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The new england journal of medicine

Review Article

Jeffrey M. Drazen, M.D., Editor Spectrum of Fibrotic Diseases

Marlies Wijsenbeek, M.D., and Vincent Cottin, M.D.​​

From the Center for Interstitial Lung Dis- iffuse parenchymal lung diseases encompass a large number eases and , Department of of conditions, with a wide range of causes, clinical manifestations, and Respiratory Medicine, Erasmus MC–Uni- versity Medical Center Rotterdam, Rot- imaging and pathological features, as well as variable outcomes. Despite terdam, the Netherlands (M.W.); and the D the intrinsic heterogeneity of this group of diseases, in most of them, the pulmo- Department of Respiratory Medicine, Na- nary alveolar walls are infiltrated by various combinations of inflammatory cells, tional Coordinating Reference Center for Rare Pulmonary Diseases, Louis Pradel fibrosis, and proliferation of certain cells that make up the normal alveolar wall. Hospital, and Claude Bernard University Since these pathologic abnormalities predominate in the lung interstitium, the — both in Lyon, France (V.C.). Address disorders are termed interstitial lung diseases (ILDs). reprint requests to Dr. Wijsenbeek at the Center for Interstitial Lung Diseases and Idiopathic (IPF) is the archetypal and most common fibrotic Sarcoidosis, Department of Respiratory ILD. IPF is characterized by an imaging and pathological pattern of usual intersti- Medicine, Erasmus MC, University Medi- tial (UIP) without an identifiable cause or association with a disease cal Center Rotterdam, 3015 GD Rotterdam, the Netherlands, or at ­m​.­wijsenbeek-lourens known to be associated with pulmonary fibrosis. It occurs more commonly in men @​­erasmusmc​.­nl. than in women (sex ratio, 7:3) and is more common in people older than 60 years 1,2 N Engl J Med 2020;383:958-68. of age than in younger people. IPF is a chronic and irreversible disease, usually DOI: 10.1056/NEJMra2005230 progressing to and death (median interval between diagnosis Copyright © 2020 Massachusetts Medical Society. and death, 3 years).3 In contrast to IPF, other ILDs are generally characterized by a younger mean age at presentation (20 to 60 years) and a more balanced sex ratio. The variable underlying pathological features of other ILDs, with fibrosis gener- ally less prominent than inflammatory infiltration, also translate into more hetero- geneous and often less severe outcomes, as compared with IPF. However, a num- ber of these other ILDs are also characterized by progressive fibrosis.4 As in any other , fibrosis in the can be a manifestation of several clinical enti- ties, and if the fibrosis is progressive, it will ultimately result in organ failure,5 causing respiratory symptoms, limited exercise capacity, an impaired quality of life, and an increased risk of death.6 ILDs are typically assigned to many disease categories for classification and management purposes, roughly on the basis of a known underlying disease (e.g., pulmonary fibrosis associated with rheumatoid ), an inciting agent (e.g., ), or the absence of a known cause (e.g., IPF).4,7 In this review, we address pulmonary fibrosis in various contexts and disease entities, emphasizing the commonalities in pathophysiological features, clinical manifestations, and diag- nostic features, as well as the similarly progressive nature of many of these diseases.

Epidemiology Although each of the individual fibrosing ILDs is rare, collectively they affect a considerable number of patients, representing a substantial burden of disease. The overall prevalence of ILD is estimated to be up to 76.0 cases per 100,000 people in Europe and 74.3 cases per 100,000 in the United States. Sarcoidosis, connective- disease (CTD)–associated ILDs, and IPF are the most common fibrotic ILDs, with an estimated prevalence of 30.2, 12.1, and 8.2 cases per 100,000, respec- tively8 (Table 1). Among all patients with fibrotic ILDs other than IPF, 13 to 40%

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have a progressive fibrosing phenotype,18 repre- pathways7 (Fig. 1). In IPF, an as yet undefined senting up to 20 patients per 100,000 people in insult to alveolar epithelial-cell integrity may ini- Europe and up to 28 patients per 100,000 in the tiate disease through the interaction between United States (Fig. S1 in the Supplementary Ap- epithelial cells and myofibroblasts.5 - pendix, available with the full text of this article tous in response to a putative, at NEJM.org).19 persistent, unknown trigger progresses to fibro- Pulmonary fibrosis occurs throughout the sis in only a small percentage of patients with world, with geographic variation.19 The prevalence sarcoidosis.13 In SSc–ILD, a combination of in- of IPF, estimated to be 8 to 60 cases per 100,000 flammation, endothelial dysfunction, and vascu- population,8,20 is higher in North America and lopathy leads to pulmonary fibrosis in a major- Europe than in the rest of the world, whereas the ity of patients, driving the .23 Studies prevalence of sarcoidosis is higher in northern investigating specific conditions suggest that Europe and among Black persons and is lower in various inflammatory responses may lead to a Japan.21 profibrotic environment and cytokine milieu (in- cluding, especially, transforming growth factor β, Pathophysiology connective-tissue growth factor, platelet-derived growth factor, and WNT and hedgehog signal- The formation of fibrosis is an essential response ing). Shared downstream pathways may activate of the body against pathogens and in normal and sustain a complex interplay leading to fibro- wound healing.22 In pulmonary fibrosis, various blast activation and differentiation into myofi- and often disease-specific triggers set off exag- broblasts, which further orchestrate fibrogene- gerated cascades of inflammatory and fibrotic sis.23 Once established, structural tissue changes responses, leading to downstream fibrotic tissue and the profibrotic milieu form a feed-forward remodeling and extracellular-matrix deposition,23 loop, leading to self-perpetuating fibrosis. which in turn perpetuate fibrosis formation (Fig. 1). Much is still unknown about the patho- Disease Entities with physiology of specific disease entities and the Pulmonary Fibrosis factors that differentiate normal wound repair from progression to fibrosis. Although triggers, ILDs can be divided into five broad clinical cate- susceptibility, and initial inflammatory respons- gories: ILDs related to distinct primary diseases es vary among diseases, the current assumption (e.g., sarcoidosis, Langerhans-cell granulomato- is that in later phases, common mechanisms play sis, , lymphangioleiomyo- a role.23 matosis, and pulmonary alveolar proteinosis); A variety of genetic studies have identified ILDs related to environmental exposures, includ- both common and rare variants that are associ- ing pneumoconiosis due to inhalation of inor- ated with enhanced susceptibility to pulmonary ganic substances and hypersensitivity pneumo- fibrosis, with remarkable similarities between nitis mostly related to inhalation of organic familial IPF and other fibrotic ILDs.24 For exam- particles (e.g., domestic or occupational expo- ple, a frequent polymorphism in the promoter of sure to mold or birds or other exposures); ILDs MUC5B, which is involved in airway clearance induced by drugs, illicit drugs, or irradiation; and bacterial host defense, is associated with ILDs associated with CTDs, including RA–ILD increased risks of IPF, with and SSc–ILD, idiopathic inflammatory myopathy, ILD25 (RA–ILD), and chronic hypersensitivity and primary Sjögren’s disease; and idiopathic (CHP)26 but not systemic sclerosis interstitial ,27 which include IPF, idio- with ILD (SSc–ILD), sarcoidosis, or antisynthe- pathic nonspecific interstitial pneumonia, and tase syndrome. Telomere shortening and telomere- other, less common entities. related gene mutations (TERT, TERC, RTEL1, and Pulmonary fibrosis can occur in the context PARN) are found in IPF, RA–ILD, and CHP.24,26 of many of these ILDs (Table 1 and Table S1). A Some rare genetic variants, such as telomere- separation can be made between pulmonary fi- related gene mutations, are clearly associated brosis in the context of underlying systemic dis- with progressive disease.24 eases, such as CTDs and sarcoidosis, and condi- Besides shared genetic risk factors, different tions that are restricted to the lung, such as CHP, ILDs have heterogeneous, overlapping initial drug-induced pulmonary fibrosis, idiopathic non-

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Prognosis 3–4 yr; poten - yr; 3–4 slowing for tial progression 40%; 35% of 35% 40%; SSc-related to due deaths possible ILD; stabilization treatment with pattern) (UIP yr (other longer or effectpatterns); on treatment of disease lung unknown about 10%; sarcoid - of 75% osis-related to due deaths disease; lung re - generally to sponsive immunomodu - lation Median survival, Median 10-Yr mortality, 10-Yr 3 survival, Median mortality, 10-Yr Management (pirfenidone, ­ nintedanib) therapy: mycopheno - therapy: IV alternatively, late; , ritux - , tocilizumab imab, (nintedanib) transplanta - lung or patients select in tion ­ immunosuppressive therapy; , myco - or abatacept, occasion - phenolate antifibrotic used; ally (nintedanib) therapy of cases used in fibrosis; progressive under is pirfenidone investigation‡ with treatment ; or glu - as azathioprine cocorticoid-sparing second-line or agent therapy; as or therapy; third-line for evidence of lack and disease; lung for antifibrotic of benefit unclear therapy Antifibrotic therapy Antifibrotic Immunosuppressive therapy Antifibrotic Stem-celltransplantation for evidence of Lack or alone Monitoring

NA Other Features women than men af - men than women multisystemic fected, auto - involvement, serologic immune (anti–Scl-70, findings anticentromere, poly - anti–RNA and antibod - III merase nail - abnormal ies), capillaroscopy fold but (ACPAs, features factor rheumatoid specific) less multi - 1:1; ratio, male involvement; organ bibasilar of absence club - and noncaseating bing; gran - epithelioid-cell giant with ulomas pathological on cells evaluation Not Characteristic of IPF Younger age, more age, Younger serologic Autoimmune Female: age; Younger

Imaging ble UIP pattern, UIP ble indeterminate UIP for pattern (and clin ­ or findings sug - course ical IPF) of gestive NSIP fibrotic pat - UIP than tern pattern UIP or NSIP over indeterminate multi - pattern, compartment involvement of (association pleu - or airways involvement) ral peribroncho - and vascular, dis - lymphatic dense tribution; perihilar fibrotic cavitated or bron - masses; distortion, chial opaci - reticular trac - and ties, bronchiec - tion UIP-like tasis; rare pattern Findings on Chest Definite or proba - or Definite common More of Predominance Upper-lobe,

Features Main Clinical finger clubbing finger pa- of (30–50% male: tients); 3:1; ratio, female yr >50 age thick - skin enon, fingertip ening, telangi - lesions, ectasia, gastro - reflux, esophageal vasculopathy arthri - symmetric joint synovitis, tis, erosions, rheuma - nodules toid organ, any in especially skin, liver, heart, eye, nodes; lymph and in - pulmonary 90% in volvement wide cases; of clinical of range phenotypes Velcro-like crackles; Velcro-like phenom - Raynaud’s stiffness, Morning diseaseMultisystem 13

10 , 12 , 9 11 fibrotic (stage IV) arthritis– ILD 3 IPF SSc–ILD Sarcoidosis, Condition Rheumatoid Clinical Characteristics of Selected Broad Categories of Pulmonary Fibrosis.* Pulmonary of Categories Broad Selected of Characteristics Clinical 1. Table

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Other Features gen not always iden - always not gen epi - recurrent tified; symptoms; sodes of lymphocytosis BAL of cases); (>20% precipitins; positive performed if biopsy, showing airway- lymphocytic centric loose infiltration, gi - and , cells ant im - clinical, among histologic and aging, nondiag - features; findings CT nostic biopsy no and biopsy or performed noncontribu - results tory Not Characteristic of IPF Offending inhaled anti - inhaled Offending discrepancy Major Imaging honeycombing, peribron - with chovascular, and upper- middle-zone distribution; at - ground-glass with tenuation and mosaicism trapping air generally tures cri - meeting not main for teria patterns Findings on Chest Reticulation and Reticulation fea - Nonspecific Features Main Clinical to inhaled par - inhaled to predomi - ticles, organic nantly of onset antigens; a over symptoms or mo 6 period of more§ me - vary; tures 60–65 age, dian nonspecific yr; with symptoms and dyspnea first- no ; diagnosis; choice auto - subtle often features immune Prolonged exposure Prolonged fea - Demographic

15 , 14 17 , 16 fibrotic hypersensi ­ pneu ­ tivity monitis fibrotic ILD Chronic Unclassifiable Condition More comprehensive information is provided in Table S1. ACPAs denotes anti–citrullinated protein antibodies, BAL bronchoalveola r lavage, DL bon monoxide, FVC forced vital capacity, ILD interstitial lung disease, IPF idiopathic pulmonary fibrosis, IV intravenous, NA n ot applicable, NSIP nonspecific pneumonia, SSc systemic sclerosis, and UIP usual interstitial pneumonia. Relative prevalence is the estimated among all patients with ILD. The trial is ongoing (ClinicalTrials.gov number, NCT02999178). A list of inhaled organic antigens that can cause fibrotic hypersensitivity pneumonitis is available at www ​ *  †  ‡  § 

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Early Phase (Underlying Disease–Specific)

Respiratory bronchiole

Environmental risk factors Type 2 alveolar Granuloma epithelial cell • Tobacco smoking • Occupational exposure Persistent • Air pollution antigen • Microaspiration • Viral Type 1 alveolar epithelial cell Normal interstitium Lymphocytes and Alveolus Aging Granuloma

Microvascular endothelial NSIP Genetic predisposition injury

Epithelial-cell Activated injury helper Exaggerated Fibrosis immune response Repaired type 2 alveolar epithelial cells Edema Chronic Normal inflammation lung tissue Partial or complete resolution

Fibroblastic focus Late Phase (Shared Self-Perpetuating Fibrosis)

Resident Alveolus fibroblast Myofibroblasts Fibroblastic focus

Myofibroblasts Fibroblasts

Epithelial-cell Extracellular differentiation matrix production Subpleural honeycombing Fibrocyte

Endothelial-cell Tissue stiffness Lung differentiation Pericyte Collagen and hypoxia remodeling Capillary

Subpleural honeycombing

Pleura

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Figure 1 (facing page). Pathogenesis and Self-Perpetuation ology and burden of fibrosis within each diag- of Pulmonary Fibrosis. nostic category, clinicians most often see The early phase, shown in the upper part of the figure, patients with CTD–ILD, IPF, CHP, sarcoidosis, or is disease-specific. It consists mostly of lymphocyte ac- unclassifiable fibrotic ILD. tivation and differentiation, autoimmunity and an exag- Currently, there is a specific interest in the gerated immune response in immune-mediated con­ potential development of fibrosis after coronavi- ditions (connective-tissue disease [CTD]–associated interstitial lung disease [ILD]), and chronic granuloma- rus disease 2019 (Covid-19). Although infection tous inflammation resulting from the persistence of an with severe acute respiratory syndrome corona- identified or unidentified antigen, which is often inhaled virus 2 (SARS-CoV-2) causes a range of pulmo- (in chronic hypersensitivity pneumonitis), or another nary symptoms, male sex, older age, obesity, and exposure (e.g., drug-induced ILD) or postulated antigen coexisting conditions appear to be risk factors (in sarcoidosis). Multiple environmental risk factors 28 (tobacco smoking, occupational exposures, air pollution, for the development of SARS. Pulmonary fibro- microaspiration, and viral infection) cause repeated in- sis is a known complication of acute respiratory jury to the pulmonary alveolar cell and may represent distress syndrome (ARDS), and there are simi- early pathogenic events, especially in idiopathic pulmo- larities in the fibroproliferative response and nary fibrosis. Aging, genetic background, and epigene- risk factors between lung fibrosis in the context tic modifications are increasingly identified as important factors in all these conditions. Most of these mechanisms of ARDS and lung fibrosis in the context of 29 take place to varying degrees in each of the fibrotic lung other diseases. Nevertheless, analysis of long- diseases, and initial triggers may be identified or may term follow-up data after ARDS29 or infection with not be identified (as in idiopathic nonspecific intersti- another strain of SARS-CoV in 200330 showed tial pneumonia [NSIP] and unclassifiable ILD). In some fibrotic changes that remained mostly stable patients, partial or complete resolution to normal lung 29 tissue will occur either spontaneously (e.g., in sarcoid- over time and had little clinical relevance. The osis), after antigen removal (e.g., in hypersensitivity long-term effect and the disease course of pul- pneumonitis), or with immunomodulatory treatment monary fibrosis caused by Covid-19 are cur- (e.g., in CTD-associated ILD). Histologic examples of rently under investigation in prospective studies. chronic inflammation are shown (hematoxylin and eo- sin), with a well-formed granuloma in sarcoidosis (top image) and a typical NSIP pattern with uniform and dif- Diagnostic Approach fuse thickening of the alveolar walls (second image). Af- ter repeated alveolar or endothelial-cell injury or immune Other than disease-specific symptoms, cough, activation and inflammation, fibroblasts can be activated progressive exertional dyspnea, and exercise by profibrotic cytokines and then proliferate and differ- limitation are the main presenting symptoms. entiate into myofibroblasts, which subsequently migrate to the alveolar interstitium and represent the “active The diagnosis is often delayed by several months front” of fibrogenesis, especially in fibroblastic foci or even years. A thorough history, including en- (third image, hematoxylin and eosin). Myofibroblasts vironmental exposures, medication use, and ex- can originate from diverse sources (e.g., the prolifera- trapulmonary signs, should be taken.2 On chest tion of resident fibroblasts and the differentiation of auscultation, fine crackles (also called Velcro epithelial cells, bone marrow–derived fibrocytes, peri- 31 cytes, and endothelial cells). The later phase of fibro- rales or crepitations) are indicative of fibrosis, genesis, which is thought to be shared by all conditions, although squeaks may be heard in patients with regardless of the initial cause or trigger, consists of ex- hypersensitivity pneumonitis. Premature graying tracellular matrix production by fibroblasts, leading to of hair and hematologic abnormalities may be a lung tissue remodeling and subpleural microscopic sign of telomeropathy-related fibrosis. In CTDs, honeycombing (bottom image, hematoxylin and eosin). The imaging and pathologic phenotype of fibrosis can pulmonary fibrosis may develop either after the vary (e.g., usual interstitial pneumonia and NSIP). Tis- underlying condition is diagnosed or before the sue stiffness and hypoxia related to remodeling, in turn, extrapulmonary manifestations are observed.32 up-regulate profibrotic cytokine pathways and myofi- Hands, joints, and skin should be thoroughly broblast activation, thereby perpetuating fibrogenesis. examined.32 Serologic testing is recommended, APC denotes antigen-presenting cell. including for antinuclear antibodies and anti– citrullinated peptide antibodies.2 If there is a specific interstitial pneumonia, and IPF.3,27 There clinical suspicion of an autoimmune condition, is also overlap between groups (e.g., drug-induced consultation with a rheumatologist and more pulmonary fibrosis in CTD and a genetic predis- extensive serologic testing are recommended. position in various ILDs). Owing to the epidemi- High-resolution computed tomographic (CT)

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scanning of the chest establishes the diagnosis Progressive Pulmonary Fibrosis of pulmonary fibrosis by revealing reticulation, architectural distortion, and lung volume loss and The natural course of untreated IPF is character- may identify patterns suggestive of specific ized by progression to respiratory failure in vir- causes (Table 1, Table S1, and Fig. S2).2,3 The UIP tually every patient with a secure diagnosis.3 In pattern is the hallmark of pulmonary fibrosis, contrast, more than half of all patients with a observed frequently in IPF, in RA–ILD, and in diagnosis of pulmonary fibrosis other than IPF advanced disease irrespective of the underlying have stable, chronic disease or improvement with condition.3,33 In contrast, the most common pat- immunomodulatory therapy.6 Despite treatment tern in SSc–ILD is that of nonspecific interstitial that is considered appropriate, however, a pro- pneumonia, which consists of mixed reticulation portion of patients will have progressive pulmo- and ground-glass attenuation to a varying ex- nary fibrosis associated with worsening respi- tent, often with traction , central ratory symptoms, a decline in lung function, a axial distribution, and sparing of the subpleural decreased quality of life, and a risk of early area. Expiratory imaging may be useful, espe- death, independent of the classification of the cially in CHP.34 Pulmonary-function testing as- ILD.6,37 Outcomes may be similar to those of IPF, sesses the level of disease impairment and is the especially in patients with a UIP pattern, such as most frequently used measure for monitoring those with RA–ILD and some patients with CHP the course of disease and response to therapy. In (Fig. S3). patients with pulmonary fibrosis, testing typi- The risk of progressive disease and the prog- cally shows a restrictive lung-function pattern nosis depend on the underlying entity (Table 1 (decreased forced vital capacity [FVC], normal and Table S1). However, the longitudinal disease or increased ratio of forced expiratory volume in course4,27 varies and needs to be identified indi- 1 second to FVC, decreased total lung capacity, vidually, since it has implications for management and low residual volume), together with a de- decisions and occasionally may lead to a reconsid- creased diffusing capacity of the lung for carbon eration of the diagnosis. No serum biomarker monoxide. However, normal lung function does has been validated for monitoring disease pro- not rule out the presence of pulmonary fibrosis. gression or assessing the respective components If the combination of clinical findings and of inflammation and fibrosis in pathogenesis. imaging is not diagnostic, more invasive diag- Scores, especially those based on sex, age, FVC, nostic procedures may be needed. Bronchoalveo- and diffusing capacity of the lung for carbon lar lavage contributes to the diagnosis of hyper- monoxide, have been developed to assess the sensitivity pneumonitis and sarcoidosis. Bronchial prognosis.38 In case series, predictors of disease mucosa and lymph-node are performed progression, despite immunomodulatory therapy, when sarcoidosis is suspected. It is recommend- include demographic characteristics (e.g., per- ed that all collected information be synthesized sons of African descent with SSc–ILD or sarcoid- by a multidisciplinary team experienced in ILD osis), more extensive disease on CT imaging, (Fig. 2), which may either establish a diagnosis greater impairment in lung function, presence of or discuss the indication for further diagnostic honeycombing33 and a UIP pattern on CT, and procedures such as thoracoscopic lung biopsy or persistence of the agent causing the disease transbronchial cryobiopsy. Weighing diagnostic (Table 1). yield and therapeutic consequences against po- There is no standard definition of disease tential risks associated with each procedure is progression in patients with pulmonary fibrosis. crucial for discussion among the members of the Because a decline in FVC is predictive of death multidisciplinary team and with the patient.35 in patients with IPF,39 it has been used as an end Consideration of the course of the disease in a point in pivotal studies of antifibrotic drugs.40 In given patient is important in guiding diagnosis a clinical trial evaluating the efficacy of anti­ and management and may reduce the need for fibrotic therapy in patients with progressive fi- invasive diagnostic procedures. Although a first- brosing ILD,41 patients were required to meet at choice diagnosis can be made with sufficient least one of the following criteria for disease confidence in the majority of cases,36 a subgroup progression within the 24 months before screen- of ILD cases remains unclassifiable even after ing: a relative decline in the FVC of 10% or more thorough assessment.16 of the predicted value, a composite of a relative

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Clinical data

Biopsy HRCT of First-choice Alternative results the chest diagnosis diagnoses

Multi- Possible need Diagnostic disciplinary for biopsy confidence discussion

15 Flow-volume Potential loop in ILD

Broncho- for disease Prognosis 10 alveolar progression Lung function lavage 5

0 Biologic features 1 2 3 4 5 6 7 8

Autoimmunity Flow (liters/sec) Exhaled Volume (liters) −5

−10

−15

Figure 2. Algorithm for the Diagnosis of Pulmonary Fibrosis. A multidisciplinary team can play a central role in the diagnosis and management of ILD. Key results of the diagnostic approach are dis- cussed by members of the team, which includes clinicians, radiologists, pathologists, and other health care providers. The participants consider all data available and propose a first-choice diagnosis, assess the need for biopsy and confidence in the diagnosis, and consider possible alternative diagnoses, the potential for disease progression, and the prognosis. On the basis of this discussion, a management decision is made. However, not everyone in the world has equal access to a multidisciplinary team, and even when a multidisciplinary team is available, resources and time may not permit a team discussion of all cases. If a case cannot be addressed by a multidisciplinary team, it is important for the treating clinician to realize that many factors (outermost purple circles) need to be considered before diag- nostic or therapeutic decisions can be made. The high-resolution CT (HRCT) scans at the upper right show a usual interstitial pneumo- nia pattern (top) and an NSIP pattern (bottom). The flow-volume loop shows a typical restrictive pattern (a decrease in forced vital capacity [FVC]) that is often seen in pulmonary fibrosis. The black line represents a predicted normal flow-volume loop for a patient of similar age, sex, height, and race, and the gray zone around it represents the 95% confidence interval. The FVC is shown on the horizontal axis as the volume from the origin to the intersection of the loop with that axis.

decline in the FVC of 5 to 10% of the predicted month intervals. Since small variations in FVC value and worsening symptoms or an increase in may be confounded by measurement errors, multi- disease extent on chest CT, or worsening symp- modal assessment of disease progression also toms and an increase in disease extent on chest includes worsening of symptoms and exercise CT. Other criteria have also been used.37,42-44 In capacity, increased fibrosis on imaging, decreased clinical practice, no threshold or rate of decline diffusing capacity of the lung for carbon monox- has been formally accepted; however, assessment ide, need for oxygen supplementation, and clinical of the progression of fibrosis is usually based on events predicting early death (acute exacerbation serial lung-function tests performed at 3-to-6- of fibrosis or nonelective hospitalization) (Fig. 3).43

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Management

Chronic hypersensitivity Idiopathic Unclassifiable SSc–ILD RA–ILD Sarcoidosis IPF pneumonitis NSIP ILD

Antigen eviction

Consider immunomodulation treatment or observation

Glucocorticoids Glucocorticoids Glucocorticoids Glucocorticoids Glucocorticoids

MMF, CPM, TCL RTX, ABA, MTX MMF MMF, AZA, or other (AZA, RTX) MMF (AZA, IFX, ADA) (AZA) immunosuppressants

Antifibrotic agents Consider antifibrotic agents (nintedanib) (pirfenidone or nintedanib)

Nonpharmacologic treatment Supplemental oxygen, psychosocial support, smoking cessation, rehabilitation, symptom palliation, end-of-life care

Reconsider Management Regular Follow-up

Monitoring of Disease Course

Disease progression Stable disease Ameliorization

Figure 3. Algorithm for the Management of Pulmonary Fibrosis. Once a diagnosis of fibrotic ILD has been made, first-line therapy consists of treatment of the underlying disorder, which is often immu- nomodulatory therapy. Depending on the underlying condition, antifibrotic therapy is considered in cases of disease progression despite appropriate first-line therapy. The sequence of medications used may depend on the individual patient and the disease entity. Nonphar- macologic treatment should be considered throughout the disease course. Monitoring for disease progression is based mainly on serial pulmonary-function tests (with progression characterized by a consistent decline in FVC), which are often combined with one or more of the following: measurement of the diffusing capacity of the lung for carbon monoxide, assessment of symptoms and exercise capacity, CT findings (with an increase in the extent of fibrosis indicating progression), measurement of oxygen saturation during exercise, and supplemental oxygen requirements. Acute exacerbations of pulmonary fibrosis also represent progressive disease. In patients with idio- pathic pulmonary fibrosis (IPF), antifibrotic agents should be offered at diagnosis. If there is disease progression, the diagnosis and treat- ment options should be reviewed before adding the treatments shown in purple. ABA denotes abatacept, ADA adalimumab, AZA azathi- oprine, CPM cyclophosphamide, IFX infliximab, MMF mycophenolate mofetil, MTX methotrexate, RA–ILD rheumatoid arthritis and ILD, RTX rituximab, SSc–ILD systemic sclerosis and ILD, and TCL tocilizumab.

Management quality of life of patients and their family mem- bers. According to the underlying condition, For most patients, a diagnosis of pulmonary fi- treatment can be aimed at ameliorating the dis- brosis is a life-altering verdict. The uncertainty ease or slowing down disease progression while about prognosis in combination with an increas- improving or maintaining quality of life45 (Fig. 3). ing symptom burden has a major effect on the Educating patients and sharing decisions are

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important, especially since there are many off- Nintedanib has been approved by the Food label treatment options with potentially serious and Drug Administration (FDA) and the Euro- side effects. Preventing exposures and events that pean Medicines Agency (EMA) for patients with may drive further disease progression is essen- SSc–ILD and for patients with chronic fibrosing tial. Avoidance of the offending antigen in pa- ILDs with a progressive phenotype. This agent is tients with CHP and cessation of tobacco smok- not associated with an improvement in function ing are priorities. Pneumococcal and but reduces the decline in FVC by about half,41 vaccinations are recommended. On the basis of supporting the notion that progressive pulmo- expert opinion, supplemental oxygen is indicated nary fibrosis may be amenable to antifibrotic in patients with resting (partial pres- therapy regardless of the underlying specific o sure of arterial oxygen [Pa 2] of <55 mm Hg, disease. Pirfenidone reduces disease progression oxygen saturation as measured by pulse oximetry in patients with progressive, unclassifiable, fi- o 44 of <89%, or Pa 2 of <60 mm Hg and cor pulmo- brotic ILD. In considering pharmacologic treat- nale or polycythemia).46 Pulmonary rehabilitation45 ment, the benefit of long-term preservation of and use of ambulatory oxygen in patients with lung function should be balanced against the isolated exertional hypoxemia47 improve the qual- risk of side effects. Many questions remain, ity of life, reduce breathlessness, and increase however, about appropriate timing and sequence walking ability. Identification and accurate treat- of these treatments. ment of coexisting conditions are essential. is an option in select patients, Future Directions although extrapulmonary disease or severe coex- isting conditions may disqualify some patients, Pulmonary fibrosis is a pathologic process that especially those with CTDs, from consideration stems from multiple underlying causes. Moni- as candidates for transplantation.48 For many toring disease progression has become a priority patients, the focus is on palliative care.49 in guiding treatment decisions. We hope that, in Decisions about pharmacologic treatment are the coming years, different biomarkers and novel guided by the underlying diagnosis and by the techniques such as molecular classifiers53 will disease course. For patients with IPF, treatment provide more insights into assessing and moni- with antifibrotic drugs (pirfenidone or nintedanib) toring fibrosis-driven as compared with inflam- is recommended.50 In most cases of fibrosing mation-driven disease activity, resulting in more ILD other than IPF, immunomodulation with the individualized targeted treatments, since it is use of glucocorticoids, immunosuppressive ther- clear that a “one size fits all” approach does not apy, or both is indicated and is generally used as apply to the broad spectrum of fibrosing dis- first-line therapy if there is a suspicion of in- eases. Current research efforts may lead to ear- flammation-driven disease.18,37,51 Except for SSc– lier diagnosis and interventions to prevent, halt, ILD and sarcoidosis, however, the evidence in sup- and potentially reverse the development of life- port of this approach is very weak.51 In patients limiting lung fibrosis. with a UIP pattern, there is theoretical concern that immunosuppression may not be beneficial or Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. might even be harmful, as was previously shown We thank Jan von der Thüsen, M.D., Ph.D., for the histologic in IPF.52 images.

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