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

Abstract

SUMMARY 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. Since 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.

Surviving sepsis campaign: research priorities for sepsis and septic shock

“…Disability rates also appear to be increased for years in survivors of sepsis compared to their pre-ICU levels, at least among older Americans and are high in many populations, driving poor measured healthrelated quality of life [148,[155][156][157][158]. While there have been no systematic efforts to map the specific conditions for which septic patients are at increased risk, there are suggestions of increased rates of malignancy, readmissions for a new sepsis episode, high rates of new cardiovascular diseases and residual immune dysregulations [142,143,[159][160][161][162][163]. Many septic patients develop new comorbidities such as chronic kidney failure, the mechanisms of which may be different than in patients with non-septic acute kidney injury [164].…”

Update of Sepsis in the Intensive Care Unit

“…That may be one reason of why so many immune and inflammation modulation RCTs in sepsis have failed to improve survival [29] .…”

“…The innate and adaptive immune systems and the inflammatory and anti-inflammatory responses may fluctuate and conflict. These complex interactions likely play an important role in the recurrent, secondary, and nosocomial infections, and other long-term outcomes of sepsis, such as hospital readmissions and late mortality [29] . To date, we are unaware of RCTs that compare different immune and inflammatory-modulating interventions in sepsis survivors after discharge.…”

“…Based on the relevance of immune system dysfunction in sepsis, interventions targeted at immunomodulation have been studied in sepsis, such as use of granulocyte and granulocyte-macrophage colony stimulating factor, interferon-γ) programmed cell death protein (PD)-1 and PD ligands (PD-L1), recombinant human interleukin (IL)-3, IL-7, and IL-15, propranolol, oxandrolone, and dronabinol [29] . IL-7 (NCT02640807) and anti PD-L1 (NCT02576457) are currently being tested in clinical trials.…”

WNT ligands contribute to the immune response during septic shock and amplify endotoxemia-driven inflammation in mice

“…Molecular mechanisms underlying the dysregulated immune response in sepsis are the subject of intense investigation, which indicates an intricate interplay between microbial components, innate immune receptors, inflammatory cytokines, the coagulation system, and immune modulators. 4 However, the failure of many clinical trials for adjunctive therapies for sepsis encourages reevaluation of the molecular drivers of sepsis-associated inflammation and pathology. 5,6 WNT ligands are secreted glycoproteins with well-characterized functions during embryogenesis and tissue homeostasis, where they orchestrate cell proliferation and polarization.…”