Refractory gastroesophageal reflux-related cough: Mechanistic insights and a rational pathway to phenotype-driven...

This narrative synthesis proposes a hypothesis-generating, phenotype-stratified management algorithm for refractory GERC based on available evidence and clinical experience; prospective multicenter validation is needed to confirm its generalizability and long-term clinical efficacy. Gastroesophageal reflux-induced cough (GERC) accounts for 10-21% of chronic cough cases, with up to 43-75% presenting without typical heartburn or regurgitation. Current diagnostic frameworks lack translation into mechanism-specific treatment algorithms, leaving clinicians with empirical trial-and-error when standard acid suppression fails. This synthesis integrates six objective diagnostic metrics-acid exposure time, non-acid reflux episodes, cough-specific symptom association probability, post-reflux swallow-induced peristaltic wave index, mean nocturnal baseline impedance, and lower esophageal sphincter dual-defect-to classify four mechanistically distinct phenotypes (Types A-D), each matched to targeted therapy based on a comprehensive narrative synthesis of published therapeutic trials. The following response rates are derived from previously published historical cohorts and are not original data from the present study. In published historical cohorts, phenotype-matched therapy was associated with superior outcomes: Type B (clearance failure/non-acid) achieved 81.5% response with prokinetic combination versus 5.3% with escalated proton pump inhibitor monotherapy; Type C (structural dual-defect) attained 92% proton pump inhibitor-free status at 5 years post-fundoplication; Type D (cough hypersensitivity) showed 72% cough improvement with transoral incisionless fundoplication in cough-predominant patients; Type A (acid-dominant) received optimized potassium-competitive acid blocker suppression as the reference pathway. Structured deprescribing minimized polypharmacy for responders, while salvage pathways prioritized surgery for mechanical phenotypes. This phenotype-driven algorithm provides a mechanism-informed framework for managing refractory GERC, translating objective diagnostic metrics into targeted therapeutic escalation. Prospective validation is warranted to confirm improved clinical outcomes and cost-effectiveness.