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

气管造口队列中的病毒性呼吸道感染：微生物组与宿主的相互作用

• 批准号: 10709010
• 负责人: Jonathan M Mansbach
• 金额: $ 86万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709010
• 关键词: Acute respiratory infection; Address; Antibiotics; Award; Bacteria; Bacterial Genes; Biological; Cause of Death; Child; Data; Disease; Ecosystem; Emergency Medicine; Enrollment; Functional disorder; Funding; Future; Gene Expression; Genes; Goals; Haemophilus influenzae; Healthcare; Hemophilus; Home; Hospital Charges; Hospitalization; Hospitals; Immune response; Infection; Inflammatory; Intensive Care; Interleukin-6; Knowledge; Link; Longitudinal Studies; Measures; Moraxella; Multicenter Studies; Nutritional; Nutritional Immunity; Oxygen; Participant; Pathogenicity; Pathway interactions; Pediatric Acute Lung Injury; Population; Prospective, cohort study; Protocols documentation; Research; Research Personnel; Sepsis; Severities; Signal Pathway; Site; Specimen; Structure; Suction; Testing; Trachea; Tracheostomy procedure; United States National Institutes of Health; Ventilator; Viral; Viral Bronchiolitis; Viral Respiratory Tract Infection; Virulence Factors; Virus; Virus Diseases; Work; aspirate; biobank; cohort; cost; health care service utilization; high risk population; host microbiome; insight; metatranscriptome; metatranscriptomics; microbial; microbiome; microbiota; mortality; pathogen; phenotypic data; respiratory colonization; respiratory microbiome; respiratory microbiota; sample collection; transcriptome; transcriptome sequencing; transcriptomics; treatment strategy; ventilation; virulence gene

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.

项目摘要 /摘要 气管切开术和家庭通风的儿童的年死亡率为5％，并且最高 所有美国儿童的医疗保健利用和费用，年度医院收费超过25亿美元。 Aris 在这类非常高风险的医疗保健超级独立人群中，死亡和住院的第一名。然而， 关于这些ARIS的病理生理学知之甚少 存在治疗途径。我们的长期目标是通过完善“一个 病原体 - 一种疾病”的ARI范式对ARI病理生物学的更生态系统的方法 为该人群制定更精确的ARI治疗策略。这项研究的目的是确定 在病毒ARI及其期间，微生物组的气道生态系统中的动力学和宿主反应 对ARI严重性的贡献。理由是，尽管大多数ARI是病毒的，但病毒感染了气道。 具有功能性细菌。在先前的气管造口研究中，我们发现血液（即较高的相对丰度） 在病毒ARI期间定植细菌。但是，尚不清楚这些血液是否代表感染 需要抗生素或与ARI严重程度有关。我们的横截面结果和其他结果表明 特异性微生物群组成的占主导地位的儿童与病毒ARI严重程度的增加有关。 现在，我们通过应用Metatranscriptomic（微生物功能）和转录组（主机）来扩展这项工作 反应）方法在18个月的儿童中纵向收集的气管抽吸物。 气管切开术和房屋通风。在我们1年R56 AI163013（Mansbach，pi）的前6个月中 优先奖，美国11家医院的现场团队将完成300名患有气管造口术的儿童 家庭通风。在2022年2月下旬，这些孩子将开始收集6个月的标本。与 急诊医学网络（EMNET）的专业知识以及儿科急性肺损伤的支持 败血症调查员（PALISI）网络，我们现在寻求完成剩余的4年工作，包括12个 更多的标本收集。使用在发病前后收集约1周收集的气管抽吸物（即 ARI的第1天，我们计划完成3个具体目标。在AIM 1中，我们将确定特定的细菌血液是否为 与较高的病毒ARI严重程度有关。在AIM 2中，我们将确定定植细菌的基础机制 成为致病性以及细菌血液如何导致病毒ARI严重程度。在AIM 3中，我们将确定是否 细菌血液与气道宿主反应和病毒ARI严重程度有关。我们的飞行员数据证明了 令人信服的支持我们的假设。这项研究的所有目标具有> 80％的功率，验证了 可概括的独立队列，并从多个身体站点创建一个强大的生物座席来测试未来 假设。这项研究的结果将为ARI病理生理学和 ARI严重程度的基础机制，包括气道微生物组与细菌血液和宿主的关系 在这个非常高风险的人群中的反应。最终，这些结果将为ARI治疗策略提供信息。