Pulmonary Manifestations of Systemic Diseases [1st ed.] 9781849841115, 9781849841122

Table of contents :
ERM_0_86_WEB.pdf......Page 0
Sarcoidosis: pulmonary manifestations and management......Page 6
Abstract......Page 7
Diagnosis......Page 8
Signs and symptoms......Page 9
Laboratory findings......Page 21
Histopathology......Page 22
Treatment......Page 23
Specific approach......Page 24
Ongoing pharmaceutical research......Page 25
Prognosis......Page 26
References......Page 37
Treatment......Page 38
Targeted therapy......Page 40
Genetic counselling......Page 75
Genetic counselling......Page 76
References......Page 77
SID......Page 97
References......Page 98
References......Page 99
Blank Page......Page 14

Citation preview

Interest in interstitial lung diseases (ILDs) has risen in recent Pantone PASTEL 9081 CMJN Pantone 200 CMJN (darker) Pantone 647 CMJN years. A large volume of basic and clinical Cyan 0 research has Cyan 0 Cyan 100 Magenta 0 Magenta 100 Magenta 56 Yellow 6 increased Yellow our70understandingYellow of0 the pathogenesis of idiopathic Black 8 Black 14 Black 24 pulmonary fibrosis (IPF) and non-IPF fibrotic ILDs. The ILD field is now evolving rapidly, with major implications for practical management. This Monograph provides expert clinical guidance on these difficult diseases, which will be helpful to both respiratory and nonrespiratory physicians alike. The initial chapters consider diagnostic issues, pulmonary function tests and techniques that are currently in development. The book then goes on to cover a variety of pulmonary manifestations of very different disease entities, such as connective tissue diseases, systemic vasculitis and much more.

Print ISBN: 978-1-84984-111-5 Online ISBN: 978-1-84984-112-2 December 2019 €60.00

9 781849 841115

ERS monograph 86

ISBN 978-1-84984-111-5 Print ISSN: 2312-508X Online ISSN: 2312-5098

Pulmonary Manifestations of Systemic Diseases

ERS monograph

ERS monograph

Pantone 200 CMJN (darker) Cyan 0 Magenta 100 Yellow 70 Black 14

Pulmonary Manifestations of Systemic Diseases

Pantone 647 CMJN Cyan 100 Magenta 56 Yellow 0 Black 24

Pantone PASTEL 9081 CMJN Cyan 0 Magenta 0 Yellow 6 Black 8

Edited by Wim A. Wuyts, Vincent Cottin, Paolo Spagnolo and Athol U. Wells

Pulmonary Manifestations of Systemic Diseases Edited by Wim A. Wuyts, Vincent Cottin, Paolo Spagnolo and Athol U. Wells Editor in Chief John R. Hurst

This book is one in a series of ERS Monographs. Each individual issue provides a comprehensive overview of one specific clinical area of respiratory health, communicating information about the most advanced techniques and systems required for its investigation. It provides factual and useful scientific detail, drawing on specific case studies and looking into the diagnosis and management of individual patients. Previously published titles in this series are listed at the back of this Monograph. ERS Monographs are available online at www.books.ersjournals.com and print copies are available from www.ersbookshop.com

Editorial Board: Mohammed AlAhmari (Dammam, Saudi Arabia), Sinthia Bosnic-Anticevich (Sydney, Australia), Sonye Danoff (Baltimore, MD, USA), Randeep Guleria (New Delhi, India), Bruce Kirenga (Kampala, Uganda), Silke Meiners (Munich, Germany) and Sheila Ramjug (Manchester, UK). Managing Editor: Rachel Gozzard European Respiratory Society, 442 Glossop Road, Sheffield, S10 2PX, UK Tel: 44 114 2672860 | E-mail: [email protected] Production and editing: Caroline Ashford-Bentley, Alyson Cann, Jonathan Hansen, Claire Marchant, Catherine Pumphrey, Kay Sharpe and Ben Watson Published by European Respiratory Society ©2019 December 2019 Print ISBN: 978-1-84984-111-5 Online ISBN: 978-1-84984-112-2 Print ISSN: 2312-508X Online ISSN: 2312-5098 Typesetting by Nova Techset Private Limited Printed by Page Bros Group Ltd, Norwich, UK All material is copyright to ­European Respiratory Society. It may not be reproduced in any way including electronic means ­without the express permission of the company. Statements in the volume reflect the views of the authors, and not necessarily those of the European Respiratory Society, editors or publishers.

ERS monograph

Contents Pulmonary Manifestations of Systemic Diseases

Number 86 December 2019

Preface

v

Guest Editors

vi

Introduction

ix

List of abbreviations

xiv

1. Multidisciplinary approach to systemic diseases: benefits for diagnosis 1 and management of complex disorders

Fabrizio Luppi, Paola Faverio and Wim A. Wuyts

2. Pulmonary function tests in multisystem disorders: prejudices and pitfalls

14

3. Quantitative CT analysis in ILD and the use of artificial intelligence on imaging of ILD Lucio Calandriello, Tahreema Matin, Helmut Prosch and Joseph Jacob

27



Claudia Valenzuela and Athol U. Wells

Connective tissue diseases 4. Rheumatoid arthritis John A. Mackintosh, Anna Stainer, Laurens J. De Sadeleer, Carmel Stock,

44

5. Inflammatory myopathies

68

6. Systemic sclerosis

90

7. Systemic lupus erythematosus, Sjögren syndrome and mixed connective tissue disease Katerina M. Antoniou, Eirini Vasarmidi, Athina Trachalaki, Eleni Bibaki

106

8. Antiphospholipid syndrome Shaney L. Barratt, John D. Pauling and Nazia Chaudhuri

124

9. Interstitial pneumonia with autoimmune features Alison M. DeDent and Aryeh Fischer

140









Wim A. Wuyts and Elisabetta A. Renzoni

Vincent Cottin, Thomas Barba, Sabine Mainbourg, Mouhamad Nasser, Claudia Valenzuela and Jean-Christophe Lega

Athol U. Wells

and Bruno Crestani

Systemic vasculitides 10. Microscopic polyangiitis and granulomatosis with polyangiitis Christian Pagnoux

153

11. Diffuse alveolar haemorrhage Martina Bonifazi, Stefan Stanel and George A. Margaritopoulos

173

12. Eosinophilic granulomatosis with polyangiitis Vincent Cottin, Kais Ahmad, Mouhamad Nasser, Claudia Valenzuela, Matthieu Groh,

188

13. Takayasu arteritis and Behçet disease

210





Benjamin Terrier and Julie Traclet

Veronica Alfieri and George A. Margaritopoulos

Other diseases with extrathoracic involvement 14. Airway and lung involvement in inflammatory bowel disease Philippe Camus and Thomas V. Colby

228

15. Liver disease: hepatopulmonary syndrome and portopulmonary hypertension

262

16. Neuromuscular diseases

278

17. Amyloidosis

296

18. Trafficking and lysosomal storage disorders

319

19. Haematological disorders and bone marrow transplant recipients

333

20. Histiocytic disorders

359

21. Immunodeficiency

374

22. Telomere syndrome

391

23. Sarcoidosis: pulmonary manifestations and management

404



Sebastiano Emanuele Torrisi, Valentin Fuhrmann, Dirk Skowasch and Michael Kreuter Elissavet Konstantelou, Eirini Pasparaki, Vasilios Tzilas, Eleni Bibaki, Yiorgos Meletis, Emmanouil Ferdoutsis, Argyris Tzouvelekis and Demosthenes Bouros Jean-Simon Rech, Pierre-Yves Brillet, Florence Jeny, Marianne Kambouchner, Hilario Nunes, Bertrand Arnulf, Dominique Valeyre and Yurdagül Uzunhan Paolo Spagnolo, Jelle R. Miedema, Jan H. von der Thüsen and Marlies S. Wijsenbeek Venerino Poletti, Sara Colella, Sara Piciucchi, Marco Chilosi, Alessandra Dubini, Sissel Kronborg-White, Sara Tomassetti and Claudia Ravaglia Davide Elia, Antonella Caminati, Roberto Cassandro and Sergio Harari Elisabeth Bendstrup and Martina Vasakova Raphael Borie, Caroline Kannengiesser and Bruno Crestani Jonas Yserbyt and Athol U. Wells

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Preface John R. Hurst

It is a pleasure to introduce this edition of the ERS Monograph, focusing on pulmonary manifestations of systemic diseases. As clinicians, we strive to care for patients by carefully evaluating the available evidence, with reference to guidelines, and by relying on our own past experiences. However, when managing people affected by rare lung diseases, this process breaks down in three main ways. First, many of us will simply not have had significant personal experience of such conditions. Secondly, guidelines may not exist and, thirdly, the available evidence may be much more limited in scope and quality. This situation is true for many of the conditions discussed in the current edition of the Monograph, and I therefore have no doubt that the content will be incredibly helpful in managing some of the most difficult conditions in pulmonology. Indeed, I believe this Monograph will be important and of interest to specialists in other fields too, who are often the primary clinician for such patients. As respiratory clinicians and scientists, we are used to working in multi-professional teams. There is perhaps nowhere that this is more necessary than in managing the pulmonary manifestations of systemic diseases. The society is indebted to the Guest Editors for doing an excellent job in curating the individual chapters. I would also like to pay tribute to the chapter authors and peer reviewers who together have delivered a relentless focus on quality. Welcome to a new go-to reference work on Pulmonary Manifestations of Systemic Diseases! Disclosures: John R. Hurst reports receiving grants, personal fees and non-financial support from pharmaceutical companies that make medicines to treat respiratory disease. This includes reimbursement for educational activities and advisory work, and support to attend meetings.

Copyright ©ERS 2019. Print ISBN: 978-1-84984-111-5. Online ISBN: 978-1-84984-112-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Guest Editors Wim A. Wuyts Wim A. Wuyts is Associated Professor at Katholieke Universiteit Leuven (Leuven, Belgium) and is Head of the Unit for Interstitial Lung Diseases in the Department of Respiratory Medicine at the University Hospitals Leuven (Leuven, Belgium) and the Laboratory of Respiratory Medicine KU Leuven. He obtained his medical degree and completed his postgraduate training in respiratory medicine at KU Leuven. He further specialised in the Department of Interstitial Lung Diseases at The Royal Brompton Hospital (London, UK), where he worked with the leading experts Professor Ron du Bois and Professor Athol U. Wells. He also further specialised in PAH in the department of Professor Marion Delcroix at the University Hospitals Leuven. From 2000 to 2004, Wim Wuyts was an investigator at the Research Foundation – Flanders (FWO; Brussels, Belgium). In 2004, he earned a PhD in medical sciences at the KU Leuven with a thesis entitled “Human airway smooth muscle cells, role in chronic inflammatory disorders of the lung”. He graduated in hospital management at the KU Leuven in 2004. He became a Senior Clinical Investigator at the FWO in 2011 and still holds this role. Wim Wuyts is the driving force behind the ILD programme at the Laboratory of Respiratory Medicine of the KU Leuven. His research interests include immunology and fibrosis in ILDs, clinical research in ILDs and clinical trials in pulmonary fibrosis. His work has appeared in peer-reviewed journals concerning ILDs, lung transplantation, PH and asthma. He is a member of various national and international task forces and scientific boards. In October 2014, he was elected as a member of the Executive Committee of WASOG (World Association of Sarcoidosis and Other Granulomatous Diseases) and he is member of the medical council of the University Hospitals Leuven. Copyright ©ERS 2019. Print ISBN: 978-1-84984-111-5. Online ISBN: 978-1-84984-112-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Vincent Cottin Vincent Cottin is Professor of Respiratory Medicine and Coordinator of the National Reference Centre for Rare Pulmonary Diseases at the Louis Pradel Hospital (Bron, France) and the Claude Bernard University Lyon (Lyon, France). The Centre has pioneered clinical care and research in patients with rare and so-called orphan lung diseases for many years, and set up the OrphaLung network (coordinated by Vincent Cottin) of 21 expert centres throughout France. The Centre was recently recognised as the institute of its kind in France to be part of the European Reference Network for ILD (ERN-LUNG, ILD). Vincent Cottin’s research interests include rare “orphan” pulmonary diseases including IIPs and especially IPF, as well as CTD-associated ILD. More specifically, he has contributed to characterising and individualising the syndrome of combined pulmonary fibrosis and emphysema, and of IPAF. He is an investigator and member of the steering committees and data safety monitoring boards of many clinical trials on IPF, and is conducting personal research on combined pulmonary fibrosis and emphysema. Vincent Cottin served as elected Head of the ERS Clinical Assembly from 2009 to 2012. He was Chief Editor of the European Respiratory Review from 2013 to 2015, and is currently Section Editor of the European Respiratory Journal and Associate Editor of European Respiratory Review and of Respiration. He recently edited a book on orphan lung diseases and is preparing a second edition. He is an appointed Fellow of the European Respiratory Society and has been awarded the European Respiratory Society Gold Medal of IPF. Paolo Spagnolo Paolo Spagnolo is Associate Professor of Respiratory Medicine and Director of the Residency Program in Respiratory Medicine at the University of Padua (Padua, Italy). He received his undergraduate training and his MD and completed his residency in respiratory medicine at the University Hospital of Bari (Bari, Italy). In 2002, he joined the Interstitial Lung Disease Unit of the Royal Brompton Hospital (London, UK), initially as clinical research fellow under the supervision of Professor Ron du Bois, and subsequently as Honorary Consultant. In 2008, he completed his PhD at Imperial College London (London, UK) under the supervision of Professor Ron du Bois and Professor Ken Welsh, with a thesis on “Genetic predisposition to clinical phenotypes of https://doi.org/10.1183/2312508X.10033319

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sarcoidosis”. Between 2008 and 2013, he was research fellow and subsequently Assistant Professor in Respiratory Medicine at the University Hospital of Modena (Modena, Italy), where he joined the Centre for Rare Lung Diseases lead by Professor Luca Richeldi. Since 2015, Paolo Spagnolo has been Associate Professor of Respiratory Medicine at the Department of Cardiac, Thoracic, Vascular Sciences and Public Health of the University Hospital of Padua. Paolo Spagnolo’s main research interests include ILD and sarcoidosis with emphasis on genetic predisposition, prediction of disease behaviour and clinical trials of novel therapies. Paolo Spagnolo is the author or co-author of over 100 journal articles, review articles and editorials. Paolo Spagnolo is a member of the editorial boards of BioMed Research International and BMJ Open Respiratory Medicine, and is a Section Editor (ILD) for Current Opinion in Pulmonary Medicine. He is the Treasurer of the WASOG (World Association of Sarcoidosis and Other Granulomatous diseases) and Secretary of the Study Group on Sarcoidosis of the European Respiratory Society. Athol U. Wells Athol U. Wells graduated at Otago University (Dunedin, New Zealand) in 1979, trained in New Zealand, and eventually moved to the UK permanently in 1999 and regrets not having done this 10 years earlier. He was given professorial status in 2005 and has focused on clinical research in ILD for the last 20 years (including diagnosis, prognostic evaluation and functional–morphological relationships). He has recently been honoured by a European Respiratory Society life-time award but does not see this as an indication that he should retire in the near future! He is very active in guideline groups and has nearly 500 peer-reviewed articles and editorials/review articles.

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Introduction Wim A. Wuyts

1

, Vincent Cottin

2

, Paolo Spagnolo3 and Athol U. Wells4

@ERSpublications Pulmonary manifestations of systemic diseases must be considered forensically and not managed by focus on a single organ. This book provides expert clinical guidance on difficult diseases, aiding respiratory and nonrespiratory physicians. http://bit.ly/36HBY4i

ILDs comprise ⩾200 separate lung disorders. The interest in these diseases has risen enormously in recent years. A large body of basic and clinical research has greatly increased our understanding of the pathogenesis of IPF and, to a lesser extent, non-IPF fibrotic ILDs. Validated and emerging antifibrotic treatments for IPF are likely to be efficacious in other pulmonary fibrotic disorders exhibiting IPF-like disease progression. The ILD field is now evolving rapidly, with major implications for practical management. However, it is important that the multiplicity of less prevalent ILDs, including those with predominantly inflammatory and mixed inflammatory/fibrotic phenotypes, are not lumped indiscriminately with inexorably progressive pulmonary fibrosis. Individual diseases must be appraised forensically. In this regard, pulmonary manifestations of systemic diseases cannot be adequately managed by focusing solely on ILDs but pose unique problems for physicians. Many systemic diseases are treated by non-respiratory specialists who do not always have expertise in assimilating pulmonary signs, symptoms and tests. Furthermore, many of these entities are extremely uncommon and this is often challenging for respiratory physicians. This Monograph, dedicated to the pulmonary manifestations of systemic disorders, provides background information and expert clinical guidance on these difficult diseases, which will be helpful to respiratory physicians and non-respiratory specialists alike. The initial chapter considers the diagnostic issues in these diseases [1]. As a first step, collaboration between different experts in medicine is a requisite in these diseases; this is a challenge, but for our patients the best is not enough. In order to establish the most confident diagnosis, collaboration is necessary as data originate from different experts in the field. The next step is to find a way to communicate these results and integrate them into the specific case for the individual patient. The best way is multidisciplinary discussion. This has been extensively tested over the years and has now become the 1 Respiratory Medicine, Unit for Interstitial Lung diseases, University Hospitals Leuven, Leuven, Belgium. 2Service de Pneumologie, Hopital L. Pradel, Lyon, France. 3University of Padova School of Medicine and Surgery, Padova, Italy. 4Interstitial Lung Disease, Royal Brompton Hospital, London, UK.

Correspondence: Wim A. Wuyts. Unit for Interstitial Lung Diseases, Dept of Respiratory Medicine, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected] Copyright ©ERS 2019. Print ISBN: 978-1-84984-111-5. Online ISBN: 978-1-84984-112-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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standard approach for evaluation of complex ILDs. We would argue that this manner of discussion should be transferred to other domains and that more non-pulmonary specialists should be added to teams. This exchange of expertise works both ways: on the one hand, it is beneficial as it raises awareness about the lungs amongst specialists in other fields, such as rheumatologists, general internists, nephrologists… On the other hand, we as pulmonologist could also learn from them in increasing our suspicion of the symptoms and signs of underlying CTD, but also by being more specific in the evaluation of only subtle biochemical abnormalities, without clinical counterpart. Another important topic covered in this Monograph is PFTs, the cornerstone of diagnosis and follow-up [2]. At first sight it might seem odd that this is covered in a book mainly intended for pulmonologists. But we are convinced that in modern literature, there are few manuscripts that bring together current knowledge and particularly the pitfalls in PFTs. We also hope that this book will be picked up by experts outside the field of pulmonary medicine so that they realise the value of PFTs, but also look for the necessary expertise within their team. The book goes on to discuss the contemporary techniques that are now in full development, such as quantitative CT analysis in ILD and the use of artificial intelligence on imaging of ILD [3]. This chapter provides a comprehensive overview of the possibilities now and in the future. In this Monograph, we have tried to cover a variety of interesting pulmonary manifestations of very different disease entities, such as CTDs, systemic vasculitis and others. The major CTDs covered are RA [4], inflammatory myopathies [5], SSc [6], Sjögren syndrome and mixed CTD [7], antiphospholipid syndrome [8] and finally, IPAF and undifferentiated CTD [9]. The chapters on systemic vasculitides comprise: microscopic polyangiitis and granulomatosis with polyangiitis [10], DAH [11], eosinophilic granulomatosis with polyangiitis [12], and pulmonary involvement in Takayasu arteritis and Behçet disease [13]. The chapters covering other diseases with extrathoracic involvement discuss bronchial and pulmonary involvement in inflammatory bowel diseases [14], the lung in liver disease [15], lung complications of neuromuscular diseases [16], amyloidosis and the lung [17], trafficking and lysosomal storage disorders (Hermansky–Pudlak, Gaucher, Niemann–Pick, Fabry, Lysinuric protein intolerance) [18], pulmonary involvement in haematological disorders and bone marrow transplant recipients [19], systemic histiocytic disorders (Langerhans and non-Langerhans cell histiocytosis, Erdheim–Chester and Rosai–Dorfman) [20], immunodeficiency [21], telomere syndrome and the lung [22], and finally, the pulmonary manifestations and management of sarcoidosis [23]. The Guest Editors very much hope that this Monograph will provide the reader with an interesting overview and update on the possible pulmonary involvement and specific treatment options of different systemic diseases. We sincerely hope that this book will be well received and will raise further interest in these diseases, leading to an increase in collaboration between different organ specialists and earlier diagnosis of patients confronted with very complex diseases that might turn their live upside down. We also hope that this book will serve as a catalyst to the development of more basic and clinical research in these intriguing diseases. x

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References 1.

2.

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6. 7.

8.

9.

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16.

17. 18.

19.

20.

Luppi F, Faverio P, Wuyts WA. Multidisciplinary approach to systemic diseases: benefits for diagnosis and management of complex disorders. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 1–13. Valenzuela C, Wells AU. Pulmonary function tests in multisystem disorders: prejudices and pitfalls. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 14–26. Calandriello L, Matin T, Prosch H, et al. Quantitative CT analysis in ILD and the use of artificial intelligence on imaging of ILD. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 27–43. Mackintosh JA, Stainer A, De Sadeleer LJ, et al. Rheumatoid arthritis. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 44–67. Cottin V, Barba T, Mainbourg S, et al. Inflammatory myopathies. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 68–89. Wells AU. Systemic sclerosis. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 90–105. Antoniou KM, Vasarmidi E, Trachalaki A, et al. Systemic lupus erythematosus, Sjögren syndrome and mixed connective tissue disease. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 106–123. Barratt SL, Pauling JD, Chaudhuri N. Antiphospholipid syndrome. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 124–139. DeDent AM, Fischer A. Interstitial pneumonia with autoimmune features. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 140–152. Pagnoux C. Microscopic polyangiitis and granulomatosis with polyangiitis. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 153–172. Bonifazi M, Stanel S, Margaritopoulos GA. Diffuse alveolar haemorrhage. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 173–187. Cottin V, Ahmad K, Nasser M, et al. Eosinophilic ganulomatosis with polyangiitis. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 188–209. Alfieri V, Margaritopoulos GA. Takayasu arteritis and Behçet disease. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 210–227. Camus P, Colby TV. Airway and lung involvement in inflammatory bowel disease. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 228–261. Torrisi SE, Fuhrmann V, Skowasch D, et al. Liver disease: hepatopulmonary syndrome and portopulmonary hypertension. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 262–277. Konstantelou E, Pasparaki E, Tzilas V, et al. Neuromuscular diseases. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 278–295. Rech J-S, Brillet P-Y, Jeny F, et al. Amyloidosis. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 296–318. Spagnolo P, Miedema JR, von der Thüsen JH, et al. Trafficking and lysosomal storage disorders. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 319–332. Poletti V, Colella S, Piciucchi S, et al. Haematological disorders and bone marrow transplant recipients. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 333–358. Elia D, Caminati A, Cassandro R, et al. Histiocytic disorders. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 359–373.

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21. Bendstrup E, Vasakova M. Immunodeficiency. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 374–390. 22. Borie R, Kannengiesser C, Crestani B. Telomere syndrome. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 391–403. 23. Yserbyt J, Wells AU. Sarcoidosis: pulmonary manifestations and management. In: Wuyts WA, Cottin V, Spagnolo P, et al. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 404–418.

Disclosures: W.A. Wuyts reports receiving the following outside the submitted work: grants from Roche and Boehringer Ingelheim paid to his institution. P. Spagnolo reports receiving the following outside the submitted work: personal fees and non-financial support from Roche Boehringer Ingelheim, Zambon, Galapagos, Chiesi and Red-X Pharma; and grants, personal fees and non-financial support from PPM Services. P. Spagnolo’s wife is employed by Novartis. A.U. Wells reports receiving the following, outside the submitted work: consultancy and speaking fees from Roche and Boehringer Ingelheim; and consultancy fees from Bayer and Blade.

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List of abbreviations BAL CT CTD DAD DAH DLCO FEV1 FVC HLA HRCT Ig IIP IL ILD IPAF IPF IPS LIP MALT NSIP OP PAH PFT PH RA SLE SSc UIP

bronchoalveolar lavage computed tomography connective tissue disease diffuse alveolar damage diffuse alveolar haemorrhage diffusing capacity of the lung for carbon monoxide forced expiratory volume in 1 s forced vital capacity human leukocyte antigen high-resolution computed tomography immunoglobulin idiopathic interstitial pneumonia interleukin interstitial lung disease interstitial pneumonia with autoimmune features idiopathic pulmonary fibrosis idiopathic pneumonia syndrome lymphocytic interstitial pneumonia mucosa-associated lymphoid tissue nonspecific interstitial pneumonia organising pneumonia pulmonary arterial hypertension pulmonary function test pulmonary hypertension rheumatoid arthritis systemic lupus erythematosus systemic sclerosis usual interstitial pneumonia

| Chapter 1 Multidisciplinary approach to systemic diseases: benefits for diagnosis and management of complex disorders Fabrizio Luppi

1

, Paola Faverio1 and Wim A. Wuyts

2

Several components of the respiratory system may be involved in multisystem diseases, such as the airways, vessels, parenchyma, pleura and respiratory muscles; in addition to the lungs, many other organs may also be involved. ILD, frequently detected in multisystem diseases, has a significant impact on morbidity and mortality in this heterogeneous group of diseases. In particular, many CTDs involve the lungs either directly or as a treatment complication. Pulmonary involvement, and particularly ILD, may be detected at any point in the natural history of a systemic disease. Therefore, a multidisciplinary approach is crucial in the diagnostic work-up, diagnostic/therapeutic decision making and during follow-up, enabling the input of different experts. This has become the current diagnostic reference standard for ILD and is reported to improve diagnostic confidence and agreement compared with the decisions of individual participants of the multidisciplinary discussion. However, many questions regarding the composition and governance of the multidisciplinary team remain unanswered, requiring further studies to better define the power of this tool with the aim of earlier and better-defined diagnosis, management and follow-up. Cite as: Luppi F, Faverio P, Wuyts WA. Multidisciplinary approach to systemic diseases: benefits for diagnosis and management of complex disorders. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 1–13 [https://doi.org/10.1183/2312508X.10013719].

@ERSpublications A multidisciplinary approach is crucial in the diagnostic process, therapeutic decision making and follow-up in the suspicion of CTD-related ILD http://bit.ly/2lDj2R7

T

here are more than 200 different disorders included under the name of ILDs. These diseases can be separated into those with an underlying disorder, such as CTDs, or known exposure (hypersensitivity pneumonitis, asbestosis, silicosis and many others) and 1

School of Medicine and Surgery, Respiratory Unit, University of Milano Bicocca, San Gerardo Hospital, ASST Monza, Monza, Italy. Unit for Interstitial Lung Diseases, Dept of Respiratory Medicine, University Hospitals Leuven, Leuven, Belgium.

2

Correspondence: Wim A. Wuyts, Unit for Interstitial Lung Diseases, Dept of Respiratory Medicine, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected] Copyright ©ERS 2019. Print ISBN: 978-1-84984-111-5. Online ISBN: 978-1-84984-112-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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the idiopathic pneumonias [1]. In the absence of exposure or an underlying cause, the disease belongs to the group of IIPs. In this group, IPF is the most frequent and most aggressive form of IIP. These disorders can have similar signs, symptoms and radiological presentation, making it a challenge to come to a confident diagnosis and appropriate treatment approach. Diagnosis includes a full work-up to exclude prior exposures or an underlying disease. In this process, the input of different specialists is necessary at different stages of the care of the patient. The first stage is the diagnostic work-up in which the input of various experts is necessary. Various studies have shown that multidisciplinary discussion (MDD) is associated with higher levels of diagnostic confidence and better interobserver agreement when compared with any single component of the multidisciplinary team alone [2–4]. Although it has become the leading methodology to ensure quality and consistency in the diagnostic process and is recommended as the “gold standard”, many questions remain regarding how to perform MDD [4, 5]. In many centres, MDD is critical for treatment decisions, and careful follow-up requires the involvement of different experts, each bringing the necessary expertise. In this regard, further research on MDD should focus on the long-term behaviour of the diagnosis. It is clear that the multidisciplinary approach is an essential part of the process not only in idiopathic but also in complex systemic disorders associated with ILD.

Complexity of the diagnostic work-up in multisystem diseases The lungs are often involved in multisystem disorders. Several components of the respiratory system may be involved, such as the airways, vessels, parenchyma, pleura and respiratory muscles. Many CTDs involve the lungs either directly or as a treatment complication [6]. Interstitial lung involvement is common within the spectrum of CTDs, particularly in SSc, RA and inflammatory idiopathic myopathies, including dermatomyositis, polymyositis and myositis associated with antisynthetase antibodies [7]. The time of onset and severity of pulmonary manifestations may vary widely, from the first sign of the disease to subclinical entities [6, 8]. When diagnosed by either a restrictive pattern on PFTs or characteristic findings on an HRCT scan, ILD is present in 25–40% of patients on average [9, 10]. However, this is likely to be an underestimate of the true prevalence of pulmonary involvement as, at autopsy, ILD is present in up to 70% of cases. Although CTD-related ILD (CTD-ILD) is in general associated with a more favourable prognosis than IIP of equivalent severity [11, 12], the presence of ILD increases morbidity and mortality among CTD patients compared with those without lung involvement [13, 14]. Nevertheless, there are some exceptions in which CTDs might not confer a better outcome, such as in patients affected by RA and presenting with a UIP pattern [15, 16]. In this condition, the outcome is no better than with the idiopathic form with a UIP pattern, called IPF. ILD may be detected at any point in the natural history of a CTD [17]. This complexity explains the importance of a multidisciplinary approach in the work-up, as illustrated in the following scenarios: 1) ILD develops in the context of an already diagnosed CTD with characteristic manifestations. However, the finding of ILD in patients with established CTD does not 2

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mean that pulmonary and extrapulmonary involvement are necessarily related. We believe that, in this context, a multidisciplinary approach is needed to explore whether the lung disease is due to other ILDs, specifically those with an environmental cause. Furthermore, because immunosuppressive treatment is widely utilised in patients with CTDs, the detection of new pulmonary infiltrates in these patients should also include in the differential diagnosis the occurrence of respiratory infections, including a wide range of pathogens, together with drug-induced toxicity, because various immunomodulatory agents are associated with pneumonitis. Therefore, the occurrence of ILD, even in the context of existing CTD, needs to trigger a comprehensive evaluation to explore all potential aetiologies, such as infection, drug toxicity, environmental and occupational exposures, familial disease, smoking-related lung disease and malignancy (figure 1). To understand whether the ILD is truly associated with the underlying CTD requires a rule-out approach: these evaluations are often enhanced by a multidisciplinary approach, involving various specialists. 2) When ILD is the first presenting manifestation of a CTD, the features of which may not yet have been identified, the ILD may initially be diagnosed as an IIP, and CTD diagnosis may be challenging, mainly because systemic symptoms can be subtle. There is no standardised approach to the assessment for underlying CTD in patients initially diagnosed as affected by IIPs. However, in clinical practice, a detailed history and physical examination are required, together with testing for circulating autoantibodies. Clinical features that need to be investigated and autoantibody panels are summarised in table 1. In this context, when clinical examinations and laboratory testing indicate suspicion of an underlying CTD, a multidisciplinary approach is of paramount importance. Thus, it is clear that ILD might be the first sign of a yet-to-be-determined CTD, so specialist follow-up is crucial. 3) Patients with interstitial pneumonia can present with some aspects of CTD but not enough to justify a full CTD diagnosis according to internationally accepted criteria. These patients, in whom it seems that the lung is the only or most clinically important manifestation of an occult CTD, are suspected of having a systemic autoimmune disease, which might be identified by the presence of circulating autoantibodies, specific

ILD in CTD

Are there any of the following conditions?

Infection

Drug toxicity

Environmental exposure

Malignancy

Occupational exposure

Smoking-related lung disease

Familial disease

No Was the diagnosis of IIP ruled out? Yes ILD secondary to CTD

Figure 1. Diagnostic flow chart for CTD-related ILD.

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Table 1. Clinical features to be investigated and autoantibody panel to be performed in the diagnostic work-up of CTD-related ILD Familial history

Symptoms

Signs

Antibody

History of autoimmune disease

Joint pain Morning stiffness Dysphagia Sicca syndrome Myalgi Oesophageal reflux Raynaud phenomenon Generalised weakness

Sclerodactyly Raynaud phenomenon Telangiectasias Digital ulcers Gottron papules Mechanics’ hands Joint swelling

Rheumatoid factor Anti-citrullinated protein antibody Antinuclear antibody Extractable nuclear antigen antibody Antineutrophil cytoplasmic antibody Antisynthetase antibody

histopathological features on surgical lung biopsy samples or subtle extrathoracic manifestations. These patients are classified as having IPAF rather than an idiopathic disease. IPAF, however, is currently a research tool rather than an established diagnosis [18]. In this specific setting, MDD may confirm the absence of criteria to define a specific CTD and decide on specific treatment and follow-up. The most sensitive tool to identify an ILD is HRCT, although its high sensitivity is combined with a low specificity. In fact, many patients with CTD show subclinical ILD defined by the presence of interstitial lung abnormalities on HRCT in asymptomatic individuals and/or without lung function abnormalities [19]. Currently, it is almost impossible to predict who will be likely to progress and who will not. Interstitial changes have been reported, for instance in more than one-third of patients with primary Sjögren syndrome [20] or SLE [21], although the prevalence of clinically significant ILD is generally considered to be + > ±) of the relative prevalence of functionally significant pulmonary disease processes in the five CTDs most commonly complicated by pulmonary disease. IM: inflammatory myopathy; SS: Sjögren syndrome. Reproduced and modified from [2] with permission.

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The advantage of this approach is that PFT trends within the normal range can be interpreted with confidence, as, for example, in cases in which individual variables start above 110% and fall to 80–90%, a decline of 25% from baseline. Using exactly the same logic, it can also be argued that baseline PFT should always be performed before the introduction of any therapy associated with drug-induced lung disease, a frequent problem in RA. With knowledge of pre-treatment PFTs, reductions in PFT variables potentially ascribable to drug-induced lung disease can be quantified. Optimal use of PFTs in the identification of pulmonary disease processes

Despite the pitfalls discussed, we favour a screening approach, with PFTs performed in all patients with SSc, polymyositis/dermatomyositis or RA, and in those patients embarking upon treatments associated with iatrogenic lung disease. In other multisystem disorders with a lower prevalence of lung involvement, it appears reasonable to reserve PFTs for patients with symptoms and/or abnormalities on chest radiography. However, based on the limitations of PFTs, the following recommendations may be helpful in multisystem diseases. First, it is suggested that PFTs are routinely performed at the time of diagnosis of CTD. Secondly, when PFT abnormalities are identified, it is essential that they be understood, based on the pattern of PFT impairment, ancillary tests (CT, echocardiography, respiratory muscle function in selected patients) and, when necessary, multidisciplinary discussion. In this way, pulmonary disease processes should be classified according to the lung compartment(s) involved. Finally, in patients with unexplained respiratory symptoms, normal PFTs do not reliably exclude clinically significant ILD, due to the confounding effect of the normal PFT range. Thoracic CT is indicated in this scenario.

Staging severity and prognostic evaluation Prejudice

A common misconception when judging staging severity and evaluating prognosis is that ILD severity is best captured by percentage predicted FVC levels. Pitfalls

Two pitfalls related to this prejudice should be noted: 1) the use of FVC to quantify ILD severity is profoundly influenced by the normal range (more so than DLCO levels); and 2) FVC levels are also altered by airway disease and extrapulmonary restriction, both in isolation and when these processes and ILD occur concurrently. General considerations

Quantifying the severity of pulmonary disease is important in order to designate clinical significance, establish a baseline for subsequent monitoring and, crucially, to facilitate prognostic evaluation. PFTs are central to this process but must be integrated with other tests, depending upon the compartment involved (e.g. ILD versus pulmonary vascular disease) and the existence of multicompartment disease. The need to integrate PFTs with other data in multisystem disorders can best be illustrated by considering the problem of quantifying ILD severity in patients with CTD-ILD with particular regard to prognostic 18

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evaluation. Accurate prognostic evaluation requires both the identification of disease processes that are intrinsically more progressive and the accurate definition of severity. In CTD-ILD, PFTs do not discriminate between the patterns of parenchymal involvement within individual disorders. Importantly, a pattern of UIP, a malignant prognostic determinant in RA, is the most frequent histological and CT pattern only in that disease (unlike other CTD-ILDs). Overlapping patterns consistent with both UIP and NSIP, or a combination of NSIP and OP, are not unusual and are frequent in RA and inflammatory myopathy, respectively. Sjögren syndrome can be viewed as a “special case”, with LIP with cystic lung disease and NSIP both frequent manifestations in patients with ILD [12, 13]. In this regard, CT provides information on the likely natural history and treated course, which is not disclosed by PFTs. Other ancillary CT findings indicative of a worse prognosis in CTD-ILD include severe traction bronchiectasis in fibrotic CTD-ILD [14], extensive fibrosis on CT in RA-ILD [15, 16] and major architectural distortion on CT in RA-ILD [17]. In SSc-ILD, CT abnormalities are often categorised as limited (20%), with a major increase in mortality associated with extensive disease [18]. In RA-ILD, in a recent large series, the extent of disease on CT, defined as limited or extensive (as in the SSc-ILD study previously cited), was a more powerful prognostic determinant than the presence of a UIP pattern [19]. In principle, it might be supposed that CT findings, capturing both the extent and the morphological pattern of ILD, should trump PFTs in the prognostic evaluation of CTD-ILDs and other multisystem disorders. However, this is emphatically not the case. The scoring of disease extent on CT requires considerable expertise and is not amenable to routine clinical practice, whereas PFTs provide immediate data on disease severity. Thus, PFTs are the correct starting point in prognostic evaluation, which can then be nuanced according to CT findings. Quantifying severity in ILD

In most ILDs, disease severity can be evaluated using characteristic PFT profiles. PFTs reflect the severity of ILD better than symptoms in patients with CTD-ILD. The disease is accompanied in most cases by systemic manifestations that influence the interpretation of respiratory symptoms. Musculoskeletal limitations represent a major confounding factor, and they contribute to the severity of dyspnoea and influence exercise tolerance. Most patients have reduced physical activity with a consequent loss of fitness [11]. For this reason, PFTs have primacy in the definition of the severity of pulmonary disease in multisystem disorders in general, and in CTD-ILD in particular. However, selecting the particular PFT variable to quantify ILD severity poses difficulties, both in isolated disease and when there are concurrent disease processes in multisystem disease. In recent years, especially in IPF, there has been a focus on FVC levels by regulatory bodies, in order to identify patient subgroups in which antifibrotic therapy is indicated. This has led to the widespread misconception that ILD severity is best quantified using FVC. However, there are many data that show clearly that FVC levels are a relatively poor measure of severity when compared with DLCO levels in ILD. In a number of analyses, DLCO levels have correlated much more strongly with disease extent on CT than FVC levels, in both IPF and SSc-ILD (despite possible confounding by vascular disease in SSc) [20]. Similarly, DLCO levels have predicted mortality more accurately than FVC in many series of https://doi.org/10.1183/2312508X.10031219

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patients with CTD-ILD, including SSc-ILD [18] and RA-ILD [15]. Thus, FVC levels are highly flawed in the evaluation of ILD severity, including prognostic evaluation. There are two reasons for the primacy of DLCO in prognostic evaluation. First, DLCO is a composite measure, calculated from measured alveolar volume (VA) (rather than FVC) and measured gas transfer coefficient (KCO, a measurement of carbon monoxide uptake per unit VA). In ILD, fibrotic ablation and/or inflammatory cell infiltration results in both a reduction in lung volume and a reduction in blood volume in ventilated lung. In evaluating severity, a PFT variable that is linked to only one of these processes must necessarily be inferior to a variable that captures both. Secondly, there is a more prosaic consideration that is often overlooked: the problem of signal to noise ratio, shown in table 2. In most ILD cohorts, average FVC levels approximate 70% of predicted normal, an average reduction of 30% (from the middle of the normal range). The normal FVC range of 80–120% means that, in individual patients, the loss of FVC from pre-morbid values, when the FVC is 70% of predicted, varies from 10% to 50%, a 5-fold variation. By contrast, taking on board the average DLCO value of approximately 50% in most ILD cohorts, there is an average disease signal of 50%, with DLCO loss varying from 30% to 70% (examined against the normal range): a 2.3-fold variation. Thus, on average, DLCO provides greater disease signal and a major reduction in the confounding effect of the normal range, compared to FVC levels. Quantifying severity of lung diseases in multisystem disorders

The discussion regarding ILD severity applies equally to idiopathic ILD and ILD in multisystem disease. However, the interpretation of PFTs in multisystem disease is often confounded by the presence of multicompartment disease. This problem can be overcome by an understanding of the characteristic PFT profiles associated with pulmonary disease processes other than ILD. Typical PFT profiles associated with disease in individual lung compartments are shown in table 3. Pulmonary vascular disease in both CTD-ILD and idiopathic vasculopathy is associated with a reduced DLCO, quantified as a reduction in KCO (synonymous with DLCO/VA). Importantly, major reductions in DLCO and KCO levels due to pulmonary vasculopathy may occur in the absence of PH, due to the large pulmonary vascular reserve. PH should be

Table 2. Signal to noise ratios when using FVC and DLCO levels as measures of ILD severity

Average % predicted value in clinical series Signal: average reduction due to disease Noise: range in reduction from the pre-morbid normal range# Signal to noise ratio

FVC

DLCO

70% 30% 10–50% (5-fold variation) 30%: 5-fold variation

50% 50% 30–70% (2.3-fold variation) 50%: 2.3-fold variation

The signal to noise ratios when FVC and DLCO levels are considered as measures of the severity of ILD show that DLCO has major advantages in quantifying disease severity due to a much higher signal to noise ratio. #: pre-morbid normal range is 80–120%.

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Table 3. Typical pulmonary function profiles in relation to disease processes within individual lung compartments

ILD

Pulmonary vascular disease Bronchiectasis Extrapulmonary restriction

Ventilatory impairment

DLCO and KCO

Arterial gases at rest

Restrictive defect

DLCO reduced, usually more reduced than lung volumes; KCO levels normal or mildly reduced DLCO reduced; DLCO and KCO severely reduced in PH DLCO highly variable

Resting hypoxia in end-stage disease

No impairment Obstructive or mixed defect Restrictive defect; reduction in peak flow in severe muscle weakness

DLCO levels low normal or mildly reduced; KCO levels supra-normal

Resting hypoxia in PH but not in less severe vasculopathy Resting hypoxia in end-stage disease In severe disease: hypercapnic respiratory failure, normal alveolar– arterial oxygen gradient

KCO: transfer coefficient of the lung for carbon monoxide. Reproduced and modified from [2] with permission.

suspected when severe resting hypoxia or major exertional oxygen desaturation is associated with a disproportionate reduction in gas transfer (severe hypoxia due to ILD complicates CTD-ILD only when disease is very advanced, unlike IPF) [21]. KCO levels have a significant advantage over the FVC/DLCO ratio as a measure of disproportionate reduction in DLCO, due to much lower measurement variability. As DLCO is calculated as a composite of measured KCO and measured VA, the FVC/DLCO ratio contains the measurement variation of KCO, VA and FVC. By contrast, KCO quantification is associated with the measurement variation of a single variable. It is revealing that, in a large SSc-ILD cohort, a 10% serial reduction in KCO was associated with increased mortality whereas a 20% rise in the FVC/DLCO ratio was required to achieve the same prognostic discrimination [22]. The emphasis on the FVC/DLCO ratio in recent decades [23, 24] is likely to reflect the fact that, in many PFT laboratories, KCO and VA values are not provided to clinicians, even though both must be measured in order to compute DLCO levels. In extrapulmonary disease, there is a restrictive ventilatory defect [25], with DLCO levels preserved or slightly reduced (due to ventilation–perfusion mismatch) and KCO levels typically rising to supra-normal values [26], as the total pulmonary blood volume changes little, even with major reductions in lung volumes. PFT impairment in respiratory muscle weakness differs little from that in other extrapulmonary restrictive processes. However, severe muscle weakness tends to be associated with disproportionate effects on the effort-dependent early part of the expiratory flow–volume curve (i.e. peak flow) [27]. Major reductions in lung volumes due to muscle disease are generally indicative of severe weakness: a reduction in muscle strength of at least 50% is required before lung volumes are reduced [28]. In severe extrapulmonary restriction, an alveolar hypoventilation profile is typically present, consisting of hypoxia, hypercapnia and a normal calculated alveolar– arterial oxygen gradient. This presentation is seen most often in respiratory muscle weakness [29]. https://doi.org/10.1183/2312508X.10031219

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In airway disease, a characteristic obstructive ventilatory defect is present. In emphysema, there is a concurrent reduction in measures of gas transfer, but in intrinsic airway disease, including asthma, isolated bronchiectasis and obliterative bronchiolitis, measures of gas transfer tend to be preserved unless disease is advanced (i.e. FEV1 1.6 in SSc, and a severe reduction in KCO (to 5% was not demonstrated, yet the patient demonstrated clinical deterioration. While there is a subtle alteration in the character of the fibrotic regions, it did not equate to a measurable difference in total ILD extent for the whole lung.

Some staging systems incorporating visual CT scores with physiological parameters have been validated in ILD, but due to limitations in observer agreement and low sensitivity are not routinely used in clinical practice or as drug trial end-points [13, 14]. Moreover, visual CT evaluation is not sensitive enough to capture short-term clinically useful changes [6, 11, 15, 16]. As antifibrotic therapies improve, more-sensitive biomarkers of disease progression will be required to capture their added therapeutic effect. There is also growing evidence that CT images may contain prognostic information that is not visually detectable but is amenable to computer-based quantification [17, 18]. These limitations provide the rationale for computer-based CT analysis. This chapter will initially outline the CT acquisition techniques that can enable optimal performance of computer analysis tools. We then mimic a clinical workflow by first describing computer analysis use in ILD diagnosis (where deep-learning methods have been the mainstay) before describing in turn the various quantitative tools that have been employed for measuring disease severity/extent in individual FLDs. We conclude by summarising the future of computer analysis in FLDs and outline the challenges that await on the journey towards regulatory agency approval.

CT acquisition technique A standardised CT acquisition protocol is essential to improve the reproducibility of computer-based image analysis. Volumetric acquisitions with contiguous or overlapped thin-section reconstruction are mandatory, with a suggested slice thickness of ∼1 mm [19]. The radiation dose ranges used to acquire ILD CT images vary widely and should be standardised [20]. At present, most CT images acquired clinically, and therefore analysed by computer tools, have utilised a dose of >1 mSv, as recommended by consensus guidelines. https://doi.org/10.1183/2312508X.10013919

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The study of the effect of iterative reconstruction techniques on computer-based textural analysis is still in its infancy, and is increasing in importance as CT images are increasingly acquired with dose-reduction techniques [19]. Indeed, studies comparing the effects of computer analysis on CT images acquired using normal, low and chest radiographyequivalent radiation doses are keenly awaited to understand the dose range at which computer analysis will be constrained. For image reconstruction, selection of a neutral kernel is optimal to avoid edge enhancement or image smoothing, and most CT manufacturers provide bespoke neutral kernels [21]. A sharper kernel can be analysed quantitatively if pre-processing image normalisation methods are used [22]. The depth of inspiration achieved during a scan is a major source of patient-related variation in lung attenuation measurements. Two possible approaches can be used to mitigate against inspiratory volume variability: respiratory gating to determine when the patient is at total lung capacity, or coaching of the patient to comply with standardised breathing instructions [21]. In order to minimise differences between different scanners, as in the case of trials where multiple centres using different scanners are involved, calibration of the scanner with test objects ( phantoms) is suggested before and during data collection [20].

Artificial intelligence Artificial intelligence (AI) is a general definition that encompasses several computer techniques meant to perform tasks usually performed by humans. The subfield of AI most commonly used in medicine is machine learning (ML) in which algorithms produce outputs based on patterns and features learned from input data [23, 24]. Deep learning is a type of ML whose characteristic is its capability to automatically identify the most predictive features in a dataset and generate models for tasks from the raw data without the need for human programming [25]. Deep learning can rely on several algorithms, but those most commonly employed in medical imaging are convolutional neural networks (CNNs). The computer architecture at the base of a CNN is inspired by the human nervous system with clusters of artificial interconnected nodes replicating the interconnections of human brain neurons [23]. The clusters of nodes in a CNN are usually organised in multiple layers: a layer that takes the input, numerous hidden layers that process the data and a layer that generates the output. Increasing the number of hidden layers allows the algorithm to deal with ever more complex tasks. When input data (i.e. images) are converted into digital data, a CNN can identify and extract imaging features that can be used to classify the data. A major advantage is the ability of a CNN to extract features that cannot be detected by the human eye [23]. In the setting of ILD, ML has already been used in several areas. These include: detecting the presence of ILD in patients with SSc following analysis of PFTs [26], diagnosing IPF or a UIP pattern through genomic analysis [27, 28], quantifying lung fibrosis on CT images [29] and providing automated classification of fibrotic ILD patterns on CT images [30]. AI and ILD diagnosis

There are several reasons for implementing AI in the study of ILDs. Visual radiological evaluation can be subject to low interobserver agreement when classifying HRCT signs of disease extent or severity. AI systems may also mitigate the potentially harmful consequences of human error in radiological reporting [31]. 30

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One of the first attempts to use neural networks in assessing radiological images of ILD dates back to 1990 when an artificial neural network was used to generate a differential diagnosis for ILD subtypes on chest radiographs [32]. In this study, the neural network was designed to distinguish among nine ILDs on the basis of radiographic and clinical data. The results showed a diagnostic performance comparable to that of accredited radiologists and superior to that of radiology residents. In more recent years, ML techniques have been applied to CT images of ILD patients to recognise and classify CT patterns, to classify FLD according to diagnostic guidelines and to quantify lung fibrosis. The first paper where a CNN was used for the classification of ILD patterns on CT was published in 2016. In this study, the CNN showed an accuracy of 85% for classifying six different patterns of disease (ground-glass opacity, reticulation, consolidation, micronodules, honeycombing, and a combination of ground-glass opacity and reticulation), plus healthy tissue, leading to seven different imaging classes. These results were obtained using a dataset of 14 696 image patches to train and test the software. The data was derived from 120 HRCT images where two radiologists had manually drawn regions of interest (ROIs) around every single pattern [33]. A study by KIM et al. [34] obtained an even higher accuracy for a CNN in classifying ROIs of HRCT images in ILD patients. In this study, an accuracy of up to 96% was achieved with a reduction in classification error between similar patterns (i.e. normal case versus emphysema, and reticular opacity versus honeycombing) as the number of layers in the CNN increased. Moreover, in this study, the CNN was compared with a more conventional classifier based on a support vector machine, achieving an increase in accuracy of 6–9%. This is believed to result from the CNN being able to automatically extract features from the data instead of using pre-defined engineered features. In both studies, however, the need for manual identification of ROIs prior to classification limited the clinical applicability of the methods in real-world clinical practice. To overcome this limitation and to obtain a more comprehensive evaluation of CT images of ILD patients, GAO et al. [35] proposed an “holistic” approach using a CNN for the classification of CT slices instead of ROIs. For comparison with previous studies, the same CNN was also used for a ROI-based classification. The accuracy of the CNN for the identification of six tissue classes (normal, emphysema, ground-glass opacity, fibrosis, micronodules and consolidation) was higher for the patch-based approach (87.9%) compared with holistic image classification (68.6%). Only one study has been published to date employing a deep-learning algorithm to provide an automatic classification of FLD on CT [30], according to international guidelines [36]. In this study, the algorithm was trained, validated and tested using a database of 1157 CT images acquired in two institutions [30]. The algorithm showed an accuracy of 76.4% for the classification of CT images into three categories provided by the 2011 consensus IPF diagnostic guidelines: UIP pattern, possible UIP pattern and inconsistent with UIP [36]. One of the main limitations of this approach was the requirement for labelling every CT image used for algorithm training by a single radiologist whose interpretation bias would have potentially affected algorithm performance. To overcome this limitation, the software was further tested with a different population of 150 CT images where the reference standard was a consensus opinion of 91 expert thoracic radiologists. Here, the software showed an accuracy of 73.3%, outperforming 60 of the 91 thoracic radiologists. Moreover, the interobserver agreement between the algorithm and the radiologists’ majority opinion (κw=0.69) was comparable to the median interobserver agreement between each thoracic radiologist and the radiologists’ majority opinion (κw=0.67). https://doi.org/10.1183/2312508X.10013919

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Quantitative CT Quantitative CT (QCT) describes the numerous computer-based CT image analysis methods developed to measure structural lung damage in ILD. QCT methods offer improved objectivity, speed, reproducibility and the ability to scale up analysis to hundreds or thousands of CT images. QCT-derived metrics demonstrate potential as prognostic imaging biomarkers with reported utility in evaluating: 1) disease severity at a single time point on a CT, and 2) disease progression, quantifying longitudinal change on sequential CT images. Novel QCT imaging biomarkers are emerging through ML or deep-learning techniques that are not appreciated by the human eye. New biomarkers represent features that have no morphological correlate or radiological descriptor. Quantification of overall lung histogram features, regional CT density changes, parenchymal textural features and other ancillary assessments by advanced algorithms have the potential to standardise and enhance the role of CT in ILD evaluation. Quantitative CT for assessing ILD severity

Most QCT methods employ density and/or texture-based analysis of varying complexity. All methods require initial segmentation of the whole lungs from surrounding chest wall structures, which should ideally be an automated process requiring minimal manual correction. Density mask techniques and evaluation of the lung-density histogram were among the first QCT methods developed to assess ILD severity [37]. Quantification of emphysema using a low-density Hounsfield unit (HU) threshold is well recognised. Similarly, high-density thresholds have been used to detect soft-tissue density in the lung, replacing air density as a result of pulmonary fibrosis [38]. For normal lung, the CT density histogram peaks at approximately −800 HU and is left skewed. The presence of fibrosis results in an increased mean lung density and decreases in the lung histogram kurtosis ( peakedness) and skewness (asymmetry) [39]. However, correlations between such density histogram metrics and survival in patients with ILD have generally been poor [40–43]. This reflects the challenge of capturing detailed regional information using a summary global density measure, often confounded by low-density structures, such as traction bronchiectasis and honeycombing, as well as air trapping in hypersensitivity pneumonitis. Newer QCT methods apply texture-based analysis to characterise, model and process imaging features at a voxel level (table 1). These methods incorporate both morphological and density features. By simulating human visual perceptual and learning processes, texture-based algorithms attempt to determine the type of abnormality (e.g. emphysema versus honeycombing versus cysts), severity (fine versus course reticulation) and disease extent [29, 37, 40, 44–46]. These complex QCT methods overlay the QCT readout onto CT images, allowing regional ILD changes to be visualised by clinicians and patients [40]. Examples of QCT tools Density histogram analysis Various CT density thresholds have been proposed for the assessment of ILD extent, including >−700 HU [47] and a range between −750 HU and −300 HU for the specific 32

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Table 1. Quantitative computer tools that evaluate lung damage on CT imaging Quantitative computer tool

CT pattern identification

CALIPER

Measures low-attenuation areas, ground-glass opacities, reticulation, honeycombing, normal lung and vessel-related structures; features identified in 15×15×15 voxel volume units on volumetric noncontrast-enhanced CT images Measures low-attenuation areas, ground-glass opacities, reticular opacity, honeycombing, normal lung, emphysema and consolidation on noncontiguous, noncontrast-enhanced CT images Measures ground-glass opacities, ground-glass reticulation, honeycombing, normal lung and emphysema on volumetric noncontrast-enhanced CT images Measures lung fibrosis (reticulation) or ILD (sum of ground-glass opacities, reticulation and honeycombing); evaluates noncontiguous, noncontrast-enhanced CT images Discriminates tissue as either fibrotic or normal: fibrotic tissue includes reticulation, traction bronchiectasis and honeycombing; evaluates noncontiguous, noncontrast-enhanced CT images Measures lung, lobar, vessel and airway volumes and fibrotic and emphysematous volumes; evaluates volumetric, noncontrast- and contrast-enhanced CT images

AQS AMFM QLF DTA FRI

CALIPER: computer-aided lung informatics for pathology evaluation and rating; AQS: automated quantification system; AMFM: adaptive multiple features method; QLF: quantitative lung fibrosis; DTA: data-driven textural analysis; FRI: functional residual imaging.

detection of ground-glass opacities [48]. Inherent advantages of the density mask technique include universal applicability and convenience, as the method is based on easily appreciated CT Hounsfield unit values. CT density histogram measures have been found to be inferior to visual fibrosis scores and PFTs for survival prediction [43]. In a study comparing histogram features with textural analysis in a cohort of 95 patients with IPF, significant density histogram changes between baseline and 1-year follow-up CT including mean CT value of the whole lungs ( p=0.003), skewness ( p3 kg over the 3 months preceding diagnosis was noted in half of the patients in the largest series [4]. 190

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Asthma

It has been suggested that the natural course of EGPA follows three phases [12]: rhinosinusitis and asthma; blood and tissue eosinophilia; and eventually, systemic vasculitis, at which time the diagnosis of EGPA can be made. Asthma is always present in EGPA, occurring at a mean age of ∼35 years. Asthma symptoms are more often perennial than seasonal [34, 51]. At diagnosis, airflow obstruction is generally moderate; however, it is characterised by a poor and incomplete response to bronchodilators [51]. Asthma occurs 3–9 years before the onset of vasculitis [11–14, 52, 53]. Asthma in EGPA is often severe and may require systemic treatment even before the onset of the systemic disease in some cases [12, 14, 51, 52, 54–57]. Albeit lacking specificity, late onset of eosinophilic asthma can to some extent be suggestive of subsequent EPGA. In a multicentre study of pulmonology departments, asthma severity was quantified as mild in 17%, moderate in 26% and severe in 57% of patients [51]. Asthma severity, however, may attenuate after the onset of vasculitis [12, 53], possibly due to the effect of systemic glucocorticoids prescribed for vasculitic manifestations [54, 58]. Other pulmonary manifestations

Eosinophilic pneumonia is relatively frequent in patients with EGPA but may be missed due to often mild clinical manifestations (especially when compared with non-respiratory organ involvement) and due to rapid resolution upon glucocorticoids that may be prescribed for asthma. It is generally comparable to idiopathic chronic eosinophilic pneumonia in presentation, but may be acute in onset and is often characterised by relatively mild pneumonia or even transient “infiltrates” [59]. At imaging, opacities consist of ground-glass attenuation and consolidation, with upper lobe and peripheral predominance [59–62]. Alternatively, patients may present with airways abnormalities that include centrilobular nodules, bronchial wall thickening and bronchiectasis [60–62]. When present, the tree-in-bud pattern suggests bronchiolar involvement that may correspond to hypereosinophilic bronchiolitis, an entity which may be idiopathic or associated with EGPA or allergic bronchopulmonary aspergillosis [63]. In contrast with granulomatosis with polyangiitis, DAH (defined as bloody BAL fluid with compatible opacities on chest radiograph and/or HRCT) is very rare in EGPA, occurring in 25% and usually >40% is also present at BAL [95]. A previous series found the mean percentage of eosinophils in BAL to be 33% [51]. Interestingly, the bronchial mucosa may look macroscopically inflammatory at fibreoptic bronchoscopy, with occasional whitish granulations [51] reminiscent of that seen in hypereosinophilic bronchiolitis [63]. Biomarkers that reflect eosinophil differentiation or degranulation have previously been described [21, 32, 96, 97]. However, it is unclear whether they reliably reflect disease activity, and their use in vivo requires validation. Nonspecific elevations of IgE levels are seen in ∼75% of patients [98], with mean levels of ∼1000 mg·L−1 [51]. 194

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a)

b)

c)

Figure 2. CT scan of the chest (parenchymal window) in a patient with eosinophilic granulomatosis with polyangiitis. a) Upper zones: centrilobular nodules and tree-in-bud opacities denoting eosinophilic bronchiolitis. b) Carina: alveolar consolidation corresponding with eosinophilic pneumonia, associated with bronchial wall thickening. c) Lower zones: alveolar consolidation, nodules, ground-glass attenuation and bronchial wall thickening.

ANCAs

Although EGPA belongs to the group of ANCA-associated vasculitides, ANCAs are found in less than half of the cases (30–40% of patients in several series). They are mainly perinuclear ANCAs with MPO specificity [3, 13, 14, 99, 100]. Different clinical phenotypes of disease have been reported in ANCA-positive and ANCAnegative patients (table 2) [3, 4, 99–101], in some cases with a genetic correlate [16, 102]. The presence of ANCA is associated with a greater risk of polyangiitis, i.e. genuine features of systemic vasculitis, especially glomerulonephritis, purpura, DAH and possibly mononeuritis multiplex (figure 3) [90]. In clinical practice, ANCAs and especially MPO-ANCAs when present support a diagnosis of EGPA. The absence of ANCAs, however, does not rule out a diagnosis of EGPA, especially in the setting of a respiratory medicine clinic (as compared to nephrology or rheumatology practice), as the eosinophilic phenotype of EGPA with frequent eosinophilic pneumonia and myocardiopathy is associated with the absence of ANCAs. Moreover, ANCA titres should not be used, either as an indication for treatment or to guide the https://doi.org/10.1183/2312508X.10014819

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Table 2. Distinct phenotypes of eosinophilic granulomatosis with polyangiitis

Frequency ANCA Predominant clinical and histopathological features

Vasculitic phenotype

Eosinophilic tissular disease phenotype

∼40% Present (mostly p-ANCA with anti-MPO specificity) Glomerular renal disease Peripheral neuropathy Purpura Biopsy-proven vasculitis

∼60% Absent Cardiac involvement (eosinophilic myocarditis) Fever Eosinophilic pneumonia

ANCA: antineutrophil cytoplasmic antibody; p-ANCA: perinuclear ANCA; MPO: myeloperoxidase.

choice of treatment. Specific evidence is lacking to explain the apparent clinical dichotomy between patients with or without ANCAs, and why only a proportion of patients with EGPA have detectable ANCAs. A pathogenic role of MPO-ANCAs has been demonstrated experimentally in mice [103]. The study showed that mice who received splenocytes from MPO-deficient mice immunised with murine MPO developed glomerulonephritis and pulmonary capillaritis.

Eosinophilic asthma Hypereosinophilic asthma EGPA (hypereosinophilic asthma with systemic manifestations) Polyangiitis MPO-ANCA

Figure 3. Schematic representation of the definition of eosinophilic granulomatosis with polyangiitis (EGPA) within the larger group of asthma, eosinophilic asthma phenotype (defined by blood eosinophils >300·mm−3 or eosinophilia in sputum or BAL) and hypereosinophilic asthma (defined by blood eosinophils >1.5 G·L−1). Within EGPA, subgroups of patients have genuine vasculitic manifestations ( polyangiitis), and some have antineutrophil cytoplasmic autoantibodies (ANCAs); the groups partly overlap. Not all patients with ANCAs have systemic manifestations, and therefore not all patients with asthma, eosinophilia and ANCAs have EGPA. Polyangiitis may be defined by the presence of biopsy-proven necrotising vasculitis of any organ, necrotising or crescentic glomerulonephritis, alveolar haemorrhage, and palpable purpura (see [90] for details). MPO: myeloperoxidase.

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Recently, ANCAs have been found in the sputum of patients with EGPA, including those without circulating ANCAs [104]. Although this opens new avenues of research to potentially assess localised dysregulated immunity, measurement of ANCAs in the sputum is not recommended in clinical practice. Differential diagnostic workup

The main differential diagnoses of EGPA are listed in table 3. Diagnosis of EGPA is usually straightforward in the setting of late-onset asthma, eosinophilia, ANCA positivity and/or symptoms related to polyangiitis; however, EGPA manifestations may mimic those of other diseases, especially in ANCA-negative patients and/or before the advent of vasculitis. An individual step-by-step diagnostic workup is therefore recommended. Notably, normal serum IgE values rule out a diagnosis of allergic bronchopulmonary aspergillosis, while high (i.e. >1000 kUI·L−1) values should lead to testing for IgE- and IgG-specific antibodies to Aspergillus, along with sputum analysis (especially in the setting of proximal bronchiectasis and mucoid impaction) [105]. Next, T-lymphocyte immunophenotyping (to detect abnormal surface phenotypes, including CD3–CD4+, CD4+CD7– and CD3+CD4–CD8–TCRαβ) is warranted in ANCA-negative patients with lymph nodes and/or skin involvement, to prevent diagnosis of the lymphocytic hypereosinophilic variant being missed [106]. Chronic eosinophilic leukaemia (formerly the myeloid variant of hypereosinophilic syndrome) has also been shown to mimic EGPA in rare cases [107], and the FIP1L1-PDGFRα fusion gene should be tested in selected cases when clinical signs (e.g. male sex, splenomegaly), biological signs (e.g. high B12 vitamin and/or tryptase levels) and/or primary resistance to glucosteroids suggest such diagnosis. Serum C-reactive levels 1500·mm−3 Eosinophilic tissue infiltration without vasculitis features on tissue biopsy Presence of FIP1L1-PDGFRα fusion gene in chronic myeloid leukaemia and clonal TCR gene rearrangement in the lymphocytic variant Chronic or subacute onset Absence of extrapulmonary involvement Peripheral blood eosinophilia usually less pronounced Acute onset Absence of extrapulmonary involvement Peripheral blood eosinophilia often absent at presentation Transient eosinophilia with pulmonary infiltrates Favourable outcome without glucocorticoids Parasitic infection (Strongyloides stercoralis, Dirofilaria immitis, Ascaris) Serum total IgE level >1000 IU·mL−1 IgE and IgG against Aspergillus fumigatus in serum Proximal bronchiectasis at chest CT Positive type I Aspergillus skin test

Idiopathic chronic eosinophilic pneumonia Idiopathic acute eosinophilic pneumonia Loeffler syndrome

Allergic bronchopulmonary aspergillosis

TCR: T-cell receptor.

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Lung function Asthma and/or airflow obstruction are present in nearly all patients with EGPA. As clinical presentation of relapsing paroxysmal dyspnoea with wheeze is not always present, PFTs are mandatory to assess airflow obstruction, which may otherwise be underestimated. Airflow obstruction is present in ∼70% of patients at diagnosis, despite inhaled bronchodilator and high-dose inhaled corticosteroid therapy for asthma, and may worsen in the 3–6 months preceding the onset of systemic disease [51, 54, 58]. Lung function improves with oral corticosteroid therapy administered systemic disease; however, airflow obstruction may persist [54, 58]. Most patients with asthma require low-dose long-term oral glucocorticoids, in addition to inhaled therapy [12, 14, 54], causing significant morbidity and susceptibility to infections [88]. Persistent airflow obstruction is particularly frequent in patients with long-term follow-up [54]. In a series of 157 patients with EGPA, 46% had persistent airflow obstruction 3 years after EGPA diagnosis; this was despite adequate inhaled corticosteroid and bronchodilator therapy in all of them, long-term oral low-dose corticosteroid therapy at a mean dose of 10 mg·day−1 of prednisone in >80% of them, and immunosuppressive therapy in 30–50% [51]. Progression of disease to long-term persistent airflow obstruction is a major cause of morbidity in patients with EGPA, and should be the main concern for pulmonologists. Whether persistent airflow obstruction can be improved by therapy targeting the IL-5 remains to be determined.

Pathology When performed, tissue and particularly lung biopsy show three defining characteristics [69, 109, 110]. 1) Vasculitis: necrotising or not, involving mainly the medium-sized pulmonary arteries, with fibrinoid necrosis of the media and eosinophilic infiltrates. 2) Extravascular granulomas. 3) Eosinophilic tissue infiltration (with palisading histiocytes and giant cells), which may involve arterial walls. Biopsies of tissues more accessible than the lung (the skin, nerve or muscle), are easier to perform, have a better safety profile, and can be useful. However, physicians must be well aware that a single tissue specimen rarely embraces all three key EGPA-defining pathological features, and therefore must not falsely rule out a diagnosis of EGPA in such a setting [14]. In the largest series of EGPA published to date, 10% Mononeuropathy or polyneuropathy Pulmonary infiltrates, nonfixed Paranasal sinus abnormality Extravascular eosinophil infiltration on biopsy findings 1992 Chapel Hill Consensus conference definition [113] Eosinophil-rich and granulomatous inflammation involving the respiratory tract Necrotising vasculitis affecting small-to-medium vessels Asthma Eosinophilia 2012 Updated Chapel Hill Consensus conference definition [2] ¶ Eosinophil-rich and necrotising granulomatous inflammation often involving the respiratory tract AND necrotising vasculitis predominantly affecting small-to-medium vessels AND associated with asthma and eosinophilia #

: diagnosis is probable when four of the six criteria are present (sensitivity 85%, specificity 99.7%). These classification criteria may be used when a diagnosis of systemic vasculitis has been established via histopathology. ¶: antineutrophil cytoplasmic antibodies are more frequent when glomerulonephritis is present.

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Table 5. Working diagnostic criteria used by COTTIN and co-authors [90, 114] 1) Asthma 2) Peripheral blood eosinophilia >1500·mm−3 and/or alveolar eosinophilia >25% 3) Extrapulmonary clinical manifestations of disease (other than rhinosinusitis), with at least one of the following: • systemic manifestations typical of the disease: mononeuritis multiplex, cardiomyopathy confidently attributed to the eosinophilic disorder or palpable purpura • any extrapulmonary manifestation with histopathological evidence of vasculitis, particularly demonstrated by a skin, muscle or nerve biopsy • any extrapulmonary manifestation with evidence of antineutrophil cytoplasmic antibodies and antimyeloperoxidase or antiproteinase 3 specificity When a single extrarespiratory manifestation attributable to the systemic disease is present, the disease may be called “forme fruste of eosinophilic granulomatosis with polyangiitis”.

Treatment and outcome Induction of remission

The indications for treatment are summarised in figure 4. Glucocorticoids are the mainstay of treatment and are sufficient to control the disease in the majority of cases. Oral prednisone is initiated at a dose of 1 mg·kg−1·day−1 for 3–4 weeks, then tapered to reach 5–10 mg·day−1 by 12 months of therapy. Initial methylprednisolone bolus (15 mg·kg−1·day−1 for 1–3 days) may be indicated in the most severe cases, especially where there is myocardial involvement. For remission induction, cyclophosphamide (three intravenous infusions of 0.6 g·m−2 intravenously each day at days 1, 15 and 30, then three additional infusions of 0.7 g·m−2 every 3 weeks) [117] should be added to glucocorticoids in patients with ⩾1 FFS-defining feature (i.e. cardiomyopathy, severe gastrointestinal involvement, renal insufficiency with

FFS 0

FFS >1 or severe forms

Induction of remission

Maintenance (18–24 months)

Prednisone 1 mg·kg–1·day–1 for 2–3 weeks then progressive tapering

Prednisone with progressive tapering

Prednisone 1 mg·kg–1·day–1 for 2–3 weeks then progressive tapering

Prednisone with progressive tapering

±i.v. methylprednisolone infusion, 7.5–15 mg·kg–1·day–1 for 1–3 days

Azathioprine 2 mg·kg–1·day–1 (or methotrexate 0.25 mg·kg–1·week–1)

Cyclophosphamide six i.v. infusions at days 0, 15 and 30 then every 3 weeks Figure 4. Schematic representation of treatment indications in eosinophilic granulomatosis with polyangiitis. FFS: five-factor score. Data from [116].

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serum creatinine >150 µmol·L−1, central nervous system involvement) [116, 118]. The dose of cyclophosphamide may be reduced to 0.5 g in individuals >65 years of age [119]. Although not included in the FFS, severe alveolar haemorrhage, eye involvement (e.g. scleritis) and/or fulminant mononeuritis multiplex also warrant the prescription of immunosuppressants. In the absence of ill-defining features, steroids alone are sufficient and, in a randomised placebo-controlled trial, azathioprine failed to either increase remission rate or prevent relapses [120]. Other treatments have been used successfully in a few cases refractory to glucocorticoids, including subcutaneous interferon-α [121], high-dose intravenous Igs, plasma exchange, cyclosporine-A [114] and rituximab [122–132]. It is hoped that rituximab may help reduce the need for cyclophosphamide in patients with severe forms of EGPA, especially those with ANCAs [132], similar to granulomatosis with polyangiitis. However, experience with rituximab is still limited in EGPA, and bronchospasm has been reported after the first infusion [133]. Therefore, rituximab should not be used routinely pending the results of ongoing trials (ClinicalTrials.gov identifier NCT02807103). Maintenance therapy

Once remission has been achieved, prolonged maintenance therapy is necessary to prevent relapses. When the criteria predicting a poor prognosis are absent, it generally consists of glucocorticoids alone, at a tapering dose [134]. Immunosuppressive therapy, especially azathioprine or MTX, is occasionally used as a corticosteroid-sparing agent in this situation, particularly in subjects who require ⩽10 mg·day−1 of prednisone; however, it may now be less frequently used due to the availability of eosinophil targeted therapy. In patients with poor prognostic criteria, maintenance therapy is generally based on azathioprine for 18–24 months. Mycophenolate mofetil may be less effective than azathioprine in the prevention of relapses [135] but MTX 0.25 mg·kg−1·week−1 is an alternative to azathioprine [136]. In a retrospective multicentre study of 17 patients with EGPA who received omalizumab (a murine anti-IgE antibody) for severe steroid-dependent asthma, alone or in association with other immunosuppressive agents, omalizumab treatment resulted in some efficacy and a corticosteroid-sparing effect, but severe flares occurred in a quarter of patients [137], and the overall effect of omalizumab in EGPA remains controversial (especially on vasculitis manifestations). Treatments targeting the IL-5 pathway

The signalling pathways that lead to the proliferation and recruitment of the tissues of the eosinophil cell line are relatively well understood [138, 139], and this has raised considerable interest in recent years with regard to the development of biological targeted therapy for eosinophilic lung diseases [140] and eosinophilic asthma [141]. Activated eosinophils release cationic proteins and a number of nuclear and cytosolic molecules, which play a role in asthma [142, 143]. Cytokine IL-5 is the main regulator of eosinophil proliferation, maturation and differentiation [138]. It is present at increased levels in the blood and tissue of patients with EGPA. As IL-5 is active at all stages of eosinophil cell involvement, it is the ideal eosinophil-specific target. Mepolizumab is a human, monoclonal antibody that binds to IL-5, preventing its interaction with its receptor on the eosinophil surface. Mepolizumab consistently reduces https://doi.org/10.1183/2312508X.10014819

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eosinophil cell counts in peripheral blood and leads to clinical improvement in patients with severe or corticosteroid-dependent eosinophilic asthma [144–148]. Following promising preliminary results in isolated cases [149–151], the efficacy and safety of mepolizumab was evaluated in a phase 3 randomised trial as add-on therapy versus placebo in 136 subjects with relapsing or refractory EGPA over a period of 52 weeks [115]. As compared with placebo, mepolizumab (300 mg every 4 weeks) led to an increased proportion of patients achieving remission, an increased duration of remission, a lower rate of relapse and a lower average daily dose of prednisolone or prednisone of ⩽4.0 mg per day during the last 4 weeks of the trial [115]. Although these results are very encouraging, it must nevertheless be underlined that only approximately half of the participants treated with mepolizumab had a predefined remission during the trial. None of the patients received mepolizumab as first-line therapy. In many patients, EGPA was considered refractory due to difficult-to-control asthma rather than genuine relapse of systemic organ involvement or vasculitis activity. Many questions remain regarding the patients with EGPA in whom mepolizumab can be used, how the response to mepolizumab can be predicted and whether mepolizumab might obviate the need for immunosuppressive therapy in selected cases with poor prognosis factors. Pending further data, mepolizumab may be used as adjunct therapy in subjects with relapsing or refractory EGPA, yet to date it is licensed for EGPA only in the USA and Japan. It is anticipated that mepolizumab may be further beneficial in cases with persistent severe asthma when the vasculitis is in remission, similar to that demonstrated in severe asthma [144–148]. Reslizumab, another monoclonal antibody against IL-5, reduces asthma exacerbations in patients with uncontrolled asthma and peripheral blood eosinophilia [152, 153], but has not been studied in EGPA. Benralizumab is a monoclonal antibody directed against the α-subunit of IL-5, which has demonstrated a sparing effect of oral glucocorticoids in severe asthma [154], particularly eosinophilic asthma [155]. In a case report, benralizumab administration reduced the serum level of MPO-ANCA in a subject with EGPA [156]; however, its effect on disease activity remains to be determined in prospective trials.

Long-term outcome and management Survival

The 5-year overall survival in EGPA is currently >90% [4, 86, 157–159]; in the era before glucocorticoids it was 1 g·day−1 Severe GI involvement (GI bleeding, perforation, infarction and/or pancreatitis) Renal insufficiency (serum creatinine >1.58 mg·dL−1 or 139 µmoL·L−1) Central nervous system involvement Cardiomyopathy

1 point 1 point 1 point 1 point 1 point

A five-factor score of 0, 1 or 2 is associated with a relative risk of mortality of 0.62, 1.35 and 2.4, respectively. GI: gastrointestinal. Data from [116].

require a change in management must be distinguished from flares of severe asthma or rhinosinusitis, generally with peripheral eosinophilia, which alone do not qualify as relapses of EGPA [118]. Morbidity

Long-term morbidity is related to: 1) side-effects of glucocorticoids and severe immunosuppression, because low-dose long-term oral glucocorticoids are required for asthma in most patients, in addition to inhaled therapy; and 2) difficult asthma with persistent airflow obstruction present in nearly half the patients [51, 54, 158]. Whether mepolizumab and other drugs targeting the IL-5 pathway will decrease the long-term burden of corticosteroid-associated adverse events needs be monitored. Prevention

Patients on long-term glucocorticoids should receive calcium and vitamin D supplementation, as well as bisphosphonates. Those receiving cyclophosphamide should benefit from prevention of Pneumocystis infection. Patients should be vaccinated against influenza and Streptococcus pneumoniae, ideally at a time period where they are treated with neither cyclophosphamide nor rituximab, which reduce the immunogenicity of vaccination [18, 161].

Conclusion As the burden of long-term morbidity remains high in patients with EGPA, largely related to the need to maintain low-dose oral glucocorticoids, research is warranted to improve management. In the future, treatment indications may be refined based on clinical or serological phenotypes (ANCA status, organ involvement with genuine polyangiitis), and possibly genotypes. Adjunction of biotherapy targeting the eosinophil cell lineage might help reduce the need for long-term corticosteroid therapy and associated adverse events.

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Disclosures: V. Cottin reports receiving grants and personal fees from Astra Zeneca for consultancy and lectures, outside the submitted work. M. Nasser reports receiving the following, outside the submitted work: sponsorship for postgraduate studies from Actelion; scientific conference sponsorship from Roche Pharma; personal fees for ongoing studies and scientific conference sponsorship from Boehringer Ingelheim. M. Groh reports receiving the following, outside the submitted work: personal fees and other support from AstraZeneca; and personal fees from GlaxoSmithKline.

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| Chapter 13 Takayasu arteritis and Behçet disease Veronica Alfieri1 and George A. Margaritopoulos2 Takayasu arteritis is a rare disease affecting mainly young women. Behçet disease is a rare systemic vasculitis affecting mainly young men; it presents a sex predisposition to a specific disease phenotype. Lung involvement is rare but can be associated with significant mortality. Unexplained pulmonary infarction in the absence of risk factors for thromboembolic disease and observation of pulmonary artery aneurysms on imaging should prompt respiratory physicians to consider these disorders. The mortality rate has declined recently due to early clinical suspicion, early diagnosis (related to the development of noninvasive diagnostic imaging) and early treatment initiation. Despite recent progress, several areas need to be further elucidated, such as pathogenesis, the definition of universally accepted diagnostic criteria, accurate assessment of disease activity and the development of outcome measures to be used as end-points in clinical trials. Cite as: Alfieri V, Margaritopoulos GA. Takayasu arteritis and Behçet disease. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 210–227 [https://doi.org/10.1183/2312508X.10014919].

@ERSpublications Lung involvement in Takayasu arteritis and Behçet disease is rare but is associated with increased mortality. Consensus about diagnostic criteria and outcome measures is required so clinical trials can be designed. http://bit.ly/2lDj2R7

Takayasu arteritis Takayasu arteritis is a chronic, granulomatous, large-vessel panarteritis that most commonly involves the aorta, its major branches and the pulmonary artery [1]. It is known as the “pulseless disease” due to the obliteration of peripheral pulses, mainly in the upper limbs. Epidemiology

There is a strong female predominance. Takayasu arteritis usually manifests in the second or third decade of life [2]. It is more prevalent among Asian patients [3]. The estimated 1 Dept of Medicine and Surgery (DiMeC), Respiratory Disease Unit, University of Parma, Parma, Italy. 2ILD Unit, Manchester University Hospital NHS FT, Wythenshawe Hospital, Manchester, UK.

Correspondence: George A. Margaritopoulos, ILD Unit, Manchester University Hospital NHS FT, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester, M23 9LT, UK. E-mail: [email protected] Copyright ©ERS 2019. Print ISBN: 978-1-84984-111-5. Online ISBN: 978-1-84984-112-2. Print ISSN: 2312-508X. Online ISSN: 23125098.

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prevalence is 40 and 4.7 cases per million in Japan and the UK, respectively [3, 4]. Prevalence has increased in Norway (25.6 cases per million) and Sweden (13.2 cases per million) due to high immigration rates from Asia and Africa in the recnt decades [5, 6]. Pathogenesis

The aetiology of Takayasu arteritis is unknown but infectious agents and genetic factors play a significant role. The strongest genetic association was established with HLA-B52 in Japanese (where HLA-B52 positivity is related with worst outcome) and other populations [7–10]. Associations with HLA-B5, HLA-A2, HLA-A9, HLA-B35 and HLA-DR4 have been noted in various ethnicities [11–17]. A large genome-wide association highlighted two independent genetic susceptibility loci in HLA class I and class II (HLA-B/MICA and HLA-DQB1/HLA-DRB1) and a genetic association with other loci (FCGR2A/FCGR3A and IL12B) [18]. A variant in the IL17F gene (rs763780) protects against the development of Takayasu arteritis [19]. Takayasu arteritis has been reported in HIV patients and in patients post-hepatitis B and influenza vaccination [20–22]. There is evidence of a possible link between Takayasu arteritis and Mycobacterium tuberculosis involving cell-mediated immunity [23]. A molecular mimicry between the mycobacterial 65-kDa heat-shock protein (HSP) and human 65-kDa HSP was observed and an autoimmune response could be triggered by mycobacterial infection [24]. The expression of 65-kDa HSP in the aortic tissue could activate the dendritic cells, which produce mediators that recruit T-cells to the vessel wall and initiate an aberrant T-cell response characterised by the release cytokines, such as interferon-γ and tumour necrosis factor (TNF)-α. These cytokines induce: 1) the coalescence of multinucleated giant cells and formation of granuloma; and 2) the differentiation and activation of macrophages. Activated macrophages release IL-1, IL-6 and several growth factors, resulting in exuberant intimal proliferation and contributing to the structural damage in the aortic wall. Subsequently, the inflammation evolves to fibrosis and to the development of degenerative changes in the media and adventitia. These changes, in combination with fibrocellular hyperplasia, result in weakening of the muscular layer, the formation of aneurysms, vascular stenosis and thrombus formation Diagnosis

Two sets of diagnostic criteria are widely used. According to the American College of Rheumatology (ACR) criteria (table 1), when at least three out of six criteria are present, there is a 90.5% sensitivity and 97.8% specificity for the diagnosis of Takayasu arteritis [1]. According to the modified Ishikawa diagnostic criteria (table 2), when two major, or one major and two minor, or four minor criteria are present, there is a 92.5% sensitivity and 95% specificity for the diagnosis of Takayasu arteritis [25]. Signs and symptoms The disease evolves in two phases. The initial inflammatory phase (called the “pre-pulseless phase”) is characterised by nonspecific constitutional symptoms, such as fatigue, anorexia, weight loss, night sweats, fever and musculoskeletal complaints. The late phase (called the “pulseless phase”) is characterised by symptoms due to arterial stenosis, aneurysm and https://doi.org/10.1183/2312508X.10014919

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Table 1. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis Criterion

Definition

Age at disease onset ⩽40 years Claudication of extremities

Development of symptoms or findings related to Takayasu arteritis age ⩽40 years Development and worsening of fatigue and discomfort while in use, especially the upper extremities Decreased pulsation of one or both brachial arteries

Decreased brachial artery pulse Blood pressure difference >10 mmHg Bruit over subclavian arteries or aorta Arteriogram abnormality

Difference of >10 mmHg in systolic blood pressure between arms Bruit audible on auscultation over one or both subclavian arteries or abdominal aorta Arteriographic narrowing or occlusion of the entire aorta, its primary branches or large arteries in the proximal upper or lower extremities, not due to arteriosclerosis, fibromuscular dysplasia or similar causes; changes usually focal or segmental

Reproduced and modified from [1] with permission.

occlusion. It seems that the involvement of the thoracic aorta and its branches is more common among females, while males have a tendency toward involvement of the abdominal aorta and its branches [26, 27]. Pulmonary involvement in Takayasu arteritis is characterised by: 1) nonspecific symptoms, such as chest pain, shortness of breath, cough, pleural effusions and haemoptysis; 2) the development of pulmonary artery aneurysms (PAAs) in segmental and subsegmental branches, which are rare but can be life threatening in cases of rapture; 3) multiple pulmonary infarctions in the absence of risk factors for thromboembolic disease; and 4) PH due to the occlusion of central or peripheral pulmonary arteries [28–30]. PH is a rare but life-threatening complication of Takayasu arteritis. It is classified in group 4 of the recent guideline document and is associated with a longer duration of Takayasu arteritis, more severe symptoms and a worse outcome [31–34]. Extrapulmonary involvement in Takayasu arteritis is characterised by: 1) symptoms of cerebral ischaemia, which occur in 11.7% of patients and may include vision loss, orthostasis or syncope, headache, vertigo, memory loss, seizures, stroke and transient ischaemic attacks; 2) involvement of the subclavian arteries, which manifests with upper extremities claudication, digital ulcers and an interarm blood pressure discrepancy of >10 mmHg; 3) involvement of the coronary arteries, which is responsible for the development of myocardial ischaemia (angina, myocardial infarction) in 4.7% of patients; 4) development of ascending aortic aneurysms, which lead to aortic regurgitation and insufficiency and, subsequently, to congestive heart failure; 5) renal artery stenosis, which is responsible for the development of renovascular hypertension in a third to one half of patients; 6) lower extremity claudication symptoms due to involvement of the iliac arteries; and 7) involvement of the abdominal aorta, which may lead to mesenteric ischaemia, characterised by abdominal pain, diarrhoea, anorexia and gastrointestinal haemorrhage [1, 28, 35, 36]. 212

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Table 2. Modified Ishikawa diagnostic criteria for Takayasu arteritis 3 major criteria Left mid subclavian artery lesion

Right mid subclavian artery lesion

Characteristic signs and symptoms of ⩾1-month duration

10 minor criteria High ESR Carotid artery tenderness Hypertension Aortic regurgitation OR annuloaortic ectasia Pulmonary artery lesion

Left mid common carotid lesion Distal brachiocephalic trunk lesion Descending thoracic aorta lesion Abdominal aorta lesion Coronary artery lesion

The most severe stenosis or occlusion present in the mid portion from the point 1 cm proximal to the vertebral artery orifice up to that 3 cm distal to the orifice determined by angiography. The most severe stenosis or occlusion present in the mid portion from the right vertebral artery orifice to the point 3-cm distal to the orifice determined by angiography. These include limb claudication, pulselessness or pulse differences in the limbs, an unobtainable or significant blood pressure difference (>10 mmHg systolic blood pressure difference in the limb), fever, neck pain, transient amaurosis, blurred vision, syncope, dyspnoea or palpitations. Unexplained persistent high ESR >20 mm·h−1 (Westergren) at diagnosis or presence of the evidence in the patient’s history. Unilateral or bilateral tenderness of common arteries on palpation. Neck muscle tenderness is unacceptable. Persistent blood pressure >140/90 mmHg brachial or >160/90 mmHg popliteal. By auscultation, Doppler echocardiography or angiography. By angiography or two-dimensional echocardiography. Lobar or segmental arterial occlusion or the equivalent determined by angiography or perfusion scintigraphy, or the presence of stenosis, aneurysm, luminal irregularity or any combination in the pulmonary trunk or in the unilateral or bilateral pulmonary arteries determined by angiography. Presence of the most severe stenosis or occlusion in the mid portion of 5 cm in length from the point 2 cm distal to its orifice, determined by angiography. Presence of the most severe stenosis or occlusion in the distal third determined by angiography. Narrowing, dilation or aneurysm, luminal irregularity or any combination, determined by angiography. Tortuosity alone is unacceptable. Narrowing, dilation or aneurysm, luminal irregularity or aneurysm combination. Documented on angiography below the age of 30 years in the absence of risk factors like hyperlipidaemia or diabetes mellitus.

ESR: erythrocyte sedimentation rate. Reproduced and modified from [25] with permission.

Laboratory findings There are no specific laboratory tests for the diagnosis and evaluation of the activity of Takayasu arteritis. Acute phase reactants, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), correlate with disease activity only in a proportion of patients [28, 37–39]. ESR has been found to be elevated in >50% of patients who are considered to be in remission [28]. In active disease, raised white blood cell counts, complement https://doi.org/10.1183/2312508X.10014919

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(C3, C4, CH50) levels, fibrinogen and IgG can be observed [40]. Serum biomarkers (IL-6, IL-8, IL-18, matrix metallopeptidase-9, vascular endothelial growth factor, anti-endothelial cell antibodies and circulating endothelial progenitor cells) have been suggested to be markers of disease activity but results have yet to be confirmed [41]. Serum levels of pentraxin-3 (PTX3) were higher in active versus inactive disease, healthy patients and patients with active infection [42]. A PTX3 level of 5.37 ng·mL−1 has a sensitivity of 82.6% and a specificity of 77.8% for the detection of active disease and PTX3 levels were independent of prednisolone dose [43]. The platelet to lymphocyte ratio and neutrophil to lymphocyte ratio were associated with active inflammation [44]. Other studies showed an increase in markers associated with inflammationinduced thrombosis and platelet dysfunction; the results need to be validated [45, 46].

Imaging Based on evidence and expert opinion, the European League Against Rheumatism (EULAR) developed recommendations for the use of imaging modalities in primary large vessel vasculitis, including giant cell arteritis and Takayasu arteritis [47].

Conventional angiography was the gold standard for the diagnosis of large vessel vasculitis. Currently, it is replaced by modalities including positron emission tomography (PET), magnetic resonance imaging (MRI), CT and ultrasound [48]. Although angiography is the best modality to describe precisely the severity of stenotic arterial lesions, it does not provide any information regarding the arterial wall morphology. Moreover, it is an invasive procedure, iodinate contrast is used, there is radiation exposure and patients may need hospitalisation due to procedural complications [47]. Currently, the use of angiography is limited to preparation for arterial revascularisation or measurement of central arterial pressure when peripheral arterial involvement precludes noninvasive blood pressure recording. In suspected Takayasu arteritis, MRI angiography should be used as the first imaging diagnostic test [47]. MRI can evaluate the stenotic and aneurysmal lesions and the vessel wall (thickening, oedema, degeneration). There is no exposure to radiation, which allows multiple evaluations in young patients. The sensitivity and specificity of MRI angiography was 100% compared to catheter-based angiography [49]. CT angiography (CTA) may also be used to image the vascular lumen and the arterial wall, allowing early stage diagnosis before significant luminal remodelling occurred [50]. In comparison with MRI, CT allows shorter acquisition times and provides images with improved anatomical detail [51]. Therefore, CTA could be particularly useful for preoperative planning when revascularisation is required. CTA has a sensitivity of 95% and a specificity of 100%, using catheter-based angiography as the gold standard [52]. PET can assess disease activity in the arterial wall, localise active vessel inflammation and provide information about the intensity of the inflammatory process [37]. PET has a pooled sensitivity of 87% and a specificity of 73% for assessment of disease activity [53]. A combination of PET and CT allows the anatomic localisation of activity and increases the sensitivity for detection of arterial wall inflammation [54]. If PET/CT is performed at an early stage, it can reveal pre-stenotic arterial disease and lead to early introduction of immunosuppression. PET has limited efficacy during follow-up and it may not be 214

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useful in predicting relapses or remission because of the persistence of the uptake of 2-fluoro-2-deoxy-D-glucose in clinically silent disease [55, 56]. Ultrasonography is a sensitive tool for evaluating localised areas of stenosis and aneurysm. It is cheap, well tolerated but can be useful only in carotid, femoral and proximal sections of subclavian arteries. It is also an operator-dependent procedure. If PH (which is present in 12% of patients) is suspected, transthoracic echocardiography should be performed. Transthoracic echocardiography may also allow for the incidental identification of specific abnormalities within the pulmonary arteries, such as luminal stenosis or occlusion [57]. Long-term monitoring for stenosis, occlusion, dilatation and/or aneurysm detection can be periodically performed using MRI angiography, CTA and/or ultrasound [47]. In the context of inflammation and/or dilatation of the aorta, MRI or CT can be used whereas a stenosis of the axillary/subclavian arteries could be followed up by ultrasound [47]. Histopathology All layers of the arterial wall are affected. Active lesions are characterised by the presence of oedema, mononuclear cell infiltration, granulomatous reaction with giant cells, necrosis in the media and adventitia, intimal fibrocellular hyperplasia, thrombus formation, with ulterior degenerative changes leading to muscular layer weakening and aneurysmal formation. Chronic lesions are characterised by patchy infiltrates containing macrophages, media scarring and fibrosis, which extends to the adventitia [58]. Treatment Timing for treatment initiation The degree of arterial injury correlates with prognosis and therefore early diagnosis and treatment is associated with a better outcome [59–61]. Increased arterial wall thickening during the active inflammatory phases of disease has been found, which suggests that arterial lesions may be reversible [62, 63]. Secondary arterial remodelling is irreversible so prevention of disease progression is the aim [61, 64].

There is no single clinical finding that accurately reflects disease activity; multi-item activity indices have therefore been proposed. The “historic” National Institute of Health (NIH) criteria have been used for decades to assess clinical activity; now, however, they are considered insufficient [28]. The Birmingham Vasculitis Activity Score (BVAS) assesses activity in the organ systems that are rarely affected in Takayasu arteritis; cardiovascular features, which predominate in Takayasu arteritis, are underrepresented [41, 65]. Although the Disease Extent Index for Takayasu’s Arteritis (DEI.Tak) is felt to be more user friendly than BVAS it only demonstrated an agreement of 68% with the physician’s global assessment [66]. The Indian Takayasu Clinical Activity Score (ITAS2010) was created to provide a quantitative score of new active disease by evaluating clinical features newly present in the prior 3 months and puts more emphasis on the cardiovascular symptoms [67]. The initial ITAS2010 form contained 44 items in six organ-based systems; elevated ESR and CRP were added later to create ITAS2010-A. The two composite scores were validated in adult Takayasu arteritis patients, demonstrated to be sensitive to change and provided quantitative grading of disease activity [67]. https://doi.org/10.1183/2312508X.10014919

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Morbidity and mortality are associated with damage due to disease activity. The Takayasu Damage Score (TADS) was derived from DEI.Tak and was created to capture the extent of damage [68]. With TADS, the emphasis is on the cardiovascular system and it records features that have been present for ⩾3 months. A limitation of its use is the difficulty of distinguishing between activity and damage in large vessels. Which agents? All patients who present with the signs and symptoms that suggest Takayasu arteritis should be referred to a specialist team for multidisciplinary diagnostic work-up and management [69]. A high dose of oral prednisolone (40–60 mg·day−1) should be administered for induction remission of active disease. Once the disease is under control, the dose should be tapered to 15–20 mg·day−1 over a period of 2–3 months, then to ⩽10 mg·day−1 after a year. A more rapid tapering should be avoided due to the high risk of relapse observed in the placebo arms of two small clinical trials [70, 71]. The most commonly used drugs for the induction and maintenance of remission are azathioprine, methotrexate, mycophenolate mofetil, leflunomide and cyclophosphamide; however, evidence is low quality and from uncontrolled prospective and retrospective case series [69, 72]. If these drugs are not efficacious, biological agents such as anti-TNF-α agents (infliximab, etanercept, adalimumab, golimumab), tocilizumab, abatacept and rituximab can be introduced [69]. A multicentre randomised controlled trial (RCT) in Takayasu arteritis enrolled 34 patients, required nearly 5 years to complete, but failed to demonstrate the efficacy of abatacept (CTLA4-Ig) in maintaining relapse-free survival over placebo [70]. Another small RCT showed a trend towards reduced hazard ratio for the time to the first relapse in patients treated with tocilizumab [73]. One prospective and several retrospective open-label uncontrolled studies/case series showed reduced activity in patients treated with anti-TNF agents but the results could have been affected by the concomitant use of corticosteroids and should be interpreted with caution [69]. Treatment as per new onset disease with high doses of oral prednisolone is recommended in cases of major relapse [69]. Despite the low quality of evidence and given the high rate of relapse, the use of second-line agents in combination with steroids is recommended at the time of diagnosis of Takayasu arteritis [69]. The choice of the agent should be decided on an individual basis.

The use of antiplatelet or anticoagulant therapy should not be routinely used for treatment of Takayasu arteritis unless it is indicated for other reasons, such as coronary heart disease and cerebrovascular disease [69]. Vascular interventions When the disease has progressed to fibrotic lesions, it is unlikely to respond to anti-inflammatory therapy and vascular interventions are required. The main indications include irreversible stenotic or obstructive vascular lesions with haemodynamic impact. The intervention should be performed during the quiescent phases of the disease and only in centres with expertise [69, 74–77]. Ongoing research

Currently, there are ongoing research projects aiming to: 1) clarify the methods of diagnosis; 2) evaluate disease activity; and 3) optimise treatment. Biomarker and outcome 216

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investigations could identify risk factors for an aggressive course leading to treatment tailored to disease severity [78]. International collaborations aim to standardise classification and diagnostic criteria to define homogeneous patient groups for RCTs [79]. Prognosis

Reported mortality ranges 3–21.0% and seems to be decreased compared with earlier series [80]. Pooled adult and childhood Takayasu arteritis series have shown varying 15-year survival rates, depending on the occurrence of arterial complications, valvular heart disease, stroke, heart failure and renovascular hypertension: they were 66.3% in patients with complications and 96.4% in those without complications [40, 76, 81].

Behçet disease Behçet disease is an inflammatory condition that was originally described by Hippocrates. In 1937, Hulusi Behçet identified the characteristic triad of symptoms, which included recurrent uveitis, oral and genital ulcerations [82, 83]. Later, Behçet disease was recognised as a multisystem inflammatory condition [84]. Behçet disease is unique among the vasculitides because it can involve both large and small vessels. Epidemiology

Behçet disease has a worldwide distribution with a clear predilection for countries across the ancient trading route known as the old Silk Road, which extends from eastern Asia to the Mediterranean basin [85]. Data from 45 population-based surveys have shown a pooled prevalence of 10.3 per 100 000 inhabitants [86]. In individual geographical areas, the prevalence (expressed as cases per 100 000 population) was 119.8 for Turkey, 31.8 for the Middle East, 4.5 for Asia, 5.3 for Southern Europe, 2.1 for Northern Europe and 3.8 for North America/the Caribbean Islands [86]. The incidence varies from 0.05 to 3.98 per 100 000 in Poland (with the limitation that only hospitalised patients were included) and China (one of the endemic areas for Behçet disease), respectively [87, 88]. Behçet disease typically occurs between the second and fourth decades of life, irrespective of country of origin and sex [89]. Onset before 15 or after 50 years is exceptional and is usually associated with a more benign course [90, 91]. There is a male predominance and a sex predisposition to a specific disease phenotype [92–97]. Males have a higher risk of vascular disease, ocular involvement, skin involvement, folliculitis and papulopustular lesions, while females have a higher risk of genital ulcers, erythema nodosum and joint involvement. Pulmonary involvement is more prevalent in young males; the mean age is 30.1 years [98]. 78% of patients with PAAs have concomitant extrapulmonary venous thrombi or thrombophlebitis. Pathogenesis

It is now believed that Behçet disease is a result of an autoimmune process triggered by an infectious or environmental agent in genetically predisposed individuals. The HLA-B*51 allele located in the major histocompatibility complex locus on chromosome 6p is a https://doi.org/10.1183/2312508X.10014919

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stronger risk factor for Turkish and Japanese patients than for Caucasian patients and confers a relative risk of 5.8 for developing Behçet disease [99, 100]. Several genes located outside the major histocompatibility complex region, such as common variants of the IL-10 and the encoding IL-23 receptor (IL23R) and IL-12 receptor β (IL12B2) genes were strongly associated with Behçet disease [101]. Factor V gene was associated with thrombosis and ocular involvement with controversial results [102]. Infectious triggers may be involved in the pathogenesis of Behçet disease. Due to increased incidence of tonsillitis and poor oral hygiene in Behçet disease, it was hypothesised that a correlation with streptococcal infections might exist [103]. The efficacy of antibacterial treatments on mucocutaneous and arthritic symptoms strengthened this hypothesis. A higher colonisation of Streptococcus species at ulcer sites than in healthy controls and patients with recurrent aphthous stomatitis was observed in a UK population study [100]. Other studies revealed that alterations of the intestinal microbiota could be related to the pathogenesis of Behçet disease [104, 105]. According to the current hypothesis, infectious agents can be involved in the pathogenesis of Behçet disease due to mimicry of microorganism antigens with human proteins. Antibodies to human and mouse neurofibrils that cross-react with Streptococcus spp. and M. tuberculosis HSPs were recently observed in Behçet disease [106]. Both innate and adaptive immune systems participate in the pathogenesis of Behçet disease [107]. The following events are observed in Behçet disease: T-cell homeostasis perturbation characterised by an expansion of T-helper cell (Th)1 and Th17 and by a decrease in regulation activity of regulatory T-cells; an increase in inflammatory cytokine such as IL-21; priming of neutrophils; endothelium dysfunction and activation. Diagnosis

The International Study Group (ISG) on Behçet disease’s criteria were published in 1990 [108]. In 2013, the diagnostic criteria were revised (International Criteria for Behçet disease (ICBD)) (table 3) [109]. A score of ⩾4 points is diagnostic for Behçet disease. In the training set, 93.9% sensitivity and 92.1% specificity were assessed, compared with 81.2% sensitivity and 95.9% specificity for the ISG criteria. In the validation set, ICBD demonstrated a sensitivity of 94.8%,

Table 3. International criteria for Behçet disease Sign/symptom

Points

Ocular lesions (anterior uveitis, posterior uveitis, retinal vasculitis) Genital aphthosis Oral aphthosis Skin lesions (pseudofolliculitis, skin aphthosis, erythema nodosum) Neurological manifestations (central, peripheral) Vascular manifestations (arterial thrombosis, large vein thrombosis, phlebitis or superficial phlebitis) Positive pathergy test#

2 2 2 1 1 1 1

The criteria are a scoring system; a score of ⩾4 indicates Behçet disease. #: test is optional. Reproduced and modified from [109] with permission.

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which was higher than that of the ISG criteria (85.0%). Specificity was lower than that of the ISG criteria (96.0%) but considered still reasonably high. Signs and symptoms Whilst rare, involvement of the pulmonary arteries is responsible for the majority of morbidity and mortality [110]. The responsible mechanism for pulmonary manifestation is related to the vasculitic nature of the disease. Behçet disease is classified as a systemic vasculitis and is included in the group of variable vessel vasculitis (vasculitis with no predominant vessel type involved, which can affect vessels of any size (small, medium and large) and type, arteries, veins and capillaries) [111].

PAAs and in situ pulmonary artery thrombosis (PAT) are present in two-thirds and one-third, respectively, of cases with involvement of the pulmonary arteries, affecting >CD

Y

N

UAO from major inflammation

CT/ MRI-FOB-PET

+

–

UC>CD

Y

N

Glottis, VC, subglottic area

CT-FOB

+

+

UC>CD

Y

N

Trachea

CT-FOB

++

+++

UC>CD

Y

N

Main bronchi: large airways

CT-FOB

+++

+++

UC>CD

Y

N

Bronchorrhea

Gross examination on FOB Imaging/serum

++

++

UC>>CD

Y

N

+

?

UC

?

?

CT-FOB

+++

++

UC>CD

Y

N

CT-FOB

+++

+

UC>CD

Y

N

CT-FOB

+++

++

UC>CD

Y

N

ABPA Scarring (± inflammation ?) Trachea Main bronchi: large airways

Deformity results from inflammation and/ scarring Infection#, malignancy, papilloma, GPA, polychondritis Infection#, malignancy, papilloma, GPA, polychondritis Infection#, malignancy, papilloma, GPA, polychondritis Chronic bronchitis, bronchiectasis from other causes Lepidic carcinoma, HSP Mucoid impaction on imaging Tracheopathia osteoplastica, relapsing polychondritis, GPA Inhalational injury Continued

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Inflammation: scarring

Competing diagnoses

Method for diagnosis

Small airways: bronchioles Inflammation

Scarring

Frequency Colectomy

UC/CD

Causal association IBD

IBD-MD

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Bronchiolocentric inflammation

HRCT/pathology

++

+

UC=CD

Y

N

Granulomatous bronchiolitis

Pathology

+

?

CD>>UC

Y

N

Difffuse panbronchiolitis pattern Obliterative SAD

Pathology

+

?

UC

Y

N

PFT/pathology

+

?

UC

Y

N

Imaging/PFT/ pathology Imaging/BAL/ pathology Imaging/ pathology Pathology

++

+

CD>UC

Y

++

–

UC>CD

Rare

+++

–

UC>CD

Y

+++

–

UC>>CD

Y

+

–

UC=CD

Rare

Very rare

–

UC

Rare

Infiltrative lung disease Eosinophilic pneumonia OP ILD with granulomas NSIP DIP

Imaging/ pathology Imaging/ pathology

Competing diagnoses

Other causes of bronchiolocentic inflammation, gases, vaping Infection (TB, Aspergillus), sarcoidosis, HSP, lentil, vaping Idiopathic panbronchiolitis

Smoking, e-cigarette, Sauropus androgynus Y ILD from non IBD-MD drugs or from other causes Y PIE due to drugs or other causes Possible Idiopathic or from other causes including drugs Y ILD due to drugs/other causes, metastatic lymphangitic spread Y Innumerable causes possible N Idiopathic, nitrofurantoin Continued

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Table 3. Continued

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Table 3. Continued Method for diagnosis

Pulmonary nodules/ masses

Effusion Pericardial surface Heart

Pericarditis Pericardial effusion/ tamponade Myocarditis

Imaging/ patholgy Imaging/ pathology Pathology Imaging/ pathology Imaging/ANCA/ pathology Chest pain/ CT/US Chest pain/ CT/US Chest pain/ ECG/US

UC/CD

CD

Competing diagnoses

IBD

IBD-MD

Y

Y

Infection, vasculitis

Y

U

Infection, vasculitis

++

+

+

ND

+ +

ND –

UC

Y Y

? N

Infection, drugs Septic embolism

+

ND

UC

?

N

Idiopathic GPA

+

+

UC∼CD

Y

Y

Viral, autoimmune, drugs

++

+

UC∼CD

Y

Y

+

+

UC∼CD

Y

Y

Malignancy, infection, autoimmune, drugs Variegated causes

Y

Y

Y

Y

++ US biopsy

Causal association

+

+

UC-CD

Malignancy, infection, autoimmune, drugs Viral infection, drug-induced, isolated chest pain Continued

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Pleural surface

Granulomatous inflammation Granulomas with necrosis Nodular OP Necrobiotic neutrophilic nodules With the features of GPA Pleuritis

Frequency Colectomy

Method for diagnosis

Therapy related

Other thoracic manifestations

Pneumonitis

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Opportunistic infections Pneumocystis jiroveci, TB Thromboembolism Fistulas PE from hypoalbuminaemia

Imaging/ pathology Imaging/BAL/ stains

Frequency Colectomy

UC/CD

Causal association IBD

IBD-MD

++

N/A

UC=CD

N

Y

++

N/A

UC=CD

?

Y

UC∼CD

N Y Indirect

Y N N

++ + +

UC

Competing diagnoses

See www.pneumotox.com for drugs/patterns See www.pneumotox.com for drugs/patterns

Myocarditis-mediated

UC: ulcerative colitis; CD: Crohn disease; MD: modifying drugs; FOB: fiberoptic bronchoscopy; Y: yes; N: no; UAO: upper airway obstruction; MRI: magnetic resonance imaging; PET: positron emission tomography; GPA: granulomatous polyangiitis; VC: vocal cords; HSP: hypersensitivity pneumonitis; ABPA: allergic bronchopulmonary aspergillosis; TB: tuberculosis; SAD: small airway disease; PIE: pulmonary infiltrates and eosinophilia; DIP: desquamative interstitial pneumonia; US: ultrasound; PE: pulmonary oedema; ND: not determined; N/A: not applicable; –: unreported; +: rare; ++ relatively common; +++: the most common manifestation overall; ?: no data. #: please refer to [127] and [131].

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mainstem bronchi [138, 150]. HRCT with planar reconstruction and MRI may demonstrate swelling and irregularity of the airway wall and reduction in airway calibre [10, 30, 150]. On microscopy, dense lymphoplasmacytic infiltrate and oedema of the mucosa match the changes on gross examination [135, 150]. Lymphocytes, neutrophils and rare eosinophils may permeate the airway mucosa up to the epithelium which may also be infiltrated [135], whereas necrosis is a rare finding [52]. The overlying airway surface facing the airway lumen may show squamous metaplasia or appear ulcerated [8, 14, 125, 148]. When present, noncaseating granulomas favour a diagnosis of Crohn disease over ulcerative colitis [16], provided infection (e.g. tuberculosis) is excluded. Although breathing heliox may temporarily help, emergent restoration of airway patency is the crux of management. Inhaled, nebulised and/or i.v. corticosteroids can normalise airway patency quickly to very quickly [52, 53, 150]. Infliximab may play a role in recalcitrant cases [29] when corticosteroids fail or produce adverse effect. Interventional endoscopy with debridement, laser, argon plasma coagulation, electrocautery, stent placement and topical injections of corticosteroids and/or mitomycin C have been used. [29, 150, 152]. Tracheal dilation using calibrated bougies or an inflatable balloon can be considered to restore airway patency at the expense of possible airway rupture and consequent mediastinitis [123]. Despite reduction of inflammation on endoscopy and microscopy with corticosteroid therapy, permanent disabling reduction of tracheal calibre, barking cough and tracheomalacia may persist [152, 153].

Tracheal, mainstem/large airway involvement Symptoms also include dry hacking cough, intolerance to perfumes or air in public swimming pool buildings (possibly because chlorine or derivatives thereof are present in ambient air), cough productive of variable amounts of sputum with minimal airway changes on imaging meeting the definition for chronic bronchitis [122], cough productive of abundant or copious sputum (i.e. bronchorrhea) or chronic bronchial “suppuration”, although evidence for an infection is usually lacking [8, 77, 154], or bilateral bronchiectasis, more prominent in the lung bases (figures 3, 4, 10–12) [8–12, 14, 77, 79]. Pseudomonas is grown far less often than in other forms of bronchiectasis [155]. Antibiotics offer little improvement and/or temporary relief [8, 77, 156].

Parallel flares of bowel and airway symptoms have been reported, as has onset of airway disease a few days or weeks [8, 48, 49, 157] and up to 40 years after colectomy [46]. Colectomy very rarely if ever cures airways disease and instead, deterioration of airway status following bowel surgery has been reported [116]. Bronchorrhea of 200 [153], 700 [77] and 800 mL per day [8] has been noted, markedly altering the social life of patients greatly affected. Pulmonary physiology may show normal findings, moderate obstructive and/or restrictive dysfunction, often with a discrepancy between clinical severity and moderate impact on pulmonary function [8]. Only modest subjective and/or objective improvement may follow inhalation of a bronchodilator agent. Patients often have normal airway responsiveness to methacholine despite marked IBD-related airway inflammation [8]. On the chest radiograph, early, mild and moderate cases may show no changes despite significant sputum production. More advanced cases may show the “dirty lung” in both bases [77]. More advanced cases exhibit tramline shadows corresponding to bronchial wall thickening especially when suppurative airway disease is present. Tubular or cystic bronchiectasis and gloved-finger shadows suggesting impaction are seen in yet more advanced or aggressive cases. https://doi.org/10.1183/2312508X.10015019

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HRCT may disclose non-uniform lung emptying consistent with peripheral airway obstruction in early cases [158], thickening of bronchial walls [51, 106] when airways are seen en face [51], centrilobular nodules and tree-in-bud consistent with subacute bronchiolitis [8, 69, 159], basilar bronchial wall thickening, small [160] or larger [8] tubulated dichotomously branched opacities known as “golf pants”, thought to represent impaction of inspissated mucoid or puriform material within distended/dilated airways [8, 10, 79, 81, 161]. Allergic bronchopulmonary aspergillosis has been evidenced in a few such cases [162]. The recent observation of e-cigarette vaping associated small airway injury should be scrutinised in every patient [163, 164]. Yet more advanced cases may show tracheal irregularities and wall thickening [150], and basilar or widespread cystic bronchiectasis along with the aforementioned changes [8, 57]. Sometimes, changes are limited to distal regions of the lung in the form of thick parenchymal bands or areas reminiscent of candle stains [165]. These are consistent with areas of upstream atelectasis-blocked peripheral airways. Mucosal maxillary and ethmoid sinus thickening is found in up to 60% of patients with ulcerative colitis-related large airway involvement [10]. Airway endoscopy can be grossly normal or show simple erythema in cases with lone cough, although mucosal biopsy may evidence inflammation [8, 14, 135]. In patients with clinically significant cough and sputum, changes are generally present [10, 135, 137, 151] in the form of erythema, oedema, bulging of the airway wall, and/or cobble stoning which may bleed easily on contact [135, 148]. Changes may predominate in the trachea or extend within and beyond mainstem bronchi. Severity of inflammation and narrowing may prevent adequate inspection of segmental and subsegmental airways. BAL may show an increased percentage of neutrophils [8, 153], which may decrease with prolonged inhaled corticosteroid therapy [8]. On microscopy, changes may resemble those in the trachea [135, 166] with a deep and dense submucosal collection of plasma cells and lymphocytes infiltrating the airway walls [135], sometimes in a bandlike fashion [166]. The epithelium undergoes squamous metaplasia and/or is ulcerated. Neutrophils and rare eosinophils may be scattered in the infiltrate and epithelium [8]. Subepithelial airway glands beneath the mucosa may be infiltrated of destroyed by the infiltrate and inflammatory cells may extend around the ducts of the bronchial glands and into the glands themselves [8, 135, 166]. Bronchiectasis unrelated to IBD shows less dense and conspicuous cellular infiltrate and may display follicular germinal centres instead [135, 166]. The infiltrate in IBD-related airway disease may extend down to distal bronchioles which, if available for examination on a biopsy or resectional specimen, show a similar pattern of inflammation, destruction and obliteration, including in terminal bronchioles while lung vessels are intact [8, 85, 123, 135]. There is histological similarity between the airways and colonic mucosa in ulcerative colitis-related large airway involvement, particularly with regards to neutrophilic infiltration, mucosal ulceration and dense underlying chronic inflammation with plasma cells [135, 166]. In those patients who respond to corticosteroid therapy, gross airway appearance may return to normal [150]. Infliximab may be considered in airway involvement non-responding to corticosteroid therapy [86]. Some patients develop irreversible changes in the form of strictures, deformities, thickening/scarring of the airway walls, airway narrowing, webs or malacia [60, 153]. Why a specific segment of the bronchial tree is involved, why some patients develop lone cough 250

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or chronic bronchitis which will stay unchanged and why others develop rapidly progressive suppurative airways disease and bronchiectasis is unknown.

Bronchiolitis: small airway involvement Small airways are defined as non-cartilaginous airways 64 years) in the presence of the other two criteria allows a diagnosis of HPS to be made [1]. Contrast-enhanced transthoracic echocardiography Contrast-enhanced transthoracic echocardiography is the best and least-invasive method to assess IPVD (figure 1) [35]. The technique involves the injection of liquid with bubbles/ contrast media through a peripheral vein to assess if and how this liquid passes through the left-heart cavities. Different agents may be used to produce bubbles, such as saline solution, mannitol, polygeline, indocyanine green and other gelatinous solutions; however, saline solution is usually preferred [36]. In healthy patients, the bubbles are usually trapped by pulmonary capillaries and are not visualised, or are only visualised late, in the left-heart cavities. In the case of HPS, bubbles can also be visualised in the left heart as they bypass the capillary bed or directly pass through intracardiac shunts. Usually, the bubbles can be observed after four to six beats in HPS, and earlier (one to three beats) in the case of

Figure 1. A 56-year-old patient with liver cirrhosis on the liver transplant list who received a further workup of dyspnoea for liver transplant evaluation. Contrast-enhanced transthoracic echocardiography shows a significantly enlarged right ventricle, right-heart catheter-proved PH.

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intracardiac shunts [1]. However, it has been reported that the detection of IPVD has no role in the presence or absence of HPS [37]. Similarly, the association between intrahepatic vascular changes and HPS is weak [38]. Given these assumptions, the detection of IPVD has a limited role in the diagnostic process of HPS. Macro-aggregated albumin lung perfusion scan A macro-aggregated albumin (99mTc-MAA) lung perfusion scan represents another modality to assess IPVD [1]. This technique consists of the injection of 99mTc-tagged albumin particles and the subsequent analysis of lung and brain perfusion scanning. In the physiological condition, brain uptake is 85% of cases within 6–12 months after LT [39, 51]. However, it is also undeniable that, after the diagnosis is made, a significant percentage of patients stay for a relative long time on the transplant list waiting for LT, dying in some cases before LT. Data on survival in patients waiting for LT are conflicting. While some studies have suggested that there was no significant difference in terms of survival between patients affected by HPS and patients without HPS, some others reported that survival is lower in HPS patients [52, 53]. Probably this difference is to be viewed in light of the different stages of the disease. From this perspective, the evaluation of specific scores, such as the model for end-stage liver disease (MELD score), may help in the selection of patients for LT, ensuring that severe cases are more rapidly transplanted [52, 53]. The grade of hypoxaemia and the high brain capitation of 99mTc-MAA represent strong predictors of post-LT mortality [39]. Given the lack of prospective studies, data on mortality are mostly derived from retrospective studies and report a survival after LT that ranges from 7.7% up to 33% [54]. https://doi.org/10.1183/2312508X.10015119

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Therefore, it has been suggested that correct identification and selection of HPS patients through the use of diagnostic criteria and the MELD score may improve post-transplant survival up to 88% after 5 years [52, 53]. Initiation of long-term oxygen therapy is recommended in patients with severe HPS [1, 55]. With regard to medical treatment, several drugs have been tested for HPS with disappointing results. The main targets were vasodilation mediated by NO and angiogenesis promoted by inflammatory cytokines. Negative results or insufficient evidence to support their use come from studies that tested a number of drugs such as octreotide, cyclo-oxygenase inhibitors, immunosuppressants, quercetin, β-blockers, paroxetine, rosuvastatin, caspase-3 inhibitors, methylene blue and inhaled iloprost [56]. Pentoxifylline, a TNF-α inhibitor that reduces NO production induced by TNF, was suggested to be effective after initial promising results on animals. However, human data are contradictory. While a study testing nine patients reported a significant improvement in oxygenation, data from a parallel study did not confirmed these results and also reported some gastrointestinal events [57–59]. Positive results were also observed after the use of garlic. Although the exact mechanism of action is not known, two studies testing garlic reported a significant improvement in oxygenation and symptoms [60, 61]. A less frequent approach in HPS patients is represented by a transjugular intrahepatic portosystemic shunt. The experience with this technique in HPS is still very limited and results are conflicting. For these reasons, this technique is reserved mainly for patients with severe HPS and is used as a bridge to transplantation [62–65]. Angiography may also serve as a therapeutic manoeuvre to treat hypoxaemia. However, this technique finds greatest utility in the presence of large arteriovenous communications and is to be reserved for these cases. Therefore, despite the constant attempts to discover effective drugs or interventional approaches, the therapy of choice for HPS remains LT.

PoPH PoPH is defined as the association of portal hypertension and PAH, considered as mean pulmonary artery pressure (mPAP) ⩾25 mmHg, pulmonary artery occlusion pressure ⩽15 mmHg and pulmonary vascular resistance (PVR) >3 Wood units [66, 67]. Data have shown that the presence of portal hypertension, more than liver disease itself, can lead to PAH with the subsequent development of PoPH [67]. In this light, PoPH can be viewed as a severe complication of portal hypertension, which has a large impact on the patient’s prognosis. Of note, the recent 6th World Symposium on Pulmonary Hypertension revisited the definition of PH and thereby also of PoPH, suggesting a new pressure level to define an abnormal elevation of mPAP >20 mmHg and the need for PVR ⩾3 Wood units to define the presence of pre-capillary PH [67]. Epidemiology and risk factors

The association between portal hypertension and PAH was described for the first time in 1951. The prevalence of PoPH ranges widely owing to different definitions and populations 268

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analysed over the years. Data derived from studies on liver cirrhosis patients reported a prevalence of PoPH ranging from 2% up to 6% [68–70]. However, more detailed information has been derived from national registries for PH, which highlighted important differences between countries in terms of the percentage of patients suffering from PAH and portal hypertension. Data from the US REVEAL Registry (Registry to evaluate early and long-term pulmonary arterial hypertension disease management) reported that 4.9% of 3900 patients with PAH also presented portal hypertension, while a higher percentage (almost 15%) was observed in the French registry [71, 72]. The frequency of PH in patients with liver disease varies with disease severity and duration. By the time of liver transplantation, 10.3% of patients had right-heart catheterisation-proven mPAP >35 mmHg [73]. A retrospective review of the UK National Registry of all-incident treatment-naïve patients with PoPH suggested a prevalence of 0.85 cases per million population [74]. Estimated median survival time was 3.75 years in this patient population, with 1-, 2-, 3- and 5-year survival rates of 85%, 73%, 60% and 35%, respectively [74]. No specific risk factors have been identified for the development of PoPH. However, it is clear that the main leading condition is the presence of portal hypertension. With regard to the predominance in females, some studies have suggested that this is probably to be viewed in light of oestrogen metabolism [75]. This hypothesis also finds confirmation in the different oestrogen signalling resulting from genetic variation of oestrogen. Epidemiological studies have reported that all types of portal hypertension or liver disease may lead to the development of PoPH. However, although the reason is unknown, a higher prevalence was interestingly reported in patients with autoimmune chronic liver disease [76]. Pathophysiology

Several factors may contribute in different ways to the development of PoPH. One pathogenic mechanism is the presence of an imbalance between vasoconstrictive and vasodilatory, and pro- and antiangiogenic factors in favour of vasodilation and angiogenesis, respectively. The presence of a chronic liver disease leads to two important consequences: on the one hand, toxic substances derived from the digestive tract, which are usually cleared by the liver, go directly into the systemic circle as a result of the presence of shunts damaging pulmonary vasculature and leading to vasodilation; on the other hand, the presence of a chronic liver disease leads to a deficiency in the production of antiangiogenic factors, thus promoting angiogenesis [77–79]. It was also demonstrated that the presence of portal hypertension, independent of chronic liver disease, promotes the production of several vasoactive mediators, which are also responsible for repetitive pulmonary vasculature injury. Moreover, similar to what has been observed in PAH, patients with PoPH develop vascular remodelling characterised by an increase of the media layer and fibrosis of the intima in vessels. This mechanism, in turn, leads to an increase and self-promoting of vasculature resistance. A primary role in the pathogenesis of PoPH is also played by inflammation. Several studies have reported the presence of high levels of pro-inflammatory cytokines in PoPH patients. As in the case of HPS, bacteria translocation due to the proliferation and increase in https://doi.org/10.1183/2312508X.10015119

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permeability of the intestinal wall may also participate in vascular remodelling due to inflammation [80]. Moreover, the presence of portocaval anastomoses and the deficiency in filter activity of the liver lead to bypassing of this first station, increasing pulmonary phagocytic activity and inflammation [81]. This event ultimately results in direct damage to the lungs. Finally, the development of a hyperdynamic circulatory syndrome, which is characterised by increased cardiac output and a decrease in systemic vascular resistance, is important in PoPH. This is characterised by an increased sympathetic tone, circulating catecholamines, venous return and pro-inflammatory mediators that contribute differently to the shear stress and induce endothelial dysfunction [78]. Diagnosis Clinical signs and symptoms PoPH is usually asymptomatic in >60% of cases. The most frequently reported symptom is dyspnoea. In more advanced stages, patients may also report fatigue and venous congestion due to the progressive liver dysfunction [67]. Physical examination may also show light-headedness, orthopnoea, syncope, haemoptysis, systolic murmur, right ventricular heave, right-sided S3 gallop, jugular vein extension, ascites and lower-leg oedema [82]. Transthoracic echocardiography and right-heart catheterisation Due to its high sensitivity and lower level of invasiveness, transthoracic echocardiography represents the first approach for the screening of PH in chronic liver diseases. Several cut-off values of systolic pulmonary artery pressure (sPAP) have been analysed to assess the presence of PH. According to a recent task force, a threshold sPAP of 50 mmHg and/or significant right ventricular hypertrophy or dysfunction were suggested as the best cut-off able to detect moderate to severe forms of PoPH with the highest positive predictive value (74%), and require right-heart catheterisation to measure haemodynamics and consistency with PoPH [55, 83]. The peak tricuspid regurgitation velocity (TRV) can be also considered a valid marker for suspected PH. A peak TRV ⩽2.8 m·s–1 in the absence of other signs of PH is associated with a low probability of PoPH, while a peak TRV ⩾2.9 m·s–1 is associated with an intermediate or high probability of PoPH [66].

However, transthoracic echocardiography may only be seen as a screening tool, while right-heart catheterisation remains the gold standard to confirm the diagnosis and may also be utilised for follow-up [66]. The recent recommendation of the 6th World Symposium on Pulmonary Hypertension states that echocardiographic screening is recommended in all patients with portal hypertension [84]. If a tricuspid regurgitant jet of >3.4 m·s−1 or right atrial or right ventricular enlargement or dysfunction is found, then further evaluation with right-heart catheterisation and referral to a PH expert centre is recommended. A complete diagnostic workup including right-heart catheterisation is required to assess disease severity, haemodynamic profile and other potential causes of PH, including lung disease, left-heart disease or chronic thromboembolic disease. Treatment

Some nonspecific medical treatments such as anticoagulants and β-blockers have been suggested for management and are used in clinical practice. However, evidence has 270

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demonstrated that the use of anticoagulation is not recommended in patients with PoPH, especially in the presence of severe hepatocellular insufficiency, thrombocytopenia or uncontrolled oesophageal varices due to the risk of haemorrhagic complications [85]. Similarly, the use of β-blockers in the prophylactic treatment of oesophageal varices should be avoided in PoPH due to the negative effects on the right ventricle [85]. Therefore, the main therapeutic approach of PoPH is the medical treatment of PH. Thus, the drugs used for the treatment of PAH have been applied to PoPH. However, given that patients with PoPH were generally excluded from clinical trials for PAH, the experience in this field is mainly derived from retrospective and observational studies [86]. Due to their pharmacokinetic profile, these drugs need to be administered with extreme caution and with close monitoring of liver enzymes. In contrast to patients with classical PAH, there is still a potential role for initial monotherapy in patients with PAH-associated portal hypertension as they were not included in randomised controlled trials of initial combination therapy. Patients with PoPH have been excluded from almost all randomised controlled trials in the PAH field (except for the PATENT study, which included 13 patients with PoPH) [87]. However, this subgroup analysis revealed that riociguat was well tolerated and improved 6-min walk distance, World Health Organization functional class and other efficacy parameters in this small subcohort of patients [87]. Endothelin receptor antagonists (ERAs) usually represent the drug of choice [88, 89]. Bosentan, a nonselective endothelin receptors A and B antagonist, was reported to be well tolerated and to improve survival in PoPH patients. Interestingly, this drug was found to be particularly active in those forms highly related to inflammation [90, 91]. Due to potentially hepatotoxic effects and the lower drug-associated liver toxicity of the newer ERAs, these have a theoretical advantage over bosentan. Ambrisentan, a selective endothelin receptor A antagonist, has also been demonstrated to be effective with a less hepatotoxic profile [92]. Recently, data from the randomised controlled PORTICO (Portopulmonary hypertension treatment with macitentan) trial (ClinicalTrials.gov identifier NCT02382016) were presented at a recent ERS congress reporting that macitentan, a third ERA, could significantly improve PVR (35%) as the primary end-point at week 12 versus placebo. Safety was consistent with previous trials; in particular, there were no hepatic safety concerns in this population [93]. Another class of drugs is phosphodiesterase type 5 inhibitors. Experience in the use of these drugs in PoPH is derived mainly from sildenafil. Evidence in this field demonstrated that sildenafil is effective in reducing PH with a good tolerability profile [94–96]. Prostanoids represent a third class currently used to treat PoPH patients. However, due to their mode of administration, which requires a continuous intravenous infusion, and the risk of bleeding and infections, the use of these drugs is very limited and is thus reserved for severe cases while waiting for LT [97, 98]. LT

LT in PoPH represents a clinical dilemma as patients are at high risk of perioperative death. Moreover, LT may reverse vascular abnormalities in only a subset of patients. Therefore, LT is to be considered only for selected patients and after achieving haemodynamic stability. After LT, PoPH, especially in its advanced stages, may worsen rapidly and right-heart failure may develop due to the increase in cardiac output of up to 300% after liver reperfusion [99]. Therefore, mortality is rather difficult to predict owing to the high https://doi.org/10.1183/2312508X.10015119

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variability in the behaviour and severity of the disease. In a large meta-analysis covering >10 years, KROWKA et al. [100] reported that mortality after LT was 100% for patients with PoPH if mPAP was >50 mmHg, 50% if mPAP was 35–50 mmHg and 0% if it was 20–30% suggests diaphragm insufficiency, usually bilateral [20, 21]. A summary of PFT abnormalities in NMDs is presented in table 3.

Table 2. Important symptoms and signs of respiratory involvement in neuromuscular diseases Respiratory muscle failure

Bulbar dysfunction

Sleep disturbance

282

Orthopnoea Dyspnoea on exertion or on immersion in water Inadequate chest expansion Insufficient cough Paradoxical abdominal motion during inspiration Abdominal muscle contraction during expiration Rapid shallow breathing Use of accessory muscles Drooling Swallowing difficulty Insufficient cough Low-volume voice, staccato/slurred speech Loss of weight Daytime sleepiness, fatigue Impaired intellectual function Morning headache Disrupted sleep Sexual dysfunction

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Table 3. Lung function testing and arterial blood gas analysis in neuromuscular diseases (NMDs) Parameter

Change in parameter with progression of NMD

FVC

Decreased Decrease of >20% in VC in supine position: inspiratory muscle (diaphragm) weakness Decreased Normal or increased Decreased Decreased Decreased Normal or decreased Normal or increased Normal RV: may be seen in inspiratory muscle weakness Increased RV: indicates combined inspiratory and expiratory muscle weakness Normal or increased Decreased Normal, increased or decreased Increased KCO: may be seen in inspiratory muscle weakness Decreased KCO: probable combined inspiratory/expiratory muscle weakness Decreased Increased Decreased Greatly decreased Greatly decreased Greatly decreased

FEV1 FEV1/FVC PEF, PCF MVV TLC FRC RV RV/TLC TLCO KCO PaO2 PaCO2 pH MIP MEP SNIP

VC: vital capacity; PEF: peak expiratory flow; PCF: peak cough flow; MVV: maximum voluntary ventilation; TLC: total lung capacity; FRC: functional residual capacity; RV: residual volume; TLCO: transfer factor of the lung for carbon monoxide; KCO: transfer coefficient of the lung for carbon monoxide; PaO2: arterial oxygen tension; PaCO2: arterial carbon dioxide tension; MIP: maximal inspiratory pressure; MEP: maximal expiratory pressure; SNIP: sniff nasal inspiratory pressure.

Other useful measurements in NMDs include: 1) maximal inspiratory (MIP) and expiratory (MEP) pressures, 2) sniff nasal inspiratory pressure (SNIP), 3) cough gastric pressure, 4) cough peak flow, 5) maximum transdiaphragmatic pressure, 6) twitch transdiaphragmatic pressure, and 7) measurement of lung and chest wall compliance [7]. Most of these are performed in expert laboratories using expensive equipment and are interventional techniques, requiring placement of catheters in the oesophagus or stomach. Extended analysis of these methods is beyond the scope of this chapter. Briefly, MIP is suggestive of global inspiratory muscle strength, whereas MEP indicates expiratory muscle strength. Both MIP and MEP depend on the maximal effort of the patient, and the predicted normal and lower limit of normal values vary considerably, depending on parameters such as sex, race, age and measurement technique. Consequently, MIP and MEP should be considered compared with the predicted values, and low measurements should be interpreted with caution. However, use of fixed cut-off values may be considered for practical reasons. SNIP has been validated in healthy individuals and patients with chronic obstructive pulmonary disease (COPD) and should also be considered in comparison with reference values [22]. SNIP and MIP are complementary tests and should be evaluated in combination with VC for a complete assessment of inspiratory muscle https://doi.org/10.1183/2312508X.10021519

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strength [21]. Peak cough flow can also be monitored: a measurement of 80% Increased RV, FRC and RV/TLC Peak cough flow 18 ng·L–1

Stage I (0 item)

HSCT 87%

No HSCT 73%

Stage II (1 item)

HSCT 72%

No HSCT 52%

Stage III (2 items)

HSCT 56%

No HSCT 31%

Stage IV (3 items)

HSCT 36%

No HSCT 10%

Figure 3. Mayo Clinic staging system (revised according to [116]). NT-proBNP: N-terminal pro-brain natriuretic peptide; dFLC: difference between involved and uninvolved free light chains; HSCT: haematopoietic stem cell transplantation. #: 4-year median overall survival estimates in the two populations used to validate the staging system, respectively treated with or without HSCT.

There are a few published randomised clinical trials involving patients with lung amyloidosis, and respiratory symptoms and function were not specifically assessed [121, 122]. Localised amyloidosis The treatment strategy depends mainly on the respiratory pattern and comes from evidence relying mainly on small case series or expert opinion.

Localised tracheobronchial amyloidosis first-line treatment is often endoscopic. Lasers, argon plasma coagulation and cryotherapy are the main techniques aimed at reducing symptoms by debulking tracheal or proximal bronchial amyloidosis lesions [123]. Bleeding and post-procedure oedema are the main complications. Endoscopic treatments have a variable impact, but there are numerous cases reported in the literature with clinical [23, 66, 68, 124] and, more rarely, functional [64] improvement. However, re-interventions are often needed, frequently on a 1-yearly basis. Endoscopic prosthesis implantation may also be added to manage localised stenosis [23, 123]. External conformational radiotherapy seems effective in some case series [125, 126], with a reported long-time functional effect [72]. It is indicated mainly when endoscopic treatment is not possible or is insufficiently effective. Promising results have been observed with a combination of endoscopic debulking and external radiotherapy [72, 127, 128], or with external radiotherapy and endoscopic brachytherapy [129]. The benefit of chemotherapy targeting plasma cells in pure localised tracheobronchial amyloidosis is unknown, with cases exceptionally reported [68], and needs to be weighed against the induced immunosuppression in a population already subject to respiratory infections. Corticosteroids alone appear to be ineffective and deleterious. Nodular localised amyloidosis rarely requires treatment. When the nodules are solitary and not accessible to biopsy, it is not rare to diagnose them a posteriori after resection for a suspected neoplasia. In these cases, recurrence was about 25% in a series of 18 patients [19]. Otherwise, the treatment choice relies mainly on the associated disease [19, 70]. Pure cystic-nodular forms often show a slow progression and the same associated disease as the nodular pattern [20, 130, 131]. Treatment is also often directed to the underlying disease, mainly MALT lymphoma and CTD. Other interstitial or composite localised forms are rare but are usually severe [53, 67]. Treatment meets that of systemic amyloidosis. One study reported a lung transplantation with good results [132]. 310

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Ongoing research Numerous drugs are tested in amyloidosis but not specifically in lung amyloidosis. Dezamizumab, an anti-SAP antibody, showed encouraging results on all forms of amyloidosis during phase I/II trials [133, 134]. The VITAL Amyloidosis Study, a phase III trial on the anti-misfolded light-chain antibody NEOD001, was stopped recently due to futility (ClinicalTrials.gov identifier NCT02312206), despite encouraging phase II results [135]. Most other trials are testing drugs used in related haemopathies, an exception being doxycycline as an add-on therapy with interesting previous observational results (table 6) [136]. Evaluation of treatments Evaluation of treatments should include both the haematological and organ response, as they can differ. The haematological response is evaluated through the difference between involved and uninvolved FLCs (dFLC) and serum immunofixation, targeting a very good partial response or better [137]. The organ response should be assessed using consensus criteria, which remain to be defined at the lung level [76]. In the absence of evidence-based data, clinical evaluation and PFTs on a 3–6-month basis and CT evaluation before and after treatment may be proposed. Pitfalls might arise from the impact of associated cardiac involvement or infections on PFTs and CT. Non-AL amyloidosis

The available data mainly concern amyloidosis in general, without a focus on respiratory involvement, which is rarely predominant in this setting. AA amyloidosis treatment is directed against the underlying disease, with a common goal of reducing the SAA concentration [138]. Table 6. Ongoing trials on AL amyloidosis (not exhaustive) Drug(s)

Daratumumab Daratumumab+CyBorD Daratumumab+BSC Daratumumab+ixazomib+dexamethasone Venetoclax+dexamethasone Immunomodulatory imide drugs Lenalidomide+dexamethasone+elotuzumab ±cyclophosphamide Pomalidomide+dexamethasone Pomalidomide+bortezomib+dexamethasone Proteasome inhibitors (other than bortezomib) Ixazomib (maintenance) Ixazomib+dexamethasone Ixazomib+cyclophosphamide+dexamethasone Daratumumab+ixazomib+dexamethasone Doxycycline

ClinicalTrials.gov identifier/ EudraCT number

NCT03201965/2016-001737-27 NCT02816476/2016-000287-42, NCT02841033 NCT03283917 NCT03000660 (suspended) NCT03252600 NCT01570387/2011-001787-22 NCT01728259 NCT03618537 NCT01659658 NCT03236792 NCT03283917 NCT02207556, NCT03401372, NCT03474458, NCT01677286

CyBorD: cyclophosphamide, bortezomib, dexamethasone; BSC: best supportive care.

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Hereditary ATTR amyloidosis treatment involves the recently developed therapies inotersen, patisiran and tafamidis [139–141]. Inotersen, a 2′-O-methoxyethyl-modified antisense oligonucleotide inhibitor, and patisiran, an RNA interference therapeutic agent, both aim to reduce transthyretin production. Tafamidis, the only agent with an indication in wild-type ATTR amyloidosis [142], prevents amyloid formation in stabilising transthyretin tetramers in their native conformation. Treatment of other amyloidoses, especially hereditary ones, is mainly supportive. The exception is amyloidosis where the liver is the predominant site of production of the protein precursor (ATTR and ApoAI amyloidosis); in this case, liver or multiple organ transplantation can be discussed [143, 144].

Prognosis Overall, amyloidosis survival is improving, as a result of better treatment of the underlying diseases in AA amyloidosis and evolving therapeutics in ATTR and AL amyloidoses [50, 115, 145]. In AL amyloidosis, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels ⩾1800 ng·L−1, troponin T ⩾0.025 µg·L−1 and a dFLC ⩾18 mg·dL−1 are associated with an increased risk of death [116]. Age and an associated multiple myeloma or bone marrow plasmocytosis ⩾10% are other independent prognostic factors [146]. Suspicion of amyloidosis (see main text and table 2)

Confirmation of diagnosis (see main text and figure 2a)

Typing of the deposits precursor protein (see main text and figure 2b)

Looking for underlying disease/mechanism (see main text)

Evaluation of the burden of disease

Respiratory pattern and clinical/ functional impact Prognostic: interstitial pattern, dyspnoea, restriction (see main text, table 3 and figure 1)

Extrarespiratory involvement Prognostic: cardiac localisation (see main text and table 4)

Global Prognostic: PS score dFLC (AL) SAA (AA)

Prognosis and treatment strategy (see main text) Figure 4. The stepwise management of lung amyloidosis. The relevant text, tables and figures in the chapter for each step are indicated. PS: performance status; dFLC: difference between involved and uninvolved free light chains; AL: light chain; SAA: serum amyloid A protein; AA: amyloid A amyloidosis.

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In respiratory amyloidosis, dyspnoea and possibly restriction might be prognostic factors independent of cardiac localisation and age [57]. Localised amyloidosis exceptionally evolves in systemic amyloidosis [18]. However, localised respiratory amyloidosis may have a poorer survival rate than other types of localised amyloidosis, due either to the associated disease, mainly in nodular amyloidosis, or to the severity of tracheobronchial or interstitial involvement. In tracheobronchial amyloidosis, if some patients remain stable after a number of years [66], mortality related to amyloidosis ranges from 13% to 43% [23, 24, 64, 67, 68, 70, 124].

Conclusion Lung amyloidosis covers a wide spectrum of presentations, linked to various precursor proteins, extrarespiratory extension and respiratory patterns. AL amyloidosis is the most prevalent type. Schematically, tracheobronchial and nodular patterns are mostly limited to the lung, while an interstitial pattern or presentations with several respiratory involvements often show associated extrarespiratory localisations. Associated diseases include mainly haematological malignancies, CTD and, more rarely, solid neoplasms. Management of lung amyloidosis, summarised in figure 4, needs a stepwise approach from diagnosis suspicion to treatment choice, including the keystone of reasoning: typing the precursor of amyloid deposits. However, numerous reported cases remain untyped, and efforts should be made to improve the typing of lung amyloidosis. Moreover, evaluation and standardisation of treatments and monitoring in lung amyloidosis are urgently needed to improve care.

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Disclosures: P.-Y. Brillet reports receiving the following, outside the submitted work: grants from Siemens General Electric; personal fees for teaching courses from Roche, LBI and GlaxoSmithKline; and personal fees for acting on a board from AstraZeneca. H. Nunes reports receiving the following, outside the submitted work: consultant and research support fees from Roche/Genentech, Boehringer Ingelheim and Sanofi; and a grant and personal fees from Gilead for work as an investigator on a clinical trial. D. Valeyre reports receiving the following, outside the submitted work: personal fees and nonfinancial support from Intermune, Roche and Boehringer Ingelheim for work as a member of a scientific advisory board on IPF. Y. Uzunhan reports receiving the following, outside the submitted work: personal fees from Boehringer Ingelheim for consultancy; personal fees from Roche; and nonfinancial support from Pfizer.

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| Chapter 18 Trafficking and lysosomal storage disorders Paolo Spagnolo1, Jelle R. Miedema2, Jan H. von der Thüsen3 and Marlies S. Wijsenbeek2 Trafficking and lysosomal storage disorders represent a large and highly heterogeneous group of inherited conditions that are increasingly being recognised. Due to the systemic nature of these disorders, virtually any organ can be involved, including the lung. Pulmonary involvement, which can range from obstructive lung disease to pulmonary fibrosis depending on the underlying disease, is a significant contributor to the overall morbidity and mortality of these conditions and can manifest either at presentation or later in the disease course. Therefore, when suspected, lung disease should be promptly investigated and treated. Despite improved knowledge and understanding of disease pathogenesis, effective treatment options remain limited, particularly for pulmonary disease. Trafficking and lysosomal storage disorders are difficult to diagnose and treat. Only the integration of a dedicated team of specialists, which is only available in expert centres, may provide adequate care for patients suffering from these disorders. Finally, as with other rare diseases, only international collaborative effort may allow the recruitment of sufficiently large populations of patients to enrol in clinical trials of novel therapies. Cite as: Spagnolo P, Miedema JR, von der Thüsen JH, et al. Trafficking and lysosomal storage disorders. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 319–332 [https://doi.org/10.1183/2312508X. 10015419].

@ERSpublications Pulmonary involvement is a major contributor to morbidity and mortality of trafficking and lysosomal storage disorders. Therefore, when suspected, it should be promptly investigated and possibly treated. http://bit.ly/2lDj2R7

L

ysosomes are cytoplasmic organelles involved in the breakdown and recycling of macromolecules, including proteins, lipids, carbohydrates and nucleic acids. Lysosomal storage diseases (LSDs) are a heterogeneous group of monogenic disorders of lysosomal catabolism, with an estimated incidence ranging from 1 in 50 000 to 1 in 250 000 live births [1]. They comprise over 70 genetically distinct conditions, most of which follow an 1 Respiratory Disease Unit, Dept of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy. 2Dept of Pulmonary Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. 3Dept of Pathology, Erasmus Medical Centre, Rotterdam, The Netherlands.

Correspondence: Paolo Spagnolo, Respiratory Disease Unit, Dept of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, via Giustiniani 2, 35128 Padova, Italy. E-mail: [email protected] Copyright ©ERS 2019. Print ISBN: 978-1-84984-111-5. Online ISBN: 978-1-84984-112-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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autosomal-recessive pattern of inheritance and are characterised by an enzyme deficiency resulting in cellular dysfunction secondary to the accumulation of nondegraded or partially degraded substrates inside lysosomes. LSDs typically manifest in infancy and childhood, although late-onset forms also occur. Depending on the specific substrate, residual activity of the mutant protein and site of accumulation, LSDs may present with a broad spectrum of clinical manifestations, often with severe morbidity and high mortality. Indeed, because LSDs are systemic disorders, virtually all organs may be involved, including the respiratory system, either at presentation or as late-onset complications [2]. As with other rare diseases, LSDs are adversely impacted by the limited knowledge of the general medical community, which translates to delayed diagnosis. In addition, they are difficult to manage due to the lack of truly effective therapies. Consequently, the emotional and social impact of these diseases on patients and their families is substantial.

Hermansky–Pudlak syndrome Hermansky–Pudlak syndrome comprises a group of rare autosomal-recessive disorders characterised by various degrees of oculocutaneous albinism (OCA) and bleeding diathesis. Other clinical characteristics such as pulmonary fibrosis, granulomatous colitis and immune defects may also occur in some forms. The first description of the disease originates from 1959, with Frantisek Hermansky and Paulus Pudlak describing two Czech patients with OCA, bleeding diathesis and unusual pigmented reticular cells in the bone marrow [3]. Hermansky–Pudlak syndrome has a prevalence of 1–2 in 1 000 000 individuals worldwide but is more common in certain populations such as Puerto Ricans, among which ∼1 in 22 individuals carry the causal mutation [4, 5]. To date, 10 genetic subtypes of the disease have been described (genes HPS1–HPS10), but the exact relationships between mutations within HPS genes and clinical expressions of the disease remain to be elucidated [5]. HPS genes encode protein complexes called biogenesis of lysosome-related organelles (BLOCs), which are expressed in many cell types. BLOCs are essential in intracellular trafficking and the formation of lysosome-related organelles such as melanosomes and platelet-dense granules and lamellar bodies (responsible for surfactant synthesis and secretion in alveolar type II cells) [6]. The pathogenesis of organ damage in Hermansky–Pudlak syndrome is unclear. However, lysosomal accumulation of ceroid lipofuscin (an amorphous, autofluorescent lipid–protein material) is believed to cause granulomatous colitis in HPS1 and lung fibrosis in HPS1, HPS2 and HPS4 [7]. All subtypes are associated with OCA, which includes hypopigmentation of the hair, skin and eyes. However, the degree of hypopigmentation is variable, with skin and hair colour ranging from white to brown but significantly paler than family members [8]. Besides retinal and iris hypopigmentation, a reduction in vision and horizontal nystagmus can also be found [7, 8]. Bleeding diathesis is also present in all patients and can vary clinically from easy bruising and epistaxis to post-partum haemorrhage and serious bleeding during surgery [5, 7]. Pulmonary fibrosis is seen in virtually all patients with HPS1 disease and in a subgroup of those with HPS2 and HPS4 disease but not in the other subtypes [4]. The onset of pulmonary fibrosis is reported as early as adolescence but more typically occurs at 30–40 years of age [7]. Chest HRCT reveals peripheral reticulation, thickened interlobular septa and fibrotic changes such as traction bronchiectasis and bronchiolectasis, sometimes associated with ground-glass opacities (figure 1) [9]. Progression of pulmonary fibrosis is variable, even in patients carrying the same HPS mutations [10]. Fibrosis may resemble 320

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Figure 1. Chest HRCT of a patient with Hermansky–Pudlak syndrome type 1 subtype, showing subpleural reticulation with traction bronchiolectasis, some inlying ground-glass opacity in the fibrotic area and discrete honeycombing.

that seen in IPF, although honeycombing, when present, is not predominantly subpleural as in UIP/IPF, and the active fibroblastic foci seen in UIP/IPF are generally not present in Hermansky–Pudlak syndrome [11]. Besides the age of onset (IPF usually affects the elderly), lung function decline and survival also differ between IPF and Hermansky–Pudlak syndrome, although acute respiratory deterioration (i.e. acute exacerbation) is a well-described, although rare, complication of the latter [12, 13]. Although early detection of fibrosis may influence survival, patients with Hermansky–Pudlak syndrome/pulmonary fibrosis (HPS-PF) die young, commonly between 40 and 60 years of age. In many patients with Hermansky–Pudlak syndrome, albinism is the first clue to diagnosis, although it can be subtle and missed; ophthalmological examination and excessive bleeding and bruising may also indicate the diagnosis. Platelet electron microscopy is recommended to evaluate the absence of dense bodies in platelets, which is the hallmark of Hermansky– Pudlak syndrome [14]. Conversely, bleeding time assessment is not reliable and is not recommended in the diagnostic work-up of this disease [7]. Genetic testing is indicated to determine the different subtypes of Hermansky–Pudlak syndrome, which may help predict clinical manifestations, thus informing on timing of follow-up and prognosis [5, 7]. Clinical features can also guide genetic testing (table 1) and, if negative, a multi-HPS gene panel can be tested [5]. If genetic testing is not available, a patient with classical disease manifestations (i.e. OCA with bleeding diathesis, pulmonary fibrosis or colitis) should be considered as having Hermansky–Pudlak syndrome. Furthermore, not all patients with clinical features of this disease carry known pathogenic mutations, suggesting the existence of additional genetic variants [15]. In patients with pulmonary fibrosis and (suspicion of) Hermansky–Pudlak syndrome, diagnostic lung biopsies should be avoided because of the risk of bleeding. Currently, there are no specific therapies for HPS-PF. As pulmonary fibrosis in Hermansky–Pudlak syndrome shares many similarities with IPF, treatment strategies that have proven effective in slowing down functional decline and disease progression in IPF https://doi.org/10.1183/2312508X.10015419

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Table 1. Clinical features of Hermansky–Pudlak syndrome that may guide genetic testing Hermansky–Pudlak syndrome subtype

Clinical features

HPS1

OCA, bleeding diathesis, nearly all pulmonary fibrosis, granulomatous colitis around 30% OCA, bleeding diathesis, pulmonary fibrosis, neutropenia or recurrent infections OCA, bleeding diathesis, more frequent in Ashkenazi Jews and central Puerto Ricans OCA, bleeding diathesis, pulmonary fibrosis OCA, bleeding diathesis OCA, bleeding diathesis, granulomatous colitis OCA, bleeding diathesis OCA, bleeding diathesis OCA, bleeding diathesis OCA, bleeding diathesis

HPS2 HPS3 HPS4 HPS5 HPS6 HPS7 HPS8 HPS9 HPS10 OCA: oculo-cutaneous albinism.

have also been investigated in Hermansky–Pudlak syndrome. A first trial showed no significant effect of pirfenidone on FVC decline, although secondary analysis suggested a beneficial effect of the drug in a subgroup of patients with FVC >50% [16]. However, a subsequent study in HPS-PF patients with more preserved lung function showed no benefit and was prematurely discontinued [17]. Small case series have suggested a clinical benefit of pirfenidone in HPS-PF [18]. Research for disease biomarkers and novel therapies is very active in HPS-PF (ClinicalTrials.gov identifier NCT02368340). Lung transplantation remains the only potentially life-extending therapy for progressive lung fibrosis. Indeed, despite the risk of bleeding, lung transplantation has been performed successfully in Hermansky–Pudlak syndrome and may represent a viable therapeutic option in a selected minority of patients [19]. Further management recommendations for HPS-PF are based mostly on experiences in IPF and include influenza and pneumococcal vaccinations, pulmonary rehabilitation and comprehensive support [20].

Gaucher disease Gaucher disease (GD) is an autosomal-recessive disorder caused by mutations in the glucocerebrosidase 1 (GBA1) gene, leading to defective glucocerebrosidase (GBA), an enzyme involved in lysosomal glycolipids degradation [21]. In affected individuals, deficient GBA leads to accumulation of insoluble glucocerebroside (glucosylceramide) and other glycolipids within the lysosomes of monocytes and macrophages. Lipid-laden and distended macrophages are referred to as Gaucher cells. Tissue accumulation of Gaucher cells may result in hepatomegaly, liver fibrosis, splenomegaly with secondary cytopenia and bone disease. In some cases, Gaucher cells can infiltrate other tissue such as the lung interstitium, alveolar spaces or pulmonary vasculature, although the exact mechanisms by which organ damage develops remain unclear [22]. GD is one of the most common LSDs, with an estimated prevalence of 0.70 to 1.75 per 100 000 [23]; disease prevalence is even higher in the Ashkenazi Jewish population [24]. 322

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Establishing the diagnosis of GD requires the detection of deficient GBA enzyme activity in peripheral blood leukocytes; however, molecular genetic testing can detect pathogenic variants within the GBA1 gene, thus confirming the diagnosis, or identifying mutation carriers [22]. Patients with GD display a wide spectrum of clinical phenotypes, ranging from asymptomatic adults to children who die from devastating neurological disease. GD is classified into three broad phenotypes based on the presence or absence of neurological involvement: type 1 (nonneuronopathic), type 2 (acute neuronopathic) and type 3 (subacute or chronic neuronopathic), with type 2 and 3 disease being less frequent than type 1 disease. Type 2 disease manifests before the first year of life with a rapidly progressive course leading to death in the early years of life, whereas patients with type 3 disease often experience a slowly progressive disease course [21, 22]. Type 1 GD (GD1), the nonneuropathic form, is often referred to as adult-type GD, but the majority of symptomatic GD1 patients are diagnosed before reaching adulthood [22]. GD1 is characterised by hepatosplenomegaly, haematological abnormalities, and clinical or radiographic bone involvement in up to 94% of patients [21, 22, 25]. Distal flaring of the femur or Erlenmeyer flask deformity is a typical sign of the disease and is found in approximately half of patients [25]. Other frequent bone complications of GD include osteopenia, bone marrow infiltration, bone infarction or avascular necrosis [25]. In patients with mild or asymptomatic GD1 disease, the diagnosis may be established at an older age or as an incidental finding. Clinically significant pulmonary involvement is described in GD2 and GD3, but is a rare finding in the adult-type GD1 [21, 26]. However, pulmonary function abnormalities are common in GD1. Indeed, in a large GD1 cohort, 68% of patients had abnormal lung function but most were asymptomatic [27]. A reduced functional residual capacity (FRC) or a reduced transfer coefficient of the lung for carbon monoxide (KCO) was found in 45% and 42% of patients, respectively [27]. The reduced FRC may be secondary to the upward displacement of the diaphragm due to hepatosplenomegaly, while the decreased KCO may be due to the accumulation of Gaucher cells in the alveolar spaces, interstitium or vascular bed [27]. Although pulmonary involvement is rare in GD1 patients, KEREM et al. [27] found some abnormality on chest radiographs in 17% of patients. When pathological, HRCT reveals mainly reticular abnormalities, compatible with infiltration of the lung interstitium by Gaucher cells. ILD may vary from minimal subpleural and basal thickening of interand intralobular septa to extensive ground-glass opacities superimposed over marked and diffuse reticular changes (“crazy-paving” pattern) [26, 28]. Prominent pulmonary arteries may reflect PH (figure 2). On pathological examination of lung biopsies, infiltration by Gaucher cells may vary from intracapillary or interstitial accumulation with lymphatic distribution to thickening of the alveolar septa and intra-alveolar infiltrates (figure 3) [29]. Occlusion of the pulmonary vasculature by Gaucher cells has been suggested as a mechanism for the development PH. Arteriovenous shunting secondary to liver involvement (hepatopulmonary syndrome) is another serious complication of GD [30]. GD is characterised by (often dramatically) increased levels of angiotensin-converting enzyme (ACE). DANILOV et al. [31] recently showed that the increased levels of ACE originate from activated splenic and/or hepatic macrophages (Gaucher cells), and that both its conformational fingerprint and kinetic characteristics differ from those of controls and patients with sarcoid granulomas, suggesting that the conformational differences in ACE may serve as a specific biomarker for GD. https://doi.org/10.1183/2312508X.10015419

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Figure 2. PH in a patient with Gaucher disease. Note the enlarged main pulmonary artery diameter.

Enzyme replacement therapy (ERT) and substrate reduction therapy are available (but costly and long-term) treatment options for GD, with the aim of reducing the accumulation of glucocerebroside in macrophages. ERT reduces splenic and hepatic volumes and improves haematological abnormalities, with only a few adverse events leading to discontinuation of treatment [22, 32]. There have also been reports of improved pulmonary disease after ERT, but the response is variable and lung involvement may persist [32]. Plasma chitotriosidase, a biomarker of macrophage activation that can be elevated in various lysosomal and nonlysosomal diseases including GD, Niemann–Pick disease, malaria, thalassaemia and fungal infections, may be useful for monitoring disease severity and effectiveness of therapy. Indeed, the chitotriosidase level usually decreases and remains stable with adequate ERT or substrate reduction therapy. However, a null CHIT1 allele is highly prevalent among GD patients, with 5% of individuals being homozygous and 35% heterozygous for this null allele in the Caucasian population. Therefore, chitotriosidase activity needs to be interpreted in the context of the CHIT1 genotype. Successful bilateral lung transplantation has been described in a patient with PH [33], but this remains a viable

a)

b)

c) *

*

*

Figure 3. a–c) Haematoxylin-eosin stained slides of lung explant specimens from a patient with Gaucher disease, demonstrating a) only focal parenchymal involvement, b) interstitial accumulation of foamy histiocytes, with a predilection for perivascular areas (asterisks denote blood vessels), and c) a typical appearance of Gaucher cells with foamy cytoplasm containing small to moderate amounts of pigment related to ceroid lipofuscin (arrow). Scale bars: a) 1 mm; b) 0.1 mm; c) 0.05 mm.

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therapeutic option for only a selected minority of patients. Future treatment options for GD may include gene therapy, despite current concerns about toxic effects [22].

Niemann–Pick disease Niemann–Pick disease (NPD), also known as sphingomyelin–cholesterol lipidosis, represents a heterogeneous group of autosomal-recessive disorders associated with abnormal storage of lipids, including cholesterol and sphingomyelin [34–37]. NPD is classified into three subtypes (types A/B and C), which, despite a common name, differ in disease mechanism, pathogenesis and clinical manifestations. NPD type A/B is characterised by deficient acid sphingomyelinase activity secondary to a mutant sphingomyelin phosphodiesterase 1 (SMPD1) gene, which results in systemic accumulation of sphingomyelin. Similar to GD, plasma levels of chitotriosidase are markedly increased in NPD type B, thus serving as an early biochemical surrogate marker of disease [38, 39]. NPD type C is caused by nonfunctional mutations within NPC1 (95% of patients) and NPC2 genes that alter intracellular lipid processing and transport, leading to abnormal storage of low-density lipoprotein–cholesterol in several organs, mainly the brain, liver and spleen. NPD type A, which has a predilection for Ashkenazi Jews and represents the severe, early-onset form of the disease, is characterised by progressive neurological degeneration leading to death by 3–4 years of age [40], whereas NPD type B, the less severe, later-onset form, is characterised by thrombocytopenia, hepatosplenomegaly and ILD with minimal/no neurological involvement. The overall prevalence of NPD type A/B is estimated to be 1 in 250 000 [1]. The diagnosis is based on elevated plasma levels of oxysterols, particularly lyso-sphingomyelin, along with the identification of pathogenic SMPD1 variants. Clinical presentation of NPD type C is generally dominated by neurological involvement, with virtually all patients ultimately developing a progressive and fatal neuropathy that manifests with cerebellar ataxia, dysarthria, dysphagia and progressive dementia. ILD and liver failure represent additional causes of death in severe cases, whereas dysphagia and chronic aspiration are common causes of recurrent respiratory infections [41]. The estimated prevalence of NPD type C is about 1 in 150 000 [36]. The lifespan of affected individuals varies widely, but patients deteriorate progressively and generally do not survive beyond the second decade. C-triol is a sensitive and specific biomarker for NPD type C, but confirmation of the diagnosis requires the identification of pathogenic variants within NPC1 or NPC2 [41]. Lung involvement is a common complication of NPD, but its exact prevalence is unknown. In a retrospective study of patients with type A (n=1), type B (n=10) and type C (n=2) disease, lung involvement, as assessed by clinical evaluation, chest radiograph, chest HRCT, PFTs and BAL fluid analysis, was observed in all cases [42]. Lung disease occurs most frequently in type B disease, with clinical presentation ranging from mild exertional dyspnoea to respiratory failure [43]. In a series of 53 patients with NPD type B, chest CT revealed ILD in 51 (98%), with upper-lobe-predominant ground-glass opacity and basal-predominant interlobular septal thickening being the most common features, often in the absence of functional abnormalities [44]. ILD may be the presenting feature of NPD type C [36], and a subset of infants carrying loss-of-function mutations within NPC2 may develop pulmonary alveolar proteinosis (PAP) and respiratory failure secondary to the accumulation of functionally inactive cholesterol-rich surfactant in alveolar macrophages [45]. Pulmonary disease may also present as endogenous lipoid pneumonia, which is characterised by the accumulation of sphingomyelin-laden, foamy-appearing macrophages (figure 4) that stain https://doi.org/10.1183/2312508X.10015419

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a)

b)

c)

Figure 4. Lung biopsy of a patient with Niemann–Pick disease characterised by a and b) diffuse and primarily intra-alveolar accumulation of foamy histiocytes, with a voluminous cytoplasm and dense “jigsaw”-like arrangement (haematoxylin-eosin stain; the arrow indicates the unaffected interalveolar septum), and c) an immunohistochemical stain for CD68 (arrow), confirming the histiocytic nature of the cells and the extent of the disease. Scale bars: a) 1 mm; b) 0.1 mm; c) 0.5 mm.

deep blue with May–Grunwald–Giemsa stain (“sea-blue histiocytes” or Niemann–Pick cells) within the bronchial wall, alveolar space, alveolar septa and lymphatic interlobular vessels [46]. When abnormal, PFTs reveal a restrictive ventilatory defect with or without reduced DLCO. There are no specific therapies for NPD, but the search for novel treatments is very active and a large number of trials are underway. In patients with NPD type B, endogenous lipid pneumonia may be treated successfully with whole-lung lavage [47]. However, progressive respiratory failure leading to death following whole-lung lavage has also been reported in an infant with the same type of NPD [48]. Lung transplantation has been performed successfully in NPD type B, although only three such cases have been reported to date [49]. The long-term outcome of NPB is highly variable. The differential diagnosis between NPD and GD may not be obvious. Indeed, HRCT findings of GD (i.e. diffuse thickening of interlobular septa and ground-glass opacity) may overlap those of NPD [31]. Microscopic analysis of BAL fluid may display lipid-laden macrophages, which are suggestive, although not pathognomonic, of NPD, or Gaucher cells, which suggest GD [31]. However, an enzyme assay enables the differential diagnosis between GD and NPD by showing reduced GBA activity and reduced acid sphingomyelinase activity, respectively, thus making lung biopsy unnecessary in the majority of cases [50].

Fabry disease Fabry disease is an X-linked LSD that results from mutations in the gene encoding α-galactosidase A (GLA), leading to deficient enzymatic activity and abnormal deposition of glycosphingolipids (predominantly globotriaosylceramide and, to a lesser extent, galactosylceramide) within the lysosomes of virtually all cell types, although vascular endothelial cells and smooth muscle cells are the main targets of the disease [51]. Abnormal storage of glycosphingolipids, which on electron microscopy appear as lamellar inclusion bodies within affected cells (figure 5) [52], causes tissue damage by both impairing perfusion, thus causing thrombosis, ischaemia and infarctions, and by triggering inflammation and fibrosis. The diagnosis requires the demonstration of deficient α-galactosidase A activity or increased levels of globotriaosylceramide in urine. The classic and most severe form of Fabry disease occurs predominantly in males and presents with neuropathic pain in the distal extremities, cutaneous vessel ectasia, and corneal and lenticular opacities, although some heterozygous females may have clinical features that resemble those of classic Fabry disease in males. This is due to an excessive number of X chromosomes carrying the normal GLA allele being inactivated during the process of X inactivation that take place in the female embryo. 326

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b)

Figure 5. a and b) Electron microscopic images of a myocardial biopsy in a patient with Fabry disease demonstrating the extensive presence of intracytoplasmic electron-dense lamellated bodies (arrows). Scale bars: 2 μm.

The disease generally begins in childhood, but late-onset variants may present in adulthood, mainly with cardiac manifestations, including left ventricular hypertrophy, arrhythmias and myocardial fibrosis [53, 54]. In the lung, progressive narrowing of the airways by glycosphingolipids accumulating in the bronchial cells causes bronchial obstruction, which was reported in 26% of female and 61% of male patients in one series [55, 56]. Occasionally, Fabry disease may manifest as pulmonary fibrosis [57] or DAH associated with renal failure (pulmonary–renal syndrome) [58]. Excessive daytime sleepiness has also been reported, but whether this is due to sleep-related breathing disorders secondary to neurological involvement or to heart failure remains unclear [59]. Death usually occurs from cardiac or cerebrovascular disease or renal failure. Safety and efficacy of ERT with recombinant GLA, which has been available for the treatment of Fabry disease since 2001 in Europe and since 2003 in the USA, has been confirmed in several trials. GERMAIN et al. [60] have recently conducted a systematic literature review of all original articles on ERT for the treatment of Fabry disease in adult patients. In males (166 publications including 36 clinical trials), ERT provided clinical benefits on several outcomes, including glomerular filtration rate, left ventricular mass, cardiac wall thickness and quality of life. Similarly, in females (67 publications, including six clinical trials), ERT was associated with improvement in cardiac parameters, quality of life and globotriaosylceramide plasma and urine levels [60]. Conversely, the efficacy of ERT on pulmonary involvement remains to be demonstrated [55]. New therapeutic approaches are being developed, such as chaperone therapy for patients with amenable mutations, but their role in the treatment of Fabry disease remains undefined.

Lysinuric protein intolerance Lysinuric protein intolerance (LPI) is an autosomal-recessive disease characterised by defective plasma membrane transport of the cationic amino acids lysine, arginine and ornithine [61]. The disease is caused by mutations in the solute carrier family 7A member 7 (SLC7A7) gene on 14q11.2, which encodes y+ LAT-1, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family. LPI is found worldwide but the highest prevalence rates have been observed in Finland and Japan (1 in https://doi.org/10.1183/2312508X.10015419

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60 000 and 1 in 57 000 newborns, respectively) [62]. The wide spectrum of clinical manifestations includes protein intolerance, anorexia, failure to thrive, growth retardation, hepatosplenomegaly and osteoporosis. Patients can present from the neonatal period to adulthood. The diagnosis of LPI requires amino acid assays in plasma and urine, revealing increased urinary excretion and low plasma concentrations of lysine, arginine and ornithine, and is confirmed by the identification of pathogenic variants within SLC7A7. Pulmonary involvement ranges from subclinical interstitial abnormalities to acute and life-threatening respiratory failure secondary to PAP [63]. In such cases, chest radiography reveals bilateral alveolar infiltrates more prominent in the perihilar regions (“butterfly” or “bat-wing” appearance), whereas HRCT shows a characteristic pattern of ground-glass opacities superimposed over thickened interlobular and intralobular septa forming polygonal shapes (“crazy paving”). In a recent retrospective study, ILD was reported in 10 out of 16 LPI patients during follow-up [64]. Notably, all 10 patients had PAP, and six of them died from respiratory failure at a mean age of 4.0 years. Similar to other forms of alveolar proteinosis, the treatment of choice is whole-lung lavage [65] whereas dietary protein restriction and citrulline supplementation do not appear to be beneficial. ILD may also develop independently from PAP; in such cases, the majority of symptomatic patients report wheezing, recurrent respiratory infections and cough, whereas PFTs typically reveal a restrictive ventilatory defect associated with a reduced DLCO [64, 66].

Mucopolysaccharidosis and mucolipidosis Mucopolysaccharidosis (MPS) and mucolipidosis (ML) comprise a group of inherited storage disorders caused by the deficiency or absence of enzymes involved in the degradation of glycosaminoglycans and oligosaccharides, respectively, leading to substrate accumulation in various tissues and organs. With the exception of the X-linked MPS II (Hunter syndrome), MPS and ML are transmitted in an autosomal-recessive manner. Both MPS and ML are characterised by a spectrum of clinical manifestations ranging from multisystem involvement, growth retardation and reduced life expectancy to a mildly abnormal clinical phenotype with a normal life span [67]. Pulmonary disease is a frequent complication of both MPS and ML, and is one of the main causes of morbidity and mortality [68]. Restrictive lung disease secondary to skeletal (chest and spine) involvement is common in MPS IV (Morquio syndrome) and MPS VI (Maroteaux–Lamy syndrome), with upper and lower respiratory tract infections (MPS I, Hurler–Scheie syndrome), sleep-disordered breathing (MPS I) and progressive airway narrowing and tracheomalacia (MPS IV) representing additional common manifestations [69]. Hypoventilation may also occur because of either neurological involvement and respiratory muscle weakness (MPS IV) or hepatosplenomegaly limiting diaphragmatic excursion [70]. Similar to MPS, respiratory manifestations of ML are highly variable and include upper respiratory infections (in childhood), pneumonia (in late childhood) and restrictive lung disease caused by stiffening of the thoracic cage, sclerosis of bronchi, and hardening and thickening of the lung interstitium (in adults) [71]. Treatment is similar to that of other forms of obstructive and restrictive lung disease and is primarily symptomatic.

Pompe disease Pompe disease (PD) is a rare autosomal-recessive disorder caused by absent or reduced functional acid α-glucosidase and is characterised by the accumulation of glycogen within 328

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the lysosomes in various tissues and organs [72]. Disease prevalence varies greatly (from 1 in 14 000 to 1 in 100 000) depending on ethnicity and geographical region [73]. Similarly variable is the spectrum of clinical phenotypes, the rate of progression and prognosis, which depend on the gene mutation involved and the level of residual acid α-glucosidase activity [74]. Classic early-onset (infantile) PD presents with diffuse muscle weakness, cardiomegaly, hypertrophic cardiomyopathy and failure to thrive, leading to death in the first year of life, mainly from progressive cardiac failure, whereas the nonclassic variant of infantile-onset PD is characterised by slowly progressive muscle weakness leading to death in early childhood from ventilatory failure [75]. Late-onset (i.e. childhood, juvenile and adult-onset) PD is characterised by proximal muscle weakness and respiratory dysfunction, which complicates up to 79% of adult-onset cases and 59% of childhood-onset cases [76]. Pulmonary dysfunction is related mainly to progressive weakness of respiratory muscles resulting in respiratory failure and alveolar hypoventilation [77]. In turn, the development of respiratory failure necessitates mechanical nocturnal and daytime ventilator support, which is associated with a reduced quality of life [75]. Recurrent pneumonia and bronchitis are additional prevalent respiratory complications [78, 79]. Although the majority of late-onset PD patients have slowly progressive disease, their life expectancy is lower compared with that of the general population, with respiratory failure representing the most frequent cause of death [80].

Concluding remarks Trafficking and LSDs represent a large and heterogeneous group of conditions with complex pathogenesis, diverse clinical manifestations, specific histopathological and radiographic features, and variable natural history and prognosis. Management of affected individuals poses a number of challenges, and only expert centres with dedicated multidisciplinary teams may ensure reliable diagnosis and adequate care, as well as participation in research, including clinical trials of pharmacological interventions. For small subgroups of patients, therapeutic options may exist, although overall treatment options are limited. Fortunately, the past decade has witnessed major advances in our knowledge and understanding of these disorders, but much work remains to be done. For instance, how multiple susceptibility alleles interact with each other and with environmental factors to determine disease risk and phenotypes is largely unknown. Ongoing basic research will hopefully provide insights into the molecular basis of disease pathogenesis, and is expected to identify diagnostic biomarkers, predictors of disease behaviour and potential targets for therapeutic intervention. To this end, international collaboration, by allowing the collection of sufficiently large cohorts of patients, is essential. It is to be hoped that this will reduce the considerable morbidity and mortality associated with these disorders.

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Recommendations for the detection and diagnosis of Niemann–Pick disease type C: an update. Neurol Clin Pract 2017; 7: 499–511. 42. Guillemot N, Troadec C, de Villemeur TB, et al. Lung disease in Niemann–Pick disease. Pulmonol 2007; 42: 1207–1214. 43. von Ranke FM, Pereira Freitas HM, Mançano AD, et al. Pulmonary involvement in Niemann–Pick disease: a state-of-the-art review. Lung 2016; 194: 511–518. 44. Mendelson DS, Wasserstein MP, Desnick RJ, et al. Type B Niemann–Pick disease: findings at chest radiography, thin-section CT, and pulmonary function testing. Radiology 2006; 238: 339–345. 45. Griese M, Brasch F, Aldana VR, et al. Respiratory disease in Niemann–Pick type C2 is caused by pulmonary alveolar proteinosis. Clin Genet 2010; 77: 119–130. 46. Nicholson AG, Florio R, Hansell DM, et al. Pulmonary involvement by Niemann–Pick disease. A report of six cases. Histopathology 2006; 48: 596–603. 47. Nicholson AG, Wells AU, Hooper J, et al. Successful treatment of endogenous lipoid pneumonia due to Niemann– Pick Type B disease with whole-lung lavage. Am J Respir Crit Care Med 2002; 165: 128–131. 48. Uyan ZS, Karadağ B, Ersu R, et al. Early pulmonary involvement in Niemann–Pick type B disease: lung lavage is not useful. Pediatr Pulmonol 2005; 40: 169–172. 49. O’Neill RS, Belousova N, Malouf MA. Pulmonary type B Niemann–Pick disease successfully treated with lung transplantation. Case Rep Transplant 2019; 2019: 9431751. 50. Castañón Martínez R, Fernández-Velilla Peña M, González Montaño MV, et al. Lung affectation in an adult patient with Niemann–Pick disease, type B. Arch Bronconeumol 2012; 48: 213–215. 51. Clarke JT. Narrative review: Fabry disease. Ann Intern Med 2007; 146: 425–433. 52. Kelly MM, Leigh R, McKenzie R, et al. Induced sputum examination: diagnosis of pulmonary involvement in Fabry’s disease. Thorax 2000; 55: 720–721. 53. Branton MH, Schiffmann R, Sabnis SG, et al. Natural history of Fabry renal disease: influence of α-galactosidase A activity and genetic mutations on clinical course. Medicine 2002; 81: 122–138. 54. Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab 2018; 123: 416–427. 55. Magage S, Lubanda JC, Susa Z, et al. Natural history of the respiratory involvement in Anderson–Fabry disease. J Inherit Metab Dis 2007; 30: 790–799. 56. Franzen DP, Nowak A, Haile SR, et al. Long-term follow-up of pulmonary function in Fabry disease: a bi-center observational study. PLoS One 2017; 12: e0180437. 57. Koskenvuo JW, Kantola IM, Nuutila P, et al. Cardiopulmonary involvement in Fabry’s disease. Acta Cardiol 2010; 65: 185–192. 58. Shirai T, Ohtake T, Kimura M, et al. Atypical Fabry’s disease presenting with cholesterol crystal embolization. Intern Med 2000; 39: 646–649. 59. Duning T, Deppe M, Keller S, et al. Excessive daytime sleepiness is a common symptom in Fabry disease. Case Rep Neurol 2009; 1: 33–40. 60. Germain DP, Elliott PM, Falissard B, et al. The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: a systematic literature review by a European panel of experts. Genet Metab Rep 2019; 19: 100454. 61. Sebastio G, Sperandeo MP, Andria G. Lysinuric protein intolerance: reviewing concepts on a multisystem disease. J Med Genet C Semin Med Genet 2011; 157C: 54–62. 62. Koizumi A, Shoji Y, Nozaki J, et al. A cluster of lysinuric protein intolerance (LPI) patients in a northern part of Iwate, Japan due to a founder effect. The Mass Screening Group. Hum Mutat 2000; 16: 270–271. 63. Olgier de Baulny O, Schiff M, Dionisi-Vici C. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol Genet Metab 2012; 106: 12–17. 64. Mauhin W, Habarou F, Gobin S, et al. 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Disclosures: P. Spagnolo reports receiving grants, personal fees and nonfinancial support from PPM Services during the conduct of this study. P. Spagnolo reports receiving the following, outside the current work: personal fees and nonfinancial support from Roche, Boehringer Ingelheim and Zambon; and personal fees from Galapagos and Chiesi. J.R. Miedema reports receiving personal fees from Roche and Boehringer Ingelheim, outside the submitted work. M.S. Wijsenbeek reports receiving the following, outside the submitted work: grants and other fees paid to his institution from Boehringer Ingelheim and Hoffman la Roche; and other fees paid to his institution from Galapagos, Respivant and Savara.

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| Chapter 19 Haematological disorders and bone marrow transplant recipients Venerino Poletti1,2, Sara Colella3, Sara Piciucchi4, Marco Chilosi5, Alessandra Dubini6, Sissel Kronborg-White2, Sara Tomassetti1 and Claudia Ravaglia1 The lungs are a clinically significant targeted organ in patients with haematological disorders. A variety of haematological disorders (mainly the lymphoproliferative ones) may have their first manifestation in the lungs or may easily spread to the lungs. Treatment-related complications, such as infections, drug-related lung injury and graft-versus-host disease (GVHD) lung manifestations, are even more clinically relevant. Diagnosis is mainly based on clinical reasoning (knowledge of the various features by which these entities manifest, the understanding of the pathogenetic mechanisms involved and, as background, strong clinical expertise in the field), the use of laboratory tests and, in a minority of cases, invasive approaches. Treatment is based on data provided by clinical trials (mainly in infections and malignancies) and on statements from expert opinions. All of these aspects are discussed in this chapter and a diagnostic algorithm is presented. Cite as: Poletti V, Colella S, Piciucchi S, et al. Haematological disorders and bone marrow transplant recipients. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 333–358 [https://doi.org/10.1183/ 2312508X.10015519].

@ERSpublications Clinicians must know mechanisms that lead to lung injury in haematological disorders, as well as the clinical profile, pathology and radiological findings by which they manifest. Treatment is a challenge but guidelines suggest validated approaches. http://bit.ly/2lDj2R7

P

ulmonary involvement in patients with haematological diseases is frequent [1]. The main factors that render the lung a clinically significant targeted organ in these patients can be summarised as follows. 1) In lung parenchyma, a variety of inflammatory cells whose precursors are in bone marrow, pass through, park in, proliferate and release microbicidal and histotoxic substances. 2) The peculiar retention of polymorphonuclear cells in the lung capillaries has been documented in experimental studies [1]. 3) Pathogenic agents are able to easily reach the lung via the airways and/or the vascular bed (the pulmonary vascular bed 1 Dept of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy. 2Dept of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark. 3Pulmonology Unit, Ospedale C Mazzoni, Ascoli Piceno, Italy. 4Dept of Radiology, Ospedale GB Morgagni, Forlì, Italy. 5University of Verona, Verona, Italy. 6Dept of Pathology, Ospedale GB Morgagni, Forlì, Italy.

Correspondence: Venerino Poletti, Pneumologia, Ospedale GB Morgagni, Via Carlo Forlanini 34, 47100, Forlì, Italy. E-mail: venerino. [email protected] Copyright ©ERS 2019. Print ISBN: 978-1-84984-111-5. Online ISBN: 978-1-84984-112-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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receives the blood from the rest of the body) and accumulate in large amounts. 4) Inflammatory/immunological reactions can be either particularly weak or strong, and can occur spontaneously or due to the toxic action of drugs and radiation, the immunodeficiency induced by haematological disorders or, finally, to the presence of immunomodulatory viruses, such as human herpes viruses (HHV) and HIV. 5) The lung parenchyma’s distinctive anatomical structure and function (interactions between air spaces and capillary vessels, gas exchange units) may render localised parenchymal damage clinically relevant. 6) The high-dose therapy used in haematopoietic cell transplantation results in toxicities directly induced by treatment and secondarily by the prolonged immunodeficiency and extended recovery process. 7) A variety of haematological disorders may first manifest in the lungs or can easily spread to the lungs [2]. 8) Allogeneic reactions may be overexpressed in the lungs. Table 1 presents a list of pulmonary disorders that have a clear link to haematological diseases and/or their treatment.

Haematological disorders manifesting ( primarily or as clinically relevant disorders) in the lungs Haematological neoplasms

Virtually all haematological neoplasms can involve the lungs (lung parenchyma, large airways or pleura) during their course and in fact are not a rare event in clinical practice. On the contrary, primary pulmonary lymphomas are rare, accounting for 50% of primary pulmonary lymphoma cases). As for other types of extranodal mucosa-associated B lymphomas, the neoplastic B-cells show features of memory post-germinal centre “marginal-zone” cells, including morphology and immunophenotype [3]. The pathogenesis of pulmonary MALT lymphomas is not completely defined but can be related to abnormal stimulation of the bronchus-associated lymphoid tissue by different triggers, including either autoimmunity (Sjögren syndrome, common variable immunodeficiency syndrome) or infection [4–6]. In contrast with other types of MALT lymphomas, such as gastric and ocular lymphomas where a microorganism’s role has been clearly established, this mechanism has been poorly defined for P-MALTL. Nevertheless, recent studies have detected the microorganism Achromobacter xylosoxidans with significant frequency [7].

As with other types of extranodal MALT lymphomas, a variety of cytogenetic abnormalities has been demonstrated in P-MALTL, including translocations and/or trisomies, which can provide very useful diagnostic information. The most frequent cytogenetic abnormalities in P-MALTL are the t(11;18)[q21;q21], observed in ⩽50% [3, 8]. In this translocation, the N-terminus of the API2 gene is fused with the C-terminus of the MALT lymphoma translocation gene 1 (MALT1), forming the protein API2-MALT1, an oncogenic fusion protein that is able to generate a stable, non-canonical nuclear factor-κB-activating fragment. API2-MALT1 translocation is specific to MALT lymphoma and frequently occurs in the absence of inflammation. t(14;18)(q32;q21) and t(1;14)( p22;q32) are observed in a proportion of P-MALTL. These chromosomal abnormalities are able to bring either the BCL10 or the MALT1 gene to the IGH locus, thus deregulating their expression. P-MALTL is a low-grade lymphoma that usually occurs at 50–60 years of age, very occasionally affecting those 80%. Therapeutic options include surgery, chemotherapy, immunotherapy and radiotherapy. In elderly patients who are asymptomatic and localised, a continued surveillance “watch and wait” approach may also be adopted [14, 15]. Transformation into a large-cell lymphoma may occur [8]. Diffuse large B-cell lymphoma as a group Diffuse large B-cell lymphoma (DLBCL) as a group is the second most common type of primary pulmonary lymphoma and most usually affects older adults in the 6th and 7th decades [3, 8, 13]. Morphological, biological and clinical studies have subdivided DLBCL into morphological variants, molecular subtypes and distinct disease entities [3]. The main morphological variants are centroblastic, immunoblastic and anaplastic. The molecular subtypes are germinal centre B-cell and the activated B-cell. However, there remain many cases that may be biologically heterogeneous, but for which there are no clear and accepted criteria for subdivision.

The centroblastic variant is characterised by cells with oval to round vesicular nuclei, multiple nuclear membrane-bound nucleoli, and scanty pale cytoplasm. The immunoblastic variant contains large lymphoid cells with round to oval vesicular nuclei 338

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and a single centrally located prominent nucleolus with scant to moderate basophilic cytoplasm. In some cases, plasmacytic differentiation may be seen, with eccentrically located nuclei. The anaplastic variant is characterised by large pleomorphic cells with bizarre irregular nuclei, often with multinucleated forms, and variable amounts of cytoplasm. Lymphoma cells are positive for CD20, CD79a, PAX5, CD10 (30–50%), BCL6 (60–90%), MUM1 (35–65%), BCL2 (47–84%) and CD5 (5–10%). Some DLBCL cases, especially the anaplastic variant, are positive for CD30. Ki67 staining is usually >40%; in some cases, it may be >90%. Cases that are CD10+ are classified as a germinal centre B-cell subtype; this also applies to cases that are CD10− but BCL6+ and MUM1−. BCL6(3q27) rearrangement is seen in ⩽30% of DLBCL. ∼20–30% of DLBCL cases have t(14;18) involving the BCL2 gene. MYC (8q24) rearrangement occurs in ∼8–14% of DLBCL cases. Cases with MYC and BCL2 and/or BCL6 rearrangement are called “double/triple-hit lymphomas” and are classified in a separate category of “High-grade B-cell lymphoma with MYC and BCL2 and/ or BCL6 rearrangement” [3]. In a minority of cases, markers for Epstein–Barr virus (EBV) infection may be detected (EBV-positive diffuse large B-cell lymphoma not otherwise specified). DLBCL manifests as a primary lung disease, usually with a nodule or a large mass, sometimes occupying most of a lobe and often accompanied by foci of necrosis. The pattern of growth is intraparenchymal or endobronchial, though it may appear with pleural effusion and pleural masses. Symptoms include cough, haemoptysis, low grade fever and asthenia. Laboratory tests are nonspecific and diagnosis requires a biopsy; small samples are usually enough. Treatment is with an R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and steroids) regimen; the 5-year progression-free and overall survival rates were found to be ∼60% and ∼65%, respectively [16]. Intravascular variant of DLBCL An intravascular variant of DLBCL has been identified, which presents without adenopathy, organomegaly or mass-forming lesions in solid organs; it is only likely to be recognised when a biopsy is performed on sites without clinical evidence of lymphomatous involvement, including the lung [2, 3, 8, 13]. The vessels are filled with aggregations of large cells with coarse chromatin and a high nucleus-to-cytoplasm ratio, clearly different from resting lymphocytes or monocytes. While there may be a prominent pulmonary component, the disease is never restricted to the lung and should be regarded as an aggressive, systemic lymphoma from the outset.

Two major patterns of clinical presentation have been recognised: the so-called classic form (mostly present in Western countries), which is characterised by symptoms related to the main organ involved, predominantly neurological or cutaneous; and a haemophagocytic syndrome-associated form, originally documented as an Asian variant, in which patients present with multiorgan failure, hepatosplenomegaly and pancytopenia. B symptoms, particularly fever, are very common in both patterns of presentation. When the lungs are mainly involved, the differential diagnosis is with a thromboembolic event or an interstitial pneumonia. CT is likely to feature ground-glass opacity, multiple centrilobular nodules, interlobular septal thickening, interstitial shadows and thickening of bronchovascular bundles, mosaic oligoaemia and pleural effusion (figure 6). 2-fluoro-2-deoxy-D-glucose (FDG)-PET may be useful in the assessment of patients with https://doi.org/10.1183/2312508X.10015519

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Figure 6. HRCT scan showing areas of mosaic oligoaemia; the hypoattenuated parenchyma is along the vascular branches. Diagnosis of intravascular large B-cell lymphoma.

this type of non-Hodgkin lymphoma. Serum LDH is highly increased and hypercalcaemia may be observed, though rarely. A random skin biopsy of normal-appearing skin and transbronchial lung biopsy (TBLB) are often helpful in making the diagnosis [17, 18]. Treatment is usually with the R-CHOP regimen, which is of benefit when a diagnosis is made in the early phases. Primary effusion lymphoma Primary effusion lymphoma is a peculiar form of malignant lymphoproliferative disorder with neoplastic cells mainly present in the pleural or peritoneal cavity or in the pericardium [3, 8]. Neoplastic cells exhibit a range of appearances, from large immunoblastic to anaplastic, and their nuclei are positive for HHV-8 latent proteins. B-cell-specific antigens are not expressed. Cytological analysis of fluid is usually diagnostic. Common treatments for primary effusion lymphoma are: cyclophosphamide, doxorubicin, vincristine, prednisone-based chemotherapy regimens alone or in combination with immunomodulatory agents (e.g. lenalidomide); proteasome inhibitors (e.g. bortezomib); or targeted therapies. Highly active antiretroviral therapy should be initiated or continued in patients with associated HIV infection [19]. Prognosis, however, remains grim. DLBCL associated with chronic inflammation DLBCL associated with chronic inflammation is a lymphoid neoplasm that is seen in cases of long-standing chronic inflammation; it is linked with EBV [3, 8, 13]. Most cases involve body cavities or narrow spaces. The prototypical form is pyothorax-associated lymphoma, which develops in the pleural cavity of patients with long-standing pyothorax [3]. A recent entity, the fibrin-associated diffuse large B-cell lymphoma with an indolent course, may manifest with pleural and pericardial effusion [3]. 340

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LYG LYG is an angiocentric and angiodestructive lymphoproliferative disorder composed of EBV-positive B-cells admixed with reactive T-cells, which usually predominate [3, 20–22]. It is more frequently observed in subjects with underlying immunodeficiency. Predisposing conditions include allogeneic organ transplantation, Wiskott–Aldrich syndrome, HIV infection and X-linked lymphoproliferative syndrome. Patients presenting without evidence of underlying immunodeficiency usually manifest reduced immune function on careful clinical or laboratory analysis. LYG is usually a disease of adulthood, which predominates in males. Whilst pulmonary involvement is often seen, LYG is more frequently multicentric with involvement of the central nervous system, skin, liver, kidneys and other organs (adrenal glands, prostate, etc.). Lymph node, splenic and bone marrow involvement are not commonly seen. Presenting pulmonary and systemic symptoms are cough, weight loss, chest pain, asthenia and low-grade fever. Haemoptysis is rarely observed.

The imaging findings of LYG in the lung are fairly well established. In ⩾80% of cases, multiple nodules are found in a bronchovascular distribution, usually in the bilateral lower lungs [2, 21]. Cavitation caused by necrosis is also seen in ∼30% of cases [2, 21]. Groundglass opacities are rarely reported. Changes in location, spontaneous remission, and re-emergence of lesions can occur. Micronodules, interlobular septal thickening and reticulonodular patterns can also be seen. Hilar or mediastinal lymph node enlargement is rare. Involvement of large airways may be documented during bronchoscopy. The differential diagnosis of LYG includes infections, primary pulmonary or metastatic neoplasms, cryptogenic OP, granulomatosis with polyangiitis, nasal-type extranodal T/natural killer cell lymphoma or IgG4-related fibroinflammatory disorder. The histological features are: angiocentric and angiodestructive polymorphous infiltrates with lymphocytes, mainly CD3+ cells, histiocytes and large atypical lymphoid cells expressing B-markers (CD20), and tissue ischaemic necrosis [8, 22]. Microscopic granulomas are characteristically absent. Grading of LYG is based on the number of atypical EBV-positive cells. Grade 1 lesions contain a minority of large atypical cells (fewer than five cells per high power field). In grade 3 lesions, the large atypical cells are readily seen and may form smaller or larger aggregates embedded in a T-lymphocyte-rich inflammatory background. Grade 1 LYG may be mimicked histologically by rare cases of pulmonary involvement, IgG4-related disease and acute pulmonary histoplasmosis [8, 22, 23]. Response to steroids is poor and mainly observed in grade 1 cases. Novel treatments, including a combination of immunotherapy and chemotherapy, have been effective in the majority of cases. However, despite treatment advances, LYG remains an aggressive disease with a relatively high-relapse rate and disease-related mortality. Extranodal natural killer T-cell lymphoma Extranodal natural killer T-cell lymphoma (ENKTCL) is predominantly seen in middle-aged men from Asia, Mexico and South America; however, it is not exceptional in Western countries [3, 8]. It presents as tumours or destructive lesions in the nasal cavity, maxillary sinuses or palate; it may also appear mainly localised to the lungs. Pulmonary (haemoptysis, chest pain) and systemic symptoms (fever, asthenia) are common [3, 13]. Laboratory tests may document an important CD4+ lymphocytopenia in peripheral blood and the disease can manifest with coexisting atypical pulmonary infections and with https://doi.org/10.1183/2312508X.10015519

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haemophagocytic syndrome [3]. CT scans show nodules or masses with an important necrotic component. ENKTCL ranges from monomorphic small/medium-sized cell lymphomas to large cell lymphomas and is characterised by frequent features of angioinvasion and angiocentrism, as well as common necrosis. The neoplastic cells usually express cytoplasmic CD3, CD2+, CD5, CD7+, CD16+/− and CD56+, and have an activated cytotoxic profile. By definition, all cases are associated with expression in the neoplastic cells of EBV latent infection markers (EBERs, latent membrane protein 1 and EBNA2). Recent studies have documented consistent programmed death ligand (PD-L)1 expression by ENKTCL neoplastic cells, suggesting that antagonisation of PD1–PD-L1 interactions may represent a therapeutic option for patients who are refractory to standard lines of chemotherapy [24]. Amyloidosis Amyloidosis related to B-cell lymphoproliferative disorders may involve the lower respiratory tract in three distinct forms: diffuse alveolar septal amyloidosis; nodular amyloidosis; and tracheobronchial amyloidosis [3, 25–27]. Ig light chains, typically λ light chains, represent the protein present in the fibril.

Diffuse alveolar septal amyloidosis is characterised by the presence of amyloid deposits in the alveolar septa. Most cases represent pulmonary manifestations of systemic amyloid light chain amyloidosis ( previously, “systemic amyloidosis”). Pleural effusion may be a manifestation of systemic amyloid light chain amyloidosis. Nodular amyloidosis is defined as one or more tumour-like amyloid deposits that involve the pulmonary parenchyma. The process is rarely associated with systemic diseases such as plasma cell myeloma; it is usually is related to a localised lymphoproliferative process, such as MALT lymphoma, even if the process is subtle. In tracheobronchial amyloidosis, amyloid is deposited in various segments of the trachea and bronchi; the B-cell clones may be hidden and difficult to document, even using molecular tests. Bronchoscopy may document irregular whitish deposits, most often diffuse, which narrow the airway lumen more or less completely (multifocal submucosal plaques). Three patterns of involvement have been described: proximal, mid- and distal airway. Subglottic stenosis may mimic granulomatous and polyangiitis or other rare forms of tracheal involvement. Light chain deposition disease COLOMBAT et al. [28] reported a very rare form of light chain deposition disease, which presented as a severe cystic lung disorder or as atypical bronchiectasis of unknown aetiology, usually requiring lung transplantation. It was hypothesised that monoclonal light chain synthesis occurs within the lungs; this was felt to be the case because of the absence of disease recurrence after bilateral lung transplantation and of serum-free light chain ratio normalisation after the procedure [28]. Histological examination of the explanted lungs has identified diffuse non-amyloid κ light chain deposits associated with a mild lymphoid infiltrate, composed of aggregates of small CD20(+), CD5(−), CD10(−) B lymphocytes reminiscent of BALT. A dominant B-cell clone may be identified using PCR. Hodgkin lymphoma Hodgkin lymphoma can appear as a primary lung disorder (though this is rare). This occurs more frequently in females, and patients are usually older than those with primary 342

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nodal disease. Reticulonodular infiltrates, single or multiple nodules (more frequently cavitated), and alveolar consolidations are the main radiographic manifestations. Patients are usually symptomatic with cough, fever, weight loss, dyspnoea, fatigue, anorexia, chest pain and itching [8, 29]. Chronic lymphoid leukaemias Chronic lymphoid leukaemias (mainly chronic lymphocytic B-cell leukaemia) can manifest as a diffuse symptomatic lung disease mimicking non-neoplastic forms of ILDs or as chronic bronchiolitis. BAL and/or transbronchial biopsy are usually diagnostic [30]. T-cell large granular lymphocytic leukaemia may appear as a cystic lung disease (figure 7). Acute and chronic myeloid leukaemias Acute and chronic myeloid leukaemias manifest as systemic disorders. However, in a series of patients with acute myelomonocytic leukaemia (probably now classified as acute myeloid leukaemia with inv(16)( p13.1 q22) or t(16;16)(p13.1;q22), resulting in CBFB-MYH1), AZOULAY et al. [31] reported a significant incidence (20%) of acute respiratory failure.

Myeloid disorders, mainly myelodysplastic syndromes and chronic myelogenous leukaemias (CML), can be complicated by pulmonary alveolar proteinosis [32, 33], seen in the large majority of cases with no serum autoantibodies against granulocyte–macrophage colony-stimulating factor. Its occurrence is significantly rarer in non-myeloid leukaemias. Myelodysplastic syndromes and lung fibrosis may have genetic links (telomeropathies). Sweet syndrome or acute febrile neutrophilic dermatosis is a systemic disorder characterised by high fever, leukocytosis and tender erythematous skin lesion. Histologically, dense

Figure 7. HRCT scan showing cysts in both lungs and patchy areas of ground-glass attenuation. 67-year-old females with a diagnosis of T-cell large granular lymphocytic leukaemia after BAL showed a significant increase in large granular lymphocytes with a T phenotype in the alveolar fluid. Other causes of cysts in the lung were excluded.

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dermal infiltrations of mature neutrophilic plaques with nuclear fragmentation and an absence of signs of vasculitis are characteristic of Sweet syndrome. Sweet syndrome can be a manifestation of a myeloproliferative disorder and can manifest, at least at onset, with prominent lung symptoms and signs ( pulmonary infiltrates due to OP or leukocytic parenchymal infiltration). Myelofibrosis Myelofibrosis is a rare Philadelphia chromosome-negative myeloid malignancy that can mimic the appearance of malignant mesothelioma and may be associated with primary PH [8]. Hyperleukocytosis The term hyperleukocytosis denotes peripheral white blood cell counts in excess of 50 000·mm–3. It has the potential to cause pulmonary leukostasis with acute respiratory failure (with diffuse ground-glass opacities or alveolar consolidations at CT scan) due to lung infiltrates consisting of neoplastic myeloid cells as the first or prominent clinical manifestation [31]. Hypereosinophilic syndrome Hypereosinophilic syndrome (HES) is the name of a group of disorders that are characterised by the persistent overproduction of eosinophils accompanied by eosinophil infiltration in multiple organs, with end-organ damage from mediator release. HES can be either primary neoplastic (clonal) HES, secondary reactive HES or idiopathic HES [34].

The World Health Organization (WHO) classification recognises the unique molecular basis of a subset of certain eosinophilic disorders by establishing the major category entitled: myeloid and lymphoid neoplasms with eosinophilia and abnormalities of platelet-derived growth factor receptor alpha (PDGFRA) PDGFR beta (PDGFRB) or fibroblast growth factor receptor 1 (FGFR-1) [3]. The diagnostic entity “chronic eosinophilic leukaemia not otherwise specified” is included in another WHO category [3]. Common non-haematological signs and symptoms of HES include weakness and fatigue, cough, dyspnoea, myalgias or angioedema, rash, fever and rhinitis. Cardiac involvement may be prominent, with cardiomyopathy, congestive heart failure, constrictive pericarditis, myocarditis, endomyocardial fibrosis, pericardial effusion. Diagnosis of HES is based on histopathology and clonal evidence of acute or chronic myeloid or lymphoproliferative disorders, which are further classified by WHO criteria. Involvement of the lungs, which is typically observed in the myeloid variant, is radiologically characterised by interstitial infiltrates, small nodules and/or focal areas of ground-glass opacities. Lymphadenopathy and pleural effusions are also noted [34]. As HES is complicated by thrombosis in many patients, a pulmonary thromboembolic event may be observed at the beginning of the disease course [3, 8]. HES associated with myeloproliferative or lymphoproliferative diseases with PDGFRA/B rearrangements is sensitive to the multikinase inhibitor imatinib. Lymphocyte-variant and idiopathic HES are initially treated with corticosteroids; hydroxyurea or interferon-α are generally used as second-line agents. HES has been successfully treated with anti-IL-5 antibodies (mepolizumab and reslizumab), which specifically target the eosinophilopoietic cytokine IL-5, and anti-CD52 antibodies (alemtuzumab). 344

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Systemic mastocytosis Previous studies have described rare cases of systemic mastocytosis associated with infiltration of the lung parenchyma by abnormal mast cells [8]. Radiographic features of parenchymal lung involvement include reticulonodular interstitial infiltrates and interstitial fibrosis. Osteosclerotic and osteolytic lesions in the vertebrae caused by marrow infiltration may also be noted. A CT scan will reveal uniformly distributed pulmonary nodules and cysts; mediastinal adenopathy may also be present [8]. Histiocytic disorders Histiocytic disorders that primarily manifest with pulmonary involvement are: Langerhans cells histiocytosis (LCH), Erdheim–Chester disease (ECD) and Rosai–Dorfman disease (RDD) [35, 36]. LCH is by far the most frequent.

Activating mutations in mitogen-activated protein kinase pathway genes, most notably BRAF V600E, as well as NRAS mutation can be detected. Recurrent mutations in the phosphoinosidite-3-kinase pathway gene have also been described. These molecular features have led to these disorders being considered as inflammatory myeloid neoplasms [3]. Cigarette smoke plays a pivotal pathogenetic role in LCH that involves the lungs. Characteristic CT scan features are nodules and cysts in LCH, and septal and subpleural thickening in ECD. Extranodal, pulmonary RDD may present as a parenchymal nodule, interstitial pneumonitis or a solitary pleura-based lesion [36]. The lesions are usually PET positive. Overlaps between these disorders have been documented because of the morphological aspects and the molecular alterations [35]. Diagnosis may not require pathological documentation in LGH when clinical–radiological features are typical. Biopsy is required in atypical cases, and always to document ECD and RDD or when treatment approaches could be driven by molecular tests. Quitting smoking is the first line therapy in LCH. Vemurafenib has been shown to have a prolonged efficacy in patients with BRAF V600 mutant ECD and LCH [37]. Neoplasms derived from follicular dendritic cells and interdigitating dendritic cell tumours/sarcomas Neoplasms derived from follicular dendritic cells and interdigitating dendritic cell tumours/ sarcomas are rare tumours that may even more rarely appear as primary lung lesions (as nodules or masses). Some follicular dendritic cell tumours arise in association with, or are preceded by, the hyaline vascular type of Castleman disease, and this may represent a precursor lesion [38]. Castleman disease

Castleman disease is a term used to identify a group of heterogeneous haematological disorders that mainly affect the lymph nodes. The spectrum of histopathology changes, and ranges from atrophic germinal centres with hypervascularisation to hyperplastic germinal centres with polytypic plasmacytosis. Unicentric Castleman disease involves a single region and generally has hyaline vascular/ hypervascular histopathological features [8]. When the thorax is involved, unicentric Castleman disease appears with mediastinal or hilar giant lymph nodes; symptoms are https://doi.org/10.1183/2312508X.10015519

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usually absent or when present they are related to the mass effect of the lesion (superior vena cava syndrome, obstruction of large airways). Very rarely it manifests as a pulmonary mass. Surgical excision is curative in the large majority of cases. Multicentric Castleman disease (MCD) involves different lymph node stations and manifests with laboratory markers of systemic inflammation. The histopathoplogical background can be classified into three groups: plasmacytic, mixed and hypervascular [39]. It is an aggressive disorder that potentially leads to fatal multiple organ dysfunction from a cytokine storm, often including IL-6. ∼50% of MCD cases are related to an uncontrolled HHV-8 infection. In such cases, HIV infection or, more rarely, another cause of immunosuppression enables HHV-8 to escape host immune control and signal for excessive cytokine production and polyclonal lymphoproliferation. In half of the HIV-negative and HHV-8-negative MCD cases, the aetiology is still unclear. In HHV-8-negative MCD cases, two clinical phenotypes have been identified [39]. Patients present with either heterogenous clinical symptoms (which can include intense episodes of thrombocytopenia, anasarca, fever/elevated C-reactive protein, renal dysfunction/reticulin myelofibrosis, organomegaly, megakaryocytic hyperplasia and normal gammaglobulin level (MCD-TAFRO)) [40] or a less intense inflammatory syndrome, normal/elevated platelet counts and polyclonal hyper-gammaglobulinemia [40, 41]. Lung involvement in MCD is characterised by lymphoplasmacyte (with lymphoid follicles) and fibroinflammatory lesions with a lymphatic distribution (visceral pleura, interlobular septa and bronchovascular bundles). Obstructive phlebitis and eosinophilic infiltration are typically absent. Plasma cells are usually clustered in sheets [42]. In HHV-8-related MCD, interstitial lymphocyte infiltrates mimicking LIP are more frequently observed. Immunohistochemistry analysis documents the presence of HHV-8 [43]. The evolution towards HHV-8-positive large B-cell lymphoma may be observed in HHV-8-related MCD. Patients often present with low-grade fever, cough and dyspnoea. HRCT of the lung may show hilar and mediastinal lymphadenopathies, multiple nodules of different sizes, cysts, patches of ground-glass opacities and LIP-like images (figure 8) [43]. The main therapeutic options include corticosteroids, immunosuppressive therapy (cyclosporin A, cyclophosphamide, etc.), rituximab or rituximab-based therapy, and anti-IL-6 therapies (e.g. tocilizumab and siltuximab) [44, 45]. Paraneoplastic autoimmune multiorgan syndrome Paraneoplastic autoimmune multiorgan syndrome is a rare disorder that manifests with severe mucocutaneous blistering and erosions (also affecting the large airways). Constrictive bronchiolitis can occur in a subset of patients [46]. Although non-Hodgkin lymphoma and chronic lymphocytic leukaemia may be the underlying malignancy, unifocal Castleman disease is the predominant cause [46]. It is characterised by severe obstructive pulmonary impairment and high mortality rates, despite immunosuppressive therapy. Patients with constrictive bronchiolitis may have skin and respiratory manifestations in the absence of a known neoplasm. Autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is characterised by nonmalignant T and B lymphoproliferation, causing splenomegaly and enlarged lymph nodes; 70% of patients also display autoimmune manifestations such as autoimmune cytopenias, Guillain–Barré 346

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Figure 8. HRCT scan of a 37-year-old Nigerian male presenting with low-grade fever and lymphoadenopathies. Centrilobular gound-glass opacities and mediastinal lymph nodes are evident. The final diagnosis was multicentric Castleman disease, which was human herpes virus (HHV)-8 positive. The patient was HIV negative.

syndrome, uveitis and hepatitis. A hallmark of ALPS is the presence of CD4−CD8− T-cell receptor αβ+ in the blood of affected individuals. Hypergammaglobulinaemia involving IgG and IgA is also frequently observed. The syndrome is caused by a defect in Fas-mediated apoptosis of lymphocytes (somatic or germline mutations in FAS, FASLG or CASP10 genes), which can thus accumulate and mediate autoimmunity. ALPS with undetermined genetic defect (ALPS-U) is a term used to categorise patients who fulfil the diagnostic criteria for ALPS but have an as yet undetermined genetic mutation. ALPS can lead to malignancies. Lung abnormalities may be detected mainly in the ALPS-U subtype [47]. Investigations are mainly undertaken in suspicion of malignant lymphoproliferative disease or infection. Patients are asymptomatic or present with dyspnoea on effort and a significant reduction of DLCO. CT scan features are: ground-glass opacities, larger nodules, tree-in-bud pattern, bronchiectasis, septal thickening, consolidation, cysts and cavitation. The BAL profile is characterised by an increase in lymphocytes. Histopathology features are a mix of mucosal lymphoid hyperplasia, bronchiectasis, interstitial lymphocytic infiltration, OP, follicular bronchiolitis and granulomatous changes. Haemoglobinopathies

In sickle cell disease (SCD), a mutated β-globin gene produces sickle haemoglobin, which results in red blood cell rigidity, red blood cell adhesion to endothelium, and haemolysis. These events activate inflammation and coagulation pathways, and cause vaso-occlusion. The clinical manifestations are therefore chronic haemolytic anaemia, recurrent painful episodes and chronic organ damage as a result of vaso-occlusion. Patients affected by SCD are also at higher risk of developing severe pneumonia due to Streptococcus pneumoniae, https://doi.org/10.1183/2312508X.10015519

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Mycoplasma pneumoniae, Chlamydia pneumoniae, Meningococcus and Legionella spp. Acute chest syndrome is seen in ∼30% of patients. It is characterised by the appearance of a new infiltrate on chest radiography or chest CT scan associated with one or more new symptoms, including fever, chest pain, cough, sputum production, dyspnoea, wheezing and hypoxia. Children have a higher incidence of fever, cough and wheezing at diagnosis, while adults are often afebrile, have shortness of breath, chills and severe pain. The usual aetiology is simultaneous vaso-occlusion, fat embolism and infection. Pulmonary fat embolus, characterised by stainable fat in pulmonary macrophages for BAL slides, is found in 44–60% of cases (figure 9). Elevation of serum phospholipase A2 may be a useful biomarker of this complication. PH is the most important and frequent chronic pulmonary complication, occurring in as many as 60% of patients [48]. Pathophysiology can involve: thrombi in the large and small arteries; cardiac decompensation caused by progressive anaemia; and potentially reversible increases in vascular tone caused by nitric oxide depletion and medial and intimal hypertrophy. Autopsy studies have shown thrombotic pulmonary arteriopathy in most patients with SCD [49]. Limited large-scale studies have been completed on targeted PAH therapy (i.e. prostacyclin agonists, endothelin receptor antagonists, soluble guanylate cyclase stimulators and phosphodiesterase-5 inhibitors) in SCD populations, and at present, no clear benefit has been demonstrated [48].

Lung injury related to treatment Infections are a frequent and often fatal complication in haematological patients. These complications (even if infectious prophylaxis during neutropenia has dramatically reduced the burden of infectious complications) are more frequent and dangerous in those who undergo allogeneic haematopoietic stem cell transplantation (HSCT) due to a prolonged period of neutropenia, in addition to other impairment of cell-mediated and humoral immunity [50, 51].

Figure 9. BAL showing macrophages containing intracytoplasmatic oil red positive vacuoles in a patient with sickle cell anaemia and acute chest syndrome (oil red, high power).

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During the several weeks of profound neutropenia that follows transplantation, pulmonary infections are most commonly caused by bacteria such as Staphylococcus aureus and gram-negative rods or to fungi such as Aspergillus. After ∼30 days, when neutrophils have returned to normal but additional immunosuppression may be required to suppress GVHD, viral infections become more common. Community-acquired pneumonia due to organisms such as S. pneumoniae is a constant concern. The incidence of bacterial pneumonias is higher in allotransplants when: myeloablative conditioning is used; the patient has GVHD; engraftment is delayed and there is a prolonged period of neutropenia; or there are indwelling devices. As with solid organ transplant recipients, appropriate prophylaxis against cytomegalovirus (CMV) and Pneumocystis jirovecii has reduced the incidence of these specific infections in this population. Haematological patients are prone to developing drug-related lung injuries because of the variety of drugs and regimens used. The list of drugs that could be the cause of lung injury is increasing constantly, and the clinical, radiological and pathological features with which lung toxicity manifests vary. Diagnosis is through exclusion; BAL and TBLB are also very supportive [52, 53]. A group of noninfectious respiratory failure syndromes has been observed throughout the post-HSCT period [54, 55]. The risk of these syndromes varies, depending on transplant type and a variety of modifiable and non-modifiable transplant and patient characteristics. In noninfectious syndromes, complications are categorised by when they occur after HSCT. It is often not possible to rule out infection at the time of initial presentation; it should be concurrently treated given the substantial mortality associated with delayed antimicrobial administration. Peri-engraftment respiratory distress syndrome

Peri-engraftment respiratory distress syndrome is a systemic capillary leak disorder that develops around the time of immune system reconstitution shortly after autologous HSCT. It is characterised by hypoxaemic respiratory failure and bilateral pulmonary infiltrates that occur in the 5 days around neutrophil engraftment, which cannot be fully explained by cardiac dysfunction or infection. The incidence of peri-engraftment respiratory distress syndrome is nearly 5% in autologous transplants. Risk factors include female sex, blood product administration, rapid engraftment and HSCT for POEMS ( polyradiculoneuropathy, organomegaly, endocrinopathy, clonal plasma cell disorder and skin changes) syndrome. Around 20 years ago, case-fatality rates were >20%; this has substantially reduced to 6% in the current era [1]. Treatment consists of short courses of high-dose corticosteroids, most commonly 1–2 mg·kg−1 methylprednisolone twice daily for 3 days, followed by a rapid taper. DAH

DAH is characterised by diffuse, bilateral pulmonary infiltrates, a progressively bloody return during BAL and >20% hemosiderin-laden macrophages in alveolar lavage fluid. Haemoptysis is infrequently observed. https://doi.org/10.1183/2312508X.10015519

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Risk factors for DAH include age >40 years, higher intensity conditioning therapies, total body irradiation, and HSCT for acute leukaemia and myelodysplastic syndrome. DAH occurs in 5–12% of HSCT recipients during the early post-transplant period, and mortality rates are high as 60–100%. Knowledge about the mechanisms that lead to DAH following HSCT is limited. Thrombocytopenia may be a cofactor in a minority of patients. Cytotoxic drugs seem to play a pivotal role. Treatment for DAH consists of high-dose corticosteroids, most commonly 500–1000 mg methylprednisolone per day for 5 days. IPS

IPS is a form of alveolar lung injury that occurs in the absence of cardiac or renal dysfunction, iatrogenic-induced circulatory overload and infection. Symptoms are consistent with those of acute respiratory distress syndrome and pulmonary imaging generally reveals diffuse, bilateral pulmonary infiltrates. DAD is the histopathological background in the large majority of cases. Up to 10% of HSCT recipients are affected by IPS, mainly those who have undergone allotransplants. IPS typically occurs during the early post-transplant period. Risk factors for IPS include higher intensity conditioning therapies, radiation administration, allogeneic transplant, age and the presence of GVHD. Mortality is 80% and even greater in those requiring respiratory support with a mechanical ventilator. IPS treatment is controversial, and no therapy has shown a favourable outcome. There has been ongoing interest in tumour necrosis factor-α inhibition as it was observed that patients with IPS have cytokine-rich BAL fluid [1]. Preliminary retrospective studies have shown promise, demonstrating increased response rates and an improved overall survival when the tumour necrosis factor-α inhibitor etanercept was added to corticosteroid therapy [56]. Further studies are needed to identify efficacious therapies. Delayed pulmonary toxicity syndrome

Delayed pulmonary toxicity syndrome (DPTS) is a combination of interstitial pneumonitis and fibrosis that occurs in the late transplant period, and can present years after HSCT. It is generally only seen in patients receiving high-dose chemotherapy, followed by autologous stem cell rescue for breast cancer. Symptoms are nonspecific and include dyspnoea, fever and nonproductive cough. Chest imaging reveals bilateral interstitial infiltrates and ground-glass opacities. DPTS is highly responsive to corticosteroids and typically has a favourable outcome. OP

OP is an interstitial and airspace disease; its symptoms mimic those of classic pneumonia. Imaging reveals nodular lesions, ground-glass attenuation and patchy peribronchovascular, peripheral, band-like alveolar consolidations. Biopsy highlights interstitial cellular 350

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pneumonitis and buds of granulation tissue in the alveolar ducts and alveoli. In a minority of cases, intra-alveolar fibrin may also be clearly evident (an acute fibrinous and OP pattern). Bronchoscopy performed using forceps or cryoprobe TBLB are useful in distinguishing OP from infectious pneumonia. Analysis of the lavage fluid will show predominant lymphocytosis, an increase in neutrophils and eosinophils, and scattered mast cells. Risk factors for OP include cyclophosphamide conditioning, total body irradiation, male allotransplantation with a female cell donor, the presence of acute or chronic GVHD (cGVHD) and HSCT for leukaemia. OP occurs in ⩽10% of HSCT recipients and is generally seen during the 100-day period after transplantation, though it can occur later. OP is usually responsive to corticosteroid therapy. Case fatality rates are reported to be ⩽20%, and are usually due to respiratory failure that is the result of relapsed, steroid refractory disease [35]. Pulmonary cytolytic thrombi

Pulmonary cytolytic thrombi is a unique noninfectious form of lung injury that may be rarely observed after bone marrow transplantation. It is characterised by the accumulation of acellular basophilic debris in the vascular structures, with associated endothelial injury and haemorrhagic necrosis [8]. Vascular injury appears to be caused by entrapment of leukocytes in the thrombi and may resolve with corticosteroid therapy. Bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS; or obliterative bronchiolitis) is a complication that follows allogeneic HSCT [57, 58]. It may also occur after autologous HSCT, though this is rare. It is considered the main lung manifestation of cGVHD. The incidence of BOS has ranged from 0% to 48% in different reports [57], but in our experience it is around 8–10% [54]. Risk factors for obliterative bronchiolitis include cGVHD, older age, the presence of lung function impairment before HSCT, viral infections (mainly CMV) of the respiratory tract and busulfan-based conditioning regimens [59, 60]. Activated donor effector T-cells target the recipient epithelial cells in the bronchioles, causing an inflammatory reaction. Toll-like receptor-4 signalling in donor-derived haematopoietic cells is also seems to be an important cause of alloimmunity. B-cells are other targetable elements in inciting and sustaining cGVHD. BOS usually occurs 7–10 months after HSCT. Symptoms are dry cough, dyspnoea and wheeze. Physical examination may reveal decreased breath sounds, wheezing and inspiratory squeaks; it also often reveals signs of GVHD outside the lung, such as skin manifestations. In a minority of patients, there are no respiratory manifestations, and the diagnosis is established via PFTs. BOS is characterised by pathological scarring of the small airways, and lymphocytic infiltration of the submucosa and epithelial cells. Lymphocytic bronchiolitis without obliterative scarring may represent the early phase of this disorder. Lymphocytic https://doi.org/10.1183/2312508X.10015519

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submucosal inflammation is also present in a large majority of cases and bronchial biopsy may show a predominantly lymphocytic and plasmacellular submucosal inflammation, with homing of lymphocytes to the basement membrane, intraepithelial transmigration of these cells, and epithelial cell apoptosis [50]. Chest radiograph is usually normal, although patients with advanced disease may have signs of hyperinflation, bronchiectasis, and areas of scarring. HRCT is more sensitive for all of the previously mentioned abnormalities and is valuable in showing air trapping and mosaic attenuation during expiration. Thickening of the wall of larger airways and cylindric bronchiectasis are also present in the majority of cases and, rarely, may represent the only manifestation of cGVD in the lungs [61]. PFTs show an obstructive pattern, with an FEV1/FVC ratio of 20% in comparison with the pre-transplant value. Diagnosis is usually based on clinical features, PFTs (including pletismography) and CT scan features. Bronchial biopsy may be useful in documenting a lymphocytic submucosal inflammation and BAL is usually performed to assess a superimposed infection [50]. Treatment of the HSCT patient with BOS involves corticosteroids, such as prednisone at 1– 1.5 mg·kg−1 daily, and intensification of immunosuppressive therapy [62]. Inhaled budesonide/formoterol has been shown to make a significant improvement in the FEV1 in patients with mild-to-severe BOS after allogeneic HSCT [63]. Macrolides, and azithromycin in particular, have been investigated as a preventative treatment [57, 58]. While the precise mechanism of action of macrolides is not known, it is believed their beneficial effects relate primarily to anti-inflammatory and immunomodulatory effects [54]. However, a recent systematic review and meta-analysis of data on the impact of azithromycin on FEV1 change, did not find sufficient evidence to support their use [64]. Rituximab has been used anecdotally. Ruxolitinib, a selective JAK1/2 inhibitor, has recently gained favour as a second-line approach in patients with steroid-refractory cGVHD [65]. In selected patients with progressive respiratory failure, lung transplantation should be considered. Cellular interstitial pneumonitis (or NSIP) and pleuroparenchymal fibroelastosis

Other manifestations of cGVHD are cellular interstitial pneumonitis (or NSIP) and pleuroparenchymal fibroelastosis. The median duration from transplantation to the diagnosis of cellular interstitial pneumonitis is 7–10 months [50], although cases with a longer time span have been reported [66]. Onset is subacute with dyspnoea and cough. CT features are mainly characterised by diffuse ground-glass attenuation and BAL presents lymphocytosis in the majority of cases [50]. Pleuroparenchymal fibroelastosis is diagnosed later (∼40–45 months). CT findings are pleuroparenchymal thickening with volume loss, and evidence of fibrosis, predominantly in the upper lobes. PFTs document restrictive impairment with an increase in residual volume. Small chronic spontaneous pneumothoraces may be the first manifestation. Progressive dyspnoea, dry cough, recurrent acute bronchitis and weight loss are the main symptoms [67, 68]. In this context, lung biopsy should be considered on a case-by-case basis, considering that complications ( prolonged air-leakage, bleeding, acute respiratory failure and death) are not infrequent, mainly when a surgical approach is adopted [69]. 352

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Antifibrotic drugs, including pirfenidone and nintedanib, have been tested in a few cases with no significant effects [70]. Lung transplantation should be considered case by case, although the results of this procedure are worse in patients with restrictive chronic respiratory failure than in those with obstructive defects [70]. A very recent study has shown that herpes viruses have an important role in the pathogenesis and progression of pulmonary complications and acute GVHD after haematopoietic cell transplantation [71]. Among early onset viral infection, HHV-6 and EBV are associated with the development of IPS, whereas CMV is associated with the development of BOS and grade II–IV acute GVHD [71]. These infections should therefore be actively prevented. Post-transplant lymphoproliferative disorders

Post-transplant lymphoproliferative disorders (PTLDs) constitute a spectrum of lymphoproliferative entities, including early lesions (which are also defined as “mononucleosis-like” and are always EBV-positive), polymorphic PTLDs (which are characterised by a mixture of B-lymphocytes with infiltrating T-lymphocytes, without necrosis) and a group of monomorphic PTLDs (which includes all non-Hodgkin lymphoma histologies). Other rare monomorphic subtypes of PTLD are multiple myeloma, plasmacytoma and Hodgkin lymphoma [3, 8, 72, 73]. EBV-associated lesions with histopathological features of LYG have also been reported [8]. Lymphoid proliferation is related to a T-cell dysfunction, which results from the conditioning regimen and, in virtually almost all cases, the presence of EBV. Incidence varies 0.6–10%. These complications usually appear in the first 6 months after transplantation. Risk factors for this disorder include EBV seronegative status at the time of transplantation, HLA-mismatched donor, T-cell depletion of the graft, anti-T-cell agents, older age of the donor and splenectomy. Benign forms have a polymorphic aspect with a predominance of plasma cells. Monomorphic lesions usually have the features of large B-cell lymphoma or, more rarely, features of Hodgkin disease. Radiographic findings vary from bilateral reticulonodular infiltrates to discrete single or multiple nodules or masses, with the latter most commonly seen in patients with high-grade histological features. Treatment consists of a reduction in immunosuppressive therapy in early and polymorphic PTLDs or, in monomorphic disorders, chemotherapy and, in the B-cell phenotypes, rituximab. Prophylactic administration of rituximab during HSCT has been proposed to prevent PTLD in high-risk patients. The presence of B symptoms, Waldeyer ring, spleen, central nervous system, and liver involvement, as well as advanced Ann-Arbor stage, is not rare.

The elements of diagnostic evaluation In patients in whom haematological disorders appear as a primary, clinically relevant pulmonary disease, diagnosis is usually only considered after analysis of the CT scan features. Only some peculiar clinical contexts and laboratory tests may suggest a diagnosis from the beginning (Sjögren syndrome and a serum monoclonal component, haemophagocytic syndrome in natural killer/T-cell lymphoproliferative disorders, nasal https://doi.org/10.1183/2312508X.10015519

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type; acute onset mimics pulmonary thromboembolism with a huge increase of serum LDH in intravascular lymphoma) [2]. In the diagnostic evaluation of the pulmonary complications in haematological patients, information should be obtained on the clinical profile of the pulmonary complication manifest, the radiographic and CT scan abnormalities, and the individual patient factors, such as exposure to toxic drugs, a history of receiving chest radiotherapy, current and previous immunosuppressive regimens and infection prophylaxis, the CMV status of the donor and recipient, and the history of previous opportunistic invasive fungal disease. Serum levels of galactomannan, glucan or DNAemia of different viruses may be useful to exclude an infection or even to identify the risk level of developing lymphoproliferative disorders, mainly in transplanted hosts [74]. Bronchoscopy with BAL has the potential to identify the cause of respiratory damage (from haematological neoplasms to infections, DAD or OP patterns) [50, 69, 70]. Recent molecular and biomarker-based assays are very sensitive in identifying the microbiological agent. However, the results they provide must be considered with caution, mainly in HSCT recipients admitted to the intensive care unit with acute respiratory failure and pulmonary infiltrates [75]. TBLB performed with regular forceps is useful for the identification of characteristic morphological patterns (DAD, OP and granulomatous inflammation) [76]. Transbronchial cryobiopsy is a promising new technique that allows the retrieval of larger and well-preserved samples, which are useful mainly when a precise categorisation of lymphoid infiltrates is needed [77, 78]. However, thrombocytopenia or coagulation defects are important contraindications. Transthoracic needle aspiration under CT, fluoroscopic or echographic guidance has a high sensitivity (70%) for the diagnosis of peripheral nodules or masses. Pneumothorax is a common complication. Medical thoracoscopy or endobronchial ultrasound/endoscopic ultrasound have a role when specific structures (hilar and/or mediastinal lymph nodes, peri-tracheobronchial or oesophageal masses, left adrenal gland or liver nodules, pleural effusion) are involved [79, 80]. In cases of acute onset (infectious and noninfectious, such as IPS, OP, DAH, etc.) the “carpe diem” concept (do the right thing exactly on time) is relevant. Obtaining diagnostic information (HRCT scans, laboratory tests) as soon as possible may be fundamental to the planning of invasive procedures during the mild respiratory failure phase [50]. If no diagnosis is made with less invasive approaches and the empirical treatment is not effective, surgical lung biopsy via video-assisted thoracoscopic may be considered. Although surgical lung biopsy has a sensitivity of 60–80%, the procedure may be associated with a worse outcome; therefore, it should be recommended primarily in patients presenting with lung infiltrates and not specific symptoms or signs, or in HSCT recipients whose surgical lung biopsy results will likely significantly alter their management [50, 72, 81, 82]. Figure 10 presents an algorithm of the diagnostic work-up of pulmonary complications after allogeneic haematopoietic stem cell transplantation. The role of a multidisciplinary approach has not yet been formally assessed. However, because of the complexity of these disorders, a strong collaboration between pulmonologists, 354

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Evaluation of presence/absence of GVHD Laboratory tests including immunological assessment and throat swab Pulmonary function/plethysmography and DLCO, when feasible (DLCO may be misleading when aplasia is present), and gas analysis

HRCT and/or angio CT when thromboembolism is suspected

Diagnosis of small airways disease (BOS): CT showing mosaic oligoaemia, expiratory air-trapping, thickened bronchial walls, bronchiectasis

Suspected vascular disease

Diffuse parenchymal lung involvement with a variety of patterns (alveolar consolidation, ground-glass attenuation, nodules with or without cavitation, crazy paving pattern, tree-in-bud pattern, reticular pattern, etc.)

Echocardiogram; angio CT; perfusional scintigraphy; right heart catheterisation

BAL and, if deemed useful (and depending on the expertise of the centre and on the risk/benefit ratio) transbronchial (cryo) lung biopsy, transthoracic fine-needle aspiration/biopsy, EBUS/EUS or even surgical biopsy [70, 71, 73]

Obstructive pulmonary impairment

Bronchial biopsy and BAL

If no specific contraindications [70,71], transbronchial lung biopsy (with cryoprobes in experienced centres) when a small vascular disease is the main hypothesis (such as intravascular lymphoma) [18]

No diagnosis

Reconsider noninvasive diagnostic tests, the positive predictive value of the CT scan pattern and advance a working diagnosis (through a multidisciplinary discussion) Figure 10. Algorithm for the diagnosis of pulmonary complications after allogeneic haematopoietic stem cell transplantation. GVHD: graft-versus-host disease; BOS: bronchiolitis obliterans syndrome; EBUS: endobronchial ultrasound; EUS: endoscopic ultrasound.

radiologists, pathologists and haematologists/immunologists in daily practice is, at least from personal experience, fundamental.

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Disclosures: S. Kronborg-White reports receiving the following, outside the submitted work: lecture and congress fees from Roche; personal fees for symposia from Boehringer Ingelheim. S. Tomassetti reports receiving the following, outside the submitted work: grants and personal fees from Roche; and personal fees from Boehringer Ingelheim.

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| Chapter 20 Histiocytic disorders Davide Elia1, Antonella Caminati1, Roberto Cassandro1 and Sergio Harari 1,2 Histiocytic disorders are characterised by the accumulation of mononuclear phagocyte system-derived cells in different organs. Langerhans cell histiocytosis (LCH), Erdheim– Chester disease (ECD) and Rosai–Dorfman disease (RDD) are the principal histiocytic disorders of the lung. LCH and ECD show clonal mutations involving genes of the mitogen-activated protein kinase pathways and are included in the same histiocytosis classification. Lung involvement in LCH may be observed along with systemic manifestations, but it occurs more often as a single organ manifestation in young smokers ( pulmonary LCH). Although ECD may show multi-organ involvement similar to LCH, it is characterised by predominant skeletal manifestations on long bones. RDD may develop as an isolated disorder or in association with autoimmune or malignant diseases, with the typical bilateral, massive and painless cervical lymphadenopathy presentation. Due to the lack of randomised clinical trials and the rarity of the condition, treatments are based on case series reports. However, a better understanding of the pathogenetic mechanisms may represent the basis for a new therapeutic option in specific phenotypes. Cite as: Elia D, Caminati A, Cassandro R, et al. Histiocytic disorders. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 359–373 [https://doi.org/10.1183/2312508X.10015819].

@ERSpublications Histiocytic disorders are characterised by the accumulation of dendritic-derived cells in different organs. Langerhans cell histiocytosis, Erdheim–Chester disease and Rosai– Dorfman disease are the principal histiocytic disorders of the lung. http://bit.ly/2lDj2R7

H

istiocytosis or histiocytic disorders are a group of diseases characterised by the accumulation of specific cells, thought to be derived from dendritic cells or macrophages. The clinical presentation ranges from a mild to a disseminated form and, occasionally, can include life-threating manifestations. In 1987, the Working Group of Histiocytosis classified >100 different subtypes of histiocytosis into three categories: Langerhans cell, non-Langerhans cell and malignant histiocytosis [1]. Recently, many other types have been identified and the different forms of

1 U.O. di Pneumologia e Terapia Semi-Intensiva Respiratoria - Servizio di Fisiopatologia Respiratoria ed Emodinamica Polmonare, Ospedale San Giuseppe - MultiMedica IRCCS, Milan, Italy. 2U.O. di Medicina Generale, Ospedale San Giuseppe - MultiMedica IRCCS, Milan, Italy.

Correspondence: Antonella Caminati, U.O. di Pneumologia e Terapia Semi-Intensiva Respiratoria - Servizio di Fisiopatologia Respiratoria ed Emodinamica Polmonare, Ospedale San Giuseppe, via S. Vittore 12 20123 Milan, Italy. E-mail [email protected] Copyright ©ERS 2019. Print ISBN: 978-1-84984-111-5. Online ISBN: 978-1-84984-112-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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histiocytosis have been gathered into five groups according to the clinical, radiological, pathological, phenotypical and/or molecular features (table 1) [2]. The rigid distinction between Langerhans and non-Langerhans cell groups has therefore been abandoned. Langerhans cell histiocytosis (LCH) and Erdheim–Chester disease (ECD), previously included in the group of non-LCH, now in fact share the same category as nearly 20% of patients with ECD also present LCH lesions [3]. Both diseases have clonal mutations which in 80% of cases involve genes from the mitogen-activated protein kinase (MAPK) pathway (figure 1a) [4–7], particularly the proto-oncogene BRAF-V600E, and blood monocytes harbouring the same mutations [8–10]. Similar MAPK pathways mutations have been reported in one third of patients affected by Rosai–Dorfman disease (RDD), suggesting a clonal origin in a subset of these patients [11, 12]. An overlap between ECD/RDD has been reported, mainly driven by the MAP2K1 gain of function mutation [13]. Furthermore, the case of a child with simultaneous mixed systemic RDD and LCH, harbouring BRAF-V600E mutation has recently been observed [14]. The systemic histiocytosis that are more frequently associated with pulmonary involvement, sharing similar biological pathways, will be described in this chapter. These are LCH, ECD and RDD. The main organ involvement in these diseases is summarised in table 2.

Epidemiology and classification LCH, ECD and RDD are rare histiocytic neoplasms of unknown aetiology. LCH can be observed in patients of all ages, with a slightly higher frequency in males. LCH forms have

Table 1. Classification of histiocytic disorders Group

Diseases

L

LCH ECD Indeterminate cell histiocytosis Mixed ECD and LCH Cutaneous non-LCH histiocytosis Cutaneous non-LCH histiocytosis with a major systemic component Primary malignant histiocytosis Secondary malignant histiocytosis Familial RDD Classical (nodal) RDD Extranodal RDD Neoplasia-associated RDD Immune disease-associated RDD Unclassified Primary HLH: Mendelian-inherited conditions leading to HLH Secondary HLH: apparently non-Mendelian HLH of unknown origin

C M R

H

LCH: Langerhans cell histiocytosis; ECD: Erdheim–Chester disease; RDD: Rosai–Dorfman disease; HLH: haemophagocytic lymphohistiocytosis. Data from [2].

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Receptor tyrosine kinase

NRAS, KRAS

Ras

BRAF, RAF1, ARAF

RAF

MEK1, MEK2

MEK

ERK1/ERK2 Figure 1. The mitogen-activated protein kinase pathways and the main mutations identified in pulmonary Langerhans cell histiocytosis, Erdheim–Chester disease and Rosai–Dorfman disease (in shaded boxes).

been classified according to the type and number of organs involved. The systemic manifestations of the disease are usually associated with a worse prognosis, particularly when the liver, spleen and haematopoietic organs (the “risk organs”) are involved. Local manifestations of LCH are often observed in the bones, skin and lungs and are associated with a better prognosis [15]. Lung involvement may be observed in the systemic forms of LCH, in 15% of patient who are 90% of the cases ( pulmonary LCH (PLCH)) [15]. Pulmonary manifestations in the contest of LCH are generally associated with the involvement of other organs; they are more frequent in children or infants without significant pulmonary clinical manifestations and are not an adverse prognostic factor [17]. The BRAF-V600E mutation has been observed in >50% of these cases [18]. Narrow sense PLCH refers to a disease with LCH lesions observed only in the lung or simultaneously in other organs without clinical manifestation; it is typical in young adult smokers. In 35–50% of the cases, an association with BRAF-V600E mutation has been detected [4]. PLCH in children is rare: six cases have been described in the literature, four of which were active smokers while in two cases, second-hand smoke exposure had been reported [19–21]. The incidence of ECD is unknown and 350 disease entities and most have a genetic origin. The most common forms of PID are common variable immunodeficiency and X-linked agammaglobulinaemia. Secondary immunodeficiency is acquired and results from chronic diseases (renal failure, diabetes mellitus and malignancies, especially haematological), acute and chronic infections, transplantation, or treatment modalities. Patients with immunodeficiencies usually present with repeated long lasting, often opportunistic, infections, autoimmune diseases and cancer. Diagnosis of immunodeficiencies is based on a high index of suspicion, immunological and, eventually, genetic analyses. Pulmonary manifestations mainly comprise sinopulmonary infections, bronchiectasis and ILDs such as granulomatous-lymphocytic ILD. Treatment of lung manifestations should go hand-in-hand with treatment/substitution of the immune defect. The prognosis depends on the severity of pulmonary involvement/infection and type of underlying disease and ranges from asymptomatic mild disease to life-threatening conditions. Cite as: Bendstrup E, Vasakova M. Immunodeficiency. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 374–390 [https://doi.org/10.1183/2312508X.10015619].

@ERSpublications Primary immunodeficiencies are rare genetic diseases while secondary immunodeficiencies are caused by systemic diseases, infections or immunosuppressive drug use. Both can result in an increased risk of severe infections, autoimmunity and cancer. http://bit.ly/2lDj2R7

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uman immunodeficiency disorders are a group of heterogeneous disorders involving the immune system and are divided into primary or secondary disorders. Primary immunodeficiency (PID) most often has a genetic origin, whereas secondary immunodeficiency (SID) is acquired and results from an acquired disease or condition (transplantation, malignancy, diabetes, malnutrition, alcohol abuse), drug use (glucocorticosteroids, non-steroid anti-inflammatory drugs, chemotherapy, biologic immunomodulatory drugs) or infections such as HIV. PID represents a heterogeneous group of disorders and is characterised by quantitative and/or qualitative/functional deficits resulting in an increased risk of infection, systemic autoimmune and inflammatory organ manifestation, dysregulation of the immune system and cancer.

1 Centre for Rare Lung Diseases, Dept of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark. 2Dept of Respiratory Medicine of 1st Faculty of Medicine, Thomayer Hospital, Prague, Czech Republic.

Correspondence: Elisabeth Bendstrup, Centre for Rare Lung Diseases, Dept of Respiratory Diseases and Allergy, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark. E-mail: [email protected] Copyright ©ERS 2019. Print ISBN: 978-1-84984-111-5. Online ISBN: 978-1-84984-112-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Even though PID is rare, the global incidence is generally more relevant than believed. Recent estimates have shown that up to six million people worldwide may live with a PID but only 27 000–60 000 are diagnosed [1]. The most common forms of PID (e.g. common variable immunodeficiency (CVID), selective IgA deficiency, IgG subclass deficiency) are typically diagnosed in adults. Thus, the underlying defect may involve different branches of the innate and/or adaptive immune response and the clinical picture may range from severe phenotypes characterised by a broad spectrum of infections to more mild diseases. Moreover, infections may not be the main clinical feature in some PIDs that might present with autoimmunity, auto-inflammation and/or cancer. In adults, clinicians are primarily confronted with SIDs, mainly associated with other diseases, infections or immunosuppressive treatment. Immunosuppressants can have non-selective or selective effects. Non-selective immunosuppressants such as corticosteroids and chemotherapy affect almost the entire immune system; however, the selective immunosuppressants are targeted to single mediators or cell types involved in the immune response, i.e. monoclonal antibodies or biologic treatment such as tumour necrosis factor (TNF)-α inhibitors, rituximab, anti-IL-1, anti-IL-12, anti-IL17 and others. SID is more frequent than PID and the frequency mainly increases due to the rapid development of new biologics for various non-infectious diseases.

Classification and epidemiology PID comprises more than 350 different entities based on more than 340 different gene defects and are now classified into nine groups by the Primary Immunodeficiencies Classification Committee of the International Union of Immunological Societies (table 1) [2, 3]. As the spectrum of disease phenotypes and immune dysregulation is broadening, the term “inborn errors of immunity” is increasingly being used instead of PID. PID can affect both the innate and acquired immune system. The most common defects are X-linked agammaglobulinaemia and CVID (57%), followed by other PIDs (14%), phagocytic disorders (9%), T-cell deficiencies (7%) and complement deficiencies (5%) [4]. PID is either classified by a genetic diagnosis or a clinical diagnosis. The European Society of Immunodeficiencies (ESID) has developed working definitions for a clinical diagnosis of PID [5]. The ESID registry encompasses more than 25 000 patients and is the platform for clinical trials and research projects [6]. The prevalence of PID varies in different studies from 41 to 83 cases per 100 000 population [1, 7]. Immunodeficiencies are generally underdiagnosed and diagnosis is often delayed, resulting in increased mortality. Patients often suffer from an increased societal and disability burden [8]. Pulmonary complications in PID such as recurrent respiratory tract infections and chronic infection-related lung diseases (e.g. bronchiectasis) are common and contribute to increased mortality. Moreover, autoimmunity such as granulomatous-lymphocytic (GL)-ILD and an increased risk of cancer contribute to increased morbidity and mortality [9].

General diagnosis Patients with immunodeficiencies have recurrent infections requiring prolonged need for intravenous antibiotic treatment, as well as opportunistic infections and symptoms of autoimmunity and sometimes malignancy. Type and onset of clinical manifestations depend on the severity of the immune defect and the type of immune response that is suppressed, completely blocked or missing due to https://doi.org/10.1183/2312508X.10015619

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Table 1. Classification of primary immunodeficiencies I

Immunodeficiencies affecting cellular and humoral immunity a. SCID defined by CD3 T-cell lymphopenia b. Combined immunodeficiencies generally less profound than severe combined immunodeficiencies II Combined immunodeficiencies with associated or syndromic features (e.g. hyper-IgE syndromes) III Predominant antibody deficiencies a. Hypogammaglobulinemia (e.g. CVID) b. Other antibody deficiencies (e.g. selective IgA deficiency) IV Diseases of immune dysregulation a. Syndromes with increased susceptibility to haemophagocytic lymphohistiocytosis or to EBV infections b. Syndromes with autoimmunity (e.g. ALPS, IPEX and syndromes with immune dysregulation with colitis) V Congenital defects of phagocyte number, function or both a. Neutropenia b. Functional defects (e.g. chronic granulomatous disease and cystic fibrosis) VII Defects in intrinsic and innate immunity a. Susceptibility to bacterial and parasitic infections b. Mendelian susceptibility to mycobacterial disease and predominant susceptibility to viral infections VII Auto-inflammatory disorders (e.g. recurrent fevers) VIII Complement deficiencies IX Phenocopies of inborn errors of immunity SCID: severe combined immunodeficiencies; CVID: common variable immunodeficiency; EBV: Epstein–Barr virus; ALPS: autoimmune lymphoproliferative syndrome; IPEX: immunodysregulation polyendocrinopathy enteropathy X-linked. Data from [1, 2].

genetic/developmental reasons. If the main defect is in the humoral immunity, the disease is manifested mainly by repeated, severe and prolonged bacterial infections. The defects of the cellular immune response are signalled by repeated, mainly opportunistic, infections and disseminated forms of infection such as mycobacterioses including tuberculosis, viral infections and mycoses. The blockade of specific immune pathways and cytokines and Mendelian susceptibility to mycobacterial infections caused by selective defects in interferon-γ, IL-12 and IL-23 can also manifest by severe infections such as tuberculosis and mycobacterioses in individuals treated with TNF-α inhibitors [10]. A positive family history, failure to thrive or syndromic features raise the suspicion of PID and prompts further investigations (figure 1). Establishing a diagnosis is difficult and patients may have different clinical presentations across age groups. Moreover, the presentation of PID in children can vary considerably from presentation in adults [11]. Important warning signs for PID can be divided into two groups: infectious and non-infectious warning signs. Infectious warning signs

Recurrent upper and lower airways infections are often the primary warning sign in both children and adults [9, 12]. Warning signs are recurrent pneumonia confirmed by radiology, particularly if located at different sites, high frequency of pneumonia for >1 year, slowly progressing disease, pneumonia that does not resolve with treatment with multiple 376

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Warning signs

Imaging

Microbiology

Pulmonary function

Immunology testing#

Recurrent and/or severe respiratory infections with common pathogens Serious infections with unusual pathogens Family history

Chest radiograph: acute evaluation in infections Chest CT Infections: radiologic signs typical for some pathogens and for immune defects Non-infectious lung involvement (granulomas, nodules, pneumatocele, bullae, bronchiectasis, ILD) Samples Noninvasively obtained immediately: blood, sputum, urine Invasively obtained: consider bronchoscopy with BAL or transbronchial biopsy if treatment not effective

Evaluation severity of lung involvement Obstructive pattern: typical in bronchiectasis Restrictive pattern: typical in ILD, e.g. GL-ILD

Leukocyte differential count, IgA, IgM, IgG and subclasses Vaccine response Flow cytometry Complement concentration and functional tests Phagocytic activity and chemotaxis Autoantibody identification

Figure 1. General diagnostic approach to patients suspected of immunodeficiencies. GL-ILD: granulomatous lymphocytic ILD. #: if basic immunological tests are normal, refer patients for second-line investigations.

types of antibiotics and finally pneumonia requiring hospital admission, administration of intravenous antibiotics or intensive care [13]. Recurrent lung infections will often result in permanent irreversible lung damage, such as thickening of the bronchial wall with the development of bronchiectasis, air trapping and atelectases. The type of microbes detected depends on the specific PID; in general, Streptococcus pneumonia and Haemophilus influenzae, followed by Mycoplasma spp., Staphylococcus spp., Moraxella spp., Pseudomonas aeruginosa, viral pathogens and, more rarely, Pneumocystis jirovecii and various fungi are identified [14]. Non-infectious warning signs

Due to better treatment and prophylaxis, non-infectious complications now impact on patients’ lives to a larger degree. ILD, specifically in patients with CVID syndrome such as GL-ILD, but also NSIP and OP are more frequently reported and sometimes in the same patient [9, 12]. Cancer, specifically types associated with virus, may also be the first sign of PID. Patients with CVID have a 300-fold increased risk of developing malignant lymphoproliferative disorders, but also gastric carcinoma and thymomas occur more frequently; benign lymphoproliferative disorders such as splenomegaly, lymphadenopathy and parenchymal lymphoid hyperplasia are other warning signs [9].

Laboratory investigations The mainstay of the diagnosis of immunodeficiencies is clinical suspicion based of the previously described symptoms leading to immunologic and sometimes genetic investigations to confirm the immunodeficiency and specify type and severity. https://doi.org/10.1183/2312508X.10015619

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Immunological investigations

The basic immunologic investigation should at least comprise the following. 1) Differential blood cell count. 2) Ig concentration in peripheral blood (IgM, IgA, IgG and IgG subclasses) to identify, for example, neutropenia, lymphopenia and hypogammaglobulinemia. 3) Antibody response through vaccination, using vaccines inducing a T-dependent (e.g. anti-tetanic) and a T-independent (e.g. anti-pneumococcal 23-valent vaccine) in case of hypogammaglobulinaemia. 4) Flow cytometry for identification of B-cells and/or T-cells (CD4, as in HIV infection, CD8 or both) defects. Mature B cells may be absent both in PID and SID (e.g. Bruton’s agammaglobulinemia and after anti-CD20 treatment). 5) Functional tests and complement concentration in peripheral blood may suggest a primary defect or an ongoing activation of the complement cascade. 6) Functional tests for measuring phagocytic activity and chemotaxis of polymorphonuclear neutrophils. 7) Autoantibody identification can be helpful in immunodeficiencies with autoimmune features or autoimmune diseases with secondary immune defects but may not be a reliable marker in antibody defects or in patients already undergoing Ig replacement therapy. Microbiological investigations

The identification of pathogens triggering the pulmonary involvement results not only in targeted antimicrobial treatment but can also help to identify the type of immune defect. Antibody deficiencies primarily results in bacterial pneumonia and defects of cell-mediated immune responses increase the susceptibility to viral and fungal infections, but also to tumours. Defects in phagocytosis and intracellular killing of the bacilli lead to persistence of bacilli in granulomas. Cytokine deficiencies, namely TNF-α, but also T-helper (Th) 1 type cytokines increase the risk of tuberculosis (table 2). Thus, microbiological investigation (smear and culture) of biologic materials, i.e. sputum, induced sputum and BAL fluid, is crucial for pathogen identification. Blood cultures, pharyngeal and nasal swabs and urine cultures may contribute as well. Transbronchial and/or surgical lung biopsy can deliver material for pathogen identification, especially in cases where other material is missing or not contributing to a diagnosis. Molecular (PCR) and immunologic methods (specific antibodies to causal antigens, Legionella and Pneumococcus antigens in urine) can contribute as well.

PFT PFTs give information about the severity of the pulmonary involvement but do not contribute to the diagnosis of a specific immune defect. In ILD, the pulmonary function pattern will be restrictive, while patients with bronchiectasis will have an obstructive pattern. Patients with PID will often experience progressive decline of lung function [15].

Imaging Chest radiographs might be used in the acute management of infectious complications of pulmonary immunodeficiencies. However, to diagnose the type of lung involvement, and to properly pronounce the suspicion of specific immune defects, CT, maybe HRCT, is needed. CT can differentiate between infectious and non-infectious lung involvement, granulomatous findings, disseminated small nodules (i.e. miliary tuberculosis), pneumatocele, bullae, bronchiectasis and fibrotic/non-fibrotic interstitial patterns. 378

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Table 2. Typical pathogens in different immune disorders Immunodeficiency

Common pathogens

B-cell deficiency

Bacteria: Streptococcus spp., Staphylococcus aureus, Haemophilus influenzae B, Neisseria meningitidis, Mycoplasma spp., Pseudomonas aeruginosa Bacteria: Mycobacterium spp., Listeria spp., Salmonella spp., Legionella spp., Nocardia spp. Virus: Cytomegalovirus, varicella zoster virus, herpes simplex virus Fungi: Pneumocystis jiroveci, Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Candida spp. Parasites: Toxoplasma gondii, Strongyloides stercoralis Bacteria: Staphylococcus aureus, Streptococcus spp., Haemophilus influenza B, Mycobacteria species, Listeria Fungi: Pneumocystis jiroveci, Candida spp., Cryptococcus neoformans, Cryptosporidium spp. Virus: Cytomegalovirus, herpes simplex virus, measles Parasites: Toxoplasma gondii, Strongyloides stercoralis Bacteria: Staphylococcus aureus, Salmonella spp., Nocardia, Mycobacterium spp. (usually non-tuberculous), Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli Fungi: Aspergillus spp., Candida spp. Bacteria: Streptococcus, Haemophilus influenza B, Neisseria meningitides, Neisseria gonorrhea

T-cell deficiency

Combined B- and T-cell deficiency

Phagocytosis deficiency

Complement deficiency

Bronchoscopy Bronchoscopy plays a pivotal role in the identification of microorganisms (e.g. bacteria including mycobacteria, virus and moulds) in the lungs. Even patients with no symptoms of respiratory infection may harbour bacteria in the lower respiratory tract [16]. BAL has an important role in obtaining material for microbiologic investigation in an immunocompromised host with pneumonia, and cytologic differential count including flow-cytometry for T-cell subsets can be useful in patients with ILD, e.g. lymphocytosis in patients with GL-ILD [17, 18]. Transbronchial biopsy can be useful in cases of suspicion of fungal and mycobacterial infections in an immunocompromised host, but also in ILD and tumours. Lung and lymph node biopsy

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Only in specific cases like the diagnostics of tumours, interstitial involvement, differentiating granulomas and abscesses from tumours and miliary dissemination of infections from metastatic spread, can a biopsy be needed. Sometimes, molecular methods can identify the pathogen in the biopsy from a lesion, i.e. mycobacteria. Lymph node biopsy from either peripheral lymph nodes or cytology specimens from bronchoscopy can contribute to the differential diagnosis between hyperplasia, granulomatous and lymphoproliferative diseases.

Treatment principles Treatment of the lung manifestations in immunodeficiency comprises antimicrobial or anticancer treatment of the specific condition and parallel treatment and/or restoration of the immune defect. Prophylaxis of infections, including opportunistic infections in cellular immune defects, is inevitable, comprising prevention of bacterial, fungal and in some cases viral infections.

Prognosis The prognosis depends on the severity and type of the underlying immune defect, severity of the non-infectious comorbidities and effectiveness of the treatment.

Primary immunodeficiencies CVID

CVID is one of the most common PID occurring in approximately 1:25 000 and affects males and females equally [19, 20]. Symptom onset is often noted in the third decennium followed by diagnosis in the fourth decennium [20]. CVID comprises a heterogeneous group of disorders characterised by hypogammaglobulinaemia, specifically a decrease in IgG, associated with a decrease in IgA and/or IgM and an impaired antibody response resulting in susceptibility to infection, and a variety of comorbidities (table 3) [5, 19]. A polygenic inheritance is likely in most cases although monogenic forms have been described. Most cases are sporadic, but in 5–25% an autosomal-dominant pattern is observed [19]. Disturbed antibody production is often the result of B-cell dysfunction but may also result from impairment of T-cell function [19]. Infections are mainly sinopulmonary (93%) including otitis media, sinusitis and pneumonia, but conjunctivitis and gastrointestinal infections are also reported and caused by encapsulated extracellular bacteria [19]. Non-infectious commonly encountered complications include: bronchiectasis (35.8%), splenomegaly (22.4%), lymphadenopathy (26.3%), granulomatous inflammation (3.9%) and idiopathic thrombocytopenic purpura (14.5%) (table 4). Non-infectious complications are strongly associated with a B-cell phenotype and patients with non-infectious complications seem to have a poorer outcome than patients with only infectious complications [21, 22]. Laboratory investigations show low levels of Igs, specifically IgG but also IgM and IgA. Approximately 20% of patients with CVID have very low levels or even absence of all Ig isotypes at presentation; vaccine responses can initially be normal but may decrease over time [19]. 380

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Table 3. Diagnosis of common variable immunodeficiency Probable common variable immunodeficiency Male or female patient with a marked decrease in IgG (2 years of age Absent isohaemaglutinins and/or poor response to vaccines Defined causes of hypogammaglobulinaemia have been excluded Possible common variable immunodeficiency Male or female patient with a marked decrease (2 years of age Absent isohaemaglutinins and/or poor response to vaccines Defined causes of hypogammaglobulinaemia have been excluded Data from [5, 18].

CVID is treated with IgG replacement therapy, either intravenously or more often subcutaneously, resulting in a reduction of infection frequency and improved quality of life [22]. Dose and treatment intervals are specific due to individual threshold levels of IgG to prevent breakthrough bacterial infections. However, CVID-related lung disease may progress despite IgG replacement therapy [19]. A starting dose of 0.4–0.6 g·kg−1·month−1 for subcutaneous Ig therapy is recommended unless bronchiectasis is present; in that case, there is then evidence for a dose of 0.6 g·kg−1·month−1. Dosing intervals vary from daily to twice weekly, weekly, or every 2–4 weeks. Under treatment of IgG is related to higher rates of respiratory infection and poorer outcomes [19]. The burden of CVID is substantial with annual comorbidity rates for bronchiectasis of 22%, autoimmunity of 23%, enteropathy of 16%, solid cancers of 6% and lymphoma of 4%, exceeding prevalence in the general population by a factor of 34.0, 7.6, 8.1, 2.4 and 32.6, respectively. The excess mortality in CVID is primarily caused by lymphomas (HR (95% CI); 5.48 (2.36–12.71), p60 years of age with TERT, TERC or RTEL1 mutations, had a telomere length >1st percentile and half of them had a telomere length >10th percentile [24]. Patients with TERT, TERC or RTEL1 mutations transmit their short telomeres independently of transmission of the mutation and telomeres shorten in younger generations [9, 27]. This epigenetic-like inheritance explains the phenomenon of genetic anticipation; the definition is an earlier onset of the disease with each generation (figure 2) [9, 39, 40]. Telomere shortening may vary from one TRG to another, and genetic anticipation may more frequently occur in carriers of TERC mutations than PARN mutations [9]. https://doi.org/10.1183/2312508X.10015719

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ILD

MDS

Figure 2. Pedigree suggestive of a telomere-related gene mutation. MDS: myelodysplatic syndrome.

Eventually, it may be possible to assess telomere length from the lung tissue of ILD patients and particularly from alveolar type 2 cells (AT2). Indeed, telomere length is reduced in AT2 from TERT mutation carriers, although it may differ in AT2 from the fibrotic or nonfibrotic region [41]. Interestingly, a cohort of ILD patients with SSc only showed reduced telomere length in the lymphocytes but not in the granulocytes; telomere length is usually given for the whole white cell population [42]. Some experts suggest analysing telomere length before genetic analysis of TRG [2, 24, 43]. Regardless, reduced telomere length has been uniformly associated with reduced overall survival or post-lung transplantation survival [32, 44].

Interaction with the at-risk MUC5B polymorphism

In 2011, a large cohort study demonstrated that rs35705950, a variant located in the promoter region of MUC5B, was associated with both FPF and IPF, and recent data suggest that several mucins genetic variants are key players in IPF pathophysiology [45, 46]. Heterozygous (GT) and homozygous (TT) carriers of rs35705950 had increased odds ratios (ORs) for disease: 6.8 (95% CI 3.9–12.0) and 20.8 (95% CI 3.8–113.7) for FPF and 9.0 (95% CI 6.2 to 13.1) and 21.8 (95% CI 5.1 to 93.5) for IPF, respectively [45, 47–53]. In a Caucasian population, the rs35705950 variant was found in ∼9% of the general population, where its presence alone was insufficient to cause disease [54]. The presence of rs35705950 has also been associated with better survival in IPF cohorts [32, 55]. 394

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The at-risk MUC5B polymorphism is seen less frequently in TRG mutation carriers with ILD than in familial or sporadic IPF cohorts [11, 32]. Indeed, in a cohort of 1510 IPF patients, 30 (3%) of the 1046 MUC5B allele risk carriers had a rare functional variant in TERT compared with 34 (7%) of the 464 MUC5B non-risk allele carriers (OR 0.40 (95% CI 0.24–0.66); p=0.0004) [32].

Pulmonary involvement ILD

The prevalence of ILD in TRG mutations carriers increases in older patients [27]. In an American cohort of TERT mutation carriers, none of the patients who were 60% [27]. Among TRG mutations carriers, patients with TERC mutations may present an ILD diagnosis at a younger age [9]. In a cohort of 114 ILD patients who were carriers of the TRG mutation, ILD was diagnosed at a mean age of 51 years (n=7) for TERC, 58 years (n=75) for TERT, 60 years (n=14) for RTEL1 and 65 years (n=19) for PARN ( p=0.03) [9, 11]. In a cohort of ILD patients with the TRG mutation, the male/female ratio was reported to be 0.5/0.7. In one series, men were younger than women at ILD diagnosis, 54 versus 63 years, respectively [40]. Tobacco smoking and other pneumotoxic exposures are frequently reported in patients with ILD and TRG mutations and are comparable to sporadic IPF cohorts (40–96%) [9, 11, 27]. The CT pattern is considered typical of UIP in 46–74% of cases (figure 3) [9, 11, 27]. The CT pattern is considered indeterminate of UIP in 13–20% of cases because of atypical features: fibrosis with upper lung predominance, centrolobular fibrosis, or a pleuro-parenchymal fibroelastosis pattern [9, 11, 27]. In patients with the TRG mutation, IPF is the most frequent ILD diagnosis (45–86%) [9, 40, 48] but rarer ILD diagnoses are unexpectedly frequent: pleuroparenchymal fibroelastosis (⩽10%), chronic hypersensitivity pneumonitis (7–11%) and unclassifiable fibrosis (19–30%) [9, 11, 27, 35]. Patient carriers of TRG mutations have been shown to have a more rapid decline of pulmonary function than patients in IPF clinical trials (130–210 mL·year−1) [56]. NEWTON et al. [9] reported a 300 mL·year−1 decline of FVC independently of TRG (TERC, TERT, RTEL1 or PARN) and the ILD diagnosis (IPF or not). Indeed, most patients with ILD and carriers of a TRG mutation will eventually die of respiratory causes [9, 11, 27]. The mean survival after ILD diagnosis is 2.8–5.2 years, which is in line with historical reported survival of IPF [57]. However, among patients with familial ILD, those with the TERT or TERC mutation may have a shorter transplant-free survival [11]. Evolution can be heterogeneous and ILD diagnosis may modify the prognosis [35, 58]. Other lung diseases Hepatopulmonary syndrome Hepatopulmonary syndrome associated with TRG mutation is frequent [59]. In a series of 42 patients with telomere syndrome who complained of dyspnoea, nine had a hepatopulmonary syndrome with minimal or no ILD. The definition of hepatopulmonary syndrome was a liver disease with evidence of intrapulmonary vascular dilatation and hypoxaemia. However, three patients did not present a known TRG mutation, despite https://doi.org/10.1183/2312508X.10015719

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a)

b)

c)

d)

Figure 3. Representative CT scans of patients with TRG mutations. a) A UIP pattern, b) a normal CT in a patient with hypoxaemia and liver cirrhosis revealing hepatopulmonary syndrome, c) ground-glass opacities superimposed with pulmonary fibrosis secondary to pneumocystis infection, and d) an inconsistent UIP pattern suggestive of pleuroparenchymal fibroelastosis.

having a typical DKC phenotype; other TRG mutations included TERT (n=4), RTEL1 (n=1) and DKC1 (n=1) [59]. Emphysema Evidence suggests that there is an increased risk of emphysema in TRG mutation carriers. When exposed to tobacco smoke, knockout TERC mice with short telomeres develop emphysema but no lung fibrosis [60]. In female smokers with severe chronic obstructive pulmonary disease and emphysema, TERT and NAF1 mutations may be found [6, 61, 62].

However, the prevalence of combined pulmonary fibrosis and emphysema (CPFE) in other cohorts of TRG mutation carriers is reported to be 13–15%, in line with usual prevalence of emphysema in IPF cohorts [9, 11, 35, 63]. Immunodeficiency Immunodeficiency has been mainly been described in children [64]. However, an opportunistic infection with Pneumocystis jirovecii in a TERC mutation carrier free of any treatment had been reported [65]. Moreover, patients with TRG mutations present an increased risk of CMV infection after lung transplantation [53]. The exact prevalence of immunodeficiency and its impact for lung transplantation need to be evaluated. 396

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Extrapulmonary manifestations Pulmonary and extra-pulmonary manifestations associated with TRG mutations have been reported as “telomere disease”, “telomeropathy” or “short telomere syndrome”, without consensual definition. Mucocutaneous involvement

DKC was the first telomeropathy associated with TRG mutations [66, 67]. DKC can be defined as having a mucocutaneous triad of reticular skin pigmentation, nail dystrophy and oral mucosal leukoplakia [68]. Mucocutaneous diseases appear in childhood, and bone-marrow failure usually appears after 10 years of age [68]. Lung fibrosis may spontaneously appear in DKC; however, after hematopoietic stem-cell transplantation, DKC patients show severe pulmonary complications, including lung fibrosis [69]. Patients with the TRG mutation and pulmonary fibrosis usually do not present the mucocutaneous triad, although 15–40% present premature hair greying (before the age of 30 years) [11, 70]. Partly because of genetic anticipation and telomere shortening, the same gene mutation can be associated with different phenotypes; descendants from patients with pulmonary fibrosis may present typical DKC [9]. Haematological involvement

TRG mutations have been associated with bone marrow failure, myelodysplasia and acute leukaemia [71–73]. The coexistence of pulmonary fibrosis and bone marrow failure, particularly in the young, increases the probability of a TRG mutation. This is unlikely to be the case in older patients (submitted observation and [74]). In patients with TRG mutations and pulmonary fibrosis, 17–27% present with anaemia, 24–41% with macrocytosis and 8–54% with thrombocytopenia [9, 11]. DKC1, TINF2 and TERC mutations may be more frequently associated with haematological involvement than TERT or RTEL1 mutations [9, 35]. Liver involvement

5–27% of patients with ILD and the TRG mutation present elevated liver enzyme levels or liver involvement [9, 11]. Carriers of TRG mutations may present cryptogenic or secondary liver cirrhosis. In a series of 86 patients who received liver transplantation, 17 (20%) had likely in silico deleterious variants of one TRG. The presence of any TRG variant was associated with an increased number of readmissions within 1 year of transplantation (OR 3.15 (95% CI 1.22–8.57)), but no association with survival was observed [75]. The risk of liver cirrhosis in cases of hepatitis C infection and probably with equivalent alcohol consumption could be increased by the presence of a TRG mutation [76, 77]. Hepatic manifestations may vary in relatives with the same mutation, normal or elevated liver enzyme levels with variable degrees of necrosis, inflammation, fibrosis and regeneration on liver histology [76]. In a series of nine patients with hepatopulmonary syndrome, six had available liver biopsies and amongst them the most common histological diagnosis was nodular regenerative https://doi.org/10.1183/2312508X.10015719

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hyperplasia (n=4/6). The final diagnosis was non-cirrhotic portal hypertension. In the same series, two patients received liver transplantations, but lung fibrosis developed 18 months later in one patient and 12 years later in the other [59]. Other manifestations

Other manifestations have been associated with TRG mutations: exudative retinopathies, central neurological disease and cerebral calcifications, gastrointestinal bleeding, radiation sensitivity, infertility, osteoporosis and renal insufficiency [64]. Whole sequencing was performed in a cohort of 92 patients with chronic kidney disease of unknown cause and identified loss-of-function mutations in PARN in two probands with tubulointerstitial fibrosis [78].

Treatment Antifibrotic therapy

The safety and efficacy of pirfenidone has recently been reported. One European multicentre retrospective study was unable to show an effect of pirfenidone on lung function decline: FVC was 161.8±31.2 mL·year−1 before and 235.0±49.7 mL·year−1 after pirfenidone initiation [79]. A post hoc analysis of two prospective phase 3 clinical trials (CAPACITY, ASCEND) evidenced 102 patient carriers of rare variants within one of the TRG mutations in the whole IPF cohort. Those patients had a more rapid decline in FVC than patients without a rare variant (1.66% versus 0.83% per month), and pirfenidone reduced the decline of FVC in this subgroup of severe patients [32]. No data have been published concerning nintedanib in such patients. Targeted therapy

Danazol is a synthetic sex hormone with androgenic properties, which could be used as a targeted therapy for pulmonary fibrosis associated with TRG mutation. In a 2-year prospective study that included 10 patients with “overt” pulmonary fibrosis and 15 with “subclinical” pulmonary fibrosis, danazol therapy was associated with stabilisation of DLCO, FVC and CT scan findings [25]. Treatment with danazol was associated with telomere elongation and haematological response in 19 (79%) of the 24 patients. However, danazol is associated with liver adverse effects and increased risk of venous thrombosis. A phase I/II trial (ANDROTELO; ClinicalTrials.gov identifier NCT03710356) with danazol in lung fibrosis has recently begun in France and includes patients with lung fibrosis and carriers of a TRG mutation. Lung transplantation

Lung transplantation is often discussed because of the young age of most patients. To date, five retrospective series have reported the outcome of lung transplantation in TRG mutation carriers [80–84]. Haematological toxicity requires an adjustment of immunosuppression in most patients. Myelodysplastic syndrome or bone marrow failure occurred in some patients, and thrombocytopenia as well as a need for platelet transfusion are frequent. In the first reported series, acute kidney failure seemed unexpectedly frequent (⩽50%) [80, 81]. Interestingly, short telomeres and TRG mutations have been associated with an increased 398

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prevalence of cytomegalovirus infection after lung transplantation [84]. In a cohort of 262 patients who received lung transplantation, patients with TERT, RTEL1 or PARN mutations (n=31, 11.8%) were reported to have a reduced post-transplantation survival (hazard ratio (HR) 1.82 (95% CI 1.07–3.08); p=0.03) and a higher risk of chronic lung allograft dysfunction (HR 2.88 (95% CI 1.42–5.87); p=0.004) [83]. However, this retrospective study did not report a higher risk of haematological complications or renal insufficiency in TRG mutation carriers [83]. Moreover, in an independent cohort, patients with a telomere length of 48 months and elevated levels of C-reactive protein [81]. Other retrospective and observational studies have demonstrated that infliximab has a steroid-sparing effect but may result in a high incidence of respiratory infections [82]. As known from large cohorts of patients with inflammatory https://doi.org/10.1183/2312508X.10015919

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bowel disease and rheumatological disorders, this class of drugs can induce fungal and mycobacterial infections and may even provoke drug-induced granulomatous inflammation. Humanised adalimumab has been studied in an observational cohort of 11 patients, showing stabilisation to mild improvement of FVC [83]. The effect of physical rehabilitation on the outcome of patients with sarcoidosis has recently been studied, as its importance on the outcome of patients with respiratory disease in general, and pulmonary sarcoidosis in particular, cannot be overestimated. A retrospective cohort study in 90 patients showed that a 12-week supervised physical training programme had a beneficial effect on 6-min walk distance (6MWD) with a reduction in fatigue score [84]. A smaller but prospective study found that physical rehabilitation improved 6MWD, was able to avoid deconditioning and improved patient coping [85]. In a trial in which patients were randomised to inspiratory muscle training or standard of care, there were beneficial effects on inspiratory muscle strength and 6MWD [86]. It is recommended that any rehabilitation programme in sarcoidosis should be adapted to the specific patient, modifying intensity, frequency and time intervals to prevent overload and early discontinuation. In general, high-frequency, low-impact exercise is recommended for frailer patients [87]. Ongoing pharmaceutical research

The search for a corticosteroid surrogate with considerably less toxicity has been ongoing for many years. Repository corticotropin injection is approved by the US Food and Drug Administration (FDA) and has biochemical properties related to adrenocorticotropic hormone, potentially upregulating the endogenous glucocorticoid effect. A multicentre, randomised, placebo-controlled study to study the use of repository corticotropin injection is currently recruiting 100 patients with pulmonary sarcoidosis in the USA (ClinicalTrials.gov identifier NCT03320070). The composite end-point includes PFTs and steroid sparing. As an inhibitor of lymphocytes, rituximab is a potentially potent immunomodulating agent. Although the importance of B-lymphocytes in the pathophysiology of sarcoidosis remains partially unknown, a prospective study in 10 patients with moderate-to-severe pulmonary disease showed a potential clinical response. Further studies are required to assess whether rituximab may play an important role in pulmonary sarcoidosis [88]. Following the data obtained from antifibrotic treatment in IPF, a multicentre, double-blinded, placebo-controlled trial with pirfenidone is currently being conducted in 60 patients with fibrosing pulmonary sarcoidosis (ClinicalTrials.gov identifier NCT03260556). Selexipag, an oral selective IP prostacyclin-receptor agonist, has been beneficial in the treatment of PAH [89]. A multicentre, randomised, placebo-controlled trial is currently underway in patients with sarcoidosis-associated PH (ClinicalTrials.gov identifier NCT03942211).

Prognosis Sarcoidosis is widely regarded as a disease with a benign course over time, with the majority of patients exhibiting resolution or stabilisation of disease activity and disability. In general, the probability of disease activation decreases with increasing patient age, 414

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although exceptions are observed most frequently in women. Disease-specific mortality rates are low on average [90] but are higher in patients with cardiac sarcoidosis and neurosarcoidosis. However, despite good outcomes in the majority of patients with pulmonary sarcoidosis, a distinct subset of patients with pulmonary disease will progress, despite immunomodulatory treatment, with a considerable risk of developing chronic respiratory failure. This subset of patients has a considerable mortality risk and typically develops extensive fibrosing pulmonary disease, PH or a combination of both [91]. These patients are strong candidates for lung transplantation. Ideally, progression to end-stage disease should be pre-empted by more intense treatment in patients with progressive disease. However, comorbidities induced by prolonged treatment with corticosteroids and immunosuppressants are important factors in driving mortality and loss of quality of life. Quality of life, as well as physical and psychosocial impairment, is a major determinant for patients with sarcoidosis. Its importance is emphasised by the fact that sarcoidosis occurs mainly in younger people, who are (were or should be) part of the active working population. As a result of fatigue, cognitive troubles in daily life (e.g. memory loss, concentration difficulties), depression and anxiety, and dysregulation of the autonomic nerve system, patients are often unable to meet the challenges of modern society. The proportion of patients who are dealing with disease-related disability in daily life largely outweighs the number of patients with life-threatening disease manifestations, and the same is true for health economical costs. The needs of these patients are more likely to be met by rehabilitation and a broader socioeconomic acceptance of the disease and its consequences in life than by novel pharmacological treatments [92].

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

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Disclosures: A.U. Wells reports receiving the following, outside the submitted work: consultancy and speaking fees from Roche and Boehringer Ingelheim; and consultancy fees from Bayer and Blade.

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Interest in interstitial lung diseases (ILDs) has risen in recent Pantone PASTEL 9081 CMJN Pantone 200 CMJN (darker) Pantone 647 CMJN years. A large volume of basic and clinical Cyan 0 research has Cyan 0 Cyan 100 Magenta 0 Magenta 100 Magenta 56 Yellow 6 increased Yellow our70understandingYellow of0 the pathogenesis of idiopathic Black 8 Black 14 Black 24 pulmonary fibrosis (IPF) and non-IPF fibrotic ILDs. The ILD field is now evolving rapidly, with major implications for practical management. This Monograph provides expert clinical guidance on these difficult diseases, which will be helpful to both respiratory and nonrespiratory physicians alike. The initial chapters consider diagnostic issues, pulmonary function tests and techniques that are currently in development. The book then goes on to cover a variety of pulmonary manifestations of very different disease entities, such as connective tissue diseases, systemic vasculitis and much more.

Print ISBN: 978-1-84984-111-5 Online ISBN: 978-1-84984-112-2 December 2019 €60.00

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ISBN 978-1-84984-111-5 Print ISSN: 2312-508X Online ISSN: 2312-5098

Pulmonary Manifestations of Systemic Diseases

ERS monograph

ERS monograph

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Pulmonary Manifestations of Systemic Diseases

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Edited by Wim A. Wuyts, Vincent Cottin, Paolo Spagnolo and Athol U. Wells