Pulmonary fibrosis may impair an individual’s ability to work. We assessed the extent, cost and factors associated with workplace productivity loss among patients with progressive pulmonary fibrosis (PPF). The multi-center ILD-PRO Registry enrolled US patients with progressive interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis. Workplace productivity loss was assessed using the Work Productivity and Activity Impairment (WPAI) questionnaire. Associations between patient characteristics and workplace productivity loss among employed patients were analyzed using logistic regression. Among 175 employed patients of 597 who completed the WPAI questionnaire, 58.3 URL: www.clinicaltrials.gov .

Rationale: Chronic lung allograft dysfunction (CLAD) hinders lung transplant success. A 2019 consensus refined CLAD diagnosis, introducing probable or definite CLAD based on persistence of lung function decline. Outcomes and risks for probable CLAD remain uncertain. Objectives: We sought to determine the prognosis and clinical risks for probable CLAD in a prospective multicenter cohort. Methods: Clinical Trials in Organ Transplantation-20 included 745 CLAD-eligible adult lung recipients at five centers and applied rigorous methods to prospectively adjudicate probable CLAD. The impact of probable CLAD on graft loss was determined using a Cox model that considered CLAD as a time-dependent covariate. Regularized Cox modeling with least absolute shrinkage and selection operator (LASSO) penalty was used to evaluate donor or recipient characteristics and the occurrence and timing of posttransplant events as probable CLAD risks. Similar analyses were performed for definite CLAD. Measurements and Main Results: Probable CLAD occurred in 29.7% of patients at 3 years posttransplant and conferred a marked increase in risk for graft loss (unadjusted hazard ratio = 4.38, P < 0.001). Most patients (80%) with probable CLAD progressed to definite CLAD. Cytomegalovirus infection and, specifically, late presence (>90 d posttransplant) of donor-specific alloantibodies, acute rejection, acute lung injury, or organizing pneumonia contributed the greatest independent information about probable CLAD risk. Definite CLAD risks were similar. Conclusions: Probable CLAD identifies patients at high risk for graft loss, supporting prospective identification of this condition for early initiation of CLAD-directed interventions. More effective strategies to prevent posttransplant cytomegalovirus, inhibit allospecific immunity, and reduce tissue injury are needed to reduce probable CLAD and improve lung recipient survival. Clinical trial registered with www.clinicaltrials.gov (NCT02631720).

Rationale: IPF is a chronic lung disease associated with high mortality. A 52-gene risk signature has been shown to be associated with transplant-free survival in patients with IPF. We investigated whether a signature based on the 7 upregulated genes of the 52-gene signature was associated with progression of IPF. Methods: The cohort comprised patients from the IPF-PRO Registry who had IPF that was diagnosed or confirmed at the enrolling center in the past 6 months. Total RNA sequencing was performed in blood samples collected at enrollment. For each patient, we calculated an “UP score” based on expression of the 7 upregulated genes of the 52-gene signature (PLBD1, TPST1, MCEMP1, IL1R2, HP, FLT3, S100A12). We analyzed the association between UP score <1 vs ≥1 (approximately the cohort median) and the composite outcome of decline in forced vital capacity (FVC) % predicted ≥10%, death, or lung transplant using Cox proportional hazards models. Median follow-up was 37.5 months. Models were adjusted for antifibrotic therapy use at enrollment only, and for antifibrotic therapy use, GAP score, oxygen use with activity, and oxygen use at rest at enrollment. The interaction between antifibrotic therapy use and UP score was assessed. Results: Among 609 patients, at enrollment, median age was 70.0 years, 74.2% were male, 49.8% were using an antifibrotic therapy. Applying the 7-gene signature, the median (min, max) UP score was 0.94 (0.0, 18.1); 309 patients (50.7%) had an UP score 0-<1. Median (Q1, Q3) FVC and diffusing capacity of the lungs for carbon monoxide (DLco) % predicted were 71.7 (60.8, 82.5) and 44.8 (34.8, 54.3) in patients with an UP score 0-<1, and 66.5 (55.1, 77.8) and 40.1 (31.7, 49.2) in those with an UP score ≥1, respectively. Compared with an UP score 0-<1, an UP score ≥1 was associated with an increased risk of the outcome in analysis adjusted for antifibrotic therapy use only (HR 1.37 [95% CI 1.13, 1.66]; p=0.001) and analysis that was also adjusted for additional clinical factors (HR 1.30 [1.07, 1.59]; p=0.009) (Figure). Use of antifibrotic therapy at enrollment did not affect the association between UP score and risk of the outcome (interaction p>0.05). Conclusions: In a contemporary cohort of patients with IPF, a 7-gene signature based on total RNA sequencing was associated with an increased risk of disease progression.

The prognostic value of patterns and quantitative measures of lung fibrosis on high-resolution computed tomography (HRCT) in patients identified as having progressive pulmonary fibrosis (PPF) has not been established. We investigated whether HRCT patterns and quantitative scores were associated with risk of progression in patients with PPF. Patients enrolled in the ILD-PRO Registry had an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis, reticular abnormality and traction bronchiectasis, and met criteria for ILD progression. HRCT images taken between 24 months prior to enrollment and 90 days after enrollment were analyzed using a machine learning algorithm to derive quantitative scores. Associations were assessed between HRCT pattern (usual interstitial pneumonia [UIP]-like versus other patterns) and tertiles of quantitative scores and measures of disease severity at enrollment, and between these patterns/tertiles at enrollment and ILD progression (relative decline in forced vital capacity [FVC] www.clinicaltrials.gov .

We evaluated relationships between changes in lung function and changes in patient-reported outcomes (PROs) in 736 patients with idiopathic pulmonary fibrosis (IPF) enrolled in the IPF-PRO Registry. Weak correlations were observed between changes in percent predicted values for forced vital capacity or diffusing capacity of the lungs (DLco) and changes in St George’s Respiratory Questionnaire (SGRQ) total and activity scores and the 12-item Short Form Survey (SF-12) physical component summary score over 12-month periods. Patients who had a deterioration in SGRQ activity score or SF-12 PCS score of ≥ 5 units had numerically larger declines in lung function than other patients, but the differences were small. The weak relationships observed between changes in lung function and changes in PROs underscore the importance of evaluating both changes in lung function and changes in HRQL in clinical practice and clinical trials.

The circulating proteome may provide insights into the pathobiology of idiopathic pulmonary fibrosis (IPF) and diagnostic or prognostic biomarkers. We applied liquid chromatography coupled to mass spectrometry to quantify the peripheral blood proteome in patients with IPF and identify proteins associated with disease severity and progression. The IPF cohort comprised 299 patients from the IPF-PRO Registry. Controls (n = 99) without known lung disease had similar distributions of age, sex and smoking status to the IPF cohort. Proteins were measured in plasma collected at enrollment using an Evosep One coupled to an Orbitrap Exploris. Data were analyzed with Spectronaut 14 with a deep experimental spectral library and were log2 transformed. Linear regression was used to compare protein abundances in the IPF versus control cohorts and identify proteins associated with disease severity measures at enrollment in the IPF cohort. Cox regression analyses were used to identify proteins associated with outcomes in the IPF cohort, split 75/25 into training and test sets. The false discovery rate was controlled at 5 www.clinicaltrials.gov .

BACKGROUND:CD26/dipeptidyl peptidase 4 inhibitors (gliptins) target proinflammatory pathways that contribute to the development of chronic lung allograft dysfunction (CLAD). We analyzed longitudinal clinical data from 6 North American lung transplant centers to elucidate the effect of gliptin exposure on CLAD development after lung transplantation. METHODS:This cohort included 6 North American lung transplant centers, 4 sites from the Clinical Trials in Organ Transplantation-20 study and 2 additional sites. First lung transplant recipients between December 2015 and August 2018 were eligible with follow-up through June 2021. Gliptin exposures before CLAD onset, in addition to CLAD risk factors, were included in the models. The primary end-point was a composite of probable CLAD, CLAD-related deaths, and CLAD-related retransplant. Cox regression models were used to assess the association between gliptin use and the CLAD composite end-point. RESULTS:Seven hundred and seventy-nine patients met inclusion criteria, with 126 (16.2%) having any gliptin exposure. Two hundred and thirty-three (29.9%) patients experienced probable CLAD composite outcome. Across all centers, gliptin exposure at any point was not associated with probable CLAD or definite CLAD across the study period. In a posthoc analysis of centers with median gliptin exposures >6 months, exposure within the first 90 days post-transplant was associated with a decreased risk of definite CLAD composite across the study period (hazard ratio [HR] 0.25; 95% confidence interval [CI], 0.07, 0.83; p < 0.05). CONCLUSIONS:The association of gliptins and CLAD is complex, but early gliptin use may help protect against CLAD if started within 90 days post-transplant and used for a prolonged period.

Within a 2-year Master of Biostatistics program, we reconsidered the mathematics requirements for admission, and also the premise that the most distinguishing feature of a top candidate is deep exposure to mathematics. Our assessment took place within a broad curriculum review intended to enhance alignment: aligning programmatic goals with job skills, aligning the use of mathematics within our curriculum with programmatic goals, aligning our admission criteria with our curriculum, and aligning our application materials with these admission criteria. We developed a specific list of mathematical skills required by the curriculum, and are revising the application materials to include self-report on applicant's exposure to and functional mastery of those skills. We illustrate how functional mastery is operationally defined. Our criteria for identifying top candidates was broadened to include those with especial skills in analytics, biology and/or communication (i.e., the three conceptual pillars of our program). Deep mathematical training is one of many ways to become a top candidate. Within STEM fields such as biostatistics, and despite the commonly held assumption that admission criteria should emphasize depth of mathematical training, a systematic analysis suggests that this assumption imposes a gratuitous requirement on applicants. Reconsidering this assumption can help remove unnecessary barriers, reduce challenges, and support success for aspiring or emerging biostatisticians from diverse or multifaceted backgrounds. It is one way to contribute to a more inclusive and equitable learning environment in our STEM discipline. We believe similar programs might benefit from performing this type of analysis and reflection.

Rationale: Progressive pulmonary fibrosis (PPF) is known to be associated with high mortality. We evaluated time to death or lung transplant among patients with PPF and different diagnoses of interstitial lung disease (ILD) in the ILD-PRO Registry. Methods: The ILD-PRO Registry is a US registry that enrolled patients who had an ILD other than idiopathic pulmonary fibrosis, reticular abnormality and traction bronchiectasis (with or without honeycombing) on HRCT, and met criteria for ILD progression within the prior 24 months. Patients were followed prospectively while receiving usual care. Using the Kaplan-Meier method, we analyzed time to death or lung transplant over 24 months in the following subgroups based on type of ILD: systemic autoimmune rheumatic disease (SARD)-ILDs, hypersensitivity pneumonitis, idiopathic non-specific interstitial pneumonia (NSIP), interstitial pneumonia with autoimmune features (IPAF), unclassifiable ILD, other ILDs. Results: Of the first 917 patients enrolled, 458 (49.9%) had SARD-ILDs, 166 (18.1%) hypersensitivity pneumonitis, 95 (10.4%) idiopathic NSIP, 78 (8.5%) IPAF, 67 (7.3%) unclassifiable ILD and 53 (5.8%) other ILDs. The probability of transplant-free survival at 24 months was 76.6%, 63.2%, 69.0%, 72.3%, 71.3% and 70.9% for patients with these ILDs, respectively (Figure). Conclusions: Patients with PPF enrolled in the ILD-PRO Registry had a high risk of death or lung transplant over the following two years. Patients with SARD-ILDs had a higher probability of transplant-free survival than patients with some other ILDs.

We used data from the IPF-PRO Registry of patients with idiopathic pulmonary fibrosis (IPF) to identify characteristics that predicted survival for a further > 5 years. Participants had IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Patients were followed prospectively. A Classification And Regression Tree (CART) was used to identify predictors of survival > 5 versus ≤ 5 years following enrollment. The following variables, assessed at enrollment, were considered: age; body mass index (BMI); former smoker; current smoker; time from first imaging evidence, symptoms, or diagnosis of IPF to enrollment; forced vital capacity (FVC)

Background Lung transplantation (LT) has been shown to improve lung function and quality of life (QoL). We sought to clarify if QoL improvements coincide with improvements in spirometry assessments in the first post-transplant year. Methods In the multicenter observational Clinical Trials in Organ Transplantation-20 study, LT recipients had longitudinal forced expiratory volume in 1 second (FEV1) and QoL measurements, specifically the St. George’s Respiratory Questionnaire (SGRQ) and 36-Item Short Form Survey (SF-36), collected at 1, 3, 6, 9, and 12 months post-LT. We assessed whether best QoL scores occurred before, simultaneously, or after best FEV1. Results Of 803 recipients, 702 met the inclusion criteria. The best total SGRQ score occurred before best FEV1 in 16.0% of patients, simultaneously in 28.3%, and afterward in 55.7%. Similarly, the best SF-36 physical score occurred before best FEV1 in 18.7% of patients, simultaneously in 32.7%, and afterward in 48.6%. Single LTs, age >65 years, male sex, and diagnosis other than cystic lung disease were associated with a higher likelihood of achieving best QoL after best FEV1. Conclusions Both spirometry and multiple physical and social QoL domains improved over the first post-LT year, but these improvements did not necessarily occur simultaneously. Nearly half of patients reached their best respiratory-specific and physical QoL scores after best FEV1; however, timing varied by recipient characteristics. As the pace of post-LT recovery is multifactorial, our findings provide insights to patients and providers regarding anticipated post-transplant changes and highlight the importance of considering both spirometry and QoL measures.

BACKGROUND:Basiliximab induction immunosuppression is increasingly employed in lung transplant recipients despite limited prospective evidence to support its use in this population. We sought to determine the relationship between basiliximab induction and development of acute rejection, chronic lung allograft dysfunction, and other clinically relevant outcomes in a multicenter lung transplant cohort with variable induction practice patterns. METHODS:We applied propensity-based statistical methods to rigorous, prospectively collected longitudinal data from 768 newly transplanted adult lung recipients at 5 North American centers (368 who received basiliximab induction immunosuppression and 400 who received no induction immunosuppression). Treatment effects were estimated using outcome-specific propensity score regression models, weighted by the outcome-specific overlap weights, and stratified by center strata. RESULTS:Basiliximab induction immunosuppression was associated with a significant reduction in any grade acute rejection (HR 0.65, 95% CI 0.46-0.92; p=0.015), organizing pneumonia histology (HR 0.38, 95% CI 0.16-0.90; p=0.028), acute lung injury histology (HR 0.28, 95% CI 0.13-0.61; p=0.001), and development of class II donor specific antibodies (HR 0.51, 95% CI 0.27-0.95; p=0.034) within the first posttransplant year. However, there was no significant association between basiliximab and development of chronic lung allograft dysfunction, mortality, or graft loss. For select infections during the first posttransplant year, there was no evidence of a difference in risk between patients who did versus did not receive basiliximab. CONCLUSIONS:Basiliximab induction immunosuppression is associated with a significant reduction in early posttransplant cellular and humoral immune events and lung injury histologies but not chronic lung allograft dysfunction or mortality.

Rationale: Although exposure to air pollution is a known risk factor for adverse pulmonary outcomes, its impact in individuals with idiopathic pulmonary fibrosis (IPF) is less well understood. Objectives: To investigate the effects of long-term exposure to air pollution on disease severity and progression in patients with IPF and to determine whether genomic factors, such as MUC5B promoter polymorphism or telomere length, modify these associations. Methods: We performed analyses at enrollment and after 1 year of follow-up in the IPF-PRO (Idiopathic Pulmonary Fibrosis Prospective Outcomes) Registry, a prospective observational registry that enrolled individuals with IPF at 46 U.S. sites from June 2014 to October 2018. Five-year average pollution exposures (particulate matter ≤2.5 μm in aerodynamic diameter [PM2.5], nitrogen dioxide, ozone) before the enrollment date were estimated at participants' residential addresses with validated national spatiotemporal models. Multivariable regression models estimated associations between pollution exposure and physiologic measurements (forced vital capacity [FVC], diffusing capacity of the lung for carbon monoxide, supplemental oxygen use at rest) and quality-of-life measurements (St. George's Respiratory Questionnaire, EuroQoL, Cough and Sputum Assessment Questionnaire) at enrollment. Cox proportional hazards models estimated associations between pollutants and a composite outcome of death, lung transplant, or >10% absolute decline in FVC percent predicted in the year after enrollment. Models were adjusted for individual-level and spatial confounders, including proxies for disease onset. Gene-environment interactions with MUC5B and telomere length were assessed. Results: Of 835 participants, 94% were non-Hispanic White individuals, 76% were male, and the mean (standard deviation) age was 70 (7.7) years. In fully adjusted analyses, higher PM2.5 exposure was associated with worse quality of life per St. George's Respiratory Questionnaire activity score (3.48 [95% confidence interval (CI), 0.64, 6.32] per 2 μg/m3 PM2.5) and EuroQoL scores (-0.04 [95% CI, -0.06, -0.01] per 2 μg/m3 PM2.5), as well as lower FVC percent predicted and lower diffusing capacity of the lung for carbon monoxide percent predicted at enrollment. Each 3 parts per billion difference in O3 exposure was associated with a 1.57% (95% CI, 0.15, 2.98) higher FVC percent predicted at enrollment, although this effect was attenuated in multipollutant models. There was no association between nitrogen dioxide and enrollment measures or between pollution exposure and 1-year outcomes and no evidence for gene-environment interactions. Conclusions: In the IPF-PRO Registry, long-term exposure to PM2.5 was associated with worse quality of life and lung function at enrollment, but not with short-term disease progression or mortality. There was no evidence of effect modification by interaction of genomic factors with pollution. The reason for the unexpected relationship between O3 exposure and higher FVC is unclear. Clinical trial registered with www.clinicaltrials.gov (NCT01915511).

Background:Prostasin is expressed in the lung epithelium where it regulates fluid and electrolyte balance via sodium channel proteolysis. We investigated whether circulating prostasin levels are associated with the presence and severity of idiopathic pulmonary fibrosis (IPF) and whether prostasin levels, or changes in them, are associated with mortality. Methods:Patients with IPF came from the IPF-PRO Registry. Controls without lung disease had a similar age/sex distribution. Prostasin was quantified in plasma taken at enrolment and, in the IPF cohort, ∼6 months post-enrolment, by immunoassay. Linear regression was used to compare prostasin levels at enrolment in patients with IPF versus controls and, in the IPF cohort, determine associations between prostasin level and lung function. Multivariable Cox proportional hazards models determined associations between prostasin level at enrolment and change in prostasin level over 6 months and respiratory death. Results:Prostasin level at enrolment was higher in patients with IPF (n=624) versus controls (n=100) (fold-difference 1.75; p<0.001). In the IPF cohort, the difference in disease severity per 1 standard deviation (sd) difference in prostasin was -3.85 for forced vital capacity % predicted and -4.24 for diffusing capacity of the lung for carbon monoxide % predicted (both p<0.001). The adjusted hazard ratio (HR) for respiratory death per 1 sd difference in prostasin at enrolment was 1.20 (95% CI 1.04-1.40, p=0.014, n=624). The adjusted HR for subsequent respiratory death per 1 sd difference in change in prostasin over 6 months was 1.33 (95% CI 1.01-1.74, p=0.041, n=290). Conclusions:Circulating prostasin is an independent marker of mortality risk in patients with IPF.

Rationale: Respiratory hospitalizations are a significant cause of morbidity and mortality in individuals with idiopathic pulmonary fibrosis (IPF). We hypothesized that higher acute exposure to particulate matter with aerodynamic diameter ≤ 2.5 microns (PM2.5) would be associated with respiratory-related hospitalizations in a registry of patients with IPF. Methods: We performed a case cross-over analysis of participants who had at least one non-transplant-related respiratory hospitalization in the IPF-PRO Registry, a multicenter registry of individuals with IPF from 46 sites across the US. Acute exposure to PM2.5 was estimated as the average concentration recorded at the Air Quality Station regulatory monitor nearest to the individual's primary residential address for each day in the week preceding the hospitalization (lag day 0 as day-of-event to lag day -6). Control days were selected using a time-stratified semisymmetric bidirectional design and included the same day of the week within the same month as the case day. Conditional logistical regression estimated the association between average PM2.5 concentration for each lag day and for the 7-day average and the odds of initial respiratory hospitalization, adjusting for time-varying confounders, including temperature, relative humidity and influenza season. We assessed for effect modification by sex, age, MUC5B genotype, telomere length and ani-fibrotic treatment using stratified analyses. Results: Of the 1002 participants enrolled in the registry, 242 had at least one respiratory-related hospitalization and valid PM2.5 estimates. In adjusted analyses, each 5µg/m3 higher PM2.5 on lag day 0 was associated with a 22% (95% confidence interval, 14% to 46%) higher odds of respiratory-related hospitalization. No significant association was observed for PM2.5 in the other days in the week or the average 7-day concentration preceding the hospitalization. There was no evidence of effect modification by the other variables assessed. Conclusions: Higher acute exposure to PM2.5 is associated with an increased risk of same-day hospitalization in individuals with IPF.