E-Cigarette or Vaping Product Use-associated Lung Injury: Developing a Research Agenda. An NIH Workshop Report.

The NHLBI convened a working group on October 23, 2019, to identify the most relevant and urgent research priorities and prevailing challenges in e-cigarette or vaping product use-associated lung injury (EVALI). Experts across multiple disciplines discussed the complexities of the EVALI outbreak, identified research priorities, and recommended strategies to address most effectively its causal factors and improve diagnosis, treatment, and prevention of this disease. Many research priorities were identified, including the need to create national and international registries of patients with EVALI, to track accurately those affected and assess outcomes. The group concluded that biospecimens from subjects with EVALI are urgently needed to help define EVALI pathogenesis and that vaping has disease risks that are disparate from smoking, with the occurrence of EVALI highlighting the importance of broadening e-cigarette research beyond comparators to smoking-related diseases.

How Small Differences in Assessed Clinical Performance Amplify to Large Differences in Grades and Awards: A Cascade With Serious Consequences for Students Underrepresented in Medicine.

While students entering medical schools are becoming more diverse, trainees in residency programs in competitive specialties and academic medicine faculty have not increased in diversity. As part of an educational continuous quality improvement process at the University of California, San Francisco, School of Medicine, the authors examined data for the classes of 2013-2016 to determine whether differences existed between underrepresented in medicine (UIM) and not-UIM students' clinical performance (clerkship director ratings and number of clerkship honors grades awarded) and honor society membership-all of which influence residency selection and academic career choices.This analysis demonstrated differences that consistently favored not-UIM students. Whereas the size and magnitude of differences in clerkship director ratings were small, UIM students received approximately half as many honors grades as not-UIM students and were three times less likely to be selected for honor society membership.The authors use these findings to illustrate the amplification cascade, a phenomenon in which small differences in assessed performance lead to larger differences in grades and selection for awards. The amplification cascade raises concerns about opportunities for UIM students to compete successfully for competitive residency programs and potentially enter academic careers. Using a fishbone diagram, a continuous quality improvement root cause analysis tool, the authors contextualize their institutional results. They describe potential causes of group differences, drawing from the education disparities literature, and propose interventions and future research. They also share countermeasures adopted at their institution and encourage other medical schools to consider similar exploration of their institutional data.

Mortality Risk Prediction in Scleroderma-Related Interstitial Lung Disease: The SADL Model.

BACKGROUND: Interstitial lung disease (ILD) is an important cause of morbidity and mortality in patients with scleroderma (Scl). Risk prediction and prognostication in patients with Scl-ILD are challenging because of heterogeneity in the disease course. METHODS: We aimed to develop a clinical mortality risk prediction model for Scl-ILD. Patients with Scl-ILD were identified from two ongoing longitudinal cohorts: 135 patients at the University of California, San Francisco (derivation cohort) and 90 patients at the Mayo Clinic (validation cohort). Using these two separate cohorts, a mortality risk prediction model was developed and validated by testing every potential candidate Cox model, each including three or four variables of a possible 19 clinical predictors, for time to death. Model discrimination was assessed using the C-index. RESULTS: Three variables were included in the final risk prediction model (SADL): ever smoking history, age, and diffusing capacity of the lung for carbon monoxide (% predicted). This continuous model had similar performance in the derivation (C-index, 0.88) and validation (C-index, 0.84) cohorts. We created a point scoring system using the combined cohort (C-index, 0.82) and used it to identify a classification with low, moderate, and high mortality risk at 3 years. CONCLUSIONS: The SADL model uses simple, readily accessible clinical variables to predict all-cause mortality in Scl-ILD.

The performance of the GAP model in patients with rheumatoid arthritis associated interstitial lung disease.

BACKGROUND: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is associated with significant morbidity and mortality. Similarities have been observed between patients with idiopathic pulmonary fibrosis (IPF) and the UIP (usual interstitial pneumonia) form of RA-ILD. The GAP (gender, age, physiology) model has been shown to predict mortality in patients with IPF, but its ability to predict mortality in RA-ILD is not known. METHODS: We identified 309 patients with RA-ILD at 4 academic centers with ongoing longitudinal cohorts of patients with ILD. The primary endpoint was mortality. To handle missing data (n = 219 subjects with complete dataset), multiple imputation by iterative chained equations was used. Using the GAP model as a baseline, we assessed improvements in mortality risk prediction achieved by incorporating additional variables. Model discrimination was assessed using the c-index, and calibration was checked by comparing observed and expected incidence of death. RESULTS: Patients had a mean age of 65 years and were predominantly female (54%). The mean forced vital capacity (FVC) % predicted was 73 and the mean diffusing capacity for carbon monoxide (DLCO) % predicted was 55. Twenty-four percent of the 236 patients with a high-resolution computed tomography scan available for review had a definite UIP pattern. The original GAP model, including gender, age, FVC%, and DLCO%, had a c-index of 0.746 in our cohort. Calibration of this model was satisfactory at 1, 2 and 3 years. Model discrimination was not meaningfully improved by adding other clinical variables. CONCLUSION: The GAP model that was derived for IPF performs similarly as a mortality risk prediction tool in RA-ILD.

The use of pretest probability increases the value of high-resolution CT in diagnosing usual interstitial pneumonia.

BACKGROUND: Recent studies have suggested that non-definitive patterns on high-resolution CT (HRCT) scan provide sufficient diagnostic specificity to forgo surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine test characteristics of non-definitive HRCT patterns for identifying histopathological usual interstitial pneumonia (UIP). METHODS: Patients with biopsy-proven interstitial lung disease (ILD) and non-definitive HRCT scans were identified from two academic ILD centres. Test characteristics for HRCT patterns as predictors of UIP on surgical lung biopsy were derived and validated in independent cohorts. RESULTS: In the derivation cohort, 64/385 (17%) had possible UIP pattern on HRCT; 321/385 (83%) had inconsistent with UIP pattern. 113/385 (29%) patients had histopathological UIP pattern in the derivation cohort. Possible UIP pattern had a specificity of 91.2% (95% CI 87.2% to 94.3%) and a positive predictive value (PPV) of 62.5% (95% CI 49.5% to 74.3%) for UIP pattern on surgical lung biopsy. The addition of age, sex and total traction bronchiectasis score improved the PPV. Inconsistent with UIP pattern demonstrated poor PPV (22.7%, 95% CI 18.3% to 27.7%). HRCT pattern specificity was nearly identical in the validation cohort (92.7%, 95% CI 82.4% to 98.0%). The substantially higher prevalence of UIP pattern in the validation cohort improved the PPV of HRCT patterns. CONCLUSIONS: A possible UIP pattern on HRCT has high specificity for UIP on surgical lung biopsy, but PPV is highly dependent on underlying prevalence. Adding clinical and radiographic features to possible UIP pattern on HRCT may provide sufficient probability of histopathological UIP across prevalence ranges to change clinical decision-making.

Early Experiences After Adopting a Quality Improvement Portfolio Into the Academic Advancement Process.

PROBLEM: Academic medical centers (AMCs) and their academic departments are increasingly assuming leadership in the education, science, and implementation of quality improvement (QI) and patient safety efforts. Fostering, recognizing, and promoting faculty leading these efforts is challenging using traditional academic metrics for advancement. APPROACH: The authors adapted a nationally developed QI portfolio, adopted it into their own department's advancement process in 2012, and tracked its utilization and impact over the first two years of implementation. OUTCOMES: Sixty-seven QI portfolios were submitted with 100% of faculty receiving their requested academic advancement. Women represented 60% of the submitted portfolios, while the Divisions of General Internal Medicine and Hospital Medicine accounted for 60% of the submissions. The remaining 40% were from faculty in 10 different specialty divisions. Faculty attitudes about the QI portfolio were overwhelmingly positive, with 83% agreeing that it "was an effective tool for helping to better recognize faculty contributions in QI work" and 85% agreeing that it "was an effective tool for elevating the importance of QI work in our department." NEXT STEPS: The QI portfolio was one part of a broader effort to create opportunities to recognize and support faculty involved in improvement work. Further adapting the tool to ensure that it complements-rather than duplicates-other elements of the advancement process is critical for continued utilization by faculty. This will also drive desired dissemination to other departments locally and other AMCs nationally who are similarly committed to cultivating faculty career paths in systems improvement.

A diagnostic model for chronic hypersensitivity pneumonitis.

The objective of this study was to develop a diagnostic model that allows for a highly specific diagnosis of chronic hypersensitivity pneumonitis using clinical and radiological variables alone. Chronic hypersensitivity pneumonitis and other interstitial lung disease cases were retrospectively identified from a longitudinal database. High-resolution CT scans were blindly scored for radiographic features (eg, ground-glass opacity, mosaic perfusion) as well as the radiologist's diagnostic impression. Candidate models were developed then evaluated using clinical and radiographic variables and assessed by the cross-validated C-statistic. Forty-four chronic hypersensitivity pneumonitis and eighty other interstitial lung disease cases were identified. Two models were selected based on their statistical performance, clinical applicability and face validity. Key model variables included age, down feather and/or bird exposure, radiographic presence of ground-glass opacity and mosaic perfusion and moderate or high confidence in the radiographic impression of chronic hypersensitivity pneumonitis. Models were internally validated with good performance, and cut-off values were established that resulted in high specificity for a diagnosis of chronic hypersensitivity pneumonitis.

Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis.

BACKGROUND: The assessment of treatment response in idiopathic pulmonary fibrosis (IPF) is complicated by the variable clinical course. We examined the variability in the rate of disease progression and evaluated the effect of continued treatment with pirfenidone in patients who experienced meaningful progression during treatment. METHODS: The source population included patients enrolled in the ASCEND and CAPACITY trials (N=1247). Pearson's correlation coefficients were used to characterise the relationship between changes in FVC during consecutive 6-month intervals in the placebo population. Outcomes following a ≥10% decline in FVC were evaluated by comparing the proportion of patients in the pirfenidone and placebo groups who experienced a ≥10% decline in FVC or death during the subsequent 6 months. RESULTS: A weak negative correlation was observed between FVC changes during consecutive intervals in the placebo population (coefficient, -0.146, p<0.001), indicating substantial variability. Thirty-four (5.5%) and 68 (10.9%) patients in the pirfenidone and placebo groups, respectively, experienced a ≥10% decline in FVC by month 6. During the subsequent 6 months, fewer patients in the pirfenidone group compared with placebo experienced a ≥10% decline in FVC or death (5.9% vs 27.9%; relative difference, 78.9%). There was one (2.9%) death in the pirfenidone group and 14 (20.6%) deaths in the placebo group (relative difference, 85.7%). CONCLUSIONS: Longitudinal FVC data from patients with IPF showed substantial intrasubject variability, underscoring the inability to reliably assess therapeutic response using serial FVC trends. In patients who progressed during treatment, continued treatment with pirfenidone resulted in a lower risk of subsequent FVC decline or death. TRIAL REGISTRATION NUMBERS: NCT01366209, NCT00287729, NCT00287716.

Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials.

BACKGROUND: Pirfenidone is an oral antifibrotic agent that has been shown to reduce the decline in lung function in patients with idiopathic pulmonary fibrosis (IPF). We performed an integrated analysis of safety data from five clinical trials evaluating pirfenidone in patients with IPF. METHODS: All patients treated with pirfenidone in the three multinational Phase 3 studies (CAPACITY (studies 004 and 006), ASCEND (study 016)) and two ongoing open-label studies (study 002 and study 012 (RECAP)) were included in the analysis. Safety outcomes were assessed during the period from the first dose until 28 days after the last dose of study drug. RESULTS: A total of 1299 patients were included in the analysis. The cumulative total exposure to pirfenidone was 3160 person exposure years (PEY). The median duration of exposure was 1.7 years (range 1 week to 9.9 years), and the mean (±SD) daily dose was 2053.8 (±484.9) mg. Gastrointestinal events (nausea (37.6%), diarrhoea (28.1%), dyspepsia (18.4%), vomiting (15.9%)) and rash (25.0%) were the most common adverse events; these were generally mild to moderate in severity and without significant clinical consequence. Elevations in alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal occurred in 40/1299 (3.1%) patients (adjusted incidence, 2.3 per 100 PEY). Elevations were generally transient and reversible with dose modification or discontinuation. CONCLUSIONS: A comprehensive analysis of safety outcomes in a large and well-defined cohort of 1299 patients with IPF who were followed prospectively for up to 9.9 years demonstrated that long-term treatment with pirfenidone is safe and generally well tolerated. TRIAL REGISTRATION NUMBERS: NCT00287716, NCT00287729, NCT00662038, NCT01366209.

Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials.

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression.All patients randomised to pirfenidone 2403 mg·day(-1) or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol.A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3-55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0-96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation.Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF.

American Thoracic Society-European Respiratory Society Classification of the Idiopathic Interstitial Pneumonias: Advances in Knowledge since 2002.

In the updated American Thoracic Society-European Respiratory Society classification of the idiopathic interstitial pneumonias (IIPs), the major entities have been preserved and grouped into (a) "chronic fibrosing IIPs" (idiopathic pulmonary fibrosis and idiopathic nonspecific interstitial pneumonia), (b) "smoking-related IIPs" (respiratory bronchiolitis-associated interstitial lung disease and desquamative interstitial pneumonia), (c) "acute or subacute IIPs" (cryptogenic organizing pneumonia and acute interstitial pneumonia), and (d) "rare IIPs" (lymphoid interstitial pneumonia and idiopathic pleuroparenchymal fibroelastosis). Furthermore, it has been acknowledged that a final diagnosis is not always achievable, and the category "unclassifiable IIP" has been proposed. The diagnostic interpretation of the IIPs is often challenging because other diseases with a known etiology (most notably, connective tissue disease and hypersensitivity pneumonitis) may show similar morphologic patterns. Indeed, more emphasis has been given to the integration of clinical, computed tomographic (CT), and pathologic findings for multidisciplinary diagnosis. Typical CT-based morphologic patterns are associated with the IIPs, and radiologists play an important role in diagnosis and characterization. Optimal CT quality and a systematic approach are both pivotal for evaluation of IIP. Interobserver variation for the various patterns encountered in the IIPs is an issue. It is important for radiologists to understand the longitudinal behavior of IIPs at serial CT examinations, especially for providing a framework for cases that are unclassifiable or in which a histologic diagnosis cannot be obtained.

Survival in interstitial pneumonia with features of autoimmune disease: a comparison of proposed criteria.

BACKGROUND: Some patients with chronic fibrosing interstitial pneumonia (IP) have clinical, serological, and morphological features suggestive of, but not diagnostic for, a connective tissue disease. Several names and diagnostic criteria for this entity have been proposed. The objective of this study was to compare the clinical characteristics and behavior of each of the proposed diagnostic criteria. METHODS: Patients with chronic fibrosing IP were identified from an ongoing, longitudinal cohort. Four published diagnostic criteria for what we generically label as "IP with features of autoimmunity" were applied to all patients to identify four unique cohorts (Kinder, Vij, Corte, and Fischer). Kaplan-Meier survival functions compared differences in survival in each cohort between patients meeting and not meeting criteria. Unadjusted and adjusted Cox proportional hazard regression models identified predictors of survival. RESULTS: The study cohort included 119 patients, 40% of whom were female. The mean age was 65.5 years. There was overlap between the four different criteria, identifying patients with similar clinical characteristics. Interstitial pneumonia patients with features of autoimmunity tended to have improved survival compared to those without these features (p-value range 0.03-0.10) on univariate analysis. After adjusting for disease severity using the gender-age-physiology score, only the Corte criteria was an independent predictor of survival (p-value 0.04). CONCLUSION: Interstitial pneumonia with features of autoimmunity may be associated with improved survival compared to those patients without these features depending on which criteria is used to define the population. These data support the efforts being made to standardize the definition.

The effect of bronchodilators on forced vital capacity measurement in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Forced vital capacity (FVC) is a key measure of disease severity in patients with idiopathic pulmonary fibrosis (IPF) and is an important clinical trial endpoint. We hypothesize that reversible airflow limitation co-exists in a subgroup of patients with IPF, and that bronchodilator use will improve the performance characteristics of FVC. METHODS: IPF patients with pre and post-bronchodilator spirometry testing performed were identified from two tertiary referral cohorts. The difference between pre and post-bronchodilator FVC (intra-test difference) was calculated. The test characteristics of pre and post-bronchodilator FVC change over time (inter-test difference) were assessed in patients with sequential spirometry, and were used to generate sample size estimates for hypothetical clinical trials using change in FVC as the primary endpoint. RESULTS: There were 551 patients, contributing 967 unique spirometry tests. The mean intra-test increase in FVC with bronchodilator use was 0.04 L (2.71 vs. 2.75 L, p < 0.001). Reversible airflow limitation (increase in FEV1 or FVC of ≥12% and ≥200 mL) occurred in 9.1% of patients. The inter-test difference in change in FVC over time were equivalent for pre and post-bronchodilator (p = 0.65), leading to similar sample size estimates in a hypothetical clinical trial using change in FVC as the primary endpoint. CONCLUSION: Approximately one in ten patients with IPF has physiological evidence of reversible airflow limitation, and bronchodilator use in these patients may improve the assessment of disease progression based on FVC change over time. Bronchodilator use does not appear to meaningfully impact the precision of FVC as an endpoint in clinical trials.

Validation of test performance characteristics and minimal clinically important difference of the 6-minute walk test in patients with idiopathic pulmonary fibrosis.

BACKGROUND: The 6-minute walk test distance (6MWD) has been shown to be a valid and responsive outcome measure in patients with idiopathic pulmonary fibrosis (IPF). The analyses were based, however, on a single phase 3 trial and require validation in an independent cohort. OBJECTIVE: To confirm the performance characteristics and estimates of minimal clinically important difference (MCID) of 6MWD in an independent cohort of patients with IPF. METHODS: Patients randomized to placebo in the phase 3 CAPACITY trials who had a baseline 6MWD measurement were included in these analyses. The 6MWD and other functional parameters (lung function, dyspnea, and health-related quality of life) were measured at baseline and 24-week intervals. Validity and responsiveness were examined using Spearman correlation coefficients. The MCID was estimated using distribution- and anchor-based methods. RESULTS: The analysis comprised 338 patients. Baseline 6MWD was significantly correlated with lung function measures, patient-reported outcomes, and quality-of-life measures (validity). Compared with baseline 6MWD, change in 6MWD (responsiveness) showed stronger correlations with change in lung function parameters and quality-of-life measures. Dyspnea measured by the University of California San Diego Shortness of Breath Questionnaire showed the strongest correlations with 6MWD (baseline: coefficient -0.35; 48-week change: coefficient -0.37; both p < 0.001). The distribution-based analyses of MCID using standard error of measurement yielded an MCID of 37 m, and distribution-based analyses by effect size resulted in 29.2 m. The MCID by anchor-based analysis using criterion referencing (health events of hospitalization or death) was 21.7 m. CONCLUSIONS: The 6MWD is a valid and responsive clinical endpoint, which provides objective and clinically meaningful information regarding functional status and near-term prognosis. These results confirm previous findings in an independent cohort of patients with IPF.

CT staging and monitoring of fibrotic interstitial lung diseases in clinical practice and treatment trials: a position paper from the Fleischner Society.

CT is increasingly being used to stage and quantify the extent of diffuse lung diseases both in clinical practice and in treatment trials. The role of CT in the assessment of patients entering treatment trials has greatly expanded as clinical researchers and pharmaceutical companies have focused their efforts on developing safe and effective drugs for interstitial lung diseases, particularly for idiopathic pulmonary fibrosis. These efforts have culminated in the simultaneous approval by the US Food and Drug Administration of two new drugs for the treatment of idiopathic pulmonary fibrosis. CT features are a key part of the inclusion criteria in many drug trials and CT is now being used to refine the type of patients enrolled. Interest in the potential use of serial CT as an effectiveness endpoint is increasing. For chronic progressive diseases, mortality may not be a feasible endpoint and many surrogate markers have been explored, ranging from pulmonary function decline to biomarkers. However, these surrogate markers are not entirely reliable and combinations of endpoints, including change in disease extent on CT, are being investigated. Methods to assess disease severity with CT range from simple visual estimates to sophisticated quantification by use of software. In this Position Paper, which cannot be regarded as a comprehensive set of guidelines in view of present knowledge, we examine the uses of serial CT in clinical practice and in drug trials and draw attention to uncertainties and challenges for future research.

A new era in idiopathic pulmonary fibrosis: considerations for future clinical trials.

The past decade has seen substantial progress in understanding the pathobiology, natural history, and clinical significance of idiopathic pulmonary fibrosis (IPF), culminating in the establishment of two effective medical therapies. Now seems an important time to reconsider the design and conduct of future IPF clinical trials. Building on lessons learned over the past decade, we use this perspective to lay out four key considerations for moving forward effectively and efficiently with the next generation of clinical trials in IPF. These are: development of a coordinated IPF clinical trials network; establishment of expectations for early phase proof of concept studies; adaptation of late-phase efficacy trial designs to the emergence of approved therapies, and; agreement on primary end-points for late phase clinical trials. Continued progress in the field of IPF will require creativity and collaboration on the part of all stakeholders. We believe that addressing these four considerations will encourage and enable investment in this new era of drug development in IPF, and will lead to more rapid development of effective therapies.

Sensitivity Analyses of the Change in FVC in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis.

BACKGROUND: FVC outcomes in clinical trials on idiopathic pulmonary fibrosis (IPF) can be substantially influenced by the analytic methodology and the handling of missing data. We conducted a series of sensitivity analyses to assess the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect on the primary end point of FVC change in a phase 3 trial evaluating pirfenidone in adults with IPF. METHODS: Source data included all 555 study participants randomized to treatment with pirfenidone or placebo in the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study. Sensitivity analyses were conducted to assess whether alternative statistical tests and methods for handling missing data influenced the observed magnitude of treatment effect on the primary end point of change from baseline to week 52 in FVC. RESULTS: The distribution of FVC change at week 52 was systematically different between the two treatment groups and favored pirfenidone in each analysis. The method used to impute missing data due to death had a marked effect on the magnitude of change in FVC in both treatment groups; however, the magnitude of treatment benefit was generally consistent on a relative basis, with an approximate 50% reduction in FVC decline observed in the pirfenidone group in each analysis. CONCLUSIONS: Our results confirm the robustness of the statistical finding on the primary end point of change in FVC in the ASCEND trial and corroborate the estimated magnitude of the pirfenidone treatment effect in patients with IPF. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01366209; URL: www.clinicaltrials.gov.

Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: analysis of a pooled cohort from three clinical trials.

BACKGROUND: Mortality is an impractical primary endpoint for clinical trials in patients with idiopathic pulmonary fibrosis who have mild-to-moderate physiological impairment because event rates are low. Change in forced vital capacity (FVC) is widely accepted as a surrogate for mortality and is the most common primary endpoint in clinical trials for this disorder. Use of hospital admission as a predictor for mortality, independent of FVC decline, has not been well defined. We aimed to ascertain the independent and combined association of hospital admission and at least a 10% decrease in FVC with all-cause mortality. METHODS: We did a pooled cohort study of 517 patients with idiopathic pulmonary fibrosis from three IPFnet multicentre randomised controlled trials. We compared the incidence of non-elective hospital admission and a 10% or greater reduction in FVC across strata of baseline physiological impairment. We used Cox proportional-hazards models to assess the risk of all-cause mortality associated with these surrogate events, occurring up to a predefined landmark timepoint. The three studies are registered at ClinicalTrials.gov, numbers NCT00650091, NCT00517933, and NCT00957242. FINDINGS: Seven patients died before the landmark timepoint. Of the 510 patients remaining, 38 (7%) were admitted to hospital up to the predefined timepoint and 58 (11%) had a categorical decrease in FVC of at least 10%. Most patients admitted to hospital did not have a 10% or greater decrease in FVC (30 vs eight). Both surrogate events were associated with subsequent time to death from any cause (hazard ratio [HR] for admission 4·05, 95% CI 1·36-12·11 vs HR for 10% or greater decline in FVC 4·68, 1·83-11·99). When causes of hospital admission were considered, only respiratory events were associated with mortality (5·97, 1·81-19·74). INTERPRETATION: Hospital admission might be an appropriate component of a clinically meaningful composite endpoint that improves the feasibility of clinical trials in idiopathic pulmonary fibrosis. Further studies are needed to refine the most appropriate definition of hospital admission for future trials. FUNDING: US National Heart, Lung, and Blood Institute (NHLBI), and The Cowlin Family Fund at the Chicago Community Trust.