The influence of developmental age on the early transcriptomic response of children with septic shock.
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ABSTRACT:
SUBMITTER: Wynn JL
PROVIDER: S-EPMC3321808 | biostudies-other | 2011
REPOSITORIES: biostudies-other
Publications
The influence of developmental age on the early transcriptomic response of children with septic shock.
Wynn James L JL Cvijanovich Natalie Z NZ Allen Geoffrey L GL Thomas Neal J NJ Freishtat Robert J RJ Anas Nick N Meyer Keith K Checchia Paul A PA Lin Richard R Shanley Thomas P TP Bigham Michael T MT Banschbach Sharon S Beckman Eileen E Wong Hector R HR
Molecular medicine (Cambridge, Mass.) 20110705 11-12
Septic shock is a frequent and costly problem among patients in the pediatric intensive care unit (PICU) and is associated with high mortality and devastating survivor morbidity. Genome-wide expression patterns can provide molecular granularity of the host response and offer insight into why large variations in outcomes exist. We derived whole-blood genome-wide expression patterns within 24 h of PICU admission from children with septic shock. We compared the transcriptome between septic shock de ...[more]
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Project description:BackgroundSevere innate immune suppression, termed immunoparalysis, is associated with increased risks of nosocomial infection and mortality in children with septic shock. Currently, immunoparalysis cannot be clinically diagnosed in children, and mechanisms remain unclear. Transcriptomic studies identify subsets of septic children with downregulation of genes within adaptive immune pathways, but assays of immune function have not been performed as part of these studies, and little is known about transcriptomic profiles of children with immunoparalysis.MethodsWe performed a nested case-control study to identify differences in RNA expression patterns between children with septic shock with immunoparalysis (defined as lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)α response < 200 pg/ml) vs those with normal LPS-induced TNFα response. Children were enrolled within 48 hours of the onset of septic shock and divided into two groups based on LPS-induced TNFα response. RNA was extracted from whole blood for RNAseq, differential expression analyses using DESeq2 software, and pathway analyses using Ingenuity Pathway Analysis.Results32 children were included in analyses. Comparing those with immunoparalysis (n =19) to those with normal TNFα response (n = 13), 2,303 transcripts were differentially expressed with absolute value fold change ≥ 1.5 and false discovery rate ≤ 0.05. The majority of downregulated pathways in children with immunoparalysis were pathways that involved interactions between innate and adaptive immune cells necessary for cell-mediated immunity, crosstalk between dendritic cells and natural killer cells, and natural killer cell signaling pathways. Upregulated pathways included those involved in humoral immunity (T helper cell type 2), corticotropin signaling, platelet activation (GP6 signaling), and leukocyte migration and extravasation.ConclusionsOur study suggests that gene expression data might be useful to identify children with immunoparalysis and identifies several key differentially regulated pathways involved in both innate and adaptive immunity. Our ongoing work in this area aims to dissect interactions between innate and adaptive immunity in septic children and to more fully elucidate patient-specific immunologic pathophysiology to guide individualized immunotherapeutic targets.
| S-EPMC8517409 | biostudies-literature
Project description:Critically ill children with septic shock enrolled in prospective observational study. Children were divided into two groups based on the presence or absence of immunoparalysis (defined by ex vivo LPS-induced TNF alpha response). Total RNA isolated and sequenced by RNAseq and differential expression analyses performed.
2021-09-25 | E-MTAB-10938 | biostudies-arrayexpress
Project description:BackgroundSeptic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock.MethodsWe performed whole blood RNA sequencing in 21 SS, 11 CS, and 5 SC. In shock patients, blood samples were collected within 16 h from ICU admission (T1), 48 h after ICU admission (T2), and at day 7 or before discharge (T3). In controls, blood samples were available at T1 and T2. Gene expression changes over time have been studied in CS, SS, and SC separately with a paired analysis. Genes with p value < 0.01 (Benjamini-Hochberg multiple test correction) were defined differentially expressed (DEGs). We used gene set enrichment analysis (GSEA) to identify the biological processes and transcriptional regulators significantly enriched in both types of shock.ResultsIn both CS and SS patients, GO terms of inflammatory response and pattern recognition receptors (PRRs) were downregulated following ICU admission, whereas gene sets of DNA replication were upregulated. At the gene level, we observed that alarmins, interleukin receptors, PRRs, inflammasome, and DNA replication genes significantly changed their expression in CS and SS, but not in SC. Analysis of transcription factor targets showed in both CS and SS patients, an enrichment of CCAAT-enhancer-binding protein beta (CEBPB) targets in genes downregulated over time and an enrichment of E2F targets in genes with an increasing expression trend.ConclusionsThis pilot study supports, within the limits of a small sample size, the role of alarmins, PRRs, DNA replication, and immunoglobulins in the pathophysiology of circulatory shock, either in the presence of infection or not. We hypothesize that these genes could be potential targets of therapeutic interventions in CS and SS.Trial registrationClinicalTrials.gov, NCT02141607. Registered 19 May 2014.
| S-EPMC6921511 | biostudies-literature
Project description:Background: Septic shock heterogeneity has important implications for the conduct of clinical trials and individual patient management. We previously addressed this heterogeneity by indentifying 3 putative subclasses of children with septic shock based on a 100-gene expression signature corresponding to adaptive immunity and glucocorticoid receptor signaling. Herein we attempted to prospectively validate the existence of these gene expression-based subclasses in a validation cohort. Methods: Gene expression mosaics were generated from the 100 class-defining genes for 82 individual patients in the validation cohort. Patients were classified into 1 of 3 subclasses (“A”, “B”, or “C”) based on color and pattern similarity relative to reference mosaics generated from the original derivation cohort. Separate classifications were conducted by 21 individual clinicians and a computer-based algorithm. After subclassification the clinical database was mined for clinical phenotyping. Results: In the final consensus subclassification generated by clinicians, subclass A patients had a higher illness severity, as measured by illness severity scores and maximal organ failure, relative to subclasses B and C. The k coefficient across all possible inter-evaluator comparisons was 0.633. Similar observations were made based on the computer-generated subclassification. Patients in subclass A were also characterized by repression of a large number of genes having functional annotations related to zinc biology. Conclusions: We have validated the existence of subclasses of children with septic shock based on a biologically relevant, 100-gene expression signature. The subclasses can be indentified by clinicians without formal bioinformatics training, at a clinically relevant time point, and have clinically relevant phenotypic differences.
2011-01-13 | GSE26378 | GEO
Project description:ObjectivesTo serially evaluate health-related quality of life during the first year after community-acquired septic shock in children with preexisting severe developmental disabilities and explore factors associated with health-related quality of life changes in these children.DesignSecondary analysis of the Life after Pediatric Sepsis Evaluation investigation.SettingTwelve academic PICU in the United States.PatientsChildren greater than or equal to 1 month and less than 18 years old identified by their family caregiver (e.g., parent/guardian) as having severe developmental disability prior to septic shock.InterventionsFamily caregivers completed the Stein-Jessop Functional Status II-R Short Form as a measure of their child's health-related quality of life at baseline (reflecting preadmission status), day 7, and months 1, 3, 6, and 12 following PICU admission. Stein-Jessop Functional Status II-R Short Form scores were linearly transformed to a 0-100 scale, with higher scores indicating better health-related quality of life.Measurements and main resultsOf 392 Life after Pediatric Sepsis Evaluation participants, 137 were identified by their caregiver as having a severe developmental disability. Sixteen children (11.6%) with severe disability died during the 12 months following septic shock. Among 121 survivors, Stein-Jessop Functional Status II-R Short Form scores declined from preadmission baseline to day 7 (70.7 ± 16.1 vs 55.6 ± 19.2; p < 0.001). Stein-Jessop Functional Status II-R Short Form scores remained below baseline through month 12 (59.1 ± 21.0, p < 0.001 vs baseline). After adjusting for baseline Stein-Jessop Functional Status II-R Short Form, the caregiver being a single parent/guardian was associated with lower month 3 Stein-Jessop Functional Status II-R Short Form scores (p = 0.041). No other baseline child or caregiver characteristic, or critical illness-related factors were significantly associated with month 3 Stein-Jessop Functional Status II-R Short Form scores.ConclusionsHealth-related quality of life among children with severe developmental disability remains, on average, below baseline during the first year following community-acquired septic shock. Children with severe disability and septic shock that are in single parent families are at increased risk. Clinical awareness of the potential for decline in health-related quality of life among disabled children is essential to prevent this adverse outcome from being missed.
| S-EPMC8099927 | biostudies-literature
Project description:Extracorporeal membrane oxygenation (ECMO) is a rescue treatment used in children and adults with reversible cardiorespiratory failure. The role of ECMO is not fully established in pediatric sepsis. In this retrospective single-center study, we aimed to investigate risk factors and survival in pediatric septic shock supported with peripheral cannulation ECMO. All patients aged 30 days to 18 years treated between 2007 and 2016 with ECMO for septic shock were included. Of 158 screened patients, 31 were enrolled in the study. The P/F ratio was 48 ± 22 mm Hg, b-lactate 8.5 ± 6.6 mmol/L, p-procalcitonin 214 (IQR 19-294) μg/L, and 2 (1-2) vasoactive drugs were infused. The number of organ failures were 3 (3-4). Ten patients were commenced on venovenous and 21 on venoarterial ECMO. Survival from ECMO was 71%, and 68% survived to hospital discharge. Hospital survival was 80% for venovenous ECMO and 62% in venoarterial support (p = 0.43). Factors associated with in-hospital mortality were high b-lactate (p = 0.015) and high creatinine (p = 0.019) at admission. Conversion between modalities was not a risk factor. Sixty percent were alive at long-term follow-up (median 6.5 years). Peripheral cannulation ECMO is feasible in pediatric septic shock. Treatment should be performed at high-volume ECMO centers experienced in sepsis, and central or peripheral type and ECMO modality according to center preference and patient's need.
| S-EPMC8797002 | biostudies-literature
Project description:Background: Septic shock heterogeneity has important implications for the conduct of clinical trials and individual patient management. We previously addressed this heterogeneity by indentifying 3 putative subclasses of children with septic shock based on a 100-gene expression signature corresponding to adaptive immunity and glucocorticoid receptor signaling. Herein we attempted to prospectively validate the existence of these gene expression-based subclasses in a validation cohort. Methods: Gene expression mosaics were generated from the 100 class-defining genes for 82 individual patients in the validation cohort. Patients were classified into 1 of 3 subclasses (“A”, “B”, or “C”) based on color and pattern similarity relative to reference mosaics generated from the original derivation cohort. Separate classifications were conducted by 21 individual clinicians and a computer-based algorithm. After subclassification the clinical database was mined for clinical phenotyping. Results: In the final consensus subclassification generated by clinicians, subclass A patients had a higher illness severity, as measured by illness severity scores and maximal organ failure, relative to subclasses B and C. The k coefficient across all possible inter-evaluator comparisons was 0.633. Similar observations were made based on the computer-generated subclassification. Patients in subclass A were also characterized by repression of a large number of genes having functional annotations related to zinc biology. Conclusions: We have validated the existence of subclasses of children with septic shock based on a biologically relevant, 100-gene expression signature. The subclasses can be indentified by clinicians without formal bioinformatics training, at a clinically relevant time point, and have clinically relevant phenotypic differences. Expression data from 82 children with septic shock and 21 normal controls were generated using whole blood-derived RNA samples representing the first 24 hours of admission to the pediatric intensive care unit. The controls were used for normalization. Subsequently, we used the expression data from 100 class defining genes to validate the existence of pediatric septic shock subclasses having phenotypic differences.
2011-01-13 | E-GEOD-26378 | biostudies-arrayexpress
Project description:BackgroundSepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches.MethodsWe performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme.ResultsAmong 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes.ConclusionsOur research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.
| S-EPMC11253460 | biostudies-literature
Project description:The Protocol-based Care for Early Septic Shock trial found no differences across alternative resuscitation strategies in all-cause mortality. A separate aim was to determine whether differences in resuscitation strategies affected trajectories of biomarkers of key pathways associated with downstream clinical outcomes of sepsis and whether there were differences in survival across treatment arms for patients with different baseline biomarker profiles.Secondary analysis of a large randomized clinical trial.Thirty-one U.S. hospitals.Six hundred twenty-eight patients with septic shock.Two resuscitation protocols versus usual care.We measured a panel of biomarkers representing four pathophysiologic domains: "inflammation" (tumor necrosis factor, interleukin-6, and -10); "coagulation" (D-dimers, thrombin-antithrombin complex); "oxidative stress" (urine isoprostane); and "tissue hypoxia" (lactate) at 0, 6, 24, and 72 hours after treatment. We analyzed whether alternative resuscitation strategies affected biomarker trajectories over 72 hours and whether effects on 90-day hospital mortality varied by baseline (time 0) biomarker profiles-both using regression models with interaction terms for treatment arms. For all baseline biomarkers, higher concentrations were associated with increased risk of death by 90 days. However, there was no significant effect of treatment assignment on subsequent biomarker trajectories. We did find evidence for heterogeneity of treatment effect of protocol-based care on mortality for patients with different baseline [interleukin-6] and [interleukin-6] × [interleukin-10] profiles, whereas patients with the lowest quartiles fared better with protocol-based care (odds ratios, 0.32 [0.13-075]; p = 0.01 and 0.32 [0.14-0.73]; p = 0.01, respectively).In patients with septic shock, alterations in inflammation, coagulation, oxidative stress, and tissue hypoxia are common and associated with adverse outcomes but are not influenced by protocol-based resuscitation compared with usual care. However, contrary to expectation, protocol-based resuscitation appeared to be superior in patients with lower concentrations of inflammatory biomarkers. The mechanisms responsible for this effect are unclear.
| S-EPMC5448291 | biostudies-literature
Project description:ObjectivesSepsis and septic shock are leading causes of in-hospital mortality. Timely treatment is crucial in improving patient outcome, yet treatment delays remain common. Early prediction of those patients with sepsis who will progress to its most severe form, septic shock, can increase the actionable window for interventions. We aim to extend a time-evolving risk score, previously developed in adult patients, to predict pediatric sepsis patients who are likely to develop septic shock before its onset, and to determine whether or not these risk scores stratify into groups with distinct temporal evolution once this prediction is made.DesignRetrospective cohort study.SettingAcademic medical center from July 1, 2016, to December 11, 2020.PatientsSix-thousand one-hundred sixty-one patients under 18 admitted to the Johns Hopkins Hospital PICU.InterventionsNone.Measurements and main resultsWe trained risk models to predict impending transition into septic shock and compute time-evolving risk scores representative of a patient's probability of developing septic shock. We obtain early prediction performance of 0.90 area under the receiver operating curve, 43% overall positive predictive value, patient-specific positive predictive value as high as 62%, and an 8.9-hour median early warning time using Sepsis-3 labels based on age-adjusted Sequential Organ Failure Assessment score. Using spectral clustering, we stratified pediatric sepsis patients into two clusters differing in septic shock prevalence, mortality, and proportion of patients adequately fluid resuscitated.ConclusionsWe demonstrate the applicability of our methodology for early prediction and stratification for risk of septic shock in pediatric sepsis patients. Through analyses of risk score evolution over time, we corroborate our past finding of an abrupt transition preceding onset of septic shock in children and are able to stratify pediatric sepsis patients using their risk score trajectories into low and high-risk categories.
| S-EPMC8208392 | biostudies-literature