Exploring the pathophysiology of post-sepsis syndrome to identify therapeutic opportunities

Abstract

Sepsis is a major health problem worldwide. As the number of sepsis cases increases, so does the number of sepsis survivors who suffer from "post-sepsis syndrome" after hospital discharge. This syndrome involves deficits in multiple systems, including the immune, cognitive, psychiatric, cardiovascular, and renal systems. Combined, these detrimental consequences lead to rehospitalizations, poorer quality of life, and increased mortality. Understanding the pathophysiology of these issues is crucial to develop new therapeutic opportunities to improve survival rate and quality of life of sepsis survivors. Such novel strategies include modulating the immune system and addressing mitochondrial dysfunction. A sepsis follow-up clinic may be useful to identify long-term health issues associated with post-sepsis syndrome and evaluate existing and novel strategies to improve the lives of sepsis survivors.

Keywords: Post-sepsis syndrome; Quality of life; Rehospitalization; Sepsis.

Fig. 1

Immune dysfunction in sepsis survivors. Early in sepsis, both inflammation and immunosuppression occur concurrently. If inflammation is uncontrolled, this leads to organ failure and death. Those that avoid early death will either return to immune homeostasis, or progress to prolonged immunosuppression that continues after discharge. Prolonged immunosuppression predisposes survivors to infections, rehospitalizations, and ultimately late death. This phenomenon is marked by impaired cytokine secretion, dysfunctional T-cells, and cellular reprogramming. It is still unknown why prolonged immunosuppression occurs; however, epigenetic processes may be involved to “lock in” certain immunophenotypes. Expansion of regulatory T-cells and myeloid derived suppressor cell (MDSC) populations also occur early in sepsis and persist after sepsis, suggesting their role in maintaining this immunosuppressive phenotype. TNFα: tumor necrosis factor alpha, IL-6: interleukin-6, DAMPs: damage-associated molecular patterns, Treg: regulatory T-cell, MDSC: myeloid derived suppressor cell.

Fig. 2

Current and future strategies to combat post-sepsis syndrome. Many sepsis survivors suffer from at least one aspect from post-sepsis syndrome, which is characterized by immune dysfunction, cognitive deficits, mental health problems, and cardiovascular/kidney disease, causing decreased quality of life and mortality. Left untreated, post-sepsis syndrome will lead to rehospitalization and recurrent sepsis, placing the patient in a lethal feedback loop. Follow up strategies include infection control, improving mental health, cardiovascular risk management, statins, and physiotherapy. Future therapies include reversing immune dysfunction, prevention of mitochondrial damage, inhibiting DAMP release, HDL restoring therapies, mesenchymal stem cell therapy and risk stratification based on endotype. (BBB: blood brain barrier, PTSD: post-traumatic stress disorder, HCW: health care worker, ICU: intensive care unit, DAMP: damage-associated molecular pattern, ROS: reactive oxygen species). Fig. 2 was created with images from Servier Medical Art (http://smart.servier.com), licensed under a Creative Common Attribution 3.0 Generic License.