Background: Small airway dysfunction (SAD) is associated with impaired asthma control, but small airway physiology is not routinely assessed in clinical practice. Previously, we demonstrated impulse oscillometry (IOS)-defined small airway dysfunction (SAD) in dual responders (DRs) upon bronchoprovocation with various allergens. Aim: To compare lung physiology using spirometry and IOS following bronchoprovocation with methacholine (M) and inhaled house dust mite (HDM) extract in corticosteroid-naïve asthmatic subjects. Methods: Non-smoking, clinically stable HDM-allergic asthmatic subjects (18-55 years, FEV1 > 70% of pred.) underwent an M and inhaled HDM challenge on two separate days. Airway response was measured by IOS and spirometry, until a drop in FEV1 ≥ 20% (PC20) from post-diluent baseline (M), and up to 8 h post-allergen (HDM). Early (EAR) and late asthmatic response (LAR) to HDM were defined as ≥20% and ≥15% fall in FEV1 from post-diluent baseline during 0-3 h and 3-8 h post-challenge, respectively. IOS parameters (Rrs5, Rrs20, Rrs5-20, Xrs5, AX, Fres) were compared between mono-responders (MRs: EAR only) and dual responders (EAR + LAR). Correlations between maximal % change from baseline after the two airway challenges were calculated for both FEV1 and IOS parameters. Results: A total of 47 subjects were included (11 MRs; 36 DRs). FEV1 % predicted did not differ between MR and DR at baseline, but DR had lower median PC20M (0.84 (range 0.07-7.51) vs. MR (2.15 (0.53-11.29)); p = 0.036). During the LAR, DRs had higher IOS values than MRs. For IOS parameters (but not for FEV1), the maximal % change from baseline following M and HDM challenge were correlated. PC20M was inversely correlated with the % change in FEV1 and the % change in Xrs5 during the LAR (r= -0.443; p = 0.0018 and r= -0.389; p = 0.0075, respectively). Conclusions: During HDM-induced LAR, changes in small airway physiology can be non-invasively detected with IOS and are associated with increased airway hyperresponsiveness and changes in small airway physiology during methacholine challenge. DRs have a small airways phenotype, which reflects a more advanced airway disease.

Center for Primary Health Care Research Department of Clinical Sciences Malmö Lund University 21428 Malmö Sweden

Department of Clinical Pharmacy and Pharmacology University Medical Centre Groningen 9700 RB Groningen The Netherlands

Department of Epidemiology and Data Sciences Amsterdam University Medical Centre 1105 AZ Amsterdam The Netherlands

Department of Microbiology Immunology and Transplantation Catholic University of Leuven 3000 Leuven Belgium

Department of Pulmonary Medicine Amsterdam University Medical Centre 1007 MB Amsterdam The Netherlands

Department of Respiratory Medicine 1st Faculty of Medicine Thomayer Hospital Charles University 12108 Prague Czech Republic

Lung Function Centre O2CO2 2582 EZ The Hague The Netherlands

QPS NL 9713 AG Groningen The Netherlands

School of Medicine University of Dundee Dundee DD1 9SY UK

University Clinic Primary Care Skåne 29189 Kristianstad Region Skåne Sweden

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