Is there value in plasma cytokine measurements in patients with severe trauma and sepsis?

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.

Cigarette Smoke Attenuates the Nasal Host Response to Streptococcus pneumoniae and Predisposes to Invasive Pneumococcal Disease in Mice

“…Pneumococcal bacteremia in mice was also associated with leukopenia, an observation that is consistent with the lymphopenia and splenic lymphocyte apoptosis described in septic patients and mouse models of sepsis (38)(39)(40). Moreover, all endpoint mice had detectable serum IL-6, which is thought to predict organ dysfunction and mortality in sepsis (41,42). These findings mirror clinical observations of cigarette smoking as a risk factor for IPD; smokers are overrepresented in the population of IPD patients at 58%, compared to 24% for control subjects (6).…”

Serum Neutrophil Gelatinase Associated Lipocalin (NGAL) Outperforms Serum Creatinine in Detecting Sepsis-Induced Acute Kidney Injury, Experiments on Bilateral Nephrectomy and Bilateral Ureter Obstruction Mouse Models

“…sNGAL is associated with serum IL-6 Serum IL-6, an important inflammatory sepsis cytokine, is used as a prognostic prediction and early biomarker of patients with sepsis (32)(33)(34). In animal experiments, Otto et al (18) explored sNGAL and several pro-and anti-inflammatory cytokines in a CLP mouse model.…”

Clearance of Selected Plasma Cytokines with Continuous Veno-Venous Hemodialysis Using Ultraflux EMiC2 versus Ultraflux AV1000S

“…Extracorporeal therapies are mainly applied to support or replace kidney function and to ameliorate uremic complications in sepsis, but there is evidence that these approaches might have effects beyond renal support by depleting inflammatory mediators, such as cytokines, chemokines, and complement factors from the circulation [8,9,10,11]. A significant portion of cytokines in the circulation, however, are bound to plasma proteins or associated with their target cells [12,] and are therefore not directly accessible to depletion by renal replacement therapies. Still, the depletion of unbound portions of these factors from the circulation may support the restoration of immune homeostasis by inducing re-equilibration of free and bound cytokine fractions.…”