Idiopathic pulmonary fibrosis

Transcription

1 Idiopathic pulmonary fibrosis Luca Richeldi, Harold R Collard, Mark G Jones Idiopathic pulmonary fibrosis is a prototype of chronic, progressive, and fibrotic lung disease. Healthy tissue is replaced by altered extracellular matrix and alveolar architecture is destroyed, which leads to decreased lung compliance, disrupted gas exchange, and ultimately respiratory failure and death. In less than a decade, understanding of the pathogenesis and management of this disease has been transformed, and two disease-modifying therapies have been approved, worldwide. In this Seminar, we summarise the presentation, pathophysiology, diagnosis, and treatment options available for patients with idiopathic pulmonary fibrosis. This disease has improved understanding of the mechanisms of lung fibrosis, and offers hope that similar approaches will transform the management of patients with other progressive fibrotic lung diseases. Epidemiology Idiopathic pulmonary fibrosis is the most common type of idiopathic interstitial pneumonia. Although the disease has been considered rare, it occurs with similar frequency to that of stomach, brain, and testicular cancers. 1,2 Incidence of idiopathic pulmonary fibrosis has risen over time, and in Europe and North America is estimated to range between 2 8 and 18 cases per people per year. 2,3 Little data are available for worldwide variation, but incidence might be lower in Asia and South America, where it is estimated to range from 0 5 to 4 2 cases per individuals per year. Idiopathic pulmonary fibrosis is more common in men and is rare in people younger than 50 years (median age at diagnosis is about 65 years). 4 6 Although disease course is variable and somewhat unpredictable, the median survival time from diagnosis is 2 4 years. 7 Pathophysiology Historically, idiopathic pulmonary fibrosis was considered a chronic inflammatory disorder, which gradually progressed to established fibrosis. However, at the turn of the century, following the recognition that antiinflammatory therapy did not improve outcome, this concept was reassessed and, subsequently, an immunosuppressive therapeutic strategy incorporating prednisolone and azathioprine was shown to increase mortality. 8,9 Idiopathic pulmonary fibrosis is now generally regarded as a consequence of multiple interacting genetic and environmental risk factors, with repetitive local micro-injuries to ageing alveolar epithelium playing a central role. These micro-injuries initiate aberrant epithelial fibroblast communication, the induction of matrix-producing myofibroblasts, and considerable extracellular matrix accumulation and remodelling of lung interstitium (figure 1). Environmental exposures Particulate inhalation is implicated in the pathogenesis and progression of idiopathic pulmonary fibrosis. A history of cigarette smoking is associated with idiopathic pulmonary fibrosis development in most patients. 10 However, multiple other environmental exposures have also been associated, including metal and wood dusts, agriculture and farming, viruses, and stone and silica. 4,11,12 Genetic factors Increasing evidence indicates that genetic susceptibility plays a part in the development of idiopathic pulmonary fibrosis. Studies 4,13 19 of familial interstitial pneumonia ie, cases affecting two or more members of the same biological family have identified rare genetic variants, including genes associated with surfactant dysfunction (SFTPC, SFTPA2) and telomere biology (TERT, TERC, PARN, RTEL). Genome-wide association studies have identified common genetic variants, which account for about a third of the risk of disease development. Although these studies do not indicate a direct causal link, the potential importance of alterations in host defence (MUC5B, ATP11A, TOLLIP), telomere maintenance (TERT, TERC, OBFC1), and epithelial barrier function (DSP, DPP9) was identified. A common gain-of-function variant in the gene MUC5B promoter region is the risk variant with the largest genetic effect on development of both familial and sporadic idiopathic pulmonary fibrosis (odds ratio 4 8 per allele). 20,21,23 27 The MUC5B variant has low penetrance and in isolation does not seem to be causative of idiopathic pulmonary fibrosis. MUC5B encodes a mucin-5b precursor protein that contributes to airway mucous production and might have an important role in lung host defense. 28,29 The site of altered MUC5B production has been localised to bronchiolar epithelium, where it is proposed to increase protein concentrations that might either enhance injury as a result of reduced mucociliary clearance or impede normal lung repair. 22,30 Search strategy and selection criteria We searched PubMed for reports published in English between Jan 1, 1996, and Oct 1, 2016, using the search terms pulmonary fibrosis, fibrosing alveolitis, usual interstitial pneumonia, and nonspecific interstitial pneumonia. We mostly selected publications from the past 5 years, although we also included highly regarded older publications. Reviews are cited to provide the reader with additional detail and references. Lancet 2017; 389: Published Online March 29, S (17) See Perspectives page 1875 Unità Operativa Complessa di Pneumologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico A. Gemelli, Rome, Italy (Prof L Richeldi MD); National Institute for Health Research Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, University of Southampton, Southampton, UK (Prof L Richeldi, M G Jones PhD); and Department of Medicine, University of California, San Francisco, San Francisco, CA, USA (H R Collard MD) Correspondence to: Prof Luca Richeldi, Unità Operativa Complessa di Pneumologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico A. Gemelli, Rome 00168, Italy luca.richeldi@unicatt.it Vol 389 May 13,

2 Dysfunctional epithelium Fibrogenesis Fibrosis Genetic susceptibility Ageing Recurrent microinjury Activation of epithelial cells Basement membrane disruption Dysregulated signalling Immune activation Epithelial cell apoptosis and senescence Fibroblast activation and proliferation Fibroblast recruitment Alveolar stem-cell exhaustion Basal cell dysfunction Abnormal extracellular matrix remodelling Bronchiolisation Honeycomb cyst formation Extracellular matrix expansion Altered extracellular matrix composition Altered extracellular matrix biomechanics Deficient fibroblast apoptosis Alveolar collapse Aberrant remodelling Figure 1: Proposed mechanisms contributing to the pathogenesis of idiopathic pulmonary fibrosis Repetitive microinjuries to ageing alveolar epithelium activates alveolar epithelial cells to secrete multiple fibrogenic growth factors, cytokines, and coagulants. This secretion leads to myofibroblast recruitment and activation from multiple sources, including resident mesenchymal cell proliferation, pericytes of the lung interstitium, circulating fibrocytes, epithelial mesenchymal transition, and endothelial mesenchymal transition. These myofibroblasts deposit increased and altered extracellular matrix, with altered biomechanical stiffness, which further contributes to myofibroblast activation in a positive feedback loop. Dysregulated repair of this injured lung parenchyma with abnormal activation of developmental pathways and bronchiolisation of the lung occurs in parallel (histopathological images magnification 250). Intriguingly, patients with idiopathic pulmonary fibrosis with the MUC5B gain-of-function variant might have a higher rate of survival than those without this variant. 31 This finding requires external validation, although in UK patients with idiopathic pulmonary fibrosis, this variant was associated with a slower decline in lung function. 26 Maladaptive repair process Identification of pathological mechanisms of fibrogenesis in idiopathic pulmonary fibrosis has been challenging; however, chronic dysregulation of type 2 alveolar epithelial cells (AEC2s) is thought to be central. AEC2s are stem cells within the lung that contribute to renewal of type 1 alveolar epithelial cells (AEC1s) during homoeostasis or after lung injury. 32,33 Loss of AEC1s and abnormal AEC2s are identified in idiopathic pulmonary fibrosis tissue, with fibroblastic foci typically located adjacent to hyperplastic or apoptotic alveolar epithelial cells. 8 In idiopathic pulmonary fibrosis tissue, premature shortening of AEC2 telomeres is observed, and shortening of AEC2 telomeres led to lung remodelling and fibrosis in a mouse model A 2016 study 37 showed that AEC2s from idiopathic pulmonary fibrosis tissue have impaired renewal capacity, consistent with AEC2 stem-cell failure. Abnormal behaviour of alveolar epithelial cells is associated with epithelial recapitulation of developmental pathways, including Wnt/b-catenin and Sonic hedgehog pathways. 38,39 Activated alveolar epithelial cells secrete numerous fibrogenic growth factors and cytokines, including transforming growth factor β (TGF β) and platelet-derived growth factor, with aberrant epithelial mesenchymal cross-talk driving the recruitment and activation of highly synthetic and contractile myofibroblasts. 40 These activated myofibroblasts deposit an increased amount of altered extracellular matrix components, which destroys normal alveolar architecture and disrupts gas exchange. Multiple sources of myofibroblasts are proposed, including resident mesenchymal cell proliferation, lung interstitium pericytes, circulating fibrocytes, epithelial mesenchymal transition, and endothelial mesenchymal transition. 33,41 Progression from a normal to an abnormal extracellular matrix in idiopathic pulmonary fibrosis is poorly understood, although evidence suggests that abnormal extracellular matrix deposition contributes to disease pathogenesis. 42,43 Changes in extracellular matrix composition alter cell behaviour considerably, and a positive feedback loop between fibroblasts and aberrant extracellular matrix promotes fibrosis. 44 Both altered extracellular matrix composition and stiffness might contribute to this process. The precise mechanisms by which extracellular matrix stiffness is transduced by fibroblasts remains unclear, but integrins, the predominant receptors for cell adhesion to extracellular matrix proteins, have a central role, with mechanosensitive protein protein interactions occurring within adhesion complexes. 45,46 Downstream of these interactions, cell force-mediated activation of latent TGF β, and intrinsic mechanotransduction via the Rho Rho kinase pathway, promotes myofibroblast differentation In parallel with abnormal extracellular matrix production is the occurrence of aberrant lung remodelling with so-called bronchiolisation of alveolar tissue. At sites of damaged alveolar epithelium, a regenerative response associated with activation of the developmental pathway occurs. 50 Abnormal activation of airway basal cells, which reside in the conducting airways down to the respiratory bronchioles and function as stem cells, is identified and might contribute to re-epithelisation of damaged alveolar epithelium and resulting bronchiolisation of alveolar spaces In a subset of patients with idiopathic pulmonary fibrosis, higher cilium gene expression was associated with increased microscopic honeycombing (characterised by well defined walls), although whether the bronchiolar abnormalities arise from de-novo bronchiolisation or from adjacent normal bronchiolar structures remains uncertain Vol 389 May 13, 2017

3 Seminar Clinical presentations, signs, and symptoms Patients typically present with non-specific symptoms of exertional dyspnoea with or without dry cough (figure 2). This presentation might initially be attributed to ageing, deconditioning, or other comorbidities (eg, smoking history, emphysema, cardiovascular disease, or obesity); therefore, clinical suspicion of idiopathic pulmonary fibrosis by primary care physicians is required to prevent diagnostic delays. Occasionally, patients will present acutely, with days to weeks of respiratory worsening, often accompanied by fever and influenza-like symptoms. These acute exacerbations require careful diagnostic distinction from other forms of acute interstitial lung disease. On physical examination, fine, high-pitched bibasilar inspiratory crackles are usually heard (audio) and digital clubbing is present in roughly 30% of patients.56 Careful attention to signs of connective tissue disease is essential to rule out associated diseases. In established disease, pulmonary function tests identify restrictive disease (reduced total lung capacity) and abnormal gas exchange (reduced capacity for carbon monoxide diffusion).4 Early disease, or disease coexisting with emphysema that pseudonormalises volumes, might demonstrate normal spirometry and plethysmography, with only an isolated reduction in diffusion. Genetic predisposition Smoking, occupational dust exposure, and other risk factors Subclinical disease (Velcro-type crackles) Onset of symptoms Diagnosis (typically age years) Disease-modifying therapy Comprehensive management Figure 2: Conceptual model of idiopathic pulmonary fibrosis across an individual s life course A B C D Diagnosis Idiopathic pulmonary fibrosis is diagnosed by identification of a pattern of usual interstitial pneumonia on the basis of radiological or histological criteria in patients without evidence of an alternative cause.4,57,58 This approach is endorsed in consensus guidelines worldwide and has helped to standardise idiopathic pulmonary fibrosis diagnosis. A major challenge to clinicians is exclusion of other idiopathic interstitial pneumonias and of known causes of interstitial lung disease, such as domestic and occupational exposures, connective tissue disease, and drug toxicity. Such exclusion is of particular importance because the usual interstitial pneumonia pattern is not exclusive to idiopathic pulmonary fibrosis and might also be associated with other conditions, including chronic hypersensitivity pneumonitis, asbestosis, connective tissue diseases, and drug toxicity. Many patients have histories of environmental exposures, medications, and symptoms that require clinicians to make judgments regarding the relevance of the cause of disease. High-resolution CT of the chest enables detailed assessment of lung parenchyma and has revolutionised the investigation of suspected idiopathic pulmonary fibrosis. Reticular opacities, associated with traction bronchiectasis and clusters of subpleural, cystic airspaces of similar diameters (typically 3 10 mm) with honeycombing, in a predominantly bilateral, peripheral, and basal distribution are typical of the usual interstitial pneumonia pattern (figure 3; video), whereas features such as mosaic attenuation, ground-glass abnormality, and nodules suggest an alternative diagnosis.4, Vol 389 May 13, 2017 Figure 3: Radiological and histological patterns of usual interstitial pneumonia Coronal reconstruction of high-resolution CT of the chest, showing the basal predominance of subpleural honeycombing, which is typical of a usual interstitial pneumonia pattern. High-resolution chest CT axial image taken at the level of the lower lobes showing multilayered subpleural honeycombing without evidence of features inconsistent with a pattern of usual interstitial pneumonia (B). Histological pattern of usual interstitial pneumonia at low power (magnification 100). Typical spatial and temporal heterogeneity can be observed with subpleural fibrosis and microscopic honeycombing, less-fibrotic central lung tissue, and fibroblast foci (C). A fibroblast focus is shown at the interface between fibrotic and less-involved lung tissue at higher power (magnification 400). The asterisk indicates the fibroblast focus (D). Patients with reticular abnormality in a subpleural, basal predominance, but without honeycombing, are considered to have a possible usual interstitial pneumonia pattern. See Online for audio See Online for video 1943

4 When high-resolution CT features are non-diagnostic, surgical lung biopsy is advised. In-hospital mortality after elective biopsy in patients younger than 65 years and with few comorbidities is less than 2%, but every patient still requires careful consideration as to whether the risks of surgical lung biopsy outweigh the potential benefits of diagnostic information. 62 In older patients, those with comorbidities (updated Charlson score >1), clinically significant physiological impairment, or for non-elective procedures, the risk is greater and surgical lung biopsy should generally be avoided. When considering undertaking surgical lung biopsy, the pretest probability of a subsequent histopathological diagnosis of usual interstitial pneumonia in patients with possible usual interstitial pneumonia on high-resolution CT is increased with older age, male sex, and the presence of traction bronchiectasis. 63,64 Histopathological findings show that the usual interstitial pneumonia pattern is characterised by interstitial fibrosis with spatial heterogeneity and patchy involvement of lung parenchyma, areas of marked fibrosis, architectural distortion, and microscopic honeycombing (cystic airspaces lined by bronchiolar epithelium, typically filled with mucin; figure 3). 4 At the interface between fibrotic and normal lung tissue are aggregates of proliferating fibroblasts and myofibroblasts fibroblastic foci within a myxoid-appearing matrix. Fibroblast foci are a key histopathological feature of usual interstitial pneumonia pattern, which represent areas of active disease, and their absence excludes a definite histopathological usual interstitial pneumonia diagnosis. In 2D fibroblastic foci are considered small, distinct lesions; however, in 3D the foci form heterogeneous structures with large variations in shape and volume. 65,66 Clinical features, imaging, and histopathology all play important roles in the diagnosis of idiopathic pulmonary fibrosis. A patient might receive an idiopathic pulmonary Disease-modifying therapy Clinical trials Patient education Smoking cessation Treatment of comorbidities Vaccination Early disease Disease-modifying treatment + Disease progression Oxygen assessment Pulmonary rehabilitation + End-of-life preferences Lung transplantation Palliative care Supplemental oxygen Advanced disease Symptom control Figure 4: A step-by-step approach to the comprehensive management of patients with idiopathic pulmonary fibrosis vs fibrosis diagnosis with varying degrees of diagnostic certainty. A dynamic multidisciplinary discussion between physicians, radiologists, and pathologists experienced in diagnosis of interstitial lung disease increases diagnostic agreement, and thus is considered the diagnostic gold standard, although a few patients remain unclassifiable. 67,68 Accurate prognostication is difficult because the natural history of idiopathic pulmonary fibrosis is highly variable. Some patients progress rapidly, others quite slowly, and others have sudden worsening after periods of stability. 4 Shortened survival time is associated with factors including older age, severe physiological impairment, low body-mass index, greater radiological disease extent, and presence of pulmonary hypertension, emphysema, and bronchogenic cancer. 7 To predict individual patient prognosis, risk models that incorporate demographic, clinical, and physiological variables have been developed, including the du Bois model 69 and the gender, age, physiology index. 70,71 This index 70 incorporates gender, age, and lung physiology variables to identify three disease stages with a 1 year mortality risk of 6%, 16%, and 39% respectively. The calculation of such an index at diagnosis might aid the clinician to refine prognosis, help to guide management decisions, such as lung transplantation timing, and allow appropriate life planning. Clinical genetic testing In individuals with a family history of interstitial lung disease suggestive of familial interstitial pneumonia, genetic testing might be appropriate after counselling because it can aid disease course prognostication and lung transplant risk stratification. Familial interstitial pneumonia transmission is thought to be autosomal dominant with reduced penetrance; however, disease penetrance of individual disease-associated genes remains unclear and so family member risk might be difficult to quantify. 72,73 Genetic testing in sporadic idiopathic pulmonary fibrosis is not recommended unless patients have a personal or family history of extrapulmonary features associated with a telomeropathy, such as aplastic anaemia, cryptogenic cirrhosis, or premature greying. 74 If such a history is identified, clinical peripheral blood mononuclear cell telomere length testing might be considered, and if telomere length is short (<10% for age), investigation for telomerase-related gene mutations should be done. 73 Clinical management Prompt referral of patients with known or suspected idiopathic pulmonary fibrosis to a centre with expertise in idiopathic pulmonary fibrosis care is advised, because delayed access is independently associated with increased risk of death. 75 Referral provides patients with access to expertise in diagnosis and management, including initiation of disease-modifying therapy, monitoring, Vol 389 May 13, 2017

5 side-effect control, and non-pharmacological support (figure 4). 4,76 In addition to idiopathic pulmonary fibrosis focused management, comorbidities commonly associated with idiopathic pulmonary fibrosis might be present, including emphysema, pulmonary hypertension, gastro-oesophageal reflux disease, and obstructive sleep apnoea Disease-modifying therapy Standardisation of idiopathic pulmonary fibrosis diagnostic criteria has enabled large, multicentre, randomised placebo-controlled trials of proposed diseasemodifying drugs. Randomised controlled trials identified that various putative therapies (eg, prednisolone and azathioprine, acetylcysteine, and warfarin) were ineffective or harmful; a landmark contribution to idiopathic pulmonary fibrosis patient care (panel). 9,83 Through these randomised controlled trials, two large phase 3 development programmes identified the first effective disease-modifying therapies for idiopathic pulmonary fibrosis nintedanib and pirfenidone. Both drugs are now approved worldwide for idiopathic pulmonary fibrosis treatment, which has transformed patient management. 89,90 Nintedanib is a tyrosine kinase inhibitor that suppresses multiple signalling receptors implicated in fibrosis pathogenesis, including fibroblast growth factor receptor, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor. 92,93 A phase 2 study of nintedanib in idiopathic pulmonary fibrosis identified a dose-dependent trend towards reduced lung function decline and reduction in acute exacerbation incidence. 94 Two subsequent phase 3 trials were done comparing nintedanib with a placebo. 89 Inclusion required a forced vital capacity of greater than or equal to 50% of the predicted value and a diffusion capacity of the lung for carbon monoxide of between 30% and 79% predicted. Over 52 weeks, relative decline in forced vital capacity was significantly less in the active treatment group than in the control group in both trials (47 9% and 55 1%). 89 In the INPULSIS-2 trial, 89 a significant difference in time to first acute exacerbation was identified. A prespecified sensitivity analysis based on pooled data from both trials of confirmed or suspected acute exacerbations adjudicated centrally by investigators masked to treatment group showed a benefit of nintedanib (hazard ratio [HR] 0 32, 95% CI ; p=0 001). 89 Post-hoc analyses, which categorised patients by age, smoking history, and forced vital capacity, showed a consistent effect of nintedanib across subgroups. 95 Pirfenidone is an orally administered pyridine with combined anti-inflammatory, antioxidant, and antifibrotic actions, although the precise mechanism of action is unknown. 96,97 Regulation of TGF β in vitro, and inhibition of fibroblast and collagen synthesis has been shown in animal models of lung fibrosis. 97 Four phase 3 trials of pirfenidone have been done since Panel: Therapies identified in clinical trials as harmful, ineffective, or effective in the treatment of idiopathic pulmonary fibrosis Potentially harmful therapies Ambrisentan 81 Everolimus 82 Prednisolone, azathioprine, acetylcysteine 9 Warfarin 83 Potentially ineffective therapies Bosentan 84 Imatinib 85 Macitentan 86 Acetylcysteine 87 Sildenafil 88 Effective disease-modifying therapies Nintedanib 89 Pirfenidone 90, The first study 98 reported a significant reduction (56 3%) in the relative decline in vital capacity in patients treated with pirfenidone. Two subsequent phase 3 trials 91 compared pirfenidone with placebo over 72 weeks. The effect of pirfenidone on forced vital capacity decline was discordant in these two trials; one trial confirmed the initial phase 3 results whereas the other trial found no significant difference between the groups. A fourth phase 3 study 90 was done over 52 weeks in patients with a forced vital capacity of 50 90% predicted and diffusion capacity for carbon monoxide of 30 90% predicted. The relative decline in forced vital capacity was significantly less in the active treatment group (54 9%) compared with the placebo group. Pooled analyses 90,99 of 1247 patients from phase 3 trials reported that fewer patients died in the pirfenidone groups than in the placebo groups (HR 0 52, 95% CI ; p=0 01) and that fewer patients had a decrease in 6 min walk distance in the pirfenidone groups than in the placebo groups. Nintedanib and pirfenidone have a similar effect on rate of decline in forced vital capacity over 1 year (figure 5) Neither drug has prospectively shown a survival benefit in these trials, although both show a trend in favour of a reduction in mortality. Therefore, the safety profile and tolerability of these drugs will influence patient and provider choice. Nintedanib and pirfenidone have good safety profiles within clinical trials, with acceptable tolerability in most patients, although roughly a fifth of patients might discontinue treatment because of sideeffects or disease progression. For both drugs, the primary safety concern is transaminitis, and both drugs require regular monitoring of liver function. Pirfenidone can cause gastrointestinal (dyspepsia and anorexia) and dermatological (photosensitivity) side-effects. 100 Nintedanib can cause gastrointestinal (diarrhoea and nausea) side- Vol 389 May 13,

6 A Relative decline in forced vital capacity (%) 0 50 Disease-modifying therapy Placebo Time (weeks) Figure 5: Effect of disease-modifying therapy on lung function decline The disease-modifying therapies nintedanib and pirfenidone roughly half the relative rate of decline of forced vital capacity compared with placebo over 52 weeks in patients with idiopathic pulmonary fibrosis Over 52 weeks the mean decline in forced vital capacity in an untreated patient with idiopathic pulmonary fibrosis is about 200 ml. Acute clinical deterioration B C the drug. 102 Side-effects are minimised with food, and in the case of nintedanib, with loperamide. Persistent sideeffects are typically responsive to temporary dose reduction or cessation. Because idiopathic pulmonary fibrosis is a chronic, invariably progressive disease most patients should begin therapy with one of these two drugs at the time of diagnosis, with exceptions for severe and, perhaps, asymptomatic disease. This recommendation is based on the notion that the earlier irreversible destruction of lung can be slowed, the more potential benefit there is to patients. The known effects of continued treatment on disease progression must be balanced against the safety and tolerability profile in individual patients to determine the value of treatment. Lung transplantation In selected patients with idiopathic pulmonary fibrosis, lung transplantation can improve quality of life and prolong survival, with a 5 year survival rate posttransplantation of about 50%. 4,103 However, only a few patients receive this intervention because of the medical complexity of the surgery and post-surgical treatment, and the restricted supply of donor organs. In view of the heterogeneity of the disease course of idiopathic pulmonary fibrosis, the optimum timing of referral for lung transplantation evaluation is unclear, but many patients are referred too late in the course of their disease. Therefore, lung transplantation should be discussed with individual patients early in their disease course and referral for evaluation should be made if objective evidence of disease progression exists. Figure 6: Radiological and histopathological changes that occur during an acute exacerbation of idiopathic pulmonary fibrosis A patient with a diagnosis of idiopathic pulmonary fibrosis with an axial chest high-resolution CT image taken at the level of the carina demonstrating subpleural reticulation and areas of traction bronchiectasis (A). The patient is admitted to hospital after the onset of worsening dyspnoea. An axial chest high-resolution CT image taken at the level of the carina in the same patient shows that the predominant pattern is a diffuse ground-glass abnormality becoming confluent with consolidation posteriorly (the so-called anterior-posterior density gradient), which is characteristic of an acute exacerbation of idiopathic pulmonary fibrosis (B). Minor respiratory motion artifact is observed because of the patient s dyspnoea during image acquisition. Although not obvious on this image, a small right pneumothorax is present and a chest drain has been positioned in the right pleural space. Surgical lung biopsy has no routine diagnostic role in cases of suspected acute exacerbation in view of high non-elective morbidity; when performed the histopathology slides identify that the alveolar septa are thickened by oedematous fibrosis and mild inflammation (C). The alveolar spaces show consolidation by fibrin and hyaline membranes, consistent with acute lung injury and diffuse alveolar damage (magnification 400). effects. 101 Treatment with nintedanib in combination with full-dose anticoagulants or in patients who have had a major bleeding event should be considered if the anticipated benefit outweighs the potential risk, in view of the theoretical increased risk of bleeding due to the antivascular endothelial growth factor receptor activity of Acute respiratory deterioration Patients with idiopathic pulmonary fibrosis might have acute respiratory deteriorations, with development of new or worsening dyspnoea and increased oxygen requirements. These events are highly significant, with median survival of only 3 4 months postevent. Acute respiratory deterioration can occur as a result of numerous known causes (eg, infection); when idiopathic, such deterioration is commonly referred to as acute exacerbation of idiopathic pulmonary fibrosis. 104 Acute exacerbation is thought to occur in roughly 5 15% of patients with idiopathic pulmonary fibrosis annually and is more common in patients with physiologically and functionally advanced disease. 105 By definition, acute exacerbation is characterised by new bilateral diffuse ground-glass opacities and consolidation on highresolution CT (figure 6). Histologically, diffuse alveolar damage is superimposed on a usual interstitial pneumonia pattern, but surgical lung biopsy should not generally be considered because of high non-elective morbidity rates. 62,106 A 2016 working group report 105 on acute exacerbation has suggested that the definition should be broadened to include any acute respiratory deterioration with new widespread alveolar abnormality Vol 389 May 13, 2017

7 on high-resolution CT of the chest not fully explained by cardiac failure or fluid overload. In patients with acute respiratory deterioration, identification of any potentially treatable causes is a priority. Extraparenchymal causes such as pulmonary embolism, pneumothorax, and pleural effusion should be excluded. If safe to do, CT angiography with highresolution CT is the diagnostic test of choice. Infection should be suspected in consistent clinical cases and managed appropriately. In cases of acute exacerbation, high-dose glucocorticoids are conditionally recommended by international guidelines; 4 however, no controlled trial data have demonstrated efficacy or safety of these drugs. 107 Guidelines make a conditional recommendation against mechanical ventilation in acute exacerbation, but this might be appropriate in selected cases, such as the bridging of a patient to lung transplantation. Symptom-focused therapy Adjunctive symptom-based management is important in view of the high symptom burden of idiopathic pulmonary fibrosis, including dyspnoea and cough. 108 In patients with chronic cough possible contributing comorbidities, such as gastro-oesophageal reflux disease, should be considered. Opiates might reduce anxiety, dyspnoea, and cough. 109 Some evidence suggests that corticosteroids could be effective in the treatment of chronic cough. 110 Symptoms are often refractory to standard pharmacological intervention. Pulmonary rehabilitation improves dyspnoea and quality of life, and might improve function status Education programmes, and patient support groups can help to minimise the effect of dyspnoea on activities of daily living and to reduce the psychological burden of idiopathic pulmonary fibrosis. Supplemental oxygen therapy should be considered to treat hypoxaemia. With advancing disease, the involvement of palliative-care physicians and end-of-life planning should be discussed in the outpatient setting. Controversies and uncertainties Diagnosis of idiopathic pulmonary fibrosis Approval of disease-modifying therapies for idiopathic pulmonary fibrosis has increased the focus on early and accurate diagnosis with the aim of improving long-term treatment outcome. The diagnostic certainty of idiopathic pulmonary fibrosis depends on the presence or absence of specific morphological criteria; the approval of safe and effective therapies provides a timely opportunity to review this approach because only patients with idiopathic pulmonary fibrosis can receive these therapies. 4 Broadening of the radiological diagnostic criteria of idiopathic pulmonary fibrosis has gained considerable interest. The presence of honeycomb lung destruction is required for a definite radiological diagnosis of idiopathic pulmonary fibrosis. Although this criterion was applied in pirfenidone trials, it was not used in nintedanib trials, in which idiopathic pulmonary fibrosis was diagnosed radiologically if either honeycomb lung destruction or traction bronchiectasis and a reticular abnormality consistent with fibrosis were present in a basal and peripheral predominance. 89,90 Post-hoc subgroup analysis 114 of these patients showed that the rate of decline in forced vital capacity was identical in both groups. Multidisciplinary team discussion was endorsed by guidelines as the gold standard for idiopathic pulmonary fibrosis diagnosis following the identification that substantial differences in the diagnosis might be reached by individuals working in isolation compared with a dynamic face-to-face interaction between clinicians, radiologists, and pathologists whereby interobserver agreement and diagnostic confidence is increased. 67 Two studies 115,116 identified that agreement between multidisciplinary teams in academic institutions is effective for a diagnosis of idiopathic pulmonary fibrosis, with multidisciplinary teams making the diagnosis of idiopathic pulmonary fibrosis with higher confidence and more frequently than clinicians or radiologists independently. However, only a small number of studies indicate how the multidisciplinary team approach is implemented in routine clinical care, and whether this affects diagnostic accuracy and treatment decisions. To standardise individual patient diagnosis increased understanding of this process is required. Interpretation of high-resolution CT scans has become increasingly important in the diagnosis of idiopathic pulmonary fibrosis, and only a few patients now undergo surgical lung biopsy. Transbronchial lung cryobiopsy with a flexible bronchoscope is an alternative method for sampling lung parenchyma proposed to have lower complication and mortality rates, although large multicentre prospective studies are required to confirm safety and diagnostic accuracy in idiopathic pulmonary fibrosis before introducing it in clinical practice. 117,118 Use of modifying therapies in patients outside of clinical trials The phase 3 studies of nintedanib and pirfenidone were designed to select a fairly homogenous population of patients with mild to moderate idiopathic pulmonary fibrosis. Patients with severe functional impairment (forced vital capacity <50% predicted or diffusion capacity of the lung for carbon monoxide <30% predicted) or major comorbidities, such as severe pulmonary hypertension, were excluded. In many countries, use of nintedanib or pirfenidone is limited by drug regulatory agency approval and reimbursement rules. Both drugs received regulatory approval in the USA without any severity threshold. 119 Although the tolerability of diseasemodifying therapy in patients with more severe physiological impairment might be reduced, in post-hoc analyses of phase 3 clinical trials no evidence suggests that therapeutic efficacy varies with disease severity, and so informed discussion with individual patients outside Vol 389 May 13,

8 For more on the EME-TIPAC trial see clinicaltrialsregister.eu, number of clinical trial settings would seem reasonable before commencing treatment. 95,120 Identification and management of non-responding patients Lung function will decline in patients with idiopathic pulmonary fibrosis despite treatment; however, clinical assessment for disease progression and therapeutic response is challenging. How to define failure to respond to treatment in an individual patient, and whether to consider cessation or alteration of therapy in patients with objective disease progression, remains unclear. Rate of change in forced vital capacity for an individual patient is variable over time; therefore, it is not possible to evaluate therapeutic response by comparison of forced vital capacity trends preceding and following the commencement of disease-modifying therapy. Post-hoc analysis of patients given pirfenidone shows that patients who have either a 10% or greater decline in forced vital capacity or hospital admission in the first 6 months of treatment still have a lower risk of forced vital capacity decline or death in the subsequent 6 months than do those given placebo. 121 In the UK, the National Institute for Health and Care Excellence recommends that nintedanib or pirfenidone be discontinued if after 12 months evidence shows disease progression (defined as a decrease in forced vital capacity of 10% predicted); however, it is unclear whether this represents treatment failure. 122 Because an individual s disease course cannot be predicted, we do not know what the rate of decline might have been without treatment nor whether withdrawal of treatment might provoke a precipitous decline. In patients with objective evidence of substantial physiological or radiological disease progression, a change of diseasemodifying therapy might be considered, whereas in patients with advanced disease in whom the treatment burden is affecting quality of life, discontinuation of treatment might be appropriate. Incorporation of genetics into routine clinical management Considerable advances have been made in understanding of the influence of genetics on the risk of developing sporadic idiopathic pulmonary fibrosis and possibly disease behaviour. Individuals with the MUC5B variant in the general population have increased prevalence of subclinical interstitial lung abnormalities, and MUC5B is most consistently associated with the risk of development of idiopathic pulmonary fibrosis. 24 Genotype might also influence response to pharmacological therapy, with a 2015 post-hoc analysis 123 showing that the TOLLIP genotype might determine a beneficial or harmful effect of acetylcysteine therapy. The translation of these findings to routine clinical practice will require robust prospective studies to define the role for genetics in diagnosis and treatment of idiopathic pulmonary fibrosis. Gastro-oesophageal reflux Gastro-oesophageal reflux disease is common in patients with idiopathic pulmonary fibrosis, and chronic silent microaspiration, as a source of repetitive lung injury, has been proposed as a risk factor for development and progression of idiopathic pulmonary fibrosis. 124,125 However, no prospective data exist that support a causative or prognostic association. Treatment of gastro-oesophageal reflux disease was associated with less radiological fibrosis and was an independent predictor of increased survival time in a retrospective analysis 126 of patients with idiopathic pulmonary fibrosis. Post-hoc analysis 127 of three randomised controlled trials found that patients taking antacid treatment had a smaller decrease in forced vital capacity than those not taking these therapies. By contrast, post-hoc analysis 128 of three phase 3 trials of pirfenidone in idiopathic pulmonary fibrosis found that antacid therapy did not improve outcomes and might be associated with increased risk of infection in patients with a forced vital capacity of less than 70% predicted. Non-acidic components of gastric acid are present in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis; as such, surgical management might prove more effective than medical antacid therapy. 129 Investigators of a single-centre retrospective trial 129 of laparoscopic antireflux surgery reported a decreased, albeit non-significant, decline in forced vital capacity. Prospective studies of treatments for gastro-oesophageal reflux disease are required for patients with idiopathic pulmonary fibrosis before the routine commencement of medical or surgical therapies for asymptomatic reflux can be considered. Microbiome and antimicrobial treatments Infection might influence fibrosis initiation and progression. 29,130 Whether alterations in the microbiome represent a causal factor or a determinant of disease behaviour possibly influenced by genetic polymorphisms such as MUC5B or TOLLIP, a surrogate finding of another disease process such as microaspiration, or a marker of lung structure derangement in idiopathic pulmonary fibrosis, remains uncertain. Studies into whether antimicrobials might influence the idiopathic pulmonary fibrosis disease course are ongoing. A phase 2 study of cotrimoxazole was done in patients with fibrotic idiopathic interstitial pneumonia following the observation of a clinical improvement in patients with advanced fibrotic lung disease treated with long-term oral cotrimoxazole. 131,132 No difference was identified in the primary endpoint of change in forced vital capacity over 12 months; however, a possible reduction in mortality was observed in patients who adhered to treatment. An ongoing phase 3 study is investigating the relevance of these findings. Biomarkers Biomarkers for diagnosis, prognosis, and response to therapy prediction could help to address controversies Vol 389 May 13, 2017

9 regarding diagnosis and management of idiopathic pulmonary fibrosis. Although numerous potential biomarkers have been studied, including genetic polymorphisms, gene expression profiles, CCL18, collagen neoepitopes, MMP7, and SPD, as yet, none is prospectively validated for clinical practice. 31, Major research efforts are ongoing towards biomarker validation through collaborative multicentre, prospective cohorts with longitudinal data collection and biobanking. Combination therapies Monotherapies only slow disease progression; therefore, a clear priority is the development of approaches to halt, or even reverse idiopathic pulmonary fibrosis. An initial step will be to study novel therapies combined with currently approved therapies. In a 2016 clinical trial, 138 the addition of the glutathione precursor acetylcysteine to pirfenidone unexpectedly increased the rate of decline in forced vital capacity, demonstrating the importance of randomised controlled trials. Studies of the drug drug interaction of pirfenidone and nintedanib are in progress, although pharmacokinetic interactions between the drugs, in particular cumulative gastrointestinal effects, might preclude this, with some evidence of a lower exposure of nintedanib when added to pirfenidone. 139 Clinical trial design in idiopathic pulmonary fibrosis has been altered by the approval of nintedanib and pirfenidone, which are now the standard of care. Identification of drugs that are superior to nintedanib and pirfenidone will probably require innovative trial design, such as use of composite endpoints. As our understanding of idiopathic pulmonary fibrosis continues to increase, novel molecular classification approaches are likely to support the addition of targeted therapies to the pleiotropic mechanisms of action of the approved drugs. Conclusions and future directions In less than 10 years, the landscape of idiopathic pulmonary fibrosis has been transformed. Many no longer consider pulmonary fibrosis to be idiopathic, with interaction between causal factors, including genetic polymorphisms, ageing, and environmental exposures, which culminate in a maladaptive repair process of injured lung. Advances in understanding of disease pathogenesis integrated with the establishment of methodologies to do large multicentre randomised controlled trials have resulted in the approval of the first drugs to modify the disease course of idiopathic pulmonary fibrosis. Despite these achievements, various problems remain. First, diagnosis of idiopathic pulmonary fibrosis can be challenging and can vary between clinicians as decisions are solely based on morphological criteria. Second, prediction of disease behaviour for individual patients is not possible because of considerable interpatient heterogeneity. Third, quantification and management of response to disease-modifying therapy is uncertain. Finally, although common pathogenic pathways of fibrosis have been proposed, it is unclear whether antifibrotic drugs with proven efficacy in idiopathic pulmonary fibrosis will translate to other fibrotic diseases with few treatment options. 140 The challenge of the next decade will be to address these questions while developing targeted therapies for use in combination with current treatments to halt fibrosis progression and maintain quality of life for patients with idiopathic pulmonary fibrosis. Contributors All authors contributed to the design and writing of this manuscript, and to the development of all figures. Declaration of interests LR reports grants and personal fees from InterMune; and personal fees from Biogen, Global Blood Therapeutics, Sanofi Aventis, Roche, ImmuneWorks, Boehringer Ingelheim, Celgene, FibroGen, Promedior, Bayer, Asahi Kasei, and Pliant Therapeutics. HRC reports personal fees from Medimmune, Bayer, Boehringer Ingelheim, Xfibra, Genoa, Gilead, Moerae Matrix, PharmAkea, Prometic, the Pulmonary Fibrosis Foundation, atyr Pharma, Global Blood Therapeutics, Veracyte, Patara, Alkermes, Takeda, Pharma Capital Partners, and Bristol-Myers Squibb, outside the submitted work. MGJ declares no competing interests. Acknowledgments MGJ acknowledges support from the Wellcome Trust through a training fellowship. We thank individuals who provided assistance with this manuscript, including Simon Walsh (Kings College London, London, UK) for the radiology images, film, and legends, Kirk Jones (University of California, San Fransisco, San Francisco, CA, USA) for the histopathology images and legends, Anuchana Patise (Southampton National Institute for Health Research [NIHR] Biomedical Research Unit, Southampton, UK) for assistance with figure preparation, Shandra Knight (National Jewish Health, Denver, CO, USA) for assistance with the literature search, and Giacomo Sgalla (Southampton NIHR Biomedical Research Unit) for provision of the acoustic recording. We apologise to the authors whose work we could not cite because of space constraints. References 1 International Agency for Research on Cancer. Cancer incidence in five continents (accessed Oct 1, 2016). 2 Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Resp J 2015; 46: Hopkins RB, Fell C, Dion G, Kolb M. Epidemiology and survival of idiopathic pulmonary fibrosis from national data in Canada. Eur Respir J 2016; 48: Raghu G, Collard HR, Egan JJ, et al, for the ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis Study Group. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161: Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006; 174: Ley B, Collard HR, King TE. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 183: Selman M, King TE, Pardo A, for the American Thoracic Society Study Group, European Respiratory Society Study Group, and American College of Chest Physicians Study Group. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134: Vol 389 May 13,