Sepsis, best defined as a systemic infection generally accompanied by bacteremia, is a frequent diagnosis leading to hospitalization. It is associated with high mortality despite advances in medical care and the availability of a broad spectrum of antibiotic therapy, and it often complicates hospitalization. Its most severe manifestation—septic shock— is the end result of many different insults. This complicates understanding of the pathogen-esis, diagnosis, and targeted treatment. Thus, host genetics should first of all allow redefinition of the sepsis syndrome leading to a more rational approach in clinical trials. To date, host factors associated with sepsis have included polymorphic genes involved in pathogen recognition, inflammation, and coagulation cascades (Table 1). The required studies will entail the identification of new and additional SNPs associated with predisposition to severe sepsis, septic shock, and death from sepsis.

The controversy surrounding immune intervention using anticytokine therapy in sepsis illustrates this point. TNFa is one key mediator of sepsis, and this led to a number of studies that used anti-TNFa antibodies as therapy. Unfortunately, the complexity in the classification of sepsis described previously has probably limited the potential use of anti-TNFa as a therapeutic agent. The basic observation is that there is a marked difference in production of TNFa among individuals, and 60% of the differences can be attributed to genetic factors (Table 1) (67). A correct classification of the sepsis syndrome into separate distinct entities may help identify those individuals most likely to benefit from better targeting of anti-TNFa therapies (68).

In addition to SNP analyses, large scale analysis of gene expression using micro-array techniques may help characterize sepsis in a more pathogenesis-oriented classification with prognostic and therapeutic consequences (69-71). Finally, identification of specific polymorphisms in drug metabolism, transporter, and receptor genes may help limit the occurrence of adverse events that complicate intensive care management.

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