Pediatric Intensive Care: Immunomodulation With Activated Protein C ex vivo

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.

Dysregulated Monocyte and Neutrophil Functional Phenotype in Infants With Neonatal Encephalopathy Requiring Therapeutic Hypothermia

“…The different comparator group makes it difficult to draw significant comparisons between the studies. Children in pediatric intensive care had decreased leukocyte CD11b LPS responses compared to healthy adult and pediatric controls, correlating with our findings ( 19 ).…”

Molecular feature of neutrophils in immune microenvironment of muscle atrophy

“… 21 As per the suggested mechanism, the damaged host cells raise alarm signals that activate antigen‐presenting cells (APCs) 19 . Moreover, the neutrophils, which act as a vital component of the immune response, play a significant role in the recruitment, activation and programming of APCs 22 . These cells respond rapidly to inflammatory signals deriving from infected or injured regions outside the circulatory system.…”

“…19 Moreover, the neutrophils, which act as a vital component of the immune response, play a significant role in the recruitment, activation and programming of APCs. 22 These cells respond rapidly to inflammatory signals deriving from infected or injured regions outside the circulatory system. Several receptors expressed by them sense a variety of soluble inflammatory mediators ranging from cytokines to bioactive lipids, to increase the aggregation of immune cells.…”

Protein C Pathway in Paediatric and Neonatal Sepsis

“…APC causes a reduction in reactive oxygen species (ROS) production after induction with LPS in adults but no difference in paediatric intensive care unit (PICU) patients. These differences in immune response to APC could explain conflicting results between the RESOLVE and PROWESS trials (98). Future studies must shift their focus to developing validated patient stratification methods if there is any hope for management of sepsis (97).…”