Abstract
OBJECTIVES: Sepsis causes significant mortality. However, most patients who die of sepsis do not present with severe infection, hampering efforts to deliver early, aggressive therapy. It is also known that the host gene expression response to infection precedes clinical illness. This study seeks to develop transcriptomic models to predict progression to sepsis or shock within 72 hours of hospitalization and to validate previously identified transcriptomic signatures in the prediction of 28-day mortality. DESIGN: Retrospective differential gene expression analysis and predictive modeling using RNA sequencing data. PATIENTS: Two hundred seventy-seven patients enrolled at four large academic medical centers; all with clinically adjudicated infection were considered for inclusion in this study. MEASUREMENTS AND MAIN RESULTS: Sepsis progression was defined as an increase in Sepsis 3 category within 72 hours. Transcriptomic data were generated using RNAseq of whole blood. Least absolute shrinkage and selection operator modeling was used to identify predictive signatures for various measures of disease progression. Four previously identified gene signatures were tested for their ability to predict 28-day mortality. There were no significant differentially expressed genes in 136 subjects with worsened Sepsis 3 category compared with 141 nonprogressor controls. There were 1,178 differentially expressed genes identified when sepsis progression was defined as ICU admission or 28-day mortality. A model based on these genes predicted progression with an area under the curve of 0.71. Validation of previously identified gene signatures to predict sepsis mortality revealed area under the receiver operating characteristic values of 0.70-0.75 and no significant difference between signatures. CONCLUSIONS: Host gene expression was unable to predict sepsis progression when defined by an increase in Sepsis-3 category, suggesting this definition is not a useful framework for transcriptomic prediction methods. However, there was a differential response when progression was defined as ICU admission or death. Validation of previously described signatures predicted 28-day mortality with insufficient accuracy to offer meaningful clinical utility.