Viral persistence & the microbiome in bronchiolitis and risk of recurrent wheeze

 描述(申请人提供)：毛细支气管炎是美国婴儿住院的头号原因。小规模队列研究(n&lt；210)表明，约50%的毛细支气管炎住院婴儿将发展为儿童哮喘。不幸的是，目前还不清楚哪些婴儿会患上哮喘，这一知识差距阻碍了初级预防工作。第35次多中心呼吸道研究合作(MARC-35)研究(U01 AI-87881；卡马戈，PI)是一项17中心前瞻性队列研究，于2014年4月完成了926名毛细支气管炎住院婴儿(85%的病房，15%的重症监护病房)的登记。在住院开始时，现场调查人员收集了鼻咽抽吸物、鼻拭子和血液，包括修改的哮喘预测指数(MAPI)和DNA所需的项目。我们也有大量的采访和医疗记录数据。在一项没有资助的附加研究中，SITE团队在住院时收集了鼻拭子，父母在住院后3周收集了鼻拭子，并在夏天孩子健康的时候再次收集了鼻拭子。有广泛的访谈和调查数据；以及全面的医疗记录。后续数据包括一年两次的家长访谈(到目前为止约90%的跟踪调查)，以及对医疗记录的年度审查。由于时机的原因，为期5年的U01补助金的主要结果是3岁前反复喘息。然而，所有参与者都同意接受6岁以下的随访，以确定是否患有哮喘。这一修订后的R01应用程序包括102名参与者在住院期间和3周后使用16S rRNA和实时PCR检测鼻拭子以及呼吸道合胞病毒和鼻病毒测序所产生的初步数据。尽管这些试验数据力度不够，但统计上没有意义的结果表明，鼻部微生物区系、病毒持久性和反复喘息之间存在新的关系。我们发现革兰氏杆菌(如莫拉氏菌)增多与增加(OR 1.8，P=0.18)和增加乳杆菌(如乳杆菌)a减少(OR 0.27，P=0.22)有关，反复喘息的几率中位数为2.2岁。类似地，我们发现革兰氏杆菌的增加与病毒持久性的增加(OR=1.9，P=0.19)和乳杆菌的减少(OR=0.14，P=0.05)有关。病毒持久性的定义是在住院3周后有相同的病毒(延迟清除)或不同的病毒(顺序感染)。病毒持续存在的儿童反复喘息的几率没有显著增加，中位年龄为2.2岁(OR 1.8，P=0.21)。使用夏季鼻拭子，我们还检查了住院期间存在的生物失调是否在几个月后持续。R01将提供资金，测试整个MARC-35队列中的近2000个鼻拭子。我们在所有目标上都有80%的力量。研究人员是由NIH资助的研究人员，他们在各自的领域拥有专业知识。这项研究推进了哮喘的初级预防，并与NIH 2009年儿科呼吸系统研究战略计划很好地匹配。

 DESCRIPTION (provided by applicant): Bronchiolitis is the #1 cause of infant hospitalization in the USA. Small cohort studies (n<210) suggest that ~50% of hospitalized infants with bronchiolitis will develop childhood asthma. Unfortunately, it remains unclear which infants will develop asthma and this knowledge gap has hindered primary prevention efforts. The 35th Multicenter Airway Research Collaboration (MARC-35) study (U01 AI-87881; Camargo, PI) is a 17-center prospective cohort study that completed enrollment of 926 infants hospitalized with bronchiolitis (85% ward, 15% intensive care unit) in April 2014. At start of the hospitalization, site investigators collected nasopharyngeal aspirates, nasal swabs, and blood, including items needed for the modified asthma predictive index (mAPI) and DNA. We also have extensive interview and medical records data. In an unfunded add-on study, site teams collected a nasal swab at hospitalization, and parents collected nasal swabs 3-weeks after the hospitalization and again over the summer when the child was healthy. There are extensive interview and survey data; and comprehensive medical records. Follow-up data include biannual parent interviews (~90% follow-up to date), and annual review of medical records. For timing reasons, the primary outcome of the 5- year U01 grant is recurrent wheezing by age 3 years. However, all participants were consented for follow-up to age 6 years to permit ascertainment of asthma. This revised R01 application includes preliminary data generated by testing nasal swabs from 102 participants at both hospitalization and 3 weeks later using 16S rRNA and real-time PCR and sequencing of respiratory syncytial virus and rhinovirus. Although these pilot data are underpowered, the statistically non-significant results suggest novel relations between the nasal microbiota, viral persistence, and recurrent wheezing. We found that increasing Gammaproteobacteria (e.g., Moraxella) was associated with an increased (OR 1.8, P=0.18), and increasing Lactobacillales (e.g., Lactobacillus) a decreased (OR 0.27, P=0.22), odds of recurrent wheezing by a median age of 2.2 years. Similarly, we found an increase in Gammaproteobacteria was associated with an increased (OR=1.9, P=0.19) and Lactobacillales with a decreased odds (OR=0.14, P=0.05) of viral persistence. Viral persistence is defined as having the same virus (delayed clearance) or a different virus (sequential infection) 3 weeks after hospitalization. And children with viral persistence had a non-significant increase in the odds of recurrent wheezing by a median age of 2.2 years (OR 1.8, P=0.21). Using the summer nasal swabs, we also examine if the dysbiosis present at hospitalization persists several months later. The R01 would provide funds to test the almost 2,000 nasal swabs from the entire MARC-35 cohort. We have >80% power in all Aims. The investigators are NIH-funded researchers with expertise in their fields. The study advances the primary prevention of asthma, and matches well with the 2009 NIH strategic plan for pediatric respiratory research.