Distinct cytokine patterns may regulate the severity of neonatal asphyxia—an observational study

Abstract

BackgroundNeuroinflammation and a systemic inflammatory reaction are important features of perinatal asphyxia. Neuroinflammation may have dual aspects being a hindrance, but also a significant help in the recovery of the CNS. We aimed to assess intracellular cytokine levels of T-lymphocytes and plasma cytokine levels in moderate and severe asphyxia in order to identify players of the inflammatory response that may influence patient outcome.MethodsWe analyzed the data of 28 term neonates requiring moderate systemic hypothermia in a single-center observational study. Blood samples were collected between 3 and 6 h of life, at 24 h, 72 h, 1 week, and 1 month of life. Neonates were divided into a moderate (n = 17) and a severe (n = 11) group based on neuroradiological and amplitude-integrated EEG characteristics. Peripheral blood mononuclear cells were assessed with flow cytometry. Cytokine plasma levels were measured using Bioplex immunoassays. Components of the kynurenine pathway were assessed by high-performance liquid chromatography.ResultsThe prevalence and extravasation of IL-1b + CD4 cells were higher in severe than in moderate asphyxia at 6 h. Based on Receiver operator curve analysis, the assessment of the prevalence of CD4+ IL-1β+ and CD4+ IL-1β+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia. Intracellular levels of TNF-α in CD4 cells were increased at all time points compared to 6 h in both groups. At 1 month, intracellular levels of TNF-α were higher in the severe group. Plasma IL-6 levels were higher at 1 week in the severe group and decreased by 1 month in the moderate group. Intracellular levels of IL-6 peaked at 24 h in both groups. Intracellular TGF-β levels were increased from 24 h onwards in the moderate group.ConclusionsIL-1β and IL-6 appear to play a key role in the early events of the inflammatory response, while TNF-α seems to be responsible for prolonged neuroinflammation, potentially contributing to a worse outcome. The assessment of the prevalence of CD4+ IL-1β+ and CD4+ IL-1β+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia.

Interleukin-1 Blockade Attenuates White Matter Inflammation and Oligodendrocyte Loss After Progressive Systematic Lipopolysaccharide Exposure in Near-Term Fetal Sheep

“…Elevated circulating levels of IL-1β are associated with impaired cerebral oxidative metabolism [18] and EEG suppression in neonates [45]. Similarly, in the present study we observed suppression of EEG power and nuchal EMG activity (re ecting reduced neural activity and fetal movement, respectively) after the rst LPS infusion, and sustained reductions in neural activity and fetal movement during the recovery period.…”

Cytokine production pattern of T lymphocytes in neonatal arterial ischemic stroke during the first month of life—a case study

“…We found no differences between NAIS and HIE in the intracellular production of IL-1β and TNF-α in CD4 or CD8 cells; however, these cytokines appear to be important in differentiating between the mild and severe form of HIE [41].…”

“…The severe group (n = 11) was formed of newborns with moderate-to-severe HIE signs on the MRI scan AND burst-suppression or continuous extremely low voltage or flat tracing background activity on aEEG OR normalization of aEEG after the 48th hour of life or never, OR early death (< 28 days). Neonates that met none of the above-listed criteria constituted the moderate group (n = 17) (mild HIE signs on MRI scans AND continuous or discontinuous normal voltage background activity on aEEG OR normalization of aEEG activity before the 48th hour of life) [41]. Pooled data from the cohort of four NAIS patients were compared to infants with HIE.…”

Fas-ligand and interleukin-6 in the cerebrospinal fluid are early predictors of hypoxic-ischemic encephalopathy and long-term outcomes after birth asphyxia in term infants

“…Intracellular cytokine levels, which closely reflect cytokine production at a cellular level and show more stable kinetics in time, have recently been analyzed in term infants requiring systemic hypothermia after perinatal asphyxia [ 27 ]. In that study, intracellular IL-6 levels in CD4+ peripheral blood mononuclear cells peaked at 24 h post-asphyxia.…”