Small Airway Dysfunction May Mediate the Association Between Body Mass Index and Severe Asthma Exacerbations

Background: Obesity is associated with poorer asthma outcomes and an increased risk of exacerbations, but the underlying mechanisms remain incompletely understood. Small airway dysfunction (SAD) may represent a key mechanistic link between excess body weight and adverse asthma outcomes. Methods: In this multicenter observational study, adult patients with asthma underwent clinical characterization, spirometry and impulse oscillometry (IOS). SAD was defined using a composite criterion based on peripheral airway resistance (R5-20), reactance area (AX) and the ratio of peripheral to total airway resistance (R5-20)/R5. Associations between body mass index (BMI), SAD and severe asthma exacerbations were assessed using multivariable regression models. Non-linear relationships were explored using generalized additive models and mediation analyses quantified the contribution of SAD to the obesity-exacerbation association. Findings: Among 1169 patients, IOS-defined SAD was significantly more prevalent in individuals with BMI≥30 kg·m-2. Increasing BMI was associated with worse oscillometric parameters (p<0.0001), following a non-linear pattern with steeper deterioration beyond BMI values of approximately 28-30 kg·m-2. SAD was independently associated with obesity (adjusted OR 2.11, 95% CI 1.56-2.86) and with severe asthma exacerbations in the previous year (adjusted OR 2.01, 95% CI 1.53-2.65, both p<0.0001). Mediation analyses showed that SAD accounted for 26%-41% of the association between obesity and exacerbation risk (p=0.004 and 0.03). Spirometric indices provided limited additional information. Interpretation: Oscillometry-defined small airways dysfunction (SAD) represents a non-linear functional trait underlying the association between obesity and severe asthma exacerbations, supporting its clinical relevance in obese patients with asthma and identifying SAD as a potential treatable trait.