Anti-Cytokine Therapy

Conclusion

Agents able to neutralize the effects of IL-1 or TNF have impressive effects in preclinical models of endotoxemia or sepsis. However, the ability of such therapies to reduce mortality or morbidity in critically ill septic patients appears to be, at best, very limited. Although it is simply possible that neither TNF-α nor IL-1 play an important role in clinical sepsis, it is more likely that the disappointing results of clinical trials reflects the heterogeneity of patient populations recruited into such studies. Both IL-1 and TNF-α are likely to be elevated early in proinflammatory cascades initiated by infection. These cytokines may be less important in perpetuating inflammatory processes once organ system dysfunction develops. In no study were patients identified and enrolled based on documented elevations in tissue or circulating levels of IL-1 or TNF-α. Therefore, it is difficult to know if the patients enrolled actually had excessive production of the cytokines being blocked. However, in the NORASEPTII study [30], a retrospective analysis of patients with detectable circulating TNF-α levels only showed a relative decrease in mortality of 9% in patients treated with anti-TNF-α antibodies. These results would suggest that even if septic patients with elevated TNF-α could be identified, the impact of anti-TNF-α therapies would be relatively modest.