Haodong Bai

Background/Objectives: Gastroesophageal reflux-induced chronic cough (GERC) is a common cause of chronic cough, and a substantial proportion of patients show an inadequate response to standard anti-reflux therapy. Psychological comorbidities, including somatic symptom disorder (SSD), have been increasingly recognized in this population. However, the prevalence and clinical characteristics of SSD in patients with GERC remain unclear. This study aimed to determine the prevalence of SSD in patients with GERC and to characterize the associated clinical and psychological features. Methods: In this prospective observational study, consecutive patients with GERC diagnosed at Tongji Hospital, Shanghai, China, between January 2024 and June 2025 were consecutively enrolled. SSD was assessed using a structured diagnostic interview based on DSM-5 criteria. Patients were categorized into SSD+ and SSD− groups. Clinical and psychological characteristics were compared between groups, and binary logistic regression was performed to identify factors associated with SSD. Results: A total of 215 patients with GERC were included, of whom 22.3% (48/215) were diagnosed with SSD. Compared with the SSD− group, patients with SSD had higher healthcare utilization, poorer response to standard anti-reflux therapy, increased cough sensitivity, poorer cough-related quality of life, and greater psychological distress. Multivariate logistic regression identified increased cough sensitivity and higher anxiety and depression scores as independent factors associated with SSD. Conclusions: SSD is relatively common in patients with GERC and is associated with cough hypersensitivity, poorer response to anti-reflux therapy, and greater psychological burden. These findings suggest that SSD may represent a clinically relevant phenotype of GERC, and patients with coexisting SSD may require more comprehensive psychosomatic assessment and multidisciplinary management.

Objective: This study was conducted to validate the involvement of the PAR2-PKC-TRPA1 pathway in cough hypersensitivity (CHS) development. Methods: Guinea pigs were divided into a blank control, a citric acid-induced enhanced cough model, and drug intervention groups. The effects of the drugs on capsaicin-induced cough responsiveness in a cough model were observed. The effects of individual and combined treatments (including PAR2 agonists, TRPA1 agonists, PAR2 antagonists, TRPA1 antagonists, PKC agonists, and PKC antagonists) on PAR2, phospho-PKC (pPKC), and TRPA1 expression in bronchial tissues and the vagus ganglion (jugular and nodose) in the cough model and control groups were assessed. Additionally, whole-cell patch-clamp recordings were conducted to evaluate the effects of the drugs on vagus ganglion neuron electrophysiological activity. Results: ① Both PAR2 antagonists and TRPA1 antagonists significantly reduced cough frequency in guinea pigs with a cough, and the PAR2 antagonist inhibited coughing induced by the TRPA1 agonist. ② Western blotting and multiplex immunohistochemistry (mIHC) indicated that PAR2, pPKCα, PKCα, and TRPA1 expression in bronchial and vagus ganglion tissues was elevated in the cough model compared with the control, with TRPA1 expression being regulated by PAR2 and PKC being involved in this regulatory process. ③ Whole-cell patch-clamp recordings demonstrated that TRPA1 agonists induced an inward current in nodose ganglion neurons, which was further amplified by PAR2 agonists; this amplification effect was blocked by PKC antagonist. Additionally, PAR2 antagonists inhibited the inward current induced by TRPA1 agonists. ④ At various concentrations, including the optimal antitussive concentration, PAR2 antagonists did not significantly affect pulse amplitude, arterial oxygen saturation, heart rate, body temperature, or respiratory rate in guinea pigs. Conclusion: PAR2 regulates TRPA1 through PKC in cough syndrome (CHS) pathogenesis, making targeting PAR2 a safe and effective therapeutic strategy for CHS.