Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children.
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ABSTRACT:
SUBMITTER: Diorio C
PROVIDER: S-EPMC7594400 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children.
Diorio Caroline C Shaw Pamela A PA Pequignot Edward E Orlenko Alena A Chen Fang F Aplenc Richard R Barrett David M DM Bassiri Hamid H Behrens Edward E DiNofia Amanda M AM Gonzalez Vanessa V Koterba Natalka N Levine Bruce L BL Maude Shannon L SL Meyer Nuala J NJ Moore Jason H JH Paessler Michele M Porter David L DL Bush Jenny L JL Siegel Don L DL Davis Megan M MM Zhang Donglan D June Carl H CH Grupp Stephan A SA Melenhorst J Joseph JJ Lacey Simon F SF Weiss Scott L SL Teachey David T DT
Blood advances 20201001 20
Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both cytokine release syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We id ...[more]
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Project description:Background: Systemic inflammation is a whole body reaction that can have an infection-positive (i.e. sepsis) or infection-negative origin. It is important to distinguish between septic and non-septic presentations early and reliably, because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on a small number of RNAs expressed in peripheral blood could be discovered that would: 1) determine which patients with systemic inflammation had sepsis; 2) be robust across independent patient cohorts; 3) be insensitive to disease severity; and 4) provide diagnostic utility. The overall goal of this study was to identify and validate such a molecular classifier. Methods and Findings: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICU). Biomarker discovery was conducted with an Australian cohort (n = 105) consisting of sepsis patients and post -surgical patients with infection-negative systemic inflammation. Using this cohort, a four-gene classifier consisting of a combination of CEACAM4, LAMP1, PLA2G7 and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte® Lab, was externally validated using RT-qPCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Cohort 1 (n=59) consisted of unambiguous septic cases and infection-negative systemic inflammation controls; SeptiCyte® Lab gave an area under curve (AUC) of 0.96 (95% CI: 0.91-1.00). ROC analysis of a more heterogeneous group of patients (Cohorts 2-5; 249 patients after excluding 37 patients with infection likelihood possible) gave an AUC of 0.89 (95% CI: 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility o f SeptiCyte® Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyte® Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyte® Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyte® Lab is a rapid molecular assay that may be clinically useful in the management of ICU patients with systemic inflammation. SIRS and Sepsis ICU patients, admission samples Retrospective, mutli-site sutdy using retrospective physician adjudication as a comparator
2015-10-24 | E-GEOD-74224 | biostudies-arrayexpress
Project description:BACKGROUND:Data that indicate vitamin A status in critically ill children with sepsis are sparse. The association between serum vitamin A levels and the clinical outcomes of sepsis has not been well assessed. The aim of this study was to assess the prevalence of vitamin A deficiency in critically ill children with sepsis and its association with clinical outcomes. METHODS:Critically ill children with sepsis admitted to the pediatric intensive care unit were engaged in this prospective study. Sex- and age-matched approximate-health children from the Department of Pediatric Surgery were enrolled as the control group. Blood samples were collected from all patients in the first 24?h of admission for the measurement of serum vitamin A status. We compared vitamin A status between the sepsis group and the control group. In addition, we compared the clinical characteristics of the two subgroups of septic patients with vitamin A deficiency and those without vitamin A deficiency. Univariate and multivariable methods were used to evaluate the association between vitamin A deficiency and septic shock. RESULTS:One hundred sixty septic children and 49 approximate-health children were enrolled in this study. Vitamin A deficiency was found in 94 (58.8%) subjects in the study group and 6 (12.2%) subjects in the control group (P?<?0.001). In septic patients, 28-day mortality and hospital mortality in patients with vitamin A deficiency were not significantly higher than that in patients without vitamin A deficiency (P?>?0.05). However, vitamin A levels were inversely associated with higher PRISM scores in septic children with VAD (r?=?-?0.260, P?=?0.012). Vitamin A deficiency was associated with septic shock with an unadjusted odds ratio (OR) of 3.297 (95% confidence interval (CI), 1.169 to 9.300; P?=?0.024). In a logistic model, vitamin A deficiency (OR, 4.630; 95% CI, 1.027-20.866; P?=?0.046), procalcitonin (OR, 1.029; 95% CI, 1.009-1.048; P?=?0.003), and the Pediatric Risk of Mortality scores (OR, 1.132; 95% CI, 1.009-1.228; P?=?0.003) were independently associated with septic shock. CONCLUSION:The prevalence of vitamin A deficiency was high in children with sepsis. Vitamin A deficiency may be a marker of mortality in critically ill children with sepsis. TRIAL REGISTRATION:Clinicaltrials.gov , NCT03598127.
| S-EPMC6670191 | biostudies-literature
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:Background: Systemic inflammation is a whole body reaction that can have an infection-positive (i.e. sepsis) or infection-negative origin. It is important to distinguish between septic and non-septic presentations early and reliably, because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on a small number of RNAs expressed in peripheral blood could be discovered that would: 1) determine which patients with systemic inflammation had sepsis; 2) be robust across independent patient cohorts; 3) be insensitive to disease severity; and 4) provide diagnostic utility. The overall goal of this study was to identify and validate such a molecular classifier. Methods and Findings: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICU). Biomarker discovery was conducted with an Australian cohort (n = 105) consisting of sepsis patients and post -surgical patients with infection-negative systemic inflammation. Using this cohort, a four-gene classifier consisting of a combination of CEACAM4, LAMP1, PLA2G7 and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte® Lab, was externally validated using RT-qPCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Cohort 1 (n=59) consisted of unambiguous septic cases and infection-negative systemic inflammation controls; SeptiCyte® Lab gave an area under curve (AUC) of 0.96 (95% CI: 0.91-1.00). ROC analysis of a more heterogeneous group of patients (Cohorts 2-5; 249 patients after excluding 37 patients with infection likelihood possible) gave an AUC of 0.89 (95% CI: 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility o f SeptiCyte® Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyte® Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyte® Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyte® Lab is a rapid molecular assay that may be clinically useful in the management of ICU patients with systemic inflammation. SIRS and Sepsis ICU patients, admission samples
2015-10-24 | GSE74224 | GEO
Project description:OBJECTIVES:Sepsis is associated with high early and total in-hospital mortality. Despite recent revisions in the diagnostic criteria for sepsis that sought to improve predictive validity for mortality, it remains difficult to identify patients at greatest risk of death. We compared the utility of nine biomarkers to predict mortality in subjects with clinically suspected bacterial sepsis. DESIGN:Cohort study. SETTING:The medical and surgical ICUs at an academic medical center. SUBJECTS:We enrolled 139 subjects who met two or more systemic inflammatory response syndrome (systemic inflammatory response syndrome) criteria and received new broad-spectrum antibacterial therapy. INTERVENTIONS:We assayed nine biomarkers (?-2 macroglobulin, C-reactive protein, ferritin, fibrinogen, haptoglobin, procalcitonin, serum amyloid A, serum amyloid P, and tissue plasminogen activator) at onset of suspected sepsis and 24, 48, and 72 hours thereafter. We compared biomarkers between groups based on both 14-day and total in-hospital mortality and evaluated the predictive validity of single and paired biomarkers via area under the receiver operating characteristic curve. MEASUREMENTS AND MAIN RESULTS:Fourteen-day mortality was 12.9%, and total in-hospital mortality was 29.5%. Serum amyloid P was significantly lower (4/4 timepoints) and tissue plasminogen activator significantly higher (3/4 timepoints) in the 14-day mortality group, and the same pattern held for total in-hospital mortality (Wilcoxon p ? 0.046 for all timepoints). Serum amyloid P and tissue plasminogen activator demonstrated the best individual predictive performance for mortality, and combinations of biomarkers including serum amyloid P and tissue plasminogen activator achieved greater predictive performance (area under the receiver operating characteristic curve > 0.76 for 14-d and 0.74 for total mortality). CONCLUSIONS:Combined biomarkers predict risk for 14-day and total mortality among subjects with suspected sepsis. Serum amyloid P and tissue plasminogen activator demonstrated the best discriminatory ability in this cohort.
| S-EPMC6010038 | biostudies-literature
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. Keywords: disease state analysis, gram-positive sepsis, gram-negative sepsis
2007-12-01 | GSE6535 | GEO
Project description:BackgroundTwo sets of diagnostic criteria of paediatric multiple organ dysfunction syndrome (MODS) were published by Proulx in 1996 and by Goldstein in 2005. We hypothesized that this changes the epidemiology of MODS. Thus, we determined the epidemiology of MODS, according to these two sets of diagnostic criteria, we studied the intra- and inter-observer reproducibility of each set of diagnostic criteria, and we compared the association between cases of MODS at paediatric intensive care unit (PICU) entry, as diagnosed by each set of diagnostic criteria, and 90-day all-cause mortality.MethodsAll consecutive patients admitted to the tertiary care PICU of Sainte-Justine Hospital, from April 21, 2009 to April 20, 2010, were considered eligible for enrolment into this prospective observational cohort study. The exclusion criteria were gestational age < 40 weeks, age < 3 days or > 18 years at PICU entry, pregnancy, admission immediately after delivery. No patients were censored. Daily monitoring using medical chart ended when the patient died or was discharged from PICU. Mortality was monitored up to death, hospital discharge, or 90 days post PICU entry, whatever happened first. Concordance rate and kappa score were calculated to assess reproducibility. The number of MODS identified with Proulx and Goldstein definitions was compared using 2-by-2 contingency tables. Student's t test or Wilcoxon signed-ranked test was used to compare continuous variables with normal or abnormal distribution, respectively. We performed a Kaplan-Meier survival analysis to assess the association between MODS at PICU entry and 90-day mortality.ResultsThe occurrence of MODS was monitored daily and prospectively in 842 consecutive patients admitted to the PICU of Sainte-Justine Hospital over 1 year. According to Proulx and Goldstein diagnostic criteria, 180 (21.4 %) and 314 patients (37.3 %) had MODS over PICU stay, respectively. Concordance of MODS diagnosis over PICU stay was 81.3 % (95 % CI 78.6-83.9 %), and kappa score was 0.56 (95 % CI 0.50-0.61). Discordance was mainly attributable to cardiovascular or neurological dysfunction criteria. The proportion of patients with MODS at PICU entry who died within 90 days was higher with MODS diagnosed with Proulx criteria (17.8 vs. 11.5 %, p = 0.038), as well as the likelihood ratio of death (4.84 vs. 2.37). On the other hand, 90-day survival rate of patients without MODS at PICU entry was similar (98.6 vs. 98.9 % (p = 0.73).ConclusionsProulx and Goldstein diagnostic criteria of paediatric MODS are not equivalent. The epidemiology of paediatric MODS varies depending on which set of diagnostic criteria is applied.
| S-EPMC4851677 | biostudies-literature
Project description:Severe sepsis (SS) in pediatric oncology patients is a leading cause of morbidity and mortality. We investigated the incidence of and risk factors for morbidity and mortality among children diagnosed with cancer from 2008 to 2012, and admitted with SS during the 3 years following cancer diagnosis. A total of 1,002 children with cancer were included, 8% of whom required pediatric intensive care unit (PICU) admission with SS. Death and/or multiple organ dysfunction syndrome occurred in 34 out of 99 PICU encounters (34%). Lactate level and history of stem-cell transplantation were significantly associated with the development of death and/or organ dysfunction ( p ?<?0.05).
| S-EPMC6687451 | biostudies-literature
Project description:ObjectivesAcute kidney injury is a major cause of morbidity and mortality in critically ill children. A growing body of evidence has shown that acute kidney injury affects immune function, yet little is known about the association between acute kidney injury and subsequent infection in pediatric patients. Our objective was to examine the association of non-septic acute kidney injury with the development of subsequent sepsis in critically ill children.DesignA single-center retrospective cohort study.SettingThe pediatric and cardiac ICUs at a tertiary pediatric care center.PatientsAll patients 0-18 years old without a history of chronic kidney disease, who did not have sepsis prior to or within the initial 48 hours of ICU admission.InterventionsNone.Measurements and main resultsWe analyzed data for 5,538 children (median age, 5.3 yr; 58.2% male), and identified 255 (4.6%) with stage 2 or 3 acute kidney injury. Suspected sepsis occurred in 46 children (18%) with stage 2 or 3 acute kidney injury compared to 286 children (5.4%) with stage 1 or no acute kidney injury. On adjusted analysis, children with stage 2 or 3 acute kidney injury had 2.05 times greater odds of developing sepsis compared to those with stage 1 or no acute kidney injury (95% CI, 1.39-3.03; p < 0.001). Looking at acute kidney injury severity, children with stage 2 and 3 acute kidney injury had a 1.79-fold (95% CI, 1.15-2.79; p = 0.01) and 3.24-fold (95% CI, 1.55-6.80; p = 0.002) increased odds of developing suspected sepsis, respectively.ConclusionsAcute kidney injury is associated with an increased risk for subsequent infection in critically ill children. These results further support the concept of acute kidney injury as a clinically relevant immunocompromised state.
| S-EPMC7790909 | biostudies-literature
Project description:Sepsis is a frequent complication in critically ill patients and highly heterogeneous that is associated with high morbidity and mortality rates, especially in the elderly population. Utilizing RNA-Sequencing (RNA-Seq) to analysis biological pathways is widely used in clinical and molecular genetics studies, but in elderly patients with sepsis are still lacking. Hence, we aim to investigate the mortality-relevant biological features and transcriptomic features in elderly patients who were admitted to intensive care unit (ICU) for sepsis.
2022-11-03 | GSE216902 | GEO