Dataset Information

NETosis and Nucleosome Biomarkers in Septic Shock and Critical COVID-19 Patients: An Observational Study.

ABSTRACT: Background: Neutrophil extracellular traps' (NETs') formation is a mechanism of defense that neutrophils deploy as an alternative to phagocytosis, to constrain the spread of microorganisms. Aim: The aim was to evaluate biomarkers of NETs' formation in a patient cohort admitted to intensive care unit (ICU) due to infection. Methods: Forty-six septic shock patients, 22 critical COVID-19 patients and 48 matched control subjects were recruited. Intact nucleosomes containing histone 3.1 (Nu.H3.1), or citrullinated histone H3R8 (Nu.Cit-H3R8), free citrullinated histone (Cit-H3), neutrophil elastase (NE) and myeloperoxidase (MPO) were measured. Results: Significant differences in Nu.H3.1 and NE levels were observed between septic shock and critical COVID-19 subjects as well as with controls (p-values < 0.05). The normalization of nucleosome levels according to the neutrophil count improved the discrimination between septic shock and critical COVID-19 patients. The ratio of Nu.Cit-H3R8 to Nu.H3.1 allowed the determination of nucleosome citrullination degree, presumably by PAD4. Conclusions: H3.1 and Cit-H3R8 nucleosomes appear to be interesting markers of global cell death and neutrophil activation when combined. Nu.H3.1 permits the evaluation of disease severity and differs between septic shock and critical COVID-19 patients, reflecting two distinct potential pathological processes in these conditions.

SUBMITTER: Morimont L

PROVIDER: S-EPMC9405965 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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NETosis and Nucleosome Biomarkers in Septic Shock and Critical COVID-19 Patients: An Observational Study.

Morimont Laure L Dechamps Mélanie M David Clara C Bouvy Céline C Gillot Constant C Haguet Hélène H Favresse Julien J Ronvaux Lorian L Candiracci Julie J Herzog Marielle M Laterre Pierre-François PF De Poortere Julien J Horman Sandrine S Beauloye Christophe C Douxfils Jonathan J

Biomolecules 20220727 8

Background: Neutrophil extracellular traps’ (NETs’) formation is a mechanism of defense that neutrophils deploy as an alternative to phagocytosis, to constrain the spread of microorganisms. Aim: The aim was to evaluate biomarkers of NETs’ formation in a patient cohort admitted to intensive care unit (ICU) due to infection. Methods: Forty-six septic shock patients, 22 critical COVID-19 patients and 48 matched control subjects were recruited. Intact nucleosomes containing histone 3.1 (Nu.H3.1), or ...[more]

PMID: 36008932

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Project description:BackgroundUnderstanding the mechanisms underlying immune dysregulation in sepsis is a major challenge in developing more individualized therapy, as early and persistent inflammation, as well as immunosuppression, play a significant role in pathophysiology. As part of the antimicrobial response, neutrophils can release extracellular traps (NETs) which neutralize and kill microorganisms. However, excessive NETs formation may also contribute to pathogenesis, tissue damage and organ dysfunction. Recently, a novel automated assay has been proposed for the routine measurement of nucleosomes H3.1 (fundamental units of chromatin) that are released during NETs formation. The aim of the present study was to measure nucleosome levels in 151 septic shock patients (according to sepsis-3 definition) and to determine association with mortality.ResultsThe nucleosome H3.1 levels (as determined by a chemiluminescence immunoassay performed on an automated immunoanalyzer system) were markedly and significantly elevated at all-time points in septic shock patients compared to the control group. Immunological parameters indicated tremendous early inflammation (IL-6 = 1335 pg/mL at day 1-2) along with marked immunosuppression (e.g., mHLA-DR = 3853 AB/C and CD4 = 338 cell /µL at day 3-4). We found significantly positive correlation between nucleosome levels and organ failure and severity scores, IL-6 concentrations and neutrophil count. Significantly higher values (day 1-2 and 3-4) were measured in non-survivor patients (28-day mortality). This association was still significant after multivariate analysis and was more pronounced with highest concentration. Early (day 1-2) increased nucleosome levels were also independently associated with 5-day mortality. At day 6-8, persistent elevated nucleosome levels were negatively correlated to mHLA-DR values.ConclusionsThis study reports a significant elevation of nucleosome in patients during a one-week follow-up. The nucleosome levels showed correlation with neutrophil count, IL-6 and were found to be independently associated with mortality assessed at day 5 or 28. Therefore, nucleosome concentration seems to be a promising biomarker for detecting hyper-inflammatory phenotype upon a patient's admission. Additional investigations are required to evaluate the potential association between sustained elevation of nucleosome and sepsis-induced immunosuppression.

Project description:BackgroundSeptic shock occurs when sepsis is related to severe hypotension and leads to a remarkable high number of deaths. The early diagnosis of septic shock is essential to reduce mortality. High-quality biomarkers can be objectively measured and evaluated as indicators to accurately predict disease diagnosis. However, single-gene prediction efficiency is inadequate; therefore, we identified a risk-score model based on gene signature to elevate predictive efficiency.MethodsThe gene expression profiles of GSE33118 and GSE26440 were downloaded from the Gene Expression Omnibus (GEO) database. These two datasets were merged, and the differentially expressed genes (DEGs) were identified using the limma package in R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments of DEGs were performed. Subsequently, Lasso regression and Boruta feature selection algorithm were combined to identify the hub genes of septic shock. GSE9692 was then subjected to weighted gene co-expression network analysis (WGCNA) to identify the septic shock-related gene modules. Subsequently, the genes within such modules that matched with septic shock-related DEGs were identified as the hub genes of septic shock. To further understand the function and signaling pathways of hub genes, we performed gene set variation analysis (GSVA) and then used the CIBERSORT tool to analyze the immune cell infiltration pattern of diseases. The diagnostic value of hub genes in septic shock was determined using receiver operating characteristic (ROC) analysis and verified using quantitative PCR (qPCR) and Western blotting in our hospital patients with septic shock.ResultsA total of 975 DEGs in the GSE33118 and GSE26440 databases were obtained, of which 30 DEGs were remarkably upregulated. With the use of Lasso regression and Boruta feature selection algorithm, six hub genes (CD177, CLEC5A, CYSTM1, MCEMP1, MMP8, and RGL4) with expression differences in septic shock were screened as potential diagnostic markers for septic shock among the significant DEGs and were further validated in the GSE9692 dataset. WGCNA was used to identify the co-expression modules and module-trait correlation. Enrichment analysis showed significant enrichment in the reactive oxygen species pathway, hypoxia, phosphatidylinositol 3-kinases (PI3K)/Protein Kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, nuclear factor-κβ/tumor necrosis factor alpha (NF-κβ/TNF-α), and interleukin-6 (IL-6)/Janus Kinase (JAK)/Signal Transducers and Activators of Transcription 3 (STAT3) signaling pathways. The receiver operating characteristic curve (ROC) of these signature genes was 0.938, 0.914, 0.939, 0.956, 0.932, and 0.914, respectively. In the immune cell infiltration analysis, the infiltration of M0 macrophages, activated mast cells, neutrophils, CD8 T cells, and naive B cells was more significant in the septic shock group. In addition, higher expression levels of CD177, CLEC5A, CYSTM1, MCEMP1, MMP8, and RGL4 messenger RNA (mRNA) were observed in peripheral blood mononuclear cells (PBMCs) isolated from septic shock patients than from healthy donors. Higher expression levels of CD177 and MMP8 proteins were also observed in the PBMCs isolated from septic shock patients than from control participants.ConclusionsCD177, CLEC5A, CYSTM1, MCEMP1, MMP8, and RGL4 were identified as hub genes, which were of considerable value in the early diagnosis of septic shock patients. These preliminary findings are of great significance for studying immune cell infiltration in the pathogenesis of septic shock, which should be further validated in clinical studies and basic studies.

Project description:BackgroundIn patients with septic shock, the skin is often chosen for the evaluation of peripheral perfusion and oxygenation. Changes in skin microcirculatory vessel oxygen saturation and relative hemoglobin concentration can be described using a mottling score or captured with hyperspectral imaging. However, the effectiveness of the mottling score in assessing microcirculation remains to be shown. We hypothesize that the mottling score in patients with septic shock is related to skin microcirculatory perfusion indices quantified by hyperspectral imaging, biomarkers that reflect endothelium activation and damage, and clinical outcome.MethodsHyperspectral imaging of the knee area was performed in 95 intensive care patients with septic shock enrolled in a single-center observational study to obtain relative oxy/deoxyhemoglobin concentration values and construct anatomical maps of skin microcirculatory saturation. The blood was sampled to obtain concentrations of thrombomodulin, plasminogen activator inhibitor-1 (PAI-1), soluble intercellular adhesion molecule-1 (ICAM-1), soluble vascular cell adhesion molecule-1 (VCAM-1), angiopoietin-2, and syndecan-1. The spectrophotometrically obtained skin microvascular perfusion indices were compared to the mottling score and biomarker concentration. The association between mottling score, skin microcirculatory perfusion indices, and 28-day mortality was also analyzed.ResultsMicrocirculatory oxygen saturation was significantly lower and total hemoglobin concentration was significantly higher in patients with a mottling score of 2 compared to those with a score of 0 (p = 0.02), with no difference between other scores. We found an association between microcirculatory oxygen saturation and PAI-1 levels (rho = - 0.3; p = 0.007). Increased mottling score and decreased microcirculatory oxygen saturation were predictive of 28-day mortality (mottling score 2 vs 0: OR 15.31, 95% CI 4.12-68.11; microcirculatory oxygen saturation: OR 0.90, 95% CI 0.85-0.95). Endothelial biomarkers did not increase the predictive value of skin microcirculatory perfusion indices.ConclusionsHigher mottling scores are associated with lower microcirculatory oxygen saturation but with significant overlap between scores. Microcirculatory oxygen saturation is a quantitative measure of peripheral oxygenation and is more specific than the mottling score in predicting 28-day mortality.

Dataset Information

NETosis and Nucleosome Biomarkers in Septic Shock and Critical COVID-19 Patients: An Observational Study.

Publications

NETosis and Nucleosome Biomarkers in Septic Shock and Critical COVID-19 Patients: An Observational Study.

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