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Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features.Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD?We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEVBoth consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEVDemonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease.

Asthma is an inflammatory disease of the airways characterized by eosinophil recruitment, eosinophil peroxidase release, and protein oxidation through bromination, which following tissue remodeling results in excretion of 3-bromotyrosine. Predicting exacerbations and reducing their frequency is critical for the treatment of severe asthma. In this study, we aimed to investigate whether urinary total conjugated bromotyrosine can discriminate asthma severity and predict asthma exacerbations. We collected urine from participants with severe ( n = 253) and nonsevere ( n = 178) asthma, and the number of adjudicated exacerbations in 1-yr longitudinal follow-up was determined among subjects enrolled in the Severe Asthma Research Program, a large-scale National Institutes of Health (NIH)-funded consortium. Urine glucuronidated bromotyrosine and total conjugated forms were quantified by hydrolysis with either glucuronidase or methanesulfonic acid, respectively, followed by liquid chromatography-tandem mass spectrometry analyses of free 3-bromotyrosine. Blood and sputum eosinophils were also counted. The majority of 3-bromotyrosine in urine was found to exist in conjugated forms, with glucuronidated bromotyrosine representing approximately a third, and free bromotyrosine less than 1% of total conjugated bromotyrosine. Total conjugated bromotyrosine was poorly correlated with blood ( r2 = 0.038) or sputum eosinophils ( r2 = 0.0069). Compared with participants with nonsevere asthma, participants with severe asthma had significantly higher urinary total conjugated bromotyrosine levels. Urinary total conjugated bromotyrosine was independently associated with asthma severity, correlated with the number of asthma exacerbations, and served as a predictor of asthma exacerbation risk over 1-yr of follow-up.

Background Clustering key clinical characteristics of participants in the Severe Asthma Research Program (SARP), a large, multicenter prospective observational study of patients with asthma and healthy controls, has led to the identification of novel asthma phenotypes. Purpose To determine whether quantitative CT (qCT) could help distinguish between clinical asthma phenotypes. Materials and Methods A retrospective cross-sectional analysis was conducted with the use of qCT images (maximal bronchodilation at total lung capacity [TLC], or inspiration, and functional residual capacity [FRC], or expiration) from the cluster phenotypes of SARP participants (cluster 1: minimal disease; cluster 2: mild, reversible; cluster 3: obese asthma; cluster 4: severe, reversible; cluster 5: severe, irreversible) enrolled between September 2001 and December 2015. Airway morphometry was performed along standard paths (RB1, RB4, RB10, LB1, and LB10). Corresponding voxels from TLC and FRC images were mapped with use of deformable image registration to characterize disease probability maps (DPMs) of functional small airway disease (fSAD), voxel-level volume changes (Jacobian), and isotropy (anisotropic deformation index [ADI]). The association between cluster assignment and qCT measures was evaluated using linear mixed models. Results A total of 455 participants were evaluated with cluster assignments and CT (mean age ± SD, 42.1 years ± 14.7; 270 women). Airway morphometry had limited ability to help discern between clusters. DPM fSAD was highest in cluster 5 (cluster 1 in SARP III: 19.0% ± 20.6; cluster 2: 18.9% ± 13.3; cluster 3: 24.9% ± 13.1; cluster 4: 24.1% ± 8.4; cluster 5: 38.8% ± 14.4

BACKGROUND: Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets. RESEARCH QUESTION: Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations? STUDY DESIGN AND METHODS: We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations. RESULTS: Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations. INTERPRETATION: Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov

Rationale: Individuals with Chronic Obstructive Pulmonary Disease (COPD) have a high prevalence of depression, which is associated with increased COPD hospitalizations and readmissions. Objectives:...

Background United States population-level data on asthma morbidity and mortality are available primarily through state-level surveys. We hypothesize that significant county-level heterogeneity may be obscured by state-level data, thus impeding focused initiatives to improve asthma outcomes. Objective To assess heterogeneity in the prevalence of uncontrolled, severe, and severe uncontrolled asthma by examining state- and county-level morbidity reflected in large administrative claims datasets and identify relationships between pharmacotherapy-based morbidity and the Centers for Disease Control and Prevention's asthma mortality data. Methods Asthma prevalence and morbidity were identified using medical and pharmacy claims from the IQVIA Longitudinal Access and Adjudication Data database (7/2015-6/2018). Heatmaps ranked prevalence of severe uncontrolled asthma by deciles in all 50 states and the District of Columbia, plus 2935 counties. Mortality in states (2016) and 3147 counties (1999-2018) was similarly mapped and ranked and contrasted with claims-based morbidity. Results Among 4,506,527 individuals with asthma, 640,936 (14.2%) received agespecific therapy for severe asthma. Of those with severe asthma, 144,232 (22.5%) filled ≥2 annual courses of systemic steroids and were designated as having severe uncontrolled asthma. Most states with high mortality had relatively few patients with severe uncontrolled asthma. A significant correlation between mortality and morbidity and trends by urban/rural and metropolitan status were found at the county level. Conclusion: Intra-state heterogeneity in the morbidity and mortality of severe uncontrolled asthma at the county level is not evident in state-level analyses. Increased local awareness of systemic corticosteroid use as an indicator of uncontrolled asthma should prompt regional educational and public health efforts to improve outcomes.

BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: By leveraging data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) and the Atopic Dermatitis Research Network (ADRN), we aim to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum (N=21,901). METHODS: We performed genome-wide association within strata of study, disease, and ancestry groups, and combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. For details, please see the Methods section in this article’s Online Repository at www.jacionline.org. RESULTS: We identified six loci at genome-wide significance (P

Summary Background We previously described the contributions of increased total airway mucin concentrations to the pathogenesis and diagnosis of the chronic bronchitic component of chronic obstructive pulmonary disease (COPD). Here, we investigated the relative contribution of each of the major airway gel-forming mucins, MUC5AC and MUC5B, to the initiation, progression, and early diagnosis of airways disease in COPD. Methods SPIROMICS was a multicentre, observational study in patients aged 40–80 years recruited from six clinical sites and additional subsites in the USA. In this analysis, MUC5AC and MUC5B were quantitated by stable isotope-labelled mass spectrometry in induced sputum samples from healthy never-smokers, ever-smokers at risk for COPD, and ever-smokers with COPD. Participants were extensively characterised using results from questionnaires, such as the COPD assessment test (CAT) and St George's Respiratory Questionnaire; quantitative CT, such as residual volume/total lung capacity ratio (RV/TLC) and parametric response mapping-functional small airway disease (PRM-fSAD); and pulmonary function tests, such as FEV1, forced vital capacity (FVC), and forced expiratory flow, midexpiratory phase (FEF25–75%). Absolute concentrations of both MUC5AC and MUC5B were related to cross-sectional (baseline, initial visit) and 3-year follow-up longitudinal data, including lung function, small airways obstruction, prospective acute exacerbations, and smoking status as primary outcomes. This study is registered with ClinicalTrials.gov (NCT01969344). Findings This analysis included 331 participants (mean age 63 years [SEM 9·40]), of whom 40 were healthy never-smokers, 90 were at-risk ever-smokers, and 201 were ever-smokers with COPD. Increased MUC5AC concentrations were more reliably associated with manifestations of COPD than were MUC5B concentrations, including decreased FEV1 and FEF25–75%, and increased prospective exacerbation frequency, RV/TLC, PRM-fSAD, and COPD assessment scores. MUC5AC concentrations were more reactive to cigarette smoke exposure than were MUC5B concentrations. Longitudinal data from 3-year follow-up visits generated a multivariate-adjusted odds ratio for two or more exacerbations of 1·24 (95% CI 1·04–1·47, p=0·015) for individuals with high baseline MUC5AC concentration. Increased MUC5AC, but not MUC5B, concentration at baseline was a significant predictor of FEV1, FEV1/FVC, FEF25–75%, and CAT score decline during the 3-year follow-up. Moreover, current smokers in the at-risk group showed raised MUC5AC concentrations at initial visits and decreased lung function over 3 years. By contrast, former smokers in the at-risk group showed normal MUC5AC concentrations at the initial visit and preserved lung function over 3 years. Interpretation These data indicate that increased MUC5AC concentration in the airways might contribute to COPD initiation, progression, exacerbation risk, and overall pathogenesis. Compared with MUC5B, greater relative changes in MUC5AC concentrations were observed as a function of COPD severity, and MUC5AC concentration seems to be an objective biomarker to detect disease in at-risk and pre-COPD individuals. These data suggest that MUC5AC-producing pathways could be potential targets for future therapeutic strategies. Thus, MUC5AC could be a novel biomarker for COPD prognosis and for testing the efficacy of therapeutic agents. Funding National Institutes of Health; National Heart, Lung, and Blood Institute.

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including metaanalyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force’s questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations:• suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes;• suggest using a blood eosinophil cut-point ≥150 μL−1 to guide anti-IL-5 initiation in adult patients with severe asthma;• suggest considering specific eosinophil (≥260 μL−1) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy;• suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4 – 5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies;• suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype;• suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels.These recommendations should be reconsidered as new evidence becomes available.

Rationale: The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain.Objectives: T...

Rationale: Some reports indicate longitudinal variability in sputum differential cell counts, whereas others describe stability. Highly variable sputum eosinophil percentages are associated with greater lung function loss than persistently elevated eosinophil percentages, but elevated neutrophils are linked to more severe asthma.Objectives: To examine sputum granulocyte stability or variability longitudinally and associations with important clinical characteristics.Methods: The SARP III (Severe Asthma Research Program III) cohort underwent comprehensive phenotype characterization at baseline and annually over 3 years. Adult subjects with acceptable sputum levels were assigned to one of three longitudinal sputum groups: eosinophils predominantly 2 SDs determined from independent, repeated baseline eosinophil percentages). Subjects were similarly assigned to one of three longitudinal neutrophil groups with a 50% cut point.Measurements and Main Results: The group with predominantly

To improve understanding of real-world asthma treatment and inform physician education, we evaluated regional variation in asthma prevalence and oral corticosteroid (OCS) use across Germany. We developed a machine learning gradient boosted tree model with IMS® Disease Analyzer electronic medical records, which cover 3% of German patients. This model had a 91% accuracy in predicting the presence of asthma and chronic obstructive pulmonary disease. We applied the model to the IMS® Longitudinal Prescription database, with 82% national coverage, to classify patients receiving treatment for airflow obstruction from October 2017–September 2018 in 63 regions in Germany. Of 2.4 million individuals under statutory health insurance with predicted high OCS use for asthma (defined as 1 tablet per day for the duration of therapy), 13.7%, 18.7%, 36.5%, 29.4%, and 1.7% were categorised as receiving Global Initiative for Asthma (GINA) Steps 1, 2, 3, 4, and 5 treatment, respectively. Approximately 7–15% of those receiving GINA Steps 1–4 treatment, and 35% of those receiving Step 5 treatment received ≥1 acute OCS prescription (duration

Fevipiprant, an oral antagonist of the prostaglandin DLUSTER-1 and LUSTER-2 were two phase 3 randomised, double-blind, placebo-controlled, parallel-group, replicate 52-week studies; LUSTER-1 took place at 174 clinical sites in 25 countries and LUSTER 2 took place at 169 clinical sites in 19 countries. Fevipiprant or placebo was added to Global Initiative for Asthma Steps 4 and 5 therapy in adolescents and adults with severe asthma. Patients aged 12 years or older with uncontrolled asthma on dual or triple asthma therapy were randomly assigned by use of interactive response technology to one of three treatment groups (once-daily fevipiprant 150 mg, fevipiprant 450 mg, or placebo) in a 1:1:1 ratio within each of the randomisation strata: peripheral blood eosinophil counts (250 cells per μL or ≥250 cells per μL), patient age (18 years or ≥18 years), and use or non-use of oral corticosteroids as part of their standard of care asthma therapy. The primary efficacy endpoint was the annualised rate of moderate to severe asthma exacerbations with 150 mg or 450 mg doses of fevipiprant once daily compared with placebo over 52 weeks, in patients with high blood eosinophil counts (≥250 cells per μL) and in the overall study population. All patients who underwent randomisation and received at least one dose of study medication were included in efficacy and safety analyses. These trials are registered with ClinicalTrials.gov, NCT02555683 (LUSTER-1) and NCT02563067 (LUSTER-2), and are complete and no longer recruiting.Between Dec 11, 2015, and Oct 25, 2018, 894 patients were randomly assigned to fevipiprant 150 mg (n=301), fevipiprant 450 mg (n=295), or placebo (n=298) in LUSTER-1. Between Dec 3, 2015, and July 10, 2018, 877 patients were randomly assigned to fevipiprant 150 mg (n=296), fevipiprant 450 mg (n=294), or placebo (n=287) in LUSTER-2. In the high eosinophil population, in LUSTER-1 the annualised rate ratio of moderate to severe exacerbations compared with placebo was 1·04 (95% CI 0·77-1·41) for fevipiprant 150 mg and 0·83 (0·61-1·14) for fevipiprant 450 mg, and in LUSTER-2 it was 0·69 (0·50-0·96) for fevipiprant 150 mg and 0·72 (0·52-1·01) for fevipiprant 450 mg. In the overall population, in LUSTER-1 the annualised rate ratio of moderate to severe exacerbations compared with placebo was 0·96 (95% CI 0·75-1·22) for fevipiprant 150 mg and 0·78 (0·61-1·01) for fevipiprant 450 mg and in LUSTER-2 it was 0·82 (0·62-1·07) for fevipiprant 150 mg and 0·76 (0·58-1·00) for fevipiprant 450 mg. In the overall pooled population of both studies, serious adverse events occurred in 53 (9%) patients in the fevipiprant 150 mg group, 50 (9%) in the fevipiprant 450 mg group, and 50 (9%) in the placebo group. Adverse events leading to death occurred in two (1%) patients in the fevipiprant 450 mg group and three (1%) in the placebo group.Although neither trial showed a statistically significant reduction in asthma exacerbations after adjusting for multiple testing, consistent and modest reductions in exacerbations rates were observed in both studies with the 450 mg dose of fevipiprant.Novartis.

Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Background: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.Research Question: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?Study Design and Methods: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10–6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).Results: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10–8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.Interpretation: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

Background Mepolizumab (100 mg delivered s.c. every 4 weeks) is indicated for add-on maintenance treatment for patients with severe eosinophilic asthma. Mepolizumab has been shown to reduce exacerbations and the requirement for daily oral corticosteroids, and improve asthma control and symptoms. However, data on the durability of the response to mepolizumab during dosing periods are limited. The aim of this study was to investigate the efficacy profile in patients with severe eosinophilic asthma over the 4-weekly dosing period for various fixed mepolizumab doses. Methods This was a post hoc analysis of data from the phase IIb/III DREAM study. Patients ≥12 years of age with severe eosinophilic asthma were randomised (1:1:1:1) to receive intravenous mepolizumab 75 mg (equivalent to 100 mg s.c.), 250 mg, 750 mg or placebo, plus standard of care, every 4 weeks for 52 weeks. The number of exacerbations and eDiary data (peak expiratory flow, rescue medication use and symptom scores) from two periods in each 4-weekly dosing interval (days 1–14 and 15–28) over the 52-week treatment period were analysed. Findings eDiary data and the proportion of patients experiencing ≥1 exacerbation were similar during the first and second 2 weeks of a dosing period across all mepolizumab doses. Interpretation These results demonstrate that the response to mepolizumab is sustained over the 4-weekly dosing period with no differences across a 10-fold dose range and supports the use of the current mepolizumab dosing regimen in patients with severe eosinophilic asthma., Post hoc analysis of data from DREAM demonstrated a sustained response to mepolizumab across the 4-weekly dosing period, suggesting therapeutic benefit is maintained between each mepolizumab dose following long-term treatment https://bit.ly/3843lH6

Combined elevated sputum eosinophils+neutrophils in asthma associated with lowest lung function, greater healthcare utilization, and longitudinally, further spirometric loss, implicating cell-cell interactions or overlapping inflammatory pathways while increased eosinophils or neutrophils alone show less effect.

Background Severe/difficult-to-treat disease occurs in 5% to 10% of patients with asthma, but accounts for more than 50% of related economic costs. Understanding factors associated with persistent very poorly controlled (VPC) asthma may improve outcomes. Objective To characterize persistent VPC asthma after more than 10 years of standard of care. Methods The Epidemiology and Natural history of asthma: Outcomes and treatment Regimens (TENOR) II (N = 341) was a multicenter, observational study of patients with severe/difficult-to-treat asthma with a single, cross-sectional visit more than 10 years after TENOR I. Persistent VPC asthma was defined as VPC asthma at TENOR I and TENOR II enrollment; without VPC asthma was defined as well- or not well-controlled asthma at either or both visits. Multivariable logistic regression assessed long-term predictors of persistent VPC asthma using TENOR I baseline variables. Results Of 327 patients, nearly half (48.0%, n = 157) had persistent VPC asthma. Comorbidities and asthma triggers were more frequent in patients with persistent VPC asthma than in patients without VPC asthma. Total geometric mean IgE was higher in patients with persistent VPC asthma (89.3 IU/mL vs 55.7 IU/mL); there was no difference in eosinophil levels. Lung function was lower in patients with persistent VPC asthma (mean % predicted pre- and postbronchodilator FEV1, 63.0% vs 82.8% and 69.6% vs 87.2%, respectively). Exacerbations in the previous year were more likely in patients with persistent VPC asthma (29.7% vs 9.0%, respectively). Predictors of persistent VPC asthma were black versus white race/ethnicity, allergic trigger count (4 vs 0), systemic corticosteroid use, and postbronchodilator FEV1 (per 10% decrease). Conclusions The burden of persistent VPC asthma is high in severe/difficult-to-treat disease; management of modifiable risk factors, maximization of lung function, and trigger avoidance may improve outcomes.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) reportedly promotes, or conversely, resolves inflammation in asthma. In this study of TRAIL and cell receptors in sputum, bronchoalveolar lavage and biopsy from subjects in the Severe Asthma Research Program at Wake Forest, the high TRAIL group had significant increases in all leucocytes, and was associated with increased type 1, type 2 and type 17 cytokines, but not type 9 interleukin 9. Two variants at loci in the TRAIL gene were associated with higher sputum levels of TRAIL. Increased TRAIL decoy receptor R3/DcR1 was observed on sputum leucocytes compared with death receptor R1/DR4, suggesting reduced apoptosis and prolonged cellular inflammation.

Background The relationship between 25-hydroxyvitamin D (25-OH-vitamin D) and COPD outcomes remains unclear. Using the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), we determined associations among baseline 25-OH-vitamin D and cross-sectional and longitudinal lung function and COPD exacerbations. Methods Serum 25-OH-vitamin D level was measured in stored samples from 1,609 SPIROMICS participants with COPD. 25-OH-vitamin D levels were modeled continuously and dichotomized as deficient ( Results Vitamin D deficiency was present in 21% of the cohort and was more prevalent in the younger, active smokers, and blacks. Vitamin D deficiency was independently associated with lower % predicted FEV1 (by 4.11%) at enrollment (95% CI, –6.90% to –1.34% predicted FEV1; P = .004), 1.27% predicted greater rate of FEV1 decline after 1 year (95% CI, –2.32% to –0.22% predicted/y; P = .02), and higher odds of any COPD exacerbation in the prior year (OR, 1.32; 95% CI, 1.00-1.74; P = .049). Each 10-ng/mL decrease in 25-OH-vitamin D was associated with lower baseline lung function (–1.04% predicted; 95% CI, –1.96% to –0.12% predicted; P = .03) and increased odds of any exacerbation in the year before enrollment (OR, 1.11; 95% CI, 1.01-1.22; P = .04). Conclusions Vitamin D deficiency is associated with worse cross-sectional and longitudinal lung function and increased odds of prior COPD exacerbations. These findings identify 25-OH-vitamin D levels as a potentially useful marker of adverse COPD-related outcomes.