Small airway dysfunction mediates the relationship between FeNO and asthma control

Background: Most of the Fractional exhaled Nitric Oxide (FeNO)'s physiological production occurs in small airways, but the relationship between FeNO and small airway disease (SAD) in asthma is 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 (IOS), and FeNO pre- and post-bronchodilation (salbutamol 400 mcg) were tested on consecutive community-treated adult asthmatic patients. Results were stratified by FeNO response (ΔFeNO), being FeNO "responder" if an increase >10% post-BD compared to the basal values were registered, and "non-responder" if ≤10%.

Results: When measured, post-BD FeNO>25ppb was found in an additional 31.5% of patients. Of the 92 patients included, 61% were classified as FeNO "responders" and 39% as "non-responders". A significant moderate-to-strong correlation was observed between ΔFeNO and R5R20, a functional marker of SAD (R=0.52, p<0.0001), while correlations between spirometry markers and ΔFeNO were not significant (p> 0.05). Both R5R20 and ΔFeNO inversely correlated with asthma control (<0.0001). By means of the causal mediation analysis modelling, 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; -3.53, p<0.0001), without a significant direct effect (β value:-4.96; 95%CI:-9.15; +0.11; p=0.056).

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 in determining asthma control in real-life.