A Transcriptomic Biomarker to Quantify Systemic Inflammation in Sepsis — A Prospective Multicenter Phase II Diagnostic Study

• Pro- and anti-inflammatory signaling occurs simultaneously in the host response to infection.
• This response is currently monitored using biomarkers restricted to the pro-inflammatory component of innate immunity.
• We developed a biomarker panel consisting of 7 transcripts that can assess both facets at the point of care.The concept that a selective, overwhelming systemic inflammation, the “Systemic Inflammatory Response Syndrome (SIRS)”, triggers organ failure subsequent to infection has lately been abandoned as it neglects parallel occurring anti-inflammatory responses or defects in the adaptive immune system.The present findings suggest that a compound panel of nucleic acid biomarkers that was developed in independent training and verification cohorts and transferred to a point-of-care platform can more comprehensively describe the host response. Quantification of an enhanced innate immunity might inform studies of anti-inflammatory therapies, while measurement of derangements in specific immunity might guide strategies to restore immune effector functions.

Development of a dysregulated immune response discriminates sepsis from uncomplicated infection. Currently used biomarkers fail to describe simultaneously occurring pro- and anti-inflammatory responses potentially amenable to therapy.Marker candidates were screened by microarray and, after transfer to a platform allowing point-of-care testing, validated in a confirmation set of 246 medical and surgical patients. We identified up-regulated pathways reflecting innate effector mechanisms, while down-regulated pathways related to adaptive lymphocyte functions. A panel of markers composed of three up- (Toll-like receptor 5; Protectin; Clusterin) and 4 down-regulated transcripts (Fibrinogen-like 2; Interleukin-7 receptor; Major histocompatibility complex class II, DP alpha1; Carboxypeptidase, vitellogenic-like) described the magnitude of immune alterations. The created gene expression score was significantly greater in patients with definite as well as with possible/probable infection than with no infection (median (Q25/Q75): 80 (60/101)) and 81 (58/97 vs. 49 (27/66), AUC-ROC = 0.812 (95%-CI 0.755–0.869), p < 0.0001). Down-regulated lymphocyte markers were associated with prognosis with good sensitivity but limited specificity.Quantifying systemic inflammation by assessment of both pro- and anti-inflammatory innate and adaptive immune responses provides a novel option to identify patients-at-risk and may facilitate immune interventions in sepsis.