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.

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.

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.

Comparison of hyperpolarized He-MRI, CT based parametric response mapping, and mucus scores in asthmatics.

The purpose of this study was to anatomically correlate ventilation defects with regions of air trapping by whole lung, lung lobe, and airway segment in the context of airway mucus plugging in asthma. A total of 34 asthmatics [13M:21F, 13 mild/moderate, median age (range) of 49.5 (36.

P2X signaling influences the production of pro-resolving and pro-inflammatory lipid mediators in alveolar macrophages derived from individuals with asthma.

Few new therapeutics exist to target airway inflammation in mild-to-moderate asthma. Alveolar macrophages regulate airway inflammation by producing proresolving eicosanoids. We hypothesized that stimulation of the purinergic receptor P2X in macrophages from individuals with asthma produces eicosanoids associated with airway inflammation and resolution, and that these responses are predicted, in part, by P2X7 pore function.

Clinical Trial Design Innovations for Precision Medicine in Asthma.

Severe asthma is a spectrum disorder with numerous subsets, many of which are defined by clinical history and a general predisposition for T2 inflammation. Most of the approved therapies for severe asthma have required clinical trial designs with population enrichment for exacerbation frequency and/or elevation of blood eosinophils. Moving beyond this framework will require trial designs that increase efficiency for studying nondominant subsets and continue to improve upon biomarker signatures.

Imaging Regional Airway Involvement of Asthma: Heterogeneity in Ventilation, Mucus Plugs and Remodeling.

The imaging of asthma using chest computed tomography (CT) is well-established (Jarjour et al., Am J Respir Crit Care Med 185(4):356-62, 2012; Castro et al., J Allergy Clin Immunol 128:467-78, 2011).

Development and Dynamic Responsiveness of the Acute Asthma Exacerbation Survey in Patients With Moderate to Severe Disease.

Background: The recall periods and response scales of existing surveys of asthma control are poorly suited for studying acute exacerbations.

Objective: To develop an instrument able to predict exacerbations after the onset of acute symptoms and with a recall window sufficiently short to study recovery.

Methods: We developed the six-item Acute Asthma Exacerbation Survey (AAES).

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.

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.

An open microfluidic coculture model of fibroblasts and eosinophils to investigate mechanisms of airway inflammation.

Interactions between fibroblasts and immune cells play an important role in tissue inflammation. Previous studies have found that eosinophils activated with interleukin-3 (IL-3) degranulate on aggregated immunoglobulin G (IgG) and release mediators that activate fibroblasts in the lung. However, these studies were done with eosinophil-conditioned media that have the capacity to investigate only one-way signaling from eosinophils to fibroblasts.

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.

Determinants of lung function across childhood in the Severe Asthma Research Program (SARP) 3.

Background: Children with asthma are at risk for low lung function extending into adulthood, but understanding of clinical predictors is incomplete.

Objective: We sought to determine phenotypic factors associated with FEV throughout childhood in the Severe Asthma Research Program 3 pediatric cohort.

Methods: Lung function was measured at baseline and annually.