Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome

Abstract

Objective To provide an appraisal of the evolving paradigms in the pathophysiology of sepsis, propose the evolution of a new phenotype of critically ill patients, its potential underlying mechanism, and its implications for the future of sepsis management and research. Design Literature search using PubMed, MEDLINE, EMBASE, and Google Scholar. Results Sepsis remains one of the most debilitating and expensive illnesses, and its incidence is not declining. What is changing is our definition(s), its clinical course, and how we manage the septic patient. Once thought to be predominantly a syndrome of over exuberant inflammation, sepsis is now recognized as a syndrome of aberrant host protective immunity. Earlier recognition and compliance with treatment bundles has fortunately led to a decline in multiple organ failure and in-hospital mortality. Unfortunately, more and more sepsis patients, especially the aged, are suffering chronic critical illness (CCI), rarely fully recover and often experience an indolent death. Patients with CCI often exhibit ‘a persistent inflammatory-immunosuppressive and catabolic syndrome’ or PICS, and it is proposed here that PICS contributes to many of these adverse clinical outcomes. The underlying cause of PICS is currently unknown, but there is increasing evidence that altered myelopoiesis, reduced effector T-cell function and expansion of immature myeloid-derived suppressor cells are all contributory. Conclusion Although newer therapeutic interventions are targeting the inflammatory, the immunosuppressive, and the protein catabolic responses individually, successful treatment of the septic patient with CCI and PICS may require a more complementary approach.

Myeloid Cell-Specific Knockout of NFI-A Improves Sepsis Survival

“…MDSCs are generated under a variety of inflammatory and infection conditions (1,2) and are best characterized by their immunosuppressive functions (4)(5)(6). They may also promote persistent inflammation and chronic infection with catabolism during chronic sepsis (7). MDSCs suppress both innate and adaptive immunity via production of immunosuppressive mediators and inhibition of T cell proliferation and activation (3,4,8).…”

Microbial recognition and danger signals in sepsis and trauma

“…In this case, it is the overabundant magnitude of the response that results in organ injury and death. With improvements in early detection and acute ICU management, more and more patients are surviving their initial insult, reestablishing homeostasis and having a relatively uncomplicated course [143]. However, a significant number of patients, commonly the aged, do not recover quickly and frequently develop a protracted and complicated ICU course.…”

Molecular and Functional Neuroscience in Immunity

“…Sepsis develops as a result of a dysregulated host response to infection (162). Innate and adaptive immune dysregulation alongside metabolic and cardiovascular complications are important contributors to sepsis pathology (164, 165). Brain functional impairment in sepsis is known as sepsis-associated encephalopathy (SAE), which is an important constituent of sepsis pathology (166).…”