Immunoparalysis in Pediatric Critical Care

Hall, Mark W.; Greathouse, Kristin; Thakkar, Rajan K.; Sribnick, Eric A.; Muszynski, Jennifer A.

doi:10.1016/j.pcl.2017.06.008

Cited by 30 publications

(21 citation statements)

References 49 publications

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“…Hyperinflammation may often coexist with a compensatory anti-inflammatory response syndrome (CARS) in sepsis and critical illness, which induces quantitative and qualitative defects in the innate and adaptive immune system [6,7]. When severe and persistent, CARS is referred to as "immunoparalysis", and has been associated with impaired anti-microbial defense, risk of superinfections and increased mortality [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…When severe and persistent, CARS is referred to as "immunoparalysis", and has been associated with impaired anti-microbial defense, risk of superinfections and increased mortality [8,9]. The immunophenotype of CARS includes increased production of anti-inflammatory cytokines such as IL-10, inefficient antigen presentation, lymphocyte apoptosis and upregulation of inhibitory molecules such as programmed cell death protein (PD)-1 [6]. Molecular analyses in CARS typically reveal downregulation of Human Leukocyte Antigen -DR isotype (HLA-DR) on monocytes, as well as impaired lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α release ex vivo [6].…”

Section: Introductionmentioning

confidence: 99%

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The anti-inflammatory cytokine response characterized by elevated interleukin-10 is a stronger predictor of severe disease and poor outcomes than the pro-inflammatory cytokine response in coronavirus disease 2019 (COVID-19)

Henry

Benoit

Vikse

et al. 2020

Clinical Chemistry and Laboratory Medicine (CCLM)

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ObjectivesSevere coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune state. While research has focused on the hyperinflammation, little research has been performed on the compensatory anti-inflammatory response. The aim of this study was to evaluate the anti-inflammatory cytokine response to COVID-19, by assessing interleukin-10 (IL-10) and IL-10/lymphocyte count ratio and their association with outcomes.MethodsAdult patients presenting to the emergency department (ED) with laboratory-confirmed COVID-19 were recruited. The primary endpoint was maximum COVID-19 severity within 30 days of index ED visit.ResultsA total of 52 COVID-19 patients were enrolled. IL-10 and IL-10/lymphocyte count were significantly higher in patients with severe disease (p<0.05), as well as in those who developed severe acute kidney injury (AKI) and new positive bacterial cultures (all p≤0.01). In multivariable analysis, a one-unit increase in IL-10 and IL-10/lymphocyte count were associated with 42% (p=0.031) and 32% (p=0.013) increased odds, respectively, of severe COVID-19. When standardized to a one-unit standard deviations scale, an increase in the IL-10 was a stronger predictor of maximum 30-day severity and severe AKI than increases in IL-6 or IL-8.ConclusionsThe hyperinflammatory response to COVID-19 is accompanied by a simultaneous anti-inflammatory response, which is associated with poor outcomes and may increase the risk of new positive bacterial cultures. IL-10 and IL-10/lymphocyte count at ED presentation were independent predictors of COVID-19 severity. Moreover, elevated IL-10 was more strongly associated with outcomes than pro-inflammatory IL-6 or IL-8. The anti-inflammatory response in COVID-19 requires further investigation to enable more precise immunomodulatory therapy against SARS-CoV-2.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The anti-inflammatory cytokine response characterized by elevated interleukin-10 is a stronger predictor of severe disease and poor outcomes than the pro-inflammatory cytokine response in coronavirus disease 2019 (COVID-19)

Henry

Benoit

Vikse

et al. 2020

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…immunoparalysis and adverse outcomes has been observed in the pediatric intensive care setting following cardiopulmonary bypass, 46 sepsis, and trauma. 48 In cooled infants with NE, chemokine-mediated leukopenic immunoparalysis was observed in infants with poor outcome at 12 months (death or NDI). 49 In vitro studies report the inhibition of pro-inflammatory TNFα production by IL-10.…”

Section: An Association Betweenmentioning

confidence: 99%

Elevated serum IL-10 is associated with severity of neonatal encephalopathy and adverse early childhood outcomes

et al. 2021

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Background Neonatal encephalopathy (NE) contributes substantially to child mortality and disability globally. We compared cytokine profiles in term Ugandan neonates with and without NE, with and without perinatal infection or inflammation and identified biomarkers predicting neonatal and early childhood outcomes. Methods In this exploratory biomarker study, serum IL-1α, IL-6, IL-8, IL-10, TNFα, and VEGF (<12 h) were compared between NE and non-NE infants with and without perinatal infection/inflammation. Neonatal (severity of NE, mortality) and early childhood (death or neurodevelopmental impairment to 2.5 years) outcomes were assessed. Predictors of outcomes were explored with multivariable linear and logistic regression and receiver-operating characteristic analyses. Results Cytokine assays on 159 NE and 157 non-NE infants were performed; data on early childhood outcomes were available for 150 and 129, respectively. NE infants had higher IL-10 (p < 0.001), higher IL-6 (p < 0.017), and lower VEGF (p < 0.001) levels. Moderate and severe NE was associated with higher IL-10 levels compared to non-NE infants (p < 0.001). Elevated IL-1α was associated with perinatal infection/inflammation (p = 0.013). Among NE infants, IL-10 predicted neonatal mortality (p = 0.01) and adverse early childhood outcome (adjusted OR 2.28, 95% CI 1.35–3.86, p = 0.002). Conclusions Our findings support a potential role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy. Impact Neonatal encephalopathy is a common cause of child death and disability globally. Inflammatory cytokines are potential biomarkers of encephalopathy severity and outcome. In this Ugandan health facility-based cohort, neonatal encephalopathy was associated with elevated serum IL-10 and IL-6, and reduced VEGF at birth. Elevated serum IL-10 within 12 h after birth predicted severity of neonatal encephalopathy, neonatal mortality, and adverse early childhood developmental outcomes, independent of perinatal infection or inflammation, and provides evidence to the contribution of the inflammatory processes. Our findings support a role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy in a sub-Saharan African cohort.

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“…Hyperinflammation may coexist with a compensatory anti-inflammatory response syndrome (CARS) in sepsis and critical illness, which induces quantitative and qualitative defects in the innate and adaptive immune system [4,5]. When severe and persistent, CARS is referred to as “immunoparalysis”, and has been associated with impaired anti-microbial defense, risk of superinfections and increased mortality [6,7].…”

Section: Introductionmentioning

confidence: 99%

Functional immunoparalysis characterized by elevated Interleukin-10 and Interleukin-10- to-Lymphocyte Count Ratio is associated with severe disease and poor outcomes in coronavirus disease 2019 (COVID-19)

Henry

Benoit

Vikse

et al. 2020

Preprint

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Objectives: Severe coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune state, called cytokine storm. While research has focused on the hyperinflammation, little research has been performed on the compensatory anti-inflammatory response which if severe may lead to a state of functional immunoparalysis. The aim of this study was to evaluate the anti-inflammatory response to COVID-19, by assessing interleukin-10 (IL-10) and IL-10/lymphocyte count ratio and their association with patient outcomes. Methods: Adult patients presenting to the emergency department (ED) with laboratory-confirmed COVID-19 were recruited. The primary endpoint was peak COVID-19 severity within 30 days of index ED visit. Additional endpoints included COVID-19 severity at ED disposition, development of severe acute kidney injury (AKI) or secondary bacterial infections. Results: A total of 52 COVID-19 patients were enrolled. IL-10 and IL-10/lymphocyte count were significantly higher in patients with severe disease at both time points (all p<0.05), as well as in those who developed severe AKI and secondary bacterial infection (all p≤0.01). In multivariable analysis, a one-unit increase in IL-10 was associated with 42% increased odds of severe COVID-19 (p=0.031), whilst a one-unit increase IL-10/lymphocyte ratio was also associated with 32% increase in odds of severe COVID-19 (p=0.013). Conclusions: The hyperinflammatory response to COVID-19 is accompanied by a simultaneous anti-inflammatory response, which is associated with poor outcomes and may increase the risk of secondary bacterial infections. IL-10 and IL-10/lymphocyte ratio at ED presentation were independent predictors of COVID-19 severity. Functional immunoparalysis in COVID-19 requires further investigation to enable more precise immunomodulatory therapy against SARS-CoV-2.

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Immunoparalysis in Pediatric Critical Care

Cited by 30 publications

References 49 publications

The anti-inflammatory cytokine response characterized by elevated interleukin-10 is a stronger predictor of severe disease and poor outcomes than the pro-inflammatory cytokine response in coronavirus disease 2019 (COVID-19)

The anti-inflammatory cytokine response characterized by elevated interleukin-10 is a stronger predictor of severe disease and poor outcomes than the pro-inflammatory cytokine response in coronavirus disease 2019 (COVID-19)

Elevated serum IL-10 is associated with severity of neonatal encephalopathy and adverse early childhood outcomes

Functional immunoparalysis characterized by elevated Interleukin-10 and Interleukin-10- to-Lymphocyte Count Ratio is associated with severe disease and poor outcomes in coronavirus disease 2019 (COVID-19)

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