Small airway dysfunction mediates the relationship between Fractional Exhaled Nitric Oxide and asthma control

Background: Most physiological production of Fractional exhaled Nitric Oxide (FeNO) occurs in the small airways, but studies on the relationship between FeNO and small airway dysfunction (SAD) in asthma are scant. Objective: To investigate the relationship between asthma control, changes of FeNO in relation to airway bronchodilation (BD), and SAD. Methods: Baseline conventional spirometry, impulse oscillometry, and FeNO pre- and post-BD (salbutamol 400 μg) were tested on consecutive community-treated adult patients with asthma. Results were stratified by FeNO response (change in FeNO [ΔFeNO]), being FeNO “responder” if the increase is greater than 10% post-BD compared with the basal values and “nonresponder” if less than or equal to 10%. Results: When measured, post-BD FeNO greater than 25 parts per billion was found in an additional 31.5% of patients. Of the 92 patients included, 61% were classified as FeNO “responders” and 39% as “nonresponders.” A significant moderate-to-strong correlation was observed between ΔFeNO and R5R20, a functional marker of SAD (R = 0.52, P < .0001), whereas the correlations between spirometry markers and ΔFeNO were not significant (P > .05). Both R5R20 and ΔFeNO inversely correlated with asthma control (P < .0001). Using causal mediation analysis modeling, the effect of asthma control on ΔFeNO was mediated by SAD, with a strong indirect effect of asthma control on ΔFeNO mediated by SAD (β value: −7.04, 95% CI: −11.80 to −3.53, P < .0001), without a significant direct effect (β value: −4.96, 95% CI: −9.15 to 0.11, P = .056). Conclusion: Changes in FeNO values pre-/post-BD can improve the identification of patients with “TH2 high” asthma. The relationship between ΔFeNO and asthma control is mainly mediated by SAD, highlighting its contribution to asthma control.