Variability of fractional exhaled nitric oxide is associated with the risk and aetiology of COPD exacerbations

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are heterogeneous in aetiology and accelerate disease progression. Here, we aimed to investigate the association of fractional exhaled nitric oxide (FeNO) and its variability with AECOPD of different aetiology.FeNO was determined in 2157 visits (1697 stable, 133 AECOPD and 327 follow-up) of 421 COPD patients from the PREVENT study, an investigator-initiated, longitudinal and interventional study, who were on daily treatment with inhaled corticosteroids/long-acting β2-agonists.Longitudinal measurements of FeNO revealed an intra-subject variability of FeNO that was significantly higher in exacerbators compared to non-exacerbators (p < 0.001) and positively associated with the number of AECOPD. As FeNO variability increased, the probability of patients to remain AECOPD-free decreased. In patients included in the highest FeNO variability quartile (≥15.0 ppb) the probability to remain free of AECOPD was only 35% as compared to 80% for patients included in the lowest FeNO variability quartile (0.50-4.39 ppb). The change of FeNO from the last stable visit to AECOPD was positively associated with the probability of viral infections and this association was stronger in current smokers than ex-smokers. In contrast, the change in FeNO from the last stable visit to an AECOPD visit was inversely associated with the probability of bacterial infections in ex-smokers but not in current smokers.FeNO variability was associated with the risk and aetiology of AECOPD differentially in current and ex-smokers.