Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation.
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ABSTRACT:
SUBMITTER: Kernan KF
PROVIDER: S-EPMC6320733 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
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Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation.
Kernan Kate F KF Ghaloul-Gonzalez Lina L Shakoory Bita B Kellum John A JA Angus Derek C DC Carcillo Joseph A JA
Genes and immunity 20180706 6
Post-hoc subgroup analysis of the negative trial of interleukin-1β receptor antagonist (IL1RA) for septic shock suggested that patients with features of macrophage activation syndrome (MAS) experienced a 50% relative risk reduction for mortality with treatment. Here we seek a genetic basis for this differential response. From 1341 patients enrolled in the ProCESS trial of early goal directed therapy for septic shock, we selected 6 patients with MAS features and the highest ferritin, for whole ex ...[more]
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Project description:Heterogeneity in sepsis-related pathobiology presents a significant challenge. Resolving this heterogeneity presents an opportunity to understand pathobiology and improve patient care. Olfactomedin-4 is a neutrophil subset marker and may contribute to sepsis heterogeneity. Our objective was to evaluate the expression of olfactomedin-4 and characterize neutrophil heterogeneity in children with septic shock.Single-center, prospective cohort, as well as secondary analysis of existing transcriptomic and proteomic databases.Tertiary care PICU.Patients from 5 days to 18 years old with septic shock were enrolled. Data collected included the expression of olfactomedin-4 messenger RNA, serum protein concentrations, and percentage of neutrophils that express olfactomedin-4.None.Secondary analysis of existing transcriptomic data demonstrated that olfactomedin-4 is the most highly expressed gene in nonsurvivors of pediatric septic shock, compared with survivors. Secondary analysis of an existing proteomic database corroborated these observations. In a prospectively enrolled cohort, we quantified the percentage of olfactomedin-4+ neutrophils in patients with septic shock. Patients with a complicated course, defined as greater than or equal to two organ failures at day 7 of septic shock or 28-day mortality, had a higher percentage of olfactomedin-4+ neutrophils, compared with those without a complicated course. By logistic regression, the percentage of olfactomedin-4+ neutrophils was independently associated with increased risk of a complicated course (odds ratio, 1.09; 95% CI, 1.01-1.17; p = 0.024).Olfactomedin-4 identifies a subpopulation of neutrophils in patients with septic shock, and those with a high percentage of olfactomedin-4+ neutrophils are at higher risk for greater organ failure burden and death. Olfactomedin-4 might serve as a marker of a pathogenic neutrophil subset in patients with septic shock.
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Project description: Not available
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Project description:BackgroundReduced cellular ATP synthesis due to impaired mitochondrial function of immune cells may be a factor influencing the immune response in septic shock. We investigate changes in mitochondrial function and bioenergetics of human monocytes and lymphocyte subsets.MethodsThirty patients with septic shock were studied at ICU admission, after 24 and 48 hours, and after resolution of shock. Enzymatic activities of citrate synthase and mitochondrial complexes I, IV, and ATP synthase and ATP content of monocytes, T-cells and B-cells and pro-inflammatory (IL-1? and IL-6) and anti-inflammatory (IL-10) cytokine plasma concentrations were compared to samples from 20 healthy volunteers.ResultsLarge variations in mitochondrial enzymatic activities of immune cells of septic patients were detected. In monocytes, maximum levels of citrate synthase activity in sepsis were significantly lower when compared to controls (p = 0.021). Maximum relative enzymatic activity (ratio relative to citrate synthase activity) of complex I (p<0.001), complex IV (p = 0.017) and ATP synthase (p<0.001) were significantly higher. In T-cells, maximum levels of citrate synthase (p = 0.583) and relative complex IV (p = 0.602) activity did not differ between patients and controls, whereas levels of relative complex I (p = 0.006) and ATP synthase (p = 0.032) were significantly higher in septic patients. In B-cells of patients, maximum levels of citrate synthase activity (p = 0.004) and relative complex I (p<0.001) were significantly higher, and mean levels of relative complex IV (p = 0.042) lower than the control values, whereas relative ATP synthase activity did not differ (p = 1.0). No significant difference in cellular ATP content was detected in any cell line (p = 0.142-0.519). No significant correlations between specific cytokines and parameters of mitochondrial enzymatic activities or ATP content were observed.ConclusionsSignificant changes of mitochondrial enzymatic activities occur in human peripheral blood immune cells in septic shock when compared to healthy controls. Assessed sub-types of immune cells showed differing patterns of regulation. Total ATP-content of human immune cells did not differ between patients in septic shock and healthy volunteers.
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Project description:IntroductionIn recent years, the incidence of sepsis has increased in critically ill HIV/AIDS patients, and the presence of severe sepsis emerged as a major determinant of outcomes in this population. The inflammatory response and deregulated cytokine production play key roles in the pathophysiology of sepsis; however, these mechanisms have not been fully characterized in HIV/AIDS septic patients.MethodsWe conducted a prospective cohort study that included HIV/AIDS and non-HIV patients with septic shock. We measured clinical parameters and biomarkers (C-reactive protein and cytokine levels) on the first day of septic shock and compared these parameters between HIV/AIDS and non-HIV patients.ResultsWe included 30 HIV/AIDS septic shock patients and 30 non-HIV septic shock patients. The HIV/AIDS patients presented low CD4 cell counts (72 [7-268] cells/mm(3)), and 17 (57%) patients were on HAART before hospital admission. Both groups were similar according to the acute severity scores and hospital mortality. The IL-6, IL-10 and G-CSF levels were associated with hospital mortality in the HIV/AIDS septic group; however, the CRP levels and the surrogates of innate immune activation (cytokines) were similar among HIV/AIDS and non-HIV septic patients. Age (odds ratio 1.05, CI 95% 1.02-1.09, p=0.002) and the IL-6 levels (odds ratio 1.00, CI 95% 1.00-1.01, p=0.05) were independent risk factors for hospital mortality.ConclusionsIL-6, IL-10 and G-CSF are biomarkers that can be used to predict prognosis and outcomes in HIV/AIDS septic patients. Although HIV/AIDS patients are immunocompromised, an innate immune response can be activated in these patients, which is similar to that in the non-HIV septic population. In addition, age and the IL-6 levels are independent risk factors for hospital mortality irrespective of HIV/AIDS disease.
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Project description:Septic shock often occurs following critically low blood pressure in patients with sepsis, and is accompanied by a high death rate. Although mitophagy is associated with infection and immune responses, its role in septic shock remains unknown. This study screened effective mitophagy-related genes (MRGs) for medical practice and depicted immune infiltration situations in patients with septic shock. Gene expression profiles of GSE131761 from the Gene Expression Omnibus database were compiled for differential analysis, weighted gene co-expression network analysis, and immune infiltration analysis, while other GSE series were used as validation datasets. A series of validation methods were used to verify the robustness of hub genes, while a nomogram and prognosis model were established for medical practice. Six genes were screened via combinations of differentially expressed genes, weighted gene co-expression network analysis, and MRGs. From this, 3 hub genes (MAP1LC3B, ULK1, and CDC37) were chosen for subsequent analysis based on different validation methods. Gene set enrichment analysis showed that leukocyte trans-endothelial migration and the p53 signaling pathway were abnormally activated during septic shock. Immune infiltration analysis indicated that the imbalance of neutrophils and CD4 naive T cells was significantly correlated with septic shock progression. A nomogram was generated based on MAP1LC3B, ULK1, and CDC37, as well as age. The stability of our model was confirmed using a calibration plot. Importantly, patients with septic shock with the 3 highly expressed hub genes displayed worse prognosis than did patients without septic shock. MAP1LC3B, ULK1, and CDC37 are considered hub MRGs in the development of septic shock and could represent promising diagnostic and prognostic biomarkers in blood tissue. The validated hub genes and immune infiltration pattern expand our knowledge on MRG functional mechanisms, which provides guidance and direction for the development of septic shock diagnostic and therapeutic markers.
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Project description:(1) Background: Sepsis is a life-threatening condition caused by an abnormal host response to infection that produces altered physiological responses causing tissue damage and can result in organ dysfunction and, in some cases, death. Although sepsis is characterized by a malfunction of the immune system leading to an altered immune response and immunosuppression, the high complexity of the pathophysiology of sepsis requires further investigation to characterize the immune response in sepsis and septic shock. (2) Methods: This study analyzes the immune-related responses occurring during the early stages of sepsis by comparing the amounts of cytokines, immune modulators and other endothelial mediators of a control group and three types of severe patients: critically ill non-septic patients, septic and septic shock patients. (3) Results: We showed that in the early stages of sepsis the innate immune system attempts to counteract infection, probably via neutrophils. Conversely, the adaptive immune system is not yet fully activated, either in septic or in septic shock patients. In addition, immunosuppressive responses and pro-coagulation signals are active in patients with septic shock. (4) Conclusions: The highest levels of IL-6 and pyroptosis-related cytokines (IL-18 and IL-1α) were found in septic shock patients, which correlated with D-dimer. Moreover, endothelial function may be affected as shown by the overexpression of adhesion molecules such as s-ICAM1 and E-Selectin during septic shock.
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Project description:For more than two decades, sepsis was defined as a microbial infection that produces fever (or hypothermia), tachycardia, tachypnoea and blood leukocyte changes. Sepsis is now increasingly being considered a dysregulated systemic inflammatory and immune response to microbial invasion that produces organ injury for which mortality rates are declining to 15-25%. Septic shock remains defined as sepsis with hyperlactataemia and concurrent hypotension requiring vasopressor therapy, with in-hospital mortality rates approaching 30-50%. With earlier recognition and more compliance to best practices, sepsis has become less of an immediate life-threatening disorder and more of a long-term chronic critical illness, often associated with prolonged inflammation, immune suppression, organ injury and lean tissue wasting. Furthermore, patients who survive sepsis have continuing risk of mortality after discharge, as well as long-term cognitive and functional deficits. Earlier recognition and improved implementation of best practices have reduced in-hospital mortality, but results from the use of immunomodulatory agents to date have been disappointing. Similarly, no biomarker can definitely diagnose sepsis or predict its clinical outcome. Because of its complexity, improvements in sepsis outcomes are likely to continue to be slow and incremental.
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