Microbiome-host interplay in viral respiratory infections: A tracheostomy cohort

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。我们的长期目标是将“一种病原体一种疾病”的ARI模式改进为 更生态系统范围的ARI病理学方法，以制定更精确的ARI治疗策略 对于这个人口。本研究的总体目标是确定生态系统内的相互作用（即， 呼吸道微生物组和宿主反应之间的关系）。理由是，虽然大多数 阿里斯是病毒性的，病毒感染功能性细菌定植的气道。在以前的气管造口术研究中， 发现了花（即，增加的相对丰度）。但 目前尚不清楚这些水华是否代表需要抗生素的感染或与ARI的严重程度有关。 我们和其他人的横断面结果显示，特定微生物群占优势的儿童 组合物与增加的病毒性ARI严重性相关。我们现在将通过应用 气管吸出物的metatranscriptomic（微生物功能）和transcriptomic（宿主反应）方法 纵向收集超过18个月的儿童气管造口术和家庭通风。到 进行这项研究，我们提出了一个10个中心，前瞻性队列的300名儿童气管造口术和家庭 这将是迄今为止在该人群中进行的最大和最全面的研究。我们将 在急诊医学网络（EMNet）的专业知识和 儿科急性肺损伤和脓毒症研究者（PALISI）网络。使用收集的气管抽吸物~1 在发病前一周和发病时（即，第一天的ARI，我们计划完成3个具体目标。在目标1中， 确定特定的细菌大量繁殖是否与较高的病毒性ARI严重程度有关。在目标2中，我们将确定 定植细菌成为致病菌的潜在机制以及细菌大量繁殖如何导致病毒感染 ARI严重程度。在目标3中，我们将确定细菌大量繁殖是否与气道宿主反应有关， ARI严重程度。我们的试点数据证明了我们的假设令人信服的支持。该研究具有>80%的功效 对于所有目标，在一个可推广的独立队列中验证结果，并创建一个强大的生物储存库 从多个生态环境中收集数据来检验未来的假设。这项研究的结果将提供 对ARI病理生理学和ARI严重程度潜在机制的基本见解，包括 呼吸道微生物组与这一非常高风险人群中的细菌大量繁殖和宿主反应有关。最后， 这些结果将为ARI的治疗策略提供信息，包括抗生素的使用。此R 01具有短期和长期 目的是全面了解这一高风险、不断增长的人群中的阿里斯。

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 refine 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 overall objective of this study is to determine the interplay within the ecosystem (i.e., between airway microbiome and host response) in the severity of viral ARI. 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., increased 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 will 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. To conduct this study, we propose a 10-center, prospective cohort of 300 children with a tracheostomy and home ventilation, which would be the largest and most comprehensive study in this population to date. We will conduct this study with the expertise of the Emergency Medicine Network (EMNet) and the support of the Pediatric Acute Lung Injury & Sepsis Investigators (PALISI) network. 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 ecological environments for testing future hypotheses. Results from this study will provide fundamental insights into ARI pathophysiology and the 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, including antibiotic use. This R01 has short- and long-term objectives to comprehensively understand ARIs in this high-risk, growing population.