Dysregulated Immunity and Immunotherapy after Sepsis

Implementation of protocolized surveillance, diagnosis, and management of septic patients, and of surgical sepsis patients in particular, is shown to result in significantly increased numbers of patients surviving their initial hospitalization. Currently, most surgical sepsis patients will rapidly recover from sepsis; however, many patients will not rapidly recover, but instead will go on to develop chronic critical illness (CCI) and experience dismal long-term outcomes. The elderly and comorbid patient is highly susceptible to death or CCI after sepsis. Here, we review aspects of the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) endotype to explain the underlying pathobiology of a dysregulated immune system in sepsis survivors who develop CCI; then, we explore targets for immunomodulatory therapy.

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Chronic Critical Illness and PICS Nutritional Strategies

Journal of Clinical Medicine ◽

10.3390/jcm10112294 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2294

Author(s):

Martin D. Rosenthal ◽

Erin L. Vanzant ◽

Frederick A. Moore

Keyword(s):

Critical Illness ◽

Low Grade ◽

Long Term Outcomes ◽

Persistent Inflammation ◽

Chronic Critical Illness ◽

Similar Phenotype ◽

Sepsis Survivors ◽

Low Grade Inflammation ◽

Nutritional Strategies

The nutritional hallmark of chronic critical illness (CCI) after sepsis is persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which results in global resistance to the anabolic effect of nutritional supplements. This ultimately leaves these patients in a downward phenotypic spiral characterized by cachexia with profound weakness, decreased capacity for rehabilitation, and immunosuppression with the propensity for sepsis recidivism. The persistent catabolism is driven by a pathologic low-grade inflammation with the inability to return to homeostasis and by ongoing increased energy expenditure. Better critical care support systems and advances in technology have led to increased intensive care unit (ICU) survival, but CCI due to PICS with poor long-term outcomes has emerged as a frequent phenotype among ICU sepsis survivors. Unfortunately, therapies to mitigate or reverse PICS-CCI are limited, and recent evidence supports that these patients fail to respond to early ICU evidence-based nutrition protocols. A lack of randomized controlled trials has limited strong recommendations for nutrition adjuncts in these patients. However, based on experience in other conditions characterized by a similar phenotype, immunonutrients aimed at counteracting inflammation, immunosuppression, and catabolism may be important for improving outcomes in PICS-CCI patients. This manuscript intends to review several immunonutrients as adjunctive therapies in treating PICS-CCI.

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Enigmatic role of coagulopathy among sepsis survivors: a review of coagulation abnormalities and their possible link to chronic critical illness

Trauma Surgery & Acute Care Open ◽

10.1136/tsaco-2020-000462 ◽

2020 ◽

Vol 5 (1) ◽

pp. e000462

Author(s):

Leah K Winer ◽

Christen Salyer ◽

Nadine Beckmann ◽

Charles C Caldwell ◽

Vanessa Nomellini

Keyword(s):

Intensive Care Unit ◽

Critical Illness ◽

Long Term Outcomes ◽

Causative Mechanism ◽

Coagulation Abnormalities ◽

Chronic Critical Illness ◽

Sepsis Survivors

There are sparse clinical data addressing the persistence of disordered coagulation in sepsis and its role in chronic critical illness. Coagulopathy in the absence of anticoagulant therapy and/or liver disease can be highly variable in sepsis, but it tends to be prolonged in patients in the intensive care unit with a length of stay greater than 14 days. These coagulation abnormalities tend to precede multisystem organ failure and persistence of these coagulation derangements can predict 28-day mortality. The studies evaluated in this review consistently link sepsis-associated coagulopathy to poor long-term outcomes and indicate that disordered coagulation is associated with unfavorable outcomes in chronic critical illness. However, the causative mechanism and the definitive link remain unclear. Longer follow-up and more granular data will be required to fully understand coagulopathy in the context of chronic critical illness.

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Persistently Elevated Glucagon-Like Peptide-1 Levels among Critically Ill Surgical Patients after Sepsis and Development of Chronic Critical Illness and Dismal Long-Term Outcomes

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2019.04.014 ◽

2019 ◽

Vol 229 (1) ◽

pp. 58-67.e1 ◽

Cited By ~ 6

Author(s):

Scott C. Brakenridge ◽

Frederick A. Moore ◽

Nicole R. Mercier ◽

Michael Cox ◽

Quron Wu ◽

...

Keyword(s):

Critical Illness ◽

Critically Ill ◽

Surgical Patients ◽

Long Term Outcomes ◽

Chronic Critical Illness ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Critically Ill Surgical Patients

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Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors

Journal of Clinical Medicine ◽

10.3390/jcm10153211 ◽

2021 ◽

Vol 10 (15) ◽

pp. 3211

Author(s):

Dijoia B. Darden ◽

Gabriela L. Ghita ◽

Zhongkai Wang ◽

Julie A. Stortz ◽

Maria-Cecilia Lopez ◽

...

Keyword(s):

Critical Illness ◽

Rapid Recovery ◽

Icu Length Of Stay ◽

Persistent Inflammation ◽

Genome Wide ◽

Chronic Critical Illness ◽

Surgical Icu ◽

Sepsis Survivors ◽

Blood Leukocyte ◽

Genome Wide Expression

Surgical sepsis has evolved into two major subpopulations: patients who rapidly recover, and those who develop chronic critical illness (CCI). Our primary aim was to determine whether CCI sepsis survivors manifest unique blood leukocyte transcriptomes in late sepsis that differ from transcriptomes among sepsis survivors with rapid recovery. In a prospective cohort study of surgical ICU patients, genome-wide expression analysis was conducted on total leukocytes in human whole blood collected on days 1 and 14 from sepsis survivors who rapidly recovered or developed CCI, defined as ICU length of stay ≥ 14 days with persistent organ dysfunction. Both sepsis patients who developed CCI and those who rapidly recovered exhibited marked changes in genome-wide expression at day 1 which remained abnormal through day 14. Although summary changes in gene expression were similar between CCI patients and subjects who rapidly recovered, CCI patients exhibited differential expression of 185 unique genes compared with rapid recovery patients at day 14 (p < 0.001). The transcriptomic patterns in sepsis survivors reveal an ongoing immune dyscrasia at the level of the blood leukocyte transcriptome, consistent with persistent inflammation and immune suppression. Furthermore, the findings highlight important genes that could compose a prognostic transcriptomic metric or serve as therapeutic targets among sepsis patients that develop CCI.

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