Airway microbiome and age 6y asthma phenotypes in 2 diverse multicenter cohorts

项目摘要/摘要 毛细支气管炎是美国婴儿住院的头号原因，约有13万人住院 每年一次。小规模队列研究(n&lt；210)表明，40%-50%的婴儿住院时患有 毛细支气管炎以后会发展成哮喘。发展小学教育面临的最大挑战 针对这一大群儿童(实际上是所有儿童)的预防战略是非常早的 识别可改变的危险因素和哮喘的异质性。第35届多中心 航空研究协作(MARC-35)研究(U01AI-087881；卡马戈，PI)是一个17个中心 完成921例毛细支气管炎住院婴儿入选的前瞻性队列研究 在2014年。在这个多样化的队列中(53%的非裔美国人或西班牙裔美国人)，调查人员收集了 生物检疫，包括住院时(中位年龄3个月)和住院时的鼻拭子 3岁考试(R01AI-114552；卡玛戈，PI)。跟踪数据包括两年一次的家长 面谈和医疗记录到5岁，到目前为止有大约90%的随访率。此UG3/UH3 应用程序将：1)扩大世界上最大的严重毛细支气管炎队列(例如，通过 6岁面对面检查以诊断和表型哮喘)，以及2)建立在我们当地MARC-43的基础上 通过增加来自四个不同地点的600名健康婴儿(总计n=720)，对120名健康婴儿进行队列。 这两组人都经历了类似的程序(例如，在儿童早期进行了连续的鼻拭子)。我们的 最重要的假设是，呼吸道摩拉氏菌的丰富与增加的风险有关。 儿童哮喘，我们的试点数据是支持的。在目标1中，我们将研究 婴幼儿早期呼吸道微生物群对重症婴幼儿6岁哮喘风险的影响 毛细支气管炎(MARC-35)。在目标2中，我们将在健康婴儿(MARC-43)中进行同样的研究。 在目标3中，我们将研究呼吸道微生物组的纵向模式之间的关系(例如， 婴儿期、3岁、6岁)对儿童哮喘风险的影响。在一个子集中 200名儿童(每个队列100名)，我们将使用全基因组鸟枪(WGS)测序来 检测婴幼儿早期细菌种类和代谢潜能与发病风险的关系 哮喘。对于所有三个目标，我们将检查哮喘表型(例如，过敏)的相关性是否有所不同 哮喘)。研究人员是美国国立卫生研究院资助的研究人员，他们正在进行一项杰出的研究 环境。拟议的项目具有创新性，通过提供强有力的证据基础 微生物组靶向干预的未来发展，推进了对原始菌的研究 预防哮喘。此外，这两个种族/族裔多元化的群体将提供 ECHO财团，提供有关人口、发展、环境的全面数据 暴露、基因和两项已经协调的多中心美国研究的结果。

PROJECT SUMMARY / ABSTRACT Bronchiolitis is the #1 cause of hospitalization in US infants, with ~130,000 hospitalizations annually. Small cohort studies (n<210) suggest that 40-50% of infants hospitalized with bronchiolitis will later develop asthma. The greatest challenges for developing primary prevention strategies for this large group of children (indeed, all children) are the very early identification of modifiable risk factors and the heterogeneity of asthma. The 35th Multicenter Airway Research Collaboration (MARC-35) study (U01AI-087881; Camargo, PI) is a 17-center prospective cohort study that completed enrollment of 921 hospitalized infants with bronchiolitis in 2014. In this diverse cohort (53% African-American or Hispanic), investigators have collected biospecimens, including nasal swabs at the index hospitalization (median age 3 months) and at an age 3y exam (R01AI-114552; Camargo, PI). Follow-up data include biannual parent interviews and medical records to age 5 years, with ~90% follow-up to date. This UG3/UH3 application would: 1) extend the largest severe bronchiolitis cohort in the world (e.g., through an age 6y in-person exam to diagnose and phenotype asthma), and 2) build on our local MARC-43 cohort of 120 healthy infants by adding 600 healthy infants from four diverse sites (total n=720). Both cohorts undergo similar procedures (e.g., serial nasal swabs during early childhood). Our overarching hypothesis is that airway Moraxella abundance is associated with increased risk of childhood asthma, and our pilot data are supportive. In Aim 1, we will investigate the relation of the airway microbiome in early infancy to risk of age 6y asthma among infants with severe bronchiolitis (MARC-35). In Aim 2, we will do the same but among healthy infants (MARC-43). In Aim 3, we will investigate the relation of longitudinal patterns of the airway microbiome (e.g., infancy, age 3y, age 6y) to risk of childhood asthma in the two cohorts combined. In a subset of 200 children (100 from each cohort), we will use whole genome shotgun (WGS) sequencing to examine the relations of bacterial species and metabolic potential in early infancy to risk of asthma. For all 3 Aims, we will examine if associations differ by asthma phenotype (e.g., allergic asthma). The investigators are NIH-funded researchers working in an outstanding research environment. The proposed project is innovative and, by providing a strong evidence base for the future development of targeted microbiome interventions, advances research on the primary prevention of asthma. Moreover, the two racially/ethnically-diverse cohorts will provide the ECHO Consortium with comprehensive data on demographics, development, environmental exposures, genetics, and outcomes from two already-harmonized, multicenter U.S. studies.