Annual fractional exhaled nitric oxide measurements and exacerbations in severe asthma: a multicenter observational cohort study

Background: Fractional exhaled nitric oxide (FeNO) reflects eosinophilic inflammation of the airways. However, the significance of longitudinal assessment of FeNO, including its variability, in the clinical course of severe asthma remains unclear. The aim of this study is to examine the association between long-term changes in FeNO and the development of exacerbations in severe asthma. Methods: Among the severe asthma patients enrolled in the Hokkaido Severe Asthma Cohort Study, 100 patients with severe asthma who completed a 3-year follow-up in which FeNO was measured annually were included. According to the FeNO level at baseline, 1 year, and 2 years, the patients were classified into three groups: the sustained high group (≥50 ppb at all three visits), the sustained low group (<25 ppb at all three visits), and the intermediate group (other). Subjects in the intermediate group were further classified into two groups based on the median value of the coefficient of variation (CV) of FeNO during the 3 years (high CV and low CV intermediate groups). Results: The sustained high group experienced shorter exacerbation-free survival and more frequent exacerbations than the sustained low group (median number of exacerbation events, 3 vs. 0, p = 0.01). In the intermediate group, the high CV group experienced shorter exacerbation-free survival than the low CV group, and the CV of FeNO was an independent contributing factor to the development of exacerbations. Conclusion: Persistence of FeNO above 50 ppb over the years as well as the presence of large variations in FeNO levels were associated with the development of exacerbations in patients with severe asthma.