Wednesday, May 14, 2025
5/14/2025
Advancing Precision Medicine for ARDS and Sepsis - Abstract: The acute respiratory distress syndrome (ARDS) and sepsis are common causes of death in critically ill patients, yet both are clinical syndromes defined by non-specific signs and symptoms which encompass major clinical and biological heterogeneity. Pre-clinical studies have identified numerous promising therapeutic agents for both ARDS and sepsis, but clinical trials of novel pharmacotherapies in these syndromes have been persistently negative, in large part due to this aforementioned heterogeneity. Thus, new approaches are needed to improve patient outcomes. We and others have identified two molecular phenotypes of ARDS and sepsis, termed “hyperinflammatory” and “hypoinflammatory,” in numerous cohorts. These phenotypes are defined by a combination of readily available clinical data and plasma protein biomarkers and have widely divergent clinical outcomes, with the hyper-inflammatory phenotype having, on average, double the in-hospital mortality of the hypoinflammatory phenotype. The hyperinflammatory phenotype appears to be a treatable trait which is present across syndromic diagnoses (i.e. in both ARDS and sepsis) and which responds preferentially to numerous therapies, including mechanical ventilation, fluid therapy, simvastatin, activated Protein C, and corticosteroids. This research has laid the foundation for a new paradigm for clinical research and treatment in critical care medicine and has already had a major impact on the field. However, several critical unanswered questions remain about the key differences in the functional immune response and/or pathogens driving these phenotypes, the biological pathways that represent key mechanistic nodes and potential druggable targets in each phenotype, and how to optimize real-time phenotyping and integrate analyses of phenotype-specific treatment responses into contemporary clinical studies. This proposal aims to address those key unanswered questions using 3 innovative and complementary strategies: (1) deep phenotyping of human samples using immunoprofiling and metagenomics, including analyses of trajectories of recovery; (2) in vivo and in silico modeling of inflammatory phenotypes to identify potentially effective targeted therapies; and (3) collaboration with clinical networks around the world to embed phenotyping into ongoing prospective studies and seek evidence for phenotype-specific treatment effect in contemporary trials. Our group is ideally positioned to address these key questions by virtue of our expertise in translational science and molecular phenotyping, including sophisticated analyses of high- dimensional data and experimental models of ARDS and sepsis, and our extensive experience studying both large RCT databases and our own hand-curated observational cohorts representing real-world patients. With the support of this new NHLBI R35 Outstanding Investigator Award, we aim to take the new paradigm developed by our current R35 from proof-of-concept to implementation in clinical research, and ultimately to impacting clinical care for our patients.
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