Cough Hypersensitivity in Gastroesophageal Reflux-Induced Chronic Cough: Insights from Reflux Monitoring and High-Resolution Manometry.

BACKGROUND: Cough hypersensitivity contributes to the heterogeneity of gastroesophageal reflux-induced chronic cough (GERC), but its associated factors remain unclear. This study aimed to investigate factors associated with cough hypersensitivity and evaluate the relative contributions of reflux characteristics and esophageal motility across reflux phenotypes. METHODS: This retrospective study included 195 patients with GERC who underwent 24-hour multichannel intraluminal impedance-pH monitoring and high-resolution esophageal manometry. Cough hypersensitivity was assessed using the Hull Airway Reflux Questionnaire (HARQ). Multivariable regression assessed independent associations with continuous HARQ scores, whereas random forest and SHAP analyses ranked the relative contributions of reflux-related and esophageal motility variables to HARQ score prediction. RESULTS: Patients with higher cough hypersensitivity exhibited increased capsaicin cough sensitivity, poorer quality of life, lower response rates to standard anti-reflux therapy (all P < 0.05), and a higher prevalence of ineffective esophageal motility (62.1% vs. 32.6%, P < 0.001). In correlation analyses, both reflux burden and esophageal motility were associated with cough hypersensitivity; however, after stratification by reflux phenotype, only esophageal motility remained associated. Multivariable regression showed an independent inverse association between DCI and HARQ scores, while machine-learning analyses ranked DCI as the leading contributor, with both analyses suggesting a more prominent relationship in non-acid GERC. CONCLUSIONS: GERC patients with heightened cough hypersensitivity had greater cough-related burden and poorer response to standard anti-reflux therapy. Esophageal motility abnormalities appear to be more closely associated with cough hypersensitivity than reflux burden, particularly in non-acid reflux phenotypes, highlighting a potential role for motility-targeted therapeutic strategies.