Positive effect of deep diaphragmatic breathing training on gastroesophageal reflux-induced chronic cough: a clinical randomized controlled study.

BACKGROUND AND OBJECTIVE: To explore the efficacy of deep diaphragmatic breathing training (DEP) in patients with gastroesophageal reflux-induced chronic cough (GERC). METHODS: A randomized controlled study was conducted involving 60 GERC patients who were divided into the intervention group and the control group (each with 30 patients). Both groups received routine medication treatment for GERC, while the intervention group received DEP training additionally. Both groups were evaluated by cough symptom scores, Hull airway reflux questionnaire (HARQ), gastroesophageal reflux diagnostic questionnaire (GerdQ), generalized anxiety disorder scale-7 (GAD-7), patient health questionnaire-9 (PHQ-9), Pittsburgh sleep quality index (PSQI), the Leicester cough questionnaire (LCQ), as well as capsaicin cough sensitivity testing, B-ultrasound and surface electromyography (sEMG) of the diaphragmatic muscles before and after treatment. The cough resolution rate and changes of the above indictors was compared between the two groups after eight weeks of treatment. RESULTS: After eight weeks of treatment, cough symptoms improved in both groups, but the cough resolution rate in the intervention group of 94% was significantly higher than that in the control group of 77% (χ2 = 6.402, P = 0.041). The intervention group showed significant improvements to the control group in GerdQ (6.13(0.35) VS 6.57(0.77)), GAD-7 (0(0;1) VS 1(0;3)), PSQI (2(1;3) VS 4(3;6)), LCQ (17.19(1.56) VS 15.88(1.92)) and PHQ-9 (0(0;0) VS 0(0;3)) after treatment. Compared to control group, sEMG activity of the diaphragmatic muscle was significantly increased in the intervention group after treatment, measured during DEP (79.00(2.49) VS 74.65 (1.93)) and quiet breathing (72.73 (1.96) VS 67.15 (2.48)). CONCLUSION: DEP training can improve cough symptoms as an adjunctive treatment in GERC patients. TRIAL REGISTRATION: The protocol was registered in February 2, 2022 via the Chinese Clinical Trials Register ( http://www.chictr.org.cn/ ) [ChiCTR2200056246].

A comparison between a gastroesophageal reflux disease questionnaire-based algorithm and multichannel intraluminal impedance-pH monitoring for the treatment of gastroesophageal reflux-induced chronic cough.

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).

A randomized, double-blinded, placebo-controlled clinical trial of duloxetine hydrochloride enteric-coated tablets in the treatment of refractory chronic cough.

INTRODUCTION: Refractory cough, a chronic cough with an unclear diagnosis or poor treatment response. The symptoms are often stubborn and persistent, causing serious complications and lowering the patient's quality of life. Cough hypersensitivity syndrome (CHS) is proposed as a potential cause, and reducing sensory nerve hyperresponsiveness is suggested as an effective treatment. However, current drugs have low efficacy and benefit rates and numerous side effects. This trail proposes using duloxetine, a selective 5-HT and norepinephrine reuptake inhibitor, as a potential treatment for refractory cough, which has shown promise in treating pain and depression. Duloxetine may inhibit pain conduction and oxidative stress in peripheral nerves by inhibiting the activity of TRPV1 channels, which play an important role in the peripheral afferent pathway of refractory cough. Meanwhile, the antidepressant effects of duloxetine may also play a role in the treatment of refractory cough. METHODS AND ANALYSIS: This is a single-center, prospective, randomized, double-blind, and controlled trial. A total of 98 individuals will be randomized in a 1:1 ratio to duloxetine group and placebo control group (starting with 20 mg QD, increasing 20 mg daily until 20 mg TID). After a screening period, the second stage runs from baseline to the 42nd (last) day of treatment, with follow-up visits on the 3rd, 7th, 14th, 21st, 28th, 35th, 42nd and 49th days. The main end-stage observation indicators include objective cough frequency, cough visual analog scale (VAS), cough symptom score, Leicester Cough Questionnaire (LCQ), and cough evaluation test (CET); the secondary end-stage observation indicators include capsaicin cough sensitivity, Patient Health Questionnaire-9 (PHQ-9), Major Depression Inventory (MDI), the Generalized Anxiety Disorder-7 scale (GAD-7), Life Events Scale (LES-32), induced sputum supernatant. The safety measures will be AEs/SAEs, vital signs, liver and kidney function, fecal occult blood test. DISCUSSION: This study is the first randomized, double-blind, and controlled clinical trial investigating the use of duloxetine in the treatment of refractory coughs. The study aims to provide a high-quality basis for evaluating the efficacy and safety of duloxetine for this condition. TRIAL REGISTRATION: Our study was registered in the Chinese Clinical Trials Register ( www.chictr.org.cn/ ) (ChiCTR2000037429) in 28/08/2020.

Psychological morbidity and chronic cough: which is predominant? A comparison of clinical characteristics.

Background: The clinical characteristics of chronic cough with pre-existing psychological co-morbidity (PCC) and chronic cough with secondary anxiety and depression (SCC) were compared to provide a basis for diagnosing and treating psychological co-morbidities in people with chronic cough. Methods: A prospective study was conducted to analyze the general clinical data between the PCC, SCC, and the chronic cough without anxiety and depression (CC) groups. A total of 203 patients with chronic cough were enrolled in the study. The final diagnosis was made in all cases using a combination of psychosomatic and respiratory diagnoses. The three groups' general clinical data, capsaicin cough sensitivity, cough symptom score, Leicester cough questionnaire (LCQ), and psychosomatic scale scores were compared among the three groups. The diagnostic value of the patient health questionnaire (PHQ)-9 and general anxiety disorder (GAD)-7 in patients with PCC and the follow-up information were analyzed. Results: Compared with the SCC group, the duration of cough in the PCC group was shorter (H = -3.54, p = 0.001), the night cough symptoms were milder (H = -4.60, p < 0.001), the total LCQ score was lower (H = -2.97, p = 0.009), and the PHQ-9 (H = 2.90, p = 0.011) and GAD-7 scores (H = 2.71, p = 0.002) were higher. When using PHQ-9 and GAD-7 scores for the combined prediction and diagnosis of PCC, the area under the curve (AUC) was 0.88, and the sensitivity and specificity were 90.0% and 73.85%, respectively. After 8 weeks of psychosomatic treatment, cough symptoms improved in the PCC group, but the psychological improvement was not significant. The psychological status of the SCC group improved after cough symptoms were ameliorated by etiologic or empirical treatment. Conclusion: The clinical characteristics of patients with PCC and SCC are different. The evaluation of psychosomatic scales is of value to distinguish between the two groups. Chronic cough patients with psychological co-morbidity benefit from the combined diagnosis of psychosomatic medicine in a timely fashion. PCC requires more attention in psychological therapy, but for SCC, targeting etiological treatment of the cough is preferred. Trial registration: The protocol was registered in the Chinese Clinical Trials Register (http://www.chictr.org.cn/) [ChiCTR2000037429].

A comparative study on the value of lower airway exhaled nitric oxide combined with small airway parameters for diagnosing cough-variant asthma.

BACKGROUND: The diagnosis of cough-variant asthma (CVA) is based on bronchial provocation test, which is challenging to be conducted. Most CVA patients have type 2 airway inflammation and small airway dysfunction. FeNO200, reflecting small airway inflammation, may be used to diagnose CVA. OBJECTIVE: This study aimed to explore and compare the value of lower airway exhaled nitric oxide (FeNO50, FeNO200, and CaNO) combined with small airway parameters for diagnosing CVA. METHODS: Chronic cough patients who attended the clinic from September 2021 to August 2022 were enrolled and divided into CVA group (n = 71) and non-CVA (NCVA) group (n = 212). The diagnostic values of FeNO50, FeNO200, concentration of alveolar nitric oxide (CaNO), maximal mid-expiratory flow (MMEF), forced expiratory flow at 75% of forced vital capacity (FEF75%) and forced expiratory flow at 50% of forced vital capacity (FEF50%) for CVA were evaluated. RESULTS: FeNO50 [39(39) ppb versus 17(12) parts per billion (ppb), p < 0.01], FeNO200 [17(14) ppb versus 8(5) ppb, p < 0.01] and CaNO [5.0(6.1) ppb versus 3.5(3.6) ppb, p < 0.01] in CVA group were significantly higher than those in NCVA group. The optimal cut-off values of FeNO50, FeNO200, and CaNO for diagnosis of CVA were 27.00 ppb [area under the curve (AUC) 0.88, sensitivity 78.87%, specificity 79.25%], 11.00 ppb (AUC 0.92, sensitivity 88.73%, specificity 81.60%) and 3.60 ppb (AUC 0.66, sensitivity 73.24%, specificity 52.36%), respectively. For diagnosing CVA, the value of FeNO200 was better than FeNO50 (p = 0.04). The optimal cut-off values of MMEF, FEF75%, and FEF50% for the diagnosis of CVA were 63.80% (AUC 0.75, sensitivity 53.52%, specificity 86.32%), 77.9% (AUC 0.74, sensitivity 57.75%, specificity 83.49%) and 73.50% (AUC 0.75, sensitivity 60.56%, specificity 80.19%), respectively. The AUCs of FeNO50 combined with MMEF, FEF75%, and FEF50% for the diagnosis of CVA were all 0.89. The AUCs of FeNO200 combined with MMEF, FEF75%, and FEF50% for the diagnosis of CVA were all 0.93. CONCLUSION: FeNO200 > 11 ppb contributed strongly for differentiating CVA from chronic cough, especially in patients with small airway dysfunction.

Mean Nocturnal Baseline Impedance (MNBI) Provides Evidence for Standardized Management Algorithms of Nonacid Gastroesophageal Reflux-Induced Chronic Cough.

Background: The clinical management of nonacid gastroesophageal reflux-induced chronic cough (GERC) is challenging, and patient response to standard antireflux therapy (omeprazole 20 mg twice daily plus mosapride 10 mg thrice daily) is suboptimal. This study aimed to identify predictors of standard antireflux therapy efficacy and provide evidence for standardized management algorithms of nonacid GERC. Methods: A total of 115 nonacid GERC patients who underwent multichannel intraluminal impedance-pH monitoring (MII-pH) were enrolled between March 2017 and March 2021. Retrospective analysis of general information and MII-pH indications were used to establish a regression analysis model for multiple factors affecting standard antireflux therapy efficacy. Results: 90 patients met the inclusion criteria, and the overall response rate to standard antireflux therapy was 55.5% (50/90). The mean nocturnal baseline impedance (MNBI) (1817.75 ± 259.26 vs. 2369.93 ± 326.35, P = 0.030) and proximal MNBI (1833.39 ± 92.16 vs. 2742.57 ± 204.64, P ≤ 0.001) of responders were lower than those of nonresponders. Weakly acid reflux (56.00 (31.70, 86.00) vs. 14.00 (14.00, 44.20), P = 0.022), nonacid reflux (61.35 (15.90.86.50) vs. 21.60 (0.00, 52.50), P = 0.008), and proximal extent (19.00 (5.04, 24.00) vs. 5.50 (2.56, 11.13), P = 0.011) were markedly higher in responders than nonresponders. Proximal MNBI (OR = 0.997, P = 0.042, and optimal cutoff = 2140 Ω) and weakly acid reflux (OR = 1.051, P = 0.029, and optimal cutoff = 45) were independent predictors of standard antireflux therapy efficacy. The combination predictive value did not show better results than either individual predictor. Conclusions: Proximal MNBI < 2140 Ω may be used to screen patients with nonacid GERC suitable for standard antireflux therapy and in standardized management algorithms for nonacid GERC. In the absence of MNBI, weakly acid reflux > 45 can be used as an auxiliary indicator.

A Study on Cough Sensitivity and Airway Inflammation in Patients with Sinobronchial Syndrome.

Objective: This study aimed to clarify the characteristics of cough-reflex sensitivity and airway inflammation in patients with sinobronchial syndrome (SBS). Methods: 39 patients with SBS, 53 patients with upper airway cough syndrome (UACS) induced by rhinitis, 33 patients with chronic sinusitis without cough, and 39 healthy controls (HCs) were enrolled between January 2013 and December 2018. All participants underwent a capsaicin cough-sensitivity test and cytology of induced sputum. The concentration of calcitonin-gene-related peptide (CGPR), histamine, prostaglandin (PG) E2, and eosinophil cationic protein (ECP) in induced sputum were measured using enzyme-linked immunosorbent assays (ELISAs). Results: The lowest concentration of capsaicin solution that induced ≥5 coughs (C5) was decreased markedly in patients with UACS induced by rhinitis compared with SBS patients (1.95 ± 2.92 vs. 31.2 ± 58.6 mol/L, P < 0.001), indicating higher cough-reflex sensitivity among UACS patients induced by rhinitis. However, there was no difference of these threshold between SBS patients and patients with sinusitis without cough and HCs. The percentage of neutrophils in sputum was increased remarkably in patients with SBS compared with HCs (40.0 ± 48.5% vs. 5.5 ± 9.0%, P < 0.001). A higher concentration of CGPR, histamine, and PGE2 was observed in induced sputum from patients with UACS induced by rhinitis than that in controls, and the ECP level was increased significantly in UACS induced by rhinitis compared with that in the other three groups. Conclusions: Cough-reflex sensitivity and airway inflammation in patients with SBS were different in patients with UACS induced by rhinitis. Thus, the mechanism of cough in those two patient populations might differ. Our study is registered in the Chinese Clinical Trials Register (https://www.chictr.org.cn/) as ChiCTR-TRC-00000152.

Diagnostic value of reflux episodes in gastroesophageal reflux-induced chronic cough: a novel predictive indicator.

Background: Multichannel intraluminal impedance and pH-monitoring (MII-pH) is an essential testing modality for gastroesophageal reflux-induced chronic cough (GERC), while the existing diagnostic criteria still have some inherent defects. This study aimed to explore the diagnostic value of a direct and objective index, reflux episodes, and related parameters in MII-pH in different types of GERC. Methods: Patients with chronic cough suspected of gastroesophageal reflux disease who successfully received MII-pH were enrolled. The differences in MII-pH parameters were analyzed among patients with different etiologies and the predictive diagnostic value of reflux episodes and related parameters were analyzed in patients with GERC, acid GERC, and non-acid GERC, and compared with existing diagnostic criteria. Results: A total of 190 patients with suspected GERC who underwent MII-pH were enrolled; 131 of these patients were finally diagnosed with GERC. When the reflux episodes were used to diagnose GERC, the area under the curve (AUC) was 0.684; when the acid reflux episodes and the ratio of acid reflux episodes were used to diagnose acid GERC, the AUCs were 0.769 and 0.854; when the non-acid reflux episodes and the ratio of non-acid reflux episodes were used to diagnose non-acid GERC, the AUCs were 0.735 and 0.705, respectively. When the non-acid reflux episodes > 58 and the proportion of non-acid reflux episodes > 68.18% were used alone or in combination to diagnose non-acid GERC, their diagnostic value was significantly better than SAP or SI (all ps < 0.05). Conclusion: The number of reflux episodes has a good diagnostic value for GERC, especially in the diagnosis of non-acid GERC.

The efficacy of gabapentin for the treatment of refractory cough associated with interstitial lung disease: study protocol for a randomized, double-blind and placebo-controlled clinical trial.

INTRODUCTION: Gabapentin, a neurotransmitter modulator, is thought to treat refractory cough associated with interstitial lung disease by improving cough hypersensitivity. METHODS/DESIGN: This is a single-center, prospective, randomized, double-blind, placebo-controlled trial. The trial will investigate the effect of a 10-week course of oral gabapentin 900 mg/day on refractory cough associated with interstitial lung disease (ILD) and explore the possible mechanisms involved in improving cough symptoms. A total of 84 individuals will be randomized in a 1:1 ratio to two treatment groups and will be followed for a total of 14 weeks from the first dose. The primary endpoint of the study will be the change in cough symptom scores at 14 weeks. The secondary endpoints include the change in Leicester Quality of Life Questionnaire (LCQ), Gastroesophageal Reflux Disease Questionnaire (Gerd Q), and Hull Airway Reflux Questionnaire (HARQ) scores; cough sensitivity (C2 and C5) values; and safety. DISCUSSION: This study will be the first randomized, controlled clinical trial to investigate gabapentin for the treatment of refractory cough associated with interstitial lung disease and provide data on efficacy, safety, and quality of life. If the study confirms that gabapentin is effective in improving refractory cough associated with interstitial lung disease, it will indicate that a deeper understanding of its mechanisms may reveal new therapeutic targets. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100045202 . Registered on 8 April 2021, www.chictr.org.cn.

Can acid exposure time replace the DeMeester score in the diagnosis of gastroesophageal reflux-induced cough?

BACKGROUND: The objective of this study was to compare the predictive accuracy of the acid exposure time (AET) with the DeMeester score (DMS) for gastroesophageal reflux-induced cough (GERC). METHODS: A total of 277 patients who underwent multichannel intraluminal impedance pH monitoring (MII-pH) were enrolled, and their clinical information and laboratory results were retrospectively analyzed. The diagnostic value of AET for GERC was compared with that of the DMS, symptom association probability (SAP), and symptom index (SI). RESULTS: A total of 236 patients met the inclusion criteria, 150 patients (63.65%) were definitely diagnosed with GERC, including 111(74%) acid GERC and 39 (26%) nonacid GERC. The optimal cutoff value of AET for diagnosing GERC was AET > 4.8%, and its diagnostic value was equal to that of DMS > 14.7 (AUC = 0.827 versus 0.818, p = 0.519) and was superior to that of SAP (AUC = 0.827 versus 0.689, p = 0.000) and SI (AUC = 0.827 versus 0.688, p = 0.000). When using both DMS > 14.7 and AET > 4.8% or either of the two for the diagnosis of GERC, the diagnosis rate was not improved over using DMS > 14.7 alone. The diagnostic value of AET and DMS for acid GERC were both high and equivalent (AUC = 0.925 versus 0.922, p = 0.95). The optimal cutoff value of AET for diagnosing acid GERC was AET > 6.2%. CONCLUSION: AET and DMS are both equal in discriminating GERC. A GERC diagnosis should be considered when AET > 4.8%, whereas an acid GERC diagnosis should be considered when AET > 6.2%.

Cough hypersensitivity in patients with metabolic syndrome: a clinical finding and its possible mechanisms.

PURPOSE: To investigate the changes of cough sensitivity in patients with metabolic syndrome and its possible mechanisms. METHOD: A total of 29 metabolic syndrome (MetS) patients with OSAHS (group-1), 22 MetS patients without OSAHS (group-2), and 25 healthy controls (group-3) were included. All participants underwent a routine physical examination and completed the gastroesophageal reflux disease questionnaire (GerdQ), and the inflammatory mediator profile were determined. The cough threshold for capsaicin, induced sputum cell count and cell classification, and inflammatory mediators in induced sputum supernatants were compared. The correlation between capsaicin cough sensitivity and various indicators in the MetS population was analyzed. RESULTS: The minimum concentration of inhaled capsaicin needed to induce ≥ 5 coughs (C5) was significantly different among three groups (H = 14.393, P = 0.001) and lower for group-1 and group-2 than it for group-3 (P = 0.002, P = 0.005). The percentage of neutrophils in induced sputum and the concentrations of calcitonin gene-related peptide (CGRP), substance P (SP), and interleukin 8 (IL-8) in the sputum supernatant of group-1 and group-2 were significantly higher than those of group-3. Besides, the pepsin concentrations were significantly different among the 3 groups (F = 129.362, P < 0.001), which significantly was highest in group-1 (P < 0.001) and lowest in group-3 (P < 0.001). Triglycerides, AHI, pepsin concentration and BMI were risk factors of increased capsaicin cough sensitivity. CONCLUSION: Increased capsaicin cough sensitivity in MetS patients is closely related to sleep apnea and gastroesophageal reflux. For patients in MetS patients without OSAHS, gastroesophageal reflux is an important factor for increased capsaicin cough sensitivity. Airway inflammation, especially airway neurogenic inflammation, may also play a role in the pathogenesis of increased capsaicin cough sensitivity. Trial registration The protocol was registered in the Chinese Clinical Trials Register ( http://www.chictr.org.cn/ ) (ChiCTR1800014768). Written informed consent was obtained from all participants before enrollment.

Drug-induced chronic cough and the possible mechanism of action.

Chronic cough is defined as a cough lasting for ≥8 weeks with a normal chest radiograph. The common causes of chronic cough are cough variant asthma (CVA), upper airway cough syndrome/postnasal drip syndrome (UACS/PNDs), eosinophilic bronchitis (EB), gastroesophageal reflux-related chronic cough (GERC) and atopic cough (AC). Drug-induced chronic cough, a rare cause of chronic cough, refers to a chronic cough caused by certain drugs. In addition to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), there are cases reporting that some drugs such as omeprazole and leflumide that can cause cough. An important step in the diagnosis and treatment of chronic cough is to determine the history of the patient with regard to any drugs that can induce chronic cough. If the cough occurs after taking the medicine, a suspected diagnosis of drug-induced cough should be established. If the cough resolution occurs within 1 to 4 weeks after drug withdrawal, it would be considered as a side effect of the medication. we should be alert to the possibility of drug-induced chronic cough after excluding CVA, UACS, EB and other common causes of chronic cough. This article reviews the relevant drugs that may cause cough and their possible mechanisms of action.

Sensitivity and specificity of combination of Hull airway reflux questionnaire and gastroesophageal reflux disease questionnaire in identifying patients with gastroesophageal reflux-induced chronic cough.

BACKGROUND: There is a need to find a simple, non-invasive and effective diagnostic tool for diagnosing gastroesophageal reflux-induced chronic cough (GERC) in clinic. This study aimed to evaluate the predictive diagnostic value of Hull airway reflux questionnaire (HARQ) and its combination with gastroesophageal reflux disease questionnaire (GerdQ) for GERC. METHODS: Chronic cough patients were enrolled and the diagnosis of GERC was established according to the chronic cough diagnosis and treatment process. The diagnostic value of HARQ and GerdQ alone or the combination of HARQ and GerdQ was analyzed. RESULTS: A total of 402 patients with chronic cough were eventually enrolled, including 166 GERC patients. When the HARQ score was used to predict the diagnosis of GERC, the area under the ROC curve was 0.796. The sensitivity and specificity were 77.19% and 77.06%, respectively. When the GerdQ was used to predict the diagnosis of GERC, the area under the ROC curve was 0.763. The sensitivity and specificity were 70.18% and 76.15%, respectively. When HARQ combined with GerdQ were used to predict the diagnosis of GERC, the area under the ROC curve was 0.848. The sensitivity and specificity were 77.19% and 79.82%, respectively. CONCLUSIONS: HARQ used to evaluate the cough hypersensitivity has a certain predictive diagnostic value for GERC. The diagnosis of GERC should be considered when the HARQ score is ≥24. The predictive diagnostic value of the combination of HARQ and GerdQ is significantly higher, which makes the diagnosis of GERC simpler, quicker and more effective.

Reflux characteristics in patients with gastroesophageal reflux-related chronic cough complicated by laryngopharyngeal reflux.

BACKGROUND: This study aimed to investigate the reflux characteristics in patients with gastroesophageal reflux-related chronic cough (GERC) complicated by laryngopharyngeal reflux (LPR). METHODS: Patients with chronic cough were recruited. Reflux symptom index (RSI) scoring, cough symptom scoring, assessment of capsaicin cough sensitivity, and multichannel intraluminal impedance and pH monitoring (MII-pH) were performed. RESULTS: RSI score in GERC patients was significantly higher than that in patients with atopic cough (AC), cough variant asthma, eosinophilic bronchitis (EB), and upper airway cough syndrome (UACS) (P<0.05). The RSI score in non-acid GERC patients was significantly higher than that in acid GERC patients (P=0.003). The cut-off value of the RSI score was defined as 19 during diagnosis of non-acid GERC. In the RSI ≥19 group, there was more proximal reflux and more significant gas and non-acid reflux, and the efficacy of a combined use of baclofen or gabapentin was better than that of the RSI <19 group (P<0.05). The efficacy of proton pump inhibitor (PPI) at a routine dosage together with prokinetic agents in the RSI <19 group was better than that in the RSI ≥19 group (P=0.009). CONCLUSIONS: LPR overlaps with GERC in part. GERC patients with higher RSI scores may present more proximal reflux, non-acid reflux, and gas reflux, and get better efficacy with neuromodulators (gabapentin or baclofen) used as an add-on therapy.

Changing etiological frequency of chronic cough in a tertiary hospital in Shanghai, China.

BACKGROUND: The frequency distributions of the etiologies of chronic cough have changed over time. This study aimed to investigate the changing etiological frequency of chronic cough in a tertiary hospital in Shanghai, China, and to explore the clinical significance. METHODS: Medical records of 1,311 patients with chronic cough who visit our hospital between January 2009 and December 2016 were retrospectively reviewed. The etiologies of chronic cough were identified according to a standardized step-by-step diagnostic protocol and the changes in the etiological frequency of chronic cough over the years were using the Chi-squared (χ2) test. RESULTS: Cough variant asthma (CVA) (449/1,311, 34.2%), gastroesophageal reflux-related chronic cough (GERC) (374/1,311, 28.5%), upper airway cough syndrome/postnasal drip syndrome (UACS/PNDs) (241/1,311, 18.4%), atopic cough (AC) (188/1,311, 14.3%), and non-asthmatic eosinophilic bronchitis (NAEB) (147/1,311, 11.2%) were the common causes of chronic cough in descending order. The post-infectious cough (PIC) (39/1,311, 3.0%) and angiotensin-converting enzyme inhibitor (ACEI)-induced cough (25/1,311, 1.9%) were less common. During the 8-year period, the proportion of CVA (χ2=72.86, P<0.0001) and UACS/PNDs (χ2=68.80, P<0.0001) decreased, while those of NAEB (χ2=51.38, P<0.0001), GERC (χ2=55.95, P<0.0001) and AC (χ2=39.09, P<0.0001) increased. CONCLUSIONS: The etiological frequency of chronic cough varies over time, and it may encourage the adjustment of the current diagnostic and therapeutic strategies for chronic cough.

Randomised clinical trial: gabapentin vs baclofen in the treatment of suspected refractory gastro-oesophageal reflux-induced chronic cough.

BACKGROUND: Neuromodulators are considered potential therapeutic options for refractory gastro-oesophageal reflux-induced chronic cough. AIM: To compare the efficacy of gabapentin and baclofen in patients with suspected refractory gastro-oesophageal reflux-induced chronic cough. METHODS: Two hundred and thirty-four patients with suspected refractory gastro-oesophageal reflux-induced chronic cough, who failed an 8-week course of omeprazole and domperidone, were recruited into the open-labelled study and randomly assigned to receive either gabapentin (maximum daily dose of 900 mg) or baclofen (maximum daily dose of 60 mg) for 8 weeks as add-on therapy to the previous treatment. The primary end point was the successful rate of cough resolution; and the secondary end-points included cough sensitivity to capsaicin and gastro-oesophageal reflux disease questionnaire score and reported side effects. RESULTS: One hundred and eleven patients in the gabapentin group and 106 in the baclofen group completed the study. The overall success rate for cough resolution was comparable (57.3% vs 53.0%, χ2  = 0.357, P = 0.550) between the two groups. In parallel, cough sensitivity to capsaicin and gastro-oesophageal reflux disease questionnaire score decreased after treatment with either gabapentin or baclofen. However, gabapentin was associated with less frequent somnolence (20.5% vs 35.0%, χ2  = 6.156, P = 0.013) and dizziness (11.1% vs 23.9%, χ2  = 6.654, P = 0.010) than baclofen. CONCLUSIONS: Gabapentin and baclofen have similar therapeutic efficacy for suspected refractory gastro-oesophageal reflux-induced chronic cough. However, gabapentin may be preferable because of fewer side effects. Trial Register: http://www.chictr.org/; No.: ChiCTR-ONC-13003066.

Cough hypersensitivity in patients with obstructive sleep apnea hypopnea syndrome.

PURPOSE: The purpose of this study was to investigate cough hypersensitivity and its potential mechanisms in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: Fifteen OSAHS patients, 12 simple snoring patients, and 15 healthy volunteers received cough sensitivity test and induced sputum cytology. Cough thresholds C2 and C5 (the minimum of capsaicin inducing ≥ 2 and ≥ 5 coughs, respectively), total cell count, cell differentials and the levels of bradykinin, histamine, prostaglandin E2, substance P, calcitonin gene-related peptide, pepsin, and interleukin-2 in the induced sputum detected by enzyme-linked immunosorbent assay were compared. The linear correlation between lgC2 and lgC5 and apnea hypopnea index, cell differentials, and inflammatory mediators in the induced sputum was calculated in OSAHS patients. RESULTS: OSAHS patients presented with a significant lower C2 and C5 (P < 0.01), increased lymphocyte but decreased macrophage and neutrophil proportions in the induced sputum (P < 0.01), and higher contents of substance P, calcitonin gene-related peptide and interleukin-2 (P < 0.01) but similar levels of bradykinin, pepsin, prostaglandin E2, and histamine (P > 0.05) in the supernatant of induced sputum, when compared with simple snoring patients and healthy volunteers. However, theses variable were comparable between simple snoring patients and healthy volunteers (P > 0.05). Finally, lgC2 or lgC5 was negatively related to apnea hypopnea index, lymphocyte percentage, and the levels of substance P, calcitonin gene-related peptide or interleukin-2 in the sputum (P < 0.01). There was a positive linear correlation between lymphocyte percentage and interleukin-2 level in the induced sputum (r = 0.63, P = 0.00). CONCLUSION: OSAHS patients have a predisposition of cough hypersensitivity associated with airway inflammation.

Association of cough hypersensitivity with tracheal TRPV1 activation and neurogenic inflammation in a novel guinea pig model of citric acid-induced chronic cough.

Objective This study was performed to establish a novel model of citric acid-induced chronic cough in guinea pigs and to investigate the pathogenesis of cough hypersensitivity. Methods Healthy conscious guinea pigs inhaled citric acid (0.4 M) for 3 minutes twice daily for 25 days. Cough reactivity was evaluated, substance P (SP) and calcitonin gene-related peptide (CGRP) in bronchoalveolar lavage fluid were detected, and transient receptor potential cation channel subfamily V member 1 (TRPV1) protein expression in the trachea and bronchus was determined. Tracheal and bronchial tissues were examined for TRPV1. Results Inhalation of 0.4 M citric acid increased coughing in a time-dependent manner: coughing peaked at 15 days and reached the lowest level at 25 days. This was accompanied by similar changes in SP, CGRP, and TRPV1 protein expression. TRPV1 was mainly observed in the mucosal and submucosal layer of the trachea and bronchi. The areas of TRPV1 positivity in the trachea and bronchi of citric acid-treated animals were significantly larger than in the control group. Conclusions Repeated inhalation of citric acid can be employed to establish a chronic cough model in guinea pigs. Cough hypersensitivity in this model is related to tracheal TRPV1 activation and neurogenic inflammation.

Changes of serum TNF-α, IL-5 and IgE levels in the patients of mycoplasma pneumonia infection with or without bronchial asthma.

OBJECTIVE: This study aimed to investigate the changes of serum levels of TNF-α, IL-5 and IgE in mycoplasma pneumonia (MP) infection patients with or without bronchial asthma and explore its clinical importance. METHODS: ELISA and Western blot assay were performed to detect the serum levels of TNF-α, IL-5 and IgE in 35 healthy subjects, 45 patients with MP infection and 40 bronchial asthma patients with MP infection. RESULTS: The serum levels of TNF-α, IL-5 and IgE in MP infection patients and asthma patients with MP infection were significantly higher than those in healthy subjects (P<0.01). Moreover, the serum levels of TNF-α, IL-5 and IgE in asthma patients with MP infection was markedly higher than those in MP infection patients (P<0.05). Correlation analysis showed serum TNF-α was positively associated with serum IL-5 (r=0.9636, P<0.01), serum TNF-α positively related to IgE (r=0.9841, P<0.01) and serum IgE positively relevant with serum IL-5 (r=0.9572, P<0.01) in asthma patients with MP infection. CONCLUSION: Our findings indicate that serum levels of TNF-α, IL-5 and IgE may play important roles in the pathogenesis of MP infection, especially in asthma patients.

Upper-airway cough syndrome with latent eosinophilic bronchitis.

Upper-airway cough syndrome often coexists with other diseases that elicit chronic cough. However, the concomitant conditions are not always relevant to chronic cough, which complicates the cause diagnosis of chronic cough. The objective of this study was to explore the diagnosis and clinical implication of upper-airway cough syndrome with latent eosinophilic bronchitis. Eleven patients with upper-airway cough syndrome and latent eosinophilic bronchitis were retrospectively analyzed for their clinical manifestations, changes of eosinophilia in induced sputum, and cough threshold with capsaicin defined as capsaicin concentration that elicits two or more coughs (C2) and five or more coughs (C5) between pretreatment and post-treatment. All patients reported a history of allergic rhinitis, showed persistent dry cough or small amounts of viscid sputum with a time course of 2-60 months (median = 7 months), and presented with symptoms and signs of rhinitis, normal lung function, and airway responsiveness. Initial eosinophil percentage in induced sputum was 3.5-8.0%. Cough disappeared after 2-5 (3 +/- 1) weeks of only oral antihistamine. With successful treatment, cough threshold C2 increased from 1.73 +/- 1.45 to 4.43 +/- 4.50 micromol/L (t = 2.64, P = 0.025) and C5 increased from 2.79 +/- 2.16 to 10.10 +/- 8.22 micromol/L (t = 3.10, P = 0.011). However, there was no significant change of eosinophil percentage in induced sputum (4.8 +/- 1.5% vs. 4.4 +/- 1.4%, t = 0.84, P = 0.427). Upper-airway cough syndrome with latent eosinophilic bronchitis is a unique condition. The recognition of the entity may avoid unnecessary use of corticosteroids.