Clinical usefulness of fractional exhaled nitric oxide for diagnosing prolonged cough

BACKGROUND: Prolonged cough is one of the troublesome symptoms commonly seen in daily practice. Especially, detection of allergic cough such as bronchial asthma (BA), cough variant asthma (CVA) and eosinophilic bronchitis without asthma (EB) is important because the prevalence of these disorders are high. We previously reported fractional exhaled nitric oxide (FeNO) can be a non-invasive marker of allergic airway inflammation. We examined whether FeNO could be applicable for the proper diagnosis of prolonged cough. METHOD: About 71 consecutive subjects complaining prolonged cough who gave informed consent for the study were enrolled. FeNO, pulmonary function tests, bronchial hyperresponsiveness (BHR), IgE, and eosinophils in induced sputum and peripheral blood were measured. Final diagnosis of the subjects was 30 with BA, 18 with CVA, 8 with EB, and 15 with other respiratory disorders (Others). RESULT: FeNO had significant correlations with non-specific IgE, mite-specific IgE, FEV/FVC, BHR, and eosinophils. The level of cedar-specific IgE was significantly higher in subjects with EB than CVA. FeNO levels in BA and CVA were significantly higher than those in EB and Others. The optimal cutoff level of FeNO was 38.8ppb with sensitivity of 79.2% and specificity of 91.3% for distinguishing BA and CVA from EB and Others. CONCLUSION: FeNO could be used as a diagnostic marker of prolonged cough, especially for the differential diagnosis BA and CVA from EB and others.     

Exhaled nitric oxide levels in patients with atopic cough and cough variant asthma

Background and objective:   Atopic cough (AC) is an established clinical entity in Japan, in which patients present with a chronic persistent non-productive cough. Exhaled nitric oxide (NO) is a biomarker of eosinophilic airway inflammation. The present study examined whether exhaled NO levels were increased in AC in comparison with cough variant asthma (CVA) and bronchial asthma (BA).
Methods:   Consecutive patients presenting with an isolated cough lasting at least 8 weeks were enrolled in the study. The aetiology of the chronic cough was determined according to the Japanese Respiratory Society guidelines for management of cough. Exhaled NO, capsaicin cough sensitivity (capsaicin concentration eliciting five or more coughs (C5)) and bronchial reversibility were measured at the patients' first visit. Bronchial responsiveness (PC20 to methacholine) was measured at their second visit following a 6-day course of bronchodilator therapy.
Results:   There were 58 patients recruited and fully investigated; of these 9 and 11 patients were diagnosed with AC and CVA, respectively, as single causes of chronic cough. Ten patients with BA who had not received corticosteroid therapy in the previous 4 weeks and who attended the same clinic in the same time period acted as controls. Exhaled NO levels in patients with AC were significantly lower than those in patients with CVA and BA. There was no significant difference in the exhaled NO levels between patients with CVA and BA.
Conclusions:   Exhaled NO may reflect eosinophilic inflammation of peripheral airways and its measurement may be useful in differentiating CVA from AC and other causes of chronic non-productive cough.     

诱导痰液分析对咳嗽变异性哮喘患者的诊断价值研究

目的 探讨诱导痰液分析在咳嗽变异性哮喘(CVA)中的临床诊断价值.方法 选取我院2009年9月-2011年8月79例变异性哮喘患者.采用超声雾化吸入3%～5%的高渗盐水进行诱导排痰,对其痰液进行嗜酸性粒细胞(EOS)百分率、肥大细胞(MC)百分率、中性粒细胞(N)及嗜酸性粒细胞阳离子蛋白(ECP)等检测,同时对1s用力呼气容积(FEVl)及ls用力呼气占预计值的百分比(FEVl占预计值%)进行测定.结果 其中有35例被临床诊断为CVA,患者的痰液中MC、EC百分率、ECP浓度、FEVl及FEVl占预计值%与对照组比较,差异均有统计学意义(P＜0.05),而与典型支气管哮喘组的比较差异无统计学意义(P＞0.05).在进行抗炎治疗之后患者的咳嗽症状很快得到缓解,对痰液中MC、EC百分率、ECP浓度、FEVl及FEVl占预计值%做出复测,结果与治疗前比较,差异有统计学意义.结论 通过痰液分析,从实验室角度阐明CVA存在气道炎症,为其诊断和治疗提供了一项可靠的评价指标.     

A Preliminary Study of PEFR Monitoring in Patients with Chronic Cough

It is important to make a differential diagnosis of cough variant asthma in patients with chronic cough. To examine whether or not peak expiratory flow rate (PEFR) is useful for the differential diagnosis of cough variant asthma in such patients, diurnal variation rates of PEFR were calculated in 23 patients who presented with dry cough lasting four or more weeks and who showed no abnormalities on chest radiographs. None of the patients had wheezes, and pulmonary function testing at the time of visit to the hospital revealed no abnormalities. During the control period, the mean diurnal variation rate of PEFR in 23 patients was 16.3 ± 7.9%. Six, nine and eight patients had PEFR diurnal variations rates of <10% (Group 1), 10–19% (Group 2), and 20% (Group 3), respectively. At week 3 of treatment with bronchodilators, only Group 3 showed a significant decrease in PEFR diurnal variation rate from 25.7% to 10.1%. The cough score decreased significantly in Group 3 only. These patients had enhanced bronchial hyperresponsiveness and showed eosinophils in induced sputum, leading to the diagnosis of cough variant asthma (CVA). After making the diagnosis of CVA, an inhaled corticosteroid or a Th2 cytokine production inhibitor suplatast tosilate was administered to patients; consequently, they showed no recurrence of cough. PEFR monitoring allowed the detection of morning dip and was suggested to be potentially useful for the differential diagnosis of cough variant asthma in patients with chronic cough.     

咳嗽变异性哮喘的临床特征及其与典型哮喘的关系

目的分析成年咳嗽变异性哮喘（CVA）患者的临床特征及其发展为哮喘的情况,探讨CVA进展为哮喘的危险因素。方法收集2002年1月至2010年1月于广州呼吸疾病研究所门诊就诊的CVA患者,记录患者的基本临床资料,包括咳嗽时相、咳嗽性质、诱发因素、伴随症状、过敏史、随访情况等。并行肺功能、支气管激发试验/PEF检测、诱导痰细胞学分类、皮肤过敏原点刺试验等检查。所有入选患者年龄≥18岁、符合我国《咳嗽的诊断与治疗指南》中CVA的诊断标准。同时给予规律吸入中等剂量的布地奈德或等效剂量的吸入激素,至少治疗8周。通过门诊及电话随访,若患者出现胸闷、喘息等典型哮喘症状或出现哮鸣音则确认其进展为哮喘,分为单纯CVA组和发展为典型哮喘组（哮喘组）;比较两组患者一般资料及实验室检查情况。结果 91例CVA患者咳嗽时相以夜间或清晨为主的发生率为74.7%,伴变应性鼻炎病史的比例为46.2%;咳嗽的主要诱发因素包括：烟雾63.5%、冷空气51.4%、上呼吸道感染47.3%、灰尘37.8%、咽喉发痒36.5%;CVA患者有74.7%诱导痰中嗜酸粒细胞（EOS）比例〉2.5%。58例患者平均随访4.2（1~8.5）年,其中8例患者（8/58,13.8%）进展为典型哮喘,单纯CVA组患者使用吸入激素时间显著长于哮喘组[12（20）周vs 6（4）周,P〈0.05],8例哮喘组患者中仅1例规律吸入激素12周以上,而其他50例单纯CVA患者中有33例规律吸入激素大于12周,两组比较差异有统计学意义（P〈0.05）。单纯CVA组各项肺功能指标、痰EOS%、外周血EOS%、皮肤过敏原点刺试验阳性率与哮喘组比较差异均无统计学意义（P〉0.05）。结论 CVA主要以夜间或清晨咳嗽为临床特征,并有近一半患者合并过敏性鼻炎,长期规范吸入激素治疗可减少CVA患者进展为典型哮喘。     

嗜酸粒细胞性支气管炎与咳嗽变异性哮喘患者的气道炎症特征的研究

目的 探究嗜酸粒细胞性支气管炎(EB)和咳嗽变异性哮喘(CVA)患者气道炎症细胞、细胞因子和炎性介质的特征,阐明两者存在不同气道炎性特征的可能机制.方法检测杭州市第一人民医院门诊收治的15例EB患者(EB组)、15例CVA患者(CVA组)、14例支气管哮喘(简称哮喘)患者(哮喘组)和14名健康体检者(健康对照组)诱导痰中嗜酸粒细胞(EOS)百分比;流式细胞仪检测白细胞介素(IL)-5及干扰素(IFN)-γ刺激的EOS表面CD69的表达;实时荧光定量PCR方法检测各组诱导痰上清液中前列腺素E2(PGE2)、白三烯C4(LTC4)、IL-5、IFN-γ mRNA的表达水平;酶联免疫吸附法(ELISA)检测各组诱导痰上清液中PGE2、LTC4、IFN-γ和IL-5蛋白表达水平.结果 EB组、CVA组、哮喘组诱导痰中EOS百分比分别为(15.8±3.2)%、(13.0±2.7)%和(11.6±4.5)%,均明显高于健康对照组的(1.0±0.4)%(均P<0.05).在IL-5和IFN-γ刺激下,EB组诱导痰中EOS表达CD69分别为1.49±0.42和1.51±0.52、CVA组分别为1.37±0.41和1.42±0.32、哮喘组分别为1.42±0.72和1.37±0.46,3组间差异无统计学意义,但较健康对照组(分别为0.42±0.21和0.39±0.12)差异均有统计学意义(均P<0.05).EB组、CVA组、哮喘组诱导痰中IL-5的mRNA及蛋白表达水平明显高于健康对照组(均P<0.05),但3组间差异无统计学意义;各组诱导痰中IFN-γ的mRNA及蛋白表达水平较健康对照组差异均无统计学意义.EB组诱导痰中PGE2浓度为(839±69)ng/L,明显高于CVA组的(33±8)ng/L、哮喘组的(25±6)ng/L和健康对照组的(24±8)ng/L(均P<0.01),后3组差异无统计学意义;EB组PGE2限速酶前列腺素氧化环化酶2(PTGS2)的mRNA水平表达量显著增加,较CVA组、哮喘组及健康对照组差异均有统计学意义(均P<0.01);CVA、EB和哮喘组诱导痰中LTC4浓度明显高于健康对照组(均P<0.05),CVA、EB及哮喘组中LTC4限速酶白三烯C4合成酶(LTC4S)的mRNA表达水平明显高于健康对照组(均P<0.05),EB组LTC4的mRNA及蛋白表达水平与CVA组和哮喘组比较,差异也有统计学意义(均P<0.05).CVA组、哮喘组诱导痰中LTC4/PGE2比值明显高于EB组(t值分别为8.67和13.12,均P<0.05).结论 EB患者诱导痰中PGE2高表达以及CVA组LTC4/PGE2比值较EB组显著增高,这两者可能是EB缺乏气道高反应性的炎症基础.

Abstract：

Objective To explore the characteristics of airway inflammatory cells, cytokines and inflammatory mediators in eosinophilic bronchitis (EB) and cough variant asthma (CVA) patients and to elucidate the underlying mechanism of distinct airway inflammation between EB and CVA. Methods This study included 15 patients with EB (EB group), 15 patients with cough variant asthma (CVA, CVA group), 14 patients with bronchial asthma (asthma group) and 14 healthy controls (healthy group). Percentage of eosinophils (EOS) in sputum induced by hypertonic saline was detected by FACS. The percentage of CD+69 EOS stimulated by interleukin-5 (IL-5) and interferon γ (IFN-γ) was also detected by FACS. The expression of leukotriene C4 synthase (LTC4S) and prostaglandin-endoperoxide synthase-2 (PTGS2) mRNA in sputum was measured by real-time PCR and the concentration of leukotriene C4 (LTC4) and prostaglandin E2(PGE2) in sputum was measured by ELISA. Results The percentage of EOS in induced sputum was 15.8±3.2 (EB group), 13.0±2.7 (CVA group) and 11.6±4.5 (asthma group), respectively, which were significantly higher than 1.0±0.4 in the healthy group. The difference was significant and the t value was 16.31, 15.23 and 14.21 respectively (P<0.05). After stimulated by IL-5 and IFN-γ, the percentage of CD+69 EOS in induced sputum was 1.5±0.4 and 1.5±0.5 (EB group), 1.4±0.4 and 1.4±0.3 (CVA group) and 1.42±0.72 and 1.37±0.46 (asthma group) respectively. There was no statistical significance between these 3 groups, but when compared with 0.4±0.2 and 0.4±0.1 in healthy group, the difference was significant(P<0.05). The expression of IL-5 mRNA and protein in induced sputum of EB group, CVA group and asthma group were higher than the healthy group and the difference was all statistically different (P<0.05), but there was no statistical significance between EB group, CVA group and asthma group. The expression of IFN-γ mRNA and protein in induced sputum of each group was not different when compared with healthy group (P＞0.05). The concentration of PGE2 in induced sputum of EB group was(839±69)ng/L, which was higher than (33±8) ng/L of CVA group, (25±6) ng/L of asthma group and (24±8) ng/L of healthy group (all P<0.01). There was no statistical difference between CVA group, asthma group and healthy group. The expression of PTGS2 in induced sputum of EB group increased significantly; when compared with CVA group, asthma group and healthy group, the difference was significant (all P<0.01). The concentration of LTC4 in induced sputum of EB group, CVA group and asthma group was all higher than the healthy group (all P<0.05). The expression of LTC4S mRNA of EB group, CVA group and asthma group was also higher than the healthy group (all P<0.05). The expression of LTC4S mRNA and LTC4 in the EB group was higher than that in the CVA group and the asthma group (P<0.05). The value of LTC4/PGE2 in the CVA group and the asthma group was higher than that in the EB group (t=8.7 and 13.1, P<0.05). Conclusion These data suggest that the difference in airway function observed in subjects with eosinophilic bronchitis and CVA (or asthma) may be due to the results of differences in PGE2 production and an imbalance between the production of bronchoconstrictor LTC4 and bronchoprotective PGE2 lipid mediators.     

嗜酸粒细胞性支气管炎患者气道炎症细胞及介质特征的探讨

目的观察嗜酸粒细胞性支气管炎(EB)诱导痰和支气管肺泡灌洗液(BALF)中细胞分类和炎症介质浓度,探讨EB的气道炎症特征。方法对43例EB(EB组)患者行诱导痰检查,将20例咳嗽变异型哮喘(CVA)患者(CVA组)、16例典型支气管哮喘(哮喘组)患者和21名健康人(健康对照组)行对照诱导痰检查,并对部分EB(11例)和CVA患者(10例)行支气管肺泡灌洗(BAL)。观察检测诱导痰、BALF中的细胞分类、嗜酸粒细胞阳离子蛋白(ECP)、白三烯C4(LTC4)和组胺的浓度。结果EB组患者诱导痰中嗜酸粒细胞(EOS)百分比为0.1130±0.1470,CVA组为0.1900±0.1800,哮喘组为0.3860±0.2670,与健康对照组(0.0020±0.0050)比较差异有统计学意义(P均<0.01);哮喘组与CVA组、CVA组与EB组比较差异均有统计学意义(P均<0.05);EB组BALF中EOS为0.011±0.016,CVA组为0.053±0.040,两组比较差异有统计学意义(P<0.05);EB组诱导痰中的ECP浓度为(0.62±0.66)mg/L、CVA组为(1.27±1.74)mg/L,对照组为(0.07±0.10)mg/L,3组间比较差异有统计学意义(P<0.01);CVA组诱导痰中的LTC4浓度为(0.65±0.62)μg/L,EB组为(0.39±0.61)μg/L,对照组为(0.15±0.11)μg/L,3组间比较差异有统计学意义(P分别<0.05、0.01);CVA组BALF中组胺浓度为(3.4±1.4)μg/L,EB组为(1.6±1.5)μg/L,两组比较差异有统计学意义(P<0.05)。结论EB组EOS炎症主要局限于中心气道,部分气道炎性介质水平低于CVA组。上述气道炎性特征可能是EB患者无非特异性气道高反应性的重要机制。     

Induced sputum eosinophils in the assessment of asthma and chronic cough

OBJECTIVE: To evaluate induced sputum eosinophils in asthma and chronic cough. DESIGN: This was an analytical, cross-sectional study set in an ambulatory respiratory clinic. SUBJECTS: Subjects (n=75) referred for evaluation of symptomatic asthma or episodic respiratory symptoms had a clinical assessment, spirometry, hypertonic saline challenge and induced sputum. Two diagnostic groups were identified. The first group comprised subjects with symptomatic asthma and variable airway obstruction (VAO) (n=32). The second group included subjects with episodic respiratory symptoms and no VAO (n=43). RESULTS: The prevalence of eosinophilic bronchitis (eosinophils >2.75%) was greatest in asthma (n=14, 44%), compared to the episodic respiratory symptoms group (n=9, 21%, P = 0.02). Clinical variables did not predict increased eosinophils (P > 0.05). Sputum eosinophils were highest in asthmatics not using inhaled corticosteroids (6.5% vs 0.5%, P = 0.02). Sputum neutrophils were higher in subjects using inhaled corticosteroid (53% vs 25%, P = 0.04). CONCLUSION: Airway inflammation with eosinophilia was common among patients presenting to a respiratory clinic, especially those with asthma who were not using inhaled corticosteroids. Induced sputum also identified eosinophilic bronchitis in those without asthma. It was not possible to detect the presence or absence of airway eosinophilia by routine clinical assessment. The results in this study imply that the assessment of induced sputum eosinophils may be a useful guide to therapy, especially in the assessment of persistent symptoms in asthmatics on corticosteroids, and in the assessment of non-asthmatic subjects with symptoms.     

咳嗽变异性哮喘患者诱导痰中神经生长因子和白细胞介素-4水平及气道炎症特征初探

目的 通过观察咳嗽变异性哮喘(CVA)患者诱导中神经生长因子(NGF)和IL-4水平,初步探讨咳嗽变异性哮喘的气道炎症特征.方法 选咳嗽变异性哮喘患者36例及健康体检者23例,对受试者进行痰诱导,查诱导痰中细胞分类计数,酶联免疫吸附法检测诱导痰中NGF和IL-4水平.结果 (1)咳嗽变异性哮喘患者诱导痰中嗜酸性粒细胞百分数为8%,显著高于健康体检者(1%),差异有统计学意义(P＜0.001).其中13例患者应用糖皮质激素联合长效β2受体激动剂(布地奈德/福莫特罗,每吸160μg/4.5μg,2吸/d)治疗1个月后,咳嗽症状明显好转,诱导痰中嗜酸性粒细胞百分数为2%,显著低于治疗前(5%),差异有统计学意义(P＜0.05);但仍高于健康体检者.(2)咳嗽变异性哮喘患者诱导痰中NGF和IL-4浓度高于健康体检者,差异有统计学意义(P＜0.05).其中13例患者经上述治疗后诱导痰中NGF和IL-4浓度下降,差异有统计学意义(P＜0.05);但仍高于健康体检者.(3)相关性分析:诱导痰中嗜酸性粒细胞计数与诱导痰上清中NGF、IL-4浓度呈正相关(r分别为0.397、0.332,P＜0.01).诱导痰上清中NGF与IL-4浓度呈正相关(r=0.728,P＜0.01).结论 神经-免疫机制与咳嗽变异性哮喘嗜酸性粒细胞性炎症密切相关,NGF和IL-4参与并介导了这一炎症.糖皮质激素联合长效β2受体激动剂吸入治疗,能显著降低诱导痰中NGF、IL-4和嗜酸性粒细胞水平,减轻嗜酸性粒细胞性炎症.

Abstract：

Objective To observe sputum cytology counts, the levels of nerve growth factor (NGF) and IL-4 in cough variant asthma (CVA) patients and the change of their levels after using glucocorticoids combined with β2-adrenergic agonists one month, and to investigate CVA's characteristics of airway inflammation. Methods Totally 36 patients with untreated CVA were selected, as well as 23 healthy controls. Coughed up sputum cells were obtained and HE strained for differential cell counting in each enrolled patient. In induced sputum's supernatant, the levels of NGF and IL-4 were determined by ELISA.Results Before treatment, CVA patients had a median eosinophils (EOS) percentage of 8%, which was significantly higher than that after treatment (2%, P＜0.05) and in healthy control group (1%, P＜0. 001). The levels of NGF and IL-4 in induced sputum of CVA group were (9. 50 ± 1.69) ng/L and (257.37 ± 53.57) ng/L. After treatment, they were (8.78±1.02) ng/L and (228.60 ±52.93)ng/L in CVA group, (6.98±0.69) ng/L and (166.44±24.75) ng/L in healthy control group. The levels of NGF and IL-4 before and after treatment in the CVA group , as compared with the healthy control group, had statistically significant differences (all P＜0.001). In CVA group before and after treatment, the level of NGF and IL-4 paired difference was significant (P＜0.001). The percentage of induced sputum EOS correlated with sputum supernatant concentrations of NGF and IL-4 (P ＜ 0.01). In induced sputum supernatant, the concentrations of NGF and IL-4 were significant correlated (P＜0.01). Conclusions Glucocorticoid joint long-term β2 agonist inhaled treatment significantly reduced NGF, IL-4 and EOS levels and reduced eosinophilic inflammation, which are closely related with the nerve-immune mechanism, NGF as well as IL-4 participated the inflammation. Induced sputum examination is non-invasive, economical,simple, easily accepted by patients, and repeatable, widely used in clinical.     

老年人慢性咳嗽的病因构成和临床分析

目的 对老年慢性咳嗽患者采取经验性治疗联合病因诊断流程要求,分析老年人慢性咳嗽的病因及诊治效果. 方法 按照我国咳嗽指南,对52例老年慢性咳嗽患者,采取经验性治疗,效果不明确者,再采取病因诊断流程,包括肺功能、支气管舒张试验或支气管激发试验、诱导痰细胞学检查、鼻窦CT、24 h食管pH值监测等检查,进行病因判断和临床治疗. 结果 52例老年慢性咳嗽患者,明确病因76例次.老年人慢性咳嗽病因依次为咳嗽变异性哮喘(CVA)23例次(30.3％),上气道咳嗽综合征(UACS) 16例次(21.1％),胃食管反流性咳嗽(GERC)12例次(15.8％),药源性咳嗽(DC)9例次(11.8％),脑血管疾病7例次(9.2％),肺间质纤维化、嗜酸粒细胞性支气管炎(EB)、变应性咳嗽(AC)、左心功能不全各1例次(各占1.3％),病因未明4例次(5.3％).单一病因31例(59.6％),二重病因11例(21.2％)、三重病因5例(9.6％)、四重病因1例(1.9％). 结论 CVA、UACS、GERC和DC是最常见的老年人慢性咳嗽的病因,遵循我国咳嗽指南,根据常见病因采取经验性治疗与病因诊断相结合,可较好适合我国基层医院的诊疗需求.     

支气管刷检嗜酸粒细胞计数在嗜酸粒细胞性支气管炎诊断中的价值

目的探讨支气管刷检嗜酸粒细胞（EOS）计数在嗜酸粒细胞性支气管炎（EB）诊断中的价值。方法选择32例EB患者（EB组）,18例咳嗽变异性哮喘患者（CVA组）,26例其它病因咳嗽患者（其它病因组）和13名健康人（健康对照组）,分别进行诱导痰、支气管刷检洗涤液和支气管肺泡灌洗液（BALF）中EOS的检测。结果EB及CVA组各标本中EOS的比例较其它病因及健康对照组明显增高（P〈0．001）;在EB及CVA组,支气管刷检洗涤液中EOS的比例显著高于诱导痰和BALF（P均〈0．叭）;支气管刷检EOS计数诊断EB的敏感性、特异性、阳性预测值和阴性预测值分别为100％、71．9％、66．7％和100％。结论经纤支镜支气管刷检EOS计数在EB的诊断中具有较重要的价值。     

不同细胞类型咳嗽变异型哮喘的临床特征分析

目的比较不同细胞类型的咳嗽变异型哮喘患者的临床特征差别。方法选择2014年12月至2017年3月在本院咳嗽门诊就诊的慢性咳嗽患者,遵循中国慢性咳嗽指南(2015版)诊治流程,在询问病史、临床症状和获得体征的基础上,进行血常规、胸片、肺通气功能+气道反应性、诱导痰细胞学分类等相关检查,依据检查结果和治疗反应,确定病因诊断,筛选出咳嗽变异型哮喘,依据诱导痰细胞学分类计数检查结果进行分组,比较不同细胞类型的成人咳嗽变异型哮喘患者的临床特征差别。结果共收集诊断明确且病因单一的成人咳嗽变异型哮喘患者114例,占所有慢性咳嗽患者的32.95%,其中男性56例(48.7%),女性58例(51.3%)。按细胞类型分类:嗜酸性粒细胞增多型23例(20.2%),中性粒细胞增多型53例(46.5%),寡细胞型14例(12.3%),混合细胞型24例(21.1%);分组比较显示:中性粒细胞增多型年龄最长(P=0.042),而嗜酸性粒细胞增高型患者的FeNo值水平最高(P<0.001);混合细胞型患者咳嗽时间最长(P=0.012),与寡细胞型相比较,混合细胞型患者有明确体育锻炼史(P=0.007)。结论不同细胞类型的成人咳嗽变异型哮喘患者的临床特征存在较明显的差别,可以用于指导临床疾病管理。     

Cough,asthma, and cysteinyl-leukotrienes

Asthma is a chronic inflammatory disease of the lower airways, involving various cells such as eosinophils, and cytokines and mediators. Cyteinyl-leukotrienes (cys-LTs) are one of the chemical mediators that play major pathophysiological roles in asthma. They are produced by eosinophils and mast cells, and induce bronchoconstriction, mucous hypersecretion, microvascular leakage, eosinophil chemotaxis and airway remodeling. Anti-leukotrienes, including leukotriene receptor antagonists (LTRAs) which block cysLT1 receptors, exert both bronchodilatory and anti-inflammatory effects and are utilized as second- to third-line controller medication of persistent asthma.Cough is a major symptom of asthma, and cough variant asthma (CVA) is an asthma phenotype that solely presents with coughing. Sputum levels of cys-LTs are increased in patients with CVA. Antitussive effects of monotherapy with LTRAs in patients with CVA have been reported. We have recently demonstrated that 4 weeks' treatment with an LTRA montelukast exerted anti-inflammatory effect as proved by a decrease of sputum eosinophils, in addition to attenuation of cough VAS and capsaicin cough sensitivity, as reported previously. Spirometry, airway responsiveness, and impulse oscillation indices (respiratory resistance and reactance) were unchanged. These results suggested that the antitussive effect of montelukast in CVA might be attributable to its anti-inflammatory ability rather than bronchodilation. The treatment did not affect sputum levels of mediators (cys-LTs, LTB₄, PGD₂, PGE₂, PGF_2α, and TXB₂). Since inhaled corticosteroid does not seem to affect cough sensitivity while attenuating cough in patients with CVA, LTRAs may involve different mechanism(s) from that of corticosteroid.LTRAs must theoretically be effective against cough of asthmatic subjects through its “anti-asthma” effects, while evidence supporting direct antitussive effects of cys-LTs on “cough receptors” is scarce. An important clinical question is that whether LTRAs involve non-specific antitussive effects. While a definite answer is not available yet, this possibility seems unlikely at the moment, although some secondary anti-inflammatory properties have been reported for montelukast. This issue needs to be clarified by future research to avoid overuse of this expensive class of medication.     

Airway inflammation in patients with symptoms suggesting asthma but with normal lung function.

The hypothesis that eosinophilic airway inflammation is present in many patients presenting with respiratory symptoms suggestive of asthma but with normal lung function was tested. Thirty-six consecutive patients presenting with these features were studied. Twenty-five asthmatics and 43 healthy volunteers served as control groups. Signs of eosinophilic inflammation in blood and induced sputum were studied. Patients with respiratory symptoms were single-blindly treated with inhaled beclomethasone dipropionate (BDP), 800 microg daily, or placebo for 3 months, and re-examined at 3 months and 1 yr. Patients with respiratory symptoms had higher numbers of blood and sputum eosinophils than healthy persons (p<0.0001), but the degree of eosinophilic inflammation was less pronounced than in asthmatics (p<0.01). Three-month's treatment with BDP significantly reduced total symptom score (p<0.001), cough score (p<0.0001), and the number of blood eosinophils (p<0.01). For cough alone, the improvement was significant compared with placebo (p<0.05). The patients were followed-up for 1 yr, and 17 (55%) still had symptoms but retained normal lung function. Four (13%) patients had developed asthma and another 10 (32%) had become free of symptoms. Using lung function measurements and induced sputum analyses, a group of patients with symptoms suggestive of asthma and signs of eosinophilic airway inflammation but without enough airflow variability to be diagnosed as asthmatics were detected. They seemed to respond favourably to inhaled beclomethasone dipropionate treatment.     

呼吸道感染后咳嗽与咳嗽变异性哮喘痰炎症细胞和气道反应性特点及其意义

目的探讨呼吸道感染后咳嗽与咳嗽变异性哮喘患者痰炎症细胞的特点及其临床意义。方法收集呼吸道感染后咳嗽（Ⅰ组,22例）和咳嗽变异性哮喘（Ⅱ组,24例）患者痰或高渗盐水诱导痰,作瑞氏染色后细胞涂片,并在显微镜下细胞分类计数,测定其通气功能和乙酰甲胆硷吸入测定气道反应性。结果Ⅰ组和Ⅱ组痰液炎症细胞总数分别为8．22×10^9／L和8．94×10^9／L,两组比较无统计学意义（P〉0．05）;而Ⅰ组嗜酸细胞和中性粒细胞的中位数分别为0．20％、5．88％,与Ⅱ组比较,两种细胞（分别为9．62％、2．48％）的组间比较差异均有显著性（P〈0．01）。Ⅱ组的气道反应性（支气管激发试验阳性100％,其PC20为1．24g／L）明显高于Ⅰ组（支气管激发试验阳性16．7％,且其PC10较高,为4．85g／L,P〈0．01）。咳嗽变异性哮喘组痰液嗜酸细胞与气道反应性指标PC10成呈显著负相关（r=-0．56,P〈0．01）。结论呼吸道感染后咳嗽与咳嗽变异性哮喘痰炎症细胞特点不同,痰中炎症细胞检查和气道反应性测定,可作为鉴别呼吸道感染后咳嗽与咳嗽变异性哮喘的一项参考指标。     

Eosinophilic airway inflammation as an underlying mechanism of undiagnosed prolonged cough in primary healthcare patients

Prolonged cough is a common problem in patients seen in general practice. Using a simple method of sputum induction and processing of sputum samples, we determined whether eosinophilic airway inflammation could be a cause of undiagnosed prolonged cough. Eighty-two patients who had had cough for more than 1 month were enrolled into the study, in six primary healthcare centres. Patients with known pulmonary disease, including asthma or chronic obstructive pulmonary disease (COPD), or who were known to have another cause of cough, or to have recently suffered from a respiratory infection, were excluded. Fifty-three healthy individuals served as controls. Sputum was induced by inhalation of 3% saline. Inflammatory cells in smears were studied semi-quantitatively. Concentrations of eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), myeloperoxidase (MPO) and human neutrophilic lipocalin (HNL) were determined. Sputum induction proved safe and adequate samples were obtained from 91%. Sputum eosinophilia (eosinophils accounting for more than 5% of all cells in smears) was present in 14 patients with prolonged cough (19%) but in no healthy individual (P=0.001). Five of the 14 individuals (36%) who exhibited sputum eosinophilia appeared to have asthma, while nine of the 14 (64%) did not. Concentrations of ECP and EPO were higher in patients with prolonged cough than in healthy individuals (P=0.02 for ECP; 0.005 for EPO).We conclude that eosinophilic airway inflammation is a fairly common cause of prolonged cough, even in patients not suffering from asthma or COPD, or in whom no other cause of cough is known to be present. Induced sputum samples obtained in health centres can be studied in a central laboratory. Detection of eosinophilic airway inflammation could aid the decision regarding treatment.     

Bronchoalveolar lavage findings in patients with chronic nonproductive cough.

Mast cells and eosinophils may play a role in the pathophysiology of chronic cough in nonasthmatics. It is unknown, however, whether degranulation of these cells occurs in the airways of such patients. Thirty-five nonsmoking patients referred with a chronic nonproductive cough (mean cough duration 76.2 months) were evaluated using a comprehensive diagnostic protocol. Bronchoalveolar lavage (BAL) cell differentials and BAL histamine, tryptase and eosinophilic cationic protein (ECP) concentrations were determined. Ten nonsmoking healthy volunteers served as controls. Diagnostic subgroups were identified: eight postnasal drip syndrome (PNDS), seven cough variant asthma (CVA), seven gastro-esophageal reflux (GOR), seven dual aetiology and six idiopathic. Nonasthmatic coughers (NAC) were characterized as those patients without bronchial hyperresponsiveness on histamine challenge and whose cough had either responded to therapy for PNDS or GOR or failed to improve with antiasthma therapy. There was a significant increase in both eosinophil and mast cell numbers (p<0.05) and in histamine levels (p = 0.027) when NAC patients were compared with controls. Tryptase and ECP levels were elevated in 7 of 23 and 6 of 23 NAC patients, respectively. In conclusion, airway inflammatory cell numbers are not only increased but also activated, suggesting an important role for airways inflammation in the pathophysiology of chronic nonproductive cough.     

Chemotherapy for malignancy induces a remission in asthma symptoms and airway inflammation but not airway hyperresponsiveness

Inflammation with infiltrations of eosinophils and mast cells into the walls of airways is considered to increase airway hyperresponsiveness (AHR), which in turn characterizes asthma. We present a child with AHR in whom the clinical course of asthma was related to eosinophilic bronchitis. Our patient was admitted at age 6 months with bronchiolitis and at age 4 years with asthma. Inhaled corticosteroids were begun at age 7 years. At age 8 he developed a meningeal sarcoma. While on chemotherapy, his asthma symptoms resolved and he no longer required prophylactic asthma treatment. After 14 months off all chemotherapy, he again had mild episodic asthma. While receiving chemotherapy for malignancy, he had an admission with a coagulase negative staphylococcal bacteremia. During sputum induction with 4.5% saline, he developed cough, wheeze, and a 20% reduction in peak expiratory flow (220 to 180 L/min) that reversed after treatment with salbutamol. The sputum cell count was 1.7 × 10⁶/ml with 1.1 × 10⁶ being neutrophils. Two weeks later and prior to the induction of the second sputum, a 21% increase in FEV₁ was recorded after bronchodilator inhalation (82% to 99% of predicted). The second sputum contained 2.7 × 10⁶/ml cells with 1.6 × 10⁶/ml neutrophils. Neither eosinophils nor mast cells were identified in the sputum. A third sputum obtained 14 months after the cessation of chemotherapy showed a sputum cell count of 16 × 10⁶/ml, with 11.6 × 10⁶ neutrophils and 0.4 × 10⁶ eosinophils; no mast cells were detected. A reversible 15% reduction in FEV₁ was detected on hypertonic saline challenge testing. This boy had persistent airway hyperreactivity and reversible airways obstruction on three occasions during and following chemotherapy. When he developed asthma symptoms, his sputum contained neutrophils and eosinophils; while on chemotherapy his sputum did not contain eosinophils and he was symptom-free and off all asthma therapy. One can speculate that chemotherapy for malignancy can induce a remission in asthma symptoms but not AHR, and remission in symptoms is associated with a lack of eosinophilic or mast cell infiltrates in the sputum. Pediatr Pulmonol. 1998; 25:74–77. © 1998 Wiley-Liss, Inc.     

支气管哮喘患者诱导痰中基质细胞衍生因子的表达及其作用

目的 测定支气管哮喘(简称哮喘)患者在糖皮质激素(简称激素)治疗前后诱导痰中基质细胞衍生因子-1(SDF-1)和白细胞介素(IL)-17的水平,探讨SDF-1在哮喘发病机制中的作用.方法 收集2009年6月至2010年9月郑州大学第一附属医院门诊及住院的慢性持续期的哮喘患者99例(按病情严重程度分为轻、中、重度组)及健康体检者30名,哮喘患者在回答哮喘控制问卷(ACQ)后,两组研究对象分别进行肺功能检测和诱导痰检查,记录FEV1占预计值%,行诱导痰炎症细胞分类计数,酶联免疫吸附试验(ELISA)法检测诱导痰中SDF-1和IL-17水平;所有哮喘患者均参照支气管哮喘指南给予规范的吸入激素为主的治疗,4周后测定诱导痰中SDF-1、IL-17的水平及炎症细胞比率.结果 轻、中、重度持续组的ACQ评分及FEV1占预计值%差异均有统计学意义(F值分别为79.271和457.448,均P<0.01).治疗前哮喘组诱导痰嗜酸粒细胞比率、IL-17水平及SDF-1水平均高于健康对照组(均P<0.01);重度哮喘患者诱导痰中两种炎症细胞比率及SDF-1和IL-17水平均高于轻度哮喘患者(均P<0.05).哮喘患者FEV1占预计值%与诱导痰中嗜酸粒细胞、中性粒细胞比率均呈负相关(r值分别为-0.316和-0.409,均P<0.05);诱导痰中SDF-1与嗜酸粒细胞比率及中性粒细胞比率呈正相关(r值分别为0.875和0.716,均P<0.01);诱导痰中IL-17与嗜酸粒细胞及中性粒细胞比率呈正相关(r值分别为0.878和0.846,均P<0.01);诱导痰中SDF-1与IL-17水平呈正相关(r=0.872,P<0.01).治疗后哮喘患者诱导痰中两种炎症细胞比率及SDF-1和IL-17水平均低于治疗前患者(均P<0.01);治疗后未控制组哮喘患者诱导痰中性粒细胞比率、SDF-1水平和IL-17水平明显高于完全控制组(均P<0.05).结论 SDF-1和IL-17通过募集炎症细胞,特别是中性粒细胞参与了哮喘气道炎症的发生,SDF-1可作为哮喘患者临床病情判定和疗效观察的参考指标.

Abstract：

Objective To evaluate concentrations of stromal cell-derived factor 1 (SDF-1) and IL-17 in induced sputum supernatants from asthmatic patients before and after treatment with glucocorticosteroids. Methods Induced sputum was collected from 30 healthy controls and 99 patients with chronic persistent asthma from 2009-2010. Sputum samples were obtained before and after 4 week treatment with inhaled glucocorticosteroids. The sputum concentrations of SDF-1 and IL-17 were measured by ELISA. Results The FEV1% and the asthma control score of patients with severe asthma were decreased as compared with patients with moderate persistent and mild persistent asthma (F=457.448 and 79.271, all P<0.01). The concentrations of SDF-1 ,IL-17 and the percentage of eosinophils were increased in asthma group compared with control subjects (all P<0.01),but the percentage of sputum neutrophils was lower than that in the healthy controls(P<0.01). The percentage of sputum neutrophils and eosinophils and the level of SDF-1 and IL-17 in patients with severe persistent asthma were significantly higher than those in patients with mild persistent asthma (all P<0.05). The percentage of sputum neutrophils and eosinophils were negatively correlated with FEV1%(r=-0.409 and -0.316,all P<0.05). The levels of IL-17 and SDF-1 were positively correlated with the percentage of sputum neutrophils and eosinophils (all P<0.01). The levels of IL-17 were positively correlated with the levels of SDF-1(r=0.872, P<0.01).After glucocorticosteroid therapy, the percentage of eosinophils and neutrophils, the levels of IL-17 and SDF-1 decreased significantly in all patients(all P<0.01), while the percentage of sputum neutrophils and the levels of IL-17and SDF-1 in uncontrolled patients increased significantly compared with the controlled and partly controlled groups(all P<0.05). Conclusions SDF-1 and IL-17 may contribute to airway inflammation in asthma by chemotactic activity towards neutrophils. The concentration of SDF-1 may be used to evaluate the inflammation and the therapeutic effects.     

Narrative Review: how long should patients with cough variant asthma or non-asthmatic eosinophilic bronchitis be treated?

The causes of chronic cough can be categorized into eosinophilic and noneosinophilic disorders, and approximately 30% to 50% of people with chronic cough have eosinophilic airway inflammation, the presence of which can be confirmed by sputum eosinophilia or elevated exhaled nitric-oxide levels. Cough variant asthma (CVA) is a phenotype of asthma which lacks wheezing or dyspnea, and consistently one of the most common causes of chronic cough worldwide. CVA and non-asthmatic eosinophilic bronchitis (NAEB) shares common feature such as chronic dry cough, eosinophilic inflammation, and development of chronic airflow obstruction (CAO) and asthma in a subset of patients. The distinctive characteristic of these conditions is the presence of airway hyperresponsiveness in CVA but not in NAEB. Coughing is responsive to bronchodilators such as beta-agonists in CVA, but such feature has not been clarified in NAEB. Inhaled corticosteroids (ICSs) are the first-line treatment, and leukotriene receptor antagonists are also effective, in patients with both CVA and NAEB. This review will give an outline of clinical and physiological features, and prognosis and its determinants of CVA and EBNA. Further, the rationale and evidence, despite limited, for the need of long-term treatment will be discussed. The development of airway remodeling due to mechanical stress to the airways exerted by long-standing coughing will also be discussed.