Host-Microbe Multiomic Profiling Predicts Mortality in Sepsis.

Sepsis is a leading cause of mortality and involves a dysregulated host response to infection. Host and microbe have historically been considered independently in studies of sepsis, limiting our understanding of key relationships driving mortality. We sought to identify host and microbial factors associated with sepsis mortality and build prognostic classifiers. We studied 321 critically ill adults and adjudicated sepsis status. From whole blood collected within 24 hours of admission we performed transcriptional profiling, and from plasma we carried out proteomics and metagenomics. We evaluated associations between in-hospital mortality and gene expression, protein levels and microbial metagenomic data, and built support vector machine-based prognostic classifiers. In patients with sepsis, mortality associated with increased expression of genes related to neutrophil degranulation, lower expression of genes related to T cell signaling, and higher interleukin-8. Mortality also associated with higher microbial mass and greater bacterial relative dominance. Similar findings were observed in a broader group that also included patients with culture-negative sepsis or indeterminate sepsis status. An integrated host-microbe metagenomic classifier predicted sepsis mortality with an area under the curve (AUC) of 0.79, and a host transcriptomic classifier performed comparably with an AUC of 0.75. Both performed better (p<0.05 by paired DeLong tests) that the APACHE-III score (AUC of 0.69). Taken together, our findings provide a conceptual advance in the understanding of host and microbial factors associated with mortality in critical illness and demonstrate a new approach to mortality prediction in sepsis.