Multicohort Analysis of Bronchial Epithelial Cell Expression in Healthy Subjects and Patients with Asthma Reveals Four Clinically Distinct Clusters.

Asthma is a heterogeneous disease with variable presentation and characteristics. There is a critical need to identify underlying molecular endotypes of asthma. We performed the largest transcriptomic analysis of 808 bronchial epithelial cell (BEC) samples across 11 independent cohorts, including 3 cohorts from the Severe Asthma Research Program (SARP).

Type 1 Immune Responses Related to Viral Infection Influence Corticosteroid Response in Asthma.

Rationale: Corticosteroid-responsive type 2 (T2) inflammation underlies the T2-high asthma endotype. However, we hypothesized that type 1 (T1) inflammation, possibly related to viral infection, may also influence corticosteroid response.

Objectives: To determine the frequency and within-patient variability of T1-high, T2-high, and T1/T2-high asthma endotypes and whether virally influenced T1-high disease influences corticosteroid response in asthma.

Development of an asthma health-care burden score as a measure of severity and predictor of remission in SARP III and U-BIOPRED: results from two major longitudinal asthma cohorts.

Background: Current asthma guidelines, including those of the European Respiratory Society (ERS) and American Thoracic Society (ATS), suboptimally predict asthma remission, disease severity, and health-care utilisation. We aimed to establish a novel approach to assess asthma severity based on asthma health-care burden data.

Methods: We analysed prospectively collected data from the Severe Asthma Research Program III (SARP III; USA) and the European Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED; 11 European countries) to calculate a composite burden score based on asthma exacerbations and health-care utilisation, which was modified to include the use of short-acting beta agonists (SABAs) to reflect asthma symptom burden.

Modification of asthma treatment efficacy by healthcare access: A reanalysis of AsthmaNet Step-Up Yellow Zone Inhaled Corticosteroids to Prevent Exacerbations (STICS) clinical trial.

Background: While randomized controlled trials (RCTs) in asthma management are designed to balance known and unknown variables across treatment groups, including social and environmental co-exposures, it remains important to consider how these co-exposures influence disease progression and treatment outcomes. The importance of considering socio-environmental co-exposures in the context of asthma is twofold: 1) asthma disproportionately affects low-income urban communities, where air pollution and chronic stress are pervasive; and 2) despite the wide range of asthma treatments, inadequate disease control persists.

Methods: In the present ancillary study of the Step-Up Yellow Zone Inhaled Corticosteroids to Prevent Exacerbations (STICS) RCT, we investigated how socio-environmental factors, such as air pollution exposure and healthcare access, modify the effect of inhaled corticosteroid (ICS) therapy in children with asthma.

Brensocatib in non-cystic fibrosis bronchiectasis: ASPEN protocol and baseline characteristics.

Introduction: Brensocatib is an investigational, oral, reversible inhibitor of dipeptidyl peptidase-1 shown to prolong time to first exacerbation in adults with bronchiectasis. Outlined here are the clinical trial design, and baseline characteristics and treatment patterns of adult patients enrolled in the phase 3 ASPEN trial (NCT04594369).

Methods: The ASPEN trial is a global study enrolling patients with a clinical history consistent with bronchiectasis (cough, chronic sputum production and/or recurrent respiratory infections), diagnosis confirmed radiologically and ≥2 exacerbations in the prior 12 months.

Increased Muc5AC and Decreased Ciliated Cells in Severe Asthma Partially Restored by Inhibition of IL-4Rα Receptor.

The role of IL-13 on the airway epithelium in severe asthma leading to airway remodeling remains poorly understood. To study IL-13-induced airway remodeling on goblet cells and cilia in the airway epithelium in severe asthma and the impact of an anti-IL4Rα antibody, dupilumab, . Quantitative computed tomography of the lungs and endobronchial biopsies and brushings were obtained in 51 participants (22 with severe asthma, 11 with nonsevere asthma, and 18 healthy participants) in SARPIII (Severe Asthma Research Program III) and measured for mucin and cilia-related proteins.

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus.

A novel DNase assay reveals low DNase activity in severe asthma.

Secreted deoxyribonucleases (DNases), such as DNase-I and DNase-IL3, degrade extracellular DNA, and endogenous DNases have roles in resolving airway inflammation and guarding against autoimmune responses to nucleotides. Subsets of patients with asthma have high airway DNA levels, but information about DNase activity in health and in asthma is lacking. To characterize DNase activity in health and in asthma, we developed a novel kinetic assay using a Taqman probe sequence that is quickly cleaved by DNase-I to produce a large product signal.

Protein-Protein interactive networks identified in bronchoalveolar lavage of severe compared to nonsevere asthma.

Introduction: Previous bronchoalveolar lavage fluid (BALF) proteomic analysis has evaluated limited numbers of subjects for only a few proteins of interest, which may differ between asthma and normal controls. Our objective was to examine a more comprehensive inflammatory biomarker panel in quantitative proteomic analysis for a large asthma cohort to identify molecular phenotypes distinguishing severe from nonsevere asthma.

Methods: Bronchoalveolar lavage fluid from 48 severe and 77 nonsevere adult asthma subjects were assessed for 75 inflammatory proteins, normalized to BALF total protein concentration.

A Novel Air Trapping Segment Score Identifies Opposing Effects of Obesity and Eosinophilia on Air Trapping in Asthma.

Density thresholds in computed tomography (CT) lung scans quantify air trapping (AT) at the whole-lung level but are not informative for AT in specific bronchopulmonary segments. To apply a segment-based measure of AT in asthma to investigate the clinical determinants of AT in asthma. In each of 19 bronchopulmonary segments in CT lung scans from 199 patients with asthma, AT was categorized as present if lung attenuation was less than -856 Hounsfield units at expiration in ⩾15% of the lung area.

Association of Sputum Eosinophilia With Easily Measured Type-2 Inflammatory Biomarkers in Untreated Mild Persistent Asthma.

Background: A multicenter clinical trial in patients with mild persistent asthma indicated that response to inhaled corticosteroids (ICS) is limited to those with sputum eosinophilia. However, testing for sputum eosinophilia is impractical in most clinical settings.

Objective: We examined associations between sputum eosinophilia and type 2 inflammatory biomarkers in untreated mild persistent asthma.

Rhinoviruses A and C elicit long-lasting antibody responses with limited cross-neutralization.

Rhinoviruses (RVs) can cause severe wheezing illnesses in young children and patients with asthma. Vaccine development has been hampered by the multitude of RV types with little information about cross-neutralization. We previously showed that neutralizing antibody (nAb) responses to RV-C are detected twofold to threefold more often than those to RV-A throughout childhood.

The Fungal Microbiome of the Upper Airway Is Associated With Future Loss of Asthma Control and Exacerbation Among Children With Asthma.

Background: Accumulating evidence suggests that the upper airway bacterial microbiota is implicated in asthma inception, severity, and exacerbation. Unlike bacterial microbiota, the role of the upper airway fungal microbiome (mycobiome) in asthma control is poorly understood.

Research Question: What are the upper airway fungal colonization patterns among children with asthma and their relationship with subsequent loss of asthma control and exacerbation of asthma?

Study Design And Methods: The study was coupled with the Step Up Yellow Zone Inhaled Corticosteroids to Prevent Exacerbations (ClinicalTrials.

Genetic analyses of chr11p15.5 region identify - associated with asthma-related phenotypes.

Objective: Genome-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).

Investigations of a combination of atopic status and age of asthma onset identify asthma subphenotypes.

Objective: 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.

CCL5 is a potential bridge between type 1 and type 2 inflammation in asthma.

Background: Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear.

Objective: We sought to understand the role of CCL5 in asthmatic T1 inflammation and how it interacts with both T1 and type 2 (T2) inflammation.

Methods: CCL5, CXCL9, and CXCL10 messenger RNA expression from sputum bulk RNA sequencing, as well as clinical and inflammatory data were obtained from the Severe Asthma Research Program III (SARP III).

Bronchial epithelial cell transcriptional responses to inhaled corticosteroids dictate severe asthmatic outcomes.

Background: Inhaled corticosteroids (CSs) are the backbone of asthma treatment, improving quality of life, exacerbation rates, and mortality. Although effective for most, a subset of patients with asthma experience CS-resistant disease despite receiving high-dose medication.

Objective: We sought to investigate the transcriptomic response of bronchial epithelial cells (BECs) to inhaled CSs.

Skeletal Muscle Adiposity and Lung Function Trajectory in the Severe Asthma Research Program.

Extrapulmonary manifestations of asthma, including fatty infiltration in tissues, may reflect systemic inflammation and influence lung function and disease severity. To determine if skeletal muscle adiposity predicts lung function trajectory in asthma. Adult SARP III (Severe Asthma Research Program III) participants with baseline computed tomography imaging and longitudinal postbronchodilator FEV% predicted (median follow-up 5 years [1,132 person-years]) were evaluated.

Urinary total conjugated 3-bromotyrosine, asthma severity, and exacerbation risk.

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.

Low CC16 mRNA Expression Levels in Bronchial Epithelial Cells Are Associated with Asthma Severity.

CC16 is a protein mainly produced by nonciliated bronchial epithelial cells (BECs) that participates in host defense. Reduced CC16 protein concentrations in BAL and serum are associated with asthma susceptibility. Few studies have investigated the relationship between CC16 and asthma progression, and none has focused on BECs.