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 (PC₂₀) <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 PC₂₀ <4 mg·mL^-1 and 27/132 (21% (95% CI 14-28%)) with PC₂₀ 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 PC₂₀ ≥16 mg·mL^-1, suggesting eosinophilic bronchitis. The prevalence of T2 inflammation was significantly higher in subjects with PC₂₀ <4 mg·mL^-1 (12/20 (60%)) than in those with PC₂₀ 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.