Infection-induced inflammation and cerebral injury in preterm infants

Abstract

Preterm birth and infectious diseases are the most common causes of neonatal and early childhood deaths worldwide. The rates of preterm birth have increased over recent decades and account for 11% of all births worldwide. Preterm infants are at significant risk of severe infection in early life and throughout childhood. Bacteraemia, inflammation, or both during the neonatal period in preterm infants is associated with adverse outcomes, including death, chronic lung disease, and neurodevelopmental impairment. Recent studies suggest that bacteraemia could trigger cerebral injury even without penetration of viable bacteria into the CNS. Here we review available evidence that supports the concept of a strong association between bacteraemia, inflammation, and cerebral injury in preterm infants, with an emphasis on the underlying biological mechanisms, clinical correlates, and translational opportunities.

Figure 1

This figure summarizes known and hypothetical pathways of bacteraemia-induced neuronal damage: (1) bacterial products on or shed from bacteria in the bloodstream activate endothelial pattern recognition receptors such TLRs triggering release of inflammatory mediators into the CNS; (2) Leak of bacterial products such as lipopolysaccharide (LPS) and bacterial lipopeptide (BLP) across the blood brain barrier that activate microglia to release inflammatory mediators; (3) Entry of leukocytes into the CNS; and (4) direct diffusion of cytokines/chemokines from the peripheral circulation across the blood-brain barrier. Hypothetical mechanisms for which there has not yet been published evidence are marked with a question mark (“?”).

Figure 2

Intracranial haemorrhage in a preterm with bacteraemia. A preterm infant born at 24 weeks gestation following onset of maternal fever grew E. coli from blood cultures obtained at 45 minutes of age. He had septic shock with coagulopathy, thrombocytopaenia and hypotension prompting inotropic support. His day 2 cranial ultrasound revealed left grade III and right grade IV intraventricular haemorrhage (A) with severe cerebellar haemorrhage (B). Note that areas of echodensity (brightness) indicate haemorrhage.

Figure 3

White matter injury in a preterm infant with necrotizing enterocolitis. A preterm infant was born at 24 weeks gestation with germinal matrix hemorrhage developed severe necrotising enterocolitis at 6 weeks of age requiring surgery. (A) ultrasound 4 weeks post- surgery revealed small cystic white matter echolucencies (arrow). (B) An MRI scan 2 weeks later at 36 weeks post-menstrual age demonstrated extensive white matter injury with periventricular gliosis and extensive encephaloclastic changes.