Clinical importance of patient-reported outcome measures in severe asthma: results from U-BIOPRED.

Rationale: Knowledge about the clinical importance of patient-reported outcome measures (PROMs) in severe asthma is limited.

Objectives: To assess whether and to what extent asthma exacerbations affect changes in PROMS over time and asthma-specific PROMs can predict exacerbations in adult patients with severe asthma in usual care.

Methods: Data of 421 patients with severe asthma (62% female; mean age 51.

Host-microbial interactions differ with age of asthma onset.

https://bit.ly/3xSa4Fe

Endotypes of severe neutrophilic and eosinophilic asthma from multi-omics integration of U-BIOPRED sputum samples.

Background: Clustering approaches using single omics platforms are increasingly used to characterise molecular phenotypes of eosinophilic and neutrophilic asthma. Effective integration of multi-omics platforms should lead towards greater refinement of asthma endotypes across molecular dimensions and indicate key targets for intervention or biomarker development.

Objectives: To determine whether multi-omics integration of sputum leads to improved granularity of the molecular classification of severe asthma.

Phenotyping asthma with airflow obstruction in middle-aged and older adults: a CADSET clinical research collaboration.

Background: The prevalence and clinical profile of asthma with airflow obstruction (AO) remain uncertain. We aimed to phenotype AO in population- and clinic-based cohorts.

Methods: This cross-sectional multicohort study included adults ≥50 years from nine CADSET cohorts with spirometry data (N=69 789).

Systems Biology in Asthma.

The application of mathematical and computational analysis, together with the modelling of biological and physiological processes, is transforming our understanding of the pathophysiology of complex diseases. This systems biology approach incorporates large amounts of genomic, transcriptomic, proteomic, metabolomic, breathomic, metagenomic and imaging data from disease sites together with deep clinical phenotyping, including patient-reported outcomes. Integration of these datasets will provide a greater understanding of the molecular pathways associated with severe asthma in each individual patient and determine their personalised treatment regime.

Haemophilus influenzae and Moraxella catarrhalis in sputum of severe asthma with inflammasome and neutrophil activation.

Background: Because of altered airway microbiome in asthma, we analysed the bacterial species in sputum of patients with severe asthma.

Methods: Whole genome sequencing was performed on induced sputum from non-smoking (SAn) and current or ex-smoker (SAs/ex) severe asthma patients, mild/moderate asthma (MMA) and healthy controls (HC). Data were analysed by asthma severity, inflammatory status and transcriptome-associated clusters (TACs).

Epithelium-derived cystatin SN inhibits house dust mite protease activity in allergic asthma.

Background: Allergen source-derived proteases are a critical factor in the formation and development of asthma. The cysteine protease activity of house dust mite (HDM) disrupts the epithelial barrier function. The expression of cystatin SN (CST1) is elevated in asthma epithelium.

Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma.

Background: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma.

Multidimensional endotyping using nasal proteomics predicts molecular phenotypes in the asthmatic airways.

Background: Unsupervised clustering of biomarkers derived from noninvasive samples such as nasal fluid is less evaluated as a tool for describing asthma endotypes.

Objective: We sought to evaluate whether protein expression in nasal fluid would identify distinct clusters of patients with asthma with specific lower airway molecular phenotypes.

Methods: Unsupervised clustering of 168 nasal inflammatory and immune proteins and Shapley values was used to stratify 43 patients with severe asthma (endotype of noneosinophilic asthma) using a 2 "modeling blocks" machine learning approach.

IL1RAP expression and the enrichment of IL-33 activation signatures in severe neutrophilic asthma.

Background: Interleukin (IL)-33 is an upstream regulator of type 2 (T2) eosinophilic inflammation and has been proposed as a key driver of some asthma phenotypes.

Objective: To derive gene signatures from in vitro studies of IL-33-stimulated cells and use these to determine IL-33-associated enrichment patterns in asthma.

Methods: Signatures downstream of IL-33 stimulation were derived from our in vitro study of human mast cells and from public datasets of in vitro stimulated human basophils, type 2 innate lymphoid cells (ILC2), regulatory T cells (Treg) and endothelial cells.

Adverse roles of mast cell chymase-1 in COPD.

Background: COPD is the third leading cause of death worldwide. Cigarette smoke (CS)-induced chronic inflammation inducing airway remodelling, emphysema and impaired lung function is the primary cause. Effective therapies are urgently needed.

Pathways linked to unresolved inflammation and airway remodelling characterize the transcriptome in two independent severe asthma cohorts.

Background And Objective: Severe asthma (SA) is a heterogeneous disease. Transcriptomic analysis contributes to the understanding of pathogenesis necessary for developing new therapies. We sought to identify and validate mechanistic pathways of SA across two independent cohorts.

Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study.

Introduction: Asthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms.

Association of Differential Mast Cell Activation with Granulocytic Inflammation in Severe Asthma.

Mast cells (MCs) play a role in inflammation and both innate and adaptive immunity, but their involvement in severe asthma (SA) remains undefined. We investigated the phenotypic characteristics of the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) asthma cohort by applying published MC activation signatures to the sputum cell transcriptome. Eighty-four participants with SA, 20 with mild/moderate asthma (MMA), and 16 healthy participants without asthma were studied.

Relationship between type 2 cytokine and inflammasome responses in obesity-associated asthma.

Background: Obesity is a risk factor for asthma, and obese asthmatic individuals are more likely to have severe, steroid-insensitive disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type 2 immunity, and eosinophilic inflammation have been described.

An altered sputum macrophage transcriptome contributes to the neutrophilic asthma endotype.

Background: Neutrophilic asthma (NA) is a clinically important asthma phenotype, the cellular and molecular basis of which is not completely understood. Airway macrophages are long-lived immune cells that exert important homeostatic and inflammatory functions which are dysregulated in asthma. Unique transcriptomic programmes reflect varied macrophage phenotypes in vitro.

Mapping atopic dermatitis and anti-IL-22 response signatures to type 2-low severe neutrophilic asthma.

Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.

Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma.

Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies.

Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma.

Background: Patients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells.

Methods: We examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort.

Instability of sputum molecular phenotypes in U-BIOPRED severe asthma.

https://bit.ly/35aj489