Identifying predictive gene expression signatures of sepsis severity

Sepsis is a common and very heterogenous syndrome defined as the life-threatening organ dysfunction caused by an aberrant host response to infection. In the earliest stages, sepsis diagnoses are often missed due to non-specific symptomatology resulting in a rapid progression to severe sepsis. Gene expression signatures that measure host immune responses have been shown to provide more sensitive prognostic tools than existing clinical criteria, permitting early prediction of high-risk patients. We recruited, from six global cohorts, 266 suspected sepsis patients in the emergency room and 82 suspected pulmonary sepsis patients in the intensive care unit with varying disease severity, and 44 healthy controls. Most recently, I analyzed 135 patients with Covid-19 disease that showed immune responses overlapping with sepsis. From this, I identified candidate gene expression signatures reflecting endotypes and severity markers, using the transcriptomics method, RNA-Seq, and statistical and computational methods. I determined that early sepsis patients could be stratified into five endotypes defined by distinct pathobiological mechanisms, including unique gene expression differences and accurate, predictive gene expression pairs. Two of the five endotypes were associated with a higher tendency towards severe sepsis and mortality, two demonstrated much lower severity, and one was relatively benign. Diverse molecular responses were also observed independently of endotypes; thus, concomitant cross-cutting severity signatures that directly predicted sepsis-induced organ dysfunction and mortality were identified, in addition to dysregulated and co-expressed module genes. The endotype signatures were often consistent with cellular shifts in neutrophil numbers and function, whereas dysregulated molecular responses like cellular reprogramming and hyperinflammation reflected prognoses. These signatures were assessed in other conditions (e.g., pancreatitis, appendicitis, myocardial infarction), which indicated the signatures captured mechanisms specific to early sepsis/sepsis. A compendium of dysregulated genes and signatures in sepsis was curated from the literature, confirming that these signatures involved wellcharacterized genes. This study demonstrated that signatures relevant to the development of life-threatening sepsis can be observed as early as first entry into the ER. These signatures will enable the development of diagnostics and targeted therapeutics, and importantly, when used early in the sepsis disease course, could prevent rapid patient deterioration, mortality, and poor long-term outcomes.Science, Faculty ofGraduat