Decreased cytokine production by mononuclear cells after severe gram-negative infections: early clinical signs and association with final outcome

Background: Failure of circulating monocytes for adequate cytokine production is a trait of sepsis-induced immunosuppression; however, its duration and association with final outcome are poorly understood. Methods: We conducted a substudy of a large randomised clinical trial. Peripheral blood mononuclear cells (PBMCs) were isolated within the first 24 h from the onset of systemic inflammatory response syndrome in 95 patients with microbiologically confirmed or clinically suspected gram-negative infections. Isolation was repeated on days 3, 7 and 10. PBMCs were stimulated for cytokine production. The study endpoints were the differences between survivors and non-survivors, the persistence of immunosuppression, and determination of admission clinical signs that can lead to early identification of the likelihood of immunosuppression. Results: PBMCs of survivors produced significantly greater concentrations of tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8, IL-10, interferon-. and granulocyte-macrophage colony-stimulating factor after day 3. Using ROC analysis, we found that TNF-a production less than 250 pg/ml after lipopolysaccharide stimulation on day 3 could discriminate patients from healthy control subjects; this was associated with a 5.18 OR of having an unfavourable outcome (p = 0.046). This trait persisted as long as day 10. Logistic regression analysis showed that cardiovascular failure on admission was the only independent predictor of defective TNF-alpha production on day 3. Conclusions: Defective TNF-alpha production is a major trait of sepsis-induced immunosuppression. It is associated with significant risk for unfavourable outcome and persists until day 10. Cardiovascular failure on admission is predictive of defective TNF-alpha production during follow-up.