Airway inflammation and hyperresponsiveness in subjects with respiratory symptoms and normal spirometry

Background Subjects without a previous history of asthma, presenting with unexplained respiratory symptoms and normal spirometry, may exhibit airway hyperresponsiveness (AHR) in association with underlying eosinophilic (type 2 (T2)) inflammation, consistent with undiagnosed asthma. However, the prevalence of undiagnosed asthma in these subjects is unknown. Methods In this observational study, inhaled corticosteroid-naïve adults without previously diagnosed lung disease reporting current respiratory symptoms and showing normal pre- and post-bronchodilator spirometry underwent fractional exhaled nitric oxide ( F ENO ) measurement, methacholine challenge testing and induced sputum analysis. AHR was defined as a provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC 20 ) <16 mg·mL −1 and T2 inflammation was defined as sputum eosinophils >2% and/or F ENO >25 ppb. Results Out of 132 subjects (mean± sd age 57.6±14.2 years, 52% female), 47 (36% (95% CI 28–44%)) showed AHR: 20/132 (15% (95% CI 9–21%)) with PC 20 <4 mg·mL −1 and 27/132 (21% (95% CI 14–28%)) with PC 20 4–15.9 mg·mL −1 . Of 130 participants for whom sputum eosinophils, F ENO or both results were obtained, 45 (35% (95% CI 27–43%)) had T2 inflammation. 14 participants (11% (95% CI 6–16%)) had sputum eosinophils >2% and PC 20 ≥16 mg·mL −1 , suggesting eosinophilic bronchitis. The prevalence of T2 inflammation was significantly higher in subjects with PC 20 <4 mg·mL −1 (12/20 (60%)) than in those with PC 20 4–15.9 mg·mL −1 (8/27 (30%)) or ≥16 mg·mL −1 (25/85 (29%)) (p=0.01). Conclusions Asthma, underlying T2 airway inflammation and eosinophilic bronchitis may remain undiagnosed in a high proportion of symptomatic subjects in the community who have normal pre- and post-bronchodilator spirometry.