Tongyangzi Zhang

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.

Cough is one of the most common complaints in respiratory outpatient clinics. Chronic cough (CC), defined as a persistent cough lasting > 8 weeks without radiologic abnormalities, affects approxima...

Objective This study aimed to investigate the clinical characteristics, cough severity, and psychosocial function differences in patients with refractory or unexplained chronic cough (RUCC) comorbid with somatic symptom disorder (SSD). It preliminarily analyzes the comorbidity features to provide a theoretical basis for comprehensive clinical diagnosis and treatment. Methods RUCC patients treated at the Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji University, were prospectively enrolled from January 2024 to March 2025. The SSD-12 questionnaire was administered to all participants, and a score greater than 16 was used to define the SSD-positive (SSD+) group; all others were classified as SSD-negative (SSD–). Cough severity and quality of life were assessed using the Cough Visual Analog Scale (VAS), Cough Symptom Score, and Leicester Cough Questionnaire (LCQ). Psychological status was evaluated using the PHQ-9 and GAD-7 scales. Patients were followed up for at least 8 weeks to compare treatment responses. Results Among the cohort of 171 patients with refractory chronic cough (RUCC), 70 (40.9%) were identified as having comorbid somatic symptom disorder (SSD+). The SSD + group had significantly higher baseline VAS scores (79.0 (62.0–89.3) vs. 61.0 (41.0–80.0), P < 0.001) and daytime cough symptom scores (3.0 (2.0–4.0) vs. 3.0 (2.0–3.0), P = 0.013) than the SSD– group, and significantly lower LCQ total scores (10.40 (8.44–12.32) vs. 14.00 (11.50–16.29), P < 0.001). The SSD + group also had significantly higher anxiety (GAD-7: 7.46 ± 4.78 vs. 2.20 ± 2.79, P < 0.001) and depression scores (PHQ-9: 7.17 ± 5.09 vs. 2.25 ± 2.80, P < 0.001). Higher baseline psychological scores in the SSD + group were associated with smaller reductions in cough VAS scores after treatment. Conclusion SSD may be associated with more severe cough symptoms, psychological distress, and reduced quality of life in RUCC patients. RUCC patients comorbid with SSD may be more difficult to treat. Trial registration Chinese Clinical Trials Register (http//www.chictr.org.cn/, ChiCTR2400079808). Registered January 12, 2024.

Background: Transient receptor potential vanilloid subtype 4 (TRPV4) is a Ca²⁺-permeable non-selective cation channel that is involved in the development of cough hypersensitivity. Purinergic 2 receptors (P2X) belong to a class of adenosine triphosphate (ATP)-gated non-selective cation channels that also play an important role in cough hypersensitivity. Nevertheless, little is known about the interaction between them for cough hypersensitivity. The present study was designed to clarify the roles of TRPV4 and ATP-P2X receptors in cough hypersensitivity, and to explore the possible involvement of ATP-P2X receptors in the development of cough hypersensitivity mediated by TRPV4. Design and Method: This study aims to establish a guinea pig model of citric acid-induced enhanced cough to confirm the effects of the TRPV4-mediated purinergic signaling pathway on cough sensitivity by testing the number of coughs, the release of ATP, and the expressions of P2X and TRPV4 receptors in the tracheal carina and vagal ganglion; recording the activity of cellular currents with the whole-cell patch clamp technique; and detecting changes in intracellular calcium flow in the vagus nerve cells. Results: The number of coughs in the TRPV4 agonist GSK1016790A-treated control group was elevated compared with that in the control group, whereas the number of coughs in the TRPV4 antagonist HC067047-treated model group was significantly reduced compared with that in the chronic cough group. When the individuals in the chronic cough group were treated with A317491, PSB12062, and A804598 (P2X3,4,7 antagonists), the number of coughs was significantly decreased. This suggests that TRPV4 and P2X3, P2X4, and P2X7 receptors have an effect on cough hyper-responsiveness in guinea pigs with chronic cough. Enzyme-linked immunosorbent assay results suggested that TRPV4 antagonist and P2X3,4,7 antagonist could differentially reduce the levels of inflammatory factor SP and CGRP in alveolar lavage fluid, and TRPV4 antagonist could reduce the ATP content in the alveolar lavage fluid of guinea pigs in the model. Western blot and immunohistochemistry results showed that, in the tracheal carina and vagal ganglion, the TRPV4 and P2X3,4,7 expression was elevated in the chronic cough group compared with the control group, and could be significantly inhibited by TRPV4 antagonist. Vagus ganglion neurons were isolated, cultured, identified, and subjected to whole-cell membrane clamp assay. When ATP was given extracellularly, a significant inward current was recorded in the examined cells of individuals in the chronic cough and control groups, and the inward current induced by ATP was higher in the chronic cough group relative to the control group. This inward current (I_ATP) was differentially blocked by P2X3, P2X4, and P2X7 antagonists. Further studies revealed that TRPV4 agonists potentiated ATP-activated currents, and the potentiated currents could still be inhibited by P2X3, P2X4, and P2X7 receptor antagonists, whereas TRPV4 inhibitors partially blocked ATP-activated currents. It is suggested that TRPV4 affects P2X3, P2X4, and P2X7 receptor-mediated ATP-activated currents. Calcium imaging also showed that TRPV4 agonists induced different degrees of calcium inward currents in the vagal neurons of the chronic cough and the control group, and the calcium inward currents were more significant in the model group. Conclusions: The TRPV4-mediated purinergic signaling pathway was identified to be involved in the development of cough hypersensitivity in guinea pigs with chronic cough; i.e., TRPV4 can lead to the release of airway epithelial ATP, which can stimulate P2X receptors on the cough receptor, and further activate the sensory afferent nerves in the peripheral airway, leading to increased cough sensitivity.

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.