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Pediatric Intensive Care: Immunomodulation With Activated Protein C ex vivo
Hassan O Eliwan1,2,3,4, William R G Watson4, Irene Regan5
1Neonatology, National Maternity Hospital, Dublin, Ireland.
Insights
Pediatric Intensive Care Unit (PICU) patients with sepsis show reduced immune responses. Activated Protein C (APC) may improve these responses, particularly in non-survivors, suggesting a potential therapeutic role.
Area of Science:
- Immunology
- Critical Care Medicine
- Pediatrics
Background:
- Sepsis is a leading cause of death in Pediatric Intensive Care Units (PICUs).
- Patients in PICUs may experience temporary immune suppression during sepsis.
- Activated Protein C (APC) possesses anti-inflammatory and cytoprotective properties, but its efficacy in sepsis is debated.
Purpose of the Study:
- To evaluate the impact of Activated Protein C (APC) on the innate immune system in pediatric sepsis patients.
- To compare immune cell responses in PICU patients with sepsis to healthy controls.
Main Methods:
- Neutrophil and monocyte responses to lipopolysaccharide (LPS) were analyzed in PICU patients and controls.
- Flow cytometry assessed cell activation (CD11b), function (ROI release), and LPS recognition (TLR4 expression).
- Immune responses were compared with and without APC treatment.
Main Results:
- PICU patients exhibited lower protein C levels and diminished LPS responses compared to controls.
- APC treatment decreased LPS-induced TLR4 expression in neutrophils from PICU patients and ROI release in adult controls.
- Non-survivors showed higher LPS-induced ROI production, which APC significantly reduced.
Conclusions:
- Reduced endotoxin reactivity in PICU patients may increase sepsis susceptibility and impair antibacterial defenses.
- APC demonstrates potential in treating critically ill PICU patients by reducing LPS-induced ROI production.
- Novel APC formulations with reduced bleeding risk and enhanced anti-inflammatory effects warrant further investigation.
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.
