Determinants of Asthma Following RSV Bronchiolitis in Early Life

描述(由申请人提供)：我们的目标是前瞻性地确定特定的遗传、生物学和免疫学特征，以及环境暴露，对早期经历严重RSV毛细支气管炎的儿童如何影响随后的哮喘、呼吸道高反应性和过敏的发展。具体地说，我们将利用自1998年以来前瞻性跟踪的已建立的严重呼吸道合胞病毒毛细支气管炎儿童队列(早期生活中的呼吸道合胞病毒毛细支气管炎，rbel-I，n=206)，以及回顾已确定的严重呼吸道合胞病毒毛细支气管炎儿童队列(波士顿呼吸道合胞病毒毛细支气管炎队列，n=200)，并在新登记的严重呼吸道合胞病毒毛细支气管炎(rbel-II，n=200)婴儿的前瞻性队列中测试来自rbel-I的关键发现。这些队列将是迄今为止规模最大的，将有600多名患有严重呼吸道合胞病毒毛细支气管炎的儿童，并将使我们能够测试关于哮喘和过敏性疾病早期病因的新假设。我们将能够评估和确认与哮喘、呼吸道高反应性、过敏性过敏和RSV易感性相关的候选基因在三个不同人群中的1500多个多态性。我们现在建议前瞻性地测试新开发的RSV-哮喘预测指数(RAPI)在该队列中的有效性，并可能修改该指数以提高其预测价值。我们将在RBEL-II中前瞻性评估免疫系统失调与呼吸道合胞病毒毛细支气管炎后哮喘发展相关的发现。在了解严重呼吸道合胞病毒毛细支气管炎期间和之后宿主的生物和免疫反应的同时，我们现在提议对与呼吸道合胞病毒易感性和哮喘、呼吸道高反应性和过敏敏感性的发展相关的候选基因进行强有力的研究，该队列包括600多名儿童及其父母(S)。考虑到这些儿童在生命早期的仔细特征，我们现在可以研究导致儿童不同喘息表型发展的潜在基因-基因和基因-环境相互作用。我们的总体假设是，在适当的遗传易感性背景下经历严重RSV毛细支气管炎的儿童，具有功能失调的免疫反应，容易患上呼吸道高反应性和哮喘。因此，我们建议：目的I：前瞻性评估呼吸道合胞病毒-哮喘预测指数(RAPI)对严重呼吸道合胞病毒毛细支气管炎后哮喘和持续喘息发展的有效性。目的II：前瞻性评估免疫系统失调，特别是树突状细胞和调节性T细胞在严重呼吸道合胞病毒毛细支气管炎后哮喘、持续喘息和过敏性致敏中的作用。目的：研究哮喘、特应性、炎症相关基因~1500多态性与哮喘、呼吸道高反应性和重症呼吸道合胞病毒毛细支气管炎后过敏反应的关系。 公共卫生相关性：我们的目标是前瞻性地确定特定的遗传、生物学和免疫学特征以及环境暴露在早期经历严重RSV毛细支气管炎的儿童中如何相互作用，从而导致哮喘、呼吸道高反应性和过敏。这项研究将是迄今为止规模最大的，包括600多名患有严重呼吸道合胞病毒毛细支气管炎的儿童，并将使我们能够测试关于哮喘和过敏性疾病早期病因的新假设。

DESCRIPTION (provided by applicant): We aim to prospectively define how specific genetic, biologic, and immunologic characteristics, along with environmental exposures, interact in children who experience severe RSV bronchiolitis early in life impact the subsequent development of asthma, airway hyperreactivity and allergy. Specifically, we will utilize a well- established cohort of children with severe RSV bronchiolitis that has been prospectively followed since 1998 (RSV Bronchiolitis in Early Life, RBEL-I, n=206), a retrospectively identified cohort of children with severe RSV bronchiolitis (Boston RSV Bronchiolitis cohort, n=200), and test our key findings from RBEL-I in a newly enrolled prospective cohort of infants with severe RSV bronchiolitis (RBEL-II, n=200). These cohorts will be the largest to date, with over 600 children with severe RSV bronchiolitis, and will enable us to test new hypotheses on the causation of asthma and allergic disorders early in life. We will be able to evaluate and confirm over 1500 polymorphisms in candidate genes associated with asthma, airway hyperreactivity, allergic sensitization and RSV susceptibility in three separate populations. We now propose to prospectively test the validity of the newly developed RSV-Asthma Predictive Index (RAPI) in this cohort as well as potentially modify this index to improve its predictive value. We will prospectively evaluate our findings of a dysregulated immune system associated with the development of asthma post-RSV bronchiolitis in RBEL-II. In concert with understanding the biologic and immunologic response of the host during and after severe RSV bronchiolitis, we are now proposing a powerful study of candidate genes associated with susceptibility to RSV and the development of asthma, airway hyperreactivity and allergic sensitization in the combined RBEL and Boston cohorts with over 600 children as well as their parent(s). Given the careful characterization of these children early in life, we will now be able to study potential gene-gene and gene-environment interactions leading to the development of different wheezing phenotypes in childhood. Our overall hypothesis is that children who experience severe RSV bronchiolitis in the context of the appropriate genetic predisposition, have a dysfunctional immune response that predisposes them to develop airway hyperreactivity and asthma. Accordingly, we propose to: Aim I: Evaluate prospectively the validity of a RSV-Asthma Predictive Index (RAPI) on the development of asthma and persistent wheezing following severe RSV bronchiolitis. Aim II: Evaluate prospectively the impact of a dysregulated immune system, specifically dendritic and regulatory T cells, on the development of asthma, persistent wheezing and allergic sensitization following severe RSV bronchiolitis. Aim III: Examine the relationships of ~1500 polymorphisms in genes associated with asthma, atopy, inflammation with the development of asthma, airway hyperreactivity, and allergic sensitization following severe RSV bronchiolitis. PUBLIC HEALTH RELEVANCE: We aim to prospectively define how specific genetic, biologic, and immunologic characteristics, along with environmental exposures, interact in children who experience severe RSV bronchiolitis early in life on the subsequent development of asthma, airway hyperreactivity and allergy. This study will be the largest to date, consisting of over 600 children with severe RSV bronchiolitis, and will enable us to test new hypotheses on the causation of asthma and allergic disorders early in life.