Oscillometry bronchodilator response testing identifies distinct pathophysiological phenotypes – a post hoc analysis of the ATLANTIS study

Background Spirometry with bronchodilator response (BDR) testing is the first-line test for asthma in international guidelines, however it has been shown to have suboptimal sensitivity for asthma diagnosis and detecting small airways dysfunction (SAD). Oscillometry with BDR may identify bronchodilator response in patients with no significant BDR by spirometry. Aims To determine whether oscillometry identifies additional BDR in the Assessment of Small Airways Involvement in Asthma (ATLANTIS) study asthma cohort compared to spirometry (ClinicalTrials.gov ID NCT02123667 ), and to characterise phenotypic differences between BDR groups. Methods Baseline data from 518 adults with objectively confirmed asthma enrolled in ATLANTIS were analysed. Differences in clinical, biomarker and physiological characteristics were assessed between BDR groups. A subset with CT imaging (208/518) and nasal RNA-seq data (n=236/518) underwent CT biomarker and differential gene expression (DGE) analysis to investigate differences in airway morphology and pathways underlying a small airways bronchodilator responsive phenotype. Results Oscillometry detected significant bronchodilator response in an additional 11% of participants not identified by spirometry, although spirometry identified more responders overall. Spirometry positive BDR only cases (Group 1) had greater airway obstruction and FeNO (p<0.05) compared with oscillometry-only BDR (Group 2). Subgroup analysis identified differentially expressed genes related to mitochondrial stress and cell adhesion in group 3 (BDR in both) versus group 1 and reduced luminal area and greater gas trapping on CT imaging (p<0.05). Interpretation Oscillometry identified additional bronchodilator-responsive participants beyond spirometry, indicating complementary physiological information. Distinct BDR patterns were associated with differing inflammatory, physiological and structural features suggesting distinct asthma phenotypes.