Viral respiratory infections in a tracheostomy cohort: Microbiome-host interplay

项目总结/摘要 气管切开和家庭通气的儿童年死亡率为5%， 医疗保健利用率和所有美国儿童的费用，每年的医院费用超过25亿美元。阿里斯 是这个非常高风险的医疗保健超级利用者人群中死亡和住院的头号原因。然而， 关于这些阿里斯的病理生理学、其严重程度的潜在机制知之甚少， 治疗途径是存在的。我们的长期目标是通过完善“一个 病原体-一种疾病”的ARI范式，以更生态系统范围的方法来研究ARI病理生物学， 为这一人群制定更精确的ARI治疗策略。本研究的目的是确定 呼吸道生态系统内的微生物组动态和病毒性ARI期间的宿主反应及其 对ARI严重程度的影响。其基本原理是，虽然大多数阿里斯是病毒，病毒感染气道殖民 功能性细菌。在以前的气管造口术研究中，我们发现了水华（即，较高的相对丰度） 在病毒性急性呼吸道感染期间的定居细菌。然而，目前还不清楚这些水华是否代表感染 需要抗生素或与ARI严重程度相关。我们和其他人的横截面结果表明， 具有特定微生物群组成优势的儿童与增加的病毒性ARI严重程度相关。 我们现在通过应用元转录组学（微生物功能）和转录组学（宿主）来扩展这项工作。 反应）的方法，纵向收集超过18个月的儿童气管吸出物， 气管切开术和家庭通风。在我们的1年R56 AI 163013（Mansbach，PI）高- 获得优先奖后，美国11家医院的现场团队将完成300名气管切开儿童的入组， 家庭通风2022年2月下旬，这些孩子将开始为期6个月的标本采集。与 急诊医学网络（EMNet）的专业知识和儿科急性肺损伤和 脓毒症调查人员（PALISI）网络，我们现在寻求完成剩余的4年工作，包括12 几个月的标本采集使用发病前约1周和发病时收集的气管抽吸物（即， 第一天的ARI，我们计划完成3个具体目标。在目标1中，我们将确定特定的细菌水华是否 与较高的病毒性ARI严重程度相关。在目标2中，我们将确定定植细菌的潜在机制 以及细菌大量繁殖如何导致病毒性ARI的严重程度。在目标3中，我们将确定 细菌大量繁殖与呼吸道宿主反应和病毒性ARI的严重程度有关。我们的试验数据表明 有力地支持了我们的假设本研究对所有目标的把握度均大于80%，验证了结果， 可推广的独立队列，并从多个身体部位创建一个强大的生物储存库，以测试未来 假设这项研究的结果将为ARI的病理生理学提供基本的见解， ARI严重程度的潜在机制，包括气道微生物组如何与细菌大量繁殖和宿主 在这一高风险人群中的反应。最终，这些结果将为ARI治疗策略提供信息。

PROJECT SUMMARY / ABSTRACT Children with tracheostomy and home ventilation have an annual mortality rate of 5%, and have the highest healthcare utilization and costs of all U.S. children, with annual hospital charges that exceed $2.5 billion. ARIs are the #1 cause of death and hospitalization in this very high-risk population of healthcare superutilizers. Yet, little is known about the pathophysiology of these ARIs, the mechanisms underlying their severity, and no treatment pathways exist. Our long term goal is to address these knowledge gaps by refining the “one pathogen-one disease” ARI paradigm to a more ecosystem-wide approach to ARI pathobiology in order to develop more precise ARI treatment strategies for this population. The objective of this study is to determine the dynamics – within the airway ecosystem – of the microbiome and host response during viral ARI and their contribution to ARI severity. The rationale is that while most ARIs are viral, viruses infect airways colonized with functional bacteria. In a previous tracheostomy study we found blooms (i.e., higher relative abundance) of a colonizing bacterium during a viral ARI. However, it remains unclear if these blooms represent infections requiring antibiotics or are associated with ARI severity. Our cross-sectional results and those of others show children with dominance of specific microbiota compositions are associated with increased viral ARI severity. We now extend this work by applying metatranscriptomic (microbial function) and transcriptomic (host response) approaches to tracheal aspirates collected longitudinally over an 18-month period from children with tracheostomy and home ventilation. In the first 6 months of our 1-year R56 AI163013 (Mansbach, PI) high- priority award, site teams at 11 U.S. hospitals will complete enrollment of 300 children with a tracheostomy and home ventilation. In late February 2022, these children will begin 6 months of specimen collection. With the expertise of the Emergency Medicine Network (EMNet) and the support of the Pediatric Acute Lung Injury & Sepsis Investigators (PALISI) network, we now seek to complete the remaining 4 years of work, including 12 more months of specimen collection. Using tracheal aspirates collected ~1 week before and at the onset (i.e., day 1) of ARI, we plan to complete 3 Specific Aims. In Aim 1 we will determine if specific bacterial blooms are related to higher viral ARI severity. In Aim 2 we will determine the mechanisms underlying colonizing bacteria becoming pathogenic and how bacterial blooms contribute to viral ARI severity. In Aim 3 we will determine if bacterial blooms are related to the airway host response and viral ARI severity. Our pilot data demonstrate compelling support for our hypotheses. This study has >80% power for all aims, validates the results in a generalizable independent cohort, and creates a robust biorepository from multiple body sites to test future hypotheses. Results from this study will provide fundamental insights into ARI pathophysiology and mechanisms underlying ARI severity including how the airway microbiome relates to bacterial blooms and host responses in this very high-risk population. Ultimately, these results will inform ARI treatment strategies.