脉冲振荡检测结合分子生物检测技术对喉源性咳嗽中变异性哮喘疾病和证候诊断作用的评价
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摘要
咳嗽变异性哮喘(Cough variant asthma,CVA)又称隐匿型哮喘或咳嗽性哮喘,是哮喘的一种特殊类型,它的特殊性就在于它几乎没有任何喘息或呼吸困难症状,咳嗽可是其唯一临床表现。临床上对该病的诊断有一定困难。我们筛选了咳嗽变异性哮喘患者,通过支气管舒张试验前后检测脉冲振荡法(Impulse osillometry,IOS)、流量-容积曲线测定以及中医证型和遗传多样性的分析,希望能发现支气管扩张试验后气道反应性差异及中医证候,试图为咳嗽变异性哮喘的早期发现及治疗提供帮助。
1、脉冲振荡系统在支气管扩张试验中的应用
我们通过观察CVA组、哮喘组、干咳组、正常组在支气管扩张试验前后通气及气道反应性状况,以及嗜酸粒细胞、中医证型情况,发现CVA组在支气管扩张试验后较干咳组及健康组R_(20)Hz及R_(35)Hz降低,且组间两两比较存在极显著性差异(P＜0.01)。FEV1增加,但无临床意义(改善率＜15%)。同时咳嗽变异性哮喘组中医分型显示风邪气结型占主要类型(69.23%);嗜酸细胞测定表明嗜酸细胞增高,68.4%超过正常水平(＞5%);支气管扩张试验后R_(20)Hz及R_(35)Hz改善率均达到15%以上,而FEV1改善率不到10%;哮喘组在支气管扩张试验前后通气及气道反应性状况均明显改善(P＜0.01);干咳组在支气管扩张试验前R_(35)Hz增高,扩张后无明显改变(＞5%)。提示:脉冲振荡系统检测在扩张试验中应用可以作为咳嗽变异性哮喘初筛的客观指标之一,结合中医证型对治疗CVA具有指导意义。
2、β_2-肾上腺素能受体基因多态性研究
通过对60例受试者采用等位基因特异性聚合酶链反应法(AS-PCR)进行β2-AR基因多态性分析。结果表明:β_2-AR基因16位点多态性分布频率显示CVA组人群,精氨酸/精氨酸(Arg/Arg)基因型占5.26%,精氨酸/甘氨酸(Arg/Gly)基因型占89.48%,甘氨酸/甘氨酸(Gly/Gly)基因型占5.26%,与哮喘组及健康组比较差异无显著性意义(P＞0.05)。等位基因频率与哮喘组及健康组比较差异无显著性意义(P＞0.05)。提示:β_2-AR16位点基因多态性与CVA及哮喘未能证实存在相关性。
3、滋阴祛风法对阴虚风燥型喉源性咳嗽疗效的临床研究
选取50例阴虚风燥型喉源性咳嗽患者,分为治疗组玄麦止咳颗粒剂30例和对照组急支糖浆20例,治疗组服用试验药品玄麦止咳颗粒剂;对照组服用对照药品急支糖浆,以临床症状和肺功能气道反应性检测作为观察指标。结果表明:治疗组临床治愈率3.3%、显效率为53.3%、有效率为40%、无效率为3.4%,对照组分别为0%、5%、35%、60%,经过统计学分析治疗组显著高于对照组,主要症状干咳、咽干、咽痒、临床治愈率、显效率、有效率、无效率指标均优于对照组;治疗组能明显降低Zrs(呼吸道总阻抗)、R5(呼吸道总黏性阻力)、R20(中心气道的黏性阻力)和R35(近咽部黏性阻力),疗效优于对照组急支糖浆。提示:滋阴祛风法具有较好的止咳功效,可明显的降低上气道阻力。中医中药通过辨证施治可以在诊治CVA中发挥重要作用。
由此,我们认为IOS在扩张试验中应用可以作为咳嗽变异性哮喘初诊提供客观帮助,同时结合中医证型对治疗CVA具有指导意义,但基因多态性与CVA或哮喘的相关性以及疗效是否与基因多态性有关仍需扩大样本做进一步研究。
Asthma is one of the most common aetiologies of chronic cough. Cough-variant asthma is considered as an asthma subset. In a subgroup of asthmatics, cough may be the predominant or sole symptom. This condition is referred to as cough variant asthma (CVA). The diagnosis of CVA often presents a challenge since physical examination and spirometric tests may be normal. In this project, we examined the changes of bronchial responsiveness and FEV1 in bronchial relaxation test, type of syndrome and polymorphism of human beta2-adrenergic receptor gene in CVA patients. We try to provide more information to the new diagnosis and treatment strategy of CVA.
To observe the objective evidences diagnosing CVA, Maximal expiratory flow-volume curve function testing and impulse oscillation (IOS) testing were completed in bronchial relaxation test. FEV1 and bronchial responsiveness were analyzed in bronchial relaxation test among CVA group and health group and asthma group and non-productive cough group. Bronchial hyperresponsiveness depression and increased FEV1 were found in bronchial relaxation test in asthma group. Moreover, there are significant differences than those of three groups(P<0.01). For CVA, hyperresponsiveness of upper airway (included R20 and R35) was more significantly depressed than that of non-productive cough group and health group(P< 0.01). However, increased FEV1 doesn't clinical significance in CVA group (improvement rate < 15%). For non-productive cough group, bronchial hyperresponsiveness of upper airway wasn't changed in bronchial relaxation test. Up to 68.4% of patients with CVA have associated increased eosinophils (EOS>5%) in peripheral blood. For type of syndrome analysis, we found that the type of pathogenic wind and qi-stagnation was major type of syndrome in CVA group (69.23%). These results suggest that IOS examination in bronchial relaxation test may be regarded as one of routine measures to filtrating pute non-productive cough and CVA.
To investigate the association between 16 locus alleles ofβ2-AR genetic polymorphism and CVA, We analyzedβ02-AR genetic polymorphisms by allele specific polymerase chain reaction (AS-PCR) test among health group, asthma group and CVA group. Results showed that the frequency of genotypeβ_2 - AR 16 loci in CVA group: Arg/ Arg was5.26%, Arg/Gly was89.48%, Gly/Gly was5.26%, which was no statistical difference compared with asthma group and healthy control (P > 0.05). There was no significant difference in the allele frequency of CVA compared with asthma control and healthy control group (P > 0.05). These results suggest thatβ2-AR 16 locus genetic polymorphism is not correlated with CVA and asthma.
We studied the curative effect using method of nourishing Yin and dispelling wind in treatment of laryngeal cough (type of yin-deficiency and wind-dryness) to explore the key role of differentiation of symptoms and signs for classification of syndrome to CVA. Fifty objects who suffered from laryngeal cough were selected. Thirty in treatment group being given Xuan mai cough instant granule and twenty in control group being given J i zhi syrup. We observed the change of clinical symptoms and airway responsiveness indexes. Results showed that clinical heal rate, notable effective rate, effective rate and inefficiency rate in treatment group respectively were 3.3%, 53.3%, 40%, 3.4% and meanwhile 0%, 5%, 35% and 60% in control group. Data analysis indicated that the curative effect of treatment group significantly higher than that of control group. Leading symptoms, Clinical heal rate, notable effective rate and effective rate were all better than those in control group. Furthermore, indexes of Zrs, R5, R20 and R35 were remarkable reduced in treatment group and the efficacy was better than control group. These results suggest that the method of nourishing Yin and dispelling wind can remarkable relieve a cough. It apparently reduced bronchial hyperresponsiveness. Traditional Chinese Medicine and material medica can play the key role by determination of treatment based in pathogenesis obtained through differentiation of symptoms and signs in the diagnosis and treatment of CVA.
Our data reported here indicated that impulse oscillation (IOS) testing in bronchial relaxation test may be regarded as one of objective measures in preliminary diagnosis of CVA. Meanwhile, there is an assisting role combining type of symptom in treatment of CVA. The relation between genetic polymorphism and CVA, such as the correlation between genetic polymorphism and CVA and between genetic polymorphism and the curative in CVA, still remains to be explored after enlarging sample size.
1、脉冲振荡系统在支气管扩张试验中的应用
我们通过观察CVA组、哮喘组、干咳组、正常组在支气管扩张试验前后通气及气道反应性状况,以及嗜酸粒细胞、中医证型情况,发现CVA组在支气管扩张试验后较干咳组及健康组R_(20)Hz及R_(35)Hz降低,且组间两两比较存在极显著性差异(P＜0.01)。FEV1增加,但无临床意义(改善率＜15%)。同时咳嗽变异性哮喘组中医分型显示风邪气结型占主要类型(69.23%);嗜酸细胞测定表明嗜酸细胞增高,68.4%超过正常水平(＞5%);支气管扩张试验后R_(20)Hz及R_(35)Hz改善率均达到15%以上,而FEV1改善率不到10%;哮喘组在支气管扩张试验前后通气及气道反应性状况均明显改善(P＜0.01);干咳组在支气管扩张试验前R_(35)Hz增高,扩张后无明显改变(＞5%)。提示:脉冲振荡系统检测在扩张试验中应用可以作为咳嗽变异性哮喘初筛的客观指标之一,结合中医证型对治疗CVA具有指导意义。
2、β_2-肾上腺素能受体基因多态性研究
通过对60例受试者采用等位基因特异性聚合酶链反应法(AS-PCR)进行β2-AR基因多态性分析。结果表明:β_2-AR基因16位点多态性分布频率显示CVA组人群,精氨酸/精氨酸(Arg/Arg)基因型占5.26%,精氨酸/甘氨酸(Arg/Gly)基因型占89.48%,甘氨酸/甘氨酸(Gly/Gly)基因型占5.26%,与哮喘组及健康组比较差异无显著性意义(P＞0.05)。等位基因频率与哮喘组及健康组比较差异无显著性意义(P＞0.05)。提示:β_2-AR16位点基因多态性与CVA及哮喘未能证实存在相关性。
3、滋阴祛风法对阴虚风燥型喉源性咳嗽疗效的临床研究
选取50例阴虚风燥型喉源性咳嗽患者,分为治疗组玄麦止咳颗粒剂30例和对照组急支糖浆20例,治疗组服用试验药品玄麦止咳颗粒剂;对照组服用对照药品急支糖浆,以临床症状和肺功能气道反应性检测作为观察指标。结果表明:治疗组临床治愈率3.3%、显效率为53.3%、有效率为40%、无效率为3.4%,对照组分别为0%、5%、35%、60%,经过统计学分析治疗组显著高于对照组,主要症状干咳、咽干、咽痒、临床治愈率、显效率、有效率、无效率指标均优于对照组;治疗组能明显降低Zrs(呼吸道总阻抗)、R5(呼吸道总黏性阻力)、R20(中心气道的黏性阻力)和R35(近咽部黏性阻力),疗效优于对照组急支糖浆。提示:滋阴祛风法具有较好的止咳功效,可明显的降低上气道阻力。中医中药通过辨证施治可以在诊治CVA中发挥重要作用。
由此,我们认为IOS在扩张试验中应用可以作为咳嗽变异性哮喘初诊提供客观帮助,同时结合中医证型对治疗CVA具有指导意义,但基因多态性与CVA或哮喘的相关性以及疗效是否与基因多态性有关仍需扩大样本做进一步研究。
Asthma is one of the most common aetiologies of chronic cough. Cough-variant asthma is considered as an asthma subset. In a subgroup of asthmatics, cough may be the predominant or sole symptom. This condition is referred to as cough variant asthma (CVA). The diagnosis of CVA often presents a challenge since physical examination and spirometric tests may be normal. In this project, we examined the changes of bronchial responsiveness and FEV1 in bronchial relaxation test, type of syndrome and polymorphism of human beta2-adrenergic receptor gene in CVA patients. We try to provide more information to the new diagnosis and treatment strategy of CVA.
To observe the objective evidences diagnosing CVA, Maximal expiratory flow-volume curve function testing and impulse oscillation (IOS) testing were completed in bronchial relaxation test. FEV1 and bronchial responsiveness were analyzed in bronchial relaxation test among CVA group and health group and asthma group and non-productive cough group. Bronchial hyperresponsiveness depression and increased FEV1 were found in bronchial relaxation test in asthma group. Moreover, there are significant differences than those of three groups(P<0.01). For CVA, hyperresponsiveness of upper airway (included R20 and R35) was more significantly depressed than that of non-productive cough group and health group(P< 0.01). However, increased FEV1 doesn't clinical significance in CVA group (improvement rate < 15%). For non-productive cough group, bronchial hyperresponsiveness of upper airway wasn't changed in bronchial relaxation test. Up to 68.4% of patients with CVA have associated increased eosinophils (EOS>5%) in peripheral blood. For type of syndrome analysis, we found that the type of pathogenic wind and qi-stagnation was major type of syndrome in CVA group (69.23%). These results suggest that IOS examination in bronchial relaxation test may be regarded as one of routine measures to filtrating pute non-productive cough and CVA.
To investigate the association between 16 locus alleles ofβ2-AR genetic polymorphism and CVA, We analyzedβ02-AR genetic polymorphisms by allele specific polymerase chain reaction (AS-PCR) test among health group, asthma group and CVA group. Results showed that the frequency of genotypeβ_2 - AR 16 loci in CVA group: Arg/ Arg was5.26%, Arg/Gly was89.48%, Gly/Gly was5.26%, which was no statistical difference compared with asthma group and healthy control (P > 0.05). There was no significant difference in the allele frequency of CVA compared with asthma control and healthy control group (P > 0.05). These results suggest thatβ2-AR 16 locus genetic polymorphism is not correlated with CVA and asthma.
We studied the curative effect using method of nourishing Yin and dispelling wind in treatment of laryngeal cough (type of yin-deficiency and wind-dryness) to explore the key role of differentiation of symptoms and signs for classification of syndrome to CVA. Fifty objects who suffered from laryngeal cough were selected. Thirty in treatment group being given Xuan mai cough instant granule and twenty in control group being given J i zhi syrup. We observed the change of clinical symptoms and airway responsiveness indexes. Results showed that clinical heal rate, notable effective rate, effective rate and inefficiency rate in treatment group respectively were 3.3%, 53.3%, 40%, 3.4% and meanwhile 0%, 5%, 35% and 60% in control group. Data analysis indicated that the curative effect of treatment group significantly higher than that of control group. Leading symptoms, Clinical heal rate, notable effective rate and effective rate were all better than those in control group. Furthermore, indexes of Zrs, R5, R20 and R35 were remarkable reduced in treatment group and the efficacy was better than control group. These results suggest that the method of nourishing Yin and dispelling wind can remarkable relieve a cough. It apparently reduced bronchial hyperresponsiveness. Traditional Chinese Medicine and material medica can play the key role by determination of treatment based in pathogenesis obtained through differentiation of symptoms and signs in the diagnosis and treatment of CVA.
Our data reported here indicated that impulse oscillation (IOS) testing in bronchial relaxation test may be regarded as one of objective measures in preliminary diagnosis of CVA. Meanwhile, there is an assisting role combining type of symptom in treatment of CVA. The relation between genetic polymorphism and CVA, such as the correlation between genetic polymorphism and CVA and between genetic polymorphism and the curative in CVA, still remains to be explored after enlarging sample size.
引文
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[48]Ohe C,Alin K,Sallomn D,et al.β2AR Ban-I Genetic Polymorphism Anal-ysis in Japanese Asthma Family[J].Am J Respir Cell Mol Biol,1995,128(1):112-118.
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[50]汪谦.现代医学实验方法.第1版[M].北京:人民卫生出版社,1997.
[1]中华医学会呼吸病学分会哮喘学组.咳嗽的诊断与治疗指南(草案)[J].中华结核和呼吸杂志,2005,28:738-744.
[2]Irwin RS,Madison JM.Anatomicaldiagnostic protocol in evaluating chronic cough with specific reference to gastroesophageal reflux disease[J].Am JMed,2000,108:126s-130s.
[3]吕寒静,邱忠民,杨忠民,等.解剖学方法对慢性咳嗽病因的诊断价值[J].同济大学学报,2003,24(5):420-422.
[4]纪村传,袁彩霞.咳嗽的病因分析与治疗对策[J].实用心脑肺血管病杂志2008,16(6):54.
[5]Irwin RS,Curley FJ,French CL.Chronic colud the spectunn and frequency of muses,key components of the diagnositic evaluntion,and outcome of specific therapy[J].Am RevRespir Dis,1990,141(3):640-647.
[6]Brightling CE,Ward R,Goh KL,et al.Iosinophilic bronchitis is an important canse of chronic cough[J].Am JRespirCritCareMed,1999,160(2):406-410
[7]KbnigP.Hiddenasthmainchildhood[J].AmJDisChild,1981,135:1053-1055.
[8]DicpinigaitisPV.Chroniccoughduetoasthma:ACCPevidence-basedclinicalpracticeguid elines[J].Chest,2006,129(1Suppl):75-9.
[9]母双.咳嗽变异型哮喘[J].中国临床医生杂志,2007,35:25-26.
[10]樊东升,崔丽英;刘晓华.咳嗽变异型哮喘的研究进展[J].内蒙古医学杂志,2006,38(2):146-7.
[11]Fuji mura M,Songurn,Kamio MT,et al.Detection of eosinophils in hypertonic saline-induced sputum in patients with chronic onoproductive cough[J].J Asthma,1997,34(2):119.
[12]赵燕妮.咳嗽变异性哮喘[J].中国社区医师,2006,22(2):10.
[13]钮善福.脉冲振荡法测定肺功能的原理及其临床应用[J].医师进修杂志,2005,28(8):5-6.
[14]郑劲平.脉冲振荡肺功能技术的临床应用[J].实用医学杂志,2001,17(8):683-684.
[15]迟翔宇,张冠琴,李怀臣.咳嗽变异性哮喘患者气道病理与临床的相关性研究[J].山东大学学报(医学版),2005,43(2):121-123.
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[1]马艳良.哮喘与β2肾上腺素受体基因多态性[J].国外医学呼吸系统分册,2001,21(2):73-75.
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[3]高光凯,王士雯,张进川.β2肾上腺素能受体及其基因多态性与支气管哮喘[J].军医进修学院学报,1998,19:71-73
[4]中华医学会呼吸病学分会哮喘学组.咳嗽的诊断与治疗指南(草案)[J].中华结核和呼吸杂志,2005,28:738-744.
[5]Kobilka BK,DixonRA,FrielleT,eta.l cDNA for the humanβ2-adrenergic receptor:a pro-teinwith multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with thatof the erceptor forplatelet-derived growth factor[J].ProcNatlAcad ScUi-SA.1987;84:46-50
[6]Liggett SB,Raymond J.Pharmacology and molecular bioloby of adrenergic receptors[M].Cate-cholamines Ballieres Clincal Endocinology and Metabolism,7Edition,Ed Bouloux PM.1993:279-306
[7]Kume H,Hall IP,Washabau RJ,Takagi K,KotlikoffMI.β-adrenergic agonists regulate KCa channels in airway smoothmuscle by cAMP-dependent and independentmechanisms[J].JClin Invest,1994;93:371-379
[8]ScottMG,Swan C,Wheatley AP,Hall IP.Identification of novel polymorphisms withinthe promoter region of the humanβ2-adrenergic receptor gene[J].Br JPharmaco.1 1999;126:841-844
[9]Swan C,ScottM,Hall IP.Role of the 5'CRE and 5'UTR polymorphisms in theβ_2adrenergic receptor expression in human airway smoothmuscle[J].Am JResp CritCareMed.2000;161:A762
[10]Ligget SB.Polymorphisms of theβ2-adrenergic receptor and asthma[J].Am J Respir Crit Care Med,1997,156:156-162.
[11]高光凯.β2肾上腺能受体及其基因多态性与支气管哮喘[J].军医进修学院学报,1998,19(1):71-73.
[12]邱玉英.受体多态性与支气管哮喘[J].国外医学呼吸分册,1999,19(3):144-146.
[13]Zhaoxi Wang,Changzhong Chen,Tianhua Niu,et al.Association of asthma withβ2-adrenergic receptor gene polymorphism and cigarette smoking[J].Am J Respir Crit Care Med,2001,163:1404-1409.
[14]Elenor Summerhill,Stephanie ALeavitt,Heidi Gidley,et al.β2-adren-ergic receptor Arg16/Arg16 genetype is associated with reduced lung function,but not with asthma,in the hutterites[J].Am J Respir Crit Med,2000,162:599-602.
[15]邱玉英,殷凯生.中国人β2受体遗传多态性与哮喘关系的研究[J].中华结核和呼吸杂志,2000,23(7):435-436.
[16]高光凯,王士雯,张进川.中国北方汉族人群支气管哮喘患者β2肾上腺能受体基因多态性研究[J].中华结核和呼吸杂志,2000,23(2):93-97.
[17]MatthiasUlbrecht,MarkusThomasHerceth,MatthiasWist,et al.Assci-ation ofβ2-adrenoceptorvariants with bronchial hyperresponsiveness[J].Am J Respir Crit Care Med,2000,161:469-474.
[18]Jane C Dewar,Bmedsci,Jane Wilkinson,et al.The glutamine 27β2-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families[J].J Allergy Clin Immunol,1997,100:261-265.
[19]Ohe C,Alin K,Sallomn D,et al.β2AR Ban-Ⅰ Genetic Polymorphism Analysis in Japanese Asthma Family[J].Am J Respir Cell Mol Biol,1995,128(1):112-118.
[20]Hancox SC,Faruqi RM,Baeuerle PA,et al.Relationship between Gly16,Glu27GeneType and β2AR Pharmaceutical Therapy on Bronchial Asthma Patients[J].Allergy Asthma Proc,1998,35:463-470.
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[3]吕寒静,邱忠民,杨忠民,等.解剖学方法对慢性咳嗽病因的诊断价值[J].同济大学学报,2003,24(5):420-422.
[4]纪村传,袁彩霞.咳嗽的病因分析与治疗对策[J].实用心脑肺血管病杂志2008,16(6):54.
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[34]Kobilka BK,DixonRA,FrielleT,eta.l cDNA for the humanβ2-adrenergic receptor:a pro-teinwith multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with thatof the ereeptor forplatelet-derived growth factor[J].ProeNatlAead ScUi-SA.1987;84:46-50
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[36]Kume H,Hall IP,Washabau RJ,Takagi K,KotlikoffMI.β-adrenergic agonists regulateKCa channels in airway smoothmuscle by cAMP-dependent and independentmechanisms[J].JClin Invest,1994;93:371-379
[37]ScottMG,Swan C,Wheatley AP,Hall IP.Identification of novel polymorphisms within the promoter region of the humanβ2-adrenergic receptor gene[J].Br JPharmaco.l 1999;126:841-844
[38]Swan C,ScottM,Hall IP.Role of the 5'CRE and 5'UTR polymorphisms in theβ2adrenergic receptor expression in human airway smoothmuscle[J].Am JResp CritCareMed.2000;161:A762
[39]Ligget SB.Polymorphisms of theβ2-adrenergic receptor and asthma[J].Am J Respir Crit Care Med,1997,156:156-162.
[40]高光凯.β2肾上腺能受体及其基因多态性与支气管哮喘[J].军医进修学院学报,1998,19(1):71-73.
[41]邱玉英.受体多态性与支气管哮喘[J].国外医学呼吸分册,1999,19(3):144-146.
[42]Zhaoxi Wang,Changzhong Chen,Tianhua Niu,et al.Association of asthma withβ2-adrenergic receptor gene polymorphism and cigarette smoking[J].Am J Respir Crit Care Med,2001,163:1 404-1 409.
[43]Elenor Summerhill,Stephanie ALeavitt,Heidi Gidley,et al.β2-adren-ergic receptor Arg16/Arg16 genetype is associated with reduced lung function,but not with asthma,in the hutterites[J].Am J Respir Crit Med,2000,162:599-602.
[44]邱玉英,殷凯生.中国人β2受体遗传多态性与哮喘关系的研究[J].中华结核和呼吸杂志,2000,23(7):435-436.
[45]高光凯,王士雯,张进川.中国北方汉族人群支气管哮喘患者β2肾上腺能受体基因多态性研究[J].中华结核和呼吸杂志,2000,23(2):93-97.
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[47]Jane C Dewar,Bmedsci,Jane Wilkinson,et al.The glutamine 27β2-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families[J].J Allergy Clin Immunol,1997,100:261-265.
[48]Ohe C,Alin K,Sallomn D,et al.β2AR Ban-I Genetic Polymorphism Anal-ysis in Japanese Asthma Family[J].Am J Respir Cell Mol Biol,1995,128(1):112-118.
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[1]中华医学会呼吸病学分会哮喘学组.咳嗽的诊断与治疗指南(草案)[J].中华结核和呼吸杂志,2005,28:738-744.
[2]Irwin RS,Madison JM.Anatomicaldiagnostic protocol in evaluating chronic cough with specific reference to gastroesophageal reflux disease[J].Am JMed,2000,108:126s-130s.
[3]吕寒静,邱忠民,杨忠民,等.解剖学方法对慢性咳嗽病因的诊断价值[J].同济大学学报,2003,24(5):420-422.
[4]纪村传,袁彩霞.咳嗽的病因分析与治疗对策[J].实用心脑肺血管病杂志2008,16(6):54.
[5]Irwin RS,Curley FJ,French CL.Chronic colud the spectunn and frequency of muses,key components of the diagnositic evaluntion,and outcome of specific therapy[J].Am RevRespir Dis,1990,141(3):640-647.
[6]Brightling CE,Ward R,Goh KL,et al.Iosinophilic bronchitis is an important canse of chronic cough[J].Am JRespirCritCareMed,1999,160(2):406-410
[7]KbnigP.Hiddenasthmainchildhood[J].AmJDisChild,1981,135:1053-1055.
[8]DicpinigaitisPV.Chroniccoughduetoasthma:ACCPevidence-basedclinicalpracticeguid elines[J].Chest,2006,129(1Suppl):75-9.
[9]母双.咳嗽变异型哮喘[J].中国临床医生杂志,2007,35:25-26.
[10]樊东升,崔丽英;刘晓华.咳嗽变异型哮喘的研究进展[J].内蒙古医学杂志,2006,38(2):146-7.
[11]Fuji mura M,Songurn,Kamio MT,et al.Detection of eosinophils in hypertonic saline-induced sputum in patients with chronic onoproductive cough[J].J Asthma,1997,34(2):119.
[12]赵燕妮.咳嗽变异性哮喘[J].中国社区医师,2006,22(2):10.
[13]钮善福.脉冲振荡法测定肺功能的原理及其临床应用[J].医师进修杂志,2005,28(8):5-6.
[14]郑劲平.脉冲振荡肺功能技术的临床应用[J].实用医学杂志,2001,17(8):683-684.
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