Search

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which novel therapies are needed. External controls (ECs) could enhance IPF trial efficiency, but the direct comparability of ECs versus concurrent controls is unknown. Objectives: To develop IPF ECs by fit-for-purpose data standards to historical randomized clinical trial (RCT), multicenter registry (Pulmonary Fibrosis Foundation Patient Registry), and electronic health record (EHR) data and to evaluate endpoint comparability among ECs and the phase II RCT of BMS-986020. Methods: After data curation, the rate of change in FVC from baseline to 26 weeks among participants receiving BMS-986020 600 mg twice daily was compared with the BMS-placebo arm and ECs using mixed-effects models with inverse probability weights. Measurements and Main Results: At 26 weeks, the rates of change in FVC were -32.71 ml for BMS-986020 and -130.09 ml for BMS-placebo (difference, 97.4 ml; 95% confidence interval [CI], 24.6-170.2), replicating the original BMS-986020 RCT. RCT ECs showed treatment effect point estimates within the 95% CI of the original BMS-986020 RCT. Pulmonary Fibrosis Foundation Patient Registry ECs and EHR ECs experienced a slower rate of FVC decline compared with the BMS-placebo arm, resulting in treatment-effect point estimates outside of the 95% CI of the original BMS-986020 RCT. Conclusions: IPF ECs generated from historical RCT placebo arms result in comparable primary treatment effects to that of the original clinical trial, whereas ECs from real-world data sources, including registry or EHR data, do not. RCT ECs may serve as a potentially useful supplement to future IPF RCTs.

Rationale: Lung transplant offers the potential to extend life for patients with idiopathic pulmonary fibrosis (IPF); yet, this therapeutic modality is only available to a small proportion of patients. Objectives: To identify clinical characteristics and social determinants of health that differentially associate with lung transplant compared with death in patients with IPF. Methods: We evaluated data from the Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry, a multicenter U.S. registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Patients were enrolled between June 2014 and October 2018. Patients who were listed for lung transplant were not eligible to enroll in the registry, but patients could be listed for transplant after enrollment. We performed a multivariable time-to-event analysis incorporating competing risks methodology to examine differential associations between prespecified covariates and the risk of lung transplant versus death. Covariates included factors related to lung transplant eligibility, clinical characteristics of IPF, and social determinants of health. Covariates were modeled as time independent or time dependent as appropriate. Results: Among 955 patients with IPF, event rates of lung transplant and death were 7.4% and 16.3%, respectively, at 2 years. Covariates with the strongest differential association were age, median zip code income, and enrollment at a center with a lung transplant program. Lung transplant was less likely (hazard ratio [HR], 0.13 [95% confidence interval (CI), 0.06-0.28] per 5-yr increase) and death more likely (HR, 1.41 [95% CI, 1.22-1.64] per 5-yr increase) among those older than 70 years of age. Higher median zip code income was associated with lung transplant (HR, 1.22 [95% CI, 1.13-1.31] per $10,000 increase) but not death (HR, 0.99 [95% CI, 0.94-1.04] per $10,000 increase). Enrollment at a center with a lung transplant program was associated with lung transplant (HR, 4.31 [95% CI, 1.76-10.54]) but not death (HR, 0.99 [95% CI, 0.69-1.43]). Oxygen use with activity was associated with both lung transplant and death, but more strongly with lung transplant. A higher number of comorbidities was associated with an increased likelihood of death but not lung transplant. Conclusions: For patients in the Idiopathic Pulmonary Fibrosis Prospective Outcomes Registry, median zip code income and access to a lung transplant center differentially impact the risk of lung transplant compared with death, regardless of disease severity measures or other transplant eligibility factors. Interventions are needed to mitigate inequalities in lung transplantation based on socioeconomic status. Clinical trial registered with www.clinicaltrials.gov (NCT01915511).

Background: Limited data are available on the association between clinically measured disease severity markers and quality of life (QOL) in idiopathic pulmonary fibrosis (IPF). The study examined the associations between objective disease severity metrics and QOL in a contemporary IPF population., Methods: This study evaluated baseline data from patients enrolled in the multicenter, US-based Idiopathic Pulmonary Fibrosis Prospective Outcomes Registry between June 2014 and July 2018. Disease severity metrics included FVC % predicted, diffusing capacity for carbon monoxide (Dlco) % predicted, supplemental oxygen use with activity, supplemental oxygen use at rest, and two summary scores (the Gender-Age-Lung Physiology index, based on gender, age, and % predicted values for Dlco and FVC; and the Composite Physiologic Index, based on % predicted values for Dlco, FVC, and FEV 1 ). Multivariable adjusted regression models were used to examine cross-sectional associations between each severity measure and St. George's Respiratory Questionnaire (SGRQ) total score., Results: Among 829 patients with complete SGRQ data, the median (interquartile range) SGRQ score at enrollment was 40 (26-53), with higher scores indicating worse QOL. Modest SGRQ impairments were observed with increasing Gender-Age-Lung Physiology score (2.9 [1.8-4.0] per 1-point increase] and with increasing Composite Physiologic Index scores (3.0 [2.4-3.6] per 5-point increase). Substantial SGRQ impairments were observed for oxygen use with activity (15.6 [12.9-18.2]), oxygen use at rest (16.2 [13.0-19.4]), and decreasing Dlco (5.0 [4.0-6.1] per 10% decrease in % predicted)., Conclusions: Objective measures of disease severity, including severity scores, physiologic parameters, and supplemental oxygen use, are associated with worse QOL in patients with IPF., Trial Registry: ClinicalTrials.gov; No.: NCT01915511; URL: www.clinicaltrials.gov., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: As an increasing number of patients exhibit concomitant cardiac and pulmonary disease, limitations of standard diagnostic criteria are more frequently encountered. Here, we apply noninvasive 129 Xe magnetic resonance imaging (MRI) and spectroscopy to identify patterns of regional gas transfer impairment and haemodynamics that are uniquely associated with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), left heart failure (LHF) and pulmonary arterial hypertension (PAH)., Methods: Healthy volunteers (n=23) and patients with COPD (n=8), IPF (n=12), LHF (n=6) and PAH (n=10) underwent 129 Xe gas transfer imaging and dynamic spectroscopy. For each patient, three-dimensional maps were generated to depict ventilation, barrier uptake ( 129 Xe dissolved in interstitial tissue) and red blood cell (RBC) transfer ( 129 Xe dissolved in RBCs). Dynamic 129 Xe spectroscopy was used to quantify cardiogenic oscillations in the RBC signal amplitude and frequency shift., Results: Compared with healthy volunteers, all patient groups exhibited decreased ventilation and RBC transfer (both p≤0.01). Patients with COPD demonstrated more ventilation and barrier defects compared with all other groups (both p≤0.02). In contrast, IPF patients demonstrated elevated barrier uptake compared with all other groups (p≤0.007), and increased RBC amplitude and shift oscillations compared with healthy volunteers (p=0.007 and p≤0.01, respectively). Patients with COPD and PAH both exhibited decreased RBC amplitude oscillations (p=0.02 and p=0.005, respectively) compared with healthy volunteers. LHF was distinguishable from PAH by enhanced RBC amplitude oscillations (p=0.01)., Conclusion: COPD, IPF, LHF and PAH each exhibit unique 129 Xe MRI and dynamic spectroscopy signatures. These metrics may help with diagnostic challenges in cardiopulmonary disease and increase understanding of regional lung function and haemodynamics at the alveolar-capillary level., Competing Interests: Conflict of interest: Z. Wang has a provisional patent for a diagnostic algorithm based on the findings in this manuscript licensed. Conflict of interest: E.A. Bier reports grants from the National Institutes of Health, during the conduct of the study; and has a provisional patent for a diagnostic algorithm based on the findings in this manuscript licensed. Conflict of interest: A. Swaminathan has nothing to disclose. Conflict of interest: K. Parikh has nothing to disclose. Conflict of interest: J. Nouls has nothing to disclose. Conflict of interest: M. He has nothing to disclose. Conflict of interest: J.G. Mammarappallil has nothing to disclose. Conflict of interest: S. Luo has nothing to disclose. Conflict of interest: B. Driehuys reports grants from the National Institutes of Health, during the conduct of the study; personal fees from and is founder and chief technology officer for Polarean Imaging, a company which produces 129Xe hyperpolarisation equipment, outside the submitted work; and has a provisional patent for a diagnostic algorithm based on the findings in this manuscript licensed. Conflict of interest: S. Rajagopal reports grants from National Institutes of Health, during the conduct of the study; and has a patent “Dynamic 129Xe Gas Exchange Spectroscopy” pending., (Copyright ©ERS 2019.)

Background: To assess the characteristics of patients enrolled in the ILD-PRO Registry. Methods: The ILD-PRO Registry is a multicentre US registry of patients with progressive pulmonary fibrosis. This registry is enrolling patients with an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis who have reticular abnormality and traction bronchiectasis on HRCT, and who meet criteria for ILD progression within the prior 24 months. Patient characteristics were analysed based on the number of patients with available data. Results: Of the first 491 patients enrolled, the majority were white (75.4%) and female (60.6%); 47.4% had a history of smoking. Reported ILDs were autoimmune disease-associated ILDs (47.2%), hypersensitivity pneumonitis (17.5%), idiopathic non-specific interstitial pneumonia (9.1%), interstitial pneumonia with autoimmune features (8.9%), unclassifiable ILD (7.6%), other ILDs (9.7%). At enrolment, median (Q1, Q3) FVC % predicted was 62.2 (49.4, 72.4) and DLco % predicted was 39.2 (30.2, 49.2). Median (Q1, Q3) total score on the St. George's Respiratory Questionnaire was 50.8 (35.9, 64.7). The most common comorbidities were gastroesophageal reflux disease (61.1%) and sleep apnoea (29.6%). Overall, 64.5% of patients were receiving immunosuppressive or cytotoxic therapy, 61.1% proton-pump inhibitors, 53.2% oral steroids, 19.8% nintedanib and 3.6% pirfenidone. Conclusions: Patients enrolled into the ILD-PRO Registry have a variety of ILD diagnoses, marked impairment in lung function and health-related quality of life, and high medication use. Longitudinal data from this registry will further our knowledge of the course of progressive pulmonary fibrosis. Trial Registration: ClinicalTrials.gov, NCT01915511; registered August 5, 2013. [ABSTRACT FROM AUTHOR]

Background: Pulmonary fibrosis (PF) is the most common disease indication for lung transplantation. Our recent work implicated an excess of rare genetic variants in the telomere-related genes TERT, RTEL1, and PARN in PF disease risk. The impact of such variants on posttransplant outcomes is uncertain. The objective of this study was to determine if patients with these PF-associated variants have altered rates of posttransplant acute rejection (AR), chronic lung allograft dysfunction (CLAD), and survival.Methods: The study cohort consisted of 262 PF lung transplant recipients previously genetically characterized by whole exome sequencing. Thirty-one patients (11.8%) had variants in TERT, RTEL1, or PARN, whereas 231 (88.2%) did not. Multivariate Cox proportional hazards models adjusted for relevant clinical variables were used to assess the outcomes of death and CLAD. The AR burden was quantified and compared over the first posttransplant year.Results: Patients with PF with disease-associated variants in TERT, RTEL1, or PARN had a significantly higher risk of death (adjusted hazard ratio [HR], 1.82; 95% CI, 1.07-3.08; P = .03) and CLAD (adjusted HR, 2.88; 95% CI, 1.42-5.87; P = .004) than patients without these variants. There was no difference in AR burden or rates of grade 3 primary graft dysfunction between the two groups.Conclusions: Rare variants in the telomere-related genes TERT, RTEL1, or PARN are associated with poor posttransplant outcomes among PF lung transplant recipients. Further research is needed to understand the biological mechanisms by which telomere-related variants increase the risk for death and CLAD. [ABSTRACT FROM AUTHOR]

B METHODS: b We used data from the IPF-PRO Registry, a multicenter, observational registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months, to evaluate PROs at the time of enrollment (June 2014 - July 2018). Funding to coordinate IPF-PRO Registry relationship with Faculty member in DCRI, which receives support from BI Please note: $5001 - $20000 Added 03/14/2019 by Laurie Snyder, source=Web Response, value=Grant/Research Support. [Extracted from the article]

B CONCLUSIONS: b Objective measures of disease severity are associated with worse QOL in contemporary IPF patients, with associations observed for composite severity metrics, physiologic parameters and supplemental oxygen use. B CLINICAL IMPLICATIONS: b IPF patients with more severe disease, particularly those who use supplemental oxygen, experience meaningful deficits in QOL. [Extracted from the article]

Introduction: Pulmonary arterial hypertension (PAH) carries significant morbidity and mortality. Its diagnosis requires meeting specific hemodynamic and clinical criteria and can be particularly challenging in patients with concomitant heart or lung disease. Hyperpolarized 129Xenon (129Xe) magnetic resonance imaging and dynamic spectroscopy may overcome these challenges, providing a non-invasive new tool to diagnose and monitor PAH. This is based on its unique cardiogenic oscillations reflected in the 129Xe spectrum as it transfers to red blood cells (RBCs, Figure). Hypothesis: We hypothesized that changes in the RBC 129Xe spectroscopic parameters will discriminate PAH from healthy volunteers, patients with left heart failure, idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD). Methods: 129Xe spectra were dynamically acquired every 20 milliseconds in all subjects. At each time point, the amplitude, chemical shift, linewidth, and phase of the 129Xe-RBC resonance was calculated. Cardiogenic oscillations in these spectral parameters were compared using the Kruskal-Wallis test, followed by pairwise comparisons with the Wilcoxon rank sum test. Results: A total of 14 healthy volunteers, 10 subjects with PAH, 5 subjects with left heart failure, 9 subjects with IPF, and 7 subjects with COPD underwent 129Xe spectroscopy. In patients with PAH, RBC amplitude oscillations were significantly reduced compared to those with IPF (p < 0.001) or healthy subjects (p = 0.0064, Figure). Oscillations in chemical shift and phase were only observed in IPF patients. Conclusions: 129Xenon dynamic spectroscopy produces different RBC signatures in patients with PAH, IPF, and healthy volunteers. 129Xe uniquely probes the alveolar-capillary interface and can thus detect the effect of arterial lesions on capillary blood volume oscillations. [ABSTRACT FROM AUTHOR]