A Transcriptomic Biomarker to Quantify Systemic Inflammation in Sepsis - A Prospective Multicenter Phase II Diagnostic Study - Bauer, M.; Giamarellos-Bourboulis, E. J.; Kortgen, A.; Moller, E.; Felsmann, K.; Cavaillon, J. M.; Guntinas-Lichius, O.; Rutschmann, O.; Ruryk, A.; Kohl, M.; Wlotzka, B.; Russwurm, S.; et al. (EBioMedicine, 2016)
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.
Keywords: journalArticle; Adaptive Immunity; Clinical utility; Gene Expression Profiling/*methods; Gene Expression Regulation; Genetic Markers/*immunology; Host response; Humans; Immunity, Innate; Oligonucleotide Array Sequence Analysis/*methods; Point-of-Care Systems; Point-of-care; Prognosis; Prospective Studies; RT-qPCR; Sensitivity and Specificity; Sepsis/*diagnosis/genetics/immunology; Transcriptomic profiling