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Blair G Fulton,1 Christopher J Ryerson1,2 1Department of Medicine, 2Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada Abstract: Major risk factors for idiopathic pulmonary fibrosis (IPF) include older age and a history of smoking, which predispose to several pulmonary and extra-pulmonary diseases. IPF can be associated with additional comorbidities through other mechanisms as either a cause or a consequence of these diseases. We review the literature regarding the management of common pulmonary and extra-pulmonary comorbidities, including chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, venous thromboembolism, sleep-disordered breathing, gastroesophageal reflux disease, coronary artery disease, depression and anxiety, and deconditioning. Recent studies have provided some guidance on the management of these diseases in IPF; however, most treatment recommendations are extrapolated from studies of non-IPF patients. Additional studies are required to more accurately determine the clinical features of these comorbidities in patients with IPF and to evaluate conventional treatments and management strategies that are beneficial in non-IPF populations. Keywords: interstitial lung disease, management, idiopathic pulmonary fibrosis, comorbidities

Background: Stress of the endoplasmic reticulum (ER) leading to activation of the unfolded protein response (UPR) and alveolar epithelial cell (AEC) apoptosis may play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our objectives were to determine whether circulating caspase-cleaved cytokeratin-18 (cCK-18) is a marker of AEC apoptosis in IPF, define the relationship of cCK-18 with activation of the UPR, and assess its utility as a diagnostic biomarker.Methods: IPF and normal lung tissues were stained with the antibody (M30) that specifically binds cCK-18. The relationship between markers of the UPR and cCK-18 was determined in AECs exposed in vitro to thapsigargin to induce ER stress. cCK-18 was measured in serum from subjects with IPF, hypersensitivity pneumonitis (HP), nonspecific interstitial pneumonia (NSIP), and control subjects.Results: cCK-18 immunoreactivity was present in AECs of IPF lung, but not in control subjects. Markers of the UPR (phosphorylated IRE-1α and spliced XBP-1) were more highly expressed in IPF type II AECs than in normal type II AECs. Phosphorylated IRE-1α and cCK-18 increased following thapsigargin-induced ER stress. Serum cCK-18 level distinguished IPF from diseased and control subjects. Serum cCK-18 was not associated with disease severity or outcome.Conclusions: cCK-18 may be a marker of AEC apoptosis and UPR activation in patients with IPF. Circulating levels of cCK-18 are increased in patients with IPF and cCK-18 may be a useful diagnostic biomarker. © 2012 Cha et al.; licensee BioMed Central Ltd.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an overall poor prognosis. A simple-to-use staging system for IPF may improve prognostication, help guide management, and facilitate research. Objective: To develop a multidimensional prognostic staging system for IPF by using commonly measured clinical and physiologic variables. Design: A clinical prediction model was developed and validated by using retrospective data from 3 large, geographically distinct cohorts. Setting: Interstitial lung disease referral centers in California, Minnesota, and Italy. Patients: 228 patients with IPF at the University of California, San Francisco (derivation cohort), and 330 patients at the Mayo Clinic and Morgagni-Pierantoni Hospital (validation cohort). Measurements: The primary outcome was mortality, treating transplantation as a competing risk. Model discrimination was assessed by the c-index, and calibration was assessed by comparing predicted and observed cumulative mortality at 1, 2, and 3 years. Results: Four variables were included in the final model: gender (G), age (A), and 2 lung physiology variables (P) (FVC and Dlco). A model using continuous predictors (GAP calculator) and a simple point-scoring system (GAP index) performed similarly in derivation (c-index of 70.8 and 69.3, respectively) and validation (c-index of 69.1 and 68.7, respectively). Three stages (stages I, II, and III) were identified based on the GAP index with 1-year mortality of 6%, 16%, and 39%, respectively. The GAP models performed similarly in pooled follow-up visits (c-index >=71.9). Limitation: Patients were drawn from academic centers and analyzed retrospectively. Conclusion: The GAP models use commonly measured clinical and physiologic variables to predict mortality in patients with IPF. Primary Funding Source: University of California, San Francisco Clinical and Translational Science Institute. [ABSTRACT FROM AUTHOR]

CONTEXT: Little is known about the treatment and correlates of dyspnea in idiopathic pulmonary fibrosis (IPF). OBJECTIVES: The objective of this systematic review was to summarize the literature regarding the treatment and correlates of dyspnea in IPF. METHODS: MEDLINE, EMBASE, and all Evidence-Based Medicine Reviews were searched for publications that evaluated treatment or correlates of dyspnea in IPF. Reference lists and recent review articles also were searched. RESULTS: The heterogeneity of included studies did not permit meta-analysis. Dyspnea improved in studies of sildenafil, pulmonary rehabilitation, and prednisone with colchicine. Additional studies of these three treatments, however, found discordant results. One study suggested that assisted ventilation delivered by facemask improved exertional dyspnea. Oxygen and opioids improve dyspnea in other chronic lung diseases, but data in IPF are limited. Correlates of dyspnea included functional and physiological measures and comorbid diseases. CONCLUSION: Sildenafil and pulmonary rehabilitation should be considered as potential therapies for dyspnea in selected patients with IPF. Supplemental oxygen and opioids may be additional potential therapies; however, the evidence supporting their use is weak. Additional research should focus on the management of functional status and comorbidities as potential treatments for dyspnea. [ABSTRACT FROM AUTHOR]

Background: Progressive pulmonary fibrosis (PFF) is of substantial interest for novel pharmacotherapy discovery, but little is known about clinical trial eligibility criteria. We evaluated eligibility criteria of PPF randomized controlled trials (RCTs), their representativeness in registry patients, and forced vital capacity (FVC) changes and mortality according to trial eligibility., Methods: A systematic search was used to identify completed and in-progress phase II and III PPF RCTs. Common clinical trial eligibility criteria used in ≥60% of previous PPF RCTs were identified. The most common criteria for PPF used in RCTs ("trial-PPF criteria") and the clinical practice guideline definition of PPF ("guideline-PPF criteria") were both applied to patients enrolled in a prospective multicenter Canadian registry. Common trial eligibility criteria were tested for their frequency and association with health outcomes in registry patients who met trial-PPF and guideline-PPF criteria., Results: Ten different definitions of PPF were used in 16 RCTs. At the time of meeting PPF definitions, 50% of 864 patients with trial-PPF and 44% of 408 patients with guideline-PPF met the common trial eligibility criteria. For both definitions, trial-eligible patients had more rapid 1-year FVC decline but better transplant-free survival than trial-ineligible patients. Patients with unclassifiable interstitial lung disease (ILD) had higher proportion of trial exclusion compared to those with connective tissue disease-associated ILD and fibrotic hypersensitivity pneumonitis. Annual FVC decline (trial-PPF: -67 to -21 mL; guideline-PPF: -116 to -41 mL) and 1-year transplant-free survival (trial-PPF: 90.5 to 97.5%; guideline-PPF: 87 to 96.2%) varied in trial-eligible patients across ILD subtypes., Conclusions: Existing RCTs use a variety of definitions for PPF with eligibility criteria that have limited representativeness. FVC decline and transplant-free survival vary according to trial eligibility and ILD subtypes., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background Interstitial lung abnormalities (ILAs) are incidental CT findings suggesting early interstitial lung disease. However ILA prevalence data are scarce in an unselected routine clinical setting. Purpose To evaluate the prevalence, underreporting rate, and potential clinical impact of ILAs recognizable on either abdominal CT scans or thoracoabdominal CT scans in a routine clinical setting of unselected patients. Materials and Methods Consecutive abdominal or thoracoabdominal CT scans from unselected inpatients and outpatients (age, ≥50 years; without any available prior chest CT and no clinical history of disease against the diagnosis of ILA) from a single-center tertiary hospital between January 2008 and December 2015 were retrospectively reviewed for the presence of ILAs and compared with the original clinical reports from the CT scans. Radiologic progression of ILA was evaluated by comparing consecutive CT points. Multivariable models adjusted for age, sex, race/ethnicity, oncologic disease, and cardiovascular disease were used to assess factors associated with odds of ILAs progression and all-cause and cause-specific mortality. Results Among 21 118 patients (median age, 72 years [IQR, 64-80 years]; 11 028 [52.2%] female patients), ILAs were observed in 362 (1.7%) patients, notably in 222 (1.0%) patients who had fibrotic features at CT. ILAs were recognized in 122 of 9415 (1.3%) and 240 of 11 703 (2.1%) of abdominal and thoracoabdominal CT scans, respectively. Of available original reports for 360 patients, 158 (43.9%) of all ILAs were not originally reported. Traction bronchiectasis index was the CT factor associated with higher odds of ILA progression (odds ratio, 3.47; 95% CI: 1.83, 6.58; P < .001). Fibrotic ILAs had a fourfold higher risk of respiratory-cause mortality (hazard ratio, 4.01; 95% CI: 2.02, 7.92; P < .001) compared with patients without ILAs. Conclusion The prevalence of ILAs was 1.7% in a large, unselected sample of patients who underwent either abdominal or thoracoabdominal CT for various clinical indications. Despite their prognostic significance, 43.9% of ILAs were unreported. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Hata in this issue.

Rationale: Cough is a key symptom in patients with fibrotic interstitial lung disease (ILD). Objectives: This study evaluated the prevalence, longitudinal change, associations, and prognostic significance of cough severity in patients with fibrotic ILD. Methods: We included consecutive patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD who completed the 100-mm Cough Severity Visual Analog Scale from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. Baseline cough severity and associations with patient demographics and clinical factors were determined. Relationships between baseline cough severity and health outcomes were evaluated. Measurements and Main Results: Patients with IPF ( n  = 1,061) had higher median baseline cough severity than those with non-IPF fibrotic ILD ( n  = 2,825) (24 vs. 20 mm; P  < 0.001), with worse cough associated with gastroesophageal reflux disease for both cohorts. Worse cough severity was independently associated with worse health-related quality of life at baseline, larger annualized decline in Dl CO , development of disease progression, and reduced transplant-free survival in both IPF and non-IPF fibrotic ILD cohorts. The IPF cohort (2.2 mm; 95% confidence interval, 1.6-2.9 mm) had larger annualized increments in cough severity than the non-IPF fibrotic ILD cohort (1.1 mm; 95% confidence interval, 0.8-1.4 mm; P  = 0.004). There was no difference in worsening cough over time comparing those receiving and not receiving ILD-targeted therapy or with and without lung function decline. Conclusions: Cough is common in patients with IPF and non-IPF fibrotic ILD, with increasing cough severity over time irrespective of ILD-targeted therapy. Patient-reported cough severity has prognostic implications on health-related quality of life, disease progression, and survival in fibrotic ILD.

The use of steroids in fibrotic interstitial lung diseases is founded on limited evidence. This modified Delphi survey sheds light on current clinical practices. Given the risks of steroids, clinical trials are needed to evaluate efficacy and harm. https://bit.ly/3VkgvbS., Competing Interests: Conflicts of interest: M. Funke-Chambour declares grants or contracts from Boehringer Ingelheim, consultancy and speaker's fees from Boehringer Ingelheim, Roche, MSD, AstraZeneca, Pfizer, GSK and Sanofi, outside this project. P. Suter has nothing to disclose. G.R. Jenkins declares grants to his institution from AstraZeneca, Biogen, Galecto, GlaxoSmithKline, Nordic Biosciences, RedX and Pliant, consultancy fees from AbbVie, Apollo Therapeutics, AstraZeneca, Brainomix, Bristol Myers Squibb, Chiesi, Cohbar, Daewoong, GlaxoSmithKline, Resolution Therapeutics and Pliant, honoraria from Boehringer Ingelheim, Chiesi, Roche, PatientMPower and AstraZeneca, payment for expert testimony from Pinsent Masons LLP, and participation on data safety or advisory board for Boehringer Ingelheim, Galapagos and Vicore, outside this project. L. Kawano-Dourado declares grants paid to their institution from Boehringer Ingelheim and Bristol Myers Squibb, and consultancy fees from Boehringer Ingelheim, outside this project. C.J. Ryerson declares grants from Boehringer Ingelheim paid to his institution, consultancy fees from Boehringer Ingelheim, Pliant Therapeutics, AstraZeneca, Trevi Therapeutics and Veracyte, payment or honoraria for lectures or presentations from Hoffmann-La Roche and Boehringer Ingelheim, and payment for expert testimony and travel support from Boehringer Ingelheim, outside this project. A.U. Wells reports consultancy fees from Roche, and payment or honoraria for lectures or presentations from Boehringer Ingelheim and Veracyte, and is President of the World Association of Sarcoidosis and Other Granulomatous Diseases, outside of the submitted work. M. Kreuter declares grants or contracts and royalties or licenses from Boehringer Ingelheim and Roche, consulting fees from Nichtraucherhelden/Sanero, Boehringer Ingelheim, Roche, BMS, GSK and AstraZeneca, and a leadership or fiduciary role for the European Respiratory Society, outside this project. K.A. Johannson declares grants paid to her institution from the University Hospital Foundation and the Three Lakes Foundation, consulting fees from Boehringer Ingelheim, Roche, Pliant Therapeutics and Brainomix, payment or honoraria for lectures or presentations and travel support from Boehringer Ingelheim, participation on a Data Safety Monitoring Board for the PFOX trial, and a stock option from Thyron SAB, outside this project., (Copyright ©The authors 2024.)

Objectives: Interstitial lung disease (ILD) in CTDs has highly variable morphology. We aimed to identify imaging features and their impact on ILD progression, mortality, and immunosuppression response., Methods: Patients with CTD-ILD had high-resolution chest CT (HRCT) reviewed by expert radiologists blinded to clinical data for overall imaging pattern [usual interstitial pneumonia (UIP); non-specific interstitial pneumonia (NSIP); organizing pneumonia (OP); fibrotic hypersensitivity pneumonitis (fHP); and other]. Transplant-free survival and change in percent-predicted forced vital capacity (FVC) were compared using Cox and linear mixed-effects models adjusted for age, sex, smoking, and baseline FVC. FVC decline after immunosuppression was compared with pre-treatment., Results: Among 645 CTD-ILD patients, the most frequent CTDs were SSc (n = 215), RA (n = 127), and inflammatory myopathies (n = 100). NSIP was the most common pattern (54%), followed by UIP (20%), fHP (9%), and OP (5%). Compared with the case for patients with UIP, FVC decline was slower in patients with NSIP (by 1.1%/year, 95% CI 0.2, 1.9) or OP (by 3.5%/year, 95% CI 2.0, 4.9), and mortality was lower in patients with NSIP [hazard ratio (HR) 0.65, 95% CI 0.45, 0.93] or OP (HR 0.18, 95% CI 0.05, 0.57), but higher in fHP (HR 1.58, 95% CI 1.01, 2.40). The extent of fibrosis also predicted FVC decline and mortality. After immunosuppression, FVC decline was slower compared with pre-treatment in NSIP (by 2.1%/year, 95% CI 1.4, 2.8), with no change for UIP or fHP., Conclusion: Multiple radiologic patterns are possible in CTD-ILD, including a fHP pattern. NSIP and OP were associated with better outcomes and response to immunosuppression, while fHP had worse survival compared with UIP., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Pulmonary hypertension (PH) is a key complication in interstitial lung disease (ILD), with recent therapeutic advances., Research Question: What are the diagnostic evaluation, epidemiologic features, associated factors, prognostic significance, and outcome measures in interventional trials for PH in patients with ILD in the current literature?, Study Design and Methods: The Ovid MEDLINE, Embase, and CENTRAL databases were searched for original research evaluating PH in participants with ILD of any cause. The definition of PH was based on the investigators' criteria., Results: Three hundred two studies were included, with varying diagnostic evaluations used to define PH. Commonly used diagnostic tests were right heart catheterization (56%) and transthoracic echocardiography (50%). The pooled prevalence for PH in general populations with ILD was 36% (95% CI, 30%-42%) using right heart catheterization and 34% (95% CI, 29%-38%) using transthoracic echocardiography. Lower diffusion capacity of the lungs for carbon monoxide, worse oxygenation status, reduced exercise capacity, increased pulmonary artery to aorta ratio and pulmonary artery diameter, and elevated serum brain natriuretic peptide consistently were associated with the presence of PH in at least 60% of reported studies. The presence of PH was associated with increased symptom burden and worse prognosis. Outcome measures in interventional trials of PH in ILD focused on changes in pulmonary vascular hemodynamics and 6-min walk distance., Interpretation: PH is a common complication in ILD with significant health impacts. A standardized definition with prospective evaluation of risk-stratified assessments for PH using identified associated risk factors is warranted. Our findings provide an evidence base for validation as surrogate end points in future PH interventional trials in ILD., Trial Registry: International Prospective Register of Systematic Reviews; No.: CRD42021255394; URL: https://www.crd.york.ac.uk/prospero/., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: Y. H. K. reports fellowship support from an NHMRC Investigator Grant, Austin Medical Research Foundation, and Royal Australasian College of Physicians, and grants from Boehringer Ingelheim during the conduct of the study. C. J. R. reports grants from Boehringer Ingelheim during the conduct of the study, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Hoffmann-La Roche, personal fees from Veracyte, personal fees from Pliant Therapeutics, personal fees from Astra Zeneca, and personal fees from Cipla Ltd. outside the submitted work. None declared (H. L. A., M. S., R. K. C., H. H. T., A. H.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The internet is a common source of health information for patients and caregivers. To date, content and information quality of YouTube videos on sarcoidosis has not been studied. The aim of our study was to investigate the content and quality of information on sarcoidosis provided by YouTube videos., Methods: Of the first 200 results under the search term "sarcoidosis," all English-language videos with content directed at patients were included. Two independent investigators assessed the content of the videos based on 25 predefined key features (content score with 0-25 points), as well as reliability and quality (HONCode score with 0-8 points, DISCERN score with 1-5 points). Misinformation contained in the videos was described qualitatively., Results: The majority of the 85 included videos were from an academic or governmental source (n = 63, 74%), and median time since upload was 33 months (IQR 10-55). Median video duration was 8 min (IQR 3-13) and had a median of 2,044 views (IQR 504 - 13,203). Quality assessment suggested partially sufficient information: mean HONCode score was 4.4 (SD 0.9) with 91% of videos having a medium quality HONCode evaluation. Mean DISCERN score was 2.3 (SD 0.5). Video content was generally poor with a mean of 10.5 points (SD 0.6). Frequently absent key features included information on the course of disease (6%), presence of substantial geographical variation (7%), and importance of screening for extrapulmonary manifestations (11%). HONCode scores were higher in videos from academic or governmental sources (p = 0.003), particularly regarding "transparency of sponsorship" (p < 0.001). DISCERN and content scores did not differ by video category., Conclusions: Most YouTube videos present incomplete information reflected in a poor content score, especially regarding screening for extrapulmonary manifestations. Quality was partially sufficient with higher scores in videos from academic or governmental sources, but often missing references and citing specific evidence. Improving patient access to trustworthy and up to date information is needed., (© 2024. The Author(s).)

Background: Previous studies have shown the importance of frailty in patients with fibrotic interstitial lung disease (ILD)., Research Question: Is the Clinical Frailty Scale (CFS) a valid tool to improve risk stratification in patients with fibrotic ILD?, Study Design and Methods: Patients with fibrotic ILD were included from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. The CFS was assessed using available information from initial ILD clinic visits. Patients were stratified into fit (CFS score 1-3), vulnerable (CFS score 4), and frail (CFS score 5-9) subgroups. Cox proportional hazards and logistic regression models with mixed effects were used to estimate time to death or lung transplantation. A derivation and validation cohort was used to establish prognostic performance. Trajectories of functional tests were compared using joint models., Results: Of the 1,587 patients with fibrotic ILD, 858 (54%) were fit, 400 (25%) were vulnerable, and 329 (21%) were frail. Frailty was a risk factor for early mortality (hazard ratio, 5.58; 95% CI, 3.64-5.76, P < .001) in the entire cohort, in individual ILD diagnoses, and after adjustment for potential confounders. Adding frailty to established risk prediction parameters improved the prognostic performance in derivation and validation cohorts. Patients in the frail subgroup had larger annual declines in FVC % predicted than patients in the fit subgroup (-2.32; 95% CI, -3.39 to -1.17 vs -1.55; 95% CI, -2.04 to -1.15, respectively; P = .02)., Interpretation: The simple and practical CFS is associated with pulmonary and physical function decline in patients with fibrotic ILD and provides additional prognostic accuracy in clinical practice., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Bronchoalveolar lavage (BAL) cellular analysis is often recommended during the initial diagnostic evaluation of fibrotic interstitial lung disease (ILD). Despite recommendation for its use, between-center heterogeneity exists and supportive data concerning the clinical utility and correlation of BAL findings with radiologic features or patterns remain sparse., Research Question: In patients with fibrotic ILD, are BAL findings associated with radiologic features, patterns, and clinical diagnoses?, Study Design and Methods: Patients with fibrotic ILD who underwent BAL for diagnostic evaluation and who were enrolled in the prospective Canadian Registry for Pulmonary Fibrosis were re-reviewed in a standardized multidisciplinary discussion (MDD). BAL was categorized according to guideline-recommended thresholds, and using thresholds of lymphocytosis > 20% and neutrophils > 4.5%. High-resolution CT (HRCT) scans were scored (blinded to clinical data) for specific features and percentage lung involvement. Radiologists classified HRCT scans according to guideline-defined patterns for idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis (fHP); then, MDD diagnoses were assigned, considering all available data., Results: Bronchoscopy with cellular analysis was performed in 209 of 1,593 patients (13%). Lymphocyte % was weakly negatively correlated with total fibrosis % (r = -0.16, P = .023) but not statistically significantly correlated with ground glass opacity % (r = 0.01, P = .94). A mixed BAL pattern was the most frequent in all radiologic patterns (range, 45%-69%), with a minority classifiable according to BAL guidelines. BAL lymphocytosis appeared with similar frequency across HRCT patterns of fHP (21%) and usual interstitial pneumonia (18%). Only 5% of patients with MDD-based fHP had a guideline-defined isolated lymphocytosis > 15%., Interpretation: BAL cellular analyses did not significantly correlate with radiologic features, guideline patterns, or MDD-based diagnoses. Ground glass opacities are often interpreted to represent pulmonary inflammation, but were not associated with BAL lymphocytosis in this cohort., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives: Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods: This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results: Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with www.clinicaltrials.gov (NCT04396756).

Background: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD)., Methods: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure., Results: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results., Conclusion: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD., Competing Interests: Competing interests: LK-D—research grants from Boehringer Ingelheim and Bristol-Myers-Squibb, research grant from the Brazilian Ministry of Health (PROADI-SUS), non-financial research support from Fisher & Paykel; personal fees from Sarava and Boehringer Ingelheim. TK—personal fees from Boehringer Ingelheim, United Therapeutics, Puretech and Veracyte. CJR—research grant from Boehringer Ingelheim; personal fees from Boehringer Ingelheim, Pliant Therapeutics, AstraZeneca, Trevi Therapeutics, Hoffmann La Roche and Cipla. PR-O—research grants from Boehringer Ingelheim, Hoffmann La Roche, CSL Behring, FibroGen, Vicore Pharma, Gilead, Galecto and Chiesi; personal fees from Boehringer Ingelheim, Hoffmann La Roche, Cipla, Tecnofarma, Respiratory Effectiveness Group and The Limbic. NC—personal fees from Boehringer Ingelheim, Liminal Biosciences, Vicor Pharma, Bridge Biotherapeutics and Transcrip. MF-C—research grants from CSL Behring, Boehringer Ingelheim and Roche; personal fees from Boehringer Ingelheim, MSD, AstraZeneca and GSK. A-MH-V—research grants from Boehringer Ingelheim and Janssen; personal fees from ARXX, Boehringer Ingelheim, Janssen, Medscape, Roche, Genentech, Bayer, Lilly and Merck Sharp & Dohme. KAJ—research grants from University Hospital Foundation and Three Lakes Foundation; personal fees from Boehringer Ingelheim, Pliant, Thyron, Brainomix and Hoffman La Roche. YHK—research grants from NHMRC, MRFF, Air Liquide Healthcare, Austin Medical Research Foundation, Lung Foundation Australia/Thoracic Society of Australia and New Zealand, and RACP. SBM—research grants from Three Lakes Foundation, NIH/NHLBI, Merck, Boehringer Ingelheim, Pliant Therapeutics, American Thoracic Society, and National Scleroderma Foundation; personal fees from Wolters Kluwer, Roche, DevPro Biopharma, Gilead, Accendatech, Cowen and APIE Therapeutics. LP—research grants from Janssen and Ferrer; personal fees from Janssen, Ferrer, United Therapeutics, MSD and Liquidia. HP—research grants from Boehringer Ingelheim, AstraZeneca and Siemens; personal fees from Boehringer Ingelheim, Sanofi, Janssen, MSD, AstraZeneca and Chiesi. MM-M—research grants from Boehringer Ingelheim and Roche; personal fees from Boehringer Ingelheim, Ferrer and Chiesi. JST—research grant from Boehringer Ingelheim; personal fees from Boehringer Ingelheim and Aflofarm. SR—personal fees from Cipla and Boehringer Ingelheim. JJ—research grants from Gilead, Microsoft research and GSK; personal fees from Boehringer Ingelheim, Roche, GSK and Takeda. DR—research grants from NIHR; personal fees from OMass Therapeutics, Sosei Heptares and GSK. LGS—personal fees from Daiichi Sankyo and Chiesi. MK—research grants from Boehringer Ingelheim and Roche; personal fees from Nichtraucherhelden/Sanero, Boehringer Ingelheim and Roche. NK—research grants from Veracyte, Boehringer Ingelheim, BMS and non-financial support from AstraZeneca; scientific founder at Thyron; personal fees from Boehringer Ingelheim, Pliant, AstraZeneca, RohBar, Veracyte, Augmanity, CSL Behring, Splisense, Galapagos, Fibrogen, GSK, Merck and Thyron; and reports Equity in Pliant and Thyron. RL—senior consultant for Berry Consultants. WA—personal fees from Boehringer Ingelheim. GJ—research grants from AstraZeneca, Biogen, Galecto, GSK, Nordic Biosciences, RedX and Pliant; personal fees from Apollo Therapeutics, AstraZeneca, Brainomix, Bristol-Myers-Squibb, Chiesi, Cohbar, Daewoong, Veracyte, GSK, Resolution Therapeutics, Pliant, Hoffmann La Roche, PatientMPower, Pinsent Masons, Galapagos and Vicore Pharma. BGB, IB-V, BW, TJ, MQ and VC have no conflicts to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: A visual analog scale (VAS) is a simple and easily administered tool for measuring the impact of disease; however, little is known about the use of a dyspnea VAS in interstitial lung disease (ILD). Objectives: To validate the use of a dyspnea VAS in a large and heterogeneous cohort of patients with fibrotic ILD, including its minimal clinically important difference (MCID), responsiveness to change, and prognostic significance. Methods: Patients with fibrotic ILD were identified from a large prospective registry. The validity of a 100-mm dyspnea VAS was assessed by testing its correlation in change score with other measures of ILD severity, including the University of California San Diego Shortness of Breath Questionnaire, the King's Brief Interstitial Lung Disease quality of life questionnaire Breathlessness and Activities Domain, the European Quality of Life VAS, forced vital capacity, and diffusing capacity of the lung for carbon monoxide. The responsiveness of the dyspnea VAS was qualitatively confirmed on the basis of there being an observable difference in the change in dyspnea VAS across tertiles of change in anchor variables. The MCID in dyspnea VAS was calculated using both anchor (linear regression) and distribution (one-half standard deviation) approaches, with anchors including the above variables that had a correlation with dyspnea VAS (| r | ≥ 0.30). The association of dyspnea VAS with time to death or transplant was determined. Results: The cohort included 826 patients with fibrotic ILD, including 127 patients with follow-up measurements at 6 months. The mean baseline dyspnea VAS was 53 ± 24 mm. Dyspnea VAS change scores were moderately correlated with the University of California San Diego Shortness of Breath Questionnaire (| r | = 0.55) and the King's Brief Interstitial Lung Disease quality of life questionnaire Breathlessness and Activities Domain (| r | = 0.44) and weakly correlated with the European Quality of Life VAS (| r | = 0.19), forced vital capacity percent predicted (| r | = 0.21), and diffusing capacity of the lung for carbon monoxide percent predicted (| r | = 0.05). The MCID was 2.7 to 4.5 using the more reliable anchor-based methods and 12.0 based on distribution-based methods. Dyspnea VAS was associated with time to death or transplant in unadjusted models and after adjustment for age and sex (hazard ratios, 1.16 and 1.15, respectively; P  < 0.05 for both). Conclusions: This study provides support for the use of the dyspnea VAS in patients with fibrotic ILD, with an estimated anchor-based MCID of 5 mm.

Background and Objective: Establishing an accurate and timely diagnosis of idiopathic pulmonary fibrosis (IPF) is essential for appropriate management and prognostication. In some cases, surgical lung biopsy (SLB) is performed but carries non-negligible risk. The objective of this retrospective study was to determine if SLB is associated with accelerated lung function decline in patients with IPF using the Canadian Registry for Pulmonary Fibrosis., Methods: Linear mixed models and Cox proportional hazards regression models were used to compare decline in forced vital capacity (FVC)%, diffusion capacity of the lung (DLCO%) and risk of death or lung transplantation between SLB and non-SLB patients. Adjustments were made for baseline age, sex, smoking history, antifibrotic use, and lung function. A similar analysis compared lung function changes 12 months pre- and post-SLB., Results: A total of 81 SLB patients and 468 non-SLB patients were included. In the SLB group, the post-biopsy annual FVC% decline was 2.0% (±0.8) in unadjusted, and 2.1% (±0.8) in adjusted models. There was no difference in FVC% decline, DLCO% decline, or time to death or lung transplantation between the two groups, in adjusted or unadjusted models (all p-values >0.07). In the pre-post SLB group, no differences were identified in FVC% decline in unadjusted or adjusted models (p = 0.07 for both)., Conclusion: No association between SLB and lung function decline or risk of death or lung transplantation was identified in this multi-centre study of patients with IPF., (© 2024 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background: Patients with fibrotic hypersensitivity pneumonitis (fHP) are frequently treated with immunosuppression to slow lung function decline; however, the impact of this treatment has not been studied across different types of antigen exposure., Research Question: In patients with fHP, do disease outcomes and response to treatment vary by antigen type?, Study Design and Methods: A multicenter interstitial lung disease database (Canadian Registry for Pulmonary Fibrosis) was used to identify patients with fHP. The causative antigen was categorized as avian, mold, unknown, or other. Treatment was defined as mycophenolate ≥ 1,000 mg/d or azathioprine ≥ 75 mg/d for ≥ 30 days. Statistical analysis included t tests, χ 2 tests, and one-way analysis of variance. Unadjusted and adjusted competing risks and Cox proportional hazards models were used to assess survival., Results: A total of 344 patients were identified with the following causative antigens: avian (n = 93; 27%), mold (n = 88; 26%), other (n = 15; 4%), and unknown (n = 148; 43%). Patient characteristics and lung function were similar among antigen groups with a mean FVC % predicted of 75 ± 20. The percent of patients treated with immunosuppression was similar between antigens with 58% of patients treated. There was no change in lung function or symptom scores with the initiation of immunosuppression in the full cohort. Immunosuppression was not associated with a change in survival for patients with avian or mold antigen (avian: hazard ratio, 0.41; 95% CI, 0.11-1.59; P = .20; mold: hazard ratio, 1.13; 95% CI, 0.26-4.97; P = .88). For patients with unknown causative antigen, survival was worse when treated with immunosuppression (hazard ratio, 2.65; 95% CI, 1.01-6.92; P = .047)., Interpretation: Response to immunosuppression varies by antigen type in patients with fHP. Additional studies are needed to test the role of immunosuppression in fHP, and particularly in those with an unknown antigen., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. W. W. reports personal fees from Boehringer Ingelheim and Astra Zeneca, outside the submitted work. V. M. reports personal fees from Boehringer Ingelheim Canada, Hoffman-La Roche Ltd, and Astra Zeneca; and reports grants from the University of Saskatchewan, Royal University Hospital Foundation, Boehringer Ingelheim, Astra Zeneca, and Hoffman-La Roche. D.-C. M. reports consultancy and speaking fees from Boehringer Ingelheim. B. Z. reports speaking fees from Boehringer Ingelheim and Abbvie. D. A. is supported by the Fonds de Recherche du Quebec en Santé, reports personal fees and grants from Boehringer Ingelheim, reports personal fees from Hoffmann-La Roche, and reports grants from the Canadian Institute for Health Research. K. A. J. reports grants from Boehringer Ingelheim, Pulmonary Fibrosis Society of Calgary, and University of Calgary School of Medicine; and reports personal fees from Boehringer Ingelheim, Roche, Three Lakes Foundation, Pliant Therapeutics, Theravance, and Blade Therapeutics. M. K. reports grants from the Canadian Institute for Health Research, Roche, Boehringer Ingelheim, Pieris, and Prometic; and reports personal fees from Boehringer Ingelheim, Roche, European Respiratory Journal, Belerophon, United Therapeutics, Nitto Denko, MitoImmune, Pieris, Abbvie, DevPro Biopharma, Horizon, Algernon, and CSL Behring. H. M. reports grants from Boehringer Ingelheim and Gilead. J. M. reports personal fees from Boehringer Ingelheim and Roche. C. J. R. reports grants from Boehringer Ingelheim; and reports personal fees from Astra Zeneca, Boehringer Ingelheim, Roche, Pliant Therapeutics, Cipla, and Veracyte. None declared (M. L. M., G. F., J. H. F., N. K., B. M., E. F.)., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Importance: Patients with interstitial lung disease (ILD) and early-stage non-small cell lung cancer (NSCLC) have been reported to be at high risk of toxic effects after stereotactic ablative radiotherapy (SABR), but for many patients, there are limited alternative treatment options., Objective: To prospectively assess the benefits and toxic effects of SABR in this patient population., Design, Setting, and Participants: This prospective cohort study was conducted at 6 academic radiation oncology institutions, 5 in Canada and 1 in Scotland, with accrual between March 7, 2019, and January 12, 2022. Patients aged 18 years or older with fibrotic ILD and a diagnosis of T1-2N0 NSCLC who were not candidates for surgical resection were enrolled., Intervention: Patients were treated with SABR to a dose of 50 Gy in 5 fractions every other day., Main Outcomes and Measures: The study prespecified that SABR would be considered worthwhile if median overall survival-the primary end point-was longer than 1 year, with a grade 3 to 4 risk of toxic effects less than 35% and a grade 5 risk of toxic effects less than 15%. Secondary end points included toxic effects, progression-free survival (PFS), local control (LC), quality-of-life outcomes, and changes in pulmonary function. Intention-to-treat analysis was conducted., Results: Thirty-nine patients enrolled and received SABR. Median age was 78 (IQR, 67-83) years and 59% (n = 23) were male. At baseline, 70% (26 of 37) of patients reported dyspnea, median forced expiratory volume in first second of expiration was 80% (IQR, 66%-90%) predicted, median forced vital capacity was 84% (IQR, 69%-94%) predicted, and median diffusion capacity of the lung for carbon monoxide was 49% (IQR, 38%-61%) predicted. Median follow-up was 19 (IQR, 14-25) months. Overall survival at 1 year was 79% (95%, CI 62%-89%; P < .001 vs the unacceptable rate), and median overall survival was 25 months (95% CI, 14 months to not reached). Median PFS was 19 months (95% CI, 13-28 months), and 2-year LC was 92% (95% CI, 69%-98%). Adverse event rates (highest grade per patient) were grade 1 to 2: n = 12 (31%), grade 3: n = 4 (10%), grade 4: n = 0, and grade 5: n = 3 (7.7%, all due to respiratory deterioration)., Conclusions and Relevance: In this trial, use of SABR in patients with fibrotic ILD met the prespecified acceptability thresholds for both toxicity and efficacy, supporting the use of SABR for curative-intent treatment after a careful discussion of risks and benefits., Trial Registration: ClinicalTrials.gov Identifier: NCT03485378.

Rationale: Particulate matter with an aerodynamic diameter ⩽2.5 μm is associated with adverse outcomes in fibrotic interstitial lung disease (fILD), but the impact of ultrafine particulates (UFPs; aerodynamic diameter ⩽100 nm) remains unknown. Objective: To evaluate UFP associations with clinical outcomes in fILD. Methods: We conducted a multicenter, prospective cohort study enrolling patients with fILD from the University of Pittsburgh Dorothy P. and Richard P. Simmons Center and the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR). Using a national-scale UFP model, we linked exposures using three approaches in the Simmons cohort (residential address geocoordinates, ZIP code centroid geocoordinates, and ZIP code average) and two in the PFF-PR for which only five-digit ZIP code was available (ZIP code centroid and ZIP code average). We tested UFP associations with transplantation-free survival using multivariable Cox proportional-hazards models, baseline percentage predicted FVC and Dl CO using multivariable linear regressions, and decline in FVC and Dl CO using linear mixed models adjusting for age, sex, smoking, race, socioeconomic status, site, particulate matter with an aerodynamic diameter ⩽2.5, and nitrogen dioxide. Measurements and Main Results: Annual mean outdoor UFP concentrations for 2017 were estimated for 1,416 Simmons and 1,919 PFF-PR patients. Increased UFP concentration was associated with transplantation-free survival in fully adjusted Simmons residential address models (hazard ratio, 1.08 per 1,000 particles/cm 3 [95% confidence interval, 1.01-1.15]; P  = 0.02) but not PFF-PR models, which used less precise linkage approaches. Higher UFP exposure was associated with lower baseline FVC and more rapid FVC decline in the Simmons registry. Conclusions: Increased UFP exposure was associated with transplantation-free survival and lung function in the cohort with precise residential location linkage. This work highlights the need for more robust regulatory networks to study the health effects of UFPs nationwide.

Background: Fibrotic interstitial lung disease (ILD) is frequently associated with abnormal oxygenation; however, little is known about the accuracy of oxygen saturation by pulse oximetry (SpO 2 ) compared with arterial blood gas (ABG) saturation (SaO 2 ), the factors that influence the partial pressure of carbon dioxide (PaCO 2 ) and the impact of PaCO 2 on outcomes in patients with fibrotic ILD., Study Design and Methods: Patients with fibrotic ILD enrolled in a large prospective registry with a room air ABG were included. Prespecified analyses included testing the correlation between SaO 2 and SpO 2 , the difference between SaO 2 and SpO 2 , the association of baseline characteristics with both the difference between SaO 2 and SpO 2 and the PaCO 2 , the association of baseline characteristics with acid-base category, and the association of PaCO 2 and acid-base category with time to death or transplant., Results: A total of 532 patients with fibrotic ILD were included. Mean resting SaO 2 was 92±4% and SpO 2 was 95±3%. Mean PaCO 2 was 38±6 mmHg, with 135 patients having PaCO 2 <35 mmHg and 62 having PaCO 2 >45 mmHg. Correlation between SaO 2 and SpO 2 was mild to moderate (r=0.39), with SpO 2 on average 3.0% higher than SaO 2 . No baseline characteristics were associated with the difference in SaO 2 and SpO 2 . Variables associated with either elevated or abnormal (elevated or low) PaCO 2 included higher smoking pack-years and lower baseline forced vital capacity (FVC). Lower baseline lung function was associated with an increased risk of chronic respiratory acidosis. PaCO 2 and acid-base status were not associated with time to death or transplant., Interpretation: SaO 2 and SpO 2 are weakly-to-moderately correlated in fibrotic ILD, with limited ability to accurately predict this difference. Abnormal PaCO 2 was associated with baseline FVC but was not associated with outcomes., Competing Interests: Competing interests: MAD reports no conflicts of interest relevant to this manuscript. KD reports no conflicts of interest relevant to this manuscript. DA reports grants and personal fees from Boehringer Ingelheim, grants from Canadian Institute for Health Research and from Fonds de Recherche du Quebec en Santé. CD reports no conflicts of interest relevant to this manuscript. JHF reports personal fees from AstraZeneca and Boehringer Ingelheim. KJ reports grants from Boehringer Ingelheim, Pulmonary Fibrosis Society of Calgary, University of Calgary School of Medicine; personal fees from Boehringer Ingelheim, Roche, Three Lakes Foundation, Pliant Therapeutics, Theravance, Blade Therapeutics. MK reports grants from Canadian Institute for Health Research, Roche, Boehringer Ingelheim, Pieris, Prometic; personal fees from Boehringer Ingelheim, Roche, European Respiratory Journal, Belerophon, United Therapeutics, Nitto Denko, MitoImmune, Pieris, AbbVie, DevPro Biopharma, Horizon, Algernon, CSL Behring. SDL reports consulting/personal fees and moderator honoraria from Boehringer-Ingelheim, honoraria from Hoffman-La Roche Ltd, grants from AstraZeneca and the University of Saskatchewan. HM reports grants from Boehringer Ingelheim and Gilead. VM reports grants from Boehringer Ingelheim, AstraZeneca, and Roche; personal fees from Boehringer Ingelheim and Roche. BM reports no conflicts of interest relevant to this manuscript. JM reports personal fees from Boehringer Ingelheim and Roche. D-CM reports personal fees from Boehringer Ingelheim. CJR reports grants from Boehringer Ingelheim; personal fees from AstraZeneca, Boehringer Ingelheim, Roche, Pliant Therapeutics, Cipla, Veracyte., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD., Design: Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only., Eligibility Criteria: Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded., Data Synthesis: The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I 2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design., Results: A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI -4.00 to 9.88, I 2 =79.3%; %DLco -2.03, 95% CI -4.38 to 0.32, I 2 =0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I 2 =0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DL CO (95% CI 2.05 to 6.79, I 2 =0.0%). AZA studies were limited. All estimates were considered very low certainty evidence., Conclusions: There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD., Prospero Registration Number: CRD42023423223., Competing Interests: Competing interests: GJ is supported by a National Institute for Health Research (NIHR) Research Professorship (NIHR reference RP-2017-08-ST2-014). GJ is a trustee of Action for Pulmonary Fibrosis and reports personal fees from Astra Zeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daewoong, Galapagos, Galecto, GlaxoSmithKline, Heptares, NuMedii, PatientMPower, Pliant, Promedior, Redx, Resolution Therapeutics, Roche, Veracyte and Vicore. CJR reports grants from Boehringer Ingelheim, and honoraria or consulting fees from Boehringer Ingelheim, Pliant Therapeutics, Astra Zeneca, Trevi Therapeutics, Veracyte, Hoffmann-La Roche, Cipla. FL, IS, LF, WA and LK-D report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

What is this summary about? This plain language summary shares results from a clinical study called INTEGRIS-IPF that was published in the American Journal of Respiratory and Critical Care Medicine in 2024. This study looked at a medicine called bexotegrast (beck-so-teh-grast) as a possible treatment for idiopathic pulmonary fibrosis (i-dee-uh-pa-thick pul-muh-ner-ee fie-bro-sis; IPF). Bexotegrast is an investigational medicine, which means that it is being studied and has not yet been approved by the US Food and Drug Administration (FDA), for people with IPF to take as a treatment. IPF is a chronic, progressive lung disease that makes it hard to breathe and gets worse over time. There is no cure for IPF, treatment includes symptom management and consideration for the use of nintedanib or pirfenidone , which may decrease the pace of disease progression.The study compared bexotegrast to a placebo (a treatment that looks identical to the medicine but has no medicinal effect) to look at how well it works and how safe it is in treating people with IPF. Most people in the study also took one of two medicines that are already approved by the FDA for IPF, pirfenidone or nintedanib .

Background: Interstitial pneumonia with autoimmune features (IPAF) has features of connective tissue disease-associated interstitial lung disease (CTD-ILD), but without meeting criteria for a specific CTD. We compared baseline characteristics, survival, and response to treatment of IPAF to both CTD-ILD and unclassifiable ILD., Methods: Measurements were extracted from a prospective registry. Baseline features and survival were compared in IPAF against both CTD-ILD and unclassifiable ILD. Linear trajectory of lung function decline (%-predicted forced vital capacity [FVC%] and diffusion capacity of the lung for carbon monoxide [DLCO%]) before and after initiation of mycophenolate or azathioprine were compared in IPAF against both CTD-ILD and unclassifiable ILD using linear mixed models., Results: Compared to CTD-ILD (n = 1240), patients with IPAF (n = 128) were older, more frequently male, and had greater smoking history. Compared to unclassifiable ILD (n = 665), patients with IPAF were younger, more frequently female, and had worse baseline lung function. IPAF had higher mortality compared to CTD-ILD and similar risk of mortality compared to unclassifiable ILD. Mycophenolate initiation was associated with stabilization of FVC% and DLCO% in all ILD subtypes except for FVC% in patients with IPAF, and azathioprine initiation with stabilization of FVC% and DLCO% in all ILD subtypes except for FVC% decline in IPAF and DLCO% decline in CTD-ILD., Conclusion: Patients with IPAF had worse survival compared to those with CTD-ILD and similar mortality to unclassifiable ILD, with treatment being associated with stabilization in lung function in all three ILDs. It is uncertain whether IPAF should be considered a distinct ILD diagnostic subgroup., Competing Interests: Declaration of competing interest CJR, NK, KAJ, DA, HM, JF, MK, NH, SV report personal fees from Boehringer Ingelheim. Conflict of interest: SV reports no conflicts of interest relevant to this manuscript. Conflict of interest: JA reports no conflicts of interest relevant to this manuscript. Conflict of interest: BZ reports no conflicts of interest relevant to this manuscript. Conflict of interest: K. Donohoe reports no conflicts of interest relevant to this manuscript. Conflict of interest: N. Hambly reports grants from Roche and Janssen; personal fees from Roche, Boehringer Ingelheim, GSK and Janssen. Conflict of interest: K.A. Johannson reports grants from Three Lakes and University Hospital Foundation. K.J. reports consulting fees from Boehringer-Ingelheim, Hoffman-La Roche Ltd, Pliant Therapeutics, Three Lakes, Thyron and Brainomix. Conflict of interest: D. Assayag reports no conflicts of interest relevant to this manuscript. Conflict of interest: J. Fisher reports no conflicts of interest relevant to this manuscript. Conflict of interest: V. Marcoux reports personal fees from Boehringer Ingelheim Canada and Hoffman-La Roche Ltd and Astra Zeneca, grants from the University of Saskatchewan, Boehringer Ingelheim, Astra Zeneca and Hoffman-La Roche. VM reports consulting fees from Boehringer Ingelheim Canada and Hoffman-La Roche Ltd. Conflict of interest: H. Manganas reports grants from Boehringer Ingelheim Canada, Hoffmann La Roche, Galapagos, BMS. Conflict of interest: N. Khalil reports no conflicts of interest relevant to this manuscript. Conflict of interest: M. Kolb reports consulting fees from Boehringer Ingelheim, Roche, Horizon, Cipla Abbvie, Bellerophon, Algernon, CSL Behring, United Therapeutics, LabCorp, Structure Therapeutics and Astra Zeneca. M. Kolb reports grants from Boehringer Ingelheim, United Therapeutics and Structure Therapeutics. M. Kolb reports payment for expert testimony from Roche. Conflict of interest: C.J. Ryerson reports grants from Boehringer Ingelheim; consulting fees from Boehringer Ingelheim, Trevi Therapeutics, Pliant Therapeutics, Astrazeneca and Veracyte., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: We aimed to assess the available evidence for corticosteroids in fibrotic interstitial lung disease (fILD) to inform the randomised embedded multifactorial adaptive platform ILD., Design: Systematic review and meta-analysis., Data Sources: We searched Embase, Medline, Cochrane CENTRAL and Web of Science databases from inception to April 17 2023., Eligibility Criteria: We included studies that compared corticosteroids with standard care, placebo or no treatment in adult patients with fILD., Data Extraction and Synthesis: We report on the change in forced vital capacity (FVC) and mortality. We used random-effects meta-analysis to estimate relative risk (RR) for dichotomous outcomes, and mean difference (MD) and standardised MDs for continuous outcomes, with 95% CIs., Results: Of the 13 229 unique citations identified, we included 10 observational studies comprising 1639 patients. Corticosteroids had an uncertain effect on mortality compared with no treatment (RR 1.03 (95% CI 0.85 to 1.25); very low certainty evidence). The effect of corticosteroids on the rate of decline in FVC (% predicted) was uncertain when compared with no treatment (MD 4.29% (95% CI -8.26% to 16.83%); very low certainty evidence). However, corticosteroids might reduce the rate of decline in FVC in patients with non-idiopathic pulmonary fibrosis (IPF) fILD (MD 10.89% (95% CI 5.25% to 16.53%); low certainty evidence), while an uncertain effect was observed in patients with IPF (MD -3.80% (95% CI -8.94% to 1.34%); very low certainty evidence)., Conclusions: The current evidence on the efficacy and safety of corticosteroids in fILD is limited and of low certainty. Randomised trials are needed to address this significant research gap., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Hypoxemia in fibrotic interstitial lung disease (ILD) indicates disease progression and is of prognostic significance. The onset of hypoxemia signifies disease progression and predicts mortality in fibrotic ILD. Accurately predicting new-onset exertional and resting hypoxemia prompts appropriate patient discussion and timely consideration of home oxygen. Objectives: We derived and externally validated a risk prediction tool for both new-onset exertional and new-onset resting hypoxemia. Methods: This study used ILD registries from Canada for the derivation cohort and from Australia and the United States for the validation cohort. New-onset exertional and resting hypoxemia were defined as nadir oxyhemoglobin saturation < 88% during 6-minute-walk tests, resting oxyhemoglobin saturation < 88%, or the initiation of ambulatory or continuous oxygen. Candidate predictors included patient demographics, ILD subtypes, and pulmonary function. Time-varying Cox regression was used to identify the top-performing prediction model according to Akaike information criterion and clinical usability. Model performance was assessed using Harrell's C-index and goodness-of-fit (GoF) likelihood ratio test. A categorized risk prediction tool was developed. Results: The best-performing prediction model for both new-onset exertional and new-onset resting hypoxemia included age, body mass index, a diagnosis of idiopathic pulmonary fibrosis, and percent predicted forced vital capacity and diffusing capacity of carbon monoxide. The risk prediction tool exhibited good performance for exertional hypoxemia (C-index, 0.70; GoF, P  = 0.85) and resting hypoxemia (C-index, 0.77; GoF, P  = 0.27) in the derivation cohort, with similar performance in the validation cohort except calibration for resting hypoxemia (GoF, P  = 0.001). Conclusions: This clinically applicable risk prediction tool predicted new-onset exertional and resting hypoxemia at 6 months in the derivation cohort and a diverse validation cohort. Suboptimal GoF in the validation cohort likely reflected overestimation of hypoxemia risk and indicated that the model is not flawed because of underestimation of hypoxemia.

Background: Clinical practice guidelines separately describe radiologic patterns of usual interstitial pneumonia (UIP) and fibrotic hypersensitivity pneumonitis (fHP), without direction on whether or how to apply these approaches concurrently within a single patient., Research Question: How can we integrate guideline-defined radiologic patterns to diagnose interstitial lung disease (ILD) and what are the pitfalls associated with described patterns that require reassessment in future guidelines?, Study Design and Methods: Patients from the Canadian Registry for Pulmonary Fibrosis underwent detailed reevaluation in standardized multidisciplinary discussion. CT scan features were quantified by chest radiologists masked to clinical data, and guideline-defined patterns were assigned. Clinical data then were provided to the radiologist and an ILD clinician, who jointly determined the leading diagnosis., Results: Clinical-radiologic diagnosis in 1,593 patients was idiopathic pulmonary fibrosis (IPF) in 26%, fHP in 12%, connective tissue disease-associated ILD (CTD-ILD) in 34%, idiopathic pneumonia with autoimmune features in 12%, and unclassifiable ILD in 10%. Typical and probable UIP patterns corresponded to a diagnosis of IPF in 66% and 57% of patients, respectively. Typical fHP pattern corresponded to an fHP clinical diagnosis in 65% of patients, whereas compatible fHP was nonspecific and associated with CTD-ILD or IPAF in 48% of patients. No pattern ruled out CTD-ILD. Gas trapping affecting > 5% of lung parenchyma on expiratory imaging was an important feature broadly separating compatible and typical fHP from other patterns (sensitivity, 0.77; specificity, 0.91)., Interpretation: An integrated approach to guideline-defined UIP and fHP patterns is feasible and supports > 5% gas trapping as an important branch point. Typical or probable UIP and typical fHP patterns have moderate predictive values for a corresponding diagnosis of IPF and fHP, although occasionally confounded by CTD-ILD; compatible fHP is nonspecific., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Millions of workers are exposed to substances known to cause occupational interstitial lung diseases (ILDs), particularly in developing countries. However, the burden of the disease is likely to be underestimated due to under-recognition, under-reporting or both. The diagnosis of occupational ILD requires a high level of suspicion and a thorough occupational history, as occupational and non-occupational ILDs may be clinically, functionally and radiologically indistinguishable, leading to delayed diagnosis and inappropriate management. A potential occupational aetiology should always be considered in the differential diagnosis of ILD, as removal from the workplace exposure, with or without treatment, is a key therapeutic intervention and may lead to significant improvement. In this article, we provide an overview of the 'traditional' inorganic dust-related ILDs but also address idiopathic pulmonary fibrosis and the immunologically mediated chronic beryllium disease, sarcoidosis and hypersensitivity pneumonitis, with emphasis on the importance of surveillance and prevention for reducing the burden of these conditions. To this end, health-care professionals should be specifically trained about the importance of occupational exposures as a potential cause of ILD., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background: Despite the known benefits of pulmonary rehabilitation (PR) for patients with chronic respiratory disease, this treatment is underused. Evidence-based guidelines should lead to greater knowledge of the proven benefits of PR, highlight the role of PR in evidence-based health care, and in turn foster referrals to and more effective delivery of PR for people with chronic respiratory disease. Methods: The multidisciplinary panel formulated six research questions addressing PR for specific patient groups (chronic obstructive pulmonary disease [COPD], interstitial lung disease, and pulmonary hypertension) and models for PR delivery (telerehabilitation, maintenance PR). Treatment effects were quantified using systematic reviews. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to formulate clinical recommendations. Recommendations: The panel made the following judgments: strong recommendations for PR for adults with stable COPD (moderate-quality evidence) and after hospitalization for COPD exacerbation (moderate-quality evidence), strong recommendation for PR for adults with interstitial lung disease (moderate-quality evidence), conditional recommendation for PR for adults with pulmonary hypertension (low-quality evidence), strong recommendation for offering the choice of center-based PR or telerehabilitation for patients with chronic respiratory disease (moderate-quality evidence), and conditional recommendation for offering either supervised maintenance PR or usual care after initial PR for adults with COPD (low-quality evidence). Conclusions: These guidelines provide the basis for evidence-based delivery of PR for people with chronic respiratory disease.

Interstitial lung disease (ILD) is a diverse group of inflammatory and fibrotic lung conditions causing significant morbidity and mortality. A multitude of factors beyond the lungs influence symptoms, health-related quality of life, disease progression and survival in patients with ILD. Despite an increasing emphasis on multidisciplinary management in ILD, the absence of a framework for assessment and delivery of comprehensive patient care poses challenges in clinical practice. The treatable traits approach is a precision medicine care model that operates on the premise of individualised multidimensional assessment for distinct traits that can be targeted by specific interventions. The potential utility of this approach has been described in airway diseases, but has not been adequately considered in ILD. Given the similar disease heterogeneity and complexity between ILD and airway diseases, we explore the concept and potential application of the treatable traits approach in ILD. A framework of aetiological, pulmonary, extrapulmonary and behavioural and lifestyle treatable traits relevant to clinical care and outcomes for patients with ILD is proposed. We further describe key research directions to evaluate the application of the treatable traits approach towards advancing patient care and health outcomes in ILD., Competing Interests: Conflict of interest: Y.H. Khor reports grants from NHMRC (investigator grant), during the conduct of the study; nonfinancial support from Air Liquide Healthcare, outside the submitted work. V. Cottin reports an unrestricted grant from Boehringer Ingelheim (paid to institution), consulting fees from AstraZeneca, Boehringer Ingelheim, Celgene/BMS, CSL Behring, Ferrer/United Therapeutics, GSK, Pliant, Pure Tech, RedX, Roche, Sanofi and Shionogi, fees for lectures and consulting from Boehringer Ingelheim, Ferrer/United Therapeutics and Roche, support for attending meetings from Boehringer Ingelheim and Roche, participation on a data and safety monitoring board for Galapagos and Galecto, and participation on a an adjudication committee for Fibrogen, outside the submitted work. A.E. Holland has nothing to disclose. Y. Inoue reports grants from Japanese Ministry of Health, Labour, and Welfare, grants from Japan Agency for Medical Desearch and Development, advisory board participation and lecture fees from Boehringer Ingelheim, Inc., lecture fees from Shionogi & Co Ltd, Kyorin Pharmaceutical Co Ltd, GSK and Novartis, and advisory board participation for Roche/Promedior, Galapagos, Taiho pharma, CSL Behring and Vicore Pharma, outside the submitted work. V.M. McDonald reports personal fees from GlaxoSmithKline, AstraZeneca and Arterial Group, grants from Ramaciotti Foundation Grant, MRFF, JHH Charitable Trust and NHMRC, outside the submitted work. J. Oldham reports grants from National Institutes of Health and Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, Roche/Genentech, Lupin Pharmaceuticals and Gatehouse Bio, and data monitoring committee participation for Novartis, Endeavor BioMedicines and Genenetch, outside the submitted work. E.A. Renzoni reports a research grant from Boehringer Ingelheim (paid to institution), payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boeringher Ingelheim, Roche and Chiesi, support for attending meetings and/or travel from Boehringer Ingelheim, and advisory board participation for Boeringher Ingelheim and Roche, outside the submitted work. A.M. Russell reports lecture fees from Boehringer Ingelheim, Hoffman La Roche, Irish Lung Fibrosis Association, Respiratory Professional Care and the Interstitial Lung Disease Interdisciplinary Network, educational resource development for Boehringer Ingelheim, and consultancy for Hoffman La Roche, Irish Lung Fibrosis Association, Respiratory Professional Care and the Interstitial Lung Disease Interdisciplinary Network, outside the submitted work. M.E. Strek reports grants or contracts from Boehringer Ingelheim and Pulmonary Fibrosis Foundation, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim and American College of Chest Physicians, and participation on Fibrogen adjudication committee, outside the submitted work; and is part of the Chair Scientific Review Committee of the Pulmonary Fibrosis Foundation. C.J. Ryerson reports grants and personal fees from Boehringer Ingelheim and Hoffmann-La Roche, personal fees from Veracyte, Pliant Therapeutics, AstraZeneca, Trevi Therapeutics and Cipla Ltd, and grants from VIDA diagnostics, outside the submitted work., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: Many patients use the internet as a source of health information. Sarcoidosis is a complex disease, and internet resources have not yet been analyzed for reliability and content on sarcoidosis., Aims: Our study aimed to investigate the content and the quality of information on sarcoidosis provided by internet resources., Methods: Google, Yahoo, and Bing were searched for the term "sarcoidosis," and the first 200 hits were saved in each case. Those websites that met the inclusion criteria (English language, no registration fees, and relevant to sarcoidosis) were then analyzed by two independent investigators for readability, quality (HON, JAMA, and DISCERN), and content (25 predefined key facts) of the provided information., Results: The websites were most commonly scientific or governmental ( n = 57, 46%), and the median time since the last update was 24 months. Quality was rated with a median JAMA score of 2 (1; 4) and a median overall DISCERN score of 2.4 (1.1; 4.1), both scores represent partially sufficient information. In total, 15% of websites had a HON certificate. Website content measured by the median key fact score was 19 (ranging from 2.5 to 25) with the lowest scores for acute vs. chronic course of the disease, screening for extrapulmonary disease, and diffuse body pain. Poor results were achieved in industry websites and blogs ( p = 0.047) with significant differences regarding definition ( p = 0.004) and evaluation ( p = 0.021)., Discussion: Sarcoidosis-related content of internet resources is partially sufficient; however, several important aspects are frequently not addressed, and the quality of information is moderate. Future directions should focus on providing reliable and comprehensive information on sarcoidosis; physicians from different disciplines and patients including self-support groups should collaborate on achieving this., Competing Interests: KB received payment for lectures from Boehringer Ingelheim and a grant from Sarkoidose-Netzwerk e.V. JF has received grant funding from the University of Toronto and the Canadian Pulmonary Fibrosis Foundation and has received honoraria from Boehringer Ingelheim and AstraZeneca. CR reports grants from Boehringer Ingelheim and Hoffman la Roche; consulting fees from Boehringer Ingelheim, Hoffman la Roche, Astra Zeneca, Veracyte, Ensho, and Pliant Therapeutics; payment for lectures from Boehringer Ingelheim, Hoffman la Roche, and Cipla Ltd.; and support for attending meetings from Cipla Ltd., and Boehringer Ingelheim (unrelated to this submission). FH reports payment for lectures from Astra Zeneca, GSK, and Chiesi and is a part of the Data Safety Monitoring Board from Apogenix. MK reports grants, consulting fees, and payment for lectures from Boehringer Ingelheim and Roche. KK was employed by Limbach Gruppe SE. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Buschulte, Höger, Ganter, Wijsenbeek, Kahn, Kriegsmann, Wilkens, Fisher, Ryerson, Herth and Kreuter.)

Objectives: We sought to 1) identify long COVID phenotypes based on patient reported outcome measures (PROMs) and 2) determine whether the phenotypes were associated with quality of life (QoL) and/or lung function., Methods: This was a longitudinal cohort study of hospitalized and non-hospitalized patients from March 2020 to January 2022 that was conducted across 4 Post-COVID Recovery Clinics in British Columbia, Canada. Latent class analysis was used to identify long COVID phenotypes using baseline PROMs (fatigue, dyspnea, cough, anxiety, depression, and post-traumatic stress disorder). We then explored the association between the phenotypes and QoL (using the EuroQoL 5 dimensions visual analogue scale [EQ5D VAS]) and lung function (using the diffusing capacity of the lung for carbon monoxide [DLCO])., Results: There were 1,344 patients enrolled in the study (mean age 51 ±15 years; 780 [58%] were females; 769 (57%) were of a non-White race). Three distinct long COVID phenotypes were identified: Class 1) fatigue and dyspnea, Class 2) anxiety and depression, and Class 3) fatigue, dyspnea, anxiety, and depression. Class 3 had a significantly lower EQ5D VAS at 3 (50±19) and 6 months (54 ± 22) compared to Classes 1 and 2 (p<0.001). The EQ5D VAS significantly improved between 3 and 6 months for Class 1 (median difference of 6.0 [95% CI, 4.0 to 8.0]) and Class 3 (median difference of 5.0 [95% CI, 0 to 8.5]). There were no differences in DLCO between the classes., Conclusions: There were 3 distinct long COVID phenotypes with different outcomes in QoL between 3 and 6 months after symptom onset. These phenotypes suggest that long COVID is a heterogeneous condition with distinct subpopulations who may have different outcomes and warrant tailored therapeutic approaches., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Wong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is challenging to manage, with a paucity of robust data to guide treatment. Our aim was to characterize the pharmacologic treatment of RA-ILD utilizing a retrospective design in a national multi-center prospective cohort, and to identify associations between treatment and change in lung function and survival., Methods: Patients with RA-ILD and a radiological pattern of non-specific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) were included. Unadjusted and adjusted linear mixed models and Cox proportional hazards models were used to compare lung function change and risk of death or lung transplant by radiologic patterns and treatment., Results: Of 161 patients with RA-ILD, UIP pattern was more common than NSIP (55.9% vs. 44.1%). Only 44/161 (27%) patients were treated over median follow-up of 4 years with medication choice appearing unrelated to patient-specific variables. Decline in forced vital capacity (FVC) was not associated with treatment. Patients with NSIP had lower risk of death or transplant, compared to UIP (P=0.0042). In patients with NSIP, there was no difference in time to death or transplant comparing treated to untreated in adjusted models [hazard ratio (HR) =0.73; 95% confidence interval (CI): 0.15-3.62; P=0.70]. Similarly, in patients with UIP, there was no difference in time to death or lung transplant between treated and untreated in adjusted models (HR =1.06; 95% CI: 0.49-2.28; P=0.89)., Conclusions: Treatment of RA-ILD is heterogeneous, with most patients in this cohort not receiving treatment. Patients with UIP had worse outcomes compared to NSIP, similar to other cohorts. Randomized clinical trials are needed to inform pharmacologic therapy in this patient population., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1820/coif). All authors report that Canadian Registry for Pulmonary Fibrosis is sponsored by Boehringer Ingelheim Canada but it has had no influence on this study design/manuscript. VM reports personal fees from Boehringer Ingelheim Canada and Hoffman-La Roche Ltd., and Astra Zeneca, grants from the University of Saskatchewan, Royal University Hospital Foundation, Boehringer Ingelheim, Astra Zeneca and Hoffman-La Roche. SL reports consulting fees and moderator honoraria from Boehringer-Ingelheim and a grant from the University of Saskatchewan. SL has served on prior advisory boards of Boehringer-Ingelheim. DA reports consulting fees from Boehringer-Ingelheim and Hoffman-La Roche, payments for a lecture from Boehringer-Ingelheim, and research grants from Boehringer Ingelheim. JHF reports grants from the Canadian Pulmonary Fibrosis Foundation and the University of Toronto, and personal fees from Boehringer-Ingelheim and AstraZeneca, outside the submitted work. JHF serves as an unpaid medical advisory board member of Canadian Pulmonary Fibrosis Foundation. SS reports advisory board participation and personal fees from Boehringer-Ingelheim, Hoffman-La Roche, and AstraZeneca. JM reports personal fees from Boehringer-Ingelheim and Hoffman-La Roche. HM reports research grants from Boehringer-Ingelheim, Galapagos, BMS and Hoffman-La Roche, personal fees from Boehringer-Ingelheim, and participates on an advisory board for Boehringer Ingelheim. CDF reports educational grants and research grants from Boehringer-Ingelheim, Roche and the Canadian Pulmonary Fibrosis Foundation; personal fees from Roche and Boehringer Ingelheim; Chair of the Board for the Canadian Pulmonary Fibrosis Foundation. NH reports research grants from Boehringer-Ingelheim and Janssen, and personal fees from Boehringer-Ingelheim, Janssen, and Hoffman-La Roche. MK serves as an unpaid editorial board member of Journal of Thoracic Disease. MK reports grants from Boehringer-Ingelheim, Hoffman-La Roche and Pieris, personal fees from Boehringer Ingelheim, Hoffman-La Roche, Horizon, Cipla, Abbvie, Bellerophon, Algernon, CSL Behring, United Therapeutics Novartis and LabCorp, participation on the advisory board of United Therapeutics Novartis and LabCorp, and allowance for serving as Chief Editor of the European Respiratory Journal. MS reports honoraria for attending symposia from Boehringer-Ingelheim. AWW reports speaker’s honoraria from Boehringer-Ingelheim and AstraZeneca. PGW reports payment for presentation from Vertex. PGW is a member of the Cystic Fibrosis Foundation Drug Safety Monitoring Board. CJR reports personal fees from Boehringer-Ingelheim, Hoffman-La Roche, Veracyte, AstraZeneca, Pliant Therapeutics, Cipla Ltd., and Ensho Health. KAJ reports grants from University Hospital Foundation, Three Lakes Foundation and University oof Calgary CSM, and personal fees from Boehringer-Ingelheim, Hoffman-La Roche, Pliant Therapeutics and Three Lakes Foundation. KAJ is a member of the board for PFOX Trial. The authors have no other conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Background: Little is known about generalisability of randomised controlled trials (RCTs) for idiopathic pulmonary fibrosis (IPF). We evaluated eligibility criteria for phase III IPF RCTs to determine their representativeness in clinical registries, and calculated forced vital capacity (FVC) changes according to eligibility criteria., Methods: Common eligibility criteria used in >60% of IPF RCTs were identified from a literature search and applied to patients with IPF from prospective Australian and Canadian registries. Additional pre-specified criteria of 6-min walk distance (6MWD) and different measures of preceding disease progression were also evaluated. Joint longitudinal-survival modelling was used to compare FVC decline according to eligibility for individual and composite criteria., Results: Out of 990 patients with IPF, 527 (53%) met all common RCT eligibility criteria at the first clinic visit, including 343 with definite IPF and 184 with radiological probable usual interstitial pneumonia pattern without histological confirmation ( i.e. provisional IPF). The percentages of eligible patients for landmark RCTs of nintedanib and pirfenidone were 19-50%. Adding 6MWD ≥150 m and different measures of preceding disease progression to the composite common criteria reduced the percentages of patients meeting eligibility to 52% (n=516) and 4-18% (n=12-61), respectively. Patients meeting the composite common criteria had less-rapid 1-year FVC decline than those who did not (-90 versus -103 mL, p=0.01). Definite IPF generally had more-rapid 1-year FVC decline compared to provisional IPF., Conclusions: Eligibility criteria of previous IPF RCTs have limited generalisability to clinical IPF populations, with FVC decline differing between eligible and ineligible populations., Competing Interests: Conflict of interest: Y.H. Khor reports fellowship support from NHMRC Investigator Grant, and support for the CARE-PF registry (with no influence on this study) from Boehringer Ingelheim, during the conduct of the study. K.A. Johannson reports personal fees, non-financial support and other from Boehringer Ingelheim, personal fees from Hoffman-La Roche Ltd, Pliant Therapeutics and Thyron, grants from University Hospital Foundation, Pulmonary Fibrosis Society of Calgary and University of Calgary Cumming School of Medicine, and personal fees and non-financial support from Three Lakes Foundation, outside the submitted work. V. Marcoux reports grants from Boehringer Ingelheim, during the conduct of the study; grants from University of British Columbia and Boehringer Ingelheim, outside the submitted work. J.H. Fisher reports grants from Boehringer Ingelheim, during the conduct of the study; grants from Canadian Pulmonary Fibrosis Foundation and University of Toronto, and personal fees from Boehringer Ingelheim and AstraZeneca, outside the submitted work. D. Assayag reports grants from Boehringer Ingelheim Canada, and lecture honoraria from Boehringer Ingelheim and Hoffman La Roche, outside the submitted work. H. Manganas reports support for the present manuscript from University of British Columbia; grants from Boehringer Ingelheim Canada, Hoffmann La Roche, Galapagos and BMS, honoraria for educational events from Boehringer Ingelheim Canada, and advisory board membership for Boehringer Ingelheim Canada, outside the submitted work. M. Kolb reports grants from Boehringer Ingelheim, Pieris and Roche, consulting fees from Boehringer Ingelheim, Roche, Horizon, Cipla, Abbvie, Bellerophon, Algernon, CSL Behring, United Therapeutics and LabCorp, lecture honoraria from Roche, Novartis and Boehringer Ingelheim, payment for expert testimony from Roche, advisory board participation with United Therapeutics and LabCorp, and reports an editorial allowance from ERJ, outside the submitted work. C.J. Ryerson reports grants from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from Boehringer Ingelheim and Hoffmann-La Roche, and personal fees from Veracyte, Pliant Therapeutics, AstraZeneca and Cipla Ltd, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT , RTEL1 , common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Background: Biological sex, gender, and race are important considerations in patients with interstitial lung diseases (ILDs)., Research Question: Does a patient's sex assigned at birth, and race, influence ILD treatment initiation?, Study Design and Methods: Patients with ILD from three longitudinal prospective registries were compared in this observational study. ILD-related medications included antifibrotics and immunomodulating medications. Race was dichotomized as "White" vs "non-White." Time to treatment initiation was determined from the date of the initial ILD registry visit to the date of first medication initiation. Proportions of treated patients were compared between groups by χ 2 test. Cox proportional analysis was used to determine how sex and race were associated with time to treatment initiation stratified by ILD diagnosis., Results: A total of 4,572 patients were included across all cohorts. The proportion of men who received treatment was higher than for women in the Canadian cohort (47% vs 40%; P < .001), and the proportion of White patients who received treatment was also higher compared with non-White patients (46% vs 36%; P < .001). In contrast, the proportion of treated men in the Chicago cohort was lower compared with women (56% vs 64%; P = .005), and that of White patients was lower compared with non-White patients (56% vs 69%; P < .001). No sex- or race-based differences in proportions of patients treated were found in the Australasian cohort. White race was significantly associated with earlier treatment initiation compared with non-White race across diagnoses in the Canadian cohort, whereas the opposite association was found in the Australasian cohort., Interpretation: Sex- and race-based differences exist in the initiation of ILD treatment, with variability across different cohorts in different countries. Reasons for these differences need to be further explored in future studies., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Exploration of cytokine levels in systemic sclerosis-associated interstitial lung disease (SSc-ILD) and idiopathic pulmonary fibrosis (IPF) is needed to find common and diverse biomolecular pathways. Circulating levels of 87 cytokines were compared amongst 19 healthy controls and consecutive patients with SSc-ILD (n = 39), SSc without ILD (n = 29), and IPF (n = 17) recruited from a Canadian centre using a log-linear model adjusted for age, sex, baseline forced vital capacity (FVC), and immunosuppressive or anti-fibrotic treatment at time of sampling. Also examined was annualized change in FVC. Four cytokines had Holm's corrected p-values less than 0.05. Eotaxin-1 levels were increased approximately two-fold in all patient categories compared to healthy controls. Interleukin-6 levels were eight-fold higher in all ILD categories compared to healthy controls. MIG/CXCL9 levels increased two-fold more in all but one patient category compared to healthy controls. Levels of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13, (ADAMTS13) were lower for all categories of patients compared to controls. No substantial association was found for any of the cytokines with FVC change. Observed cytokine differences suggest both common and diverse pathways leading to pulmonary fibrosis. Further studies evaluating longitudinal change of these molecules would be informative., (© 2023. The Author(s).)