The immune system's role in sepsis progression, resolution, and long-term outcome

Abstract

Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti-inflammatory responses. With advances in intensive care medicine and goal-directed interventions, early 30-day sepsis mortality has diminished, only to steadily escalate long after "recovery" from acute events. As so many sepsis survivors succumb later to persistent, recurrent, nosocomial, and secondary infections, many investigators have turned their attention to the long-term sepsis-induced alterations in cellular immune function. Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations. Understanding that sepsis-associated immune cell defects correlate with long-term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long-term patient outcomes. These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long-term sepsis mortality.

Keywords: adaptive immune dysfunction; immune suppression sepsis; inflammation; innate immune dysfunction; sepsis.

Figure 1. Earlier Conceptual View and Definition of Systemic Inflammatory Response Syndrome (SIRS), Sepsis, Severe Sepsis, and Septic Shock

(A.) The concept of an infection exceeding local regional control and inducing an inflammatory SIRS response has been the fundamental premise conceptualizing sepsis for over two decades. (B.) Until recently, sepsis was defined as the constellation of symptoms occurring when a bacterial, viral or fungal infection leads to a systemic inflammatory response syndrome, including fever, leukocytosis or leukopenia, and decreased vascular resistance frequently leading to hypotension (septic shock), organ failure (severe sepsis) and death. However, confounding the prior definition of sepsis is that other states of inflammation such as pancreatitis, trauma and burns can also produce a SIRS response making the definition overly nebulous and misapplied in many instances. (C.) In addition to the conceptual vagueness, the prior sepsis definition also implied that SIRS criteria possess adequate specificity and sensitivity to define and diagnose sepsis which is not always the case. Moreover, the prior sepsis model inferred that sepsis always follows a linear trajectory from SIRS through severe sepsis and septic shock, which is offend times does not occur. Adapted from Bone RC et al: Chest. 1992,101:1644–55.

Figure 2. The Third International Consensus Definitions for Sepsis and Septic Shock

The current definitions for sepsis and septic shock were developed to address the limitations of previous definitions that were over focused on SIRS and inflammation. In addition, the Sepsis-3 also dispelled the longstanding notion that SIRS criteria possess adequate specificity and sensitivity to define and diagnose sepsis. Lastly, the report debunked the misleading model that sepsis always follows a linear continuum from the SIRS through severe sepsis and septic shock, and declared the term “severe sepsis” redundant and unnecessary. Instead, the Consensus report recommends that sepsis be defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection.

Figure 3. Organ Dysfunction in Sepsis and Associated Mortality

The Sepsis-3 consensus report defined organ dysfunction by an increase in the Sequential Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an inhospital mortality greater than 10%.

Figure 4. Definition of Septic Shock and Associated Mortality

Septic shock is now defined as a subset of sepsis in which profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Clinically, patients with septic shock can be identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mmHg or greater and serum lactate level greater than 2 mmol/L (>18mg/dL) in the absence of hypovolemia with in-hospital mortality rates greater than 40%.

Figure 5. Bedside Criteria Defined to Identify

To identify patients with the highest probability of poor outcome associated with sepsis, a new bedside clinical score named the quickSOFA (qSOFA) was created which consist of at least 2 of the following clinical criteria including, respiratory rate of 22/min or greater, altered mentation (GCS 14), or systolic blood pressure of 100mmHg or less.

Figure 6. Past and Present Mortality Distribution Sepsis

(A.) Classically, the mortality distribution from sepsis occurred in a biphasic pattern, with an initial peak due to inadequate resuscitation resulting in cardiac and pulmonary failure and a second peak at several weeks from persistent organ dysfunction. Considering the recent trends in physiologic frailty, the growing elderly population, and mounting long-term mortality, a trimodal distribution is more indicative of the current sepsis-associated mortality. (B.) The two early peaks in mortality still do exist but with much less magnitude than in the past. The third and largest upswing occurs beginning at 2–3 months after sepsis and continues to steeply climb as time progresses. This delay in sepsis mortality is attributed to significant advances in ICU care that keeps the elderly and co-morbidly challenged patients alive longer despite ongoing immune, physiologic, metabolomics and biochemical aberrations.

Figure 7. Inflammatory vs Anti-Inflammatory Responses

An ongoing debate persist as to whether innate and adaptive immune dysfunction or inflammatory and anti-inflammatory processes are more detrimental to overall sepsis survival. In the past, the inflammatory response was thought to drive early mortality in the initial days of sepsis, and the compensatory anti-inflammatory response was thought to induce mortality weeks later through immune suppression and organ failure. However new insights gathered from septic patient tissue samples and severely injured trauma patients, have identified an enduring and simultaneous inflammatory and anti-inflammatory state of affairs driven by dysfunctional innate and suppressed adaptive immunity that together culminate in persistent organ injury, infectious complications requiring hospital readmission, and ultimately patient death. It is evident that the inflammatory and anti-inflammatory responses and innate and adaptive immune systems are each equally important, continually in a state of fluctuation, and ever at odds with one another, as sepsis recovery progresses. This perpetual state of immunologic yin and yang is thought to drive ongoing inflammation, facilitate organ injury, and enable infectious complications that all preclude durable sepsis survival.

Figure 8. Alterations in Metabolic Function Determine Immune Phenotype

Immune cells rely on oxidative phosphorylation and β-oxidation as energy sources for ATP production to maintain cellular equipoise at homeostasis. However, after stimulation, leukocytes shift their metabolism toward aerobic glycolysis in a process known as the Warburg effect. In this metabolic shift, cellular energy is predominantly manufactured by an increase in glycolysis followed by lactic acid fermentation (lactate production) in the cytosol, rather than a low rate of glycolysis followed by oxidation of pyruvate in mitochondria. Hypoxia-inducible factor–1a(HIF-1a) and the mammalian target of rapamycin (mTOR) are major drivers of this metabolic switch and hence determines cellular fate. These metabolic shifts have been incriminated in immune suppression and secondary infection progression in humans. A clearer understanding of the metabolic checkpoints that control immune cell function, transition, and maturation will provide new insights for modulating systemic inflammation, cellular immunity, and sepsis recovery.