A Transcriptomic Severity Metric that Predicts Clinical Outcomes in Critically Ill Surgical Sepsis Patients

Purpose Prognostic metrics for the rapid and accurate prediction of sepsis severity that could elicit a meaningful change in clinical practice are currently lacking. Here, we evaluated a whole blood, multiplex host mRNA expression metric, Inflammatix-Severity-2 (IMX-SEV-2), for identifying septic, hospitalized patients for 30-day mortality, development of chronic critical illness (CCI), discharge disposition, and/or secondary infections. Methods This is a retrospective, validation cohort analysis of a prospectively enrolled 335 patient study with surgical sepsis treated in the surgical intensive care unit. Whole blood collected in PAXgene ® Blood RNA collection tubes at 24 hours post sepsis diagnosis was analyzed using a custom 29-mRNA classifier (IMX-SEV-2) in a CLIA-CAP-accredited diagnostic laboratory using the NanoString FLEX ® profiler. Results Among patients meeting Sepsis-3 criteria, the IMX-SEV-2 severity score was significantly better (p<0.05) at predicting secondary infections (AUROC 0.71) and adverse clinical outcomes (AUROC 0.75) than C-reactive protein (CRP), absolute lymphocyte counts (ALC), total white blood cell (WBC) count, age and Charlson comorbidity index (and better, albeit nonsignificantly, than IL-6 and APACHE II). Using multivariate logistic regression analysis, only combining the Charlson comorbidity index (AUROC 0.80) or APACHE II (AUROC 0.81) with the IMX-SEV-2 significantly improved prediction of adverse clinical outcomes, and combining with the Charlson comorbidity index for predicting 30-day mortality (AUROC 0.79). Conclusions The IMX-SEV-2 severity score was superior at predicting secondary infections and overall adverse clinical outcomes versus other common metrics. Importantly, combining a rapidly measured transcriptomic metric with clinical or physiologic indices has sufficient precision to optimize resource utilization and allow adjustments to patient management that may improve outcomes in surgical sepsis. Hospitalized patients who are septic and present with an elevated IMX-SEV2 severity score and pre-existing comorbidities would be strong candidates for clinical interventions aimed at reducing the risk of secondary infections and adverse clinical outcomes.