Pathogenesis of sepsis: new concepts and implications for future treatment

doi:10.1136/bmj.326.7383.262

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Pierre-Yves Bochud, research fellowa,
Thierry Calandra (Thierry.Calandra@chuv.hospvd.ch), associate professorb

^a Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103-8904, USA
^b Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland

Correspondence to: T Calandra

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

Sources and methods

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.

Epidemiology and importance of severe sepsis and septic shock

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 …