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

项目总结/摘要 细支气管炎是美国婴儿住院的头号原因，约有13万例住院 每年。小队列研究（n<210）表明，40-50%的婴儿住院与 细支气管炎以后会发展成哮喘。发展小学面临的最大挑战 针对这一大批儿童（实际上是所有儿童）的预防战略是非常早期的， 识别可改变的风险因素和哮喘的异质性。第35届多中心 气道研究协作（MARC-35）研究（U 01 AI-087881; Camargo，PI）是一项17个中心的研究， 一项前瞻性队列研究，完成了921例毛细支气管炎住院婴儿的入组 2014年在这个多样化的队列（53%的非洲裔美国人或西班牙裔）中，研究人员收集了 生物标本，包括首次住院时的鼻拭子（中位年龄3个月）和 3岁检查（R 01 AI-114552; Camargo，PI）。随访数据包括一年两次的父母 访谈和医疗记录，直到5岁，到目前为止，随访率约为90%。UG3/UH3 应用将：1）扩展世界上最大的严重细支气管炎群组（例如，通过 年龄6岁的人在现场考试诊断和表型哮喘），和2）建立在我们当地的MARC-43 120名健康婴儿的队列，增加了来自四个不同地点的600名健康婴儿（总n=720）。 两个队列都经历了类似的程序（例如，儿童早期的连续鼻拭子）。我们 总体假设是，气道莫拉菌丰度与以下风险增加相关： 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 婴幼儿早期气道微生物群与6岁以上重度哮喘患儿发生哮喘风险 细支气管炎（MARC-35）。在目标2中，我们将做同样的事情，但在健康婴儿中（MARC-43）。 在目标3中，我们将研究气道微生物组的纵向模式（例如， 婴儿期、3岁、6岁）与儿童期哮喘风险的关系。的子集中 200名儿童（每个队列100名），我们将使用全基因组鸟枪（WGS）测序， 研究细菌种类和婴儿早期代谢潜力与 哮喘对于所有3个目标，我们将检查是否存在哮喘表型的相关性（例如，过敏 哮喘）。研究人员是NIH资助的研究人员，他们在一项杰出的研究中工作， 环境拟议的项目具有创新性，通过提供强有力的证据基础， 有针对性的微生物组干预措施的未来发展，推进了对主要微生物的研究 预防哮喘。此外，这两个种族/族裔多样化的群体将提供 ECHO联合会，提供人口、发展、环境 暴露、遗传学和来自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.