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ObjectiveGenome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) in chr11p15.5 region associated with asthma and idiopathic interstitial pneumonias (IIPs). We sought to identify functional genes for asthma by combining SNPs and mRNA expression in bronchial epithelial cells (BEC) in the Severe Asthma Research Program (SARP).MethodsCorrelation analyses of mRNA expression of six candidate genes (AP2A2, MUC6, MUC2, MUC5AC, MUC5B, and TOLLIP) and asthma phenotypes were performed in the longitudinal cohort (n = 156) with RNAseq in BEC, and replicated in the cross-sectional cohort (n = 155). eQTL (n = 114) and genetic association analysis of asthma severity (426 severe vs. 531 non-severe asthma) were performed, and compared with previously published GWASs of IIPs and asthma.ResultsHigher expression of AP2A2 and MUC5AC and lower expression of MUC5B in BEC were correlated with asthma, asthma exacerbations, and T2 biomarkers (P  0.8).ConclusionsSNPs associated with asthma in chr11p15.5 region are not associated with asthma severity neither with IIPs. Higher expression of MUC5AC and lower expression of MUC5B are risk for asthma but protective for IIPs.

AbstractObjectiveMethodsResultsConclusionAlthough the efficacy of mepolizumab in reducing exacerbations and oral corticosteroid (OCS) use in severe asthma is well-established, real-world long-term effectiveness data are limited. This study evaluated the real-world impact of mepolizumab treatment in patients with severe asthma over a 4-year follow-up period.This was a retrospective cohort study of patients with asthma initiating mepolizumab (index date: first claim, November 2015–September 2019) using the Merative MarketScan Commercial and Medicare Databases. Outcomes included asthma exacerbations, OCS use, and exacerbation-related healthcare resource utilization (HCRU) and costs, assessed 12-months pre-index (baseline) and annually during the 4-year follow-up period.Among 189 eligible patients, mean asthma exacerbation rate (AER) declined progressively from baseline during follow-up: AER decreased by 53.8% at Year 1 and 73.8% by Year 4 (p < 0.001). The annual OCS prescription rate reduced from baseline by 41.1% at Year 1 and 62.2% at Year 4 (p < 0.001). The proportion of patients with both no exacerbations and no OCS use progressively increased from 6.4% at baseline to 18.5% at Year 1 and 41.8% at Year 4. Exacerbation-related HCRU including inpatient, emergency room, and outpatient office visits decreased from baseline (9.0%, 21.7%, and 78.8%, respectively), at Year 1 (3.2%, 12.2%, and 49.2%), and Year 4 (0.0%, 4.8%, and 31.8%). Exacerbation-related healthcare costs declined from $4,635 at baseline to $1,487 at Year 1 and $217 at Year 4 (p < 0.001).Patients treated with mepolizumab demonstrated progressive and sustained long-term, real-world reductions in exacerbation frequency, OCS dependency, and exacerbation-related HCRU and costs over 4 years. [ABSTRACT FROM AUTHOR]

Subphenotypes of asthma may be determined by age onset and atopic status. We sought to characterize early or late onset atopic asthma with fungal or non-fungal sensitization (AAFS or AANFS) and non-atopic asthma (NAA) in children and adults in the Severe Asthma Research Program (SARP). SARP is an ongoing project involving well-phenotyped patients with mild to severe asthma. Phenotypic comparisons were performed using Kruskal-Wallis or chi-square test. Genetic association analyses were performed using logistic or linear regression. Airway hyper-responsiveness, total serum IgE levels, and T2 biomarkers showed an increasing trend from NAA to AANFS and then to AAFS. Children and adults with early onset asthma had greater % of AAFS than adults with late onset asthma (46% and 40% vs. 32%; P < 0.00001). In children, AAFS and AANFS had lower % predicted FEV1 (86% and 91% vs. 97%) and greater % of patients with severe asthma than NAA (61% and 59% vs. 43%). In adults with early or late onset asthma, NAA had greater % of patients with severe asthma than AANFS and AAFS (61% vs. 40% and 37% or 56% vs. 44% and 49%). The G allele of rs2872507 in GSDMB had higher frequency in AAFS than AANFS and NAA (0.63 vs. 0.55 and 0.55), and associated with earlier age onset and asthma severity. Early or late onset AAFS, AANFS, and NAA have shared and distinct phenotypic characteristics in children and adults. AAFS is a complex disorder involving genetic susceptibility and environmental factors. [ABSTRACT FROM AUTHOR]

For patients with severe asthma (SA), overestimation of asthma control may lead to poorer outcomes. The objective of this study was to assess concurrent patient and specialist assessments of asthma control and treatment effectiveness among a large US cohort of SA patients. CHRONICLE is an ongoing observational study of patients with SA treated by US subspecialists. Asthma control was assessed using the patient-completed Asthma Control Test™ (ACT™) and specialist clinical assessment of control. Treatment effectiveness was measured using the Global Evaluation of Treatment Effectiveness (GETE) completed by patients and specialists. 1109 patients who completed online surveys at enrollment were included. 14%, 28%, 25%, and 33% of patients had ACT™ scores of 5–9, 10–15, 16–19, and 20–25, respectively. Compared with 67% of patients with uncontrolled asthma by ACT™, 44% were uncontrolled by specialist assessment. 54% of patients who were uncontrolled according to the ACT™ were rated as controlled by specialists, demonstrating overestimation of asthma control. Based on ACT™ score, asthma control was more frequent among patients treated with biologics compared to other treatments. Using the GETE, 90% of patients reported treatment effectiveness compared with 71% of specialists. Patient and specialist treatment effectiveness categorizations agreed 73% of the time. Specialists commonly overestimated asthma control relative to ACT™ scores. Patients reported treatment effectiveness more frequently than specialists. These findings emphasize the importance of validated instruments to assess asthma control and reduce potential treatment gaps associated with patient-specialist discordance. ClinicalTrials.gov Identifier: NCT03373045. [ABSTRACT FROM AUTHOR]

Background: To better understand the changes in pulmonary physiology related to asthma severity following bronchoscopy, we performed scheduled pre- and post-procedure spirometry on subjects undergoing bronchoscopy in our research program.Methods: Control subjects and asthma subjects were recruited for bronchoscopy. On the day of bronchoscopy, subjects underwent spirometry pre-bronchoscopy and then up to three sets within 2 hour following the completion of bronchoscopy. A subset of patients had a second bronchoscopy after 2 weeks of treatment with oral prednisolone (40mg daily).Results: A total of 92 subjects had at least one bronchoscopy (12 control subjects, 56 nonsevere asthma (NSA), 24 severe asthma (SA)). The SA and NSA groups had similar decreases in forced expiratory volume in 1 second (FEV1) (−20±13% vs.−19±16%,p= 0.92) and forced vital capacity (FVC) (−20±12% vs.−20±14%,p= 0.80), but no change in FEV1/FVC ratio. The control and NSA group had more rapid recovery of both FEV1 and FVC by 2 hour compared to the SA group (p= 0.01). In the subset of 36 subjects (22 NSA, 14 SA) who underwent a second bronchoscopy following the administration of oral prednisolone for 14 days, steroids resulted in more rapid recovery of lung function (p< 0.04).Conclusion: Following bronchoscopy the lung function of NSA subjects recovered more quickly than SA subjects. Treatment with oral corticosteroids was associated with a quicker recovery of FEV1 which suggests an inflammatory mechanism for these changes in lung compliance. [ABSTRACT FROM AUTHOR]