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.

Analysis of Microarray-Identified Genes and MicroRNAs Associated with Idiopathic Pulmonary Fibrosis.

The aim of this study was to identify potential microRNAs and genes associated with idiopathic pulmonary fibrosis (IPF) through web-available microarrays. The microRNA microarray dataset GSE32538 and the mRNA datasets GSE32537, GSE53845, and GSE10667 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DE-miRNAs)/genes (DEGs) were screened with GEO2R, and their associations with IPF were analyzed by comprehensive bioinformatic analyses. A total of 45 DE-microRNAs were identified between IPF and control tissues, whereas 67 common DEGs were determined to exhibit the same expression trends in all three microarrays. Furthermore, functional analysis indicated that microRNAs in cancer and ECM-receptor interaction were the most significant pathways and were enriched by the 45 DE-miRNAs and 67 common DEGs. Finally, we predicted potential microRNA-target interactions between 17 DE-miRNAs and 17 DEGs by using at least three online programs. A microRNA-mediated regulatory network among the DE-miRNAs and DEGs was constructed that might shed new light on potential biomarkers for the prediction of IPF progression.

Efficiency and safety of pulmonary rehabilitation in acute exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary rehabilitation (PR) is able to improve dyspnea, endurance capacity, and health-related quality of life in chronic obstructive pulmonary disease (COPD) patients, but it is rarely used in China. This study aimed to assess the effectiveness and safety of PR after exacerbation of COPD. MATERIAL AND METHODS: Patients admitted to hospital due to an exacerbation of COPD were randomized to receive either PR or routine care (control group). The PR program was performed from the second day of admission until discharge. The pre-post changes in 6-minute walk distance (6MWD), self-reported quality of life (QOL) assessed by CAT score and CRQ-SAS score, and activity of daily life assessed by ADL-D score were determined. The perceived end-effort dyspnea (Borg scale) was measured throughout the study. RESULTS: A total of 101 patients were enrolled, of whom 7 withdrew after randomization, and 94 completed this study. There were 66 patients in the PR group and 28 in the control group. The 6MWD, resting SpO2, and exercise Borg dyspnea score were significantly improved in the PR group. In addition, the PR group had greater improvement in the total CRQ-SAS score and had a lower CAT score. Significant improvements were also found in the ADL-D and BODE index in the PR group. No adverse events were recorded during exercise. CONCLUSIONS: Our study provides evidence that it is safe and feasible to apply an early PR in patients with acute exacerbation of COPD.

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.

Transmission electron microscopy of sputum deposition in the diagnosis of pulmonary alveolar proteinosis.

OBJECTIVE: To clarify the diagnostic value of sputum in pulmonary alveolar proteinosis (PAP) through transmission electron microscopy (TEM) of sputum deposition (SD). METHODS: Eleven SD samples and 9 bronchoalveolar lavage (BAL) sediments from a PAP group including 11 patients were observed by TEM and compared with sputum direct smear, BAL cytology, and lung biopsy histopathology. Eleven healthy adults were chosen as controls. RESULTS: The 11 sputum smears from the PAP group showed no diagnostic component, but TEM of SD revealed 7 of 11 samples had many myelin-like lamellar bodies with degeneration in the cytoplasm of macrophages, alveolar epithelial cells, and extracellular spaces, which suggested PAP. Especially, 2 patients on whom lung biopsy could not be performed and who failed to be diagnosed by BAL fluid were finally diagnosed by TEM of SD. TEM of BAL sediments showed 7 of 9 cases had diagnostic myelin-like lamellar bodies. No statistical significance was found between BAL fluid and SD by TEM. The control group didn't show diagnostic components by cytology or TEM of SD. CONCLUSION: TEM of SD is an important noninvasive diagnostic method especially for patients against lung biopsy and BAL.

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.

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.

Efficacy of sequential three-step empirical therapy for chronic cough.

BACKGROUND: Empirical three-step therapy has been proved in just one hospital. This study aimed to demonstrate applicability of the sequential empirical three-step therapy for chronic cough in different clinical settings. METHODS: Sequential empirical three-step therapy was given to patients with chronic cough in one tertiary and three secondary care respiratory clinics. Recruiters were initially treated with methoxyphenamine compound as the first-step therapy, followed by corticosteroids as the second-step therapy and the combination of a proton-pump inhibitor and a prokinetic agent as the third-step therapy. The efficacy of the therapy was verified according to the changes in cough symptom score between pre- and post-treatment, and compared among the different clinics. RESULTS: In total 155 patients in one tertiary clinic and 193 patients in secondary care clinics were recruited. The total dropout ratio is significantly higher in the secondary care clinics than that in the tertiary clinic (9.3% versus 3.2%, p = 0.023). The therapeutic success rate for cough was 38.7% at first-step therapy, 32.3% at second-step therapy and 20.0% at third-step therapy in the tertiary clinic, and comparable to corresponding 49.7%, 31.1% and 4.1% in secondary care clinics. Furthermore, the overall cough resolution rate was not significantly different (91.0% versus 85.0%, p = 0.091). However, the efficacy of the third-step therapy is much higher (20.0% versus 4.1%, p = 0.001) in the tertiary clinic than in the secondary care clinics. CONCLUSIONS: Sequential empirical three-step therapy is universally efficacious and useful for management of chronic cough in different clinical settings.

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.

Refractory chronic cough due to gastroesophageal reflux: Definition, mechanism and management.

Refractory chronic cough due to gastroesophageal reflux is a troublesome condition unresponsive to the standard medical anti-reflux therapy. Its underlying mechanisms may include incomplete acid suppression, non-acid reflux, transient lower esophageal sphincter relaxations and esophageal hypersensitivity. The diagnosis of this disorder depends on both the findings of multi-channel intraluminal impedance-pH monitoring and the subsequent intensified anti-reflux therapy. The strategies of pharmacological treatment for refractory chronic cough due to reflux include the optimization of proton pump inhibitors and add-on therapies with histamine H2 receptor antagonists, baclofen and gabapentin. However, the further study is needed to satisfy its management.

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.

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.

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.

Gastro-esophageal reflux induced cough with airway hyperresponsiveness.

To investigate the characteristics of gastroesophageal reflux induced cough (GERC) with airway hyperresponsiveness (AHR). Compared to patients with GERC alone and healthy subjects, cough sensitivity, multi-channel intraluminal impedance combined with pH monitoring and airway inflammation were evaluated in patients with GERC and AHR. 23 patients were definitely diagnosed as acid reflux induced GERC, 9 patients developed AHR concomitantly. When compared with GERC patients, patients with AHR had significantly increased number of proximal extent episodes (21.5 (28.6) vs. 7.5 (1.8), Z = -2.038, P = 0.042) and increased proportion of proximal extent episodes to total refluxes episodes (24.5 (13.5)% vs. 4.2 (7.3)%, Z = -2.138, P = 0.032), and the level of IL-8 in the airway of these patients was significantly higher than that in healthy subjects (71.1 (64.0) vs. 24.3 (35.2) pg/ml, Z = -2.013, P = 0.044). Gastroesophageal reflux may cause neutrophilic airway inflammation due to the acid reflux into the airway, which results in AHR. However, AHR is not definitely able to cause chronic cough. Thus differential diagnosis is required in clinical practice.

A noninvasive examination for the diagnosis of pulmonary alveolar proteinosis: induced sputum in conjunction with transmission electron microscopy.

Transmission electron microscopy (TEM) of sputum deposition (SD) is an important method to assist in the diagnosis of pulmonary alveolar proteinosis (PAP). However, the low positive rate and poor quality of slices restrict the application of sputum samples in the diagnosis of PAP. Furthermore, it can be more difficult to obtain a sufficient amount of sample for TEM if the patients have little or no sputum. In this paper, we successfully diagnosed a patient with PAP using induced sputum deposition (ISD) with TEM, which is a novel and noninvasive method for PAP diagnosis. Therefore, ISD combined with TEM can be an effective method for PAP diagnosis, especially when a lung biopsy and bronchoalveolar lavage (BAL) cannot be performed, or little or no sputum can be obtained.

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.