Longitudinal analysis of respiratory tract microbiome change and sequence-based infection diagnosis during mechanical ventilation

项目总结 下呼吸道感染(LRTI)经常导致呼吸衰竭，需要机械治疗。 呼吸机和呼吸机相关肺炎是依赖于 机械通风。尽管LRTI在重症监护中具有临床重要性，但呼吸动力学 机械通气期间可能与感染和呼吸道风险相对应的肠道微生物群 定义LRTI的肠道微生物组特征仍然知之甚少。拟议的研究将利用深度 危重病患者上呼吸道和下呼吸道标本中16S rRNA基因序列分析 机械通风受试者，以提高对医疗保健相关微生物群的了解 变化，LRTI微生物生态，LRTI发病机制。这项研究将(1)定义纵向变化 机械通气时上、下呼吸道细菌菌群的分布； 确定与临床相关的呼吸道微生物群落结构特征 LRTI的诊断和LRTI的缺失；以及(3)评估16S rRNA基因测序对 确定引起下呼吸道感染的细菌病原体。执行这些具体目标将阐明 医疗保健暴露与呼吸道微生物群变化以及呼吸道微生物群变化之间的关系 肠道微生物群变化与下呼吸道感染的发病机制。因此，拟议的研究将构成一个基础 独立从事以患者为中心的研究，致力于提高对医疗保健的理解- 相关微生物群的变化和感染。AIMS的执行也将提供主要的调查员 具有指导大型观察性微生物组研究的基本经验，并接受过基本的 需要先进的统计和生物信息学方法来分析患者之间的相互作用 因素(潜在疾病、抗生素暴露等)、微生物生态和感染。研究方案 与职业发展计划相匹配，该计划利用了加州大学的广泛资源 宾夕法尼亚州，并利用一个导师委员会在广泛的，互补的专业知识 传染病流行病学，医疗保健相关感染，深度测序方法，微生物学， 和重症监护。艾宾·劳滕巴赫博士、弗雷德里克·D·布什曼博士和罗纳德·G·科尔曼博士将支持 在勾勒出的作为独立临床调查员的成功职业生涯的道路上，首席研究员。

PROJECT SUMMARY Lower respiratory tract infection (LRTI) frequently contributes to respiratory failure that requires mechanical ventilation, and ventilator-associated pneumonia is a feared complication in patients dependent upon mechanical ventilation. Despite the clinical importance of LRTI in critical care, the dynamics of the respiratory tract microbiome during mechanical ventilation that may correspond with risk for infection and the respiratory tract microbiome features that define LRTI remain poorly understood. The proposed study will utilize deep sequencing of the 16S rRNA gene from upper and lower respiratory tract samples obtained from critically ill, mechanically ventilated subjects in order to improve understanding of healthcare-associated microbiome change, LRTI microbial ecology, and LRTI pathogenesis. The study will (1) define the longitudinal change that occurs in the upper and lower respiratory tract bacterial microbiome during mechanical ventilation; (2) determine the features of respiratory tract microbiome community structure that correlate with the clinical diagnosis of LRTI and with the absence of LRTI; and (3) evaluate the ability of 16S rRNA gene sequencing to identify bacterial pathogens responsible for LRTI. Execution of these specific aims will elucidate the relationships between healthcare exposures and respiratory tract microbiome change, and between respiratory tract microbiome change and LRTI pathogenesis. The proposed study will thus form a foundation for an independent career in patient-oriented research dedicated to improving understanding of healthcare- associated microbiome change and infection. Execution of the aims will also provide the primary investigator with essential experience directing a large, observational microbiome study and with essential training in the advanced statistical and bioinformatics methods necessary to analyze the interaction between patient-level factors (underlying disease, antibiotic exposure, etc), microbial ecology, and infection. The research proposal is paired with a career development plan that makes use of the extensive resources of the University of Pennsylvania, and which capitalizes on a mentorship committee with broad, complementary expertise in infectious diseases epidemiology, healthcare-associated infection, deep sequencing methods, microbiology, and critical care. Dr. Ebbing Lautenbach, Dr. Frederic D. Bushman, and Dr. Ronald G. Collman will support the primary investigator in the outlined path towards a successful career as an independent clinical investigator.