Abstract

Objective: Sepsis is major cause of morbidity and mortality in the Pediatric Intensive Care Unit (PICU). PICU patients may develop transient immune deficiency during sepsis. Activated Protein C (APC) has significant anti-inflammatory and cytoprotective effects. Clinical trials of APC in adult sepsis initially showed improved outcome but recent trials showed no benefit in adults or children. We aimed to assess the effects of APC treatment on innate immune responses in children.Design and Subjects: We compared neutrophil and monocyte responses to lipopolysaccharide (LPS) with and without APC treatment in PICU patients at the time of evaluation for sepsis compared with healthy adults and age-matched pediatric controls. We used flow cytometry to examine cell activation (CD11b expression), function [intracellular reactive oxygen intermediate (ROI) release] and LPS recognition [Toll like Receptor 4 (TLR4) expression].Results: PICU patients had significantly decreased protein c levels and LPS responses compared with adult and pediatric controls for all parameters. APC reduced LPS-induced neutrophil PICU TLR4 and adult ROI (p < 0.05). PICU non-survivors had increased LPS induced neutrophil and monocyte ROI production vs. survivors which was significantly reduced by APC.Conclusion: PICU patients demonstrate significantly reduced endotoxin reactivity which may predispose them to sepsis and alter effective antibacterial responses. APC reduces LPS-induced ROI production in adults and may have a role in treating severely compromised PICU patients especially given that newer APC forms are associated with decreased bleeding risk and enhanced anti-inflammatory effects.

Highlights

  • Sepsis is the 2nd leading cause of death in children and the 4th leading cause of death in infants

  • We aimed to investigate neutrophil and monocyte CD11b/TLR4 expression and reactive oxygen intermediate (ROI) production following LPS stimulation in pediatric sepsis patients ex vivo and to investigate the effect of Activated Protein C (APC) treatment on these responses

  • There were 15 adult controls, 25 pediatric controls and 15 Pediatric Intensive Care Unit (PICU) patients enrolled in this study

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Summary

Introduction

Sepsis is the 2nd leading cause of death in children and the 4th leading cause of death in infants. The incidence of sepsis in USA is 0.56/1,000 children with an overall mortality of 10.6% and an overall cost of almost 2 billion dollars per annum [1]. Sepsis is characterized by a systemic inflammatory response to infection and may result in tissue damage, multi-organ dysfunction (MOD), and death. Persistent activation of leukocytes may contribute to this process while excessive leukocyte elimination may contribute to immunoparesis, bacterial overgrowth, and death. Establishing a balance between over-activation of leukocytes and excessive leukocyte elimination reduces tissue damage and mortality [2]. We were interested in studying immune cell LPS recognition, activation and adhesion in Pediatric Intensive Care Unit (PICU) patients

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