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Rationale: The molecular mechanisms underlying acute exacerbations of idiopathic pulmonary fibrosis (IPF) are poorly understood. We studied the global gene expression signature of acute exacerbations of IPF.Objectives: To understand the gene expression patterns of acute exacerbations of IPF.Methods: RNA was extracted from 23 stable IPF lungs, 8 IPF lungs with acute exacerbation (IPF-AEx), and 15 control lungs and used for hybridization on Agilent gene expression microarrays. Functional analysis of genes was performed with Spotfire and Genomica. Gene validations for MMP1, MMP7, AGER, DEFA1-3, COL1A2, and CCNA2 were performed by real-time quantitative reverse transcription-polymerase chain reaction. Immunohistochemistry and in situ terminal deoxynucleotidyltransferase dUTP nick end-labeling assays were performed on the same tissues used for the microarray. ELISA for alpha-defensins was performed on plasma from control subjects, patients with stable IPF, and patients with IPF-AEx.Measurements and Main Results: Gene expression patterns in IPF-AEx and IPF samples were similar for the genes that distinguish IPF from control lungs. Five hundred and seventy-nine genes were differentially expressed (false discovery rate < 5%) between stable IPF and IPF-AEx. Functional analysis of these genes did not indicate any evidence of an infectious or overwhelming inflammatory etiology. CCNA2 and alpha-defensins were among the most up-regulated genes. CCNA2 and alpha-defensin protein levels were also higher and localized to the epithelium of IPF-AEx, where widespread apoptosis was also detected. alpha-Defensin protein levels were increased in the peripheral blood of patients with IPF-AEx.Conclusions: Our results indicate that IPF-AEx is characterized by enhanced epithelial injury and proliferation, as reflected by increases in CCNA2 and alpha-defensins and apoptosis of epithelium. The concomitant increase in alpha-defensins in the peripheral blood and lungs may suggest their use as biomarkers for this disorder. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis is an idiopathic multiorgan disease with variable clinical outcomes. Comprehensive analysis of sarcoidosis mortality in U.S. Veterans is lacking., Research Questions: What are the trends in all-cause mortality among U.S. Veterans with sarcoidosis, and how are these trends influenced by demographics, Black vs. White racial disparities, and geographic variability in relation to mortality?, Study Design and Methods: Using Veterans Health Administration (VHA) electronic health records (EHR), we conducted a population-based, retrospective cohort study of adjusted all-cause mortality 2004-2022 among Veterans diagnosed with sarcoidosis who received care through the VHA. Demographics, region of residence, service branch, tobacco use, and comorbidities were extracted from EHR. Annual trends in all-cause mortality and patient-level characteristics associated with mortality were examined with multivariable ungrouped Poisson regression. We visualized trends and analyzed state-by-state mortality using the marginal means procedure. In subgroup analysis (2015-2022), we considered the impact of neighborhood-level socioeconomic disparities using the area deprivation index (ADI)., Results: In all, 23,745 Veterans were diagnosed with sarcoidosis between 2004 and 2019 and followed through 2022. After adjustment, including age and sex, all-cause mortality increased annually by 4.7% (P<0.0001) and was 6.4% higher in Black than White Veterans (mortality rate ratio=1.064, P=0.02). A subgroup analysis comparing models with and without ADI adjustment showed no meaningful change in mortality trends. Risk factors for increased all-cause mortality included older age, male sex, Black race, and Northeast residence, and lower risk with "Other" service branches. Despite distinct geographical variations in mortality rates, no clear patterns emerged., Interpretation: Mortality among Veterans with sarcoidosis is rising. Differences identified by service branch and higher risk among male Veterans raise questions about differences in environmental exposures. The narrower racial disparities and smaller impact of ADI than in other studies may highlight the role of universal healthcare access in achieving equitable outcomes., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: None disclosed

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

Rationale: Recent data suggest that the localisation of airway epithelial cells in the distal lung in idiopathic pulmonary fibrosis (IPF) may drive pathology. We set out to discover whether chemokines expressed in these ectopic airway epithelial cells may contribute to the pathogenesis of IPF., Methods: We analysed whole lung and single-cell transcriptomic data obtained from patients with IPF. In addition, we measured chemokine levels in blood, bronchoalveolar lavage (BAL) of IPF patients and air-liquid interface cultures. We employed ex vivo donor and IPF lung fibroblasts and an animal model of pulmonary fibrosis to test the effects of chemokine signalling on fibroblast function., Results: By analysis of whole-lung transcriptomics, protein and BAL, we discovered that CXCL6 (a member of the interleukin-8 family) was increased in patients with IPF. Elevated CXCL6 levels in the BAL of two cohorts of patients with IPF were associated with poor survival (hazard ratio of death or progression 1.89, 95% CI 1.16-3.08; n=179, p=0.01). By immunostaining and single-cell RNA sequencing, CXCL6 was detected in secretory cells. Administration of mCXCL5 (LIX, murine CXCL6 homologue) to mice increased collagen synthesis with and without bleomycin. CXCL6 increased collagen I levels in donor and IPF fibroblasts 4.4-fold and 1.7-fold, respectively. Both silencing of and chemical inhibition of CXCR1/2 blocked the effects of CXCL6 on collagen, while overexpression of CXCR2 increased collagen I levels 4.5-fold in IPF fibroblasts., Conclusions: CXCL6 is expressed in ectopic airway epithelial cells. Elevated levels of CXCL6 are associated with IPF mortality. CXCL6-driven collagen synthesis represents a functional consequence of ectopic localisation of airway epithelial cells in IPF., Competing Interests: Conflict of interest: N. Kaminski is a scientific founder at Thyron, and served as a consultant to Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Optikira, AstraZeneca, RohBar, Veracyte, Augmanity, CSL Behring, Galapagos and Thyron over the last 3 years, reports equity in Pliant and Thyron, and grants from Veracyte, Boehringer Ingelheim and BMS, and non-financial support from MiRagen and AstraZeneca. R. Lafyatis reports grants from Bristol Meyer Squib, Corbus, Formation, Moderna, Regeneron, Pfizer and Kiniksa, outside the submitted work, and served as a consultant with Bristol Meyers Squibb, Formation, Sanofi, Boehringer Ingelheim, Merck and Genentech/Roche. A. Prasse reports personal fees and non-financial support from Boehringer Ingelheim and Roche, personal fees from Novartis, AstraZeneca, Amgen, Pliant and Nitto Denko, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

High-resolution computed tomography (HRCT) imaging is critical for diagnostic evaluation of Idiopathic Pulmonary Fibrosis (IPF). However, several other interstitial lung diseases (ILDs) often exhibit radiologic pattern similar to IPF on HRCT making the diagnosis of the disease difficult. Therefore, biomarkers that distinguish IPF from other ILDs can be a valuable aid in diagnosis. Using mass spectrometry, we performed proteomic analysis of plasma extracellular vesicles (EVs) in patients diagnosed with IPF, chronic hypersensitivity pneumonitis, nonspecific interstitial pneumonitis, and healthy subjects. A five-protein signature was identified by lasso regression and was validated in an independent cohort using ELISA. The five-protein signature derived from mass spectrometry data showed an area under the receiver operating characteristic curve of 0.915 (95%CI: 0.819-1.011) and 0.958 (95%CI: 0.882-1.034) for differentiating IPF from other ILDs and from healthy subjects, respectively. Stepwise backwards elimination yielded a model with 3 and 2 proteins for discriminating IPF from other ILDs and healthy subjects, respectively, without compromising diagnostic accuracy. In summary, we discovered and validated EV protein biomarkers for differential diagnosis of IPF in independent cohorts. Interestingly, the biomarker panel could also distinguish IPF and healthy subjects with high accuracy. The biomarkers need to be evaluated in large prospective cohorts to establish their clinical utility., Competing Interests: A.K.P. is employed with Izon Science US Ltd. The company has no role in design of the study and acquisition of experimental data and interpretation. All other authors have no conflict of interests., (© 2023 The Authors. Journal of Extracellular Biology published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

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

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) whose outcomes are worsened with air pollution exposures. DNA methylation (DNAm) patterns are altered in lungs and blood from patients with IPF, but the relationship between air pollution exposures and DNAm patterns in IPF remains unexplored. This study aimed to evaluate the association of PM 2.5 and constituent components with global DNAm in patients with IPF. Patients enrolled in either the University of Pittsburgh Simmons Center for ILD Registry (Simmons) or the U.S.-wide Pulmonary Fibrosis Foundation (PFF) Patient Registry with peripheral blood DNA samples were included. The averages of monthly exposures to PM 2.5 and constituents over 1-year and 3-months pre-blood collection were matched to patient residential coordinates using satellite-derived hybrid models. Global DNAm percentage (%5 mC) was determined using the ELISA-based MethylFlash assay. Associations of pollutants with %5 mC were assessed using beta-regression, Cox models for mortality, and linear regression for baseline lung function. Mediation proportion was determined for models where pollutant-mortality and pollutant-%5 mC associations were significant. Inclusion criteria were met by 313 Simmons and 746 PFF patients with IPF. Higher PM 2.5 3-month exposures prior to blood collection were associated with higher %5 mC in Simmons (β = 0.02, 95%CI 0.0003-0.05, p = 0.047), with trends in the same direction in the 1-year period in both cohorts. Higher exposures to sulfate, nitrate, ammonium, and black carbon constituents were associated with higher %5 mC in multiple models. Percent 5 mC was not associated with IPF mortality or lung function, but was found to mediate between 2 and 5% of the associations of PM 2.5 , sulfate, and ammonium with mortality. In conclusion, we found that higher global DNAm is a novel biomarker for increased PM 2.5 and anthropogenic constituent exposure in patients with IPF. Mechanistic research is needed to determine if DNAm has pathogenic relevance in mediating associations between pollutants and mortality in IPF., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gillian C. Goobie reports financial support was provided by Pulmonary Fibrosis Foundation. Gillian C. Goobie reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. Kathleen O. Lindell reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. Daniel J. Kass reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. S. Mehdi Nouraie reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. Christopher J. Ryerson reports a relationship with Boehringer Ingelheim Canada Ltd that includes: funding grants. Christopher J. Ryerson reports a relationship with Hoffmann-La Roche Limited that includes:. Kerri A. Johannson reports a relationship with Boehringer Ingelheim Canada Ltd that includes: consulting or advisory and funding grants. Kerri A. Johannson reports a relationship with Three Lakes Foundation that includes: consulting or advisory and funding grants. Kerri A. Johannson reports a relationship with Hoffmann-La Roche Limited that includes: consulting or advisory. James P. Fabisiak reports a relationship with Heinz Endowments that includes: funding grants. Daniel J. Kass reports a relationship with National Institutes of Health that includes: funding grants. Yingze Zhang reports a relationship with National Institutes of Health that includes: funding grants., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Importance: Particulate matter 2.5 μm or less in diameter (PM2.5) is associated with adverse outcomes for patients with idiopathic pulmonary fibrosis, but its association with other fibrotic interstitial lung diseases (fILDs) and the association of PM2.5 composition with adverse outcomes remain unclear., Objective: To investigate the association of PM2.5 exposure with mortality and lung function among patients with fILD., Design, Setting, and Participants: In this multicenter, international, prospective cohort study, patients were enrolled in the Simmons Center for Interstitial Lung Disease Registry at the University of Pittsburgh in Pittsburgh, Pennsylvania; 42 sites of the Pulmonary Fibrosis Foundation Registry; and 8 sites of the Canadian Registry for Pulmonary Fibrosis. A total of 6683 patients with fILD were included (Simmons, 1424; Pulmonary Fibrosis Foundation, 1870; and Canadian Registry for Pulmonary Fibrosis, 3389). Data were analyzed from June 1, 2021, to August 2, 2022., Exposures: Exposure to PM2.5 and its constituents was estimated with hybrid models, combining satellite-derived aerosol optical depth with chemical transport models and ground-based PM2.5 measurements., Main Outcomes and Measures: Multivariable linear regression was used to test associations of exposures 5 years before enrollment with baseline forced vital capacity and diffusion capacity for carbon monoxide. Multivariable Cox models were used to test associations of exposure in the 5 years before censoring with mortality, and linear mixed models were used to test associations of exposure with a decrease in lung function. Multiconstituent analyses were performed with quantile-based g-computation. Cohort effect estimates were meta-analyzed. Models were adjusted for age, sex, smoking history, race, a socioeconomic variable, and site (only for Pulmonary Fibrosis Foundation and Canadian Registry for Pulmonary Fibrosis cohorts)., Results: Median follow-up across the 3 cohorts was 2.9 years (IQR, 1.5-4.5 years), with death for 28% of patients and lung transplant for 10% of patients. Of the 6683 patients in the cohort, 3653 were men (55%), 205 were Black (3.1%), and 5609 were White (84.0%). Median (IQR) age at enrollment across all cohorts was 66 (58-73) years. A PM2.5 exposure of 8 μg/m3 or more was associated with a hazard ratio for mortality of 4.40 (95% CI, 3.51-5.51) in the Simmons cohort, 1.71 (95% CI, 1.32-2.21) in the Pulmonary Fibrosis Foundation cohort, and 1.45 (95% CI, 1.18-1.79) in the Canadian Registry for Pulmonary Fibrosis cohort. Increasing exposure to sulfate, nitrate, and ammonium PM2.5 constituents was associated with increased mortality across all cohorts, and multiconstituent models demonstrated that these constituents tended to be associated with the most adverse outcomes with regard to mortality and baseline lung function. Meta-analyses revealed consistent associations of exposure to sulfate and ammonium with mortality and with the rate of decrease in forced vital capacity and diffusion capacity of carbon monoxide and an association of increasing levels of PM2.5 multiconstituent mixture with all outcomes., Conclusions and Relevance: This cohort study found that exposure to PM2.5 was associated with baseline severity, disease progression, and mortality among patients with fILD and that sulfate, ammonium, and nitrate constituents were associated with the most harm, highlighting the need for reductions in human-derived sources of pollution.

Rationale: Treatment options for idiopathic pulmonary fibrosis (IPF) are limited. Objectives: To evaluate the efficacy and safety of BG00011, an anti-α v β 6 IgG1 monoclonal antibody, in the treatment of patients with IPF. Methods: In a phase IIb randomized, double-blind, placebo-controlled trial, patients with IPF (FVC ⩾50% predicted, on or off background therapy) were randomized 1:1 to once-weekly subcutaneous BG00011 56 mg or placebo. The primary endpoint was FVC change from baseline at Week 52. Because of early trial termination (imbalance in adverse events and lack of clinical benefit), endpoints were evaluated at Week 26 as an exploratory analysis. Measurements and Main Results: One hundred six patients were randomized and received at least one dose of BG00011 ( n  = 54) or placebo ( n  = 52). At Week 26, there was no significant difference in FVC change from baseline between patients who received BG00011 ( n  = 20) or placebo ( n  = 23), least squares mean (SE) -0.097 L (0.0600) versus -0.056 L (0.0593), respectively ( P  = 0.268). However, after Week 26, patients in the BG00011 group showed a worsening trend. Eight (44.4%) of 18 who received BG00011 and 4 (18.2%) of 22 who received placebo showed worsening of fibrosis on high-resolution computed tomography at the end of treatment. IPF exacerbation/or progression was reported in 13 patients (all in the BG00011 group). Serious adverse events occurred more frequently in BG00011 patients, including four deaths. Conclusions: The results do not support the continued clinical development of BG00011. Further research is warranted to identify new treatment strategies that modify inflammatory and fibrotic pathways in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT03573505).

Background: This multicentre, international, prospective cohort study evaluated whether patients with pulmonary sarcoidosis living in neighbourhoods with greater material and social disadvantage experience worse clinical outcomes., Methods: The area deprivation index and the Canadian Index of Multiple Deprivation evaluate neighbourhood-level disadvantage in the US and Canada, with higher scores reflecting greater disadvantage. Multivariable linear regression evaluated associations of disadvantage with baseline forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide ( D LCO ) and linear mixed effects models for associations with rate of FVC or D LCO decline, and competing hazards models were used for survival analyses in the US cohort, evaluating competing outcomes of death or lung transplantation. Adjustments were made for age at diagnosis, sex, race and smoking history., Results: We included 477 US and 122 Canadian patients with sarcoidosis. Higher disadvantage was not associated with survival or baseline FVC. The highest disadvantage quartile was associated with lower baseline D LCO in the US cohort (β = -6.80, 95% CI -13.16 to -0.44, p=0.04), with similar findings in the Canadian cohort (β = -7.47, 95% CI -20.28 to 5.33, p=0.25); with more rapid decline in FVC and D LCO in the US cohort (FVC β = -0.40, 95% CI -0.70 to -0.11, p=0.007; D LCO β = -0.59, 95% CI -0.95 to -0.23, p=0.001); and with more rapid FVC decline in the Canadian cohort (FVC β = -0.80, 95% CI -1.37 to -0.24, p=0.003)., Conclusion: Patients with sarcoidosis living in high disadvantage neighbourhoods experience worse baseline lung function and more rapid lung function decline, highlighting the need for better understanding of how neighbourhood-level factors impact individual patient outcomes., Competing Interests: Conflict of interest: G.C. Goobie receives research funding and support through the Pulmonary Fibrosis Foundation Scholars Award Program and the University of British Columbia Clinician Investigator Program. C.J. Ryerson, D. Assayag and M.R.J. Kolb report personal fees and grants from Boehringer Ingelheim and Hoffman La Roche outside the submitted work. K.A. Johannson reports personal fees, nonfinancial support and other support from Boehringer Ingelheim and the Three Lakes Foundation, personal fees from Hoffman-La Roche Ltd, and grants from the University Hospital Foundation, the University of Calgary Cumming School of Medicine, and the Pulmonary Fibrosis Society of Calgary. V. Marcoux reports grants and personal fees from Boehringer Ingelheim Canada, Hoffman La-Roche Ltd and AstraZeneca, and grants from the University of Saskatchewan and the Royal University Hospital Foundation. M.R.J. Kolb also reports personal fees and grants from GSK, Gilead, Actelion, Respivert, Genoa, Alkermes, Pharmaxis, Prometric, Indalo and Third Pole. H. Manganas reports grants from Hoffman-La Roche Ltd, Galapagos and BMS, and personal fees and research grants from Boehringer Ingelheim. D. Assayag also reports personal fees and grants from Novartis. J.H. Fisher reports grants from the Canadian Pulmonary Fibrosis Foundation, and personal fees from Boehringer Ingelheim and AstraZeneca, outside of the submitted work. D.J. Kass is supported in part by AR060780, HL133232, UL1 TR001857 and AR076024 (NIH grants), Boehringer Ingelheim grants, and receives collaborative research funding from Regeneron Pharmaceuticals, outside of the submitted work. Y. Zhang is supported in part by AR076024 (NIH grant). S. Keil, E. Schikowski, N. Khalil, X. Chen, K.F. Gibson and K.O. Lindell report no competing interests. S.M. Nouraie receives grant support from Boehringer Ingelheim USA., (Copyright ©The authors 2022.)

Background: Idiopathic pulmonary fibrosis (IPF) is the most common indication for lung transplantation in North America and variants in telomere-maintenance genes are the most common identifiable cause of IPF. We reasoned that younger IPF patients are more likely to undergo lung transplantation and we hypothesized that lung transplant recipients would be enriched for individuals with telomere-mediated disease due to the earlier onset and more severe disease in these patients., Methods: Individuals with IPF who underwent lung transplantation or were evaluated in an interstitial lung disease specialty clinic who did not undergo lung transplantation were examined. Genetic evaluation was completed via whole genome sequencing (WGS) of 426 individuals and targeted sequencing for 5 individuals. Rare variants in genes previously associated with IPF were classified using the American College of Medical Genetics guidelines. Telomere length from WGS data was measured using TelSeq software. Patient characteristics were collected via medical record review., Results: Of 431 individuals, 149 underwent lung transplantation for IPF. The median age of diagnosis of transplanted vs non-transplanted individuals was significantly younger (60 years vs 70 years, respectively, p<0.0001). IPF lung transplant recipients (IPF-LTRs) were twice as likely to have telomere-related rare variants compared to non-transplanted individuals (24% vs 12%, respectively, p=0.0013). IPF-LTRs had shorter telomeres than non-transplanted IPF patients (p=0.0028) and >85% had telomeres below the age-adjusted mean. Post-transplant survival and CLAD were similar amongst IPF-LTRs with rare variants in telomere-maintenance genes compared to those without, as well as in those with short telomeres versus longer telomeres., Conclusions: There is an enrichment for telomere-maintenance gene variants and short telomeres among IPF-LTRs. However, transplant outcomes of survival and CLAD do not differ by gene variants or telomere length within IPF-LTRs. Our findings support individual with telomere-mediated disease should not be excluded from lung transplantation and focusing research efforts on therapies directed toward individuals with short-telomere mediated disease., Competing Interests: Conflict of interest This project was supported by National Heart, Lung, and Blood Institute Grant R01HL135062 (JA), R01 HL133184 (JM), UPMC Immune Transplant and Therapy Center, UPMC Genomics Research Center, Kathleen Ford Fund for Lung Transplant Research, The Richard P. Simmons Chair for Interstitial Lung Disease, and the Simmons Genetics Research Fund., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: Fibrotic interstitial lung disease (fILD) is a group of pathologic entities characterized by scarring of the lungs and high morbidity and mortality. Research investigating how socioeconomic and residential factors impact outcomes in patients with fILD is lacking. Objectives: To determine the association between neighborhood-level disadvantage and presentation severity, disease progression, lung transplantation, and mortality in patients with fILD from the United States and Canada. Methods: We performed a multicenter, international, prospective cohort study of 4,729 patients with fILD from one U.S. and eight Canadian ILD registry sites. Neighborhood-level disadvantage was measured by the area deprivation index in the United States and the Canadian Index of Multiple Deprivation in Canada. Measurements and Main Results: In the U.S. but not in the Canadian cohort, patients with fILD living in neighborhoods with the greatest disadvantage (top quartile) experience the highest risk of mortality (hazard ratio = 1.51, P  = 0.002), and in subgroups of patients with idiopathic pulmonary fibrosis, the top quartile of disadvantage experienced the lowest odds of lung transplantation (odds ratio = 0.46, P  = 0.04). Greater disadvantage was associated with reduced baseline DL CO in both cohorts, but it was not associated with baseline FVC or FVC or DL CO decline in either cohort. Conclusions: Patients with fILD who live in areas with greater neighborhood-level disadvantage in the United States experience higher mortality, and patients with idiopathic pulmonary fibrosis experience lower odds of lung transplantation. These disparities are not seen in Canadian patients, which may indicate differences in access to care between the United States and Canada.

Background: Sarcoidosis is a multisystem granulomatous disease of unknown origin with a variable and often unpredictable course and pattern of organ involvement. In this study we sought to identify specific bronchoalveolar lavage (BAL) cell gene expression patterns indicative of distinct disease phenotypic traits., Methods: RNA sequencing by Ion Torrent Proton was performed on BAL cells obtained from 215 well-characterised patients with pulmonary sarcoidosis enrolled in the multicentre Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Weighted gene co-expression network analysis and nonparametric statistics were used to analyse genome-wide BAL transcriptome. Validation of results was performed using a microarray expression dataset of an independent sarcoidosis cohort (Freiburg, Germany; n=50)., Results: Our supervised analysis found associations between distinct transcriptional programmes and major pulmonary phenotypic manifestations of sarcoidosis including T-helper type 1 (Th1) and Th17 pathways associated with hilar lymphadenopathy, transforming growth factor-β1 (TGFB1) and mechanistic target of rapamycin (MTOR) signalling with parenchymal involvement, and interleukin (IL)-7 and IL-2 with airway involvement. Our unsupervised analysis revealed gene modules that uncovered four potential sarcoidosis endotypes including hilar lymphadenopathy with increased acute T-cell immune response; extraocular organ involvement with PI3K activation pathways; chronic and multiorgan disease with increased immune response pathways; and multiorgan involvement, with increased IL-1 and IL-18 immune and inflammatory responses. We validated the occurrence of these endotypes using gene expression, pulmonary function tests and cell differentials from Freiburg., Conclusion: Taken together, our results identify BAL gene expression programmes that characterise major pulmonary sarcoidosis phenotypes and suggest the presence of distinct disease molecular endotypes., Competing Interests: Conflict of interest: M. Vukmirovic has nothing to disclose. Conflict of interest: X. Yan has nothing to disclose. Conflict of interest: K.F. Gibson has nothing to disclose. Conflict of interest: M. Gulati reports grants from NIH, during the conduct of the study; personal fees for advisory board work and other (PI/publication committee) from Boehringer Ingelheim, other (lectures) from France Foundation, other (PI/centre director) from Pulmonary Fibrosis Foundation, grants from NIH and Sarcoidosis Research Foundation, outside the submitted work. Conflict of interest: J.C. Schupp has nothing to disclose. Conflict of interest: G. DeIuliis has nothing to disclose. Conflict of interest: T.S. Adams has nothing to disclose. Conflict of interest: B. Hu has nothing to disclose. Conflict of interest: A. Mihaljinec has nothing to disclose. Conflict of interest: T.N. Woolard has nothing to disclose. Conflict of interest: H. Lynn has nothing to disclose. Conflict of interest: N. Emeagwali has nothing to disclose. Conflict of interest: E.L Herzog reports grants from NIH, Sanofi, Bristol Myers and Promedior, personal fees for consultancy from Boehringer Ingelheim and Pfizer, outside the submitted work. Conflict of interest: E.S. Chen has nothing to disclose. Conflict of interest: A. Morris reports grants from NIH, during the conduct of the study. Conflict of interest: J.K. Leader has nothing to disclose. Conflict of interest: Y. Zhang has nothing to disclose. Conflict of interest: J.G.N. Garcia has nothing to disclose. Conflict of interest: L.A. Maier grants from NIH (1U01 HL112695-01, U01 HL112707-03) and NIH/NCRR (UL1TRR002535), during the conduct of the study; grants from National Institutes of Health (1R01 HL127461-01A1, R01HL136681-01A1, 1R01 HL140357-01A1, R01HL136681-01A1), FSR, University of Cinncinati under a Mallinckrodt foundation, MNK14344100, ATYR1923-C-002, outside the submitted work; and is a member of the FSR scientific advisory board, for which no compensation is received. Conflict of interest: R.G. Collman reports grants from National Institutes of Health, during the conduct of the study. Conflict of interest: W.P. Drake has nothing to disclose. Conflict of interest: M.J. Becich reports grants from NCATS, NCI, PCORI, NHLBI and CDC NIOSH, other (startup) from SpIntellx, during the conduct of the study; other (startup) from SpIntellx, outside the submitted work; and has patents SpIntellx (multiple) pending. Conflict of interest: H. Hochheiser has nothing to disclose. Conflict of interest: S.R. Wisniewski has nothing to disclose. Conflict of interest: P.V. Benos has nothing to disclose. Conflict of interest: D.R. Moller reports grants from NHLBI (1U01HL112708), during the conduct of the study; personal fees for consultancy from Merck, aTYR and Roivant, personal fees for advisory board work from SarcoMed, personal fees for consultancy/witness from Legal Expert, other (royalties) from Hodder Education and Taylor & Francis Group, outside the submitted work; has patents number 9,683,999 B2 issued, and number 9,977,029 B2 issued; is Chairman and Chief Technical Officer of Sarcoidosis Diagnostic Testing, LLC (a company whose goal is to develop a diagnostic blood test for sarcoidosis) and has received funding including past salary support under the NHLBI STTR programme, grant R41 HL129728 more than 3 years ago; and is a former member of the Scientific Advisory Board of the Foundation for Sarcoidosis Research. Conflict of interest: A. Prasse reports personal fees for lectures and consultancy and non-financial support for meeting attendance from Boehringer Ingelheim and Roche, personal fees for lectures from Novartis and AstraZeneca, personal fees for consultancy from Amgen, Pliant and Nitto Denko, outside the submitted work. Conflict of interest: L.L. Koth has nothing to disclose. Conflict of interest: N. Kaminski reports personal fees for consultancy and/or advisory board work from Biogen Idec, Boehringer Ingelheim, Third Rock, Samumed, NuMedii, Indaloo, Theravance, LifeMax, Three Lake Partners, RohBar and Pliant, non-financial support from Miragen, equity with Pliant, a grant from Veracyte; all outside the submitted work; and has a patent New Therapies in Pulmonary Fibrosis and on Peripheral Blood Gene Expression that have been licensed to Biotech., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Rationale: Patients with idiopathic pulmonary fibrosis (IPF) and their caregivers experience stress, symptom burden, poor quality of life, and inadequate preparedness for end-of-life (EOL) care planning as the disease progresses. The hypothesis for this study was that the early introduction of palliative care in the course of IPF would improve knowledge and preparation for EOL, patient-reported outcomes, and advance care planning in patients with IPF and their caregivers. Objectives: We sought to determine the feasibility, acceptability, and efficacy of a nurse-led early palliative care intervention entitled "A Program of SUPPORT" (Symptom management, Understanding the disease, Pulmonary rehabilitation, Palliative care, Oxygen therapy, Research participation, and Transplantation) in patients with IPF and their caregivers. Methods: Patients with IPF (diagnosed in the year previous to their initial center visit) from the University of Pittsburgh Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease at University of Pittsburgh Medical Center-together with their caregivers-were randomized to receive the intervention "A Program of SUPPORT" or usual care. This included a total of three research visits aligned with their clinic visit over a period of 6 to 8 months. We measured feasibility, acceptability, and efficacy of this intervention. Results: A total of 136 patient/caregiver dyads were eligible, and a total of 76 dyads were enrolled and participated. Participants were predominately White males >65 years old. Thirteen percent did not have an identified caregiver. Feasibility was limited; 56% of eligible dyads were enrolled. Eligible dyads (24%) were interested in participating but too fatigued to stay after their clinic visit. There was high attrition (20% of participants died before the study was completed). "A Program of SUPPORT" was acceptable to participants. Efficacy demonstrated a significant improvement in caregiver's knowledge, disease preparedness, and confidence in caring for the patient as well as an improvement in knowledge and advance care planning completion in patient participants. Conclusions: Patients with IPF and their caregivers have unmet needs regarding knowledge of their disease, self-management strategies, and preparedness for EOL planning. This nurse-led intervention demonstrated acceptability and efficacy in knowledge and advance care planning completion in patients and in knowledge, disease preparedness, and confidence in caregivers. Future research should identify additional strategies, including telemedicine resources to reach additional patients and their caregivers earlier in their disease course. Clinical trial registered with clinicaltrials.gov (NCT02929017).

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that causes early onset pulmonary emphysema and airways obstruction. The complete mechanisms via which AATD causes lung disease are not fully understood. To improve our understanding of the pathogenesis of AATD, we investigated gene expression profiles of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMCs) in AATD individuals., Methods: We performed RNA-Seq on RNA extracted from matched BAL and PBMC samples isolated from 89 subjects enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Subjects were stratified by genotype and augmentation therapy. Supervised and unsupervised differential gene expression analyses were performed using Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene profiles associated with subjects' clinical variables. The genes in the most significant WGCNA module were used to cluster AATD individuals. Gene validation was performed by NanoString nCounter Gene Expression Assay., Result: We observed modest effects of AATD genotype and augmentation therapy on gene expression. When WGCNA was applied to BAL transcriptome, one gene module, ME31 (2312 genes), correlated with the highest number of clinical variables and was functionally enriched with numerous immune T-lymphocyte related pathways. This gene module identified two distinct clusters of AATD individuals with different disease severity and distinct PBMC gene expression patterns., Conclusions: We successfully identified novel clusters of AATD individuals where severity correlated with increased immune response independent of individuals' genotype and augmentation therapy. These findings may suggest the presence of previously unrecognised disease endotypes in AATD that associate with T-lymphocyte immunity and disease severity., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with a median survival of 3-4 years from time of initial diagnosis, similar to the time course of many malignancies. A hallmark of IPF is its unpredictable disease course, ranging from long periods of clinical stability to acute exacerbations with rapid decompensation. As the disease progresses, patients with chronic cough and progressive exertional dyspnea become oxygen dependent. They may experience significant distress due to concurrent depression, anxiety, and fatigue, which often lead to increased symptom burden and decreased quality of life. Despite these complications, palliative care is an underutilized, and often underappreciated, resource before end-of-life care in this population. While there is growing recognition about early palliative care in IPF, current data suggest referral patterns vary widely based on institutional practices. In addition to focusing on symptom management, there is emphasis on supplemental oxygen use, pulmonary rehabilitation, quality of life, and end-of-life care. Importantly, increased use of support groups and national foundation forums have served as venues for further disease education, communication, and advanced care planning outside of the hospital settings. The purpose of this review article is to discuss the clinical features of IPF, the role of palliative care in chronic disease management, current data supporting benefits of palliative care in IPF, its role in symptom management, and practices to help patients and their caregivers achieve their best quality of life.

Objective: Interstitial lung disease (ILD) is a frequent complication of rheumatoid arthritis (RA), occurring in up to 40% of patients during the course of their disease. Early diagnosis is critical, particularly given the shared clinicoepidemiologic features between advanced rheumatoid arthritis-associated ILD (RA-ILD) and idiopathic pulmonary fibrosis (IPF). This study was undertaken to define the molecular basis of this overlap through comparative profiling of serum proteins in RA-ILD and IPF., Methods: Multiplex enzyme-linked immunosorbent assays (ELISAs) were used to profile 45 protein biomarkers encompassing cytokines/chemokines, growth factors, and matrix metalloproteinases (MMPs) in sera obtained from RA patients with ILD and those without, individuals with IPF, and healthy controls. Levels of selected serum proteins were compared between patient subgroups using adjusted linear regression, principal component analysis (PCA), and least absolute shrinkage and selection operator (LASSO) modeling., Results: Multiplex ELISA-based assessment of sera from 2 independent cohorts (Veterans Affairs [VA] and Non-VA) revealed a number of non-overlapping biomarkers distinguishing RA-ILD from RA without ILD (RA-no ILD) in adjusted regression models. Parallel analysis of sera from IPF patients also yielded a discriminatory panel of protein markers in models adjusted for age/sex/smoking, which showed differential overlap with profiles linked to RA-ILD in the VA cohort versus the Non-VA cohort. PCA revealed several distinct functional groups of RA-ILD-associated markers that, in the VA cohort, encompassed proinflammatory cytokines/chemokines as well as 2 different subsets of MMPs. Finally, LASSO regression modeling in the Non-VA and VA cohorts revealed distinct biomarker combinations capable of discriminating RA-ILD from RA-no ILD., Conclusion: Comparative serum protein biomarker profiling represents a viable method for distinguishing RA-ILD from RA-no ILD and identifying population-specific mediators shared with IPF., (© 2019, American College of Rheumatology.)

In this retrospective study of a randomised trial of simtuzumab in idiopathic pulmonary fibrosis (IPF), prodromal decline in forced vital capacity (FVC) was significantly associated with increased risk of mortality, respiratory and all-cause hospitalisations, and categorical disease progression. Predictive modelling of progression-free survival event risk was used to assess the effect of population enrichment for patients at risk of rapid progression of IPF; C-index values were 0.64 (death), 0.69 (disease progression), and 0.72 (adjudicated respiratory hospitalisation) and 0.76 (all-cause hospitalisation). Predictive modelling may be a useful tool for improving efficiency of clinical trials with categorical end points., Competing Interests: Competing interests: GR has provided consultation for Gilead Sciences, Inc., for this work; for Bellerophon, Biogen, Boehringer Ingelheim, BMS, FibroGen, Gilead Sciences, Inc., Nitto, Promedior, Roche-Genentech, Sanofi-Aventis and Veracyte outside the submitted work; and has received research grants from the National Institutes of Health (NIH) for idiopathic pulmonary fibrosis studies outside the submitted work. BL reports speaker fees from Genentech outside the submitted work. KKB reports grants from the National Heart, Lung, and Blood Institute(NHLBI); grants and consulting fees from Actelion; Amgen; and Gilead Sciences, Inc.; and personal fees from Aeolus, Almirall, Altitude Pharma, AstraZeneca, Bayer, Biogen/Stromedix, Boehringer Ingelheim, Celgene, Centocor, FibroGen, Galecto, GlaxoSmithKline, MedImmune, Novartis, Pfizer, Promedior, ProMetic, Roche/Genentech, Sanofi/Genzyme and Veracyte. VC reports personal fees from Actelion, Bayer, Biogen Idec, Boehringer Ingelheim, Gilead Sciences, Inc., GlaxoSmithKline, Merck Sharp and Dohme, Novartis, Pfizer, Roche/InterMune and Sanofi; grants from Actelion, Boehringer Ingelheim, GlaxoSmithKline, Pfizer and Roche; and personal fees from Boehringer Ingelheim outside the submitted work. KFG, PWN and JWS declare no competing interests. RJK reports personal fees from Boehringer Ingelheim, Genentech, MedImmune and Gilead Sciences, Inc.; and other fees from Afferent and Bristol-Myers Squibb outside the submitted work. DJL reports grants from Gilead Sciences, Inc., during the conduct of the study; grants and personal fees from Boehringer Ingelheim; personal fees from Degge Group; France Foundation; Genentech; Gilead Sciences, Inc., and Veracyte; grants from Bayer, FibroGen and Global Blood Therapeutics; and grants, consulting fees and institutional support from Pulmonary Fibrosis Foundation outside the submitted work. AUW reports personal fees from Actelion, Bayer, Boehringer Ingelheim, InterMune and Roche during the conduct of the study. TPW reports grants from Gilead Sciences, Inc., during the conduct of the study; personal fees from Boehringer Ingelheim; Genentech and Gilead Sciences, Inc.; and grants from Boehringer Ingelheim, Celgene, Genentech, Global Blood, Kadmon, Pulmonary Fibrosis Foundation Therapeutics and Sanofi outside the submitted work. DAL reports grants from NHLBI and grants and consulting fees from Boehringer Ingelheim, Parexel, Roche/Genentech, Siemens and Veracyte outside the submitted work. SH reports consulting for Parexel during the conduct of the study and for Boehringer Ingelheim outside this study; and has a patent system and method for automatic detection and quantification of pathology using dynamic feature classification pending to National Jewish Health. EM is an employee of bioMérieux. KFG, SDP, VS, QG and JSS are employees and may hold stock in Gilead Sciences, Inc. At the time of writing, TGOR was an employee of and a stockholder in Gilead Sciences, Inc. FJM reports personal fees from the Adept, Academic Continuing Medical Education, American Thoracic Society, Afferent, Axon Communication, Boehringer Ingelheim, Clarion, Falco, Genentech, Ikaria/Bellerophon, Kadmon, National Association for Continuing Education, Nycomed/Takeda, Pfizer, Potomac and Veracyte; grants from the NIH; nonfinancial support from Biogen/Stromedix, Boehringer Ingelheim, Centocor and Gilead Sciences, Inc.; and other support from Bayer, Boehringer Ingelheim, Genentech and Veracyte during the conduct of the study; grants, personal fees and nonfinancial support from AstraZeneca, GlaxoSmithKline and Nycomed/Takeda; grants and personal fees from Forest; grants from BioScale; personal fees from Amgen, Annenberg, Axon, Boehringer Ingelheim, California Society for Allergy and Immunology, CME Incite, ConCert, Genentech, HayMarket, Ikaria/Bellerophon, Informa, Integritas, InThought, Janssen, Lucid, Methodist Hospital, Miller Medical, National Association for Continuing Education, Novartis, Paradigm, Pearl, Peer Voice, Pfizer, Prime, Roche, Sunovion, Theravance, Unity Biotechnology, UptoDate, WebMD and Western Society of Allergy and Immunology; nonfinancial support from Annenberg, California Society for Allergy and Immunology, CME Incite, ConCert, Genentech, Janssen, Miller Medical, National Association for Continuing Education, Novartis, Pearl, Pfizer, Roche, Sunovion, Theravance, WebMD and Western Society of Allergy and Immunology; and other support from GlaxoSmithKline and Merio outside the submitted work., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 ( Gdf15 ), as the most significantly upregulated secreted protein. Gdf15 expression is induced in response to telomere dysfunction and bleomycin challenge in mice. Gdf15 mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, GDF15 mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of GDF15 , and circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that GDF15 is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes.

Background: Cluster headache is the most severe primary headache disorder. A genetic basis has long been suggested by family and twin studies; however, little is understood about the genetic variants that contribute to cluster headache susceptibility., Methods: We conducted a literature search of the MEDLINE database using the PubMed search engine to identify all human genetic studies for cluster headache. In this article we provide a review of those genetic studies, along with an overview of the pathophysiology of cluster headache and a brief review of migraine genetics, which have both been significant drivers of cluster headache candidate gene selection., Results: The investigation of cluster headache genetic etiology has been dominated by candidate gene studies. Candidate selection has largely been driven by the pathophysiology, such as the striking rhythmic nature of the attacks, which spurred close examination of the circadian rhythm genes CLOCK and HCRTR2 . More recently, unbiased genetic approaches such as genome-wide association studies (GWAS) have yielded new genetic avenues of interest including ADCYAP1R1 and MME ., Conclusions: The majority of candidate genes studied for cluster headache suffer from poor reproducibility. Broader genetic interrogation through larger unbiased GWAS, exome, and whole genome studies may provide more robust candidates, and in turn provide a clearer understanding of the causes of cluster headache.

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases ( n  = 3,624) and control subjects ( n  = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1 ) individual common variants via logistic regression and 2 ) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele ( P  = 9.60 × 10 -295 ). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with an unpredictable course and a median survival of three to four years. This timeline challenges providers to approach diagnosis, oxygen therapy, rehabilitation, transplantation, and end-of-life discussions in limited encounters. There is currently no widely accepted guideline for determining when IPF patients should be referred to palliative care (PC). Objective: We sought to describe the patient and clinical factors associated with PC referral, as well as its impact on mortality and location of death. We also aimed to examine temporal trends in PC referral in this population. Materials and Methods: Patient data were retrospectively extracted from the health system repository of our specialty referral center for all new IPF patients evaluated between 2000 and 2016 ( n  = 828). Exclusion criteria included transplant recipients and patients who did not have IPF. Results: One hundred twelve (13.5%) IPF patients received formal PC referral. Recipients were older at diagnosis (72 years vs. 69 years, p  < 0.001), had higher frequency of Charlson Comorbidity Index ≥1 (55% vs. 42%, p  = 0.011), resided closer to our institution (16 miles vs. 54 miles, p  < 0.001), and had a higher number of total outpatient visits (7 vs. 4, p  < 0.001). PC was associated with less in-hospital death (44% vs. 60%, p  = 0.006) and more in-home and hospice death (56% vs. 40%, p  = 0.006). Conclusions: IPF patients referred to PC were older with more severe comorbidities, resided closer to our specialty referral center, and had more outpatient follow-up. This was associated with more in-home and hospice deaths. The patient-provider relationship and frequency of follow-up visits likely play important roles in the introduction of end-of-life discussions.

Background and Objective: Molecular biomarkers are needed to refine prognostication and phenotyping of pulmonary hypertension (PH) patients. S100A12 is an emerging biomarker of various inflammatory diseases. This study aims to determine the prognostic value of S100A12 in PH., Methods: Exploratory microarray analysis performed on peripheral blood mononuclear cells (PBMC) collected from idiopathic pulmonary fibrosis (IPF) patients suggested an association between S100A12 and both PH and mortality. So the current study was designed to evaluate for an association between S100A12 in peripheral blood collected from two well-phenotyped PH cohorts in two other centres to derive and validate an association between S100A12 protein serum concentrations and mortality., Results: The majority of the patients in the discovery and validation cohorts were either World Health Organization (WHO) group 1 (pulmonary arterial hypertension (PAH)) or 3 (lung disease-associated) PH. In the discovery PH cohort, S100A12 was significantly increased in patients with PH (n = 51) compared to controls (n = 22) (29.8 vs 15.7 ng/mL, P < 0.001) and negatively correlated with cardiac output (r = -0.58, P < 0.001) in PH patients. When S100A12 data were pooled from both cohorts, PAH and non-PAH PH patients had higher S100A12 compared to healthy external controls (32.6, 30.9, 15.7 ng/mL; P < 0.001). S100A12 was associated with an increased risk in overall mortality in PH patients in both the discovery (n = 51; P = 0.008) and validation (n = 40; P < 0.001) cohorts., Conclusion: S100A12 levels are increased in PH patients and are associated with increased mortality., (© 2018 Asian Pacific Society of Respirology.)

Introduction: Idiopathic pulmonary fibrosis (IPF), a progressive life-limiting lung disease affects approximately 128 000 newly diagnosed individuals in the USA annually. IPF, a disease of ageing associated with intense medical and financial burden, is expected to grow in incidence globally. Median survival from diagnosis is 3.8 years, and many of these patients succumb to a rapid death within 6 months. Despite the fatal prognosis, we have found that patients and caregivers often fail to understand the poor prognosis as the disease relentlessly progresses. Based on feedback from patients and families living with IPF, we developed the S-Symptom Management, U-Understanding the Disease, P-Pulmonary Rehabilitation, P-Palliative Care, O-Oxygen Therapy, R-Research Considerations and T-Transplantation ('SUPPORT') intervention to increase knowledge of the disease, teach self-management strategies and facilitate preparedness with end of life (EOL) planning., Methods: This study is a randomised trial to test the efficacy of SUPPORT intervention compared with routine care in patients with IPF and their caregivers delivered after three clinical visits. We are recruiting a cohort of 64 new IPF patient/caregiver dyads (32 for each dyad)., Results: The trial will evaluate whether the SUPPORT intervention decreases stress, improves symptom burden, quality of life, preparedness and advance care planning for patients and caregivers, quality of dying and death for caregivers if the patient dies during the course of the study, as well as assess the impact of primary palliative care on healthcare resource use near the EOL., Conclusion: By increasing knowledge of the disease, teaching self-management strategies and facilitating preparedness with EOL planning, we will address a critical gap in the care of patients with IPF., Trial Registration Number: NCT02929017; Pre-results., Competing Interests: Competing interests: None declared.

Background: The clinical course of idiopathic pulmonary fibrosis (IPF) is unpredictable. Clinical prediction tools are not accurate enough to predict disease outcomes., Methods: We enrolled patients with IPF diagnosis in a six-cohort study at Yale University (New Haven, CT, USA), Imperial College London (London, UK), University of Chicago (Chicago, IL, USA), University of Pittsburgh (Pittsburgh, PA, USA), University of Freiburg (Freiburg im Breisgau, Germany), and Brigham and Women's Hospital-Harvard Medical School (Boston, MA, USA). Peripheral blood mononuclear cells or whole blood were collected at baseline from 425 participants and from 98 patients (23%) during 4-6 years' follow-up. A 52-gene signature was measured by the nCounter analysis system in four cohorts and extracted from microarray data (GeneChip) in the other two. We used the Scoring Algorithm for Molecular Subphenotypes (SAMS) to classify patients into low-risk or high-risk groups based on the 52-gene signature. We studied mortality with a competing risk model and transplant-free survival with a Cox proportional hazards model. We analysed timecourse data and response to antifibrotic drugs with linear mixed effect models., Findings: The application of SAMS to the 52-gene signature identified two groups of patients with IPF (low-risk and high-risk), with significant differences in mortality or transplant-free survival in each of the six cohorts (hazard ratio [HR] range 2·03-4·37). Pooled data showed similar results for mortality (HR 2·18, 95% CI 1·53-3·09; p<0·0001) or transplant-free survival (2·04, 1·52-2·74; p<0·0001). Adding 52-gene risk profiles to the Gender, Age, and Physiology index significantly improved its mortality predictive accuracy. Temporal changes in SAMS scores were associated with changes in forced vital capacity (FVC) in two cohorts. Untreated patients did not shift their risk profile over time. A simultaneous increase in up score and decrease in down score was predictive of decreased transplant-free survival (3·18, 1·16-8·76; p=0·025) in the Pittsburgh cohort. A simultaneous decrease in up score and increase in down score after initiation of antifibrotic drugs was associated with a significant (p=0·0050) improvement in FVC in the Yale cohort., Interpretation: The peripheral blood 52-gene expression signature is predictive of outcome in patients with IPF. The potential value of the 52-gene signature in predicting response to therapy should be determined in prospective studies., Funding: The Pulmonary Fibrosis Foundation, the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, and the National Heart, Lung, and Blood Institute of the US National Institutes of Health., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To compare the survival outcomes between myositis-associated usual interstitial pneumonia (MA-UIP) and idiopathic pulmonary fibrosis (IPF-UIP)., Methods: Adult MA-UIP and IPF-UIP patients were identified using CTD and IPF registries. The MA-UIP cohort included myositis or anti-synthetase syndrome patients with interstitial lung disease while manifesting UIP on high-resolution CT chest and/or a lung biopsy revealing UIP histology. IPF subjects met American Thoracic Society criteria and similarly had UIP histopathology. Kaplan-Meier survival curves compared cumulative and pulmonary event-free survival (event = transplant or death) between (i) all MA-UIP and IPF-UIP subjects, (ii) MA-UIP with biopsy proven UIP (n = 25) vs IPF-UIP subjects matched for age, gender and baseline forced vital capacity (±10%). Cox proportional hazards ratios compared the survival controlling for co-variates., Results: Eighty-one IPF-UIP and 43 MA-UIP subjects were identified. The median cumulative and event-free survival time in IPF vs MA-UIP was 5.25/1.8 years vs 16.2/10.8 years, respectively. Cumulative and event-free survival was significantly worse in IPF-UIP vs MA-UIP [hazards ratio of IPF-UIP was 2.9 (95% CI: 1.5, 5.6) and 5.0 (95% CI: 2.8, 8.7) (P < 0.001), respectively]. IPF-UIP event-free survival (but not cumulative) remained significantly worse than MA-UIP with a hazards ratio of 6.4 (95% CI: 3.0, 13.8) after controlling for age at interstitial lung disease diagnosis, gender, ethnicity and baseline forced vital capacity%. Respiratory failure was the most common cause of death in both groups. A sub-analysis of 25 biopsy-proven MA-UIP subjects showed similar results., Conclusion: MA-UIP patients demonstrated a significant survival advantage over a matched IPF cohort, suggesting that despite similar histological and radiographic findings at presentation, the prognosis of MA-UIP is superior to that of IPF-UIP., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: Palliative care has been recommended as a means to assist patients with idiopathic pulmonary fibrosis (IPF) in managing symptom burden and advanced care planning. Timing of referral is important because although most patients display a gradually progressive course, a minority experience acute deterioration, an outcome associated with high mortality., Aim: To describe characteristics of IPF patients referred to a specialty lung disease center over a 10-year period who experienced acute deterioration and subsequent intensive care unit (ICU) admission, including frequency and timing of referral to palliative care., Design: Retrospective review., Setting/participants: We identified 106 patients admitted to the ICU with acute deterioration due to a respiratory or nonrespiratory cause. Variables examined included demographics, date of first center visit, forced vital capacity, diffusing capacity of the lung for carbon monoxide (DLCO), and palliative care referral., Results: ICU admission occurred early (median 9.5 months) and, for 34%, within four months of their first center visit. For nearly one-half of these patients, ICU admission occurred before their third clinic visit. Only 4 (3.8%) patients received a palliative care referral before ICU admission. The majority (77%) died during ICU admission. With exception of the relationship between DLCO% predicted at first visit and time to ICU admission (r = 0.32, p = 0.005), no variables identified those most likely to experience acute deterioration., Conclusion: Due to high mortality associated with ICU admission, patients and families should be informed about palliative care early following diagnosis of IPF.

Background: Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the efficacy and safety of simtuzumab, a monoclonal antibody against LOXL2, in patients with IPF., Methods: In this randomised, double-blind, phase 2 trial, we recruited patients aged 45-85 years with definite IPF diagnosed prior to 3 years of screening from 183 hospitals and respiratory clinics in 14 countries. Eligible patients, stratified by baseline forced vital capacity (FVC), serum LOXL2 (sLOXL2) concentrations, and pirfenidone and nintedanib use, were randomly assigned (1:1) to inject 125 mg/mL simtuzumab or placebo subcutaneously once a week. The primary endpoints were progression-free survival, defined as time to all-cause death or a categorical decrease from baseline in FVC % predicted, in the intention-to-treat population, in patients with sLOXL2 concentrations in the 50th percentile or higher, and in patients with sLOXL2 concentrations in the 75th percentile or higher. Treatment duration was event-driven, and interim analyses were planned and conducted after approximately 120 and 200 progression-free survival events, respectively, occurred. We compared treatment groups with the stratified log-rank test. This study is registered with ClinicalTrials.gov, number NCT01769196., Findings: Patients with IPF were recruited between Jan 31, 2013, and June 1, 2015. The intention-to-treat population included 544 randomly assigned patients (272 patients in both groups), and the safety population included 543 randomly assigned patients who received at least one dose of study medication. The study was terminated when the second interim analysis met the prespecified futility stopping criteria in the intention-to-treat population. We noted no difference in progression-free survival between simtuzumab and placebo in the intention-to-treat population (median progression free survival times of 12·6 months and 15·4 months for simtuzumab and placebo, respectively; stratified HR 1·13, 95% CI 0·88-1·45; p=0·329) and in patients with baseline sLOXL2 in the 50th percentile or higher (median progression-free survival 11·7 months and 14·3 months for simtuzumab and placebo, respectively; stratified HR 1·03, 95% CI 0·74-1·43; p=0·851), or in the 75th percentile or higher (median progression-free survival 11·6 months and 16·9 months for simtuzumab and placebo, respectively; stratified HR 1·20, 95% CI 0·72-2·00; p=0·475). The incidence of adverse events and serious adverse events was similar between treatment groups. The most common adverse events in both the simtuzumab and placebo groups were dyspnoea, cough, upper respiratory tract infection, and worsening of IPF; and the most common grade 3 or 4 adverse events were worsening of IPF, dyspnoea, and pneumonia., Interpretation: Simtuzumab did not improve progression-free survival in a well-defined population of patients with IPF. Our data do not support the use of simtuzumab for patients with IPF., Funding: Gilead Sciences Inc., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: To explore the perceptions of palliative care (PC) needs in patients with idiopathic pulmonary fibrosis (IPF) and their caregivers., Background: IPF carries a poor prognosis with most patients succumbing to their illness at a rate comparable to aggressive cancers. No prior studies have comprehensively explored perceptions of PC needs from those currently living with the disease, caring for someone living with the disease, and who cared for a deceased family member., Methods: Thematic analysis of focus group content was obtained from thirteen participants., Results: Four themes described frustration with the diagnostic process and education received, overwhelming symptom burden, hesitance to engage in advance care planning, and comfort in receiving care from pulmonary specialty center because of resources., Conclusions: Findings support that patients and caregivers have informational needs and high symptom burden, but limited understanding of the potential benefits of PC. Future studies are needed to identify optimal ways to introduce early PC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose of Review: Sarcoidosis is a chronic granulomatous disease typically affecting the lung, lymph nodes, and other organ systems. Evidence suggests that the morbidity and mortality rates for sarcoidosis in the USA are rising, despite widespread use of anti-inflammatory therapies. In this review, we survey new therapies that target specific inflammatory pathways in other diseases (such as rheumatoid arthritis, Crohn's disease, and psoriasis) that are similar to pathways relevant to sarcoidosis immunopathogenesis, and therefore, represent potentially new sarcoidosis therapies., Recent Findings: Immunopathogenesis of sarcoidosis has been well elucidated over the past few years. There is abundant evidence for T-cell activation in sarcoidosis leading to activation of both Th1 and Th17 inflammatory cascades. Therapies targeting T-cell activation, Th1 pathways (such as the interleukin-6 inhibitors), Th17 pathway mediators, and others have been Food and Drug Administration approved or under investigation to treat a variety of autoimmune inflammatory diseases, but have not been studied in sarcoidosis. Targeting the p38 mitogen-activated protein kinases and the ubiquitine proteasome system with new agents may also represent a novel therapeutic option for patients with sarcoidosis., Summary: Rising morbidity and mortality rates for patients with sarcoidosis strongly support the need to develop more effective anti-inflammatory therapies to treat chronic disease., Competing Interests: There are no conflicts of interest.

Heat shock protein 27 (Hsp27) is a molecular chaperone highly expressed in aggressive cancers, where it is involved in numerous pro-tumorigenic signaling pathways. Using functional genomics we identified for the first time that Hsp27 regulates the gene signature of transcriptional co-activators YAP and TAZ, which are negatively regulated by the Hippo Tumor Suppressor pathway. The Hippo pathway inactivates YAP by phosphorylating and increasing its cytoplasmic retention with the 14.3.3 proteins. Gain and loss of function experiments in prostate, breast and lung cancer cells showed that Hsp27 knockdown induced YAP phosphorylation and cytoplasmic localization while overexpression of Hsp27 displayed opposite results. Mechanistically, Hsp27 regulates the Hippo pathway by accelerating the proteasomal degradation of ubiquitinated MST1, the core Hippo kinase, resulting in reduced phosphorylation/activity of LATS1 and MOB1, its downstream effectors. Importantly, our in vitro results were supported by data from human tumors; clinically, high expression of Hsp27 in prostate tumors is correlated with increased expression of YAP gene signature and reduced phosphorylation of YAP in lung and invasive breast cancer clinical samples. This study reveals for the first time a link between Hsp27 and the Hippo cascade, providing a novel mechanism of deregulation of this tumor suppressor pathway across multiple cancers.

Background: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci., Results: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta  = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16))., Conclusions: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.

The objective of this study was to determine the safety and efficacy of carlumab in the treatment of idiopathic pulmonary fibrosis (IPF).A phase 2, randomised, double-blind placebo-controlled dose-ranging study was conducted in patients with IPF (n=126). Patients were randomised to carlumab (1 mg·kg(-1), 5 mg·kg(-1), or 15 mg·kg(-1)) or placebo every 4 weeks. The primary endpoint was the rate of percentage change in forced vital capacity (FVC). Secondary endpoints were time to disease progression, absolute change in FVC, relative change in diffusing capacity of the lung for carbon monoxide (DLCO), and St George's Respiratory Questionnaire (SGRQ) total score.Due to a pre-planned, unfavourable interim benefit-risk analysis, dosing was suspended. The rate of percentage change in FVC showed no treatment effect (placebo -0.582%, 1 mg·kg(-1) -0.533%, 5 mg·kg(-1) -0.799% and 15 mg·kg(-1) -0.470%; p=0.261). All active treatment groups showed a greater decline in FVC (1 mg·kg(-1) -290 mL, 5 mg·kg(-1) -370 mL and 15 mg·kg(-1) -320 mL) compared with placebo (-130 mL). No effect on disease progression, DLCO, infection rates or mortality was observed. SGRQ scores showed a nonsignificant trend toward worsening with active treatment. Unexpectedly, free CC-chemokine ligand 2 levels were elevated above baseline at both 24 and 52 weeks. A higher proportion of patients with one or more serious adverse events was observed in the 5 mg·kg(-1) group (53.1%) compared with 1 mg·kg(-1) (15.2%), 15 mg·kg(-1) (21.9%) and placebo (46.4%), although no unexpected serious adverse events were noted.Although dosing was stopped prematurely, it is unlikely that carlumab provides benefit to IPF patients., (Copyright ©ERS 2015.)