, Lomago D, Yousem SA: Recurrent sarcoidosis in lung transplant allografts: granulomas are of recipient origin. Diagn Mol Pathol 2005;14:140–145. 33 Shorr AF, Helman DL, Davies DB, Nathan SD: Sarcoidosis, race, and short-term outcomes following lung transplantation. Chest 2004;125: 990–996. 34 Simeon CP, Armadans L, Fonollosa V, Solans R, Selva A, Villar M, et al: Mortality and prognostic factors in Spanish patients with systemic sclerosis. Rheumatology (Oxford) 2003;42:71–75. 35 Morgan C, Knight C, Lunt M, Black CM, Silman AJ: Predictors of end stage lung disease in a cohort of patients with scleroderma. Ann Rheum Dis 2003;62:146–150. 36 White B, Moore WC, Wigley FM, Xiao HQ, Wise RA: Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis. Ann Intern Med 2000;132:947–954. 37 Wallaert B, Hatron PY, Grosbois JM, Tonnel AB, Devulder B, Voisin C: Subclinical pulmonary involvement in collagen-vascular diseases assessed by bronchoalveolar lavage: relationship between alveolitis and subsequent changes in lung function. Am Rev Respir Dis 1986;133:574–580. 38 Rosas V, Conte JV, Yang SC, Gaine SP, Borja M, Wigley FM, et al: Lung transplantation and systemic sclerosis. Ann Transplant 2000;5: 38–43. 39 Trulock EP, Edwards LB, Taylor DO, Boucek MM, Keck BM, Hertz MI: The Registry of the International Society for Heart and Lung

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Transplantation: twenty-first official adult lung and heart-lung transplant report – 2004. J Heart Lung Transplant 2004;23:804–815. van Den BERG JW, Geertsma A, van Der BIJ, Koeter GH, de BOER WJ, Postma DS, et al: Bronchiolitis obliterans syndrome after lung transplantation and health-related quality of life. Am J Respir Crit Care Med 2000;161: 1937–1941. Rodrigue JR, Baz MA, Kanasky WF Jr, Macnaughton KL: Does lung transplantation improve health-related quality of life? The University of Florida experience. J Heart Lung Transplant 2005;24:755–763. Gross CR, Savik K, Bolman RM III, Hertz MI: Long-term health status and quality of life outcomes of lung transplant recipients. Chest 1995;108:1587–1593. Rutherford RM, Fisher AJ, Hilton C, Forty J, Hasan A, Gould FK, et al: Functional status and quality of life in patients surviving 10 years after lung transplantation. Am J Transplant 2005;5:1099–1104. Yates B, Murphy DM, Forrest IA, Ward C, Rutherford RM, Fisher AJ, et al: Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2005;172:772–775. Davis RD Jr, Lau CL, Eubanks S, Messier RH, Hadjiliadis D, Steele MP, et al: Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg 2003;125:533–542. van Den BERG JW, van Enckevort PJ, TenVergert EM, Postma DS, van der BW, Koeter GH: Bronchiolitis obliterans syndrome and additional costs of lung transplantation. Chest 2000;118:1648–1652.

A. Boehler, MD Clinic of Pulmonary Medicine and Lung Transplant Program, C HOER 27 University Hospital Ramistrasse 100 CH–8091 Zurich (Switzerland) Tel. ⫹41 44 255 1111, Fax ⫹41 44 363 5901 E-Mail [email protected]

Author Index

Agostini, C. 87 Bauer, P.C. 285 Baughman, R.P. 58 Behr, J. 117 Boehler, A. 332 Caminati, A. 264 Camus, P. 212 Casoni, G. 292 Chilosi, M. 44, 292, 307 Clement, A. 324 Cohen Tervaert, J.W. 110 Collard, H.R. 175 Cordier, J.-F. 238 Costabel, U. 285 Damoiseaux, J.G.M.C. 110 Desai, S.R. 29 Drent, M. 58 du Bois, R.M. 70

Fishbein, M.C. 11, 196 Flaherty, K.R. 160

Olson, A.L. 250 Poletti, V. 44, 292, 307

Gomez, A.D. 2 Guzman, J. 285

Raghu, G. 22

Harari, S. 264 Hoyles, R.K. 185

Schwarz, M.I. 250 Semenzato, G. 87

Irani, S. 332

Tomassetti, S. 307

Johnson, S.R. 275

Vogelmeier, C. 139

Keating, D.T.K. 148 King, T.E., Jr. 2

Wasfi, Y.S. Weigt, S.S. Wells, A.U. White, E.S.

Lazor, R. 238 Lynch, J.P., III 11, 196

Egan, J.J. 148

Martinez, F.J. 160 McCullagh, B. 148 Meyer, K.C. 58 Miorin, M. 87 Murer, B. 44

Facco, M. 87 Fauroux, B. 324

Newman, L.S. 128 Noble, P.W. 101

128 11 29, 185 196

Yang, S. 22 Zinzani, P.L. 307 Zompatori, M. 292

341

Subject Index

Abciximab, diffuse alveolar hemorrhage 260 N-acetylcysteine (NAC) idiopathic pulmonary fibrosis management 155, 156 interstitial lung disease management 120, 121, 125 Acute eosinophilic pneumonia drug-induced infiltrative lung disease 221 radiation therapy induction 234 Acute eosinophilic pneumonia, idiopathic disease clinical assessment 242, 243 definition 242 diagnosis 243 epidemiology 242 etiology and pathogenesis 242 investigations 243 natural history and prognosis 243, 244 pathology 242 treatment 244 Acute interstitial pneumonia bronchoscopy findings 182 clinical assessment 182 computed tomography findings 36, 182 diagnosis 182 epidemiology 181 etiology 182 immunohistochemistry 47 natural history and prognosis 182 pathology 182 treatment 182

342

Acute organizing pneumonia, drug-induced infiltrative lung disease 224 Alveolar epithelium idiopathic pulmonary fibrosis role 102, 103 usual interstitial pneumonia 45, 46 Amiodarone acute pulmonary toxicity 219, 222 diffuse alveolar hemorrhage 260 pneumonitis 226–229 Angiomyolipoma, lymphangioleiomyomatosis management 281, 282 Angiotensin-converting enzyme (ACE), sarcoidosis role 83 Ankylosing spondylitis clinical features 192 investigations 192 pathogenesis 191 pathology 191, 192 predisposing factors 191 prognosis and natural history 192 pulmonary fibrosis screening and management 192–194 Antineutrophil cytoplasmic antibodies (ANCA), see Vasculitis Azathioprine idiopathic pulmonary fibrosis management 153, 154 interstitial lung disease management 118, 125 sarcoidosis management 136 systemic sclerosis pulmonary fibrosis management 193

Wegener’s granulomatosis management 203 Behçet’s disease clinical features 208, 209 diffuse alveolar hemorrhage 256, 257 epidemiology 209 histopathology 209 pathogenesis 205, 206 treatment 209 Biopsy, see Lung biopsy Bosentan, interstitial lung disease management 121, 122 Bronchiolitis, see also Respiratory bronchiolitis-associated interstitial lung disease anatomy 292, 293 classification 293 definition 292, 293 diagnosis 305 epithelial cell injury and regeneration 295, 296 etiology connective vascular disease 300 cryptogenic bronchiolitis 303, 304 diffuse panbronchiolitis 302, 303 drugs 299, 300 immunodeficiency 305 infection 299 inflammatory bowel disease 300 irritants 298, 299 lung transplant 300–302 neuroendocrine cell hyperplasia 302 paraneoplastic pemphigus 302

histopathology 293–295 inflammatory reactions 296, 297 pathogenesis 295 pulmonary function testing 298 radiographic findings 297, 298 Bronchoalveolar lavage (BAL) complications 59 diagnostic approach 59 diffuse interstitial lung disease alveolar macrophages 61, 62 clinical uses 58, 59 culture and stains 64 disease-specific stains 64, 66 eosinophils 63 lymphocytes 62, 63 mast cells 63, 64 neutrophils 63 plasma cells 63 fluid processing 60, 61 hypersensitivity pneumonitis 143, 144 idiopathic pulmonary fibrosis 152 pediatric interstitial lung disease 327 pulmonary Langerhans cell histiocytosis 270 technique 59, 60 Bronchocentric granulomatosis, features 207 Bronchoscopy, diffuse parenchymal lung disease diagnosis 18, 19 Castleman’s disease, see Multicentric Castleman’s disease Chemokine receptors granuloma formation role 91, 92 sarcoidosis role 82 systemic sclerosis role 76 ‘Chemotherapy lung’, features 219, 222 Chest radiography diffuse parenchymal lung disease diagnosis 13, 15 drug-induced infiltrative lung disease 214 hypersensitivity pneumonitis 143 interstitial lung disease diagnosis 26, 27 Children, see Interstitial lung disease Chloroquine, sarcoidosis management 136 Chronic eosinophilic pneumonia computed tomography findings 41 idiopathic disease clinical assessment 241 definition 240 diagnosis 241 epidemiology 240 etiology and pathogenesis 240 investigations 241 natural history and prognosis 242 pathology 240 treatment 242

Subject Index

Churg-Strauss angiitis, see Churg-Strauss syndrome Churg-Strauss syndrome clinical assessment 244, 245 clinical features 206, 207 definition 244 diagnosis 245, 246 epidemiology 244 etiology and pathogenesis 244 histopathology 205 investigations 245, 246 natural history and prognosis 246 pathogenesis 205, 206 pathology 244 treatment 207, 246 Colchicine, interstitial lung disease management 119 Complement receptors gene polymorphisms in sporadic interstitial lung disease 74 sarcoidosis role 81 Computed tomography (CT) bronchiolitis 297, 298 diffuse interstitial lung disease acute interstitial pneumonia 36, 182 chronic eosinophilic pneumonia 41 cryptogenic organizing pneumonia 35, 36, 180 desquamative interstitial pneumonia 34, 35, 178 diagnostic utility 32 diseases of known cause 32 hypersensitivity pneumonitis 37, 38 idiopathic interstitial pneumonias 32 idiopathic pulmonary fibrosis/usual interstitial pneumonia 32, 33, 151, 152 Langerhans’ cell histiocytosis 38, 39, 268–270 lymphangioleiomyomatosis 39 lymphangitis carcinomatosis 40, 41 lymphocytic interstitial pneumonitis 36, 181 nonspecific interstitial pneumonia 33, 34, 165–168, 171 pulmonary alveolar proteinosis 39, 40, 287 respiratory bronchiolitis-associated interstitial lung disease 34, 35, 176 sarcoidosis 37 technical considerations 30, 32 Wegener’s granulomatosis 40 diffuse parenchymal lung disease diagnosis 15

drug-induced infiltrative lung disease 214 hypersensitivity pneumonitis 143 interstitial lung disease diagnosis 27 pediatric interstitial lung disease 326, 327 sarcoidosis findings 131–133 Corticosteroids, see Prednisone Cryptogenic bronchiolitis, features 303, 304 Cryptogenic organizing pneumonia (COP) bronchoscopy findings 180 clinical assessment 179, 180 computed tomography findings 35, 36, 180 diagnosis 180 differential diagnosis 48 epidemiology 179 etiology 179 histopathology 47, 48 natural history and prognosis 180 pathology 179 treatment 180 Cyclophosphamide idiopathic pulmonary fibrosis management 154 interstitial lung disease management 118, 125 sarcoidosis management 136 systemic sclerosis pulmonary fibrosis management 193 Wegener’s granulomatosis management 203 Dendritic cell, granuloma formation role 89 Dermatomyositis, see Polymyositis/dermatomyositis Desquamative interstitial pneumonia bronchoscopy findings 178 classification 8 clinical assessment 178 computed tomography findings 34, 35, 178 drug-induced infiltrative lung disease 230 epidemiology 177 etiology 177, 178 histopathology 53 natural history and prognosis 178 pathology 178 respiratory bronchiolitis-associated interstitial lung disease relationship 179 treatment 178, 179 Diffuse alveolar hemorrhage clinical assessment and investigations 251–253 diagnosis 253, 254

343

Diffuse alveolar hemorrhage (continued) etiology chemicals 259 drugs 260 Goodpasture’s syndrome 257, 258 idiopathic pulmonary hemosiderosis 258, 259 overview 250 pulmonary capillary hemangiomatosis 260, 261 natural history, management, and prognosis in specific diseases Behçet’s syndrome 256, 257 drug-induced capillaritis 257 Henoch-Schönlein purpura 257 isolated pulmonary capillaritis 255, 256 microscopic polyangiitis 255 mixed cryoglobulinemia 257 systemic lupus erythematosus 256 Wegener’s granulomatosis 254, 255 pathology 251 Diffuse interstitial lung disease (DILD) classification for radiological diagnosis 29–31 diagnosis bronchoalveolar lavage, see Bronchoalveolar lavage chest radiography 30 computed tomography, see Computed tomography Diffuse panbronchiolitis, features 302, 303 Diffuse parenchymal lung disease (DPLD), see also specific diseases classification ATS/ERS classification 4–7, 11 desquamative interstitial pneumonia and undifferentiated interstitial pneumonia 8 goal 8 historical perspective 2–4 idiopathic interstitial pneumonias 5, 7, 8 nonspecific interstitial pneumonia and usual interstitial pneumonia 8 revision 8, 9 diagnosis blood studies 16 bronchoscopy 18, 19 chest radiographs 13, 15 clinical features 15, 16 clinical history demographics 12 exposures 12 genetics 12 lung biopsy 19 physical examination 12, 13

344

Subject Index

pulmonary function tests 16, 18 treatment response 19 lung transplantation, see Lung transplantation Drug-induced capillaritis, features 257 Drug-induced infiltrative lung disease acute alveolar hemorrhage 224 acute drug-induced infiltrative lung disease 218, 220 acute eosinophilic pneumonia 221 acute methotrexate pneumonitis 220, 221 acute organizing pneumonia 224 acute pulmonary edema 222–224 amiodarone acute pulmonary toxicity 222 pneumonitis 226–229 cellular nonspecific pneumonia 225 ‘chemotherapy lung’ 222 classification 213 clinical presentation 213 desquamative interstitial pneumonia 230 diagnosis 216–218 drug-induced systemic condition association 232, 233 drug types 215, 216 exogenous lipoid pneumonia 231 granulomatosis 231 incidence 212, 216 organizing pneumonia 229, 230 pulmonary fibrosis 230 pulmonary infiltrates and eosinophilia 225, 226 risk factors 213, 215 sarcoidosis 231 transient pulmonary infiltrates 224, 225 vascular involvement 231, 232 Drug rash with eosinophilia and systemic symptoms (DRESS), lung involvement 232 Endothelin, therapeutic targeting 121, 156 Eosinophil, bronchoalveolar lavage fluid findings 63 Erdheim-Chester disease, histopathology 55 Etanercept idiopathic pulmonary fibrosis management 156 interstitial lung disease management 122 sarcoidosis management 136, 137 Extrinsic allergic alveolitis differential diagnosis 51, 52 histopathology 51, 52 FG-3019 antibody, interstitial lung disease management 122 Fibronectin, systemic sclerosis role 76

Goodpasture’s syndrome, diffuse alveolar hemorrhage 257, 258 Granulocyte-macrophage colony-stimulating factor (GM-CSF) granuloma formation role 91 pulmonary alveolar proteinosis management 289 Granuloma cell proliferation and survival 95 cellular initiation dendritic cells 89 immune cell interactions 93–95 macrophages 89–92 neutrophils 93 phases 88 T cells 92, 93 definition 87 etiology 87 fibrosis 95–97 immunoregulation loss 96, 97 Henoch-Schönlein purpura, diffuse alveolar hemorrhage 257 Hermansky-Pudlak syndrome, genetics 72 Hodgkin’s disease, lung 315, 319, 320 Hypereosinophilic syndrome clinical features 247 definition 246 diagnosis 247 investigations 247 pathogenesis 246, 247 prognosis 247, 248 treatment 247, 248 Hypersensitivity pneumonitis clinical features 142, 143 computed tomography findings 37, 38 definition 139 differential diagnosis 51, 52, 144, 145 epidemiology 139 etiology 139–141 histopathology 51, 52 investigations bronchoalveolar lavage 143, 144 chest radiography 143 computed tomography 143 laboratory tests 143 lung biopsy 144 provocation tests 144 pulmonary function testing 143 natural history and prognosis 145 pathogenesis 141, 142 pathology 142 treatment 145, 146 Idiopathic eosinophilic pneumonia acute eosinophilic pneumonia clinical assessment 242, 243 definition 242

diagnosis 243 epidemiology 242 etiology and pathogenesis 242 investigations 243 natural history and prognosis 243, 244 pathology 242 treatment 244 chronic eosinophilic pneumonia clinical assessment 241 definition 240 diagnosis 241 epidemiology 240 etiology and pathogenesis 240 investigations 241 natural history and prognosis 242 pathology 240 treatment 242 Churg-Strauss syndrome clinical assessment 244, 245 definition 244 diagnosis 245, 246 epidemiology 244 etiology and pathogenesis 244 investigations 245, 246 natural history and prognosis 246 pathology 244 treatment 246 classification 238, 239 diagnosis 238–240 hypereosinophilic syndrome clinical features 247 definition 246 diagnosis 247 investigations 247 pathogenesis 246, 247 prognosis 247, 248 treatment 247, 248 Idiopathic interstitial pneumonias classification 5, 7, 8 computed tomography findings 32 Idiopathic pulmonary fibrosis (IPF) acute exacerbations 153 clinical features 150, 151 differential diagnosis 150, 151 epidemiology 149, 150 familial lung fibrosis genetics adults 72 children 71, 72 histological classification 150 investigations bronchoalveolar lavage 152 computed tomography findings 32, 33, 151, 152 laboratory tests 151 lung biopsy 152, 153 pulmonary function testing 152

Subject Index

pathogenesis acute exacerbation features 107 alveolar epithelial cell role 102, 103 fibroblast homeostasis 105 fibrogenic cytokines 104 growth factors 104, 105 host response 106, 107 inflammatory hypothesis 102 matrix remodeling 104 myofibroblasts 105, 106 overview 148, 149 vascular remodeling 103, 104 prognosis 101, 153 risk factors 150 severity markers 153 treatment 153–157, 334, 335 Idiopathic pulmonary hemosiderosis, diffuse alveolar hemorrhage 258, 259 Imatinib mesylate idiopathic pulmonary fibrosis management 156, 157 interstitial lung disease management 122 Inflammatory bowel disease (IBD), bronchiolitis obliterans 300 Infliximab, sarcoidosis management 137 Inhibitor kappa B-alpha, sarcoidosis role 81 Insulin-like growth factor-1 (IGF-1), idiopathic pulmonary fibrosis role 105 Interferon-␥ (IFN-␥) gene polymorphisms in sporadic interstitial lung disease 74 granuloma formation role 93 idiopathic pulmonary fibrosis management 155 interstitial lung disease management 119 Interleukin-1 granuloma formation role 90 receptor antagonist and interstitial lung disease studies 73 sarcoidosis role 82 Interleukin-2, granuloma formation role 92 Interleukin-4, granuloma formation role 92 Interleukin-6, granuloma formation role 90, 91 Interleukin-8 idiopathic pulmonary fibrosis role 102 levels in interstitial lung disease 74 Interleukin-10 gene polymorphisms in sporadic interstitial lung disease 74 granuloma formation role 92 Interleukin-12, granuloma formation role 91 Interleukin-13, granuloma formation role 92, 93 Interleukin-15, granuloma formation role 91

Interleukin-17, granuloma formation role 93 Interleukin-18 granuloma formation role 91 sarcoidosis role 82 Interleukin-23, granuloma formation role 91 Interstitial lung disease (ILD), see also Diffuse interstitial lung disease children classification 328, 329 diagnosis 326–328 epidemiology 324 pathogenesis 324–326 prognosis 329, 330 treatment 329 classification 70, 71 defects (p53) 73 epidemiology 22 genetics familial lung fibrosis 71, 72 overview 71 sporadic disease 72–74 medical history chest radiography 26, 27 demographics 23 exercise testing 28 exposures 24 extrapulmonary symptoms 23 family history 23, 24 laboratory testing 25, 26 onset of symptoms 23 physical examination extrapulmonary signs 24, 25 pulmonary signs 24 pulmonary function testing 26 treatment antiangiogenic therapy 123, 124 anticoagulant therapy 121 antifibrogenic therapy 121, 122 antifibrotic therapy 119, 120 anti-inflammatory therapy 118 antioxidant therapy 120, 121 epithelial-mesenchymal interaction targeting 122, 123 gene therapy prospects 124 overview of approaches 117, 118 practical recommendations 125 stem cell targeting 124 Interstitial pneumonia classification ATS/ERS classification 4–7 desquamative interstitial pneumonia and undifferentiated interstitial pneumonia 8 goal 8 historical perspective 2–4 idiopathic interstitial pneumonias 5, 7, 8 nonspecific interstitial pneumonia and usual interstitial pneumonia 8 revision 8, 9

345

Isolated pulmonary capillaritis, diffuse alveolar hemorrhage 255, 256 Langerhans’ cell histiocytosis, see Pulmonary Langerhans’ cell histiocytosis Lung biopsy diffuse parenchymal lung disease diagnosis 19 hypersensitivity pneumonitis 144 idiopathic pulmonary fibrosis 152, 153 pediatric interstitial lung disease 327, 328 Lung transplantation bronchiolitis 300–302 collagen vascular disease 337, 338 contraindications 333 eligibility 333 historical perspective 332 idiopathic pulmonary fibrosis management 157, 334, 335 indications in diffuse parenchymal lung disease 333, 334 lymphangioleiomyomatosis 281, 335, 336 nonspecific interstitial pneumonia 335 outcomes 338, 339 posttransplant lymphoproliferative disorder 315, 320 prospects 339 pulmonary Langerhans’ cell histiocytosis 336, 337 sarcoidosis 337 Lymphangioleiomyomatosis clinical assessment 277, 278 computed tomography findings 39, 278, 279 definition 275 epidemiology 275, 276 histopathology 55 investigations 278–280 natural history and prognosis 280, 281 pathogenesis 276 pathology 277 treatment 281, 282, 335, 336 Lymphangitis carcinomatosis, computed tomography findings 40, 41 Lymphocyte, bronchoalveolar lavage fluid findings 62, 63 Lymphocytic interstitial pneumonitis (LIP) bronchoscopy findings 181 clinical assessment 181, 310, 311 computed tomography findings 36, 181 diagnosis 181 epidemiology 180, 181 etiology 181 histopathology 50 natural history and prognosis 181 pathology 181 treatment 181, 311

346

Subject Index

Lymphoid granulomatosis, features 207, 208 Lymphoproliferative lung disease classification 307, 308 primary lymphomas diagnosis and staging 316, 317 Hodgkin’s disease 314, 315, 320 non-Hodgkin’s lymphoma follicular lymphoma 312 histology and molecular biology 317, 318 mucosa-associated lymphoid tissue (MALT) lymphoma features 311–312 rare forms 313, 314 types 311 posttransplant lymphoproliferative disorder 315, 320 T cell lymphoma 314, 315, 319 treatment 320, 321 reactive pulmonary lymphoproliferative disease 308–311 secondary lymphomas 321 Macrophage bronchoalveolar lavage fluid findings 61, 62 granuloma formation role 89–95 Major histocompatibility complex (MHC) sarcoidosis role HLA class I 78 HLA class II 78, 79 systemic sclerosis studies 76 Mast cell, bronchoalveolar lavage fluid findings 63, 64 Methotrexate acute pneumonitis 220, 221 sarcoidosis management 136 Microscopic polyangiitis clinical features 204 histopathology 204 treatment 204, 205 Mixed cryoglobulinemia, diffuse alveolar hemorrhage 257 Multicentric Castleman’s disease (MCD) reactive pulmonary lymphoproliferative disease 309 treatment 309 Myofibroblast, idiopathic pulmonary fibrosis role 105, 106 Necrotizing sarcoid angiitis and granulomatosis (NSG), features 207 Neutrophil bronchoalveolar lavage fluid findings 63 granuloma formation role 93 Non-Hodgkin’s lymphoma (NHL) follicular lymphoma 312

histology and molecular biology 317, 318 mucosa-associated lymphoid tissue (MALT) lymphoma features 311–312 rare forms 313, 314 types 311 Nonspecific interstitial pneumonia (NSIP) cellular nonspecific pneumonia 225 classification 8 clinical characteristics 163–165 computed tomography findings 33, 34, 165–168, 171 definition 160 diagnosis 171 differential diagnosis 49, 50 epidemiology 160 etiology 160, 161 histopathology 48–50, 162, 163 natural history and prognosis 170–172 pathogenesis 161, 162 treatment 172, 335 Paraneoplastic pemphigus, bronchiolitis 302 Paraquat, pulmonary fibrosis induction 230 Penicillamine diffuse alveolar hemorrhage 259, 260 interstitial lung disease management 119 Pentoxifylline, sarcoidosis management 136, 137 Physical examination, diffuse parenchymal lung disease diagnosis 12 Pirfenidone idiopathic pulmonary fibrosis management 155 interstitial lung disease management 119, 120, 125 Plasma cell, bronchoalveolar lavage fluid findings 63 Plasminogen activating inhibitor-1 (PAI-1), levels in interstitial lung disease 74 Platelet-derived growth factor (PDGF), idiopathic pulmonary fibrosis role 105, 106 Polyarteritis nodosa clinical features 204 treatment 204 Polymyositis/dermatomyositis clinical features 189 investigations 189 pathogenesis 189 pathology 189 predisposing factors 189 prevalence 185, 186 prognosis and natural history 190 pulmonary fibrosis screening and management 192–194

Posttransplant lymphoproliferative disorder (PTLD), features 315, 320 Prednisone hypersensitivity pneumonitis management 145, 146 idiopathic pulmonary fibrosis management 153 interstitial lung disease management 118, 125 polymyositis/dermatomyositis, pulmonary fibrosis management 193 sarcoidosis management 135, 136 Wegener’s granulomatosis management 203 Progesterone, lymphangioleiomyomatosis management 282 Pulmonary alveolar proteinosis (PAP) clinical assessment 287 computed tomography findings 39, 40, 287 definition 285 diagnosis 288 epidemiology 286 etiology 286 investigations 287, 288 management 288, 289 pathogenesis 286 pathology 287 prognosis 290 Pulmonary capillary hemangiomatosis, diffuse alveolar hemorrhage 260, 261 Pulmonary function test (PFT), diffuse parenchymal lung disease diagnosis 16, 18 bronchiolitis 298 hypersensitivity pneumonitis 143 idiopathic pulmonary fibrosis 152 interstitial lung disease diagnosis 26 pediatric interstitial lung disease 327 Pulmonary Langerhans’ cell histiocytosis (PLCH) bronchoalveolar lavage 270 clinical assessment 267 computed tomography findings 38, 39, 268–270 definition 264, 265 diagnosis 271 epidemiology 265 etiology 266 histopathology 53, 54 lung transplantation 336, 337 natural history and prognosis 271, 272 pathogenesis 265, 266 pathology 266, 267 treatment 272 Pulmonary vasculitis, see Vasculitis Radiation therapy, lung effects 233, 234

Subject Index

Rapamycin, interstitial lung disease management 122 Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) clinical assessment 176 clinical features 304 computed tomography findings 34, 35, 176 desquamative interstitial pneumonia relationship 179 diagnosis 176 epidemiology 175 etiology 175 histopathology 52, 53 natural history and prognosis 176 pathology 175 treatment 176 Rheumatoid arthritis clinical features 188 investigations 188, 189 pathogenesis 188 pathology 188 predisposing factors 188 prognosis and natural history 189 Rosai-Dorfman disease, histopathology 55, 56 Sarcoidosis clinical assessment 131–134 computed tomography findings 37 definition 128 diagnosis 135 drug-induced sarcoidosis 231 epidemiology 128 etiology 129, 130 genetics angiotensin-converting enzyme 83 chemokine receptors 82 complement receptors 81 familial disease 77, 78 inhibitor kappa B-alpha 81 interleukin-1 82 interleukin-18 82 major histocompatibility complex HLA class I 78 HLA class II 78, 79 tumor necrosis factor-␣ 82 histopathology 50, 51 investigations 134, 135 lung transplantation 337 natural history and prognosis 135 pathogenesis 130 pathology 130 treatment 135–137 Sclerosis, see Systemic sclerosis Sjögren’s syndrome clinical features 191 investigations 191 pathogenesis 191

pathology 191 predisposing factors 191 prognosis and natural history 191 pulmonary fibrosis screening and management 192–194 Smoking, interstitial lung disease risks 52 Statins, idiopathic pulmonary fibrosis management 156 Surfactant proteins gene polymorphisms in sporadic interstitial lung disease 73 mutations in childhood disease 326 SP-C gene defects in familial lung fibrosis 71, 72 Systemic lupus erythematosus (SLE) clinical features 190 diffuse alveolar hemorrhage 256 drug-induced lupus 232, 233 investigations 190 pathogenesis 190 pathology 190 predisposing factors 190 prognosis and natural history 190, 191 pulmonary fibrosis screening and management 192–194 Systemic sclerosis clinical features 187 investigations 187 lung disease genetics chemokine receptors 76 fibronectin 76 major histocompatibility complex 76 tumor necrosis factor-␣ 76 pathogenesis 186, 187 pathology 187 predisposing factors 186 prevalence 185, 186 prognosis and natural history 187, 188 pulmonary fibrosis screening and management 192–194 Takayasu’s arteritis clinical features 210 diagnosis 209 epidemiology 209 histopathology 209, 210 pulmonary manifestations 210 treatment 210 T cell, granuloma formation role 92–95 T cell lymphoma, lung 314, 315, 319 Transforming growth factor-␤ (TGF-␤) gene polymorphisms in sporadic interstitial lung disease 74 idiopathic pulmonary fibrosis role 104–106 receptor microsatellite instability and interstitial lung disease defects 73 therapeutic targeting 156

347

Transfusion-related acute lung injury (TRALI), features 219, 223, 224 Trimethoprim/sulfamethoxazole, Wegener’s granulomatosis management 203 Tumor necrosis factor-␣ (TNF-␣) gene polymorphisms in sporadic interstitial lung disease 73, 74 granuloma formation role 91 sarcoidosis role 82 systemic sclerosis role 76 therapeutic targeting 122, 156 Usual interstitial pneumonia (UIP), see also Idiopathic pulmonary fibrosis classification 8 computed tomography findings 32, 33 histopathology alveolar epithelium 45, 46 bronchiolar injury and repair 46

348

Subject Index

fibroblast foci 46 fibrosis and remodeling 46 immunohistochemistry 46, 47 inflammation 46 pattern 44, 45 prognosis 102 Vascular endothelial growth factor (VEGF) idiopathic pulmonary fibrosis role 104 therapeutic targeting 124 Vasculitis, see also specific diseases anti-glomerular basement membrane disease overview 114 pathogenicity of antibodies 114, 115 antineutrophil cytoplasmic antibody-associated vasculitis antibody types 196 diseases 111, 112

epidemiology 197 induction 112 pathophysiology animal studies 113, 114 in vitro studies 112, 113 classification 110, 111 pathophysiology 110, 111 polyarteritis nodosa 204 pulmonary capillaritis 197, 198 secondary forms 110, 111 Warfarin, idiopathic pulmonary fibrosis management 154 Wegener’s granulomatosis clinical manifestations 198–203 computed tomography findings 40 histological features 198, 199 laboratory features 203 treatment 203

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Diffuse Parenchymal Lung Disease (Progress in Respiratory Research)

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Infectious Disease Modelling Research Progress

Cystic Fibrosis in the 21st Century (Progress in Respiratory Research)

Lung Biology in Health & Disease Volume 157 Respiratory-Circulatory Interactions in Health & Disease

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Lymphocyte Trafficking in Health and Disease (Progress in Inflammation Research)

Lung Development and Regeneration (Lung Biology in Health and Disease)

Lung Biology in Health & Disease Volume 178 Respiratory Infections in Allergy and Asthma

Overcoming Steroid Insensitivity in Respiratory Disease

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Lung Biology in Health & Disease Volume 173 Respiratory Control and Disorders in the Newborn

Lung Biology in Health & Disease Volume 173 Respiratory Control and Disorders in the Newborn

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Pleural Disease, Second Edition (Lung Biology in Health and Disease)

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