Short-Term Longitudinal Variation in FeNO Predicts Future Moderate-to-Severe Exacerbations in COPD Patients on Triple Therapy: A Prospective Cohort Study

Background Fractional exhaled nitric oxide (FeNO) reflects type 2 airway inflammation, yet the prognostic utility of longitudinal FeNO changes in chronic obstructive pulmonary disease (COPD) remains unclear. We aim to explore whether 6-month FeNO-variation patterns predict subsequent moderate-to-severe exacerbations in COPD patients receiving triple therapy. Methods We prospectively evaluated COPD patients receiving triple inhaled therapy from 2023 to 2024. Four FeNO-related variables used to derive FeNO-variation phenotypes via K-means unsupervised clustering. Results Three distinct FeNO-variation phenotypes were identified: a High FeNO–Persistently Elevated subtype (Cluster 1, 11.2%), a High FeNO–Declining subtype (Cluster 2, 20.3%), and a Low FeNO–Stable subtype (Cluster 3, 68.5%). During 6–12 months follow up, 75 patients (33.8%) experienced a moderate-to-severe exacerbation. Compared with Cluster 3, both Cluster 1 (OR 6.97, 95% CI 2.38–20.47) and Cluster 2 (OR 20.08, 95% CI 7.01–57.58) were independently associated with future exacerbations (P<0.001). The final prediction model incorporating FeNO variation phenotypes demonstrated excellent discrimination (AUC 0.889) and provided greater net clinical benefit than models using traditional clinical predictors alone (p=0.004). Subgroup analyses revealed consistent effect sizes across categories of age, prior-year exacerbations, baseline FEV 1 % predicted, symptom burden, smoking status, and proportion of days covered (PDC), supporting the robustness and internal consistency of the FeNO-variation phenotyping approach. Conclusion Short-term longitudinal FeNO variation over 6 months was independently associated with future moderate-to-severe exacerbations in COPD patients receiving triple therapy, supporting risk stratification and hypothesis generation for future interventional studies rather than direct treatment guidance.