Background: Sepsis is a global health problem associated with significant morbidity and mortality. Detrimental sepsis effects are attributed to a "cytokine storm." However, anti-cytokine therapies have failed to lower sepsis mortality. We aim to characterize levels of key cytokines in sepsis patients and healthy controls and relate TNF levels to patient characteristics and outcomes. Methods: We performed a systematic review and meta-analysis. Medline, Embase, Cochrane Library, and Web of Science Core Collection databases were searched from 1985 to May 2020 for studies in English. We included randomized controlled trials (RCTs), controlled trials, cohort studies, case series, and cross-sectional studies that reported mean levels of cytokines in the circulation thought to be relevant for sepsis pathogenesis. We also evaluated concentrations of these cytokines in healthy persons. Quality in Prognosis Studies tool was used to assess the methodological quality of included studies. We extracted summary data from published reports. Data analyses were performed using a random-effects model to estimate pooled odds ratios (OR) with 95% confidence intervals for cytokine levels and mortality. This systematic review is registered in PROSPERO (CRD42020179800). Findings: We identified 3654 records, and 104 studies were included with a total of 3250 participants. The pooled estimated mean TNF concentration in sepsis patients was 58.4 pg/ml (95% Confidence Interval or CI 39.8-85.8 pg/ml) and 5.5 pg/ml (95% CI 3.8-8.0 pg/ml) in healthy controls. Pooled estimate means for IL-1{beta} and IFN{gamma} in sepsis patients were 21.8 pg/ml and 63.3 pg/ml, respectively. Elevated TNF concentrations associated with increased 28-day sepsis mortality (p=0.001). In subgroup analyses, TNF levels did not relate to sepsis source, sepsis severity, or sequential organ failure assessment (SOFA) score. Interpretation: TNF concentration in sepsis is increased approximately 10-fold compared to healthy persons, and TNF associated with sepsis mortality but not with sepsis severity. The concept that elevated cytokines cause sepsis should be revisited in the context of these data.
Proinflammatory Cytokine Levels in Sepsis and in Health and TNFÎ± Association with Sepsis Mortality and patient characteristics: a Systematic Review and Meta-analysis