Mild-to-severe traumatic brain injury in children: altered cytokines reflect severity

Abstract

Background Paediatric traumatic brain injury (TBI) is recognised to have significant longer-term neurocognitive effects. Childhood is a time of high risk for head injury. Functional recovery is variable with a combination of any or all of physical, cognitive and emotional impairment. Immune activation and alteration in cytokine levels are present following TBI which may differ from adults. Methods Pro- and anti-inflammatory cytokines including Interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, IL-17A, Tumor Necrosis Factor (TNF)-α and Interferon (IFN)-γ were examined at baseline and following in vitro treatment with endotoxin of whole blood, in the following children: severe TBI (sTBI: initial Glasgow coma scale(GCS) ≤ 8), mild TBI (mTBI; GCS 14/15) at 0-4d and at 10-14d post-TBI and compared to healthy age-matched controls. Results The study enrolled 208 children, including 110 with TBI cohort (n = 104 mild; 6 severe) and controls (n = 98). At baseline all children with TBI had increased IL-6. The mTBI group had significantly increased IFN-γ versus controls. In sTBI at baseline, IFN-γ was decreased compared to controls. At baseline IL-8, IL-10, IL-17A, and TNF-α were decreased in mTBI compared to controls. This persisted at 2 week post-mTBI. The AUC for detecting mTBI was 0.801 CI (0.73–086) using IL6/IL10 ratio. mTBI showed a greater fold change in IL-8 and TNF-α in response to endotoxin stimulation, a response that persisted at 2 weeks. Children with sTBI did not have a significant IL-6 response to endotoxin, but did show an increase in IL-17A. Conclusion Children with all TBI including mTBI show altered cytokine profiles and altered endotoxin responses. Although cytokines increased in sTBI especially in response to endotoxin, suppressed responses were found in mTBI coupled with persistent immune dysfunction post-injury.

Minimally invasive serial collection of cerebrospinal fluid reveals sex-dependent differences in neuroinflammation in a rat model of mild traumatic brain injury

“…reported that IL-2, TNFα, and VEGF were all significantly increased in the CSF of adult mTBI patients 17 months post-injury 8 . While our results do not fully reflect what has been published in sex blended clinical studies, it is important to note that while these studies are sex blended, they are still predominantly male patient populations with almost a 2:1 male:female ratio 8,21,36,38 . To fully understand these published results, as well as our results in this study, it is vital to separate the sexes and compare the injury response in each sex.…”

“…Ryan et al . reported that TNFα and IL-10 were significantly decreased, while IL-6 was significantly increased in blood sampled from pediatric mTBI patients within 2 weeks of injury 21 . Gard et al .…”

“…IFNγ has been widely studied as a biomarker for mTBI, however there is little agreement across studies due to a lack of uniformity in study designs. In sex blended studies, IFNγ has been shown to be significantly increased acutely after mTBI in blood samples from children 21 and adults 36 . Further, in a sex blended longitudinal study collecting blood samples from adult mTBI patients at admission to 12 months post injury by Chaban and colleagues, IFNγ was shown to be significantly affected by injury in a two-way mixed effects analysis 38 .…”

“…In a study analyzing whole blood from pediatric TBI patients, severe TBI caused greater concentrations of TNFα, IL-6, IL-8, and IL-10 compared to mTBI. However, mTBI patients experience a greater concentration of IFNγ and IL-17A 21 . While some overlap of the neuroinflammatory response across TBI severities is expected, studies investigating the temporal dynamics of neuroinflammation after mTBI are still needed to uncover the mechanisms behind PCS, as well as to identify potential biomarkers that can be leveraged to develop more reliable point-of-care diagnostics and therapeutic strategies.…”

“…Again, these patients were recruited from injuries serious enough to warrant a trip to the emergency room 36 . Ryan et al reported that TNFα and IL-10 were significantly decreased, while IL-6 was significantly increased in blood sampled from pediatric mTBI patients within 2 weeks of injury 21 . Gard et al reported that IL-2, TNFα, and VEGF were all significantly increased in the CSF of adult mTBI patients 17 months post-injury 8 .…”