Cerebrospinal Fluid Markers of Macrophage and Lymphocyte Activation After Traumatic Brain Injury in Children

Traumatic brain injury is the most common cause of death and disability in children with nearly 500,000 children suffering from TBI each year (1). Unfortunately, specific therapies are lacking with existing treatment primarily being supportive. Given that the tools to reverse primary tissue injury after TBI are currently lacking, significant effort is being placed on identifying means of manipulating secondary injury pathways that follow TBI and contribute to ongoing cellular dysfunction and death. Inflammation is one such secondary process that may represent a therapeutic target following TBI. Inflammation following experimental TBI has been well documented and is mediated by both CNS immune cells as well as those of the peripheral immune system following disruption of the blood-brain barrier (BBB)(2). There are also reports identifying cellular inflammation after TBI in adult patients (3, 4). There are caveats in regard to manipulating neuroinflammation; however, as it has been shown to have both beneficial and detrimental roles following TBI. These divergent roles likely depend on timing (5, 6), severity (7), and type of injury (8), as well as on age (9), genetics (10), and other factors. As such, strategies will be required that harness the beneficial effects such as repair, trophic factor release, and debridement, while minimizing undesirable effects such as edema and supraphysiologic inflammation. (11). Identifying markers of an aberrant or supraphysiologic inflammatory state would thus be useful in attempting to strategically manipulate the neuroinflammatory response after TBI. An extreme example of an aberrant inflammatory state is hemophagocytic lymphohistiocytosis (HLH), a condition of immune dysregulation resulting in hyper-inflammation due to uncontrolled macrophage and T-cell activation. A case definition of HLH requires diagnostic criteria identifying macrophage and T-cell activation, including measurement of ferritin and soluble interleukin-2 receptor α (sIL-2Rα), respectively (12). More recently soluble cluster of differentiation 163 (sCD163) has also been suggested to be a marker of macrophage activation (13). Neurological involvement is common in HLH, occurring in 30–50% of cases at presentation (12), and includes neuroinflammation, necrosis, white matter abnormalities, and hemorrhage (14). Coincidentally, Rooms et al. (15) reported a series of three children with brain injuries suspected to be caused by abusive head trauma (AHT) that met diagnostic laboratory criteria for HLH raising concerns that AHT may lead to systemic activation of the immune system, or that systemic macrophage or resident microglial activation could cause intracranial findings that could be misconstrued as findings of child abuse (15). While the pathophysiology of CNS involvement in HLH is not completely understood, it likely is in part due to local uncontrolled macrophage and T-cell activation. These studies raise the question of whether excessive CNS immune activation could be triggered by an inciting event such as trauma, and whether this could be identified by similar markers of macrophage/microglial and T-cell activation. Accordingly, the purpose of this study was to investigate the presence of markers of macrophage/microglial and T-cell activation in pediatric TBI, as characterized by elevations in cerebrospinal fluid (CSF) sCD163, ferritin, and sIL-2Rα. While previous studies have looked at various markers of inflammation following pediatric TBI (16–21), this is the first study looking specifically for the presence of markers of macrophage and T-cell activation. These findings may represent a means for identification of patients likely to respond to strategies targeting cellular inflammation, and/or a means for therapeutic drug monitoring for future clinical trials targeting inflammation after TBI.