Shengyuan Wang

Chronic cough is defined as a cough lasting no less than 8 weeks, and 10%–42% of patients with chronic cough retain their cough after comprehensive examination and treatment. The terms idiopathic chronic cough (ICC), unexplained chronic cough (UCC), and refractory chronic cough (RCC) are frequently used to describe this clinical condition. However, these terms are often used interchangeably in articles, leading to heterogeneity in the populations included in the studies and compromising the value of the findings in guiding clinical practice. This article aims to clarify the current terminological confusion by reviewing the definitions and relationships among ICC, UCC, and RCC in the literature, and to discuss the emerging role of cough hypersensitivity syndrome (CHS) as an important pathophysiological framework for understanding chronic cough, with a focus on its clinical value, current challenges, and future perspectives.

Background: Cough variant asthma (CVA) is a common cause of chronic cough but remains underdiagnosed due to limited access to bronchial provocation test. Objective: To develop a clinical prediction model for CVA based on more accessible indicators. Design: A single-center retrospective cohort study. Methods: A retrospective cohort of patients with chronic cough from January 2024 to December 2024 was included. The patients were randomly divided into a training set and an internal validation set at a ratio of 7:3. Univariable and multivariable logistic regression analyses were used to identify independent predictors of CVA. A nomogram prediction model was constructed based on these factors. The predictive performance of the nomogram was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Results: A total of 323 patients with chronic cough were included, with 226 assigned to the training set (45 with CVA, 181 with non-CVA) and 97 to the internal validation set (23 with CVA, 74 with non-CVA). Multivariable logistic regression analysis identified increased eosinophils in induced sputum, elevated peripheral blood eosinophil count (PBEC), raised FeNO ₅₀ , and reduced maximal mid-expiratory flow (MMEF) as independent predictors of CVA (all p < 0.05). The nomogram model developed based on these indicators demonstrated strong discriminative ability, with area under the ROC curve (AUC) of 0.93 in the training set and 0.92 in the internal validation set. Calibration curves indicated favorable predictive performance of the model. DCA confirmed net clinical benefit. Conclusion: The CVA clinical prediction model based on induced sputum cytology, PBEC, FeNO ₅₀ and MMEF shows excellent discrimination, accuracy, calibration, and clinical applicability.

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.

Interstitial lung disease (ILD) is a group of diseases involving diffuse pulmonary parenchymal lesions and alveolar inflammation and interstitial fibrosis. Telomeres are repetitive DNA sequences at the end of chromosomes to maintain structural integrity and telomerase can prevent telomere shortening. Telomerase abnormalities such as related gene mutations lead to decrease in telomerase activity and telomere shortening. It has been proven that telomere shortening and telomerase abnormalities are related to the occurrence and development of ILD. Telomere shortening occurs in different types of ILD patients and is associated with prognosis. Gene therapy targeting telomerase exhibits therapeutic potential. The paper elaborates on the progress of telomere shortening in the diagnosis, differential diagnosis, treatment, and prognosis of ILD in recent years, in order to demonstrate its potential and promises and to be helpful for clinical diagnosis and treatment.

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.

Background: Empiric therapy with multichannel intraluminal impedance-pH monitoring (MII-pH) has been used for the initial treatment of gastroesophageal reflux-induced chronic cough (GERC). However, an algorithm based on the gastroesophageal reflux disease questionnaire (GerdQ) has the potential to achieve a simple, structured, and effective treatment approach for patients with GERC. Objectives: This study compared the efficacy of anti-reflux therapy based on GerdQ (new structured pathway, NSP) with medical treatment after MII-pH examination (ordinary clinical pathway, OCP) in the management of GERC. Design: For the NSP, we adapted the GerdQ score to establish the basis for a treatment algorithm. For the OCP, treatment was determined using the MII-pH examination results. Methods: The non-inferiority (NI) hypothesis was used to evaluate NSP versus OCP. Results: Overall, the NSP and OCP-based therapeutic algorithms have similar efficacy for GERC [NI analysis: 95% confidence interval (CI), −4.97 to 17.73, p = 0.009; superiority analysis: p = 0.420]. Moreover, the cough symptom scores and cough threshold improved faster in the NSP group than in the OCP group at week 8 ( p < 0.05). In the subgroup analyses using the GerdQ and GerdQ impact scale (GIS) scores, patients with low-likelihood GERC (GerdQ < 8) were more likely to benefit from OCP (NI analysis: 95% CI, −19.73 to 18.02, p = 0.213). On the other hand, in patients with high-likelihood and low-reflux impact GERC patients (GerdQ > 8 and GIS < 4), the NSP arm was not inferior to the standard treatment of OCP (NI analysis: 95% CI, −8.85 to 28.21%, p = 0.04; superiority analysis: p = 0.339), indicating that GerdQ- and GIS-guided diagnosis and management of patients with GERC could be an alternative to MII-pH management, especially in settings with reduced medical resources. Conclusions: The use of the GerdQ algorithm should be considered when handling patients with GERC in the primary care setting. Trial registration: This research was registered in the Chinese Clinical Trials Registry (ChiCTR-ODT-12001899).

Background: The current available diagnostic criteria for gastroesophageal reflux-related chronic cough (GERC) dominated by non-acid reflux is imperfect. The post-reflux swallow-induced peristaltic wave index (PSPWI) is a parameter reflecting esophageal clearance function. Objectives: This study aims to investigate its diagnostic value for non-acid GERC. Design: This study sought to compare the diagnostic value of PSPWI in different types of GERC, particularly non-acid GERC, and explore the clinical significance of PSPWI in the diagnosis of non-acid GERC through diagnostic experiments. Methods: A retrospective analysis was performed based on 223 patients with suspected GERC who underwent multichannel intraluminal impedance-pH monitoring (MII-pH) in the outpatient clinic of our department from August 2016 to June 2021. Their clinical information, laboratory test results, and treatment responses were assessed and the underlying etiologies of chronic cough were categorized. The predictive value of the PSPWI in diagnosing different types of GERC, especially non-acid GERC, was analyzed and compared. Results: A total of 195 patients with chronic cough who met the inclusion criteria underwent MII-pH monitoring. 143 patients had a definitive diagnosis of GERC, including 98 with acid GERC and 45 with non-acid GERC. The diagnostic value of PSPWI alone was moderate for GERC with an area under the working curve (AUC) 0.760, but poor for non-acid GERC with an AUC of 0.569. However, PSPWI < 39.8% combining with acid exposure time (AET) ⩽ 6.2% demonstrated a moderate diagnostic value for non-acid GERC, with an AUC of 0.722. When PSPWI < 39.8% combined with a non-acid reflux ratio >68.75%, the diagnostic value for non-acid GERC was improved (AUC_ROC = 0.80 versus AUC_ROC = 0.722, p < 0.05), which was significantly superior to non-acid symptom index (AUC_ROC = 0.804 versus AUC_ROC = 0.550, p < 0.05) and non-acid symptom association probability (AUC_ROC = 0.804 versus AUC_ROC = 0.571, p < 0.05). Conclusion: PSPWI < 39.8% and AET ⩽ 6.2% have demonstrated good diagnostic value for non-acid GERC. The diagnostic value was further improved when combined with non-acid reflux ratio >68.75%.

Background: The efficacy of behavioral cough suppression therapy (BCST) for refractory chronic cough (RCC) and unexplained chronic cough (UCC) remains unclear due to limited evidence from small-scale single-center studies. Objective: To compile and assess the quality of evidence from randomized controlled trials to evaluate the effectiveness of BCST. Design: This study included randomized controlled studies and self-controlled studies related to BCST involving adult patients with RCC or UCC. Data sources and methods: We conducted an extensive search of various English and Chinese databases (e.g., PubMed, CNKI, CBM, VIP, and Wanfang Data Journal Full-text Database) and the Clinical Trial Registration website up to April 2024. The selected studies underwent meta-analysis to investigate the impact of BCST on the patient’s quality of life and cough frequency. Results: The included 12 studies showed that BCST significantly improved the Leicester Cough Questionnaire scores of the patients (MD = 4.50, 95% CI (4.03, 4.97), p < 0.001) compared to the simple verbal education group. In addition, a significant reduction in objective cough frequency was observed in patients compared to before BCST, with a statistically significant difference (MD = −8.06, 95% CI (−9.71, −6.41), p < 0.001). Other measures of cough symptoms, such as symptom scores, Visual Analog Scale (VAS) scores, and Cough Severity Index (CSI) also showed improvement. Conclusion: This meta-analysis revealed positive therapeutic effects of BCST in patients with RCC/UCC, potentially advancing its application in broader clinical settings. Trial registration: This study was registered on PROSPERO with the registration number CRD42024530746.

Zhang M, et al. Allergy Asthma Immunol Res. 2023 Nov;15(6):795-811. https://doi.org/10.4168/aair.2023.15.6.795