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通讯作者:

刘虎,E⁃mail:liuhu@njmu.edu.cn

中图分类号:R777.31

文献标识码:A

文章编号:1007-4368(2021)08-1252-06

DOI:10.7655/NYDXBNS20210823

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目录contents

    摘要

    过敏性结膜炎是儿童常见眼表疾病,然而对于儿童过敏性结膜炎的研究报道却较为匮乏。各国儿童过敏性结膜炎患病率逐年上升,且病程长、易反复,严重影响患儿生活质量。了解儿童过敏性结膜炎的流行病学特征及其相关危险因素的最新研究进展,可帮助临床医师提高对儿童这一特殊人群过敏性结膜炎的理解和重视。因此,有必要将目前儿童过敏性结膜炎的流行病学特征及其相关危险因素研究进展予以综述。

    Abstract

    Allergic conjunctivitis is a common ocular surface disease in children,but the research reports on allergic conjunctivitis in children are relatively scarce. The prevalence of allergic conjunctivitis in children in various countries is increasing year by year and the disease course is long and easy to recur,which seriously affects the quality of life of children. Understanding the epidemiological characteristics of children’s allergic conjunctivitis and the latest research progress of related risk factors can help clinicians to improve their understanding and attention to children’s allergic conjunctivitis. Therefore,it is necessary to review the current epidemiological characteristics and related risk factors of children with allergic conjunctivitis.

  • 过敏性结膜炎(allergic conjunctivitis,AC)是结膜对过敏原刺激产生超敏反应所引起的一类疾病,以Ⅰ型和Ⅳ型超敏反应为主[1],患者常以眼红、眼痒为主诉就医。近期研究表明AC在儿童晚期或青少年时期达到发病顶峰,已成为小儿眼病专家最为关注的儿童眼表问题之一[2]。AC可造成泪膜稳定性下降从而导致角膜上皮损伤,严重者可引起角膜溃疡、圆锥角膜和角膜缘干细胞损伤等一系列并发症,影响视觉,甚至引起神经精神症状、行为异常等,不仅严重降低患儿的生活质量,而且增加疾病的总体负担,因此必须对儿童AC给予足够重视[2-6]

  • 儿童AC在世界各地人群中患病率差异较大,从3.4%~40.0%不等[7-8],这种差异甚至出现在同一国家的不同地区。这些差异似乎反映了疾病的高度异质性,也反映了种族、过敏原种类和环境危险因素的差异。尽管其患病率较高,但由于儿童较难准确表达自身症状,临床检查配合度偏低,常造成此病的漏诊、误诊,临床治疗效果欠佳[9]。目前,国际上关于儿童AC的流行病学研究不在少数,但研究方法不完全相同,结论亦具有一定差异性。此文旨在对国内外关于儿童AC的流行病学特征及其相关影响因素研究进行综述,为今后我国更好地进行儿童AC的流行病学研究奠定基础。

  • 1 儿童AC流行病学研究方法

  • 目前国内外关于儿童AC的流行病学研究均已开展。多数是基于人群的横断面研究,多采用国际儿童哮喘和变态反应研究(the International Study of Asthma and Allergies in Childhood,ISAAC)给出的问卷:ISAAC问卷[10],并根据各国各地区情况进行改良。该问卷被认为是评估儿童过敏性疾病比较准确的方法。该问卷主要由儿童家长或监护人和青少年本人填写,问卷中关于儿童过敏性鼻结膜炎 (allergic rhinoconjunctivitis,ARC)的核心问题集中在过去1年的症状,如:“没有感冒或流感时是否有打喷嚏、流鼻涕或鼻塞问题”和“这种鼻子问题是否伴有眼痒或者流泪”;根据鼻子问题影响儿童日常活动的程度来评估病情的严重性。该问卷使用了基于标准化方法的疾病症状,以便在不同国家之间进行比较,甚至可以比较在不同时间获得的数据。缺点是该问卷先定义了过敏性鼻炎(allergic rhini⁃ tis,AR),而ARC只有在AR出现后才被标记,这将低估孤立性AC的患病率。

  • 使用基于症状的问卷时,AC各亚型不能被准确诊断。为评估各亚型的患病率,通常需要进行眼科检查来诊断。因此,基于门诊就诊的调查已用于评估眼部过敏性疾病亚型的患病率[11-12]。这些研究关注在AC常见症状如眼痒、流泪、畏光、异物感等,体征如结膜充血、滤泡、乳头、角膜染色以及出现症状的时间及频率、严重性、既往就诊情况等。然而这种研究设计往往会导致患病率被高估,并不能准确评估AC在一般人群中的真实患病率(表1)。

  • 2 儿童AC流行病学特征

  • ISAAC Ⅲ的结果表明,13~14岁儿童的ARC总体患病率为14.6%[12],其流行程度因国家和地区而异。在非洲(18.0%)和拉丁美洲(17.3%)患病率最高,而在北欧和东欧(9.2%)则最低。在同一国家的不同地区也观察到患病率的巨大差异。例如与邻近地区或城市相比,亚太地区的大城市,包括胡志明市、曼谷和香港儿童ARC的患病率较高。该结果表明需要在一个国家或地区的基础上对患病率进行进一步监测。此外,该研究发现ARC的患病率呈增长趋势。与Ⅰ期研究结果相比,Ⅲ期研究中6~7岁以及13~14岁儿童的ARC患病率几乎在全球范围内上升[12],其他研究中也显示儿童AC患病率呈上升趋势[2026]

  • 表1 基于人群的儿童AC患病率研究

  • Table1 The population⁃based study on the prevalence of children with AC

  • VKC:春季角结膜炎,vernal keratoconjunctivitis。

  • 国内一项佛山市中小学生过敏性疾病的流行病学调查显示,6~8岁儿童AC的患病率为5.2%, 12~14岁儿童AC的患病率为2.46%,AC的患病率随年龄增长呈现下降趋势[14]。上海一项基于ISAAC问卷的7~9岁(幼龄组)和12~14岁(青少年组)眼部过敏调查中,AC总患病率为28%;幼龄组的患病率更高(10.2%),且日常生活更易受到AC引起的不同程度的影响[15]

  • 3 儿童AC相关影响因素

  • 3.1 年龄

  • 国外研究发现随着年龄增长,儿童AC患病率逐渐上升[7],但我国中小学生AC流行病学调查显示小学生AC患病率比中学生偏高[14-15]。国外统计资料认为AC的患病率及发病率从婴幼儿时期急剧上升,在儿童早期达到顶峰,随后在青春期后期逐渐下降[13]。这通常被认为是儿童AC的自然病程,这一现象常存在于其他过敏性疾病如特应性皮炎[29]。可能随着年龄增长,儿童对AC的不适症状耐受度增高,导致在部分研究中由儿童自述的症状比例降低。

  • 3.2 性别

  • 性别与AC的关系尚无定论。既往部分研究认为男孩的AC患病率要显著高于女孩,可能是男孩户外活动时间较多,更易受到环境污染物的影响[131720]; Das等[13] 认为进入青春期后,男孩的AC发病率和患病率均下降,考虑雄激素可能影响过敏的易感性和耐受性;Geraldini等[18] 发现巴西青少年女性更易患AC;而在哮喘患儿中,男孩患哮喘的概率是女孩的2倍,但成年后女性转变为主导地位,可能是青春期升高的男性睾丸激素及其代谢产物具有一定的免疫抑制作用,可预防过敏性疾病[30];也有少数研究发现儿童AC可能不存在性别差异[31]。研究方法中的差异性也可能会得出不同结论。性别与AC的关系需进一步的研究证实。

  • 3.3 烟草暴露

  • 烟草暴露与ARC及AC的相关性研究结论存在矛盾。横断面研究中,母亲孕期吸烟会增加儿童患ARC的风险[928],且二手烟是儿童AC的危险因素之一[19],但Alemayehu等[26] 认为二手烟的暴露与儿童ARC不存在显著相关性。欧洲出生队列研究表示孕期烟草暴露并不会增加儿童及青少年ARC的风险,但孕期母亲吸烟≥10支/d会增加儿童ARC的风险,而胎儿期至青少年期的二手烟暴露则不会增加ARC的风险[32]。妊娠期间暴露于母体的烟草可能改变新生儿的非特异性免疫和特异性免疫、气道内黏膜纤毛清除率和T淋巴细胞功能等,从而引起鼻塞等症状。而烟草中的有害成分增加呼吸道反应性,使抵抗各种病原体的免疫反应受损,从而加强了过敏原的作用,使体内IgE水平升高。

  • 3.4 剖宫产

  • 哥伦比亚一项基于ISAAC问卷的ARC研究认为剖宫产可能是6~7岁儿童ARC的危险因素[30]。至今尚未有类似结论的其他文献报道。既往一项荟萃分析表明剖宫产与儿童AR相关[33],而多项研究表明,剖宫产婴儿的肠道菌群与经阴道分娩的婴儿肠道菌群存在差异。不同研究一致显示,与非过敏儿童相比,剖宫产儿童肠道内艰难梭菌定植高,双歧杆菌和乳酸菌计数低。剖宫产引起的胎儿肠道菌群改变是否会影响儿童ARC或AC需更多的研究支持。

  • 3.5 过敏原

  • 儿童AC常见的过敏原主要分为两类,一类是吸入性过敏原,主要为螨虫、室内灰尘、花粉等;一类是食入性过敏原,主要为鸡蛋、鱼虾蟹类、牛奶等。急性AC患儿对花草的过敏反应更为剧烈,而室内尘螨引起慢性AC的可能性较大[1224]。国外文献报道儿童居住在潮湿或有霉菌的房间以及与动物密切接触更易出现眼部过敏[1926]。Ⅰ型超敏反应是急性AC的发病机制,在Ⅰ型超敏反应中,过敏原如花粉等初次接触机体时,产生IgE抗体,当过敏原再次接触机体时,与肥大细胞膜上IgE结合,激活肥大细胞脱颗粒,释放组胺、花生四烯酸和白介素等物质,最终导致结膜出现炎症表现[39],患者出现结膜充血、水肿、瘙痒、流泪等不适症状。

  • 3.6 过敏性疾病家族史

  • 早期研究显示有哮喘和/或AR家族史的儿童AC患病风险会增加[14192224],而患有眼部过敏的青少年出现哮喘、鼻炎和特应性皮炎的风险增加[18]。多数研究发现父母或兄弟姐妹患有过敏性疾病,儿童过敏性疾病的风险会显著增加,这在儿童常见的过敏性疾病如AR、哮喘、特应性皮炎中已得到共识[92326]。不难理解,这些表明AC的发生易受遗传因素影响。但目前似乎尚缺乏关于AC遗传相关基因表型的详细报道。

  • 3.7 环境污染

  • 在埃塞俄比亚及印度,室内空气污染如使用煤油或柴火做饭会增加儿童ARC的风险[2428],而室外污染如住宅附近有卡车通行与ARC存在强烈的相关性[1928]。一些基础研究发现结膜上皮暴露于碳氢化合物和汽车尾气微粒可刺激炎症因子合成与分泌,包括趋化肽(可募集炎症细胞)、白细胞介素[34],促进结膜反应。空气中汽车微粒可刺激与慢性AC有关的IL⁃17炎症途径;而较高水平的可吸入颗粒物(particulate matter 2.5,PM2.5)、NO2、SO2、O3和气温会增加AC儿童就诊的概率[35-37];不断升高的气温、降水和更恶劣的天气会使花粉季节延长,室内和室外霉菌的生存能力变强,儿童更易暴露于这些过敏原中[38]。随着工业化和城市化的快速发展,空气质量问题和其他环境健康问题正严重影响人类生存环境,眼表直接暴露于外环境中,因此眼表密集的神经对环境化学物质极为敏感,更容易受到气候及环境因素的影响[39]

  • 3.8 其他过敏性疾病

  • AC儿童常伴随出现AR,其次是哮喘及特应性皮炎等[9132430]。虽然AC与ARC存在较多相似之处,但相关临床研究证实[40],两种疾病的严重程度和发病情况均具有统计学差异,提示AC与ARC是有很多类似症状的不同部位疾病。在俄罗斯,3~6岁儿童AC与AR的合并患病率高达42%[17];在西班牙9岁儿童中,61%的AR儿童同时患有AC[21]。AC与AR通常合并存在,其主要原因可能是:①解剖位置的关联性,生理上眼、鼻部通过鼻泪管相通;病理上结膜与鼻黏膜均属于黏膜上皮,过敏原在激发AR的同时也会导致AC;②过敏原的重叠性,过敏原的重叠以及非人为可干预的过敏原(如花粉),使两者易联合患病且反复发作;③发病机制的相似性,AC和AR通常都是由IgE介导的Ⅰ型变态反应。

  • 近年来,越来越多的研究报道AR与哮喘的关系,产生了“一个呼吸道,一种疾病”与“过敏性鼻气管炎”的概念[40]。这也可能是哮喘儿童易患AC的原因。既往研究显示,AC可能是儿童特应性皮炎的危险因素[23];丹麦一项出生队列研究发现特应性皮炎是14岁儿童ARC的危险因素[21]。很多文献均已报道“atopic march”现象,即在过敏性疾病中,过敏原最初通过接触特应性皮炎的表皮,导致其他过敏性疾病如AR、AC、哮喘和食物过敏等[41]

  • 3.9 药物

  • 婴幼儿时期使用抗生素可使儿童患AC的风险增加1.42倍;结膜黏膜表面存在正常菌群,长期应用抗生素可引起正常菌群失调,结膜免疫防御功能下降[42-43];其次抗生素会导致免疫反应偏向于Th1反应,而不是Th2反应,而后者更有利于过敏的发展[2830]。在出生第1年内使用对乙酰氨基酚及近1年使用对乙酰氨基酚≥1次可能是儿童ARC的危险因素[2830],对乙酰氨基酚能够降低机体抗氧化应激能力和促进Th2反应。

  • 3.10 其他因素

  • 母亲受教育水平被发现是儿童AC的一个危险因素。可能原因是较高的教育水平与更高的社会经济地位、更好的症状意识和对问题的理解、更可靠的反应有关,儿童能获得更好的诊断和治疗机会[30]。每天看电视超过3h与ARC显著相关,该研究认为看电视是久坐活动,易使儿童患上肥胖症,因此容易引起过敏[2830]。而日本一项针对儿童肥胖与过敏性疾病的研究显示肥胖儿童的ARC患病率比正常儿童偏低[44],肥胖儿童中脂肪细胞因子数量变化的净效应可能使Th1/Th2平衡偏向Th1,并增强了Th1介导的炎症反应。

  • 4 总结

  • 儿童群体的特殊性增加了儿童AC诊治难度。由于AC可能与其他形式的过敏相关并反复发作,会严重影响儿童和青少年的生活质量。目前儿童AC的流行病学研究相对匮乏,且多数通过父母填写的问卷获取信息,缺少眼科检查获取的体征等。我国仍然缺乏大样本儿童AC流行病学研究数据。近年来随着社会环境的变化,AC的患病率逐步上升,明确其相关危险因素可进一步加强儿童眼表疾病防控。

  • 综上所述,AC在儿童中较常见,且常与其他过敏性疾病合并发生,但相关危险因素较复杂且尚存在很多不明,应加强对儿童AC的早期认识与干预,减少AC对眼表的损伤。目前对于儿童AC的认识还处于早期阶段,仍需要大样本儿童AC流行病学研究数据明确其危险因素及疾病的发展机制。

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