Immunomodulation strategies in the critically ill

• Severe sepsis is the result of an infectious stimulus that triggers a hyper-inflammatory response and results in multiple organ failure. This hyper immune response triggers a phase of immunoparalysis that results in the patient’s inability to resist and clear infections, causing the delayed mortality observed is some septic patients.
• The inflammatory and coagulation cascades are closely linked such that a significant aspect of the disease process is attributed to the activation of the coagulation cascade by circulating inflammatory mediators.
• Therapeutic approaches to sepsis have targeted the hyper-inflammatory response, inhibition of the subsequent coagulation cascade, and immunostimulation during the immunoparalysis phase.
• Proven beneficial therapies for sepsis are limited to the mechanical eradication of the source of infection, antibiotics to clear the organism, the judicious use of fluids to support organ perfusion, and oxygen supplementation. Studies evaluating immunotherapeutics for the treatment of severe sepsis have failed to show efficacy in clinical trials.
• Further research may demonstrate effectiveness using a strategy of targeting therapies based on an improved identification of the patient’s phase of sepsis, use of combination therapies, a better understanding and strategy aimed at specific host-organism interactions, and /or better specified therapies in relation to identified biomarkers.

Conclusion:

• Studies evaluating the use of immunotherapeutics for severe sepsis are plagued with multiple confounding factors including the pre-dominant phase of sepsis (hyperimmune versus hypoimmune), differing offending organisms, differing host-organism interactions, heterogeneity in the patient populations, and underpowered study designs.
• Perhaps the correct immunotherapy will need to be tailored in order to decrease the immune response in the hyperimmune phase and increase it during the hypoimmune phase. In order to do so, better markers of these phases of sepsis are needed. Further studies may also find more efficacy in using multiple therapies simultaneously to obtain best results.
• Finally, there exists a close interaction between in the immune and coagulation system. Further study of this link and therapies to temper the coagulation cascade many prove to be a successful modality of therapy in order to halt the body’s progression to multiple organ failure.