PROJECT SUMMARY The Acute Respiratory Distress Syndrome (ARDS), pneumonia and sepsis are life-threatening conditions whose clinical and biological manifestations are frequently interwoven: pneumonia is a common cause of sepsis, and both are predisposing conditions for ARDS. While progress has been made to reduce mortality in these conditions, their significant heterogeneity is a major factor limiting therapeutic progress. Future interventions must be informed by an improved understanding of phenotypes and endotypes within these conditions to better design clinical trials. The proposed Great Lakes Clinical Center (GLCC) of the ARDS, Pneumonia and Sepsis (APS) Consortium, consisting of the University of Michigan, Henry Ford Hospital, the University of Cincinnati, and the University of Chicago will screen, enroll, collect data and transport biospecimens on at least 1000 patients of this 5000-patient observational study over a 6-year period. Clinical information and biospecimens from the index hospitalization and from long-term follow up at 3, 6 and 12 months will be collected. Biospecimens will include blood, stool, pharyngeal swabs, and endotracheal aspirates. Specimens will be transported to the Clinical Coordinating Center for storage and future analysis. The rich database we propose will provide investigators with innumerable opportunities to biologically interrogate the heterogeneity of APS patients. Included in this database are opportunities for investigators to study clinical disease trajectories; blood cytokines, DNA, RNA, and metabolites; gastrointestinal and respiratory microbiota; and chest and body imaging. In addition, we propose two unique data collection approaches: morphometric characterization of CT images (to rigorously characterize body composition) and nasal epithelial curettage (to study the host transcriptomic response within the respiratory tract). We also propose a Center-specific study that will elucidate the role of the microbiome in the development, trajectory, and recovery of ARDS, pneumonia, and sepsis. The microbiome is an important yet incompletely understood source of biologic heterogeneity, and represents a highly promising treatment target. Yet we lack an actionable understanding of its role in these conditions. Our team will leverage the above-described specimen and data collection with field-leading methodological expertise to (Aim 1) identify the pathways by which gut and respiratory microbiota participate in the acute development and trajectory of sepsis, ARDS, and pneumonia and (Aim 2) determine the microbial and metabolic pathways by which gut microbiota influence long-term recovery after these conditions. We will use cutting-edge molecular techniques to characterize the microbiome and its metabolic products, and we will use sophisticated causal inference analyses to study the mediating role of the microbiome in clinical outcomes. By interrogating the role of the microbiome in the development, trajectory, and recovery of these conditions, this project will facilitate the development of microbiome-targeted therapies for their prevention and treatment.

PROJECT NARRATIVE The Great Lakes Clinical Center (GLCC) of the ARDS, Pneumonia and Sepsis (APS) Consortium, consisting of the University of Michigan, Henry Ford Hospital, the University of Cincinnati, and the University of Chicago, is proposing a rich, consortium-wide collection of clinical data and biomarker specimens of patients hospitalized with ARDS, pneumonia, and sepsis which will provide investigators with a broad opportunity to identify endotypes and subphenotypes of these conditions and better inform future clinical trials. The GLCC will screen, enroll, and collect data and biospecimens on a cohort of more than 1,000 hospitalized patients with these conditions at our 4 sites, including data from follow-up at 3, 6 and 12 months. In addition, we propose a Center-specific study that will (Aim 1) identify the pathways by which gut and respiratory microbiota participate in the acute development and trajectory of sepsis, ARDS, and pneumonia and (Aim 2) determine the microbial and metabolic pathways by which gut microbiota influence long-term recovery after these conditions.