Host Gene Expression to Predict Sepsis Progression*

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.

Extending the ‘host response’ paradigm from sepsis to cardiogenic shock: evidence, limitations and opportunities

“…The hypothesis is that these gene-expression groupings reflect fundamental differences in the host response, which are not better explained by known clinical covariates like age, sex, blood cell proportions, causative organism or immunosuppression. Clinical outcomes can then be compared across the subgroups, with association found for mortality after adjusting for known confounders in sepsis by different research teams [ 87 ] or worsening of a clinical score [ 90 , 91 ].…”

Assessment of Infection Progression per Host Gene Expression*

“…The article submitted by Fiorino et al (3) reflects good utilization of previously collated clinical data and biospecimens, within the confines of a secondary, retrospective analysis. At least for their primary end point, the authors report negative study results.…”

“…In this issue of Critical Care Medicine , Fiorino et al (3) from Duke University, focus on R, the response of the host during infection, and examine host gene expression to predict infection/sepsis progression, with an ultimate clinical objective of predicting progression of infection/sepsis (sometimes confusing as the terms are used interchangeably) before it is readily clinically apparent. As the authors emphasize, delays in infection/sepsis treatment increase the risk of mortality (4, 5).…”

“…Although the investigation by Fiorino et al (3) reports overall negative results, it also suggests alterations in future study design to evaluate this exciting novel technology more precisely. Early, longitudinal assessment of messenger RNA expression, where each patient can serve as their own control, among populations at high risk for sepsis, is likely to yield important patient-centered, clinically meaningful findings.…”