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在生命早期经历严重RSV细支气管炎的儿童中，特定的遗传、生物和免疫特征以及环境暴露如何相互作用，影响随后哮喘、气道高反应性和过敏的发展。具体来说，我们将利用自1998年以来已建立的严重RSV细支气管炎儿童队列（早期RSV细支气管炎，rbel - 1, n=206），一个回顾性确定的严重RSV细支气管炎儿童队列（波士顿RSV细支气管炎队列，n=200），并在新入组的严重RSV细支气管炎婴儿前瞻性队列（rbel - 2, n=200）中验证rbel - 1的主要发现。这些队列将是迄今为止最大的，有600多名患有严重呼吸道合胞病毒细支气管炎的儿童，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。我们将能够在三个不同的人群中评估和确认与哮喘、气道高反应性、过敏致敏和RSV易感性相关的1500多个候选基因多态性。我们现在建议对新开发的rsv -哮喘预测指数（RAPI）在该队列中的有效性进行前瞻性测试，并可能对该指数进行修改以提高其预测价值。我们将前瞻性地评估我们在RBEL-II中发现的与哮喘后rsv细支气管炎发展相关的免疫系统失调。为了了解宿主在严重RSV细支气管炎期间和之后的生物学和免疫反应，我们现在提议在RBEL和Boston联合队列中对600多名儿童及其父母进行RSV易感性和哮喘、气道高反应性和过敏性致敏相关的候选基因进行强有力的研究。鉴于这些儿童在生命早期的仔细特征，我们现在将能够研究潜在的基因-基因和基因-环境相互作用导致儿童时期不同喘息表型的发展。我们的总体假设是，在适当的遗传易感性背景下，患有严重RSV细支气管炎的儿童具有功能失调的免疫反应，使他们容易发生气道高反应性和哮喘。因此，我们提出：目的一：前瞻性评估RSV-哮喘预测指数（RAPI）对严重RSV细支气管炎后哮喘和持续喘息发展的有效性。目的II：前瞻性评估失调的免疫系统，特别是树突状和调节性T细胞，对严重RSV细支气管炎后哮喘、持续性喘息和过敏性致敏发展的影响。目的III：检查哮喘、特应性、炎症与哮喘、气道高反应性和严重RSV细支气管炎后过敏性致敏相关基因的约1500个多态性的关系。

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.