Immunomodulation in Sepsis and Infection

Abstract

Sepsis is a life-threatening organ dysfunction induced after the dysregulated host response to an infectious microbial insult. Despite the existing progress of our understanding of the mechanisms leading to this dysregulated host response, therapeutic modalities have not been changed. The early administration of antimicrobials remains the mainstay of treatment. Antimicrobials should be given to their highest tolerated dose within the first hour from start of organ failures since every hour of delay increases by 7. 6% the risk for unfavorable outcome [1]. The high mortality of severe sepsis, despite antimicrobial therapy, originally led to the development of several treatment strategies that interfere with the immune system. These strategies aimed to modulate the dysregulated immune response of the host in order to improve the final outcome. Although the clinical development of these strategies was initiated already 30 years ago, none has received broad acceptance, and there is considerable debate among experts on the appropriateness of each treatment. As a typical example, drotrecogin alfa, a recombinant analogue of activated protein C which was the only drug ever licensed for severe sepsis and septic shock, was withdrawn from the market in 2010 due to lack of efficacy as proved by the PROWESS-SHOCK study. The debatable success of treatments that are available is mostly due to the fact that we have only recently started to recognize what constitutes the immune status of the host when clinical signs of sepsis appear and what the ideal treatment should be. We currently know that not all patients have a pro-inflammatory response when sepsis appears; some already show signs of an anti-inflammatory process which is probably the cascade that ultimately leads to multiple organ dysfunction (MODS) and death [2]. The pro-inflammatory response is characterized by a huge cytokine storm, whereas during the anti-inflammatory stage, the excessive pro-inflammatory reaction is suppressed. At this stage, blood monocytes are no longer able to generate adequate amounts of cytokines, neutrophil capacity for phagocytosis is downregulated, and Th2 lymphocyte responses predominate.