Anti-cytokine therapies in response to systemic infection

In the past 5 y, the 28 d mortality in patients with sepsis syndrome has decreased somewhat but still ranges from 30% to 40%; mortality in those patients with septic shock and multiple organ failure is higher. This high mortality is observed despite intensive care units that deliver hemodynamic, metabolic, ventilatory, and renal support. Clearly some patients survive the ordeal but it remains frustrating not being able to stop the downhill course leading to multiple organ failure and death in these patients. New therapies have been sought and tested, including those preventing the biologic activity of two pro-inflammatory cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF). Based on animal studies, anti-TNF and IL-1 therapy has been used to "rescue" the patient who continues to deteriorate in the face of considerable support efforts. Unfortunately, these anticytokine therapies have not dramatically reduced 28 d mortality in double-blind, placebo-controlled trials involving nearly 10000 patients, although there is a consistent but statistically nonsignificant decrease in mortality associated with anticytokine therapies. On the other hand, the same anti-TNF and IL-1-based therapies have made a dramatic improvement in the local inflammation and progression of rheumatoid arthritis. It appears that systemic inflammation of sepsis requires more than anticytokine monotherapy to significantly reduce mortality.