The search for biomarkers in the critically ill: a cautionary tale.

The search for biomarkers has been described as a dismal patchwork of fragmented research. We review biomarkers in sepsis in the critically ill in terms of conventional single circulating proteins. Despite sepsis biomarker publications trebling over the past 6 years, currently only one, procalcitonin, has materialised promise. We survey genomic biomarker initiatives, single nucleotide polymorphisms (SNPs) and gene signatures. Despite many SNP associations with sepsis susceptibility and a limited number of genome-wide association studies, the status of these associations is that of genomic signposts only. The standing of gene signatures in the paradigmatic discipline, breast cancer, is described. Uncertainties in the understanding of the sepsis process are documented - the dissociation between blood and tissue element activity, or compartmentalisation. The paradox of the active search for gene signatures to refine the sepsis phenotype and discover target subtypes for new therapies in the absence of such therapies is presented.