European Respiratory Society
Pulmonary Manifestations of Systemic Diseases

Interest in interstitial lung diseases (ILDs) has risen in recent years. A large volume of basic and clinical research has increased our understanding of the pathogenesis of idiopathic 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.

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  • ERS Monograph
  1. Page v
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  4. Page 1
    Abstract
    Wim A. Wuyts, Unit for Interstitial Lung Diseases, Dept of Respiratory Medicine, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: wim.wuyts@uzleuven.be

    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].

  5. Page 14
    Abstract
    Athol U. Wells, Interstitial Lung Disease Unit, Royal Brompton Hospital, Sydney St, London, SW3 6HP, UK. E-mail: rbhild@rbht.nhs.uk

    The accurate use of PFTs in multisystem disorders requires a clear understanding of both the nature of multisystem disease and the inherent limitations of PFTs. In multisystem disorders, pulmonary disease may arise in one or more lung compartments, resulting in highly variable patterns of pulmonary function impairment. The detection of pulmonary disease and the accurate quantification of disease severity (with a view to prognostic evaluation) requires the multidisciplinary integration of PFTs, symptoms and ancillary tests such as thoracic CT and echocardiography. With regard to both goals, the integration of all available data is necessary to offset the confounding effect of the normal PFT range, as pre-morbid PFT data are seldom available. PFTs are the cornerstone of monitoring pulmonary disease progression but measurement variability and the existence of multicompartment disease complicate the use of PFTs for this purpose in isolation. Apparently definitive serial PFT trends may, in reality, represent supervening disease processes in other lung compartments or, in patients receiving immunosuppressive therapy, infection or drug-induced lung disease. In conclusion, PFTs have a key role in multisystem disorders in the identification of pulmonary disease, evaluation of disease severity and monitoring but must always be integrated with all other available data.

    Cite as: Valenzuela C, Wells AU. Pulmonary function tests in multisystem disorders: prejudices and pitfalls. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 14–26 [https://doi.org/10.1183/2312508X.10031219].

  6. Page 27
    Abstract
    Joseph Jacob, Dept of Respiratory Medicine, First Floor, Rayne Institute, University College London, London WC1E 6JJ, UK. E-mail: j.jacob@ucl.ac.uk

    Advances in computer technology over the past decade, particularly in the field of medical image analysis, have permitted the identification, characterisation and quantitation of abnormalities that can be used to diagnose disease or determine disease severity. On CT imaging performed in patients with ILD, deep-learning computer algorithms now demonstrate comparable performance with trained observers in the identification of a UIP pattern, which is associated with a poor prognosis in several fibrosing ILDs. Computer tools that quantify individual voxel-level CT features have also come of age and can predict mortality with greater power than visual CT analysis scores. As these tools become more established, they have the potential to improve the sensitivity with which minor degrees of disease progression are identified. Currently, PFTs are the gold standard measure used to assess clinical deterioration. However, the variation associated with pulmonary function measurements may mask the presence of small but genuine functional decline, which in the future could be confirmed by computer tools. The current chapter will describe the latest advances in quantitative CT analysis and deep learning as related to ILDs and suggest potential future directions for this rapidly advancing field.

    Cite as: 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., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 27–43 [https://doi.org/10.1183/2312508X.10013919].

    1. Page 44
      Abstract
      John A. Mackintosh, Dept of Thoracic Medicine, The Prince Charles Hospital, Rode Road, Chermside, Brisbane, Queensland 4032, Australia. E-mail: john.mackintosh@health.qld.gov.au

      RA may be complicated by pulmonary disease involving any compartment of the lung, which can manifest before, synchronously or after the development of articular disease. Genetic and environmental factors combine to increase the risk of certain pulmonary manifestations, in particular ILD. Interestingly, RA-associated ILD (RA-ILD) and IPF share many common features, in terms of both genotype and phenotype. For patients with RA presenting with respiratory symptoms, a thorough evaluation is necessary, including full lung function tests. CT is necessary to define the specific disease process. Management decisions should be individualised, incorporating both pharmacological and nonpharmacological strategies. The management of RA-ILD is made more challenging by the pulmonary toxicities of commonly used disease-modifying therapies. Despite long-standing knowledge of the associations between RA and ILD, clinical trial evidence is sorely lacking. Fortunately, there are pioneering studies under way designed to fill this evidence gap.

      Cite as: Mackintosh JA, Stainer A, De Sadeleer LJ, et al. Rheumatoid arthritis. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 44–67 [https://doi.org/10.1183/2312508X.10014019].

    2. Page 68
      Abstract
      Vincent Cottin, Service de Pneumologie, Hôpital Louis Pradel, 28 avenue Doyen Lepine, F-69677 Lyon Cedex, France. E-mail: vincent.cottin@chu-lyon.fr

      Lung involvement is present in 75% of patients with inflammatory myopathy. It is the main cause of morbidity and mortality in inflammatory myopathy. When present, lung involvement associated with inflammatory myopathy predominantly consists in interstitial lung disease. Classification into phenotypes (mainly dermatomyositis, overlap myositis including anti-synthetase syndrome, and polymyositis) and identification of the autoantibody contribute to the stratification of the risk of lung involvement. The CT pattern often suggests NSIP and/or OP. BAL is helpful for ruling out infection. Surgical lung biopsy is generally not indicated if a diagnosis of inflammatory myopathy is already established. Anti-synthetase syndrome (mechanics' hands, Raynaud phenomenon, myositis often mild or absent, and the presence of an anti-transfer RNA synthetase antibody) is associated with a 70% risk of ILD. An upfront combination of immunosuppressive drugs and corticosteroids is often required for life-threatening rapidly progressive ILD; in contrast, stable or slowly progressive forms of chronic ILD may be managed using low-dose corticosteroids and/or long-term oral immunosuppressive drugs. Rituximab has shown promising results in refractory or rapidly progressive forms of ILD.

      Cite as: Cottin V, Barba T, Mainbourg S, et al. Inflammatory myopathies. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 68–89 [https://doi.org/10.1183/2312508X.10014119].

    3. Page 90
      Abstract
      A.U. Wells, Interstitial Lung Disease Unit, Royal Brompton Hospital, Sydney Street, Chelsea, London SW3 6HP, UK. E-mail: rbhild@rbht.nhs.uk

      In SSc, pulmonary involvement is the most frequent cause of death. SSc-associated ILD (SSc-ILD) is more prevalent in diffuse cutaneous systemic disease but is also present in a large minority of patients with limited cutaneous disease. PH is also a major source of morbidity and mortality but lies beyond the scope of this chapter. The pathogenesis of SSc-ILD can be broadly separated into susceptibility associated with genetic profiles and autoantibody status, disease initiation due to inflammation and epithelial injury, and ongoing progression driven by both inflammatory and profibrotic pathways. NSIP is the most frequent histological finding. SSc-ILD is most reliably identified by CT. Pulmonary function evaluation is central both to the evaluation of SSc-ILD severity and to accurate monitoring. Decisions on the introduction of therapy are heavily influenced by disease severity, the duration of systemic disease and evidence of ongoing progression. Routine treatment consists of immunosuppressive therapy (cyclophosphamide, mycophenolate mofetil or azathioprine). Recent data suggest roles for rituximab and antifibrotic therapy in selected patients.

      Cite as: Wells AU. Systemic sclerosis. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 90–105 [https://doi.org/10.1183/2312508X.10014219].

    4. Page 106
      Abstract
      K.M. Antoniou, Dept of Respiratory Medicine, Laboratory of Molecular and Cellular Pneumonology, Medical School, University of Crete, Heraklion, Greece. E-mail: kantoniou@med.uoc.gr

      The lung is a frequent target of autoimmune-mediated injury in patients with rheumatic diseases. SLE, Sjögren syndrome (SS) and mixed CTD (MCTD) can affect virtually all anatomical structures of the respiratory tract and manifest as asymptomatic, clinically significant or severe life-threatening disease. Pleural disease is the most common lung manifestation in SLE and MCTD, with SS primarily affecting the airways. ILD can present in all three diseases with different clinical presentations, ranging from minimal significant pulmonary restriction to severe progressive pulmonary fibrosis. Lung involvement in CTDs has a tremendous impact on morbidity, mortality and quality of life, and early recognition and interventions are imperative to limit morbidity and mortality in this group of patients. Nonspecific respiratory involvement (i.e. infection, pulmonary embolism, left-heart failure) may coexist with specific lung manifestations.

      Cite as: 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., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 106–123 [https://doi.org/10.1183/2312508X.10014319].

    5. Page 124
      Abstract
      S.L. Barratt, North Bristol NHS Trust, Southmead Hospital, Bristol BS6 7PZ, UK. E-mail: shaney.barratt@nbt.nhs.uk

      Antiphospholipid syndrome (APS) is a multisystem autoimmune disease characterised by thrombus formation (arterial and venous), cardiac disease, neurological features and pregnancy-related complications. APS can result in a wide range of pulmonary complications including pulmonary thromboembolic disease, PH and DAH, clinically mimicking idiopathic disorders. The interpretation of antiphospholipid antibody screening relies on an understanding of the background prevalence of these antibodies and factors increasing the likelihood of false-positive results such as age, recent infection and malignancy. Respiratory physicians should be discouraged from the use of direct anticoagulant therapies in the management of APS. This chapter outlines the major clinical and laboratory features of APS. A practical approach to the assessment and management of APS-related pulmonary disease will be presented. The extrapulmonary clinical and laboratory features that raise the possibility of underlying APS are highlighted to ensure that respiratory physicians are equipped to consider, diagnose and treat APS-related pulmonary disease in a timely fashion.

      Cite as: Barratt SL, Pauling JD, Chaudhuri N. Antiphospholipid syndrome. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 124–139 [https://doi.org/10.1183/2312508X.10014419].

    6. Page 140
      Abstract
      Aryeh Fischer, Bristol-Myers Squibb Company, 3401 Princeton Pike, Lawrenceville, NJ 08648, USA. E-mail: aryeh.fischer@bms.com

      The European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of CTD-associated ILD developed the “IPAF” construct as an initial step to uniformly define, identify and study patients who have features suggestive of an autoimmune ILD, yet lack those of a characterisable CTD. Single-centre cohort studies of IPAF patients have led to important insights and spurred increasing interdisciplinary collaboration, and suggestions for modification of the criteria have been offered. The IPAF classification represents an important first step towards furthering our understanding of the natural history of this cohort with uniform nomenclature and a standardised set of criteria. Prospective evaluations and interdisciplinary, multicentre collaborations will hopefully inform best practices for management of this cohort. This chapter discusses the background that spurred the IPAF construct, reviews cohort studies of IPAF patients and what they have taught us about the IPAF phenotype, and offers insights into future directions in this arena.

      Cite as: DeDent AM, Fischer A. Interstitial pneumonia with autoimmune features. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 140–152 [https://doi.org/10.1183/2312508X.10026019].

    1. Page 153
      Abstract
      Christian Pagnoux, Vasculitis Clinic, Mount Sinai Hospital, 60 Murray Street, Ste 2-220, Toronto, Ontario, M5T 3L9, Canada. E-mail: christian.pagnoux@sinaihealthsystem.ca

      Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are the most frequent antineutrophil cytoplasm antibody (ANCA)-associated vasculitides, with an estimated annual incidence and prevalence of 2–12 and 23–160 cases per million population, respectively. Both GPA and MPA can involve major organs and be life threatening. They have some similarities but also several important clinical and biological differences. ANCAs are detectable in 90% of patients with systemic GPA, mainly proteinase 3-ANCA, and in ≤90% of MPA patients, mostly myeloperoxidase-ANCA. Despite their rarity and still unknown cause(s), research has been very active over the past decades and has led to recent changes in the treatment approach. Glucocorticoids and conventional cytotoxic immunosuppressants have been used since the early 1970s; however, since the early 2000s, several targeted biological agents, including rituximab, have been found to be effective alternatives to both induce and maintain remission, still combined with glucocorticoids but at lower doses or for a shorter duration. Investigations are ongoing to further optimise treatments and improve outcomes, because relapse and disease- or treatment-related damage remain common.

      Cite as: Pagnoux C. Microscopic polyangiitis and granulomatosis with polyangiitis. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 153–172 [https://doi.org/10.1183/2312508X.10014619].

    2. Page 173
      Abstract
      George A. Margaritopoulos, ILD Unit, Manchester University Hospital NHS FT, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester M23 9LT, UK. E-mail: georgios.margaritopoulos@mft.nhs.uk

      DAH refers to a clinical syndrome resulting from injury to the alveolar capillaries, arterioles and venules that leads to the accumulation of red blood cells in the distal air spaces. DAH is a life-threatening condition associated with haemoptysis, anaemia, diffuse lung infiltration and acute respiratory failure. The causes of DAH can be broadly divided according to the underlying histological pattern into pulmonary capillaritis, bland haemorrhage or DAD; or according to the underlying mechanism as immune or nonimmune. DAH can either be suspected based on the clinical presentation and imaging features, or diagnosed with high confidence when sequential BAL samples show an increasing red blood cell count and when biopsy samples (pulmonary or renal) are available. Identification of the underlying cause leads to the early introduction of treatment and, where possible, to elimination of triggering factors, both of which are associated with increased survival.

      Cite as: Bonifazi M, Stanel S, Margaritopoulos GA. Diffuse alveolar haemorrhage. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 173–187 [https://doi.org/10.1183/2312508X.10014719].

    3. Page 188
      Abstract
      Vincent Cottin, Service de Pneumologie, Hôpital Louis Pradel, 28 avenue Doyen Lepine, F-69677 Lyon Cedex, France. E-mail: vincent.cottin@chu-lyon.fr

      Eosinophilic granulomatosis with polyangiitis is a systemic disease characterised by asthma, blood and tissue eosinophilia, and systemic manifestations, which can affect any organ. ∼40% of patients have antineutrophil cytoplasmic antibodies (ANCAs) with specificity for myeloperoxidase, associated with a greater prevalence of glomerulonephritis, purpura, biopsy-proven vasculitis and mononeuritis multiplex, and a lower prevalence of eosinophilic pneumonia and cardiomyopathy. Genuine vasculitis, however, can occur in the absence of ANCAs. Induction of remission is based on systemic glucocorticoids, associated with pulses of cyclophosphamide in cases with poor prognostic factors. Maintenance therapy consists of low-dose oral glucocorticoids, often associated with conventional immunosuppressants (azathioprine, methotrexate). Mepolizumab increased the remission rate and reduced the required dose of oral glucocorticoids in patients with relapsing or refractory disease, mainly related to flares of asthma. However, its role in the treatment algorithm remains to be determined. Although 5-year survival is 90–95%, quality of life is frequently impaired by severe asthma, persistent airflow obstruction, peripheral neuropathy and treatment-related adverse effects.

      Cite as: Cottin V, Ahmad K, Nasser M, et al. Eosinophilic granulomatosis with polyangiitis. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 188–209 [https://doi.org/10.1183/2312508X.10014819].

    4. Page 210
      Abstract
      George A. Margaritopoulos, ILD Unit, Manchester University Hospital NHS FT, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester, M23 9LT, UK. E-mail: georgios.margaritopoulos@mft.nhs.uk

      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].

    1. Page 228
      Abstract
      Philippe Camus, Centre Hospitalier Universitaire de Dijon, CHU, Rue Marion, Dijon, 21033, France. E-mail: philippecamus1@gmail.com

      The thoracic manifestations that may occur at any time in inflammatory bowel disease (IBD) patients encompass a wide variety of patterns: large and/or major airway inflammation and scarring, subacute and/or chronic bronchiolitis, e.g. ILDs such as organising or eosinophilic pneumonia, neutrophilic or granulomatous lung nodules, serositis, myocarditis and/or pneumomediastinum. Airway disease occurs more often post-colectomy, contrasting with ILD that may develop both in patients exposed to drugs, as well as in those off any medication. Provided alternative aetiologies and an infection are properly ruled out, corticosteroid therapy (inhaled and/or oral or parenteral) is the mainstay of management of IBD-related airway involvement. Oral corticosteroid therapy can be useful to treat significant IBD- or drug-related ILD.

      Cite as: Camus P, Colby TV. Airway and lung involvement in inflammatory bowel disease. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 228–261 [https://doi.org/10.1183/2312508X.10015019].

    2. Page 262
      Abstract
      Michael Kreuter, Center for Interstitial and Rare Lung Diseases, Thoraxklinik, University of Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany. E-mail: kreuter@uni-heidelberg.de

      Lung involvement in the context of chronic hepatic diseases is not rare and often represents a misdiagnosed condition. Hepatopulmonary syndrome and portopulmonary hypertension are conditions with the most impact related to chronic liver diseases involving lungs. Several different pathogenic mechanisms are involved in their development, ultimately leading to respiratory insufficiency. The lack of dedicated studies and targeted therapies has led to conflicting results and the emerging need to investigate this important topic further.

      Cite as: Torrisi SE, Fuhrmann V, Skowasch D, et al. Liver disease: hepatopulmonary syndrome and portopulmonary hypertension. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 262–277 [https://doi.org/10.1183/2312508X.10015119].

    3. Page 278
      Abstract
      Demosthenes Bouros, Interstitial Lung Diseases Unit, Medical School, National and Kapodistrian University of Athens, Hospital for Diseases of the Chest “Sotiria”, Messogion Avenue 152, Athens 11527, Greece. E-mail: dbouros@med.uoa.gr

      A wide range of neuromuscular diseases (NMDs) may result in dysfunction of the ventilatory pump and consequently lead to complications such as respiratory failure, sleep disorder, aspiration pneumonia and death. Respiratory disorders are the primary cause of mortality in NMDs, and appropriate management of patients can prevent complications and prolong survival. The most essential interventions to manage lung complications of NMDs include noninvasive mechanical ventilation and airway clearance techniques.

      Cite as: Konstantelou E, Pasparaki E, Tzilas V, et al. Neuromuscular diseases. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 278–295 [https://doi.org/10.1183/2312508X.10021519].

    4. Page 296
      Abstract
      Yurdagül Uzunhan, Pneumology Dept, Avicenne Hospital, 125 Rue de Stalingrad, Bobigny, France. E-mail: yurdagul.uzunhan@aphp.fr

      Amyloidosis can affect all parts of the respiratory tract. Tracheobronchial, nodular and interstitial patterns are the main entities observed. A composite pattern combining several involvements is frequent. Amyloidosis may be limited to the lung or be part of a systemic amyloidosis associated or not with haematological malignancy or CTDs. Typing the precursor protein of the amyloid deposits is crucial. Light-chain (AL) amyloidosis is common in lung amyloidosis, followed by amyloid A (AA), transthyretin (ATTR) and leukocyte chemotactic factor 2 (ALECT2) amyloidosis. While many cases remain untyped, improvements in typing are expected using mass spectrometry. In addition to typing of the deposits, assessing the respiratory involvement and extension to other organs, notably the heart, and looking for underlying diseases inform the prognosis and help to choose the best treatment. In asymptomatic lung amyloidosis, therapeutic abstention with regular follow-up is recommended. Percutaneous endoscopic debulking or prosthesis implantation and radiotherapy are treatments of symptomatic tracheobronchial amyloidosis. Chemotherapy and autologous haematopoietic stem cell transplantation are discussed in systemic AL amyloidosis and more rarely in localised lung amyloidosis.

      Cite as: Rech J-S, Brillet P-Y, Jeny F, et al. Amyloidosis. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 296–318 [https://doi.org/10.1183/2312508X.10021719].

    5. Page 319
      Abstract
      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: paolo.spagnolo@unipd.it

      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].

    6. Page 333
      Abstract
      Venerino Poletti, Pneumologia, Ospedale GB Morgagni, Via Carlo Forlanini 34, 47100, Forlì, Italy. E-mail: venerino.poletti@gmail.com

      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].

    7. Page 359
      Abstract
      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 lafitta@libero.it

      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].

    8. Page 374
      Abstract
      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: kabend@rm.dk

      Immunodeficiencies are a group of heterogeneous disorders involving the innate and adaptive immune system. Primary immunodeficiency (PID) comprises >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].

    9. Page 391
      Abstract
      Raphael Borie, Service de Pneumologie A, Hôpital Bichat, 46 rue Henri Huchard, 75877 Paris CEDEX 18, France. E-mail: raphael.borie@aphp.fr

      Genetic studies of familial forms of ILD led to the discovery of telomere-related gene (TRG) mutations (TERT, TERC, RTEL1, PARN, DKC1, TINF2 and NAF1), initially discovered in a disease called dyskeratosis congenita. Heterozygous mutations are detected in ∼30% of familial forms of ILD but might also be evidenced in sporadic ILD patients, particularly in the younger patients or in association with haematological, hepatic or skin disease. TRG mutations may be associated with IPF but also with non-IPF ILDs, including idiopathic and secondary ILDs, such as hypersensitivity pneumonitis. The presence of a TRG mutation could be associated with a more rapid decline of FVC or a worse prognosis after lung transplantation, though the usual ILD treatments should be proposed. Some TRG mutations are associated with immunodeficiency or hepatopulmonary syndrome, whereas a specific increased risk of emphysema is a matter of debate. Patients and relatives should be aware of genetic analysis to at least reduce environmental lung toxicities.

      Cite as: Borie R, Kannengiesser C, Crestani B. Telomere syndrome. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 391–403 [https://doi.org/10.1183/2312508X.10015719].

    10. Page 404
      Abstract
      Jonas Yserbyt, Dept of Respiratory Diseases, University Hospitals KU Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: jonas.yserbyt@uzleuven.be

      The clinical presentation and management of sarcoidosis is most often determined by its pulmonary manifestations. Organ-specific variability of sarcoidosis is guided by distinct epidemiological determinants. The diagnosis of sarcoidosis can be challenging as a result of the variation in clinical presentations both in location of the disease and symptomatology. Specifically for the respiratory system, many patients present with incidental radiological findings, compatible with pulmonary sarcoidosis. Although some clinical findings are specific for sarcoidosis, in the majority of cases, the diagnosis is based on the coexistence of compatible clinical, radiological, serological and histopathological features. The therapeutic approach to pulmonary sarcoidosis is based on a combination of counselling, pharmacotherapy and rehabilitation. The selection of patients for and the timing of immunosuppressive therapy is based on clinical reasoning, rather than scientific evidence. The majority of patients with sarcoidosis do not require immunosuppression, as the overall prognosis of sarcoidosis is good with a low mortality. However, a minority of patients developing fibrotic lung disease or PH have dangerous sarcoidosis and require careful evaluation and prolonged treatment.

      Cite as: Yserbyt J, Wells AU. Sarcoidosis: pulmonary manifestations and management. In: Wuyts WA, Cottin V, Spagnolo P, et al., eds. Pulmonary Manifestations of Systemic Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 404–418 [https://doi.org/10.1183/2312508X.10015919].