Xianghuai Xu

Therapeutic efficacy of baclofen in refractory gastroesophageal reflux-induced chronic cough

AIM To evaluate the efficacy and safety of baclofen for treatment of refractory gastroesophageal reflux-induced chronic cough (GERC) unresponsive to standard anti-reflux therapy. METHODS Sixteen patients with refractory GERC were given an 8-wk course of baclofen 20 mg three times a day as an add-on therapy to omeprazole. Changes in the cough symptom score, cough threshold to capsaicin, reflux symptom score and possible adverse effects were determined after treatment. The variables of multi-channel intraluminal impedance combined with pH monitoring were compared between responders and non-responders to baclofen. RESULTS Twelve of 16 patients completed treatment. Cough disappeared or improved in 56.3% (9/16) of patients, including 6 patients with acid reflux-induced cough (66.7%) and 3 patients with non-acid reflux-induced cough (33.3%). With baclofen treatment, the cough symptom score began to decrease at week 2, was clearly decreased at week 6 and reached a minimum at week 8. At the end of therapy, the lowest concentration of capsaicin required for induction of ≥ 2 and ≥ 5 coughs increased from 0.98 (1.46) to 1.95 (6.82) μmol/L (Z = -2.281, P = 0.024) and from 1.95 (7.31) to 7.8 (13.65) μmol/L (Z = -2.433, P = 0.014), respectively, and the reflux symptom score decreased from 8.0 ± 1.6 to 6.8 ± 0.8 (t = 2.454, P = 0.023). The number of acid reflux episodes was significantly lower in responders than in non-responders. The main adverse effects were somnolence, dizziness and fatigue. CONCLUSION Baclofen is a useful, but suboptimal treatment option for refractory GERC.

Successful resolution of refractory chronic cough induced by gastroesophageal reflux with treatment of baclofen

Gastroesophageal reflux induced cough is a common cause of chronic cough, and proton pump inhibitors are a standard therapy. However, the patients unresponsive to the standard therapy are difficult to treat and remain a challenge to doctors. Here, we summarized the experience of successful resolution of refractory chronic cough due to gastroesophageal reflux with baclofen in three patients. It is concluded that baclofen may be a viable option for gastroesophageal reflux induced cough unresponsive to proton pump inhibitor therapy.

Comparison of Gastroesophageal Reflux Disease Questionnaire and Multichannel Intraluminal Impedance pH Monitoring in Identifying Patients With Chronic Cough Responsive to Antireflux Therapy

BACKGROUND Empirical therapy has been recommended as an initial clinical approach for treating gastroesophageal reflux-induced chronic cough (GERC). This study compared the predictive accuracy of the Gastroesophageal Reflux Disease Questionnaire (GerdQ) with the accuracy of multichannel intraluminal impedance pH monitoring (MII-pH) for GERC. METHODS A total of 126 consecutive patients with potential GERC were recruited to undergo MII-pH and complete the GerdQ. A final diagnosis of GERC was made after favorable response to consequent medicinal antireflux therapy, regardless of laboratory findings. The predictive accuracy of the GerdQ for GERC was assessed and compared with that of MII-pH. RESULTS GERC was confirmed in 102 of 126 patients (81.0%); cough was due to acid reflux in 55 (53.9%) and nonacid reflux in 47 (46.1%). The optimal cutoff point of the GerdQ for predicting GERC was defined as 8.0 according to the highest Youden index of 0.584, with a sensitivity of 66.7%, specificity of 91.7%, positive predictive value of 97.1%, and negative predictive value of 42.9%. A subanalysis for only acid GERC showed further improvement in the predictive accuracy of the GerdQ, corresponding to a sensitivity of 90.9%, specificity of 78.6%, positive predictive value of 71.4%, and negative predictive value of 96.4%. However, a meaningful GerdQ cutoff point for prediction of nonacid GERC could not be determined. In general, MII-pH was superior to the GerdQ for predicting GERC and acid GERC. CONCLUSIONS The GerdQ can be used for predicting acid GERC but not nonacid GERC and is inferior to MII-pH. TRIAL REGISTRY Chinese Clinical Trial Registry; No.: ChiCTR-ODT-12001899; URL: www.chictr.org.

Advances in upper airway cough syndrome

Upper airway cough syndrome (UACS), previously referred to as postnasal drip syndrome, is one of the most common causes of chronic cough. However, the pathogenesis of UACS/postnasal drip syndrome remains unclear, and physicians in countries throughout the world have different definitions and ways of treating this disease. The various proposed pathogeneses of UACS include the early postnasal drip theory, subsequent chronic airway inflammation theory, and a recent sensory neural hypersensitivity theory. Additionally, some researchers suggest that UACS is a clinical phenotype of cough hypersensitivity syndrome. While the general principles involved in treating UACS are similar throughout the world, the specific details of treatment differ. This review summarizes the various definitions, pathogenic mechanisms, treatments, and other aspects of UACS, to aid clinicians in expanding their knowledge of how to diagnose and treat this syndrome.

Capsaicin-sensitive cough receptors in lower airway are responsible for cough hypersensitivity in patients with upper airway cough syndrome.

Background Cough hypersensitivity may be related to the pathogenesis of upper airway cough syndrome (UACS). The purpose of the study was to investigate the role of capsaicin-sensitive cough receptors on the laryngopharynx and lower airway in the cough hypersensitivity of patients with UACS. Material/Methods 59 patients with UACS, 33 patients with rhinitis/sinusitis without cough, and 39 healthy volunteers were recruited for the study. Cough threshold C5, defined as the lowest concentration of capsaicin required for the induction of ≥5 coughs upon esposure to capsaicin, were determined at baseline and after laryngopharngeal anesthesia with lidocaine in all the subjects. After induced sputum cytology, the concentrations of histamine, prostaglandin E2 (PGE2), and calcitonin-gene-related peptide (CGPR) in the induced sputum were measured by ELISA. In 15 patients with UACS, sputum cytology and measurement of the above mediators were repeated after successful therapy. Results C5 response to capsaicin was significantly lower in the UACS group than in the rhinitis/sinusitis group and healthy control groups [3.9 (0.98, 7.8) μmol/L vs. 7.8 (3.9, 93.75) μmol/L vs. 31.2 (15.6, 62.5) μmol/L, H=40.12, P=0.000]. Laryngopharngeal anesthesia with lidocaine dramatically increased C5 to capsaicin in the subjects of all 3 groups by a similar degree, but the increase in the UACS group was still the lowest, with an increased level of histamine, PGE2, and CGRP in the induced sputum. When cough resolved with the treatment of cetirizine alone or in combination with erythromycin, the levels of CGRP and histamine in the induced sputum decreased significantly in 15 patients with UACS, with no obvious change in cell differential or concentration of PGE2 in the induced sputum. Conclusions Laryngeal TRPV1 plays an important role in cough sensitivity, but sensitization of capsaicin-sensitive cough receptors in the lower airway may be more responsible for the cough hypersensitivity in patients with UACS.

Comparison of clinical characteristics of chronic cough due to non-acid and acid gastroesophageal reflux

Little is known about non‐acid gastroesophageal reflux‐induced chronic cough (GERC). The purpose of the study is to explore the clinical characteristics of non‐acid GERC.

A stepwise protocol for the treatment of refractory gastroesophageal reflux-induced chronic cough

BACKGROUND Refractory gastroesophageal reflux-induced chronic cough (GERC) is difficult to manage. The purpose of the study is to evaluate the efficacy of a novel stepwise protocol for treating this condition. METHODS A total of 103 consecutive patients with suspected refractory reflux-induced chronic cough failing to a standard anti-reflux therapy were treated with a stepwise therapy. Treatment commences with high-dose omeprazole and, if necessary, is escalated to subsequent sequential treatment with ranitidine and finally baclofen. The primary end-point was overall cough resolution, and the secondary end-point was cough resolution after each treatment step. RESULTS High-dose omeprazole eliminated or improved cough in 28.1% of patients (n=29). Further stepwise of treatment with the addition of ranitide yielded a favorable response in an additional 12.6% (n=13) of patients, and subsequent escalation to baclofen provoked response in another 36.9% (n=38) of patients. Overall, this stepwise protocol was successful in 77.6% (n=80) of patients. The diurnal cough symptom score fell from 3 [1] to 1 [0] (Z=6.316, P=0.000), and the nocturnal cough symptom score decreased from 1 [1] to 0 [1] (Z=-4.511, P=0.000), with a corresponding reduction in the Gastroesophageal Reflux Diagnostic Questionnaire score from 8.6±1.7 to 6.8±0.7 (t=3.612, P=0.000). Conversely, the cough threshold C2 to capsaicin was increased from 0.49 (0.49) µmol/L to 1.95 (2.92) µmol/L (Z=-5.892, P=0.000), and the cough threshold C5 was increased from 1.95 (2.92) µmol/L to 7.8 (5.85) µmol/L (Z=-5.171, P=0.000). CONCLUSIONS Sequential stepwise anti-reflux therapy is a useful therapeutic strategy for refractory reflux-induced chronic cough.

Diagnosis and treatment of patients with nonacid gastroesophageal reflux-induced chronic cough

Gastroesophageal reflux (GER) is one of the most common causes of chronic cough, and chronic cough due to GER represents a subtype of GER-related diseases. Gastroesophageal reflux-induced chronic cough (GERC) can be divided into two subgroups based on the pH of the GER. Nonacid GERC is less common than acid GERC, and its diagnosis and treatment strategy have not been standardized. However, nonacid GERC usually presents with its unique set of characteristics and features upon diagnosis and treatment in the clinic. Although the underlying molecular mechanism of nonacid GERC is not fully understood, it is considered to be associated with reflux theory, reflex theory and airway hypersensitivity. Multi-channel intraluminal impedance combined with pH monitoring is a promising new technique that can detect both acid and nonacid reflux, and our findings as well as those of others have shown its usefulness in diagnosing nonacid GERC. Development of new diagnostic techniques has led to an increased rate of nonacid GERC diagnosis. We summarize our experience in the diagnosis and treatment of nonacid GERC and provide a guide for future therapeutic approaches.

Cough hypersensitivity in patients with obstructive sleep apnea hypopnea syndrome

PurposeThe purpose of this study was to investigate cough hypersensitivity and its potential mechanisms in patients with obstructive sleep apnea hypopnea syndrome (OSAHS).MethodsFifteen 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.ResultsOSAHS 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).ConclusionOSAHS 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.