Monitoring Immune Dysfunction in Septic Patients: Toward Tailored Immunotherapy

Septic syndromes represent a major although largely under-recognized healthcare problem worldwide accounting for thousands of deaths every year [1–3]. Mortality remains high ranging from 20 % for sepsis to over 50 % for septic shock despite almost 20 years of anti-inflammatory clinical trials [1–3]. 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 [1]; 2) The postulate that death after sepsis is solely due to an overwhelming pro-inflammatory immune response may actually be inaccurate [1, 3]. Indeed, several lines of evidence have now established that death from septic shock is probably due to the effect of distinct mechanisms over time [1–3]. 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 [1, 3]. Concomitantly, the body develops compensatory mechanisms to prevent overwhelming inflammation and dampen an overzealous anti-infectious response [1–3]. 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) [1, 3]. Indeed, considerable clinical and experimental evidence indicates that patients rapidly present with numerous compromised immune functions [1, 3].