Anticytokine Therapies in Patients with Severe Sepsis and Septic Shock

Considerable progress has been made in the understanding of the pathogenesis of inflammation and sepsis over the last 20 yr (1). One of the most significant achievement in this area has been the recognition of the central role played by the innate immune system in the host defenses against invasive pathogens. Innate immune responses are activated when a pathogen crosses the host natural defense barriers. Soluble factors (acute-phase proteins and components of the complement and coagulation systems) and pattern recognition receptors (CD14 and the Toll-like receptors [TLR]) expressed on cells of the myelo-monocytic lineage (monocytes, macrophages, neutrophils, dendritic cells) are essential components of the host defense system. When bound to pattern recognition receptors of innate immune cells, microbial products stimulate the production and release of a multitude of effector molecules, including cytokines, that serve to activate the inflammatory and immune responses whose aim is to eliminate the invasive micro-organism. The innate immune response must be tightly regulated. Failure to mount an appropriate defense response might have dramatic consequences for the host. On the one hand, quantitative or qualitative defects of the innate immune system may result in overwhelming infections, whereas disproportionate inflammatory reactions may lead to vascular collapse, tissue injury and multi-organ dysfunction, as is seen in patients with severe sepsis and septic shock. Numerous studies have shown that high levels of proinflammatory cytokines are associated with poor outcome in patients with septic shock. This has led investigators to postulate that treatment strategies aimed at modulating the production of proinflammatory cytokines or at inhibiting their activity, once they are released in tissues or in the systemic circulation, may improve the outcome of patients with severe sepsis or septic shock.