Monitoring Immune Dysfunction in Septic Patients: Toward Tailored Immunotherapy

摘要

Septic syndromes represent a major although largely under-recognized healthcare problem worldwide accounting for thousands of deaths every year [ – ]. Mortality remains high ranging from 20 % for sepsis to over 50 % for septic shock despite almost 20 years of anti-inflammatory clinical trials [ – ]. The inability of these therapies to mitigate the devastating effects of this condition indicates that the initial hypotheses for sepsis pathophysiology may have been misconstrued or inadequately addressed. Two major explanations have been proposed: 1) Septic patients have mainly been treated as a group despite the extreme heterogeneity characterizing this population [ ]; 2) The postulate that death after sepsis is solely due to an overwhelming pro-inflammatory immune response may actually be inaccurate [ , ]. Indeed, several lines of evidence have now established that death from septic shock is probably due to the effect of distinct mechanisms over time [ – ]. Early in the course of the disease, a massive release of inflammatory mediators (normally designed to trigger an immune response against pathogens) is occurring that may be responsible for organ dysfunction and hypoperfusion [ , ]. Concomitantly, the body develops compensatory mechanisms to prevent overwhelming inflammation and dampen an over-zealous anti-infectious response [ – ]. These negative feedback mechanisms, although having protective effects during the first initial hours, may paradoxically become deleterious as they persist over time leading to immune paralysis (Fig. 1) [ , ]. Indeed, considerable clinical and experimental evidence indicates that patients rapidly present with numerous compromised immune functions [ , ]. As our capacity to treat patients during the very first hours of shock has improved (early and aggressive initial supportive therapy) [ ], many patients now survive this critical step but eventually die later in a state of immunosuppression that is illustrated by difficulty fighting the primary bacterial infection and decreased resistance to secondary nosocomial infections [ , ]. Consequently, immunostimulatory therapies are now considered as an innovative strategy for the treatment of sepsis [ , ]. However, the first critical step is to be able to identify patients who would actually benefit from these therapies [ , ]. Indeed, in the absence of specific clinical signs of immune status, it is critical to determine the best biological tools to stratify patients according to their immune status (a missing step in most previous clinical trials) [ – ]. This would define the right action (i.e., stimulating innate immunity and/or adaptive immunity, blocking apoptosis, restoring other altered functions) at the right time (early or delayed treatment) in the right patient (individualized/tailored therapy).