Multimorbidity Phenotypes and Effects on Endothelium in Critically Ill Patients with Sepsis and Sepsis-induced ARDS

Project Summary / Abstract Acute respiratory distress syndrome (ARDS) is a common, costly, and often fatal inflammatory lung injury with an in-hospital mortality rate exceeding 40%. The leading cause is sepsis, termed sepsis-induced ARDS (si- ARDS). The incidence of ARDS spikes during bacterial and viral outbreaks, such as the H1N1 and COVID-19 pandemics. Chronic comorbidities, particularly metabolic syndrome (MetS), are independently associated with increased ARDS severity, highlighting a critical gap in understanding and managing these patients. This project aims to address the research gap surrounding multimorbidity and its effects on si-ARDS via endothelial-extracellular vesicle (EV) dysregulation. Our central hypothesis is that patients' baseline comorbidities influence EV intercellular cargo, which in turn affects the pulmonary endothelial cell (EC) response in si-ARDS, explaining clinical heterogeneity. The long-term goal is to define ICU subphenotypes based on multimorbidity status and explore how chronic conditions affect the endothelial-EV response to septic insults and lung injury to inform novel therapeutic strategies. We will leverage the Sepsis ECMO and ARDS (SEA) biorepository, an established biobank at Rhode Island Hospital's medical ICU, with over 260 participants enrolled. The study aims to validate preliminary observations in a larger, more diverse cohort of participants while isolating EVs for mechanistic experiments. We propose to: Aim 1: Identify subphenotypes of sepsis and si-ARDS participants based on chronic comorbidities via unsupervised cluster analysis and test each subphenotype's associations with clinical outcomes such as si- ARDS development and severity, mechanical ventilation, ICU length of stay, and in-hospital mortality. Aim 2: Determine and compare how EVs isolated from si-ARDS subphenotypes affect EC function. Aim 2a: Characterize and compare isolated EVs by cellular origin, then co-incubate EVs with naïve human pulmonary microvascular ECs and perform EC function assays. Aim 2b: Conduct mediation analysis to determine what portion of the observed risk between si-ARDS subphenotypes and clinical outcomes is mediated by EV-EC interaction. This innovative approach aims to phenotype sepsis and si-ARDS patients based on naturally co-occurring comorbidity clusters and unravel EV-EC interactions driving these subphenotypes, providing critical insights for precision-based treatments and preparing for future pandemics.