Effect of montelukast in a guinea pig model of cough variant asthma

Cough variant asthma is known as a major cause of chronic cough. Fundamental features of cough variant asthma are prolonged non-productive cough responding to bronchodilator therapy, no history of wheezing or dyspnea attack, normal cough sensitivity and slightly increased bronchial responsiveness. Recently, we reported the animal model of cough variant asthma. The aim of this study was to clarify the involvement of cysteinyl leukotrienes (cysLTs) in this model by using a specific leukotriene receptor antagonist, montelukast. Cough number and specific airway resistance (sRaw) were measured during the antigen inhalation (1.5 min) and following 18.5 min, which was carried out 72 h after the first antigen inhalation in actively sensitized guinea pigs, and then total cell number and cell differentials in bronchoalveolar lavage fluid (BALF) were measured. Montelukast significantly reduced the antigen re-inhalation-induced cough, increase in sRaw, and increase in total cell number in BALF. In conclusion, cysLTs may play an important part in antigen-induced cough associated with bronchoconstriction and airway inflammation in cough variant asthma.     

白三烯与咳嗽变异性哮喘

1972年由Glauser提出咳嗽变异性哮喘(cough variantasthma,CVA),这是一种特殊类型的支气管哮喘(简称哮喘),其发病机制和病理生理学表现与典型哮喘相似,但以咳嗽为唯一或主要临床表现,无明显喘息、气促等症状或体征,有呼吸道高反应性。CVA被认为是由嗜酸粒细胞(Eos)、肥大细胞和T细胞等多种炎症细胞参与的慢性、非特异性、变     

Cough variant asthma and atopic cough

Chronic cough has been reported to be the fifth most common complaint seen by primary care physicians in the world, the third in Italy. Chronic cough in non-smoking, non-treated with ACE-inhibitor adults with normal chest radiogram could be a symptom of asthma and can be sub-classified into: cough-variant asthma, atopic cough, and eosinophilic bronchitis. This review discusses the differential diagnosis of these three disorders.     

人副流感病毒三型感染对豚鼠咳嗽敏感性的影响

目的 研究人副流感病毒3型(PIV3)感染对豚鼠咳嗽敏感性(CRS)的影响.方法 将雄性SPF级豚鼠60只按随机数字表法分成对照组、感染6 d组、感染12 d组、感染28 d组、感染42 d组和哮喘组,每组10只.病毒株为PIV3,经体外细胞培养扩增后,通过滴鼻方法接种于感染组豚鼠呼吸道;对照组接种细胞培养基;哮喘组给予卵清白蛋白致敏及诱发哮喘.辣椒素刺激后用BUXCO肺功能仪测定各组豚鼠CRS,同时测定气道高反应性(AHR),并行BALF细胞学检测及肺组织病理学观察.结果感染后6、12、28和42 d组豚鼠CRS[中位数(四分位数间距)]分别为7.50(5.25)、7.30(7.25)、8.40(9.75)和8.20(5.50)CCnt(咳嗽总次数),均高于对照组的2.50(3.00)CCnt(均P<0.05),感染后42 d组升高最明显;哮喘组CRS为3.90(1.75)CCnt,与对照组比较差异无统计学意义(P=0.18).感染后6 d组豚鼠AHR明显;感染组豚鼠BALF中炎症细胞总数均较对照组明显升高,感染6 d和12 d组淋巴细胞明显升高.病理学检查显示感染组豚鼠急性期气道炎症表现为主,未见明显的肺实质炎症.结论 PIV3感染导致豚鼠CRS在急性和亚急性咳嗽期动态增高,CRS升高可能是豚鼠病毒感染引起咳嗽的关键特征.     

Predictors for typical asthma onset from cough variant asthma.

Cough variant asthma is recognized to be a precursor of asthma or preasthmatic state because nearly 30% patients with cough variant asthma develop typical asthma within several years. However, predictors for risk of typical asthma onset from cough variant asthma are unknown. Forty-one patients with cough variant asthma (median age 50 years, 13 men and 28 women), who had undertaken spirometry, bronchial reversibility test, methacholine provocation test, measurements of peripheral blood eosinophil count, serum total IgE, and specific IgE to common allergens, and induced sputum eosinophil count at presentation, were followed up with special emphasis on typical asthma onset during 1 year or more (median 4 years, range 1-12.4). Long-term inhaled corticosteroids (ICS) were taken in 27 patients. Univariate and multivariate logistic analyses were performed to determine the predictors for typical asthma onset. Asthma onset was recognized in 7 patients. Bronchial hyperresponsiveness, peripheral blood eosinophil count, and no use of ICS were significant predictors for the typical asthma onset by univariate analysis. However, only bronchial hyperresponsiveness was the significant predictor when multivariate analysis was used (adjusted OR 0.028, 95% CI 0.001-0.783, p = 0.0355). Bronchial hyperresponsiveness may be the most important predictor for risk of typical asthma onset from cough variant asthma.     

神经生长因子与咳嗽变异性哮喘

咳嗽变异性哮喘是指以慢性咳嗽为主要或惟一临床表现的一种特殊类型的哮喘.目前发病机制尚不十分清楚.神经生长因子(nerve growth factor,NGF)是神经营养家族中成员之一.随着NGF在慢性咳嗽患者诱导痰中的发现,对NGF在咳嗽变异性哮喘发病机制中的作用引起人们的重视.研究发现,NGF是一种多功能的细胞生长和调节因子,对免疫细胞的生长、分化、激活可产生重要影响,从而参与咳嗽变异性哮喘的免疫失衡.因此,NGF是联系免疫细胞与神经细胞之间的双向信号分子.因而对NGF的研究,有助于探讨咳嗽变异性哮喘发病机制.     

Heightened cough response to bronchoconstriction in cough variant asthma

Background and objective: The pathophysiology of cough variant asthma (CVA) is poorly understood. We compared bronchoconstriction‐triggered cough between CVA patients and normal control (NC) subjects. Methods: There were two protocols in the study. We measured bronchial responsiveness to methacholine (MCh) and counted the number of coughs in nine CVA patients and seven NC subjects (Study A). Using partial and full flow–volume curves, expiratory flow of the partial flow–volume curve at 40% above residual volume level (PEF40) and FEV₁ were used to measure bronchoconstriction. Mild bronchoconstriction was defined as a 35% fall in PEF40 (PC₃₅‐PEF40), and more severe bronchoconstriction as a 20% fall in FEV₁ (PC₂₀‐FEV₁). In study B, the same measurements were obtained in six CVA patients before and after therapy. Results: In study A, more coughs were provoked at PC₃₅‐PEF40 in CVA patients (median, 60 coughs/32 min post challenge; range, 12–135) than in NC subjects (median, 0/32 min; range, 0–13; P < 0.05). At PC₂₀‐FEV₁, more coughs were provoked in CVA patients (median, 60/32 min; range, 12–150) than in NC subjects (median, 20/32 min; range, 0–54; P < 0.05). In study B, the six CVA patients who underwent re‐examination after treatment had less coughs at PC₃₅‐PEF40 (median, 3/32 min; range, 0–14) and PC₂₀‐FEV1 (median, 13/32 min; range, 3–26) after therapy than before therapy (median, 54/32 min; range, 33–125 and 52/32 min, 45–96, respectively; P < 0.05). Conclusions: We identified heightened cough response to bronchoconstriction as a feature of CVA.     

A breath sound analysis in children with cough variant asthma

Background

Cough variant asthma (CVA) is characterized by a chronic cough and bronchial hyperresponsiveness without confirmation of wheezing. Using a breath sound analyzer, we evaluate the characteristics of breath sound in children with CVA.

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。     

呼出气一氧化氮在咳嗽变异性哮喘中的应用价值

咳嗽变异性哮喘是慢性咳嗽的常见原因之一,其发病率高,发病年龄广,易被误诊为慢性支气管炎而延误治疗,进而发展为典型哮喘。近年来,呼出气一氧化氮作为一种无创、简单、及时、重复性高的炎症标志物广泛应用于临床,对于咳嗽变异性哮喘诊断、治疗以及监测管理方面具有重大意义,故本文将对呼出气一氧化氮在咳嗽变异性哮喘中的应用进行综述。     

咳嗽变异型哮喘气道反应性特点及其判定标准

目的探讨比气道传导率（sGaw）测定咳嗽变异型哮喘（CVA）的气道反应性特点及阳性判定标准,并与慢性阻塞性肺疾病（COPD）患者进行鉴别。方法对30例CVA、133例典型哮喘（BA）、37例COPD、52名正常健康人行最大呼气流量容积曲线（MEFV）、气道阻力（Raw）、气道反应性测定。结果（1）缓解期CVA患者呼气流量指标［最大呼气流量（PEF）、最大呼气中段流量（MMEF）、一秒钟用力呼气容积占用力肺活量比值（FEV1／FVC）］与健康对照组比较,差异无显著性（P＞0．05）;多数（67％）CVA患者Raw增高,sGaw下降。与BA患者比较差异无显著性（P＞0．05）。（2）以35％时吸入的乙酰甲胆碱浓度（PC35SGaw）＜8g／L为界,100％CVA、BA患者呈气道局反应性,其乙酰甲胆碱（MCH）均值为1．0g／L左右;COPD组5例阳性（13．5％）,阳性者MCH均值为5．24g／L。（3）以PC35sGaw＜4g／L为界,对CVA的敏感度判定为96．7％,特异度为97．3％,可信限为99％。（4）推出PC35sGaw计算公式,并与作图法比较结果完全吻合。结论以sGaw为气道反应性测定指标不但敏感,且有助于CVA与COPD的鉴别诊断,建议以PC35sGaw＜8g／L为气道反应性增高,而PC35sGaw＜4g／L为高度怀疑CVA。     

Airway wall thickening in patients with cough variant asthma and nonasthmatic chronic cough

BACKGROUND: Chronic cough, which may be of asthmatic or nonasthmatic origin, is an important clinical issue. Airway inflammation, and remodeling demonstrated by subbasement membrane thickening has been associated with cough variant asthma (CVA) as well as with nonasthmatic chronic cough (NAC). CT studies have shown airway wall thickening in patients with asthma who wheeze. We examined airway wall thickness by CT in adult patients with chronic cough and examined its pathophysiologic implication. METHODS: Nonsmoking, steroid-na?ve patients with CVA (n = 27), NAC (n = 26), and healthy control subjects (n = 15) were studied. Airway dimensions were assessed by a validated CT technique, in which we measured airway wall area (WA) corrected by body surface area (BSA), the ratio of WA to outer wall area (percentage of wall area [WA%]), absolute wall thickness (T)/ square root BSA, and airway luminal area/BSA of a segmental bronchus. Correlations between CT parameters and clinical indexes such as disease duration and cough sensitivity were examined. RESULTS: In patients with CVA, WA/BSA, WA%, and T/ square root BSA were all significantly greater than those in control subjects. In patients with NAC, WA/BSA and T/ square root BSA were significantly greater than in control subjects. The increase of WA/BSA and T/ square root BSA of NAC patients was less than that of CVA patients. In a subset of patients with NAC, WA% correlated with capsaicin cough sensitivity (n = 9, r = 0.75, p = 0.034). CONCLUSIONS: Walls of central airways are thickened in patients with CVA, and also to a lesser degree in patients with NAC. Airway wall thickening in NAC may be associated with cough hypersensitivity.     

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.     

The role of eosinophils, neutrophils and lymphocytes for the development of bronchial hyperresponsiveness in a guinea pig model of asthma

To elucidate the role of eosinophils, neutrophils and lymphocytes for the development of bronchial hyperresponsiveness (BHR) following antigen exposure, we have developed a guinea pig model of BHR. Guinea pigs immunized by repeated exposure to aerosolized ovalbumin (OA) were intravenously given metopirone, a cortisol synthesis inhibitor, 24 hrs before and 30 min before antigen challenge, and to prevent death from immediate severe bronchoconstriction, chlorpheniramine maleate was also injected. After antigen challenge with high dose of OA, LAR occurred in twelve of fifteen animals (80%) and the bronchial responsiveness to acetylcholine (Ach) was significantly increased. Histologic examination at 72 h showed a significant increase in the number of eosinophils but not neutrophils within the tracheal walls. However, there was no significant correlation between the change in bronchial responsiveness to Ach at 24 h and the number of eosinophil in the tracheal wall at 72 h. When guinea pigs were treated with Cyclosporin A or FK506, T-lymphocyte selective immunosuppressive agents, from the beginning of immunization period, both eosinophil infiltration and an increase in bronchial responsiveness were inhibited. These results suggest that eosinophils and T-lymphocytes may play an important role in the development of bronchial hyperresponsiveness.     

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。     

慢性干咳伴有气道高反应性即是咳嗽变异性哮喘吗？

目的评价气道反应性测定在咳嗽变异性哮喘（ＣＶＡ）诊断中的价值。方法１２４例慢性干咳患者经气道反应性测定后，分为咳嗽气道高反应阳性组（ＣＢＨ－Ｐ组）３５例，咳嗽气道高反应阴性组（ＣＢＨ－Ｎ组）３３例。观察常规肺功能、抗原皮肤点刺试验阳性率、血嗜酸性粒细胞计数、血ＩｇＥ水平、泼尼松试验阳性率并随访２年后发展成典型哮喘例数。结果３５例ＣＢＨ－Ｐ组一秒钟用力呼气容积占用力肺活量比值（ＦＥＶ１％）为７４±１０（Ｐ＜０．０１），３３例ＣＢＨ－Ｎ组为８３±１０（Ｐ＜０．０５）。抗原皮肤点刺试验阳性率ＣＢＨ－Ｐ组为５１％，ＣＢＨ－Ｎ组为１２％；血嗜酸性粒细胞计数ＣＢＨ－Ｐ组为０．５±０．１×１０９／Ｌ，ＣＢＨ－Ｎ组为０．３±０．１×１０９／Ｌ；泼尼松试验阳性率ＣＢＨ－Ｐ组为８３％，ＣＢＨ－Ｎ组为１５％。随访２年后发展成典型哮喘例数中ＣＢＨ－Ｐ组有１６例发展成典型哮喘。在ＣＢＨ－Ｐ组中发展成典型哮喘与未发展成典型哮喘患者在皮肤抗原点刺试验阳性率、常规肺功能、反应阈值（Ｄｍｉｎ）及致喘阈值（Ｄｃｗ／Ｄｍｉｎ）等方面差异均无显著性。结论气道反应性测定是诊断ＣＶＡ的重要依据，但不是唯一的诊断标准，还应结合其它临床资料综合判断