Pathogen-specific host response in critically ill patients with blood stream infections: a nested case–control study

Abstract

Background: Knowledge of the contribution of the pathogen to the heterogeneity of the host response to infection is limited. We aimed to compare the host response in critically ill patients with a bloodstream infection (BSI). Methods: RNA profiles were determined in blood obtained between one day before and after a positive blood culture. Differential expression and pathway analyses were performed on independent patients’ samples by RNA sequencing (discovery) or microarray (validation). Additional patients were included for the discovery and validation of transcriptome classifiers of pathogen-specific BSIs. Twenty biomarkers reflecting key host response pathways were measured in blood. Findings: We included 341 patients, among which 255 with BSI, 25 with viral infection and 61 non-infectious controls. The cultured pathogen explained 41·8% of the blood transcriptomic variance in patients with BSI. Gene set enrichment analysis showed a global resemblance between monomicrobial BSIs caused by Streptococcus, Staphylococcus aureus and Escherichia coli, which were clearly different from BSI caused by coagulase-negative staphylococci or Enterococcus. BSI by Streptococcus was associated with the highest number of differentially expressed genes, indicating strong innate and adaptive immune activation. An eight-gene streptococcal classifier performed well across different Streptococcus species, and was validated in external cohorts. Plasma biomarker profiling showed that E. coli BSI was associated with the strongest response in the cytokine and systemic inflammation domain, and S. aureus BSI with the strongest endothelial cell activation. Interpretation: The causative pathogen explains a substantial part of the heterogeneity of the host response in critically ill patients with BSI. Funding: Center for Translational Molecular Medicine and the European Commission.