Sepsis-induced immune dysfunction: can immune therapies reduce mortality?

Abstract

Sepsis is a systemic inflammatory response induced by an infection, leading to organ dysfunction and mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the interplay between inflammatory and antiinflammatory responses. With advances in intensive care management and goal-directed interventions, early sepsis mortality has diminished, only to surge later after "recovery" from acute events, prompting a search for sepsis-induced alterations in immune function. Sepsis is well known to alter innate and adaptive immune responses for sustained periods after clinical "recovery," with immunosuppression being a prominent example of such alterations. Recent studies have centered on immune-modulatory therapy. These efforts are focused on defining and reversing the persistent immune cell dysfunction that is associated with mortality long after the acute events of sepsis have resolved.

Figure 2. Immune dysregulation in sepsis.

New insights into immune dysregulation have been gained using samples from deceased septic patients as well as from severely injured trauma patients. These studies demonstrate an enduring inflammatory state driven by dysfunctional innate and suppressed adaptive immunity that culminates in persistent organ injury and death of the patient. Although the initial inflammatory process, if unabated, contributes to organ failure and early mortality, this process is largely ameliorated by improvements in patient management protocols. However, considering that the vast majority of sepsis survivors are elderly with highly comorbid conditions, the short-term gains in survival have merely been pushed back by several months to a year. Although theories about the processes underlying this observation are numerous, the widespread consensus is that persistent derangements in innate and adaptive immune system cellular function are the main culprits driving long-term mortality.

Figure 1. Historical and current sepsis mortality distribution.

(A) Historically, sepsis deaths have occurred in a biphasic distribution, with an initial early peak at several days due to inadequate resuscitation, resulting in cardiac and pulmonary failure, and a late peak at several weeks due to persistent organ injury and failure. Considering the recent trend in sepsis outcomes, the elderly population, and mounting long-term mortality, a trimodal distribution may be more indicative of the current sepsis-associated death distribution. (B) The two early peaks in mortality exist, albeit with much lower magnitude than in the past. The third upswing occurs approximately 60 to 90 days after sepsis and continues to soar as time progresses. This delay in sepsis mortality is thought to be the consequence of the more sophisticated ICU care that keeps elderly and comorbidly challenged patients alive longer in spite of ongoing immune, physiologic, and biochemical aberrations.