Expression Patterns of Airway Fluid Cytokines From Intubated Children With Pediatric Acute Respiratory Distress Syndrome

OBJECTIVES:. Pediatric acute respiratory distress syndrome (PARDS) is a heterogeneous illness affecting 6% of mechanically ventilated children and with an overall mortality of 17%. Studies in PARDS have mainly focused on plasma biomarkers which may not reflect airway biomarkers. We lack adequate understanding of the inflammatory mediators and underlying immune responses in the airways of PARDS patients. Our objective was to compare the levels of cytokines in the airway fluid of intubated children with severe versus nonsevere acute respiratory distress syndrome. DESIGN:. Prospective observational cohort study. SETTING:. Single 36-bed quaternary care academic safety-net hospital PICU. PATIENTS:. Children intubated for acute respiratory failure between January 2018 and November 2021 stratified by Pediatric Acute Lung Injury Consensus Conference-1 criteria for PARDS. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. We measured levels of 23 cytokines, chemokines, and protein biomarkers in the tracheal aspirate from 82 intubated children, between 14 days and 17 years old, at risk for or with PARDS. Levels of interleukin-4, -5, -7, -8, -12(p-70), -17a, -21, and fractalkine were higher in patients with severe versus nonsevere PARDS. There were no associations between airway and plasma cytokines. CONCLUSIONS:. Proinflammatory cytokines are elevated in the airway fluid from intubated children with severe PARDS and reflect diverse patterns of airway inflammation

Bioenergetic Crisis in ICU-Acquired Weakness Gene Signatures Was Associated With Sepsis-Related Mortality: A Brief Report

OBJECTIVES:. To investigate the relationship between ICU-acquired weakness (ICUAW) signatures and sepsis-related mortality using gene expression from the blood within 24 hours of sepsis onset. DESIGN:. Observational study using differential gene expression analysis. SETTING:. Publicly available gene expression profile GSE54514, single-center medical and surgical ICU. PATIENTS:. Patients with primary bacteremia- and respiratory-triggered sepsis including 8 nonsurvivors and 13 survivors who were 18 years old and older and admitted to ICU. MEASUREMENTS AND MAIN RESULTS:. Among validated 526 ICUAW gene signatures, differential gene expression analysis controlling for age identified 38 significantly expressed genes between nonsurvivors and survivors. Functional enrichment analysis of differentially expressed ICUAW genes identified impaired cadherin binding, sarcomere formation, and energy metabolism among nonsurvivors. CONCLUSIONS:. Our findings demonstrated a biological association between sepsis-related mortality and ICUAW signatures in the early phase of sepsis. Defects in energy metabolism and muscle fiber formation were associated with sepsis-related mortality

Dysfunctional neutrophil type 1 interferon responses in preschool children with recurrent wheezing and IL-4–mediated aeroallergen sensitization

Background: The innate mechanisms associated with viral exacerbations in preschool children with recurrent wheezing are not understood. Objective: We sought to assess differential gene expression in blood neutrophils from preschool children with recurrent wheezing, stratified by aeroallergen sensitization, at baseline and after exposure to polyinosinic:polycytidylic acid (poly(I:C)) and also to examine whether poly(I:C)-stimulated blood neutrophils influenced airway epithelial gene expression. Methods: Blood neutrophils were purified and cultured overnight with poly(I:C) and underwent next-generation sequencing with Reactome pathway analysis. Primary human small airway epithelial cells were treated with poly(I:C)-treated neutrophil culture supernatants and were analyzed for type 1 interferon gene expression with a targeted array. Symptoms and exacerbations were assessed in participants over 12 months. Results: A total of 436 genes were differently expressed in neutrophils from children with versus without aeroallergen sensitization at baseline, with significant downregulation of type 1 interferons. These type 1 interferons were significantly upregulated in sensitized children after poly(I:C) stimulation. Confirmatory experiments demonstrated similar upregulation of type 1 interferons in IL-4–treated neutrophils stimulated with poly(I:C). Poly(I:C)-treated neutrophil supernatants from children with aeroallergen sensitization also induced a type 1 interferon response in epithelial cells. Children with aeroallergen sensitization also had higher symptom scores during exacerbations, and these symptom differences persisted for 3 days after prednisolone treatment. Conclusions: Type 1 interferon responses are dysregulated in preschool children with aeroallergen sensitization, which is in turn associated with exacerbation severity. Given the importance of type 1 interferon signaling in viral resolution, additional studies of neutrophil type 1 interferon responses are needed in this population