孟鲁司特治疗呼吸道合胞病毒毛细支气管炎症状及反复喘息疗效研究

doi:10.12114/j.issn.1007-9572.2019.00.314

摘要/Abstract

摘要： 背景　呼吸道合胞病毒（RSV）毛细支气管炎易出现反复喘息，且下呼吸道分泌物中半胱氨酸白三烯（CysLTs）水平升高。而孟鲁司特是一种白三烯受体拮抗剂，关于其治疗RSV毛细支气管炎症状的研究相对较少。目的　探讨孟鲁司特改善婴幼儿RSV毛细支气管炎后症状及减轻反复喘息发作的有效性和安全性。方法　2015年6月—2017年6月连续纳入在潍坊市妇幼保健院出院的RSV毛细支气管炎患儿，随机分为治疗组、对照组。Ⅰ期，治疗组：口服孟鲁司特颗粒（4 mg）12周，1次/d；对照组：口服安慰剂12周，1次/d。对两组无症状天数、个人日记评分进行评估。随访9个月（Ⅱ期），观察Ⅰ+Ⅱ期反复喘息人数和医疗资源应用情况等。依据意向性分析（ITT）原则，应用全分析集（FAS）分析数据。结果　共纳入研究对象186例，治疗组92例，对照组94例。治疗组完成Ⅰ期研究的患儿为89例，对照组为90例；治疗组完成Ⅰ+Ⅱ期的患儿为84例，对照组为86例。治疗组平均依从性为97.8%（7 560/7 728），对照组平均依从性为97.4%（7 690/7 896），两组患儿平均依从性比较，差异无统计学意义（χ2=3.16，P=0.07）。在Ⅰ期研究期间，两组无症状天数、日间无症状天数、夜间无症状天数、个人日记评分比较，差异均无统计学意义（P>0.05）。在整个研究过程中（Ⅰ+Ⅱ期），治疗组RSV毛细支气管炎喘息复发人数少于对照组（P<0.05），治疗组喘息患儿出现2次及以上喘息比例低于对照组（χ2=5.14，P=0.02）。Ⅰ+Ⅱ期研究期间治疗组医疗资源应用人数、β-受体激动剂应用人数、糖皮质激素应用人数、住院人数低于对照组（P<0.05）。在事后亚组分析中，治疗组有湿疹史与父母哮喘史的患儿中无症状天数〔（49.7±20.2）、（51.3±20.9）d〕多于对照组〔（36.3±20.4）、（37.8±19.3）d〕（t=2.19，P=0.03；t=2.24，P=0.03）。整个研究过程中没有患儿因不良反应退出研究，两组间胃肠道紊乱、皮疹、转氨酶升高发生率比较，差异均无统计学意义（χ2=0.23，P=0.63；χ2=0.03，P=0.86；χ2=0.15，P=0.69）。结论　口服孟鲁司特（4 mg）12周不能改善RSV毛细支气管炎患儿呼吸道症状，但能降低患儿反复喘息发作次数。口服孟鲁司特（4 mg）有一定效果且安全。

关键词: 细支气管炎, 病毒性；呼吸道合胞病毒；孟鲁司特；喘息；治疗结果

Abstract: Background　Respiratory syncytial virus（RSV）bronchiolitis is prone to recurrent wheezing，and the concentration of CysLTs in lower respiratory tract secretions is elevated.There are relatively few studies about montelukast，a leukotriene receptor antagonist，in the treatment of symptoms after RSV bronchiolitis.Objective　To explore the effectiveness and safety of montelukast in the treatment of symptoms after RSV bronchiolitis in infants.Methods　Consecutive infant patients with RSV bronchiolitis discharged from Weifang Maternal and Child Health Hospital from June 2015 to June 2017 were enrolled and were randomly divided into treatment group and control group，treated with montelukast oral granules 4 mg，once daily，for 12 weeks，placebo，once daily，for 12 weeks respectively（Ⅰ phase）.Symptom-free days and personal diary about RSV bronchiolitis were evaluated in all infants.Nine-month follow-up（Ⅱ phase）was performed.Number of infants with recurrent wheezing and use of medical resources during Ⅰ + Ⅱphases were analyzed.Data were analyzed by full analysis set（FAS），a classic intention-to-treat analysis.Results　A total of 186 infants were enrolled（92 in the treatment group，and 94 in the control group），179 of them（89 in the treatment group，and 90 in the control group）completed the Ⅰ-phase intervention，and finally 170 completed the interventions in bothⅠ + Ⅱphases（84 in the treatment group，and 86 in the control group）．The average compliance was 97.8%（7 560/7 728）in the treatment group，and 97.4%（7 690/7 896）in the control group，showing no significant difference between the groups（χ2=3.16，P=0.07）．During the study period of Ⅰ phase, there was no significant difference in the number of symptom-free days，symptom-free daytime，symptom-free at night and personal diary about RSV bronchiolitis between the two groups（P>0.05）. During the whole study period（Ⅰ + Ⅱ phases），the number of patients with wheezing after RSV bronchiolitis in the treatment group was less than that in the control group（P<0.05）．In the first nine months of follow-up，the treatment group had lower prevalence rate of recurrent wheezing（χ2=5.14，P=0.02）．The numbers of using medical resources，beta-receptor agonists，and glucocorticoids，and hospitalization during the whole study period in the treatment group was less than that in the control group（P<0.05）．The number of asymptomatic days was significantly different between those with eczema history in the treatment group and those in the control group〔（49.7±20.2）vs（36.3±20.4）〕（t=2.19，P=0.03），and between those with parental asthma history in the treatment group and those in the control group〔（51.3±20.9）vs（37.8±19.3）〕（t=2.24，P=0.03）．During the whole study，no children withdrew from the study because of adverse reactions.There were no significant differences of the rate of gastrointestinal disorders，rash ， elevated transaminase between the two groups（χ2=0.23，P=0.63；χ2=0.03，P=0.86；χ2=0.15，P=0.69）．Conclusion　Although the treatment with montelukast oral granules（4 mg，once daily，for 12 weeks）could not improve the respiratory symptoms after RSV bronchiolitis，it could decrease the recurrence frequency of wheezing.This treatment is safe and effective to some extent.

Key words: Bronchiolitis, viral；Respiratory syncytial viruses；Montelukast；Wheezing；Treatment outcome

王执勇,李树青,钱秀玲. 孟鲁司特治疗呼吸道合胞病毒毛细支气管炎症状及反复喘息疗效研究[J]. 中国全科医学, 2020, 23(8): 929-934. DOI: 10.12114/j.issn.1007-9572.2019.00.314.
WANG Zhiyong,LI Shuqing,QIAN Xiuling. Efficacy of Montelukast in Treating Symptoms and Recurrent Wheezing after RSV Bronchiolitis in Infants　[J]. Chinese General Practice, 2020, 23(8): 929-934. DOI: 10.12114/j.issn.1007-9572.2019.00.314.

参考文献

［1］《中华儿科杂志》编辑委员会，中华医学会儿科学分会呼吸学组.毛细支气管炎诊断、治疗与预防专家共识（2014年版）［J］．中华儿科杂志，2015，53（3）：168-171．DOI：10.3760/cma.j.issn.0578-1310.2015.03.003.
Chinese Pediatric Journal Editorial Board，Chinese Medical Association Pediatrics Branch Respiratory Group.Expert consensus on diagnosis，treatment and prevention of bronchiolitis（2014 edition）［J］．Chinese Journal of Pediatrics，2015，53（3）：168-171．DOI：10.3760/cma.j.issn.0578-1310.2015.03.003.
［2］刘恩梅，陈慧中.努力提高中国儿科医生规范诊治毛细支气管炎的水平［J］．中华儿科杂志，2015，53（3）：161-163．DOI：10.3760/cma.j.issn.0578-1310.2015.03.001.
LIU E M，CHEN H Z.Strive to improve the standard of diagnosis and treatment of bronchiolitis in Chinese pediatricians［J］．Chinese Journal of Pediatrics，2015，53（3）：161-163．DOI：10.3760/cma.j.issn.0578-1310.2015.03.001.
［3］RALSTON S L，LIEBERTHAL A S，MEISSNER H C，et al．Clinical practice guideline：the diagnosis，management，and prevention of bronchiolitis［J］．Pediatrics，2014，134（5）：e1474-1502．DOI：10.1542/peds.2014-2742.
［4］MILLER E K，GEBRETSADIK T，CARROLL K N，et al．Viral etiologies of infant bronchiolitis，croup and upper respiratory illness during 4 consecutive years［J］．Pediatr Infect Dis J，2013，32（9）：950-955．DOI：10.1097/INF.0b013e31829b7e43.
［5］OPENSHAW P J，DEAN G S，CULLEY F J.Links between respiratory syncytial virus bronchiolitis and childhood asthma：clinical and research approaches［J］．Pediatr Infect Dis J，2003，22（2 Suppl）：S58-64；discussion S64-65．DOI：10.1097/01.inf.0000053887.26571.eb.
［6］SCHAUER U，HOFFJAN S，BITTSCHEIDT J，et al．RSV bronchiolitis and risk of wheeze and allergic sensitisation in the first year of life［J］．Eur Respir J，2002，20（5）：1277-1283.
［7］ERIKSSON M，BENNET R，NILSSON A.Wheezing following lower respiratory tract infections with respiratory syncytial virus and influenza a in infancy［J］．Pediatr Allergy Immunol，2000，11（3）：193-197.
［8］STEIN R T，SHERRILL D，MORGAN W J，et al．Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years［J］．Lancet，1999，354（9178）：541-545．DOI：10.1016/S0140-6736（98）10321-5.
［9］HENDERSON J，HILLIARD T N，SHERRIFF A，et al．Hospitalization for RSV bronchiolitis before 12 months of age and subsequent asthma，atopy and wheeze：a longitudinal birth cohort study［J］．Pediatr Allergy Immunol，2005，16（5）：386-392．DOI：10.1111/j.1399-3038.2005.00298.x.
［10］SIGURS N，GUSTAFSSON P M，BJARNASON R，et al．Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13［J］．Am J Respir Crit Care Med，2005，171（2）：137-141．DOI：10.1164/rccm.200406-730OC.
［11］GOETGHEBUER T，ISLES K，MOORE C，et al．Genetic predisposition to wheeze following respiratory syncytial virus bronchiolitis［J］．Clin Exp Allergy，2004，34（5）：801-803．DOI：10.1111/j.1365-2222.2004.1947.x.
［12］MARTINEZ F D.Respiratory syncytial virus bronchiolitis and the pathogenesis of childhood asthma［J］．Pediatr Infect Dis J，2003，22（2 Suppl）：S76-82．DOI：10.1097/01.inf.0000053889.39392.a7.
［13］KIM C K，KOH J Y，HAN T H，et al．Increased levels of BAL cysteinyl leukotrienesinacute［corrected］RSV bronchiolitis［J］．Acta Paediatr，2006，95（4）：479-485．DOI：10.1080/08035250600554268.
［14］DA DALT L，CALLEGARO S，CARRARO S，et al．Nasal lavage leukotrienes in infants with RSV bronchiolitis［J］．Pediatr Allergy Immunol，2007，18（2）：100-104．DOI：10.1111/j.1399-3038.2006.00500.x.
［15］MCCARTHY M K，WEINBERG J B.Eicosanoids and respiratory viral infection：coordinators of inflammation and potential therapeutic targets［J］．Mediators Inflamm，2012，2012（3）：236345．DOI：10.1155/2012/236345.
［16］DIMOVA-YANEVA D，RUSSELL D，MAIN M，et al．Eosinophil activation and cysteinyl leukotriene production in infants with respiratory syncytial virus bronchiolitis［J］．Clin Exp Allergy，2004，34（4）：555-558．DOI：10.1111/j.1365-2222.2004.1918.x.
［17］BISGAARD H.Leukotriene modifiers in pediatric asthma management［J］．Pediatrics，2001，107（2）：381-390．DOI：10.1542/peds.107.2.381.
［18］MONTUSCHI P.Leukotrienes，antileukotrienes and asthma［J］．Mini Rev Med Chem，2008，8（7）：647-656．DOI：10.2174/138955708784567395.
［19］LOWELL D I，LISTER G，VON KOSS H，et al．Wheezing in infants：the response to epinephrine［J］．Pediatrics，1987，79（6）：939-945.
［20］BISGAARD H，FLORES-NUNEZ A，GOH A，et al．Study of montelukast for the treatment of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children［J］．Am J Respir Crit Care Med，2008，178（8）：854-860．DOI：10.1164/rccm.200706-910OC.
［21］SANTANELLO N C，NORQUIST J M，NELSEN L M，et al．Validation of a pediatric caregiver diary to measure symptoms of postacute respiratory syncytial virus bronchiolitis［J］．Pediatr Pulmonol，2005，40（1）：31-38．DOI：10.1002/ppul.20232.
［22］张学中，张建方.药品临床研究中的ITT原则［J］．中国新药杂志，2000，9（1）：21-22．DOI：10.3321/j.issn:1003-3734.2000.01.007.
ZHANG X Z，ZHANG J F.ITT principles in clinical research of drugs［J］．Chinese Journal of New Drugs，2000，9（1）：21-22．DOI：10.3321/j.issn:1003-3734.2000.01.007.
［23］PELKONEN A S，MALMSTR?M K，SARNA S，et al．The effect of montelukast on respiratory symptoms and lung function in wheezy infants［J］．Eur Respir J，2013，41（3）：664-670．DOI：10.1183/09031936.00173411.
［24］BISGAARD H.A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis［J］．Am J Respir Crit Care Med，2003，167（3）：379-383．DOI：10.1164/rccm.200207-747OC.
［25］MCNAMARA P S，FLANAGAN B F，BALDWIN L M，et al．Interleukin 9 production in the lungs of infants with severe respiratory syncytial virus bronchiolitis［J］．Lancet，2004，363（9414）：1031-1037．DOI：10.1016/S0140-6736（04）15838-8.
［26］MCNAMARA P S，RITSON P，SELBY A，et al．Bronchoalveolar lavage cellularity in infants with severe respiratory syncytial virus bronchiolitis［J］．Arch Dis Child，2003，88（10）：922-926.
［27］HORNSLETH A，LOLAND L，LARSEN L B.Cytokines and chemokines in respiratory secretion and severity of disease in infants with respiratory syncytial virus（RSV）infection［J］．J Clin Virol，2001，21（2）：163-170.
［28］HARRISON A M，BONVILLE C A，ROSENBERG H F，et al．Respiratory syncytical virus-induced chemokine expression in the lower airways：eosinophil recruitment and degranulation［J］．Am J Respir Crit Care Med，1999，159（6）：1918-1924．DOI：10.1164/ajrccm.159.6.9805083.
［29］SMYTH R L，MOBBS K J，O'HEA U，et al．Respiratory syncytial virus bronchiolitis：disease severity，interleukin-8，and virus genotype［J］．Pediatr Pulmonol，2002，33（5）：339-346.
［30］BONT L，RAMILO O.The relationship between RSV bronchiolitis and recurrent wheeze：the chicken and the egg［J］．Early Hum Dev，2011，87（Suppl 1）：S51-54．DOI：10.1016/j.earlhumdev.2011.01.011.
［31］KIM C K，CHOI J，KIM H B，et al．A randomized intervention of montelukast for post-bronchiolitis：effect on eosinophil degranulation［J］．J Pediatr，2010，156（5）：749-754．DOI：10.1016/j.jpeds.2009.12.001.
［32］白珺，徐佩茹.孟鲁司特治疗毛细支气管炎的多中心随机三盲对照研究［J］．中国循证医学杂志，2010，10（9）：1011-1015．DOI：10.3969/j.issn.1672-2531.2010.09.003.
BAI J，XU P R.Montelukast in the treatment of bronchiolitis，a multi-center，randomized，three-blind，placebo-controlled trial［J］．Chinese Journal of Evidence-Based Medicine，2010，10（9）：1011-1015．DOI：10.3969/j.issn.1672-2531.2010.09.003.
［33］PIEDIMONTE G，RENZETTI G，AUAIS A，et al．Leukotriene synthesis during respiratory syncytial virus bronchiolitis：influence of age and atopy［J］．Pediatr Pulmonol，2005，40（4）：285-291．DOI：10.1002/ppul.20285.
［34］VAN ADELSBERG J，MOY J，WEI L X，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（6）：971-979．DOI：10.1185/030079905X48456.

[1]	张盛鑫，袁林，卓志强，李明珍，童秀斌. 呼出气一氧化氮和潮气呼吸肺功能检测在毛细支气管炎中的应用价值[J]. 中国全科医学, 2021, 24(5): 551-554.
[2]	李芹，高文杰，张蕾，安淑华* . 麻疹并发闭塞性细支气管炎患儿六例临床分析[J]. 中国全科医学, 2017, 20(6): 751-754.
[3]	李权恒1，安淑华1*，李金英1，张琳2，张蕾1，董伟然1. 丙酸倍氯米松雾化治疗毛细支气管炎的疗效研究[J]. 中国全科医学, 2017, 20(35): 4438-4441.