Zhaoqian Gong, Hailun Huang, Xueying Zhao, Yuling Hu, Meijia Chen, Junrao Wang, Guiling Xu, Junwen Huang, Ying Chen, Liyu Yang, Wenqu Zhao, Yanmei Ye, Haijin Zhao
Triple therapy was associated with the greatest average improvement in SGRQ total score in stable COPD, but its incremental benefit over dual bronchodilation was modest and below the conventional SGRQ minimal clinically important difference. Treatment escalation should therefore be individualized, balancing potential quality-of-life gains against pneumonia risk with ICS-containing regimens.
BACKGROUND: Fractional exhaled nitric oxide (F ENO) reflects type 2 airway inflammation, yet the prognostic utility of longitudinal F ENO changes in COPD remains unclear. We aim to explore whether 6-month F ENO 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 F ENO-related variables were used to derive F ENO variation phenotypes via K-means unsupervised clustering.
RESULTS: Three distinct F ENO-variation phenotypes were identified: a High F ENO-Persistently Elevated subtype (Cluster 1, 11.2%), a High F ENO-Declining subtype (Cluster 2, 20.3%) and a Low F ENO-Stable subtype (Cluster 3, 68.5%). During 6-12 months of 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 F ENO 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 FEV1 % predicted, symptom burden, smoking status and proportion of days covered, supporting the robustness and internal consistency of the F ENO-variation phenotyping approach.
CONCLUSION: Short-term longitudinal F ENO 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.