Abstract
For the past thirty years, since IL-1β and TNFα were first cloned, there have been efforts to measure plasma cytokine concentrations in patients with severe sepsis and trauma, and to use these measurements to predict clinical outcome and response to therapies. The numbers of cytokines and chemokines that have been measured in the plasma have literally exploded with the development of multiplex immune approaches. Dozens of relatively small cohort studies have shown plasma cytokine concentrations correlating with outcome in sepsis and trauma. Despite what appears to be a consensus that plasma cytokine concentrations should be useful in the clinical setting, only two cytokines, IL-6 and procalcitonin, have approached routine clinical use. IL-6 has been used as a research tool for entry into sepsis-intervention trials, while procalcitonin is being used clinically at a large number of institutions to distinguish sepsis from other inflammatory processes. For most cytokines, the relative lack of sensitivity and specificity of individual or multiplex cytokine measurements has hindered their utility to predict clinical trajectory in individual patients. The problem rests with a general misunderstanding of cytokine biology, failing to appreciate the general paracrine nature of these mediators, the presence of binding proteins, chaperones and inhibitors in the plasma, and the rapid clearance of these proteins by binding to cell receptors and clearance predominantly by the kidney. The future of using plasma cytokine measurements as an indicator of sepsis/trauma severity or predicting outcome is generally behind us, although there is optimism that procalcitonin measurements may ultimately prove to have utility in the diagnosis of severe sepsis.