清肺涤痰平喘法治疗台湾小儿热哮证的临床研究
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摘要
哮喘是儿童时期最常见的呼吸道慢性疾病之一。近年来世界各国哮喘的发病率均呈现逐渐上升的趋势,发达国家儿童哮喘的患病率高达10%以上。2000年我国儿童哮喘的平均患病率为1.97%,比1990年上升了64.80%。据台湾台北市研究数据显示,儿童哮喘患病率在1974年为1.30%,在1994年则为10.70%,2002年的报告已接近20%,一直呈现上升趋势,值得警惕与担忧。由于哮喘为一种反复发作性疾病,难以根治,所以严重影响患儿的身心健康,也给患儿家长带来了沉重的经济负担和精神压力。台湾哮喘患儿众多,患者多求助中医。据临床观察,由于台湾地理气候特点及患儿体质特点,小儿哮喘以热哮证居多。定喘汤是古代治疗热哮证的名方,是否可用于台湾哮喘患儿,疗效如何?本文就此做临床观察研究,并作出客观评估。
目的
本研究在温习古今文献及既往临床经验的基础上,针对小儿热哮证设计临床试验,同时应用临床试验前的数据分析以建立台湾小儿哮喘的流行病学资料。客观评价清肺涤痰平喘法治疗小儿热哮证的临床疗效；比较中医、西医、中西医结合三种治疗方案在小儿热哮证治疗中的有效性与安全性。进一步探讨疾病疗效评价方法,以为建立新的、更为客观的,且能显示中医药治疗本病优势和特色的疗效评价方法建立基础。
方法
采用区组随机、对照、部分双盲的临床研究方法,对120例确诊为热哮证的患儿,分为3组,A组(西药基础治疗加定喘汤组)30例、B组(西药基础治疗加安慰剂组)30例、C组(定喘汤组)60例,7天为1个疗程,随访不少于12周。主要的评估指标为主症积分、次症积分、热哮证证候严重程度改善情况、整体症状改善情况、西药用量、肺功能(FEV1、FVC)、呼吸道敏感度和血中IgE、组织胺及LTC4浓度变化等。同时分析上述量化指标与热哮证的相关性。比较3组的临床疗效以及其安全性。采用SPSS13.0软件对结果进行统计分析,包括t检验、卡方检验等分析。
结果
本组共观察120例患儿,均完成全部疗程,绝大多数患儿在治疗1周内见效。主症积分变化、次症积分变化、热哮证证候严重程度改善情况,3组治疗前后均有显著差异(p<0.05),治疗后优于治疗前,组间比较则A组疗效明显优于B组、C组。A组methacholine激发测试(0.51±1.05mg/ml vs.0.26±0.84mg/ml p=0.034),整体症状改善及药物减量(p=0.004),治疗后明显改善；B组、C组则未见类似变化。主症的咳嗽、咯痰痰鸣,次症的二便,热哮证证候严重程度改善,C组较B组为佳(p<0.05)。另外,虽然3组均无法显著降低血中IgE,但IgE高的患儿治疗反应比较好。
此外,我们利用进入临床试验前的数据,进一步分析发现台湾小儿热哮证约占70%,热哮证患儿肺功能显著低于非热哮证患儿(FEV1,p=0.030)；热哮证越明显,肺功能越差(FEV1vs呼吸道指标,p=0.034)；经中西医结合治疗后,热哮证明显改善(p<0.00001)；肺功能亦有改善但无统计学差异；证候指标中,黄痰组FVC改善程度显著优于非黄痰组(p=0.026)。
结论
在台湾小儿哮喘中,热哮证约占70%。热哮证患儿肺功能显著低于非热哮证者；热哮证越明显,肺功能越差；经中西医结合治疗后,热哮证明显改善；单纯中药组比单纯西药组改善热哮证若干证候的效果较好。定喘汤、西药均可有效治疗小儿热哮证,但西药加定喘汤组的中西医结合治疗疗效更佳。
Asthma is the most popular chronic disease in children and no radical treatment till now. In recently, the prevalence of children asthma is increasing, and it is even getting higer up to 10% in developing country. The prevalence of asthma in children was 1.97% in 2000, compared with an increase of 64.80% in 1990. According to research data of Taibei, Taiwan, it shows that prevalence was 1.30% in 1974, compared to 10.70% in 1994 and nearly 20% in 2002. It has shown an upward trend, and worthy of attention and concern. Because of a chronic, recurrent disease and difficult to cure disease, so asthma not only seriously affects children health, but also brought a heavy financial burden and mental stress to children parents. Traditional Chinese medicine (TCM) has a long history of application for patients in clinics. Because of the characteristics of Taiwan's geography and climate and physical characteristics of children, most of children asthma is the heat pattern. Ding Chuan Tang (DCT) is one of the formulas especially in treatment of heat pattern asthma. Is it necessarily that TCM should be based on diagnostic pattern identification? How about is the efficacy? Both problems are we concerned.
Objective
We foccused on children asthma of heat pattern for clinical trials in this study and also used the run-in period data analysis to establish the epidemiological data of asthma in children in Taiwan. We evaluate clinical effect of TCM methods objectively and to evaluate the safety of TCM methods on children's asthma of heat pattern syndrome. We further discuss the method of effect evaluation and establish a new effect evaluation method on children's asthma of heat pattern syndrome.
Methods
We design a randomized, parallel-group, multicenter clinical trial of 120 patients diagnosed as hot pattern children with asthma, divided into 3 groups, A group (Western medicine therapy plus DCT therapy group) 30 cases, B group (Western medicine therapy plus placebo group) 30 cases, C group (DCT therapy group) 60 cases.7 days for a course of treatment and follow-up is not less than 12 weeks.Chinese symptoms and signs, heat pattern severity score, self recorded daily symptom scores, medication scores, and morning and evening peak expiratory flow rates were returned during first week and the monthly clinic. Pulmonary function test, methacholine challenge test, and serum inflammatory mediators were measured before and at the end of the trial. The relationship between the above objective parameters and heat severity and patterns will be analyzed by statistics.
Results
Total 120 asthmatic children (A group 30; B group 30; C group 60) completed the clinical study. All the three groups patients achieve significant improvement on objective efficacy of major symptoms, major symptom scores, minor symptom scores, heat pattern severity (p<0.05). The combined treatment group is significantly better than the other two groups. At the end of the treatment period, airway hyper-responsiveness determined by logPC20 was significantly improved in the DCT group (0.51±1.05 mg/ml vs.0.26±0.84 mg/ml, p=0.034), however, no significant change was found in the other two group. Besides, the total clinical and medication reduced parameters showed improvement in the A group (p=0.004). About the main symptoms of cough, sputum expectoration, symptoms of stool and urine, and the heat asthma severity improvement, C group is better than the B group (p<0.05). In addition, although the three groups were not significantly lower blood IgE, but children with high IgE response to treatment is better.
In addition, we use the data before enrolled the clinical trial, and further analysis showed that heat pattern children asthma is about 70% in Taiwan. The poor pulmonary function was seen in patients of heat-pattern group than non-heat-pattern group (FEV1, p=0.030). The more heat severity was seen, the more poor pulmonary lung function was noted (FEV1 vs SC,p=0.034). After treatment, the heat severity got significant improvement (p<0.00001), and pulmonary function got improvement, too. Within all of the diagnostic parameters, yellowish phlegm is highly associated with pulmonary function (FVC, p=0.119), and the change of FVC shows significant difference (-5.97±1.87 vs.5.22±6.03% predicted, p=0.026).
Conclusion
In Taiwan Heat Pattern Children asthma is about 70%.The poor pulmonary function was seen in patients of heat-pattern group. The more heat severity was seen, the poor pulmonary lung function was noted. After treatment, the heat severity got significant improvement on all three groups. Chinese medicine only group got better improvement than western medicine only group in the heat physical effects. Both DCT and fluticasone may treat asthma, however, combined treatment group got better efficacy.
目的
本研究在温习古今文献及既往临床经验的基础上,针对小儿热哮证设计临床试验,同时应用临床试验前的数据分析以建立台湾小儿哮喘的流行病学资料。客观评价清肺涤痰平喘法治疗小儿热哮证的临床疗效；比较中医、西医、中西医结合三种治疗方案在小儿热哮证治疗中的有效性与安全性。进一步探讨疾病疗效评价方法,以为建立新的、更为客观的,且能显示中医药治疗本病优势和特色的疗效评价方法建立基础。
方法
采用区组随机、对照、部分双盲的临床研究方法,对120例确诊为热哮证的患儿,分为3组,A组(西药基础治疗加定喘汤组)30例、B组(西药基础治疗加安慰剂组)30例、C组(定喘汤组)60例,7天为1个疗程,随访不少于12周。主要的评估指标为主症积分、次症积分、热哮证证候严重程度改善情况、整体症状改善情况、西药用量、肺功能(FEV1、FVC)、呼吸道敏感度和血中IgE、组织胺及LTC4浓度变化等。同时分析上述量化指标与热哮证的相关性。比较3组的临床疗效以及其安全性。采用SPSS13.0软件对结果进行统计分析,包括t检验、卡方检验等分析。
结果
本组共观察120例患儿,均完成全部疗程,绝大多数患儿在治疗1周内见效。主症积分变化、次症积分变化、热哮证证候严重程度改善情况,3组治疗前后均有显著差异(p<0.05),治疗后优于治疗前,组间比较则A组疗效明显优于B组、C组。A组methacholine激发测试(0.51±1.05mg/ml vs.0.26±0.84mg/ml p=0.034),整体症状改善及药物减量(p=0.004),治疗后明显改善；B组、C组则未见类似变化。主症的咳嗽、咯痰痰鸣,次症的二便,热哮证证候严重程度改善,C组较B组为佳(p<0.05)。另外,虽然3组均无法显著降低血中IgE,但IgE高的患儿治疗反应比较好。
此外,我们利用进入临床试验前的数据,进一步分析发现台湾小儿热哮证约占70%,热哮证患儿肺功能显著低于非热哮证患儿(FEV1,p=0.030)；热哮证越明显,肺功能越差(FEV1vs呼吸道指标,p=0.034)；经中西医结合治疗后,热哮证明显改善(p<0.00001)；肺功能亦有改善但无统计学差异；证候指标中,黄痰组FVC改善程度显著优于非黄痰组(p=0.026)。
结论
在台湾小儿哮喘中,热哮证约占70%。热哮证患儿肺功能显著低于非热哮证者；热哮证越明显,肺功能越差；经中西医结合治疗后,热哮证明显改善；单纯中药组比单纯西药组改善热哮证若干证候的效果较好。定喘汤、西药均可有效治疗小儿热哮证,但西药加定喘汤组的中西医结合治疗疗效更佳。
Asthma is the most popular chronic disease in children and no radical treatment till now. In recently, the prevalence of children asthma is increasing, and it is even getting higer up to 10% in developing country. The prevalence of asthma in children was 1.97% in 2000, compared with an increase of 64.80% in 1990. According to research data of Taibei, Taiwan, it shows that prevalence was 1.30% in 1974, compared to 10.70% in 1994 and nearly 20% in 2002. It has shown an upward trend, and worthy of attention and concern. Because of a chronic, recurrent disease and difficult to cure disease, so asthma not only seriously affects children health, but also brought a heavy financial burden and mental stress to children parents. Traditional Chinese medicine (TCM) has a long history of application for patients in clinics. Because of the characteristics of Taiwan's geography and climate and physical characteristics of children, most of children asthma is the heat pattern. Ding Chuan Tang (DCT) is one of the formulas especially in treatment of heat pattern asthma. Is it necessarily that TCM should be based on diagnostic pattern identification? How about is the efficacy? Both problems are we concerned.
Objective
We foccused on children asthma of heat pattern for clinical trials in this study and also used the run-in period data analysis to establish the epidemiological data of asthma in children in Taiwan. We evaluate clinical effect of TCM methods objectively and to evaluate the safety of TCM methods on children's asthma of heat pattern syndrome. We further discuss the method of effect evaluation and establish a new effect evaluation method on children's asthma of heat pattern syndrome.
Methods
We design a randomized, parallel-group, multicenter clinical trial of 120 patients diagnosed as hot pattern children with asthma, divided into 3 groups, A group (Western medicine therapy plus DCT therapy group) 30 cases, B group (Western medicine therapy plus placebo group) 30 cases, C group (DCT therapy group) 60 cases.7 days for a course of treatment and follow-up is not less than 12 weeks.Chinese symptoms and signs, heat pattern severity score, self recorded daily symptom scores, medication scores, and morning and evening peak expiratory flow rates were returned during first week and the monthly clinic. Pulmonary function test, methacholine challenge test, and serum inflammatory mediators were measured before and at the end of the trial. The relationship between the above objective parameters and heat severity and patterns will be analyzed by statistics.
Results
Total 120 asthmatic children (A group 30; B group 30; C group 60) completed the clinical study. All the three groups patients achieve significant improvement on objective efficacy of major symptoms, major symptom scores, minor symptom scores, heat pattern severity (p<0.05). The combined treatment group is significantly better than the other two groups. At the end of the treatment period, airway hyper-responsiveness determined by logPC20 was significantly improved in the DCT group (0.51±1.05 mg/ml vs.0.26±0.84 mg/ml, p=0.034), however, no significant change was found in the other two group. Besides, the total clinical and medication reduced parameters showed improvement in the A group (p=0.004). About the main symptoms of cough, sputum expectoration, symptoms of stool and urine, and the heat asthma severity improvement, C group is better than the B group (p<0.05). In addition, although the three groups were not significantly lower blood IgE, but children with high IgE response to treatment is better.
In addition, we use the data before enrolled the clinical trial, and further analysis showed that heat pattern children asthma is about 70% in Taiwan. The poor pulmonary function was seen in patients of heat-pattern group than non-heat-pattern group (FEV1, p=0.030). The more heat severity was seen, the more poor pulmonary lung function was noted (FEV1 vs SC,p=0.034). After treatment, the heat severity got significant improvement (p<0.00001), and pulmonary function got improvement, too. Within all of the diagnostic parameters, yellowish phlegm is highly associated with pulmonary function (FVC, p=0.119), and the change of FVC shows significant difference (-5.97±1.87 vs.5.22±6.03% predicted, p=0.026).
Conclusion
In Taiwan Heat Pattern Children asthma is about 70%.The poor pulmonary function was seen in patients of heat-pattern group. The more heat severity was seen, the poor pulmonary lung function was noted. After treatment, the heat severity got significant improvement on all three groups. Chinese medicine only group got better improvement than western medicine only group in the heat physical effects. Both DCT and fluticasone may treat asthma, however, combined treatment group got better efficacy.
引文
[1]陈育智.中国儿童哮喘防治近况[J].中华儿科杂志,2004,42(2)：81.
[2]陈育智,陈再历,马煜,等.中国城区儿童哮喘患病率调查[J].中华儿科杂志,2003,41(2)：123-127.
[3]Hsieh KH, Shen JJ. Prevalence of childhood asthma in Taipei, Taiwan, and other Asian Pacific countries [J].J Asthma,1988,25:73-82.
[4]Kao CC, See LC, Yan DC, et al. Times trends and seasonal variations in hospital admissions for childhood asthma in Taiwan from 1990 to 1998 [J].Asian Pacific J Allergy Immunol,2001,19:63-68.
[5]Martinez FD. Maturation of immune responses at the beginning of asthma [J]. J Allergy Clin Immunol, 1999,103:355-361.
[6]Holt PG, Upham JW, Sly PD. Contemporaneous maturation of immunologic and respiratory functions during early childhood:implications for development of asthma prevention strategies [J].J Allergy Clin Immunol,2005,116:16-24.
[7]Wenzel S. Physiologic and pathologic abnormalities in severe asthma [J]. Clin Chest Med,2006, 27:29-40.
[8]Hoffjan S, Ostrovnaja I, Nicolae D, et al. Genetic variation in immunoregulatory pathways and atopic phenotypes in infancy [J].Allergy Clin Immunol,2004,113:511-518.
[9]Meyers DA, Postma DS, Stine OC, et al. Genome screen for asthma and bronchial hyperresponsiveness: interactions with passive smoke exposure [J].J Allergy Clin Immunol,2005,115:1169-1175.
[10]Heaton T,Rowe J,Turner S, et al. An immunoepidemiological approach to asthma:identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children [J].Lancet,2005, 365:142-149.
[11]Denburg JA, Sehmi R, Saito H, et al. Systemic aspects of allergic disease:bone marrow responses [J].J Allergy Clin Immunol,2000,106:S242-S246.
[12]Meiler F, Zimmermann M, Blaser K, et al. T-cell subsets in the pathogenesis of human asthma [J].Curr Allergy Asthma Rep,2006,6:91-96.
[13]Smart JM, Kemp AS. Increased Th1 and Th2 allergen-induced cytokine responses in children with atopic disease [J].Clin Exp Allergy,2002,32:796-802.
[14]Gern JE, Brooks GD, Meyer P, et al. Bidirectional interactions between viral respiratory illnesses and cytokine responses in the first year of life [J].J Allergy Clin Immunol,2006,117:72-78.
[15]Dahl ME, Dabbagh K, Liggitt D, et al. Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells [J].Nat Immunol,2004,5:337-343.
[16]Akbari O, DeKruyff RH, Umetsu DT. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen [J].Nat Immunol,2001,2:725-731.
[17]Lewkowich IP, Herman NS, Schleifer KW, et al. CD4+CD25+T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function [J].J Exp Med, 2005,202:1549-1561.
[18]Johansson SG, Bieber T, Dahl R, et al.Revised nomenclature for allergy for global use:report of the Nomenclature Review Committee of the World Allergy Organization, October 2003 [J].J Allergy Clin Immunol,2004,113:832-836.
[19]Burrows B, Martinez FD, Halonen M, et al. Association of asthma with serum IgE levels and skin-test reactivity to allergens [J].N Engl J Med,1989,320:271-277.
[20]Xepapadaki P, Papadopoulos NG, Bossios A, et al.Duration of postviral airway hyperresponsiveness in children with asthma:effect of atopy [J].J Allergy Clin Immunol,2005,116:299-304.
[21]Wark PA, Johnston SL, Bucchieri F, et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus [J].J Exp Med,2005,201:937-947.
[22]van den Toorn LM, Overbeek SE, et al. Airway inflammation is present during clinical remission of atopic asthma [J].Am J Respir Crit Care Med,2001,164:2107-2113.
[23]Bousquet J, Jeffery PK, Busse WW, et al. Asthma. From bronchoconstriction to airways inflammation and remodeling [J].Am J Respir Crit Care Med,2000,161:1720-1745.
[24]Davies DE, Wicks J, Powell RM, et al. Airway remodeling in asthma:new insights [J].J Allergy Clin Immunol,2003,111:215-225.
[25]Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma [J].N Engl J Med,2006,354:1985-1997.
[26]Barbato A, Turato G, Baraldo S, et al. Airway inflammation in childhood asthma [J].Am J Respir Crit Care Med,2003,168:798-803.
[27]Pohunek P, Warner JO, Turzikova J, et al.Markers of eosinophilic inflammation and tissue re-modelling in children before clinically diagnosed bronchial asthma [J].Pediatr Allergy Immunol,2005,16:43-51.
[28]Payne DN, Rogers AV, Adelroth E, et al. Early thickening of the reticular basement membrane in children with difficult asthma [J].Am J Respir Crit Care Med,2003,167:78-82.
[29]Cokugras H, Akcakaya N, Seckin, et al. Ultrastructural examination of bronchial biopsy specimens from children with moderate asthma [J].Thorax,2001,56:25-29.
[30]Marguet C, Jouen-Boedes F, Dean TP, et al. Bronchoalveolar cell profiles in children with asthma, infantile wheeze, chronic cough, or cystic fibrosis [J].Am J Respir Crit Care Med,1999,159:1533-1540.
[31]de Blic J, Tillie-Leblond I, Tonnel AB, et al. Difficult asthma in children:an analysis of airway inflammation [J].J Allergy Clin Immunol,2004,113:94-100.
[32]Baraldi E, Dario C, Ongaro R, et al. Exhaled nitric oxide concentrations during treatment of wheezing exacerbation in infants and young children [J].Am J Respir Crit Care Med,1999,159:1284-1288.
[33]Montgomery GL, Tepper RS. Changes in airway reactivity with age in normal infants and young children [J].Am Rev Respir Dis,1990,142:1372-1376.
[34]Gold MS, Kemp AS. Atopic disease in childhood [J].Med J Aust,2005,182:298-304.
[35]Hall CB, Wakefield D, Rowe TM, et al. Diagnosing pediatric asthma:validating the Easy Breathing Survey [J].J Pediatr,2001,139:267-272.
[36]Elphick HE, Sherlock P, Foxall G, et al. Survey of respiratory sounds in infants [J].Arch Dis Child, 2001,84:35-39.
[37]Illi S, von ME, Lau S, et al.Perennial allergen sensitisation early in life and chronic asthma in children:a birth cohort study [J].Lancet,2006,368:763-770.
[38]Castro-Rodriguez JA, Holberg CJ, Wright AL, et al. A clinical index to define risk of asthma in young children with recurrent wheezing [J].Am J Respir Crit Care Med,2000,162:1403-1406.
[39]Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood [J].N Engl J Med,2003,349:1414-1422.
[40]Nickel R, Kulig M, Forster J, et al.Sensitization to hen's egg at the age of twelve months is predictive for allergic sensitization to common indoor and outdoor allergens at the age of three years [J].J Allergy Clin Immunol,1997,99:613-617.
[41]Host A, Andrae S, Charkin S, et al. Allergy testing in children:why, who, when and how? [J].Allergy, 2003,58:559-569.
[42]Wood RA. Skin testing:making the most of every prick [J].Ann Allergy Asthma Immunol, 2002,88:347-349.
[43]Fiocchi A, Besana R, Ryden AC, et al. Differential diagnosis of IgE-mediated allergy in young children with wheezing or eczema symptoms using a single blood test [J].Ann Allergy Asthma Immunol, 2004,93:328-333
[44]Nordvall SL, Janson C, Kalm-Stephens P, et al. Exhaled nitric oxide in a population-based study of asthma and allergy in schoolchildren [J]. Allergy,2005,60:469-475
[45]Spahn JD, Chipps BE. Office-based objective measures in childhood asthma [J].J Pediatr, 2006,148:11-15.
[46]Nair SJ, Daigle KL, DeCuir P, et al. The influence of pulmonary function testing on the management of asthma in children [J].J Pediatr,2005,147:797-801.
[48]Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing [J].Eur Respir J,2005,26:153-161.
[49]Covar RA, Spahn JD, Martin RJ, et al. Safety and application of induced sputum analysis in childhood asthma [J] J Allergy Clin Immunol,2004,114:575-582.
[50]Saglani S, Nicholson AG, Scallan M, et al. Investigation of young children with severe recurrent wheeze: any clinical benefit? [J].Eur Respir J,2006,27:29-35.
[51]Gore C, Custovic A. Primary and secondary prevention of allergic airway disease [J].Paediatr Respir Rev, 2003,4:213-224.
[52]Walters EH, Walters J. Inhaled short acting beta2-agonist use in chronic asthma:regular versus as needed treatment [J].Cochrane Database Syst Rev,2003,CD001285.
[53]Sheffer AL, Silverman M, Woolcock AJ, et al. Long-term safety of once-daily budesonide in patients with early-onset mild persistent asthma:results of the Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study [J].Ann Allergy Asthma Immunol,2005,94:48-54
[54]Jonasson G, Carlsen KH, Mowinckel P. Asthma drug adherence in a long term clinical trial [J].Arch Dis Child,2000,83:330-333.
[55]Wolthers OD, Allen DB. Inhaled corticosteroids, growth, and compliance [J].N Engl J Med, 2002,347:1210-1211.
[56]Randell TL, Donaghue KC, Ambler GR, et al. Safety of the newer inhaled corticosteroids in childhood asthma [J].Paediatr Drugs,2003,5:481-504.
[57]Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma [J].N Engl J Med,2000,343:1054-1063.
[58]Sizonenko PC. Effects of inhaled or nasal glucocorticosteroids on adrenal function and growth [J] J Pediatr Endocrinol Metab,2002,15:5-26.
[59]Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial [J].Lancet,2003,361:1071-1076.
[60]Heuck C, Wolthers OD, Hansen M, et al. Short-term growth and collagen turnover in asthmatic adolescents treated with the inhaled glucocorticoid budesonide [J].Steroids,1997,62:659-664.
[61]Schou AJ, Plomgaard AM, Thomsen K, et al. Lower leg growth suppression caused by inhaled glucocorticoids is not accompanied by reduced thickness of the cutis or subcutis [J].Acta Paediatr, 2004,93:623-627.
[62]Wolthers OD. Short-term growth and adrenal function in children with asthma treated with inhaled beclomethasone dipropionate hydrofluoroalkane-134a [J].Pediatr Allergy Immunol,2006,17:613-619.
[63]Heuck C, Wolthers OD, Kollerup G, et al. Adverse effects of inhaled budesonide (800 micrograms) on growth and collagen turnover in children with asthma:a double-blind comparison of once-daily versus twice-daily administration [J].J Pediatr,1998,133:608-612.
[64]Baum WF, Schneyer U, Lantzsch AM, et al. Delay of growth and development in children with bronchial asthma, atopic dermatitis and allergic rhinitis [J].Exp Clin Endocrinol Diabetes,2002,110:53-59
[65]Norjavaara E, Gerhardsson DV, Lindmark B. Reduced height in swedish men with asthma at the age of conscription for military service [J].J Pediatr,2000,137:25-29.
[66]Sim D, Griffiths A, Armstrong D, et al. Adrenal suppression from high-dose inhaled fluticasone propionate in children with asthma [J].Eur Respir J,2003,21:633-636.
[67]Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy:A systematic review and meta-analysis [J].Arch Intern Med,1999,159:941-955.
[68]Priftis KN, Papadimitriou A, Gatsopoulou E, et al. The effect of inhaled budesonide on adrenal and growth suppression in asthmatic children [J].Eur Respir J,2006,27:316-320.
[69]Allen DB. Inhaled steroids for children:effects on growth, bone, and adrenal function [J].Endocrinol Metab Clin North Am,2005,34:555-564.
[70]Roux C, Kolta S, Desfougeres JL, et al. Long-term safety of fluticasone propionate and nedocromil sodium on bone in children with asthma [J].Pediatrics,2003,111:e706-e713
[71]Priftis KN, Papadimitriou A, Gatsopoulou E, et al. The effect of inhaled budesonide on adrenal and growth suppression in asthmatic children [J].Eur Respir J,2006,27:316-320.
[72]Van Adelsberg J, Moy J, Wei LX, et al. Safety, tolerability, and exploratory efficacy of montelukast in 6-to 24-month-old patients with asthma [J].Curr Med Res Opin,2005,21:971-979.
[73]Martinez FD. Safety of long-acting beta-agonists-an urgent need to clear the air [J].N Engl J Med, 2005,353:2637-2639.
[74]Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial:a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol [J].Chest, 2006,129:15-26.
[75]Bisgaard H, Szefler S. Long-acting beta2 agonists and paediatric asthma [J].Lancet,2006,367:286-288.
[76]Ellis EF. Theophylline toxicity [J].J Allergy Clin Immunol,1985,76:297-301.
[77]沈自尹.肾阳虚证的定位研究[J].中国中西医结合杂志,1997,17：50-52.
[78]游明谦,许清祥.过敏性疾病传统医学辨证之研究[J].中国医药学院中国医学研究所,2002,15：136.
[79]胡龙才主编.常见过敏性疾病的中医治疗[M].台北：正中书局,2001：1-16.
[80]Kao ST, Chang JD, Hisue TR, et al. The effect of Ma-Xing-Gan-Shi-Tang on Dermatophagoides pteronyssinus-induced asthmatic guinea pigs [J].Mid Taiwan Journal of Medicine,1999,4:62-68.
[81]Kao ST, Lin CS, Hsieh CC, et al. Effect of Xiao-QingLong-Tang on bronchoconstriction and airway eosinophil infiltration in ovalbumin sensitized guinea pigs in vivo and vitro studies [J].Allergy,2001, 56:1164-1171.
[82]Kao ST, Yeh TJ, Hsieh CC, et al. The effect of Ma-Xing-Gan-Shi-Tang on respiratory resistance and airway leukocyte infiltration in asthmatic guinea pigs [J].Immunopharmacology & Immunotoxicology,2001, 23:445-458.
[83]Kao ST, Yeh TJ, Hsieh CC, et al. Effect of San-Ao-Tang on immediate and late airway response and leukocyte infiltration in asthmatic guinea pigs [J].Immunopharmacology & Immunotoxicology,2000, 22:143-162.
[84]Kao ST, Wang SD, Wang JY, et al. The effect of Chinese herbal medicine, Xiao-Qing-Long-Tong (XQLT) on allergen-induced bronchial inflammation in mite-sensitized mice [J].Allergy,2000,55:1127-1133.
[85]国家中医药管理局.中医病证诊断疗效标准[M].南京：南京大学出版社,1995：77.
[86]江育仁主编：中医儿科学[M].台北：知音出版社,1994：49-51.
[87]刘彦清.加温定喘汤治疗重症哮喘36例[J].湖北中医杂志,1997,19(2)：17-19.
[88]刘永霞.化瘀定喘汤治疗高原重症哮喘60例[J].甘肃中医学院学报,1995,12(3)：14-17.
[89]李竹英,张纬,关永杰,等.定喘汤加减治疗支气管哮喘60例临床观察[J].中医药学报,1996,(6)：15-16.
[90]胥丹桂.定喘汤加减治疗小儿哮喘发作期的疗效观察[J].中国农村医学,1998,26(6)：42-44.
[91]赵风达.洪广祥运用疏利气机法治疗支气管哮喘的经验[J].中国医药学报,1993,8：31-3.
[92]崔红生,武维屏,赵燕荣,等.哮喘宁煎剂治疗支气管哮喘急性发作期的临床研究[J].北京中医药大学学报,1999,22：57-60.
[93]崔红生,杨保林,武维屏.哮病探析[J].中国医药学报,2000,15：59-62.
[94]崔红生、赵蓝才.武维屏从肝辨治支气管哮喘经验撷要[J].中国医药学报,1999,14：49-51.
[95]洪广祥.“痰瘀伏肺”是哮喘发病的夙根[J].江苏中医药,2007,39(6)：1-2.
[96]张颖,邓仁敏,施红.略论中医治疗哮喘“夙根”的思路[J].中医文献杂志,1999,3(2)：12-14.
[97]裘生梁,徐俪颖,鲁建锋.论脾虚为支气管哮喘之“宿根”[J].浙江中西医结合杂志,2009,19(3)：154-156.
[98]石亚杰,许娟.哮喘缓解期从肾论治机理探讨[J].江苏中医药.2005,26(8)：3-4.
[99]于文娟,许海生,陈利国.从哮有“夙根”谈哮病从肝论治的机理[J].时珍国医国药,2006,17(3)：445-446.
[100]壮健.试论喘有夙根[J].新中医,2000,32(6)：3-4.
[101]赵霞,苏树蓉.100例哮喘患儿体质调查及分型研究[J].成都中医药大学学报,2001,24(3)：16-17.
[102]郭奕斌,吕英,蔡浩武,等.广东肾虚型哮喘病ACE基因的遗传多态性[J].中国优生与遗传杂志2006,14(8)：20-22.
[103]许清祥,徐昀耀,李明宪.中医平喘方剂对于过敏原特异性呼吸道发炎反应的作用机转评估[J]中医药杂志,2000,11：]11-21.
[104]沈建忠,谢贵雄,谢明村,等.柴朴汤对卵蛋白过敏原诱发天竺鼠气喘之影响[J].中国医药学院杂志,1997,6：13-26.
[105]Chapman L D, Morleg J.eosinophil accumulation and airway hyperreactivity[J].Eur Respir J,1996, 9(22):133-141.
[106]陈梁,朱锦善,辜树荣,等.畅肺防喘方对哮喘模型大鼠支气管肺泡灌洗液中白细胞及嗜酸性粒细胞的影响[J].医药导报,2009,28(4)：439-440.
[107]Ziment I, Tashkin DP. Alternative medicine for allergy and asthma [J]. J Allergy Clin Immunol,2000, 106:603-614.
[108]Huntley A, Ernst E. Herbal medicines for asthma:a systematic review [J].Thorax,2000,55:925-929.
[109]Oldendick R, Coker AL, Wieland D, et al. Population-based survey of complementary and alternative medicine usage, patient satisfaction, and physician involvement:South Carolina Complementary Medicine
Program Baseline Research Team [J].South Med J,2000,93:375-381.
[110]Shopiro GG. Asthma therapy in the United States in 1996 [J].Allergology International.1997:46:1.
[111]黄璟隆,史丽珠,曹景雄,等.台湾地区医师对气喘治疗现况调查[M].台湾卫生署国民健康局,2002：20
[112]杨江,韩新民,孙轶秋,等.活血通腑法治疗儿童热性哮喘76例临床观察[J].新中医,2007,39(11)：31-33.
[113]李建保,田金娜,刘小凡.丹龙定喘丸治疗哮喘缓解期患儿63例临床观察[J].中医杂志,2007,48(5)：422-423.
[114]曹建梅,王明明,陆力生.冬病夏治中药穴位贴敷法治疗儿童哮喘缓解期临床观察[J].中医儿科杂志,2006,2(6)：33-35.
[115]蔡建新.咳喘三伏贴防治小儿哮喘临床观察[J].光明中医,2008,23(2)：143-145.
[116]王璇珠,吴前方.鱼腥草雾化吸入辅助治疗小儿支气管哮喘的疗效观察[J].河北医学,2004,10(7)：60]-603.
[117]Zou P, Gu FQ, Liao WJ. Clinical study on treating asthma of cold type with Wenyang Tonglulo mixture [J].Chung Kuo Ching His I Chieh Ho Tsa Chih,1996,16:529-532.
[118]Hsieh KH. Evaluation of efficacy of traditional Chinese medicines in the treatment of childhood bronchial asthma:clinical trial, immunological tests and animal study. Taiwan Asthma Study Group[J].Pediatr Allergy Immunol,1996,7:130-140.
[119]Bensoussan A, Talley NJ, Hing M, et al. Treatment of irritable bowel syndrome with Chinese herbal medicine:A randomized controlled trial [J]. JAMA,1998,280:1585-1589.
[120]Li XM, Huang CK, Zhang TF, et al. The Chinese herbal medicine formula MSSM-002 suppresses allergic airway hyperactivity and modulates TH1/TH2 responses in a murine model of allergic asthma [J].J Allergy Clin Immunol,2000,106:603-614.
[121]Srivastava K, Teper AA, Zhang TF, et al. Immunomodulatory effect of the antiasthma Chinese herbal medicine formula MSSM-002 on TH2 cells [J].J Allergy Clin Immunol,2004,113:268-276.
[122]梁月华,李薪萍,任红.寒证热证时中枢、内脏、尿内儿茶酚胺及5-羟色胺的变化[J].中医杂志,1991,12：38-40.
[123]朱富华,张玉堂,李敏悟.定喘汤治疗支气管哮喘30例峰速值的疗效观察[J].陕西中医,2001,22：577.
[124]沈建忠,许权维,黄璟隆,等.气喘病人服用中药前后血中ECP、IgE及T细胞变化[J].Journal of Chinese Medical Science,2002,3:53-64.
[125]简小云,黄兆祺,赖听,等.定喘汤对哮喘患者TNF-α,IL-6的影响[J].现代中西医结合杂志,2002,11：1307-1309.
[126]汪受传.儿科名医证治精华[M].上海：上海中医药大学出版社,2004：101-102.
[127]吴敏.700例哮喘儿童患病情况及中医辨证资料计算机数据库统计分析[J].上海中医药杂 志,1992,6：25。
[128]李家发,李德顺.定喘汤及其拆方化痰平喘抗炎作用实验研究[J].中国实验方剂学杂志,2002,8(5)：40-41.
[129]Chin-Kan Chan, Ming-Lin Kuo, Jiann-Jong Shen, et al. Ding Chuan Tang, a Chinese herb decoction, could improve airway hyper-responsiveness in a clinical trial[J].Pediatra Allergy Immunol,2006,17:316-322.
[130]林纯菁,郭敏玲.探讨传统中药对人类周边血球细胞细胞素表现之影响[D].长庚大学基础医学研究所,2000.
[131]中华医学会儿科学分会呼吸学组.儿童支气管哮喘防治常规(试行)[J].中华儿科杂志,2003,42(2)：101.
[132]Bethesda,MD NHLBI/WHO Workshop Report 2008. Global Strategy for Asthma Management and Prevention [M].National Institute of Health, National Heart, Lung, and Blood Institute, Publication No. 02-3659,2008.
[133]赵霞,汪受传,韩新民,等.小儿哮喘中医诊疗指南.中医儿科杂志[J],2008,4(3)：4-6.
[134]Ngoc PL, Gold DR, Tzianabos AO, et al. Cytokines, allergy, and asthma[J]. Curr Opin Allergy Clin Immunol,2005,5(2):161-166.
[135]孙雯,俞建,时毓民,等.中药槐耳调节哮喘缓解期儿童外周血单个核细胞Th1/Th2平衡的基因及蛋白水平研究[J].中华中医药杂志,2009,24(7)：915-917.
[136]刘仁慧,郭忻.培本方调节哮喘大鼠Th1/Th2失衡作用的实验研究[J].山东中医药大学学报,2008,32(5)：423-425.
[137]Davis BE, Cockcroft DW. Extrapolation of methacholine PC20 [J].Chest,2002,122:1499-1500.
[138]Chai H, Farr RS, Froehlich LA, et al. Standardization of bronchial inhalation challenge procedures [J].J Allergy Clin Immunol,1975,56:323-327.
[139]Chiappara G, Gagliardo R, Siena A, et al. Airway remodeling in the pathogenesis of asthma [J].Curr Opin Allergy Clin Immunol,2001,1:85-93.
[140]Roorda RJ, Gerritsen J, van Aalderen WM, et al.Follow-up of asthma from childhood to adulthood:influence of potential childhood risk factors on the outcome of pulmonary function and bronchial responsiveness in adulthood [J].J Allergy Clin Immunol,1994,93:575-584.
[141]Schmidt D, Rabe KF. Immune mechanisms of smooth muscle hyperreactivity in asthma [J].J. Allergy Clin Immunol,2000,105:673-682.
[142]Chedevergne F, Le Bourgeois M, de Blic J, et al. The role of inflammation in childhood asthma [J]. Arch Dis Child,2000,82 (Suppl.2):116-119.
[143]Zhou J. Comzposite recipe of Chinese medicine, the natural combination of chemicals and mechanism of multi-target action [J]. Chin J Integr Tradit West Med,1998,18:67.
[144]Lu W. Chinese herbal medicine for irritable bowel syndrome [J]. JAMA,1999,282:1035-1037.
[145]Chen KK, Schmidt CE. The action of ephedrine:the active principle of the Chinese drug Ma Huang [J]. J Pharmacol Exp Ther,1924,24:339-342.
[146]Li MH, Zhang H, Yang B. Effects of Ginkgo leaf concentrated oral liquor in treating asthma [J]. Chung Kuo Ching Hsi I Chieh Ho Tsa Chih,1997,17:216-218.
[147]Li MH, Liu YH, Yang BY. Clinical observation on treatment of asthma in moderate degree with fluticasone inhalation combined with jinacon [J]. Chung Kuo Ching Hsi I Chieh Ho Tsa Chih,2001,21: 819-821.
[148]Ni J, Dong J, Wu G. Experimental study on effect of antagonizing platelet-activating factor and histamine of synthetic Ginkgolide F in guinea pigs [J]. Zhongguo Zhong Xi Yi Jie He Za Zhi,2000, 20:365-367.
[149]Makino T, Furuta Y, Wakushima H, et al. Anti-allergic effect of Perilla frutescens and its active constituents [J]. Phytother Res,2003,17:240-243.
[150]Simons FE, Villa JR, Lee BW, et al. Montelukast added to budesonide in children with persistent asthma: a randomized, double-blind, crossover study [J]. J Pediatr,2001,:138:694-698.
[151]Huang JL, Wang SY, Hsieh KH. Effect of short-term exposure to low levels of SO2 and NOx on pulmonary function and methacholine and allergen bronchial sensitivities in asthmatic children [J]. Arch Environ Health,1991,46:296-299.
[152]Hsieh KH. Evaluation of efficacy of traditional Chinese medicines in the treatment of childhood bronchial asthma:clinical trial, immunological tests and animal study. Taiwan asthma study group [J]. Pediatr Allergy Immunol,1996,7:130-140.
[153]宋立人总编.中华本草[M].上海：上海科学技术出版社,1999.
[154]周钊鹤,赵霞.小儿哮喘与体质的关系探讨[J].山东中医药大学学报,2009,,3(2)：113-114.
[155]中华医学会呼吸病学分会哮喘学组.支气管哮喘防治指南(支气管哮喘的定义、诊断、治疗和管理方案)[J].中华哮喘杂志(电子版),2008,2(1)：3-13.
[2]陈育智,陈再历,马煜,等.中国城区儿童哮喘患病率调查[J].中华儿科杂志,2003,41(2)：123-127.
[3]Hsieh KH, Shen JJ. Prevalence of childhood asthma in Taipei, Taiwan, and other Asian Pacific countries [J].J Asthma,1988,25:73-82.
[4]Kao CC, See LC, Yan DC, et al. Times trends and seasonal variations in hospital admissions for childhood asthma in Taiwan from 1990 to 1998 [J].Asian Pacific J Allergy Immunol,2001,19:63-68.
[5]Martinez FD. Maturation of immune responses at the beginning of asthma [J]. J Allergy Clin Immunol, 1999,103:355-361.
[6]Holt PG, Upham JW, Sly PD. Contemporaneous maturation of immunologic and respiratory functions during early childhood:implications for development of asthma prevention strategies [J].J Allergy Clin Immunol,2005,116:16-24.
[7]Wenzel S. Physiologic and pathologic abnormalities in severe asthma [J]. Clin Chest Med,2006, 27:29-40.
[8]Hoffjan S, Ostrovnaja I, Nicolae D, et al. Genetic variation in immunoregulatory pathways and atopic phenotypes in infancy [J].Allergy Clin Immunol,2004,113:511-518.
[9]Meyers DA, Postma DS, Stine OC, et al. Genome screen for asthma and bronchial hyperresponsiveness: interactions with passive smoke exposure [J].J Allergy Clin Immunol,2005,115:1169-1175.
[10]Heaton T,Rowe J,Turner S, et al. An immunoepidemiological approach to asthma:identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children [J].Lancet,2005, 365:142-149.
[11]Denburg JA, Sehmi R, Saito H, et al. Systemic aspects of allergic disease:bone marrow responses [J].J Allergy Clin Immunol,2000,106:S242-S246.
[12]Meiler F, Zimmermann M, Blaser K, et al. T-cell subsets in the pathogenesis of human asthma [J].Curr Allergy Asthma Rep,2006,6:91-96.
[13]Smart JM, Kemp AS. Increased Th1 and Th2 allergen-induced cytokine responses in children with atopic disease [J].Clin Exp Allergy,2002,32:796-802.
[14]Gern JE, Brooks GD, Meyer P, et al. Bidirectional interactions between viral respiratory illnesses and cytokine responses in the first year of life [J].J Allergy Clin Immunol,2006,117:72-78.
[15]Dahl ME, Dabbagh K, Liggitt D, et al. Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells [J].Nat Immunol,2004,5:337-343.
[16]Akbari O, DeKruyff RH, Umetsu DT. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen [J].Nat Immunol,2001,2:725-731.
[17]Lewkowich IP, Herman NS, Schleifer KW, et al. CD4+CD25+T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function [J].J Exp Med, 2005,202:1549-1561.
[18]Johansson SG, Bieber T, Dahl R, et al.Revised nomenclature for allergy for global use:report of the Nomenclature Review Committee of the World Allergy Organization, October 2003 [J].J Allergy Clin Immunol,2004,113:832-836.
[19]Burrows B, Martinez FD, Halonen M, et al. Association of asthma with serum IgE levels and skin-test reactivity to allergens [J].N Engl J Med,1989,320:271-277.
[20]Xepapadaki P, Papadopoulos NG, Bossios A, et al.Duration of postviral airway hyperresponsiveness in children with asthma:effect of atopy [J].J Allergy Clin Immunol,2005,116:299-304.
[21]Wark PA, Johnston SL, Bucchieri F, et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus [J].J Exp Med,2005,201:937-947.
[22]van den Toorn LM, Overbeek SE, et al. Airway inflammation is present during clinical remission of atopic asthma [J].Am J Respir Crit Care Med,2001,164:2107-2113.
[23]Bousquet J, Jeffery PK, Busse WW, et al. Asthma. From bronchoconstriction to airways inflammation and remodeling [J].Am J Respir Crit Care Med,2000,161:1720-1745.
[24]Davies DE, Wicks J, Powell RM, et al. Airway remodeling in asthma:new insights [J].J Allergy Clin Immunol,2003,111:215-225.
[25]Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma [J].N Engl J Med,2006,354:1985-1997.
[26]Barbato A, Turato G, Baraldo S, et al. Airway inflammation in childhood asthma [J].Am J Respir Crit Care Med,2003,168:798-803.
[27]Pohunek P, Warner JO, Turzikova J, et al.Markers of eosinophilic inflammation and tissue re-modelling in children before clinically diagnosed bronchial asthma [J].Pediatr Allergy Immunol,2005,16:43-51.
[28]Payne DN, Rogers AV, Adelroth E, et al. Early thickening of the reticular basement membrane in children with difficult asthma [J].Am J Respir Crit Care Med,2003,167:78-82.
[29]Cokugras H, Akcakaya N, Seckin, et al. Ultrastructural examination of bronchial biopsy specimens from children with moderate asthma [J].Thorax,2001,56:25-29.
[30]Marguet C, Jouen-Boedes F, Dean TP, et al. Bronchoalveolar cell profiles in children with asthma, infantile wheeze, chronic cough, or cystic fibrosis [J].Am J Respir Crit Care Med,1999,159:1533-1540.
[31]de Blic J, Tillie-Leblond I, Tonnel AB, et al. Difficult asthma in children:an analysis of airway inflammation [J].J Allergy Clin Immunol,2004,113:94-100.
[32]Baraldi E, Dario C, Ongaro R, et al. Exhaled nitric oxide concentrations during treatment of wheezing exacerbation in infants and young children [J].Am J Respir Crit Care Med,1999,159:1284-1288.
[33]Montgomery GL, Tepper RS. Changes in airway reactivity with age in normal infants and young children [J].Am Rev Respir Dis,1990,142:1372-1376.
[34]Gold MS, Kemp AS. Atopic disease in childhood [J].Med J Aust,2005,182:298-304.
[35]Hall CB, Wakefield D, Rowe TM, et al. Diagnosing pediatric asthma:validating the Easy Breathing Survey [J].J Pediatr,2001,139:267-272.
[36]Elphick HE, Sherlock P, Foxall G, et al. Survey of respiratory sounds in infants [J].Arch Dis Child, 2001,84:35-39.
[37]Illi S, von ME, Lau S, et al.Perennial allergen sensitisation early in life and chronic asthma in children:a birth cohort study [J].Lancet,2006,368:763-770.
[38]Castro-Rodriguez JA, Holberg CJ, Wright AL, et al. A clinical index to define risk of asthma in young children with recurrent wheezing [J].Am J Respir Crit Care Med,2000,162:1403-1406.
[39]Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood [J].N Engl J Med,2003,349:1414-1422.
[40]Nickel R, Kulig M, Forster J, et al.Sensitization to hen's egg at the age of twelve months is predictive for allergic sensitization to common indoor and outdoor allergens at the age of three years [J].J Allergy Clin Immunol,1997,99:613-617.
[41]Host A, Andrae S, Charkin S, et al. Allergy testing in children:why, who, when and how? [J].Allergy, 2003,58:559-569.
[42]Wood RA. Skin testing:making the most of every prick [J].Ann Allergy Asthma Immunol, 2002,88:347-349.
[43]Fiocchi A, Besana R, Ryden AC, et al. Differential diagnosis of IgE-mediated allergy in young children with wheezing or eczema symptoms using a single blood test [J].Ann Allergy Asthma Immunol, 2004,93:328-333
[44]Nordvall SL, Janson C, Kalm-Stephens P, et al. Exhaled nitric oxide in a population-based study of asthma and allergy in schoolchildren [J]. Allergy,2005,60:469-475
[45]Spahn JD, Chipps BE. Office-based objective measures in childhood asthma [J].J Pediatr, 2006,148:11-15.
[46]Nair SJ, Daigle KL, DeCuir P, et al. The influence of pulmonary function testing on the management of asthma in children [J].J Pediatr,2005,147:797-801.
[48]Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing [J].Eur Respir J,2005,26:153-161.
[49]Covar RA, Spahn JD, Martin RJ, et al. Safety and application of induced sputum analysis in childhood asthma [J] J Allergy Clin Immunol,2004,114:575-582.
[50]Saglani S, Nicholson AG, Scallan M, et al. Investigation of young children with severe recurrent wheeze: any clinical benefit? [J].Eur Respir J,2006,27:29-35.
[51]Gore C, Custovic A. Primary and secondary prevention of allergic airway disease [J].Paediatr Respir Rev, 2003,4:213-224.
[52]Walters EH, Walters J. Inhaled short acting beta2-agonist use in chronic asthma:regular versus as needed treatment [J].Cochrane Database Syst Rev,2003,CD001285.
[53]Sheffer AL, Silverman M, Woolcock AJ, et al. Long-term safety of once-daily budesonide in patients with early-onset mild persistent asthma:results of the Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study [J].Ann Allergy Asthma Immunol,2005,94:48-54
[54]Jonasson G, Carlsen KH, Mowinckel P. Asthma drug adherence in a long term clinical trial [J].Arch Dis Child,2000,83:330-333.
[55]Wolthers OD, Allen DB. Inhaled corticosteroids, growth, and compliance [J].N Engl J Med, 2002,347:1210-1211.
[56]Randell TL, Donaghue KC, Ambler GR, et al. Safety of the newer inhaled corticosteroids in childhood asthma [J].Paediatr Drugs,2003,5:481-504.
[57]Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma [J].N Engl J Med,2000,343:1054-1063.
[58]Sizonenko PC. Effects of inhaled or nasal glucocorticosteroids on adrenal function and growth [J] J Pediatr Endocrinol Metab,2002,15:5-26.
[59]Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial [J].Lancet,2003,361:1071-1076.
[60]Heuck C, Wolthers OD, Hansen M, et al. Short-term growth and collagen turnover in asthmatic adolescents treated with the inhaled glucocorticoid budesonide [J].Steroids,1997,62:659-664.
[61]Schou AJ, Plomgaard AM, Thomsen K, et al. Lower leg growth suppression caused by inhaled glucocorticoids is not accompanied by reduced thickness of the cutis or subcutis [J].Acta Paediatr, 2004,93:623-627.
[62]Wolthers OD. Short-term growth and adrenal function in children with asthma treated with inhaled beclomethasone dipropionate hydrofluoroalkane-134a [J].Pediatr Allergy Immunol,2006,17:613-619.
[63]Heuck C, Wolthers OD, Kollerup G, et al. Adverse effects of inhaled budesonide (800 micrograms) on growth and collagen turnover in children with asthma:a double-blind comparison of once-daily versus twice-daily administration [J].J Pediatr,1998,133:608-612.
[64]Baum WF, Schneyer U, Lantzsch AM, et al. Delay of growth and development in children with bronchial asthma, atopic dermatitis and allergic rhinitis [J].Exp Clin Endocrinol Diabetes,2002,110:53-59
[65]Norjavaara E, Gerhardsson DV, Lindmark B. Reduced height in swedish men with asthma at the age of conscription for military service [J].J Pediatr,2000,137:25-29.
[66]Sim D, Griffiths A, Armstrong D, et al. Adrenal suppression from high-dose inhaled fluticasone propionate in children with asthma [J].Eur Respir J,2003,21:633-636.
[67]Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy:A systematic review and meta-analysis [J].Arch Intern Med,1999,159:941-955.
[68]Priftis KN, Papadimitriou A, Gatsopoulou E, et al. The effect of inhaled budesonide on adrenal and growth suppression in asthmatic children [J].Eur Respir J,2006,27:316-320.
[69]Allen DB. Inhaled steroids for children:effects on growth, bone, and adrenal function [J].Endocrinol Metab Clin North Am,2005,34:555-564.
[70]Roux C, Kolta S, Desfougeres JL, et al. Long-term safety of fluticasone propionate and nedocromil sodium on bone in children with asthma [J].Pediatrics,2003,111:e706-e713
[71]Priftis KN, Papadimitriou A, Gatsopoulou E, et al. The effect of inhaled budesonide on adrenal and growth suppression in asthmatic children [J].Eur Respir J,2006,27:316-320.
[72]Van Adelsberg J, Moy J, Wei LX, et al. Safety, tolerability, and exploratory efficacy of montelukast in 6-to 24-month-old patients with asthma [J].Curr Med Res Opin,2005,21:971-979.
[73]Martinez FD. Safety of long-acting beta-agonists-an urgent need to clear the air [J].N Engl J Med, 2005,353:2637-2639.
[74]Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial:a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol [J].Chest, 2006,129:15-26.
[75]Bisgaard H, Szefler S. Long-acting beta2 agonists and paediatric asthma [J].Lancet,2006,367:286-288.
[76]Ellis EF. Theophylline toxicity [J].J Allergy Clin Immunol,1985,76:297-301.
[77]沈自尹.肾阳虚证的定位研究[J].中国中西医结合杂志,1997,17：50-52.
[78]游明谦,许清祥.过敏性疾病传统医学辨证之研究[J].中国医药学院中国医学研究所,2002,15：136.
[79]胡龙才主编.常见过敏性疾病的中医治疗[M].台北：正中书局,2001：1-16.
[80]Kao ST, Chang JD, Hisue TR, et al. The effect of Ma-Xing-Gan-Shi-Tang on Dermatophagoides pteronyssinus-induced asthmatic guinea pigs [J].Mid Taiwan Journal of Medicine,1999,4:62-68.
[81]Kao ST, Lin CS, Hsieh CC, et al. Effect of Xiao-QingLong-Tang on bronchoconstriction and airway eosinophil infiltration in ovalbumin sensitized guinea pigs in vivo and vitro studies [J].Allergy,2001, 56:1164-1171.
[82]Kao ST, Yeh TJ, Hsieh CC, et al. The effect of Ma-Xing-Gan-Shi-Tang on respiratory resistance and airway leukocyte infiltration in asthmatic guinea pigs [J].Immunopharmacology & Immunotoxicology,2001, 23:445-458.
[83]Kao ST, Yeh TJ, Hsieh CC, et al. Effect of San-Ao-Tang on immediate and late airway response and leukocyte infiltration in asthmatic guinea pigs [J].Immunopharmacology & Immunotoxicology,2000, 22:143-162.
[84]Kao ST, Wang SD, Wang JY, et al. The effect of Chinese herbal medicine, Xiao-Qing-Long-Tong (XQLT) on allergen-induced bronchial inflammation in mite-sensitized mice [J].Allergy,2000,55:1127-1133.
[85]国家中医药管理局.中医病证诊断疗效标准[M].南京：南京大学出版社,1995：77.
[86]江育仁主编：中医儿科学[M].台北：知音出版社,1994：49-51.
[87]刘彦清.加温定喘汤治疗重症哮喘36例[J].湖北中医杂志,1997,19(2)：17-19.
[88]刘永霞.化瘀定喘汤治疗高原重症哮喘60例[J].甘肃中医学院学报,1995,12(3)：14-17.
[89]李竹英,张纬,关永杰,等.定喘汤加减治疗支气管哮喘60例临床观察[J].中医药学报,1996,(6)：15-16.
[90]胥丹桂.定喘汤加减治疗小儿哮喘发作期的疗效观察[J].中国农村医学,1998,26(6)：42-44.
[91]赵风达.洪广祥运用疏利气机法治疗支气管哮喘的经验[J].中国医药学报,1993,8：31-3.
[92]崔红生,武维屏,赵燕荣,等.哮喘宁煎剂治疗支气管哮喘急性发作期的临床研究[J].北京中医药大学学报,1999,22：57-60.
[93]崔红生,杨保林,武维屏.哮病探析[J].中国医药学报,2000,15：59-62.
[94]崔红生、赵蓝才.武维屏从肝辨治支气管哮喘经验撷要[J].中国医药学报,1999,14：49-51.
[95]洪广祥.“痰瘀伏肺”是哮喘发病的夙根[J].江苏中医药,2007,39(6)：1-2.
[96]张颖,邓仁敏,施红.略论中医治疗哮喘“夙根”的思路[J].中医文献杂志,1999,3(2)：12-14.
[97]裘生梁,徐俪颖,鲁建锋.论脾虚为支气管哮喘之“宿根”[J].浙江中西医结合杂志,2009,19(3)：154-156.
[98]石亚杰,许娟.哮喘缓解期从肾论治机理探讨[J].江苏中医药.2005,26(8)：3-4.
[99]于文娟,许海生,陈利国.从哮有“夙根”谈哮病从肝论治的机理[J].时珍国医国药,2006,17(3)：445-446.
[100]壮健.试论喘有夙根[J].新中医,2000,32(6)：3-4.
[101]赵霞,苏树蓉.100例哮喘患儿体质调查及分型研究[J].成都中医药大学学报,2001,24(3)：16-17.
[102]郭奕斌,吕英,蔡浩武,等.广东肾虚型哮喘病ACE基因的遗传多态性[J].中国优生与遗传杂志2006,14(8)：20-22.
[103]许清祥,徐昀耀,李明宪.中医平喘方剂对于过敏原特异性呼吸道发炎反应的作用机转评估[J]中医药杂志,2000,11：]11-21.
[104]沈建忠,谢贵雄,谢明村,等.柴朴汤对卵蛋白过敏原诱发天竺鼠气喘之影响[J].中国医药学院杂志,1997,6：13-26.
[105]Chapman L D, Morleg J.eosinophil accumulation and airway hyperreactivity[J].Eur Respir J,1996, 9(22):133-141.
[106]陈梁,朱锦善,辜树荣,等.畅肺防喘方对哮喘模型大鼠支气管肺泡灌洗液中白细胞及嗜酸性粒细胞的影响[J].医药导报,2009,28(4)：439-440.
[107]Ziment I, Tashkin DP. Alternative medicine for allergy and asthma [J]. J Allergy Clin Immunol,2000, 106:603-614.
[108]Huntley A, Ernst E. Herbal medicines for asthma:a systematic review [J].Thorax,2000,55:925-929.
[109]Oldendick R, Coker AL, Wieland D, et al. Population-based survey of complementary and alternative medicine usage, patient satisfaction, and physician involvement:South Carolina Complementary Medicine
Program Baseline Research Team [J].South Med J,2000,93:375-381.
[110]Shopiro GG. Asthma therapy in the United States in 1996 [J].Allergology International.1997:46:1.
[111]黄璟隆,史丽珠,曹景雄,等.台湾地区医师对气喘治疗现况调查[M].台湾卫生署国民健康局,2002：20
[112]杨江,韩新民,孙轶秋,等.活血通腑法治疗儿童热性哮喘76例临床观察[J].新中医,2007,39(11)：31-33.
[113]李建保,田金娜,刘小凡.丹龙定喘丸治疗哮喘缓解期患儿63例临床观察[J].中医杂志,2007,48(5)：422-423.
[114]曹建梅,王明明,陆力生.冬病夏治中药穴位贴敷法治疗儿童哮喘缓解期临床观察[J].中医儿科杂志,2006,2(6)：33-35.
[115]蔡建新.咳喘三伏贴防治小儿哮喘临床观察[J].光明中医,2008,23(2)：143-145.
[116]王璇珠,吴前方.鱼腥草雾化吸入辅助治疗小儿支气管哮喘的疗效观察[J].河北医学,2004,10(7)：60]-603.
[117]Zou P, Gu FQ, Liao WJ. Clinical study on treating asthma of cold type with Wenyang Tonglulo mixture [J].Chung Kuo Ching His I Chieh Ho Tsa Chih,1996,16:529-532.
[118]Hsieh KH. Evaluation of efficacy of traditional Chinese medicines in the treatment of childhood bronchial asthma:clinical trial, immunological tests and animal study. Taiwan Asthma Study Group[J].Pediatr Allergy Immunol,1996,7:130-140.
[119]Bensoussan A, Talley NJ, Hing M, et al. Treatment of irritable bowel syndrome with Chinese herbal medicine:A randomized controlled trial [J]. JAMA,1998,280:1585-1589.
[120]Li XM, Huang CK, Zhang TF, et al. The Chinese herbal medicine formula MSSM-002 suppresses allergic airway hyperactivity and modulates TH1/TH2 responses in a murine model of allergic asthma [J].J Allergy Clin Immunol,2000,106:603-614.
[121]Srivastava K, Teper AA, Zhang TF, et al. Immunomodulatory effect of the antiasthma Chinese herbal medicine formula MSSM-002 on TH2 cells [J].J Allergy Clin Immunol,2004,113:268-276.
[122]梁月华,李薪萍,任红.寒证热证时中枢、内脏、尿内儿茶酚胺及5-羟色胺的变化[J].中医杂志,1991,12：38-40.
[123]朱富华,张玉堂,李敏悟.定喘汤治疗支气管哮喘30例峰速值的疗效观察[J].陕西中医,2001,22：577.
[124]沈建忠,许权维,黄璟隆,等.气喘病人服用中药前后血中ECP、IgE及T细胞变化[J].Journal of Chinese Medical Science,2002,3:53-64.
[125]简小云,黄兆祺,赖听,等.定喘汤对哮喘患者TNF-α,IL-6的影响[J].现代中西医结合杂志,2002,11：1307-1309.
[126]汪受传.儿科名医证治精华[M].上海：上海中医药大学出版社,2004：101-102.
[127]吴敏.700例哮喘儿童患病情况及中医辨证资料计算机数据库统计分析[J].上海中医药杂 志,1992,6：25。
[128]李家发,李德顺.定喘汤及其拆方化痰平喘抗炎作用实验研究[J].中国实验方剂学杂志,2002,8(5)：40-41.
[129]Chin-Kan Chan, Ming-Lin Kuo, Jiann-Jong Shen, et al. Ding Chuan Tang, a Chinese herb decoction, could improve airway hyper-responsiveness in a clinical trial[J].Pediatra Allergy Immunol,2006,17:316-322.
[130]林纯菁,郭敏玲.探讨传统中药对人类周边血球细胞细胞素表现之影响[D].长庚大学基础医学研究所,2000.
[131]中华医学会儿科学分会呼吸学组.儿童支气管哮喘防治常规(试行)[J].中华儿科杂志,2003,42(2)：101.
[132]Bethesda,MD NHLBI/WHO Workshop Report 2008. Global Strategy for Asthma Management and Prevention [M].National Institute of Health, National Heart, Lung, and Blood Institute, Publication No. 02-3659,2008.
[133]赵霞,汪受传,韩新民,等.小儿哮喘中医诊疗指南.中医儿科杂志[J],2008,4(3)：4-6.
[134]Ngoc PL, Gold DR, Tzianabos AO, et al. Cytokines, allergy, and asthma[J]. Curr Opin Allergy Clin Immunol,2005,5(2):161-166.
[135]孙雯,俞建,时毓民,等.中药槐耳调节哮喘缓解期儿童外周血单个核细胞Th1/Th2平衡的基因及蛋白水平研究[J].中华中医药杂志,2009,24(7)：915-917.
[136]刘仁慧,郭忻.培本方调节哮喘大鼠Th1/Th2失衡作用的实验研究[J].山东中医药大学学报,2008,32(5)：423-425.
[137]Davis BE, Cockcroft DW. Extrapolation of methacholine PC20 [J].Chest,2002,122:1499-1500.
[138]Chai H, Farr RS, Froehlich LA, et al. Standardization of bronchial inhalation challenge procedures [J].J Allergy Clin Immunol,1975,56:323-327.
[139]Chiappara G, Gagliardo R, Siena A, et al. Airway remodeling in the pathogenesis of asthma [J].Curr Opin Allergy Clin Immunol,2001,1:85-93.
[140]Roorda RJ, Gerritsen J, van Aalderen WM, et al.Follow-up of asthma from childhood to adulthood:influence of potential childhood risk factors on the outcome of pulmonary function and bronchial responsiveness in adulthood [J].J Allergy Clin Immunol,1994,93:575-584.
[141]Schmidt D, Rabe KF. Immune mechanisms of smooth muscle hyperreactivity in asthma [J].J. Allergy Clin Immunol,2000,105:673-682.
[142]Chedevergne F, Le Bourgeois M, de Blic J, et al. The role of inflammation in childhood asthma [J]. Arch Dis Child,2000,82 (Suppl.2):116-119.
[143]Zhou J. Comzposite recipe of Chinese medicine, the natural combination of chemicals and mechanism of multi-target action [J]. Chin J Integr Tradit West Med,1998,18:67.
[144]Lu W. Chinese herbal medicine for irritable bowel syndrome [J]. JAMA,1999,282:1035-1037.
[145]Chen KK, Schmidt CE. The action of ephedrine:the active principle of the Chinese drug Ma Huang [J]. J Pharmacol Exp Ther,1924,24:339-342.
[146]Li MH, Zhang H, Yang B. Effects of Ginkgo leaf concentrated oral liquor in treating asthma [J]. Chung Kuo Ching Hsi I Chieh Ho Tsa Chih,1997,17:216-218.
[147]Li MH, Liu YH, Yang BY. Clinical observation on treatment of asthma in moderate degree with fluticasone inhalation combined with jinacon [J]. Chung Kuo Ching Hsi I Chieh Ho Tsa Chih,2001,21: 819-821.
[148]Ni J, Dong J, Wu G. Experimental study on effect of antagonizing platelet-activating factor and histamine of synthetic Ginkgolide F in guinea pigs [J]. Zhongguo Zhong Xi Yi Jie He Za Zhi,2000, 20:365-367.
[149]Makino T, Furuta Y, Wakushima H, et al. Anti-allergic effect of Perilla frutescens and its active constituents [J]. Phytother Res,2003,17:240-243.
[150]Simons FE, Villa JR, Lee BW, et al. Montelukast added to budesonide in children with persistent asthma: a randomized, double-blind, crossover study [J]. J Pediatr,2001,:138:694-698.
[151]Huang JL, Wang SY, Hsieh KH. Effect of short-term exposure to low levels of SO2 and NOx on pulmonary function and methacholine and allergen bronchial sensitivities in asthmatic children [J]. Arch Environ Health,1991,46:296-299.
[152]Hsieh KH. Evaluation of efficacy of traditional Chinese medicines in the treatment of childhood bronchial asthma:clinical trial, immunological tests and animal study. Taiwan asthma study group [J]. Pediatr Allergy Immunol,1996,7:130-140.
[153]宋立人总编.中华本草[M].上海：上海科学技术出版社,1999.
[154]周钊鹤,赵霞.小儿哮喘与体质的关系探讨[J].山东中医药大学学报,2009,,3(2)：113-114.
[155]中华医学会呼吸病学分会哮喘学组.支气管哮喘防治指南(支气管哮喘的定义、诊断、治疗和管理方案)[J].中华哮喘杂志(电子版),2008,2(1)：3-13.