Bronchodilator response is linked with uncontrolled moderate-to-severe childhood asthma and elevated IL-4 and IL-13

Abstract

Background: Bronchodilator response (BDR) is a key clinical feature in childhood asthma, but its relation to asthma pathophysiology is not fully understood. This study examines the associations between BDR, disease control, and serum cytokines/chemokines in children with moderate-to-severe asthma (MSA).

Methods: BDR was assessed in 140 children (aged 6-17 years, 41% females) from the SysPharmPediA cohort using the ERS/ATS 2022 guidelines (ΔFEV₁ >10% predicted) and z-score (ΔFEV₁-z-score >0.78) post-bronchodilator definitions. Risk of uncontrolled asthma in relation to BDR was estimated by a logistic regression model, adjusting for baseline lung function, age, sex, BMI z-score, ethnicity, country, season, GINA step, and smoking exposure. Thirty-nine serum proteins were measured using Luminex Multiplex Assay; levels below the detection limit (LOD) were imputed as LOD/√2, and proteins with >40% missing values across samples were excluded. Children with high and low BDR were compared for serum proteins by linear regression model, adjusting for covariates and applying false discovery rate correction.

Results: Children with high BDR (21%) had significantly higher odds of uncontrolled asthma (adjusted OR ≈ 3.22, 95% CIs: 1.07-11.3) and more frequent severe exacerbations in the past year compared with those with low BDR (70% vs. 46%, p < .05). High-BDR children showed elevated serum levels of IL-13, IL-4, TNF-α, IL-6, IL-7, IL-8, IL-1β, and MMP-1 (q < 0.05).

Conclusion: In children with MSA, a high BDR is independently associated with poorer asthma control and a distinct systemic inflammatory profile involving T2 and non-T2 mediators. BDR may serve as a marker for asthma phenotyping.

Keywords: asthma control; bronchodilator response; moderate‐to‐severe pediatric asthma; non‐invasive phenotyping; type 2 inflammation.