Cytokine Dysregulation Persists in Childhood Post Neonatal Encephalopathy

Abstract

Objective: Cytokines are possible mediators of neuroinflammation and associated with adverse outcome in neonatal encephalopathy (NE). Our aim was to explore cytokine response in children with Neonatal Encephalopathy (NE) at school age compared to age-matched controls. Method: Follow up at school age, children who had NE and age-matched controls were assessed for their cytokine responses and neurodevelopment outcome. Pro- and anti-inflammatory cytokines in the serum, [Interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, IL-18, Tumor necrosis factor (TNF)-α, TNF β, Interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), IL-10 & IL-1RA] were measured at baseline and in response to in vitro stimulation with lipopolysaccharide (LPS: endotoxin). Results: GM­-CSF, TNF-β, IL-2 IL-6, IL-8, IL-10, and IL-18 were significantly elevated at school age following NE (n=40) compared to controls (n=37). A significant rise in GM-CSF, IL-8, TNF-α, IL-1β, & IL-6 were seen in NE group following LPS stimulation. Relative LPS hypo-responsiveness was also noted in children with severe NE with IL-10, VEGF, EPO and TNF-β. Elevated TNF-β was associated with low gross motor scores on assessment at school age. Conclusion: School-age children post-NE had significantly altered cytokine responses to endotoxin compared to controls. TNF-β was associated with adverse developmental outcomes. This suggests the inflammatory process may persist into childhood and a longer therapeutic window may be available for immunomodulatory adjunctive therapies.

Sustained peripheral immune hyper-reactivity (SPIHR): an enduring biomarker of altered inflammatory responses in adult rats after perinatal brain injury

“…Similar findings have been documented in children with Down Syndrome [97,98] and after exposure to opioids [59,70]. On the other hand, decreased levels of pro-inflammatory cytokines in sera and PBMC supernatants have been found in response to LPS stimulation in critically ill patients in intensive care [99,100], and in children with neonatal encephalopathy who received hypothermia [100,101]. Hyporeactivity to LPS stimulation has also been observed in children with CP when IL-2, IL-6, IL-1α and IL-1β were studied [100].…”

Preterm birth and sustained inflammation: consequences for the neonate

“…Hence, follow-up examinations are needed to ascertain SI in a clinical context. Notably, inflammatory processes cannot only be sustained over a long time in preterm infants but also in term infants who survived neonatal encephalopathy [ 31 ].…”

Dysregulation of multiple signaling pathways: A possible cause of cerebral palsy

“…Hypo-responsiveness of LPS in various cytokines among schoolchildren demonstrates an altered immune response. 29 A study conducted by Huang et al 30 investigated the association of umbilical cord blood cytokines with CP in premature babies. They performed enzyme-linked immunoassay technique and identified a significantly high level of IL-8, PGE2, and myeloperoxidase (MPO) level in preterm babies with a gestation period of 32 weeks when compared to full-term babies.…”