The serum proteomic signatures associated with organ dysfunction based on Phoenix criteria in pediatric sepsis
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ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Yucai Zhang
PROVIDER: PXD068707 | iProX | Mon Sep 22 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:Normal children, children with SIRS, children with sepsis, and children with septic shock. Objectives: To advance our biological understanding of pediatric septic shock, we measured the genome-level expression profiles of critically ill children representing the systemic inflammatory response syndrome (SIRS), sepsis, and septic shock spectrum. Experiment Overall Design: Prospective observational study involving microarray-based bioinformatics.
2009-01-05 | E-GEOD-13904 | biostudies-arrayexpress
Project description:Expression data from CD8+ T cells and CD68+ monocytes from patients with hemophagocytic lymphohistiocytosis, sepsis, and persistent systemic inflammatory response syndrome Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by pathologic immune activation in which prompt recognition and initiation of immune suppression is essential for survival. Children with HLH have many overlapping clinical features with critically ill children with sepsis and persistent systemic inflammatory response syndrome (SIRS) in whom alternative therapies are indicated. To determine if plasma biomarkers could differentiate HLH from other inflammatory conditions and to better define a ‘core inflammatory signature’ of HLH, concentrations of inflammatory plasma proteins were compared in 40 patients with HLH to 47 pediatric patients with severe sepsis or SIRS. Seventeen of 135 analytes were significantly different in HLH plasma compared to SIRS/sepsis, including increased interferon-gamma (IFNg)-regulated chemokines CXCL9, CXCL10 and CXCL11. Further, a 5-analyte plasma protein classifier including these chemokines was able to differentiate HLH from SIRS/sepsis. Gene expression in CD8+ T cells and CD68+ monocytes from blood were also enriched for IFNg pathway signatures in peripheral blood cells from patients with HLH compared to SIRS/sepsis. This study identifies differential expression of inflammatory proteins as a diagnostic strategy to identify critically ill children with HLH. Further, comprehensive unbiased analysis of inflammatory plasma proteins and global gene expression demonstrates that IFNg signaling is uniquely elevated in HLH. In addition to demonstrating the ability of diagnostic criteria for HLH, sepsis and SIRS to identify groups with distinct inflammatory patterns, results from this study support the potential for prospective evaluation of inflammatory biomarkers to aid in diagnosis of and optimizing therapeutic strategies for children with distinctive hyperinflammatory syndromes.
2021-05-16 | GSE150707 | GEO
Project description:Pediatric sepsis is a leading cause of mortality in children across the world. Within pediatric sepsis, how developmental age-specific host immune response impact on the occurrence and development of pediatric sepsis is still unknown, especially between infants and toddlers, which were the major susceptible age groups in sepsis. Experimental design In this study, we applied a nested case-control study strategy and analyzed the plasma proteomes of pediatric sepsis patients between infants and toddlers in comparison to their age-matched controls respectively. Each age group consists of three subgroups with different outcomes. One hundred and ten plasma samples were pooled into 16 samples for quantitative identification by LC-MS/MS. Results It was totally quantified 677 proteins. In comparison to toddlers, infant sepsis patients were characteristic with dominant neutrophil-mediated defense, suppressed adaptive immunity and NK-mediated cytotoxicity. Besides, pentose phosphate pathway was more up-regulated in infants and associated with poor outcome. Moreover, combined Hp and Thbs1 with the AUC value of 0.958 (95%CI, 0.868, 1.000) was confirmed as potential infant-adapted prognostic marker of poor outcome in sepsis. Conclusion and clinical relevance Our proteomic analysis of age-associated pediatric sepsis combined with clinical laboratory data provided a comprehensive insight into the complex, multifactorial heterogeneous host response to pediatric sepsis and allowed identification of critical differences between infant and toddler sepsis. Moreover, we confirmed that combined Hp and Thbs1 is more infant-adapted and serves as a potential prognostic biomarker for poor outcome of infant sepsis, promoting the application of age-adapted precision medicine in pediatric sepsis.
2021-11-01 | PXD026656 | Pride
Project description:Objective: It is unclear whether the host response of gram-positive sepsis differs from gram-negative sepsis at a transcriptome level. Using microarray technology, we compared the gene-expression profiles of gram-positive sepsis and gram-negative sepsis in critically ill patients. Design: A prospective cross-sectional study. Setting: A 20-bed general intensive care unit of a tertiary referral hospital. Patients: Seventy-two patients admitted to the intensive care unit. Interventions: Intravenous blood was collected for leukocyte separation and RNA extraction. Microarray experiements were then performed examing the expression level of 19,232 genes in each sample. Measurements and Main Results: There was no difference in the expression profile between gram-positive and gram-negative sepsis. The finding remained unchanged even when genes with lower expression level were included or after statistical stringency was lowered. There were, however, ninety-four genes differentially expressed between sepsis and control patients. These genes included those involved in immune regulation, inflammation and mitochondrial function. Hierarchical cluster analysis confirmed that the difference in gene expression profile existed between sepsis and control patients, but not between gram-positive and gram-negative patients. Conclusion: Gram-positive and gram-negative sepsis share a common host response at a transcriptome level. These findings support the hypothesis that the septic response is non-specific and is designed to provide a more general response that can be elicited by a wide range of different micro-organisms. The study included seventy-two critically ill patients admitted to the intensive care unit (ICU) of Nepean Hospital, Sydney, Australia. Of these, fifty-five patients were diagnosed to have sepsis, as confirmed by microbiological culture. The remaining seventeen patients did not have sepsis and were therefore used as controls. The study was approved by the hospital ethics committee and informed consent was obtained from all patients or their relatives. Patient Samples. Whole blood was taken from each patient on admission to ICU. Neutrophils were separated from whole blood using density-gradient separation with Ficoll-PaqueP P(Amersham). Subsequent neutrophil RNA extraction was performed using guanidinium thiocyanate (Ambion). Microarray Experiment. The neutrophil RNA was converted to cDNA, fluorescently labeled and hybridized to its complimentary sequences on the microarray (Invitrogen). The fluorescent signals on each micrroarray were captured using the GenePix 4000B laser scanner (Axon Instruments). Expression level of each gene was represented by the intensity of its fluorescent signal. Data Extraction. All signal intensity values were processed using background-subtraction method. Prior to analysis, all values were log-transformed and normalized by fitting a print-tip group Lowess curve. Normalization minimizes bias due to dye chemistry, signal intensity or location of a gene on the array. It ensures the detection of genes that are truly differentially expressed, instead of those caused by experimental artifacts or variation in the hybridization process. After normalization, genes that had more than 50% of data missing were removed. We then selected genes that had at least 80% of the data showing two-fold changes from the geneâs median values. After filtering, 1617 genes were available for further analysis.
2010-05-25 | E-GEOD-6535 | biostudies-arrayexpress
Project description:Sepsis is a life-threatening condition caused by a dysregulated immune response to infection, leading to organ failure. Despite its significant global burden, the underlying mechanisms of immune dysfunction in sepsis remain incompletely understood. This study explores the role of DNA methylation in white blood cells in sepsis pathogenesis by assessing a prospective case-control study comparing DNA methylation profiles between patients with community-acquired sepsis and matched controls with similar infections who did not develop sepsis. Blood samples were collected within 24 hours of hospital admission, and DNA methylation was analyzed using Illumina MethylationEPIC 850 v2 arrays and bisulfite pyrosequencing. The discovery cohort (n=32) identified 4,640 differentially methylated positions (DMPs), with notable hypomethylation in immune-related genes. Functional enrichment analysis revealed significant involvement of these genes in immune processes, including neutrophil activation and monocyte differentiation. Key findings highlighted hypomethylation of SERPINA1, AZU1, MPO, and SLX4, which was validated in an independent cohort (n=28). Correlation analyses demonstrated significant associations between the methylation levels of these genes and clinical severity markers, such as SOFA score and procalcitonin levels. Notably, SLX4 hypomethylation showed the highest predictive value for poor prognosis (AUC 0.821), while SERPINA1 hypomethylation exhibited strong diagnostic potential for sepsis (AUC 0.858). Our findings suggest that DNA methylation changes, particularly in immune-related genes, could serve as valuable biomarkers for diagnosing sepsis and predicting patient outcomes. Further research is warranted to confirm their clinical utility and explore potential therapeutic targets.
2025-01-24 | GSE285813 | GEO
Project description:Clinical study of critically ill patients with sepsis and sepsis-related ARDS with whole blood RNA collected within the first 24 hours of admission Goal of the study was to determine whether biologically relevant genes were identified to be differentially expressed genes in patients with sepsis alone and sepsis with ARDS Prospective observational study, case cohort design
2015-04-01 | E-GEOD-66890 | biostudies-arrayexpress
Project description:Streptococcus pneumoniae is a major cause of invasive diseases, such as pneumoniae, meningitis and sepsis resulting in high mortality. The molecular mechanisms and disease developing mechanism underlying pneumococcal infection remain unknown. Previously, we reported that S. pneumoniae β-galactosidase (BgaA) is evolutionarily conserved and contributes to pneumococcal pathogenesis in mouse sepsis model. BgaA is also known to play a role in pneumococcal growth, resistance to human neutrophil opsonophagocytic killing, bacterial adherence to human epithelial cells. In this study, since the detailed role that BgaA plays in sepsis remain unknown, we focused on the role of BgaA in pneumococcal sepsis. Our in vitro assays showed that BgaA promoted bacterial association with human lung epithelial and vascular endothelium cells. BgaA also contributes to pneumococcal survival with human blood by suppressing neutrophils killing, whereas BgaA did not affect pneumococcal survival in mouse blood. In a mouse sepsis model, mice infected with S. pneumoniae bgaA deletion mutant strain exhibited up-regulated host innate immunity pathways, and suppressed tissue damages and blood coagulation as compared to mice infected with the wild-type strain. These results suggest that BgaA works as a multifunctional virulence factor for inducing host tissue damages and blood coagulation. BgaA could be an attractive target for drug and vaccine development.
2022-07-18 | GSE190418 | GEO
Project description:The project examines the mechanisms of neutrophil dysfunction during sepsis. Our work uncovered the central role of cell free circulating histones in eliminating mature neutrophil in favour of immature cells and characterized the mechanisms that regulate their release following systemic infection. Mature and immature neutrophil Ly6Ghigh and Ly6Glow populations isolated from the spleens of WT and TCRα-deficient mice either naïve or infected with C. albicans were characterized. In addition, these populations were compared to neutrophils isolated from WT mice receiving Clodronate-liposomes and recombinant G-CSF. These studies demonstrated that T-cell derived histones drive the release of G-CSF in the spleen and progressively eliminate mature neutrophils by shortening their lifespan. Finally, we conducted proteomic analysis of plasmas isolated from patients with microbial sepsis to correlate markers of neutrophil death to plasma cytokine and histone levels, confirming the pathogenic role these molecules play during sepsis in humans.
2022-07-01 | PXD034391 | Pride
Project description:Introduction: Sepsis is a complex immunological response to infection characterized by early hyperinflammation followed by severe and protracted immunosuppression, suggesting that a multi-marker approach has the greatest clinical utility for early detection, within a clinical environment focused on SIRS differentiation. Pre-clinical research using an equine sepsis model identified a panel of gene expression biomarkers that define the early aberrant immune activation. Thus, the primary objective was to apply these gene expression biomarkers to distinguish patients with sepsis from those who had undergone major open surgery and had clinical outcomes consistent with systemic inflammation due to physical trauma and wound healing. Methods: This was a multi-centre, prospective clinical trial conducted across 4 tertiary critical care settings in Australia. Sepsis patients were recruited if they met the 1992 Consensus Statement criteria and had clinical evidence of systemic infection based on microbiology diagnoses (n=27). Participants in the post-surgical (PS) group were recruited pre-operatively and blood samples collected within 24 hours following surgery (n=38). Healthy controls (HC) included hospital staff with no known concurrent illnesses (n=20). Each participant had minimally 5ml of PAXgene blood collected for leucocyte RNA isolation and gene expression analyses. Affymetrix array and multiplex tandem (MT)-PCR studies were conducted to evaluate transcriptional profiles in circulating white blood cells applying a set of 42 molecular markers that had been identified a priori. A LogitBoost algorithm was used to create a machine learning diagnostic rule to predict sepsis outcomes. Results: Based on preliminary microarray analyses comparing HC and sepsis groups. A panel of 42-gene expression markers were identified that represented key innate and adaptive immune function, cell cycling, WBC differentiation, extracellular remodelling and immune modulation pathways. Comparisons against GEO data confirmed the definitive separation of the sepsis cohort. Quantitative PCR results suggest the capacity for this test to differentiate severe systemic inflammation from HC is 92%. AUC ROC curve findings demonstrated sepsis prediction within a mixed inflammatory population, was between 86 - 92%. Conclusions: This novel molecular biomarker test has a clinically relevant sensitivity and specificity profile, and has the capacity for early detection of sepsis via the monitoring of critical care patients. GEO Note: Data made available represents the preliminary microarray investigation performed on Human U133 Plus 2.0 GeneChips (Affymetrix), assaying 41 patient samples (Sepsis n=10, Post-Surgical n=11, Control n=20). This was a multi-centre, prospective clinical trial conducted across 4 tertiary critical care settings in Australia. Sepsis patients were recruited if they met the 1992 Consensus Statement criteria and had clinical evidence of systemic infection based on microbiology diagnoses (n=27). Participants in the post-surgical (PS) group were recruited pre-operatively and blood samples collected within 24 hours following surgery (n=38). Healthy controls (HC) included hospital staff with no known concurrent illnesses (n=20). Each participant had minimally 5ml of PAXgene blood collected for leucocyte RNA isolation and gene expression analyses. The GEO data represents the preliminary microarray investigation performed on Human U133 Plus 2.0 GeneChips (Affymetrix), assaying 41 patient samples (Sepsis n=10, Post-Surgical n=11, Control n=20).
2011-11-01 | E-GEOD-28750 | biostudies-arrayexpress
Project description:Background: COVID-19 and sepsis represent formidable public health challenges, characterized by incompletely elucidated molecular mechanisms. Elucidating the interplay between COVID-19 and sepsis, particularly in geriatric patients suffering from sepsis-induced acute respiratory distress syndrome (ARDS), is of paramount importance for identifying potential therapeutic interventions to mitigate hospitalization and mortality risks.We employed bioinformatics and systems biology approaches to identify hub genes, shared pathways, molecular biomarkers, and candidate therapeutics for managing COVID-19, sepsis, and sepsis-induced ARDS. We corroborated these hub genes utilizing murine sepsis-ARDS models and blood samples derived from geriatric patients afflicted by sepsis-induced ARDS.Results: Our investigation revealed 189 differentially expressed genes (DEGs) shared among COVID-19 and sepsis datasets. We constructed a protein-protein interaction network, unearthing pivotal hub genes and modules. Notably, nine hub genes displayed significant alterations and correlations with critical inflammatory mediators of pulmonary injury in murine septic lungs. Simultaneously, 12 displayed significant changes and correlations with a neutrophil-recruiting chemokine in geriatric patients with sepsis-induced ARDS. Of these, six hub genes (CD247, CD2, CD40LG, KLRB1, LCN2, RETN) showed significant alterations across COVID-19, sepsis, and geriatric sepsis-induced ARDS. Our single-cell RNA sequencing analysis of hub genes across 3 diverse immune cell types furnished insights into disease pathogenesis. Functional analysis underscored the interconnection between sepsis/sepsis-ARDS and COVID-19, enabling us to pinpoint potential therapeutic targets, transcription factor-gene interactions, DEG-microRNA co-regulatory networks, and prospective drug and chemical compound interactions involving hub genes.Our investigation offers potential therapeutic targets/biomarkers, sheds light on the immune response in geriatric patients with sepsis-induced ARDS, emphasizes the association between sepsis/sepsis-ARDS and COVID-19, and proposes novel avenues for targeted therapies.
2023-09-01 | GSE242127 | GEO