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. 2025 Jul;13(7):1743-1754.e12.
doi: 10.1016/j.jaip.2025.03.017. Epub 2025 Mar 20.

Dysfunctional Breathing and Depression Are Core Extrapulmonary and Behavior/Risk Factor Traits in Type 2-High Severe Asthma

Yuto Hamada  1 , Peter G Gibson  2 , Vanessa L Clark  3 , Hayley Lewthwaite  4 , Michael Fricker  5 , Dennis Thomas  4 , Vanessa M McDonald  6
Affiliations
Free article

Dysfunctional Breathing and Depression Are Core Extrapulmonary and Behavior/Risk Factor Traits in Type 2-High Severe Asthma

Yuto Hamada et al. J Allergy Clin Immunol Pract. 2025 Jul.
Free article

Abstract

Background: Obesity and smoking are core treatable traits (TTs) in type 2 (T2)-low asthma, contributing to its pathophysiology. In contrast, core extrapulmonary and behavior/risk factor traits remain unclear in T2-high asthma.

Objective: This study aimed to identify core extrapulmonary and behavior/risk factor traits for T2-high asthma.

Methods: A cross-sectional study was conducted on 187 people (aged ≥18 years) with severe asthma who completed a multidimensional assessment. T2-high asthma was defined as blood eosinophils ≥150 cells/μL and/or fractional exhaled nitric oxide ≥20 ppb. Core TTs in T2-high asthma were identified among 9 extrapulmonary traits and 4 behavior/risk factor traits, using network analysis and dominance analysis for the Asthma Control Questionnaire scores, the Asthma Quality of Life Questionnaire scores, exacerbation frequency, and lung function. Associations between the identified core TTs and biomarkers were examined in participants with T2-high asthma.

Results: Of 187 participants, 151 (80.7%) had T2-high severe asthma. Dysfunctional breathing and depression had higher values of node strength than other TTs, contributing most to worse asthma symptoms, poorer quality of life, and frequent exacerbations in T2-high asthma. These conditions in T2-high asthma were associated with elevated systemic inflammation, including blood neutrophils, neutrophil-lymphocyte ratio, and serum high-sensitivity C-reactive protein, independent of obesity, oral corticosteroid dose, and anxiety.

Conclusions: Core extrapulmonary and behavior/risk factor traits in T2-high severe asthma were dysfunctional breathing and depression, contributing to worse asthma outcomes, suggesting that core TTs may differ between asthma inflammatory phenotypes. Elevated systemic inflammation may help in recognizing the presence of dysfunctional breathing and depression in T2-high severe asthma.

Keywords: Depression; Dysfunctional breathing; Severe asthma; Systemic inflammation; Treatable traits; Type 2 inflammation; Type 2–high asthma.

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