FeNO as a Treatable Trait in Chronic Cough: Insights from the PROCOUGH Study

Type 2 (T2) inflammatory biomarkers are established therapeutic targets in asthma and non-asthmatic eosinophilic bronchitis (NAEB), but their relevance in chronic cough remains unclear. Therefore, the objective of our study was to evaluate the relationship between T2 biomarkers and cough outcomes, and to determine their ability to predict treatment response and cough control.

This post-hoc analysis of the prospective PROCOUGH cohort included 100 patients with chronic cough. Patients underwent comprehensive phenotyping and were classified as chronic cough secondary to asthma/NAEB (CC_Ast/EB) or refractory chronic cough (RCC). Patients with CC_Ast/EB received inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) therapy, while those without evidence of T2 inflammation or who had failed ICS/LABA were treated with neuromodulators. Cough outcomes included 24-h cough frequency, Leicester cough questionnaire (LCQ), and cough severity visual analogue scale (VAS). Baseline and post-treatment FeNO, blood eosinophils, and sputum eosinophils were measured. Correlation, logistic regression, and receiver operating characteristic (ROC) analyses were performed.

Baseline FeNO and sputum eosinophils were higher in CC_Ast/EB than RCC. In CC_Ast/EB, ICS/LABA treatment reduced FeNO and sputum eosinophils and improved cough frequency, LCQ, and VAS. However, only changes in FeNO correlated with changes in cough frequency (r = 0.43, p = 0.007). In multivariable analysis, baseline FeNO independently predicted cough control (OR 1.03, 95% CI 1.00-1.05). FeNO demonstrated modest discriminatory ability for predicting treatment response (AUC = 0.73) and cough control (AUC = 0.75), with an optimal threshold of approximately 26 ppb.

FeNO represents a modest predictor of treatment response and cough control in chronic cough but not RCC. These findings support its role as a treatable trait.