International multi-cohort analysis identifies novel framework for quantifying immune dysregulation in critical illness: results of the SUBSPACE consortium.

Progress in the management of critical care syndromes such as sepsis, Acute Respiratory Distress Syndrome (ARDS), and trauma has slowed over the last two decades, limited by the inherent heterogeneity within syndromic illnesses. Numerous immune endotypes have been proposed in sepsis and critical care, however the overlap of the endotypes is unclear, limiting clinical translation. The SUBSPACE consortium is an international consortium that aims to advance precision medicine through the sharing of transcriptomic data.

Diagnostic Validation of the Updated Pediatric Sepsis Biomarker Risk II for Acute Kidney Injury Prediction Model in Pediatric Septic Shock.

Objectives: We previously derived the updated Pediatric Sepsis Biomarker Risk for Acute Kidney Injury (PERSEVERE-II AKI) prediction model, which had robust diagnostic test characteristics for severe AKI on day 3 (D3 severe AKI) of septic shock. We now sought to validate this model in an independent cohort of children to the one in which the model was developed.

Design: A secondary analysis of a multicenter, prospective, observational study carried out from January 2019 to December 2022.

Biological basis of critical illness subclasses: from the bedside to the bench and back again.

Critical illness syndromes including sepsis, acute respiratory distress syndrome, and acute kidney injury (AKI) are associated with high in-hospital mortality and long-term adverse health outcomes among survivors. Despite advancements in care, clinical and biological heterogeneity among patients continues to hamper identification of efficacious therapies. Precision medicine offers hope by identifying patient subclasses based on clinical, laboratory, biomarker and 'omic' data and potentially facilitating better alignment of interventions.

Biomarker Assessment of a High-Risk, Data-Driven Pediatric Sepsis Phenotype Characterized by Persistent Hypoxemia, Encephalopathy, and Shock.

Objectives: Identification of children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes remains a challenge. We sought to the determine reproducibility of the data-driven "persistent hypoxemia, encephalopathy, and shock" (PHES) phenotype and determine its association with inflammatory and endothelial biomarkers, as well as biomarker-based pediatric risk strata.

Design: We retrained and validated a random forest classifier using organ dysfunction subscores in the 2012-2018 electronic health record (EHR) dataset used to derive the PHES phenotype.

Revisiting Post-ICU Admission Fluid Balance Across Pediatric Sepsis Mortality Risk Strata: A Secondary Analysis of a Prospective Observational Cohort Study.

Objectives: Post-ICU admission cumulative positive fluid balance (PFB) is associated with increased mortality among critically ill patients. We sought to test whether this risk varied across biomarker-based risk strata upon adjusting for illness severity, presence of severe acute kidney injury (acute kidney injury), and use of continuous renal replacement therapy (CRRT) in pediatric septic shock.

Design: Ongoing multicenter prospective observational cohort.

Machine learning-driven identification of the gene-expression signature associated with a persistent multiple organ dysfunction trajectory in critical illness.

Background: Multiple organ dysfunction syndrome (MODS) disproportionately drives morbidity and mortality among critically ill patients. However, we lack a comprehensive understanding of its pathobiology. Identification of genes associated with a persistent MODS trajectory may shed light on underlying biology and allow for accurate prediction of those at-risk.

External validation of the modified sepsis renal angina index for prediction of severe acute kidney injury in children with septic shock.

Background: Acute kidney injury (AKI) occurs commonly in pediatric septic shock and increases morbidity and mortality. Early identification of high-risk patients can facilitate targeted intervention to improve outcomes. We previously modified the renal angina index (RAI), a validated AKI prediction tool, to improve specificity in this population (sRAI).

SERUM HUMANIN IN PEDIATRIC SEPTIC SHOCK-ASSOCIATED MULTIPLE-ORGAN DYSFUNCTION SYNDROME.

Background: Multiple-organ dysfunction syndrome disproportionately contributes to pediatric sepsis morbidity. Humanin (HN) is a small peptide encoded by mitochondrial DNA and thought to exert cytoprotective effects in endothelial cells and platelets. We sought to test the association between serum HN (sHN) concentrations and multiple-organ dysfunction syndrome in a prospectively enrolled cohort of pediatric septic shock.

Distinct clinical phenotypes in paediatric cancer patients with sepsis are associated with different outcomes-an international multicentre retrospective study.

Background: Identifying phenotypes in sepsis patients may enable precision medicine approaches. However, the generalisability of these phenotypes to specific patient populations is unclear. Given that paediatric cancer patients with sepsis have different host response and pathogen profiles and higher mortality rates when compared to non-cancer patients, we determined whether unique, reproducible, and clinically-relevant sepsis phenotypes exist in this specific patient population.

A MACHINE LEARNING MODEL DERIVED FROM ANALYSIS OF TIME-COURSE GENE-EXPRESSION DATASETS REVEALS TEMPORALLY STABLE GENE MARKERS PREDICTIVE OF SEPSIS MORTALITY.

Sepsis is associated with significant mortality and morbidity among critically ill patients admitted to intensive care units and represents a major health challenge globally. Given the significant clinical and biological heterogeneity among patients and the dynamic nature of the host immune response, identifying those at high risk of poor outcomes remains a critical challenge. Here, we performed secondary analysis of publicly available time-series gene-expression datasets from peripheral blood of patients admitted to the intensive care unit to elucidate temporally stable gene-expression markers between sepsis survivors and nonsurvivors.

External validation and biomarker assessment of a high-risk, data-driven pediatric sepsis phenotype characterized by persistent hypoxemia, encephalopathy, and shock.

Objective: Identification of children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes remains a challenge. Data-driven phenotyping approaches that leverage electronic health record (EHR) data hold promise given the widespread availability of EHRs. We sought to externally validate the data-driven 'persistent hypoxemia, encephalopathy, and shock' (PHES) phenotype and determine its association with inflammatory and endothelial biomarkers, as well as biomarker-based pediatric risk-strata.

SERUM SOLUBLE ENDOGLIN IN PEDIATRIC SEPTIC SHOCK-ASSOCIATED MULTIPLE ORGAN DYSFUNCTION SYNDROME.

Background: Endothelial activation is a key driver of multiple organ dysfunction syndrome (MODS). Soluble endoglin (sENG) is expressed by mature and progenitor endothelial cells and thought to have angiogenic properties. We sought to determine the association between sENG and pediatric sepsis-associated MODS.

Revisiting post-ICU admission fluid balance across pediatric sepsis mortality risk strata: A secondary analyses from a prospective observational cohort study.

Introduction: Post-ICU admission cumulative positive fluid balance (PFB) is associated with increased mortality among critically ill patients. We sought to test whether this risk varied across biomarker-based risk strata upon adjusting for illness severity, presence of severe acute kidney injury (AKI), and use of renal replacement therapy (CRRT) in pediatric septic shock.

Design: Ongoing multi-center prospective observational cohort.

Prognostic and predictive value of endothelial dysfunction biomarkers in sepsis-associated acute kidney injury: risk-stratified analysis from a prospective observational cohort of pediatric septic shock.

Background: Sepsis-associated acute kidney injury (SA-AKI) is associated with high morbidity, with no current therapies available beyond continuous renal replacement therapy (CRRT). Systemic inflammation and endothelial dysfunction are key drivers of SA-AKI. We sought to measure differences between endothelial dysfunction markers among children with and without SA-AKI, test whether this association varied across inflammatory biomarker-based risk strata, and develop prediction models to identify those at highest risk of SA-AKI.

Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1.

Background: Sepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics. PCSK9 loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults.

Derivation, Validation, and Clinical Relevance of a Pediatric Sepsis Phenotype With Persistent Hypoxemia, Encephalopathy, and Shock.

Objectives: Untangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of targeted therapies. Our aim was to analyze the organ dysfunction trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify reproducible and clinically relevant sepsis phenotypes and determine if they are associated with heterogeneity of treatment effect (HTE) to common therapies.

Design: Multicenter observational cohort study.

Biomarker-based risk model to predict persistent multiple organ dysfunctions after congenital heart surgery: a prospective observational cohort study.

Background: Multiple organ dysfunction syndrome (MODS) is an important cause of post-operative morbidity and mortality for children undergoing cardiac surgery requiring cardiopulmonary bypass (CPB). Dysregulated inflammation is widely regarded as a key contributor to bypass-related MODS pathobiology, with considerable overlap of pathways associated with septic shock. The pediatric sepsis biomarker risk model (PERSEVERE) is comprised of seven protein biomarkers of inflammation and reliably predicts baseline risk of mortality and organ dysfunction among critically ill children with septic shock.

Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1.

Sepsis is associated with significant mortality, yet there are no efficacious therapies beyond antibiotics and supportive care. In adult sepsis studies, PCSK9 loss-of-function (LOF) and inhibition has shown therapeutic promise, likely through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance. In contrast, we previously demonstrated higher mortality in septic juvenile hosts with LOF.

Biomarker-based risk model to predict persistent multiple organ dysfunctions after congenital heart surgery â€" A prospective observational cohort study.

Multiple organ dysfunction syndrome (MODS) is an important cause of post-operative morbidity and mortality for children undergoing cardiac surgery requiring cardiopulmonary bypass (CPB). Dysregulated inflammation is widely regarded as a key contributor to bypass-related MODS pathobiology, with considerable overlap of pathways associated with septic shock. The pediatric sepsis biomarker risk model (PERSEVERE) is comprised of seven protein biomarkers of inflammation, and reliably predicts baseline risk of mortality and organ dysfunction among critically ill children with septic shock.

Integrated PERSEVERE and endothelial biomarker risk model predicts death and persistent MODS in pediatric septic shock: a secondary analysis of a prospective observational study.

Background: Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock.

Proprotein Convertase Subtilisin/Kexin Type 9 Loss-of-Function Is Detrimental to the Juvenile Host With Septic Shock.

Objectives: Proprotein convertase subtilisin/kexin type 9 is a central regulator of lipid metabolism and has been implicated in regulating the host response to sepsis. Proprotein convertase subtilisin/kexin type 9 loss-of-function is associated with improved sepsis outcomes in the adult host through increased hepatic bacterial clearance. Thus, there is interest in leveraging proprotein convertase subtilisin/kexin type 9 inhibitors as a therapeutic strategy in adults with sepsis.