[Optimal cut-off point of symptom association probability in the diagnosis of gastroesophageal reflux-induced chronic cough].

OBJECTIVE: To explore the optimal cut-off point of symptom association probability (SAP) in the diagnosis of gastroesophageal reflux-induced chronic cough (GERC) and therefore to improve the diagnostic accuracy. METHODS: Patients with suspected GERC consecutively referred to our respiratory clinic were enrolled into this prospective study between July 2011 and February 2013. After multi-channel intraluminal esophageal impedance and pH monitoring, SAP was calculated by associating the cough recordings on the patients' diary with the detected reflux. GERC was confirmed when there was a favorable response to the following anti-reflux therapy despite the laboratory findings. The optimal cutoff point of SAP was defined according to the highest Youden index. Then, the sensitivity, specificity, positive and negative predictive values, the area under the curve of ROC, and the Kappa value for the optimal cut-off point of SAP was calculated and compared to those of SAP standards currently used in China or generally accepted in the diagnosis of GERC. RESULTS: During the study period, 103 patients with suspected GERC were recruited. Among them, GERC was confirmed in 87 patients (84.5%), including 54 patients (62.1%) due to acid reflux and 33 patients (37.9%) due to non-acid reflux. The optimal cut-off point of SAP was defined at ≥ 80% based on the highest Youden index of 0.372. For the diagnosis of GERC, SAP ≥ 80% had the area under the curve of ROC of 0.686, the Kappa value of 0.264, the sensitivity of 74.7%, the specificity of 62.5%, positive predictive value of 91.5% and negative predictive value of 31.3% respectively, which were superior to those of SAP ≥ 75% currently used in China, and to those of SAP ≥ 95% ( the generally accepted cut-off) in that the balance between higher sensitivity and higher specificity was maintained. When combined with DeMeester score ≥ 12.7, the diagnostic accuracy of SAP ≥ 80% was further improved, with the area under the curve of ROC of 0.820, the Kappa value of 0.689, the sensitivity of 87.0%, the specificity of 76.0%, positive predictive value of 94.1% and negative predictive value of 80.0%. CONCLUSION: SAP ≥ 80% may be a more suitable standard for the diagnosis of GERC.

[The diagnostic value of multichannel intraluminal esophageal impedance and pH monitoring in gastroesophageal reflux-related cough].

OBJECTIVE: To evaluate the diagnostic value and limitation of multichannel intraluminal esophageal impedance and pH (MII-pH) monitoring on the diagnosis of gastroesophageal reflux-related chronic cough (GERC). METHODS: The patients with suspicious GERC consecutively referred to our respiratory clinic between May 2010 and July 2011 underwent a MII-pH monitoring, and received anti-reflux drug therapy, irrespective of the laboratory findings. Chronic cough due to gastroesophageal reflux was determined when there was a favorable response to anti-reflux therapy. Then, the sensitivity, specificity, false positive and negative rate, total consistence, positively and negatively predictive value, the area under the curve of ROC and the Kappa value of the laboratory investigation were calculated for the diagnosis of GERC. RESULTS: During the research period, 56 patients completed MII-pH monitoring. Among them, the abnormal reflux was found in 35 patients, and GERC was finally confirmed in 30 patients (85.7%) including 25 patients (83.3%) due to acid reflux and 5 patients (16.7%) due to non-acid reflux. In the remaining 21 patients with normal reflux episodes, 6 patients (28.6%) could be explained by non-acid reflux for their cough because of a relatively predominant weakly acid reflux and favorable response to empirical anti-reflux therapy. For the diagnosis of GERC, MII-pH monitoring had the sensitivity of 83.3%, the specificity of 75.0%, false positive rate of 25.0%, false negative rate of 16.7%, total consistence of 80.4%, positive predictive value of 85.7%, negative predictive value of 71.4%, the area under the curve of ROC of 0.792 and Kappa value of 0.577 respectively. CONCLUSION: MII-pH is a sensitive and reliable tool for the diagnosis of GERC due to its ability to detect both acid and non-acid reflux.

[The ultrastructural features of sputum deposition and its value in the diagnosis of pulmonary alveolar proteinosis].

OBJECTIVE: To investigate the ultrastructural features of sputum deposition (SD) and its value in the diagnosis of pulmonary alveolar proteinosis (PAP). METHODS: Seven patients with PAP diagnosed by lung biopsy and cytology were enrolled in this study. The patients consisted of 5 men and 2 women, whose median age was 48 years (range 36 to 73). SD and bronchoalveolar lavage fluid (BALF) sediment were made into ultrathin sections and observed under transmission electron microscope (TEM), respectively. Seven cases of control group composed of 4 men and 3 women whose median age was 49 years (range 39 to 68) including 3 cases of bacterial pneumonia, two cases of COPD and 2 cases of exudative pulmonary tuberculosis. Each SD was made into ultrathin section, and compared with the experimental group. RESULTS: In PAP group, Periodic acid-schiff (PAS) staining was performed on 7 sputum smears and none of them was tested positive for any components with diagnostic interest. Four cases from the 7 paraffin-embed sections of BALF sediment by microscopic examination suggested PAP. Under TEM, BALF sediment showed that many lamellar bodies existed in and outside alveolar epithelial cells, and 5 specimens were consistent with PAP diagnosis. Compared with BALF sediment, SD had apparent degeneration with more myelin phagosomes in the cytoplasm of macrophages, more lamellar bodies in alveolar epithelial cells, and lots of lamellar bodies in the shape of concentric circle in the extracellular spaces. Four from the 7 SD samples were consistent with the diagnosis of PAP. No significant difference was found between SD and BALF in the diagnosis of PAP by electronic examination (P > 0.05). In the 7 cases of control group no drifting osmiophilic lamellar bodies in extracellular space were detected. CONCLUSIONS: The osmiophilic lamellar bodies with diagnostic value were found in SD and BALF of patients with PAP. TEM of SD in combination with clinical manifestations and radiologic findings can make a definitive diagnosis of PAP, especially for those patients who have contraindications to lung biopsy and lung lavage.

Discrepancy between presumptive and definite causes of chronic cough.

BACKGROUND: The current diagnostic algorithms for chronic cough require the establishment of the primary presumptive causes followed by the confirmation of diagnosis with the specific therapies. The aim of the study was to investigate the discrepancy between presumptive and definite causes and its clinical implication. METHODS: A total of 109 patients with chronic cough underwent laboratory investigations to identify the cause of cough; including sinus computerized tomography (if needed), histamine bronchial provocation, induced sputum cytology and 24-hour esophageal pH or multi-channel intraluminal impedance combined with pH monitoring. The presumptive causes were confirmed by treating them sequentially. The difference between presumptive and definite causes of chronic cough was compared. RESULTS: Single cause was more frequent in the definite diagnosis than in the presumptive diagnosis (78.9% vs. 54.1%, χ(2) = 15.01, P = 0.0001). In contrast, multiple causes were significantly fewer in definite diagnosis than in the presumptive diagnosis (15.6% vs. 37.6%, χ(2) = 13.53, P = 0.0002). There was a discrepancy between definite and presumptive causes in 30 patients (27.5%). Compared with the presumptive causes, definite upper airway cough syndrome (24.8% vs. 11.9%, χ(2) = 6.0, P = 0.01) and gastroesophageal reflux disease (6.4% vs. 0, χ(2) = 7.23, P = 0.007) was more frequent as a single cause of chronic cough while cough variant asthma plus gastroesophageal reflux disease (3.7% vs. 11.9%, χ(2) = 5.17, P = 0.02) and upper airway cough syndrome plus nonasthmatic eosinophilic bronchitis (0 vs. 9.2%, χ(2) = 10.48, P = 0.001) were fewer as multiple causes of chronic cough. CONCLUSIONS: A discrepancy was common between presumptive and definite causes of chronic cough. To treat presumptive causes sequentially may be a suitable solution for avoidance of erroneous multiple causes and possible over-treatment.

[Changes in the spectrum and frequency of causes for chronic cough: a retrospective analysis].

OBJECTIVE: To investigate the changing patterns of the spectrum and frequency of causes for chronic cough, and to explore its clinical implications. METHODS: Nine hundred and forty patients consecutively referred to Department of Respiratory Medicine for evaluation of chronic cough between January 2004 and December 2008 were collected and divided into 5 groups by periods of 5 years. The causes of cough had been primarily evaluated according to a step-by-step protocol and confirmed by the specific therapy. The changes in spectrum and frequency of causes were retrospectively analyzed by chi2 test. RESULTS: The common causes of chronic cough were cough variant asthma (n = 437, 46%), upper airway cough syndrome/postnasal drip syndrome (n = 304, 32%), eosinophilic bronchitis (n = 87, 9%), gastroesophageal reflux-related chronic cough (n = 83, 9%), postinfectious cough (n = 60, 6%) and angiotensin-converting enzyme inhibitors-induced cough (n = 46, 5%) in descending order. There were significant differences in the distribution and frequency of etiologies when analyzed by year (chi2 = 60.6, P = 0.0001). During a 5-year period, chronic cough due to cough variant asthma increased from 44% to 51% (chi2 = 12.8, P = 0.010), upper airway cough syndrome/postnasal drip syndrome decreased from 49% to 29% (chi2 = 20.1, P = 0.001), and gastroesophageal reflux increased from 2% to 10% (chi2 = 17.6, P = 0.002). However, chronic cough associated with eosinophilic bronchitis, postinfection and angiotensin-converting enzyme inhibitors remained stable. CONCLUSION: The common causes of chronic cough vary with time, which may have an impact on the strategy for the management of chronic cough.

Effects of phosphodiesterase 4 inhibitor on cough response in guinea pigs sensitized and challenged with ovalbumin.

BACKGROUND: There is currently considerable interest in the potential value of selective inhibitors of cyclic nucleotide phosphodiesterase 4 in the treatment of asthma. However, whether they influence eosinophilic airway inflammation-associated cough remains unclear. The objective of this study was to investigate the effects of selective phosphodiesterase 4 inhibitor SB207499 on cough response and airway inflammation in guinea pigs sensitized and challenged with ovalbumin. METHODS: Forty sensitized guinea pigs were randomly divided into four groups: control (n = 10), challenge (n = 10), SB207499 (n = 10) and aminophylline (n = 10), then challenged with aerosol of 1% ovalbumin or saline. Two hours later, animals were intraperitoneally injected with either saline, 25 mg/kg of SB207499 or aminophylline. At the 24th hour, the injection was repeated with 2.5 mg/kg and 25 mg/kg SB207499 or aminophylline, then cough response to inhaled capsaicin and airway responsiveness to methacholine inducing a 150% of the peak airway pressure to the baseline (PC150) was measured. Finally, total cell number and differentials in bronchoalveolar lavage fluid were analysed. RESULTS: The cough frequency per 3 minutes and PC150 in the challenge group were (22 +/- 4) times/3 minutes and (198 +/- 54) microg/ml, which were significantly different from (6 +/- 2) times/3 minutes and (691 +/- 81) microg/ml in the control group (P < 0.05, respectively). The injection of 25 mg/kg SB207499 significantly inhibited the increased cough response and airway hyperresponsiveness, the cough frequency and PC150 in guinea pigs were (13 +/- 2) times/3 minutes and (680 +/- 81) microg/ml (P < 0.05), which differed significantly from (18 +/- 2) times/3 minutes and (400 +/- 86) microg/ml after the administration of the same dose of aminophylline (P < 0.05). The inhibition of SB207499 on cough response was dose-dependent. Similarly, SB207499 decreased the total cell number and percentage of eosinophils in bronchoalveolar lavage fluid to (2.1 +/- 0.5) x 10(6)/ml and (20 +/- 5)% respectively, which were significantly different from (3.2 +/- 0.5) x 10(6)/ml and (29 +/- 5)% in the aminophylline group (P < 0.05, respectively) or (4.2 +/- 0.7) x 10(6)/ml and (35 +/- 4)% in the challenge group (P < 0.05, respectively). CONCLUSION: Phosphodiesterase 4 inhibitor may be more useful than aminophylline for cough associated with eosinophilic airway inflammation via inhibiting airway inflammation and airway hyperresponsiveness.

[The experimental study on the inhibitory effect of tripterine on airway inflammation in asthmatic mice].

OBJECTIVE: To investigate the effect and mechanism of tripterine on airway inflammation in asthmatic mice. METHODS: 30 BALB/c mice were randomly divided into a control group, an asthmatic group (ovalbumin-sensitized) and a tripterine (1 mg/kg, introperitoneally)-treated group. Pathologic changes in lung tissues, number of eosinophils in bronchoalveolar lavage fluid (BALF) and expression of stem cell factor (SCF) protein in lung were observed. In vitro, we established coculture system of bone marrow derived-mast cells from C57B6 mice and fibroblast NIH3T3, which were then treated by 2 micro mol/L of tripterine, and compared with NIH3T3 and mast cells. Concentration of histamine and eotaxin in supernants of coculture was measured by fluorometry and ELISA respectively, and expression of SCF protein in fibroblasts from cocultures was analyzed with immunohistochemistry. RESULTS: Compared with the asthmatic group, less inflammatory cell infiltration in lung tissues was observed in the tripterine-treated group. There was significant difference in the number of eosinophils in BALF between the tripterine-treated group [(0.56 +/- 0.03) x 10(6)/L] and the asthmatic group [(1.25 +/- 0.40) x 10(6)/L, P < 0.05]. So was the expression of SCF protein in lung tissue [0.74 +/- 0.20, 2.50 +/- 0.19, P < 0.01]. In vitro, the concentration of histamine and eotaxin in coculture supernants and the expression of SCF protein in fibroblasts from coculture were (3.83 +/- 0.41) ng/ml, (5.79 +/- 0.40) ng/ml and (95 +/- 3)%, respectively; after tripterine intervention, the data changed to (2.88 +/- 0.35) ng/ml, (4.24 +/- 0.29) ng/ml, (17 +/- 5)% (all P < 0.01). CONCLUSIONS: Tripterine might suppress airway inflammation in asthmatic mice, probably by downregulating the expression of SCF in fibroblasts, then inhibiting the production of histamine and eotaxin in mast cells.