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Rationale: In the absence of a surgical lung biopsy, patients diagnosed with idiopathic pulmonary fibrosis (IPF) in clinical practice could participate in the INPULSIS trials of nintedanib if they had honeycombing and/or traction bronchiectasis plus reticulation, without atypical features of usual interstitial pneumonia (UIP), on high-resolution computed tomography (HRCT). Thus, the patients in these trials represented patients with definite UIP and a large subgroup of patients with possible UIP. Objectives: To investigate the potential impact of diagnostic subgroups on the progression of IPF and the effect of nintedanib. Methods: We conducted a post hoc subgroup analysis of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy versus patients without either, using pooled data from the INPULSIS trials. Measurements and Main Results: Seven hundred twenty-three (68.1%) patients had honeycombing and/or biopsy, and 338 (31.9%) patients had no honeycombing or biopsy. In these subgroups, respectively, the adjusted annual rate of decline in FVC in patients treated with placebo was 2225.7 and 2221.0 ml/yr, and the nintedanib versus placebo difference in the adjusted annual rate of declineinFVCwas117.0ml/yr(95%confidenceinterval,76.3-157.8) and 98.9 ml/yr (95% confidence interval, 36.4-161.5). There was no significant treatment-by-subgroup interaction (P = 0.8139). Adverse events were similar between the subgroups. Conclusions: Patients with IPF diagnosed in clinical practice who had possible UIP with traction bronchiectasis on HRCT and had not undergonesurgicallungbiopsyhaddiseasethatprogressedinasimilar way, and responded similarly to nintedanib, to that of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy.

The continuing struggle in the field of interstitial lung diseases (ILDs) has long been how best to classify disease on the basis of etiology or shared pathogenetic mechanisms. In the era of antifibrotic therapeutics of proven efficacy, accurate diagnosis is more important than ever. The articles published in 2018 reflect this ongoing debate in the medical community. The year 2018 led to new recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF) with active efforts to do the same for chronic hypersensitivity pneumonitis (CHP). Over the past two decades, international agreement on diagnostic criteria of IPF allowed a deeper understanding of disease mechanisms to be reached and facilitated the achievement of outstanding therapeutic goals. However, continual reclassification should not restrain efforts aimed at the discovery of therapies that can be beneficial for patients with diverse forms of progressive fibrotic disease, who so desperately need interventions that improve both quality of life and lifespan. With an exciting array of new therapeutic targets emerging from basic laboratory investigations, the responsibility of balancing careful phenotyping while addressing compelling clinical needs via efficient trial design will rest on the respiratory community. Additional work highlights the need for pulmonologists to be advocates for the protection and support of their patients. Within the scope of this paper, we review the latest advances in diagnosis, management, and pathogenesis of IPF, which is still the focus of most of the published research in the field of ILD. We then revise the most relevant evidence published on non-IPF fibrotic lung disease, acknowledging that in the future more attention should be focused on finding efficacious treatments for those patients with progressive disease, regardless of specific etiologies and strict classification schemes.

Rationale: The level of diagnostic likelihood at which physicians prescribe antifibrotic therapy without requesting surgical lung biopsy (SLB) in patients suspected of idiopathic pulmonary fibrosis (IPF) is unknown. Objectives: To determine how often physicians advocate SLB in patient subgroups defined by IPF likelihood and risk associated with SLB, and to identify the level of diagnostic likelihood at which physicians prescribe antifibrotic therapy with requesting SLB. Methods: An international cohort of respiratory physicians evaluated 60 cases of interstitial lung disease, giving: 1) differential diagnoses with diagnostic likelihood; 2) a decision on the need for SLB; and 3) initial management. Diagnoses were stratified according to diagnostic likelihood bands described by Ryerson and colleagues. Measurements and Main Results: A total of 404 physicians evaluated the 60 cases (24,240 physician-patient evaluations). IPF was part of the differential diagnosis in 9,958/24,240 (41.1%) of all physician-patient evaluations. SLB was requested in 8.1%, 29.6%, and 48.4% of definite, provisional high-confidence and provisional low-confidence diagnoses of IPF, respectively. In 63.0% of provisional high-confidence IPF diagnoses, antifibrotic therapy was prescribed without requesting SLB. No significant mortality difference was observed between cases given a definite diagnosis of IPF (90-100% diagnostic likelihood) and cases given a provisional high-confidence IPF diagnosis (hazard ratio, 0.97; P = 0.65; 95% confidence interval, 0.90-1.04). Conclusions: Most respiratory physicians prescribe antifibrotic therapy without requesting an SLB if a provisional high-confidence diagnosis or "working diagnosis" of IPF can be made (likelihood>70%). SLB is recommended in only a minority of patients with suspected, but not definite, IPF.

Idiopathic pulmonary fibrosis (IPF) is a progressivediseasewithamediansurvivalof 3–5 years (1, 2). The approval of nintedanib and pirfenidone by regulatory agencies worldwide has dramatically altered the landscape for testing new drugs for IPF treatment. These drugs slowed the progression of the FVC decline observed in IPF cohorts in phase III randomized, double-blind, placebo-controlled trials (3, 4).

Measurements and Main Results: On-treatment gastrointestinal adverse events were reported in 37 of 53 patients (69.8%) treated with nintedanib with add-on pirfenidone and 27 of 51 patients (52.9%) treated with nintedanib alone. Predose plasma trough concentrations of nintedanib were similar when it was administered alone or with add-on pirfenidone. Mean (SE) changes from baseline in FVC at Week 12 were 213.3 (17.4) ml and 240.9 (31.4) ml in patients treated with nintedanib with add-on pirfenidone (n = 48) and nintedanib alone (n = 44), respectively. Conclusions: Nintedanib with add-on pirfenidone had a manageable safety and tolerability profile in patients with IPF, in line with the adverse event profiles of each drug. These data support further research into combination regimens in the treatment of IPF. Rationale: Nintedanib and pirfenidone slow the progression of idiopathic pulmonary fibrosis (IPF), but the disease continues to progress. More data are needed on the safety and efficacy of combination therapy with nintedanib and add-on pirfenidone. Objectives: To investigate safety, tolerability, and pharmacokinetic and exploratory efficacy endpoints in patients treated with nintedanib and add-on pirfenidone versus nintedanib alone. Methods: Patients with IPF and FVC greater than or equal to 50% predicted at screening who completed a 4- to 5-week run-in with nintedanib 150 mg twice daily without dose reduction or treatment interruption were randomized to receive nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times daily) or nintedanib 150 mg twice daily alone in an open-label manner for 12 weeks. The primary endpoint was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to Week 12. Analyses were descriptive and exploratory.

Background: This document provides clinical recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF). It represents a collaborative effort between the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. Methods: The evidence syntheses were discussed and recommendations formulated by a multidisciplinary committee of IPF experts. The evidence was appraised and recommendations were formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Results: The guideline panel updated the diagnostic criteria for IPF Previously defined patterns of usual interstitial pneumonia (UIP) were refined to patterns of UIP, probable UIP, indeterminate, and alternate diagnosis. For patients with newly detected interstitial lung disease (ILD) who have a high-resolution computed tomography scan pattern of probable UIP, indeterminate, or an alternative diagnosis, conditional recommendations were made for performing BAL and surgical lung biopsy; because of lack of evidence, no recommendation was made for or against performing transbronchial lung biopsy or lung cryobiopsy. In contrast, for patients with newly detected ILD who have a high-resolution computed tomography scan pattern of UIP, strong recommendations were made against performing surgical lung biopsy, transbronchial lung biopsy, and lung cryobiopsy, and a conditional recommendation was made against performing BAL. Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs. Conclusions: The guideline panel provided recommendations related to the diagnosis of IPF.

Background: This document updates the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guideline on idiopathic pulmonary fibrosis treatment. Methods: Systematic reviews and, when appropriate, meta-analyses were performed to summarize all available evidence pertinent to our questions. The evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and then discussed by a multidisciplinary panel. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. Results: After considering the confidence in effect estimates, the importance of outcomes studied, desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications to health equity, recommendations were made for or against specific treatment interventions. Conclusions: The panel formulated and provided the rationale for recommendations in favor of or against treatment interventions for idiopathic pulmonary fibrosis.