Circulating metabolic profile in idiopathic pulmonary fibrosis: data from the IPF-PRO Registry.

BACKGROUND: The circulating metabolome, reflecting underlying cellular processes and disease biology, has not been fully characterized in patients with idiopathic pulmonary fibrosis (IPF). We evaluated whether circulating levels of metabolites correlate with the presence of IPF, with the severity of IPF, or with the risk of clinically relevant outcomes among patients with IPF. METHODS: We analyzed enrollment plasma samples from 300 patients with IPF in the IPF-PRO Registry and 100 individuals without known lung disease using a set of targeted metabolomics and clinical analyte modules. Linear regression was used to compare metabolite and clinical analyte levels between patients with IPF and controls and to determine associations between metabolite levels and measures of disease severity in patients with IPF. Unadjusted and adjusted univariable Cox regression models were used to evaluate associations between circulating metabolites and the risk of mortality or disease progression among patients with IPF. RESULTS: Levels of 64 metabolites and 5 clinical analytes were significantly different between patients with IPF and controls. Among analytes with greatest differences were non-esterified fatty acids, multiple long-chain acylcarnitines, and select ceramides, levels of which were higher among patients with IPF versus controls. Levels of the branched-chain amino acids valine and leucine/isoleucine were inversely correlated with measures of disease severity. After adjusting for clinical factors known to influence outcomes, higher levels of the acylcarnitine C:16-OH/C:14-DC were associated with all-cause mortality, lower levels of the acylcarnitine C16:1-OH/C14:1DC were associated with all-cause mortality, respiratory death, and respiratory death or lung transplant, and higher levels of the sphingomyelin d43:2 were associated with the risk of respiratory death or lung transplantation. CONCLUSIONS: IPF has a distinct circulating metabolic profile characterized by increased levels of non-esterified fatty acids, long-chain acylcarnitines, and ceramides, which may suggest a more catabolic environment that enhances lipid mobilization and metabolism. We identified select metabolites that were highly correlated with measures of disease severity or the risk of disease progression and that may be developed further as biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov; No: NCT01915511; URL: www. CLINICALTRIALS: gov .

Development and validation of primary graft dysfunction predictive algorithm for lung transplant candidates.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Accurate prediction of PGD risk could inform donor approaches and perioperative care planning. We sought to develop a clinically useful, generalizable PGD prediction model to aid in transplant decision-making. METHODS: We derived a predictive model in a prospective cohort study of subjects from 2012 to 2018, followed by a single-center external validation. We used regularized (lasso) logistic regression to evaluate the predictive ability of clinically available PGD predictors and developed a user interface for clinical application. Using decision curve analysis, we quantified the net benefit of the model across a range of PGD risk thresholds and assessed model calibration and discrimination. RESULTS: The PGD predictive model included distance from donor hospital to recipient transplant center, recipient age, predicted total lung capacity, lung allocation score (LAS), body mass index, pulmonary artery mean pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor smoking status; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The model offers decision-making net benefit in the PGD risk range of 10% to 75% in the derivation centers and 2% to 10% in the validation cohort, a range incorporating the incidence in that cohort. CONCLUSION: We developed a clinically useful PGD predictive algorithm across a range of PGD risk thresholds to support transplant decision-making, posttransplant care, and enrich samples for PGD treatment trials.

The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).

Prevalence and significance of clonal hematopoiesis of indeterminate potential in lung transplant recipients.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition of somatic mutations that leads to an expanded blood cell clone, has been associated with development of a pro-inflammatory state. An enhanced or dysregulated inflammatory response may contribute to rejection after lung transplantation, however the prevalence of CHIP in lung recipients and influence of CHIP on allograft outcomes is unknown. METHODS: We analyzed whole-exome sequencing data in 279 lung recipients to detect CHIP, defined by pre-specified somatic mutations in 74 genes known to promote clonal expansion of hematopoietic stem cells. We compared the burden of acute rejection (AR) over the first post-transplant year in lung recipients with vs. without CHIP using multivariable ordinal regression. Multivariate Cox proportional hazards models were used to assess the association between CHIP and CLAD-free survival. An exploratory analysis evaluated the association between the number of CHIP-associated variants and chronic lung allograft dysfunction (CLAD)-free survival. RESULTS: We detected 64 CHIP-associated mutations in 45 individuals (15.7%), most commonly in TET2 (10.8%), DNMT3A (9.2%), and U2AF1 (9.2%). Patients with CHIP tended to be older but did not significantly differ from patients without CHIP in terms of race or native lung disease. Patients with CHIP did not have a higher incidence of AR over the first post-transplant year (p = 0.45) or a significantly increased risk of death or CLAD (adjusted HR 1.25, 95% CI 0.88-1.78). We did observe a significant association between the number of CHIP variants and CLAD-free survival, specifically patients with 2 or more CHIP-associated variants had an increased risk for death or CLAD (adjusted HR 3.79, 95% CI 1.98-7.27). CONCLUSIONS: Lung recipients have a higher prevalence of CHIP and a larger variety of genes with CHIP-associated mutations compared with previous reports for the general population. CHIP did not increase the risk of AR, CLAD, or death in lung recipients.

Lung function trajectories in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease characterised by decline in lung function. We evaluated trajectories of forced vital capacity (FVC) and diffusing capacity (DLco) in a cohort of patients with IPF. METHODS: Patients with IPF that was diagnosed or confirmed at the enrolling centre in the previous 6 months were enrolled into the IPF-PRO Registry between June 2014 and October 2018. Patients were followed prospectively, with lung function data collected as part of routine clinical care. Mean trajectories of FVC and DLco % predicted in all patients and in subgroups by characteristics assessed at enrolment were estimated using a joint model that accounted for factors such as disease severity and visit patterns. RESULTS: Of 1002 patients in the registry, 941 had ≥ 1 FVC and/or DLco measurement after enrolment. The median (Q1, Q3) follow-up period was 35.1 (18.9, 47.2) months. Overall, mean estimated declines in FVC and DLco % predicted were 2.8% and 2.9% per year, respectively. There was no evidence that the mean trajectories of FVC or DLco had a non-linear relationship with time at the population level. Patients who were male, white, had a family history of ILD, were using oxygen, or had prior/current use of antifibrotic therapy at enrolment had greater rates of decline in FVC % predicted. Patients who were male or white had greater rates of decline in DLco % predicted. CONCLUSIONS: Data from the IPF-PRO Registry suggest a constant rate of decline in lung function over a prolonged period, supporting the inexorably progressive nature of IPF. A graphical abstract summarising the data in this manuscript is available at: https://www.usscicomms.com/respiratory/IPF-PRORegistry_LungFunctionTrajectories . TRIAL REGISTRATION: NCT01915511.

External Control Arms in Idiopathic Pulmonary Fibrosis Using Clinical Trial and Real-World Data Sources.

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.

Integrative multi-omics analysis reveals novel idiopathic pulmonary fibrosis endotypes associated with disease progression.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix in the pulmonary interstitium and progressive functional decline. We hypothesized that integration of multi-omics data would identify clinically meaningful molecular endotypes of IPF. METHODS: The IPF-PRO Registry is a prospective registry of patients with IPF. Proteomic and transcriptomic (including total RNA [toRNA] and microRNA [miRNA]) analyses were performed using blood collected at enrollment. Molecular data were integrated using Similarity Network Fusion, followed by unsupervised spectral clustering to identify molecular subtypes. Cox proportional hazards models tested the relationship between these subtypes and progression-free and transplant-free survival. The molecular subtypes were compared to risk groups based on a previously described 52-gene (toRNA expression) signature. Biological characteristics of the molecular subtypes were evaluated via linear regression differential expression and canonical pathways (Ingenuity Pathway Analysis [IPA]) over-representation analyses. RESULTS: Among 232 subjects, two molecular subtypes were identified. Subtype 1 (n = 105, 45.3%) and Subtype 2 (n = 127, 54.7%) had similar distributions of age (70.1 +/- 8.1 vs. 69.3 +/- 7.6 years; p = 0.31) and sex (79.1% vs. 70.1% males, p = 0.16). Subtype 1 had more severe disease based on composite physiologic index (CPI) (55.8 vs. 51.2; p = 0.002). After adjusting for CPI and antifibrotic treatment at enrollment, subtype 1 experienced shorter progression-free survival (HR 1.79, 95% CI 1.28,2.56; p = 0.0008) and similar transplant-free survival (HR 1.30, 95% CI 0.87,1.96; p = 0.20) as subtype 2. There was little agreement in the distribution of subjects to the molecular subtypes and the risk groups based on 52-gene signature (kappa = 0.04, 95% CI= -0.08, 0.17), and the 52-gene signature risk groups were associated with differences in transplant-free but not progression-free survival. Based on heatmaps and differential expression analyses, proteins and miRNAs (but not toRNA) contributed to classification of subjects to the molecular subtypes. The IPA showed enrichment in pulmonary fibrosis-relevant pathways, including mTOR, VEGF, PDGF, and B-cell receptor signaling. CONCLUSIONS: Integration of transcriptomic and proteomic data from blood enabled identification of clinically meaningful molecular endotypes of IPF. If validated, these endotypes could facilitate identification of individuals likely to experience disease progression and enrichment of clinical trials. TRIAL REGISTRATION: NCT01915511.

Evaluation of host cellular responses to Epstein-Barr virus (EBV) in adult lung transplant patients with EBV-associated diseases.

Epstein-Barr virus (EBV) reactivation is commonly observed in lung transplant recipients (LTRs). However, cellular immune responses to EBV in adult LTRs have not been well described. We aimed to study CD4/CD8 ratio, EBV-specific T cells polyfunctional responses and phenotypic changes in natural killer (NK) cells in adult LTRs presenting with EBV-associated diseases. The CD4/CD8 ratio was significantly decreased in LTRs with EBV DNAemia compared with LTRs without EBV DNAemia and healthy controls (HCs). Stimulation with EBV lytic antigen BZLF1 peptide pools induced significant individual and polyfunctional responses from CD8+ CD69+ T cells. Frequencies of CD8+ CD69+ T cells expressing CD107a were significantly higher in LTRs without EBV DNAemia than in LTRs with DNAemia. Frequencies of CD8+ CD69+ T cells concurrently expressing CD107a, IFN-γ, and TNF-α were significantly greater in LTRs with and without EBV DNAemia than in HCs. Finally, BZLF1 induced significantly higher frequencies of CD8+ CD69+ T cells expressing CD107a and IFN-γ in LTRs without EBV DNAemia when compared with EBNA3B. Frequency of more differentiated CD56dim CD16pos NK cells was significantly decreased in LTRs with EBV DNAemia and PTLD compared with HCs. In conclusion, we noted the presence of significant changes in circulating cellular immune responses to EBV in adult LTRs.

BAL Fluid Eosinophilia Associates With Chronic Lung Allograft Dysfunction Risk: A Multicenter Study.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading cause of death among lung transplant recipients. Eosinophils, effector cells of type 2 immunity, are implicated in the pathobiology of many lung diseases, and prior studies suggest their presence associates with acute rejection or CLAD after lung transplantation. RESEARCH QUESTION: Does histologic allograft injury or respiratory microbiology correlate with the presence of eosinophils in BAL fluid (BALF)? Does early posttransplant BALF eosinophilia associate with future CLAD development, including after adjustment for other known risk factors? STUDY DESIGN AND METHODS: We analyzed BALF cell count, microbiology, and biopsy data from a multicenter cohort of 531 lung recipients with 2,592 bronchoscopies over the first posttransplant year. Generalized estimating equation models were used to examine the correlation of allograft histology or BALF microbiology with the presence of BALF eosinophils. Multivariable Cox regression was used to determine the association between ≥ 1% BALF eosinophils in the first posttransplant year and definite CLAD. Expression of eosinophil-relevant genes was quantified in CLAD and transplant control tissues. RESULTS: The odds of BALF eosinophils being present was significantly higher at the time of acute rejection and nonrejection lung injury histologies and during pulmonary fungal detection. Early posttransplant ≥ 1% BALF eosinophils significantly and independently increased the risk for definite CLAD development (adjusted hazard ratio, 2.04; P = .009). Tissue expression of eotaxins, IL-13-related genes, and the epithelial-derived cytokines IL-33 and thymic stromal lymphoprotein were significantly increased in CLAD. INTERPRETATION: BALF eosinophilia was an independent predictor of future CLAD risk across a multicenter lung recipient cohort. Additionally, type 2 inflammatory signals were induced in established CLAD. These data underscore the need for mechanistic and clinical studies to clarify the role of type 2 pathway-specific interventions in CLAD prevention or treatment.

Effect of Antifibrotic Therapy on Survival in Patients With Idiopathic Pulmonary Fibrosis.

PURPOSE: Real-world studies have reported reduced mortality in patients with idiopathic pulmonary fibrosis (IPF) treated with antifibrotic therapy; however, the initiation or discontinuation of therapy during these studies may have introduced bias. This study investigated the effect of antifibrotic therapy on mortality and other outcomes in patients with IPF using causal inference methodology. METHODS: Data from a multicenter US registry of patients with IPF were used to assess the effect of antifibrotic therapy (nintedanib or pirfenidone) on death, death or lung transplant, respiratory-related hospitalization, and acute worsening of IPF (defined as any health care encounter deemed due to acute worsening of IPF). This study used the Gran method, which accounts for differences in patient characteristics and for treatment initiations and discontinuations during follow-up. The analysis cohort was limited to patients who started antifibrotic therapy on or after the day of enrollment or had never taken it. FINDINGS: Among the 499 patients analyzed, 352 (70.5%) received antifibrotic therapy. Estimated event rates of death at 1 year were 6.6% (95% CI, 6.1-7.1) for treated patients and 10.2% (95% CI, 9.5-10.9) for control patients. There was a numerical reduction in the risk of death (hazard ratio [HR], 0.53; 95% CI, 0.28-1.03; P = 0.060) but numerical increases in risks of respiratory-related hospitalization (HR, 1.88; 95% CI, 0.90-3.92; P = 0.091) and acute worsening of IPF (HR, 1.71; 95% CI, 0.36-8.09; P = 0.496) in treated versus control patients. IMPLICATIONS: Analyses based on causal inference methodology suggest that patients with IPF who receive antifibrotic therapy have improved survival.

Reflux Surgery in Lung Transplantation: A Multicenter Retrospective Study.

BACKGROUND: Aspiration has been associated with graft dysfunction after lung transplantation, leading some to advocate for selective use of fundoplication despite minimal data supporting this practice. METHODS: We performed a multicenter retrospective study at 4 academic lung transplant centers to determine the association of gastroesophageal reflux disease and fundoplication with bronchiolitis obliterans syndrome and survival using Cox multivariable regression. RESULTS: Of 542 patients, 136 (25.1%) underwent fundoplication; 99 (18%) were found to have reflux disease without undergoing fundoplication. Blanking the first year after transplantation, fundoplication was not associated with a benefit regarding freedom from bronchiolitis obliterans syndrome (hazard ratio [HR], 0.93; 95% CI, 0.58-1.49) or death (HR, 0.97; 95% CI, 0.47-1.99) compared with reflux disease without fundoplication. However, a time-dependent adjusted analysis found a slight decrease in mortality (HR, 0.59; 95% CI, 0.28-1.23; P = .157), bronchiolitis obliterans syndrome (HR, 0.68; 95% CI, 0.42-1.11; P = .126), and combined bronchiolitis obliterans syndrome or death (HR, 0.66; 95% CI, 0.42-1.04; P = .073) in the fundoplication group compared with the gastroesophageal reflux disease group. CONCLUSIONS: Although a statistically significant benefit from fundoplication was not determined because of limited sample size, follow-up, and potential for selection bias, a randomized, prospective study is still warranted.

Risk of Atherosclerotic Cardiovascular Disease Hospitalizations after COPD Hospitalization among Older Adults.

BACKGROUND: Meta-analyses have suggested the risk of atherosclerotic cardiovascular disease (ASCVD) events is significantly higher after a chronic obstructive pulmonary disease (COPD) exacerbation. However, these studies have been limited to highly selected patient populations potentially not generalizable to the broader population of COPD. METHODS: We assessed the risk of ASCVD hospitalizations after COPD hospitalization compared to before COPD hospitalization and identified patient factors associated with ASCVD hospitalizations after COPD hospitalization. This retrospective cohort study used claims data from 920,550 Medicare beneficiaries hospitalized for COPD from 2016-2019 in the US. The primary outcome was risk of a ASCVD hospitalization composite outcome (myocardial infarction, percutaneous coronary intervention, coronary artery by-pass graft surgery, stroke, or transient ischemic attack) in the 1 year after-COPD hospitalization relative to the 1 year before-COPD hospitalization. Time from discharge to a composite ASCVD hospitalization outcome was modeled using an extension of the Cox Proportional-Hazards model, the Anderson-Gill model with adjustment for patient characteristics. Additional analyses evaluated for interactions in subgroups and risk factors associated with the composite ASCVD hospitalization outcome. RESULTS: Among 920,550 patients (mean age, 73 years) the hazard ratio estimate (HR; 95% CI) for the composite ASCVD hospitalization outcome after-COPD hospitalization vs before-COPD hospitalization was 0.99 (0.97, 1.02; p = 0.53) following adjustment. We observed 3 subgroups that were significantly associated with higher risk for ASCVD hospitalizations after COPD hospitalization: 76+ years old, women, COPD hospitalization severity. Among the 19 characteristics evaluated, 10 were significantly associated with higher risk of CVD events 1 year after COPD hospitalization with hyperlipidemia (2.78; 2.67, 2.90) and history of cardiovascular disease (1.77; 1.72 1.83) associated with the greatest risk. CONCLUSION: Among Medicare beneficiaries hospitalized for COPD, the risk of ASCVD hospitalizations was not significantly increased after COPD-hospitalization relative to before-COPD hospitalization. Although, we identified age 76+ years old, female sex, and COPD hospitalization severity as high risk subgroups and 10 risk factors associated with increased risk of ASCVD events after-COPD hospitalization. Further research is needed to characterize the COPD exacerbation populations at highest ASCVD hospitalization risk.

Lung Allograft Microbiome Association with Gastroesophageal Reflux, Inflammation, and Allograft Dysfunction.

Rationale: It remains unclear how gastroesophageal reflux disease (GERD) affects allograft microbial community composition in lung transplant recipients and its impact on lung allograft inflammation and function. Objectives: Our objective was to compare the allograft microbiota in lung transplant recipients with or without clinically diagnosed GERD in the first year after transplant and assess associations between GERD, allograft microbiota, inflammation, and acute and chronic lung allograft dysfunction (ALAD and CLAD). Methods: A total of 268 BAL samples were collected from 75 lung transplant recipients at a single transplant center every 3 months after transplant for 1 year. Ten transplant recipients from a separate transplant center provided samples before and after antireflux Nissen fundoplication surgery. Microbial community composition and density were measured using 16S ribosomal RNA gene sequencing and quantitative polymerase chain reaction, respectively, and inflammatory markers and bile acids were quantified. Measurements and Main Results: We observed a range of allograft community composition with three discernible types (labeled community state types [CSTs] 1-3). Transplant recipients with GERD were more likely to have CST1, characterized by high bacterial density and relative abundance of the oropharyngeal colonizing genera Prevotella and Veillonella. GERD was associated with more frequent transitions to CST1. CST1 was associated with lower inflammatory cytokine concentrations than pathogen-dominated CST3 across the range of microbial densities observed. Cox proportional hazard models revealed associations between CST3 and the development of ALAD/CLAD. Nissen fundoplication decreased bacterial load and proinflammatory cytokines. Conclusions: GERD was associated with a high bacterial density, Prevotella- and Veillonella-dominated CST1. CST3, but not CST1 or GERD, was associated with inflammation and early development of ALAD and CLAD. Nissen fundoplication was associated with a reduction in microbial density in BAL fluid samples, especially the CST1-specific genus, Prevotella.

Rare and Common Variants in KIF15 Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis.

Rationale: Genetic studies of idiopathic pulmonary fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified. Objectives: To identify genes enriched with rare deleterious variants in IPF and familial pulmonary fibrosis. Methods: We performed gene burden analysis of whole-exome data, tested single variants for disease association, conducted KIF15 (kinesin family member 15) functional studies, and examined human lung single-cell RNA sequencing data. Measurements and Main Results: Gene burden analysis of 1,725 cases and 23,509 control subjects identified heterozygous rare deleterious variants in KIF15, a kinesin involved in spindle separation during mitosis, and three telomere-related genes (TERT [telomerase reverse transcriptase], RTEL1 [regulator of telomere elongation helicase 1], and PARN [poly(A)-specific ribonuclease]). KIF15 was implicated in autosomal-dominant models of rare deleterious variants (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.7-8.8; P = 2.55 × 10-7) and rare protein-truncating variants (OR, 7.6; 95% CI, 3.3-17.1; P = 8.12 × 10-7). Meta-analyses of the discovery and replication cohorts, including 2,966 cases and 29,817 control subjects, confirm the involvement of KIF15 plus the three telomere-related genes. A common variant within a KIF15 intron (rs74341405; OR, 1.6; 95% CI, 1.4-1.9; P = 5.63 × 10-10) is associated with IPF risk, confirming a prior report. Lymphoblastoid cells from individuals heterozygous for the common variant have decreased KIF15 and reduced rates of cell growth. Cell proliferation is dependent on KIF15 in the presence of an inhibitor of Eg5/KIF11, which has partially redundant function. KIF15 is expressed specifically in replicating human lung cells and shows diminished expression in replicating epithelial cells of patients with IPF. Conclusions: Both rare deleterious variants and common variants in KIF15 link a nontelomerase pathway of cell proliferation with IPF susceptibility.

LPA1 antagonist BMS-986020 changes collagen dynamics and exerts antifibrotic effects in vitro and in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited treatment options. A phase 2 trial (NCT01766817) showed that twice-daily treatment with BMS-986020, a lysophosphatidic acid receptor 1 (LPA1) antagonist, significantly decreased the slope of forced vital capacity (FVC) decline over 26 weeks compared with placebo in patients with IPF. This analysis aimed to better understand the impact of LPA1 antagonism on extracellular matrix (ECM)-neoepitope biomarkers and lung function through a post hoc analysis of the phase 2 study, along with an in vitro fibrogenesis model. METHODS: Serum levels of nine ECM-neoepitope biomarkers were measured in patients with IPF. The association of biomarkers with baseline and change from baseline FVC and quantitative lung fibrosis as measured with high-resolution computed tomography, and differences between treatment arms using linear mixed models, were assessed. The Scar-in-a-Jar in vitro fibrogenesis model was used to further elucidate the antifibrotic mechanism of BMS-986020. RESULTS: In 140 patients with IPF, baseline ECM-neoepitope biomarker levels did not predict FVC progression but was significantly correlated with baseline FVC and lung fibrosis measurements. Most serum ECM-neoepitope biomarker levels were significantly reduced following BMS-986020 treatment compared with placebo, and several of the reductions correlated with FVC and/or lung fibrosis improvement. In the Scar-in-a-Jar in vitro model, BMS-986020 potently inhibited LPA1-induced fibrogenesis. CONCLUSIONS: BMS-986020 reduced serum ECM-neoepitope biomarkers, which were previously associated with IPF prognosis. In vitro, LPA promoted fibrogenesis, which was LPA1 dependent and inhibited by BMS-986020. Together these data elucidate a novel antifibrotic mechanism of action for pharmacological LPA1 blockade. Trial registration ClinicalTrials.gov identifier: NCT01766817; First posted: January 11, 2013; https://clinicaltrials.gov/ct2/show/NCT01766817 .

E-cigarette and food flavoring diacetyl alters airway cell morphology, inflammatory and antiviral response, and susceptibility to SARS-CoV-2.

Diacetyl (DA) is an α-diketone that is used to flavor microwave popcorn, coffee, and e-cigarettes. Occupational exposure to high levels of DA causes impaired lung function and obstructive airway disease. Additionally, lower levels of DA exposure dampen host defenses in vitro. Understanding DA's impact on lung epithelium is important for delineating exposure risk on lung health. In this study, we assessed the impact of DA on normal human bronchial epithelial cell (NHBEC) morphology, transcriptional profiles, and susceptibility to SARS-CoV-2 infection. Transcriptomic analysis demonstrated cilia dysregulation, an increase in hypoxia and sterile inflammation associated pathways, and decreased expression of interferon-stimulated genes after DA exposure. Additionally, DA exposure resulted in cilia loss and increased hyaluronan production. After SARS-CoV-2 infection, both genomic and subgenomic SARS-CoV-2 RNA were increased in DA vapor- compared to vehicle-exposed NHBECs. This work suggests that transcriptomic and physiologic changes induced by DA vapor exposure damage cilia and increase host susceptibility to SARS-CoV-2.

Association of Circulating Proteins with Death or Lung Transplant in Patients with Idiopathic Pulmonary Fibrosis in the IPF-PRO Registry Cohort.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a variable clinical course. Biomarkers that predict patient outcomes are needed. We leveraged data from 300 patients in the multicenter IPF-PRO Registry to determine associations between circulating proteins and the composite outcome of respiratory death or lung transplant. Plasma collected at enrollment was analyzed using aptamer-based proteomics (1305 proteins). Over a median follow-up of 30.4 months, there were 76 respiratory deaths and 26 lung transplants. In unadjusted univariable analyses, 61 proteins were significantly associated with the outcome (hazard ratio > 2 or < 0.5, corrected p ≤ 0.05). In multivariable analyses, a set of 4 clinical measures and 47 unique proteins predicted the probability of respiratory death or lung transplant with an optimism-corrected C-index of 0.76. Our results suggest that select circulating proteins strongly associate with the risk of mortality in patients with IPF and confer information independent of clinical measures.

Disparities in Lung Transplant among Patients with Idiopathic Pulmonary Fibrosis: An Analysis of the IPF-PRO Registry.

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).

Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA1) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD).

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA1-6). Signalling via LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA1 antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD. METHODS AND ANALYSIS: This phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort. ETHICS AND DISSEMINATION: This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT04308681.