Science, medicine, and the future: Pathogenesis of sepsis: new concepts and implications for future treatment

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Abstract
Severe sepsis and septic shock are important causes of death in intensive care units. Although our understanding of the pathogenesis of inflammation and sepsis has improved, until recently this has not translated into clinical benefit. Several new treatment approaches have given encouraging results. Evidence suggests that the way forward is to develop pathogen specific regimens rather than assume that one treatment fits all. #### Summary points Bacterial cell walls, endotoxins, and exotoxins are powerful activators of innate and acquired immune responses Molecules expressed by pathogens interact with Toll-like receptors on immune cells, activating the immune response Cytokines are important in the pathogenesis of sepsis Susceptibility to sepsis may be due to inherited or acquired mutations of innate immune genes Severe sepsis and septic shock are clinical manifestations of a dysregulated immune response to invasive pathogens Adjunctive therapy with low dose steroids, activated protein C or early supportive care can reduce mortality from severe sepsis and septic shock Pathogen recognition receptors (such as Toll-like receptors) and mediators of sepsis (such as macrophage migration inhibitory factor) might be novel targets for treatment We selected articles for this review by searching Medline using the keywords sepsis, therapy, and Toll-like receptors. We concentrated on publications on the pathogenesis of sepsis and treatment of septic shock. As the number of references that could be cited was limited, we have often referenced review articles rather than original publications. Severe sepsis and septic shock are life threatening complications of infections and the most common cause of death in intensive care units. However, a lack of widely accepted definitions of these complications has made it difficult to obtain accurate estimates of their frequency. A study published by the Centers for Disease Control in the United States indicated that the incidence of septicaemia had increased from 73.6 per 100 000 patients in …