UNICORN; Underlying mechanisms in Neonatal Immune Metabolic Dysregulation and Brain Injury

Abstract

Introduction: Neonatal encephalopathy (NE) is a clinically defined syndrome of disturbed neurologic function, in the earliest days of life. NE has a multifactorial aetiology and causes significant mortality and neurological morbidity. Therapeutic hypothermia (TH) is the only available treatment, but morbidity and mortality rates remain high. There is an urgent need for adjunctive therapies to improve neurodevelopmental outcomes. Persistent systemic inflammation has been implicated in the pathogenesis of NE. Identification of novel inflammatory biomarker combinations helped to determine the aetiology of NE and in the development of new adjunctive therapies.

Methods: Infants with NE and age matched controls were included to explore their inflammatory phenotype and mitochondrial function to assess immune dysregulation at baseline and following LPS stimulation. This detailed inflammatory phenotype was then correlated with their clinical outcome. Alongside the translational work, a systematic review of biomarkers in NE to predict outcome and a number of clinical management improvement initiatives were prepared.

Results: Infants with NE had a dysregulated inflammatory response and their whole blood hypo- responsive to endotoxin stimulation in contrast to the robust innate immune response from term control infants. The inflammatory phenotype correlated with NE clinical outcomes. Management guidelines and two animations on TH were developed in collaboration with parents and best evidenced based review.

Conclusion: Systemic inflammation is important in the pathogenesis of NE. Improving the understanding of this inflammatory signature has aided in revealing the pathophysiology, identified relevant biomarkers of severity and shows promise towards new adjunctive therapies.