Dataset Information

Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response.

ABSTRACT: OBJECTIVE:We previously identified septic shock endotypes A and B based on 100 genes reflecting adaptive immunity and glucocorticoid receptor signaling. The endotypes differ with respect to outcome and corticosteroid responsiveness. We determined whether endotypes change during the initial 3 days of illness, and whether changes are associated with outcomes. DESIGN:Observational cohort study including existing and newly enrolled participants. SETTING:Multiple PICUs. PATIENTS:Children with septic shock. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We measured the 100 endotyping genes at day 1 and day 3 of illness in 375 patients. We determined if endotype assignment changes over time, and whether changing endotype is associated with corticosteroid response and outcomes. We used multivariable logistic regression to adjust for illness severity, age, and comorbidity burden. Among the 132 subjects assigned to endotype A on day 1, 56 (42%) transitioned to endotype B by day 3. Among 243 subjects assigned to endotype B on day 1, 77 (32%) transitioned to endotype A by day 3. Assignment to endotype A on day 1 was associated with increased odds of mortality. This risk was modified by the subsequent day 3 endotype assignment. Corticosteroids were associated with increased risk of mortality among subjects who persisted as endotype A. CONCLUSIONS:A substantial proportion of children with septic shock transition endotypes during the acute phase of illness. The risk of poor outcome and the response to corticosteroids change with changes in endotype assignment. Patients persisting as endotype A are at highest risk of poor outcomes.

SUBMITTER: Wong HR

PROVIDER: S-EPMC5825261 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response.

Wong Hector R HR Cvijanovich Natalie Z NZ Anas Nick N Allen Geoffrey L GL Thomas Neal J NJ Bigham Michael T MT Weiss Scott L SL Fitzgerald Julie C JC Checchia Paul A PA Meyer Keith K Quasney Michael M Hall Mark M Gedeit Rainer R Freishtat Robert J RJ Nowak Jeffrey J Lutfi Riad R Gertz Shira S Grunwell Jocelyn R JR Lindsell Christopher J CJ

Critical care medicine 20180301 3

<h4>Objective</h4>We previously identified septic shock endotypes A and B based on 100 genes reflecting adaptive immunity and glucocorticoid receptor signaling. The endotypes differ with respect to outcome and corticosteroid responsiveness. We determined whether endotypes change during the initial 3 days of illness, and whether changes are associated with outcomes.<h4>Design</h4>Observational cohort study including existing and newly enrolled participants.<h4>Setting</h4>Multiple PICUs.<h4>Patie ...[more]

PMID: 29252929

Similar Datasets

Project description:ObjectivesWe previously reported gene expression-based endotypes of pediatric septic shock, endotypes A and B, and that corticosteroid exposure was independently associated with increased mortality among pediatric endotype A patients. The Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial tested the efficacy of vasopressin as initial vasopressor therapy for septic shock among adult patients, when compared with norepinephrine. Patients who reached a prespecified dose of either vasopressor were further randomized to receive hydrocortisone or placebo. A proportion of patients in the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial had transcriptomic data generated at baseline using whole blood-derived messenger RNA. We used the publicly available transcriptomic data from the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial to assign the study subjects to pediatric septic shock endotype A or B, and tested the hypothesis that hydrocortisone treatment is associated with increased mortality among patients in endotype A.DesignSecondary analysis of publicly available transcriptomic data.SettingMultiple adult ICUs.PatientsAdults with septic shock randomized to hydrocortisone (n = 47) or placebo (n = 50).InterventionsRandomization to the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial experimental arms.Measurements and main resultsEndotype A patients receiving hydrocortisone had a mortality rate of 46%, whereas endotype A patients receiving placebo had a mortality rate of 22% (p = 0.105). In contrast, the mortality rates for endotype B patients receiving hydrocortisone or placebo were 19% and 22%, respectively. The odds of death were more than three times greater in endotype A patients receiving hydrocortisone than endotype A patients receiving placebo (p = 0.05).ConclusionsThis exploratory analysis provides further evidence that corticosteroid exposure may be associated with increased mortality among septic shock endotype A patients.

Project description:ObjectivesTo 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.DesignProspective observational study involving microarray-based bioinformatics.SettingMultiple pediatric intensive care units in the United States.PatientsChildren <or=10 years of age: 18 normal controls, 22 meeting criteria for SIRS, 32 meeting criteria for sepsis, and 67 meeting criteria for septic shock on day 1. The available day 3 samples included 20 patients still meeting sepsis criteria, 39 patients still meeting septic shock criteria, and 24 patients meeting the exclusive day 3 category, SIRS resolved.InterventionsNone other than standard care.Measurements and main resultsLongitudinal analyses were focused on gene expression relative to control samples and patients having paired day 1 and day 3 samples. The longitudinal analysis focused on up-regulated genes revealed common patterns of up-regulated gene expression, primarily corresponding to inflammation and innate immunity, across all patient groups on day 1. These patterns of up-regulated gene expression persisted on day 3 in patients with septic shock, but not to the same degree in the other patient classes. The longitudinal analysis focused on down-regulated genes demonstrated gene repression corresponding to adaptive immunity-specific signaling pathways and was most prominent in patients with septic shock on days 1 and 3. Gene network analyses based on direct comparisons across the SIRS, sepsis, and septic shock spectrum, and all available patients in the database, demonstrated unique repression of gene networks in patients with septic shock corresponding to major histocompatibility complex antigen presentation. Finally, analyses focused on repression of genes corresponding to zinc-related biology demonstrated that this pattern of gene repression is unique to patients with septic shock.ConclusionsAlthough some common patterns of gene expression exist across the pediatric SIRS, sepsis, and septic shock spectrum, septic shock is particularly characterized by repression of genes corresponding to adaptive immunity and zinc-related biology.

Dataset Information

Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response.

Publications

Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets