Background: Finding a simple, effective and rapid diagnostic method to improve the diagnosis of gastroesophageal reflux-induced chronic cough (GERC) is indicated. Our objective was to determine the diagnostic value of the pepsin concentration in saliva and induced sputum for GERC.Methods: 171 patients with chronic cough were enrolled. The diagnosis and treatment followed the chronic cough diagnosis and treatment protocol. Saliva and induced sputum were collected, and the pepsin concentration was determined using Peptest. A Gastroesophageal Reflux Diagnostic Questionnaire (GerdQ) was completed. The diagnostic value of the pepsin concentration in saliva and induced sputum for GERC was analysed and compared.Results: The salivary pepsin concentration predicted GERC with an area under the receiver operating characteristic curve (AUC) of 0.845. The optimal cut-off value was 76.10 ng·mL⁻¹, the sensitivity was 83.58% and the specificity was 82.69%. The pepsin concentration in the induced sputum supernatant for GERC had an AUC of 0.523. When GerdQ was used for GERC diagnosis, the AUC was 0.670 and the diagnostic value of salivary pepsin was better compared to GerdQ (DeLong test, p=0.0008). Salivary pepsin had a comparable diagnostic value to GerdQ (AUC 0.779versus0.826; p=0.4199) in acidic GERC. Salivary pepsin had superior diagnostic value compared to GerdQ (AUC 0.830versus0.533; p76.10 ng·mL⁻¹is of good diagnostic value for GERC, especially in non-acidic GERC. The pepsin concentration in induced sputum has a low diagnostic value.

Background: Genetic polymorphisms in the 15q25 region have been associated with the risk of lung cancer (LC). However, studies have yielded conflicting results. Methods: Searches were conducted in databases, including PubMed, EMbase, Web of Science, CNKI, and Wanfang, for case-control studies up to August 1, 2019. After retrieving eligible studies and data extraction, we calculated pooled odds ratios with 95% confidence intervals. In the meta-analysis, we included 32 publications with a total of 52,795 patients with LC and 97,493 control cases to evaluate the polymorphisms in the CHRNA5/A3/B4 gene cluster in the 15q25 region. Results: Data of the meta-analysis showed a significantly increased risk of LC in the presence of genetic polymorphisms (rs1051730, rs16969968, rs8034191). In the smoking subgroup, the CHRNA3 rs1051730 polymorphism was found to contribute to LC risk using following 5 models: the allelic model, the homozygous model, the heterozygous model, the dominant model, and the recessive model. Thus, the rs1051730 polymorphism may modify LC susceptibility under the condition of smoking. Stratification studies for CHRNA5-rs8034191 showed that Caucasian groups with the wild-type genotype (C/C) may be susceptible to LC in all 5 models. No significant relationship between CHRNA3 rs6495309 or rs3743073 and LC susceptibility was found. However, Asians with the rs3743037 B-allele showed an obviously higher risk of LC susceptibility than the Caucasian population, observed via allelic, heterozygous, and dominant models. Conclusions: The 3 polymorphisms of rs1051730, rs16969968 and rs8034191 in the CHRNA5/A3/B4 gene cluster in the 15q25 region were associated with LC risk, which might be influenced by ethnicity and smoking status.

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.

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 results of empirical trials with proton pump inhibitors (PPIs) for management of gastro-oesophageal reflux-induced chronic cough (GERC) have resulted in considerable controversy, and the mechanism of PPI refractoriness remains unclear. Our study aims to identify the predictors of PPI refractoriness of GERC in a retrospective clinical study.Methods: In total, 128 GERC patients were enrolled between March 2018 and October 2022. Regression analysis was utilised to create a model for predicting PPI-refractory of GERC using retrospective analysis of the general data and MII-pH indicators.Results: The post-reflux swallow induced peristaltic wave index (PSPWI) was lower in the PPI-refractory group than the PPI-responsive group (33.89±7.38versus39.45±9.47, respectively, p<0.001), as were the mean nocturnal baseline impedance (MNBI) and proximal MNBI (2092.11 (IQR: 652.23)]versus2426.52 (IQR: 917.39) Ω, respectively, p=0.012; 1599.50 (IQR: 1206.63)versus2274.50 (IQR: 1775.29) Ω, respectively, p=0.001). Multivariate logistic regression analysis identified the PSPWI (odds ratio 0.919, p=0.001) as an independent predictor of PPI-refractory GERC.Conclusions: The diagnostic value of both proximal MNBI ≤39.90% and MNBI ≤2233.58 Ω had moderate sensitivity (71.67%) and specificity (75.00%) to identify PPI-refractory GERC.