Evidence for Persistent Immune Suppression in Patients Who Develop Chronic Critical Illness After Sepsis

Stortz, Julie A.; Murphy, Tyler; Raymond, Steven L.; Mira, Juan C.; Ungaro, Ricardo; Dirain, Marvin; Nacionales, Dina C.; Loftus, Tyler J.; Wang, Zhongkai; Ozrazgat‐Baslanti, Tezcan; Ghita, Gabriela; Brumback, Babette; Mohr, Alicia M.; Bïhorac, Azra; Efron, Philip A.; Moldawer, Lyle L.; Moore, Frederick A.; Brakenridge, Scott C.

doi:10.1097/shk.0000000000000981

Cited by 110 publications

(135 citation statements)

References 32 publications

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“…The clinical component of this translational research program was a 5-year prospective longitudinal cohort study which collected the data included in this manuscript. Other reports from this team science effort indicate that PICS-CCI in surgical ICU sepsis and trauma patients is a valid concept [25][26][27].…”

Section: Study Population Rationalementioning

confidence: 99%

Phenotypic heterogeneity by site of infection in surgical sepsis: a prospective longitudinal study

et al. 2020

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Background: The role of site of infection in sepsis has been poorly characterized. Additionally, sepsis epidemiology has evolved. Early mortality has decreased, but many survivors now progress into chronic critical illness (CCI). This study sought to determine if there were significant differences in the host response and current epidemiology of surgical sepsis categorized by site of infection.Study design: This is a longitudinal study of surgical sepsis patients characterized by baseline predisposition, insult characteristics, serial biomarkers, hospital outcomes, and long-term outcomes. Patients were categorized into five anatomic sites of infection. Results:The 316 study patients were predominantly Caucasian; half were male, with a mean age of 62 years, high comorbidity burden, and low 30-day mortality (10%). The primary sites were abdominal (44%), pulmonary (19%), skin/soft tissue (S/ST, 17%), genitourinary (GU, 12%), and vascular (7%). Most abdominal infections were present on admission and required source control. Comparatively, they had more prolonged proinflammation, immunosuppression, and persistent organ dysfunction. Their long-term outcome was poor with 37% CCI (defined as > 14 in ICU with organ dysfunction), 49% poor discharge dispositions, and 30% 1-year mortality. Most pulmonary infections were hospitalacquired pneumonia. They had similar protracted proinflammation and organ dysfunction, but immunosuppression normalized. Long-term outcomes are similarly poor (54% CCI, 47% poor disposition, 32% 1-year mortality). S/ST and GU infections occurred in younger patients with fewer comorbidities, less perturbed immune responses, and faster resolution of organ dysfunction. Comparatively, S/ST had better long-term outcomes (23% CCI, 39% poor disposition, 13% 1-year mortality) and GU had the best (10% CCI, 20% poor disposition, 10% 1-year mortality). Vascular sepsis patients were older males, with more comorbidities. Proinflammation was blunted with baseline immunosuppression and organ dysfunction that persisted. They had the worst long-term outcomes (38% CCI, 67% poor disposition, 57% 1-year mortality). Conclusion: There are notable differences in baseline predisposition, host responses, and clinical outcomes by site of infection in surgical sepsis. While previous studies have focused on differences in hospital mortality, this study provides unique insights into the host response and long-term outcomes associated with different sites of infection.

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Section: Study Population Rationalementioning

confidence: 99%

Phenotypic heterogeneity by site of infection in surgical sepsis: a prospective longitudinal study

et al. 2020

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“…Possible means to monitor the extent of immune dysfunction due to PD‐1/PD‐L1‐mediated mechanisms include flow cytometric expression of PD‐1 or PD‐L1 on immune effector cells. Recently, circulating levels of sPD‐L1 have been reported to be a marker for persistent immune suppression in patients who develop chronic critical illness after sepsis . In summary, checkpoint blockade is one of the most promising strategies to counter immunosuppressive sepsis in the future.…”

Section: Discussionmentioning

confidence: 99%

Immunoadjuvant therapy in sepsis: novel strategies for immunosuppressive sepsis coming down the pike

Watanabe

Thampy

Hotchkiss

2018

Acute Medicine & Surgery

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Recent efforts have focused on immunoadjuvant therapies for sepsis. The host inflammatory response consequent to initial exposure to pathogens is often followed by anti‐inflammatory forces, resulting in increased morbidity and mortality in such critically ill patients. In the subacute stage of sepsis, apoptosis (type I programmed cell death) and subsequently autophagy (type II programmed cell death) have been attracting recent research interest. Although many patients may die during the initial cytokine storm, those who survive this phase might acquire defining characteristics of profound immunosuppression, including failure to clear the primary infection, development of secondary opportunistic infections, and reactivation of latent viruses. Both types of cell death are currently thought to be associated with this subacute immunosuppressive phase of sepsis, and acceleration of autophagy might alleviate immunosuppression through regulation of apoptosis of key immune effector cells. Programmed cell death 1 (PD‐1) and its corresponding ligand play a major pathological role in immunosuppression not only in cancer but also in sepsis. Positive costimulatory pathways in T cells, such as CD28 signaling, permit the effector T cell to expand, persist, and effectively clear antigen. However, PD‐1 is a negative costimulatory pathway on T cells that broadly enhances immunosuppressive signals across the innate and adaptive immune system. To counter this immunosuppression in sepsis, checkpoint blockade has garnered attention in an area of clinical research. In this review, we introduce some approaches of immunotherapy using anti‐PD‐1 antibody in infectious diseases and share our future perspectives.

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“…Moreover, in critically ill patients, low vitamin D status has been associated with symptoms of muscle frailty, such as delayed weaning from mechanical ventilation . Severe deconditioning related to muscle wasting in the ICU is associated with long‐term physical and functional disability, CCI, PICS, and increased mortality . Indeed, in a recent large RCT of critically ill patients (see supplemental data), subgroup analysis at 6‐month follow‐up suggested improved functional status in those who received vitamin D supplementation compared with controls.…”

Section: Discussionmentioning

confidence: 99%

“…Over the past several decades, as mortality from critical illness has continued to decline, assessments of other long‐term, patient‐centered outcomes have become of greater interest. Indeed, roughly 5%–10% of intensive care unit (ICU) survivors transition to chronic critical illness (CCI), including a phenotype recently described as persistent inflammation, immunosuppression, and catabolism syndrome (PICS) . Both CCI and PICS are associated with poor long‐term outcomes and are often accompanied by severe limitations in daily functioning as well as continued dependence on many intensive care resources outside of the acute care setting .…”

Section: Introductionmentioning

confidence: 99%

Admission 25‐Hydroxyvitamin D Levels Are Associated With Functional Status at Time of Discharge from Intensive Care Unit in Critically Ill Surgical Patients

et al. 2018

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Background: Vitamin D status is associated with length of stay (LOS) and discharge destination in critically ill patients. To further understand this relationship, we investigated whether admission 25-hydroxyvitaminD (25OHD) levels are associated with discharge functional status in the intensive care unit (ICU). Methods: In this retrospective study, data from 2 surgical ICUs at a large teaching hospital were analyzed. 25OHD levels were measured within 24 hours of ICU admission and Functional Status Score for the ICU (FSS-ICU) was calculated within 24 hours of ICU discharge for all patients. To investigate the association of vitamin D status with FSS-ICU, we constructed linear and logistic regression models, controlling for body mass index, Nutrition Risk in the Critically Ill score, ICU LOS, and cumulative protein or caloric deficit during ICU admission. Results: Mean 25OHD level and FSS-ICU was 19 (SD 8) ng/mL and 17 (SD 4), respectively, in the analytic cohort (n = 300). Each unit increase in 25OHD level was associated with a 0.2 increment in FSS-ICU (β = .20; 95% CI 0.14-0.25). Patients with 25OHD levels <20 ng/mL had >3-fold risk of low FSS-ICU (<17) compared with patients with 25OHD >20 ng/mL (OR 3.45; 95% CI 1.96-6.08). Conclusions: Our results suggest that vitamin D status at admission is associated with discharge FSS-ICU in critically ill surgical patients. Future studies are needed to validate our results, to build upon our findings, and to determine whether optimizing 25OHD levels can improve functional status and other important clinical outcomes in ICU patients. (Nutr Clin Pract. 2019;34:572-580) Keywords critical illness; fatigue; functional status; intensive care unit; vitamin D; vitamin D deficiency From the

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Evidence for Persistent Immune Suppression in Patients Who Develop Chronic Critical Illness After Sepsis

Cited by 110 publications

References 32 publications

Phenotypic heterogeneity by site of infection in surgical sepsis: a prospective longitudinal study

Phenotypic heterogeneity by site of infection in surgical sepsis: a prospective longitudinal study

Immunoadjuvant therapy in sepsis: novel strategies for immunosuppressive sepsis coming down the pike

Admission 25‐Hydroxyvitamin D Levels Are Associated With Functional Status at Time of Discharge from Intensive Care Unit in Critically Ill Surgical Patients

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