毛细支气管炎后反复喘息的危险因素研究现状

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陈赛男 王宇清

苏州大学附属儿童医院呼吸科 215003

   毛细支气管炎是以喘憋为主要表现的下呼吸道感染性疾病，多见于2岁以下，主要由病毒感染引起。有研究表明高达58%的毛细支气管炎患儿在三岁前发生了反复喘息[1]，45%的毛支炎患儿发展为哮喘[2]。本文主要就毛细支气管炎后反复喘息的危险因素研究情况进行如下综述。

   1、性别

   Waseem等[3]对毛细支气管炎后发生哮喘的资料分析显示，男性患儿更易发展为哮喘，这可能与激素水平、肺泡Ⅱ型上皮细胞发育有关。Heli V等[4]的一项出生队列研究也发现男性是哮喘的高危因素。在Bozaykut A 等[5] 一项对500名毛支患儿的前瞻性研究中，高达61%的男性在毛细支气管炎后期发生了3次以上的喘息，提示男性是毛细支气管炎患儿发生反复喘息的危险因素。

   2、是否母乳喂养

   母乳中富含IgA，婴儿主要从母乳中获得IgA，而IgA具有抗感染作用，可以减轻由于呼吸道炎症造成的上皮细胞损伤，从而降低婴幼儿喘息性疾病的发生率。有研究发现，母乳喂养可以减少毛支后反复喘息的发生，并且喘息发作次数和持续时间随着母乳喂养时间的延长而减少[5]。Dixon[6]认为与配方奶粉喂养的婴儿相比，母乳喂养的婴儿具有免疫优势，母乳喂养不仅可以降低婴儿期感染的发生率，还可以减少反复喘息或哮喘的倾向。

   3、维生素D水平

   反复喘息与血清维生素D水平密切相关[7, 8]。Helene M等[9]研究发现母亲怀孕期间补充维生素D可显著降低后代反复喘息或哮喘的风险，尤其是血清25-(OH)D水平≥30ng/ml的孕妇，其风险几乎减半。因此，维生素D缺乏可以被视为毛细支气管炎后反复喘息的一个危险因素。

   4、家族哮喘史

   家族哮喘史被认为是毛细支气管炎后发生反复喘息的独立危险因素[10]。最近一项研究表明，父母双方都有哮喘病史，将会导致子女患哮喘的风险增加一倍[11]。Törmänen S等[12]一项前瞻性研究中发现在138名毛细支气管炎患儿中，11-13岁时被诊断为哮喘的占13%，其哮喘风险是普通人口的两倍，母亲哮喘史是其发生哮喘的唯一独立危险因素。Koponen P等[13]的研究亦发现母亲哮喘史是儿童早期哮喘重要的独立危险因素。

   5、被动吸烟

   国内外均有报道表明母亲孕期吸烟可导致婴儿气道发育受损、肺功能功能减退，从而导致反复喘息的发生[14, 15]。除此之外，婴幼儿期的烟草暴露与反复喘息亦有着因果联系[16]，被动吸烟可以影响儿童早期肺部发育和肺功能，影响儿童对病毒性病原体的易感性，从而增加反复喘息发生的机率。

   6、病情严重程度

   早期重度毛细支气管炎会增加儿童反复喘息或哮喘的风险。Lu S等[17]一项对343例RSV所致毛支患儿的纵向、观察性研究发现，病情轻重程度可作为患儿发生哮喘的预测因素。刘雄诚等[18]通过对150例毛细支气管炎患儿2年的随访研究亦发现重型毛细支气管炎是患儿在毛细支气管炎后发展为哮喘的独立危险因素。

   7、病毒感染的种类

   呼吸道合胞病毒（RSV）是引起毛细支气管炎的首位病毒[16, 19]。国外许多研究发现，罹患RSV毛细支气管炎的婴幼儿后期发生反复喘息的风险增加[20, 21]，被诊断RSV感染的毛细支气管炎患儿约50％将发生儿童哮喘[22]。婴幼儿的肺部尚未发育成熟，RSV感染可以引起肺部上皮细胞慢性反应性变化，从而增加患儿发生喘息的易感性[22]。Raffaella N等[23]的研究结果显示病毒因素可能是通过直接增强宿主的免疫应答发挥作用，毛细支气管炎后反复喘息不仅与RSV相关，且与其病毒载量呈正相关。

   大量统计学研究显示，鼻病毒（RV）是引起毛支的居于第二位的常见病毒。Lu Liu等[24]的meta分析显示患儿3岁前因鼻病毒感染诱发喘息，其后发生反复喘息甚至哮喘的风险增加。F. Midulla等[10]通过对313名因毛细支气管炎住院的患儿进行一年的随访发现鼻病毒感染可以成为毛支后反复喘息的预测因子。

   8、血清IgE水平

   血清总IgE的水平与反复喘息患儿的哮喘预测指数相关[25]。血清总IgE及鸡蛋蛋白和牛奶的特异性IgE水平升高会增加患儿四岁时哮喘的发生率[26]，提示婴幼儿喘息与过敏相关，可以通过对毛细支气管炎患儿血IgE水平的检测预测反复喘息的发生。

   9、过敏体质

   过敏体质与反复喘息或哮喘密切相关[3, 27]。（1）第一次急性严重喘息发作期诊断的过敏体质与学龄前的气道反应性增加和肺功能降低有关[28]。（2）变应性鼻炎是哮喘发病的独立危险因素[25, 29]。lauhkonen等[30]通过对102个毛细支气管炎患儿的前瞻性随访研究显示，哮喘与过敏性鼻炎相关。还有研究表明儿童鼻炎的严重程度亦与哮喘密切相关[31]。（3）湿疹是毛细支气管炎后反复喘息甚至发生哮喘的危险因素[32, 33]。（4）嗜酸性粒细胞在包括哮喘和湿疹在内的特应性疾病的发病机制和发展中起着关键作用[34, 35]。MidullaF等[36]研究表明婴儿毛细支气管炎后36个月发生反复喘息与血嗜酸性粒细胞增多有关。

   10、细胞因子

   一项三年的随访研究显示，TNF-α可作为预测3岁以下儿童发展为持续喘息的生物标志物[37]。Bertrand P等[38]研究观察到IL-3可作为RSV毛细支气管炎患儿反复喘息的预测因子。Sugai K等[39]研究发现在反复喘息患儿的鼻咽分泌物中，首次喘息时的MIP-1α水平被认为是可以预测反复喘息的指标。MMP-9被认为与哮喘关系密切，活化后参与维持细胞外基质的稳定，细胞因子、生长因子及激素等可以上调 MMP-9 的表达，而 TIMP-1则可使之失活及降解[40]。

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