The chronic consequences of severe sepsis

The early events of severe sepsis set in motion a cascade of events that significantly contributes to the morbidity and mortality observed during the first few days of this syndrome. Although sepsis is a deadly, acute disease, survivors also suffer long‐term consequences. Clinical data underscore subsequent high mortality rates associated with patients who are long‐term survivors of the acute septic episode. Within 1 year of surviving severe sepsis, there is a 26% predicted mortality rate, and many patients succumb to lung complications. In this review, we focus on the cellular and molecular mechanisms that dictate the longer‐term sequela of sepsis and related lung injury. We have established a murine model of experimental sepsis [cecal ligation and puncture (CLP)], which results in an approximate 60% survival rate. Our studies have demonstrated that these survivors are susceptible to a fungal infection with 100% mortality when challenged 3 days or 15 days post‐recovery from the initial CLP. This increased mortality correlates with changes in cytokines and Toll‐like receptor expression and alterations in lung leukocyte populations. We hypothesize that the lung becomes predisposed to nosocomial infections for extended periods of time after severe sepsis via mechanisms that include alterations in inflammatory cytokines and an increase in immunomodulatory chemokines, such as monocyte chemoattractant protein‐1 and C10. These mediators may alter the innate‐immune response by affecting dendritic cells and macrophages, which could provide a mechanism for the immunosuppression observed following sepsis.