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Systemic Innate Immune Dysregulation in Severe Neonatal Brain Injury

Presented at the Neonatal Society 2013 Autumn Meeting.

O’Hare FM1,2,3, Watson RWG2, O’Neill A2, Blanco A2, Sweetman D1,3, Murphy J1,2,7, Twomey A1, O’Donnell C1,3,7, Lynch B1,4, Donoghue V1,5, Molloy EJ1,2,6,7

1 Paediatrics, National Maternity Hospital, Holles Street, Dublin, Ireland
2 School of Medicine & Medical Sciences, University College Dublin, Ireland
3 National Children’s Research Centre, Ireland
4 Neurology, Children’s University Hospital, Temple Street, Dublin, Ireland
5 Radiology, Children’s University Hospital, Temple Street, Dublin, Ireland
6 Paediatrics, Royal College of Surgeons in Ireland
7 Neonatology, Our Lady’s Children’s Hospital, Ireland

Background: Inflammatory cytokines may play a role in the final common pathway in the pathogenesis of hypoxic-ischaemic injury in experimental models and elevated Toll-like receptor 4 (TLR4) expression is associated with worse outcome in adult and animal models of brain injury. Our aim was to profile the systemic inflammatory response over the first week of life in infants at risk of neonatal encephalopathy (NE) and correlate early cytokine as well as neutrophil and monocyte endotoxin responses with outcome.

Methods: Prospective observational study in a tertiary referral university hospital including 41 infants requiring resuscitation at birth who had 10 cytokines measured serially in the first week of life. In a subgroup (n=22) we also measured serial neutrophil and monocyte CD11b, (Reactive oxygen intermediates) ROI and TLR4 before and after lipopolysaccharide (LPS;endotoxin) stimulation ex vivo and compared to neonatal controls. This study was approved by the ethics committee and written informed consent was obtained. The project was funded by the National Children’s Research Centre, Ireland.

Results: Infants with NE and abnormal neuroimaging had significantly elevated Interleukin(IL)-8 concentrations at birth with increased Granulocyte macrophage colony stimulating factor (GM-CSF) (day 2) and lower Interferon(IFN)-γ, Tumour Necrosis Factor (TNF)-α, Vascular Endothelial Growth Factor (VEGF)(Day 3) and IL-1α, IL-10 (Day 7). Significantly elevated levels of IL-8 and TNF-α in the first 24 hours were associated with mortality. All neonates requiring resuscitation at delivery had higher neutrophil and monocyte CD11b and TLR4 expression compared with adults and neonatal controls. Neonates with abnormal neuroimaging and/or NE II/III had increased CD11b, ROI and TLR4. Increased PMN TLR4 expression was associated with increased mortality in NE.

Conclusion: Serum cytokine changes and innate immune dysregulation in the first week of life predict mortality, severity of NE and abnormal neuroimaging. This persistent inflammatory response may be amenable to immunomodulation.

Corresponding author: elesean@hotmail.com

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