Traumatic brain injury (TBI) is a major social and clinical issue because it is one of the leading causes of mortality or permanent disability in children and adolescents worldwide (1). Pediatric TBI has exhibited various unique characteristics compared with adult TBI, which may be explained by age-related anatomical and physiological differences (2). While the clinical management of TBI has improved significantly in recent years, children with moderate or severe TBI (MS-TBI) continue to have poor clinical outcomes (2).

Predicting outcomes is critical for satisfactory pediatric TBI care. Undeniably, individual prognosis prediction contributes to improved clinical decision-making and helps minimize secondary brain injury (SBI). Computerized tomography (CT) is routinely performed to evaluate structural lesions in pediatric TBI because of its availability and speed. Indeed, it has been studied for its predictive value for mortality and functional outcomes in both individual injury characteristics and composite grading systems, including the Rotterdam CT score (3), Marshall CT classification (4), and Helsinki CT scoring system (5). However, few studies have comprehensively examined and compared the predictive values of admission CT imaging characteristics in pediatric TBI.

Hemodynamic alterations and systemic inflammation are always present in patients who sustain TBI (6). Additionally, complete blood counts are frequently performed as non-invasive laboratory procedures in clinical practice. Peripheral blood counts, including neutrophil, lymphocyte, and platelet counts, have previously been used to assess central nervous system and peripheral inflammation following injury (7). Recently, several inflammation-based prognostic scores, including the neutrophil-to-lymphocyte ratio (NLR) (8), platelet-to-lymphocyte ratio (PLR) (9), lymphocyte-to-monocyte ratio (LMR) (10) and systemic immune-inflammation index (SII) (11) have been demonstrated to accurately predict outcomes in patients with neurological diseases such as stroke, subarachnoid hemorrhage (SAH), and Alzheimer's disease (12–14). Indeed, these are low-cost and reproducible diagnostics that can be quickly calculated from a blood sample collected under simple laboratory conditions and can identify the mortality risk associated with TBI. However, no study has evaluated the predictive value of these scores in pediatric TBI.

Therefore, the purpose of this study was to retrospectively evaluate and compare the prognostic values of initial CT scan findings and blood test-based inflammation scores in a cohort of 104 children with TBI. Moreover, we established an accessible and easy-to-use nomogram to predict early mortality in pediatric TBI based on intake examinations.

TBI is an injury to the cranium and its intracranial components produced by an external mechanical force, which changes the brain's structure and function (17). Primary and SBI is a pathological process following TBI (18). Primary brain injury occurs when the brain tissue is subjected to mechanical force, resulting in axonal, vascular, and glial cell damage. SBI occurs due to the initiation of inflammatory cascades by the release of different inflammatory chemicals and neurotransmitters from the injured neuronal and glial cells in the brain (19).

Currently, the GCS is the most commonly used technique for assessing the severity of TBI. On the other hand, GCS is a collection of clinical descriptive data that does not include structural information about cerebral abnormalities. Additionally, the GCS had a low prognostic value in the early stages post-injury, and neurological examination in children is challenging. More importantly, a history of neurological illnesses and the presence of an EDH during the intermediate waking state may affect the accuracy of GCS (20). As a result, finding efficient biomarkers for the prognosis of pediatric TBI from admission examinations is critical. The predictive value of inflammation scores in pediatric TBI cases with a combination of intake CT findings is still unclear and has not been extensively explored. To bridge this gap, the present study, for the first time, compared the predictive values of various inflammation prognostic scores and CT scan parameters in a large cohort of 104 children with MS-TBI.

In this study, ROC analysis was applied to determine the optimal cut-off values of various blood test parameters (Table 2). In the training cohort, the univariate and multivariate logistic regression analyses demonstrated that the basal cistern, sex, and PLR could independently predict early death in pediatric patients with MS-TBI (Table 3). To further facilitate clinical practice, we constructed a nomogram for prognosis prediction (Figure 2). The C-index and AUCs demonstrated that the nomogram significantly outperformed current CT scoring systems, including the Rotterdam CT, Marshall CT, and Helsinki CT scores in both the training and validation cohorts (Table 4). All these data demonstrated that the current nomogram could serve as a preferable model for pediatric patients with MS-TBI.

The mechanism underlying the excellent predictive value of the newly developed nomogram may be explained as follows. PLR was initially introduced to represent systemic inflammation and to estimate the prognosis of patients with cancer and autoimmune diseases (21, 22). Recent research has demonstrated that PLR is a simple parameter that can be used to predict clinical outcomes in patients with stroke, cerebral hemorrhage, and SAH (13, 23–26). In response to physiological stress, such as traumatic injury, the body produces more cortisol, whose elevated levels can result in lymphopenia (27); the higher the physiological stress, the higher the cortisol level, which results in a decrease in the body's lymphocyte count. Contrastingly, an increased lymphocyte count indicates a more targeted immune response and a more persistent inflammatory pathway (28). Moreover, lymphocytes represent a more tightly controlled inflammatory route, and apoptosis induced by lymphocytes is less harmful to neighboring cells than other cell death models caused by uncontrolled inflammation (29). Thus, a decreased lymphocyte count post-TBI may reflect the damaging effect of the inflammatory response, resulting in an exacerbated SBI post-TBI. On the other hand, along with their well-known hemostatic functions, platelets play an active role in inflammation regulation. While platelets bind to coagulation factors, they also include a large variety of inflammatory factors, such as TNF-α, interleukins, and serotonin, all of which are involved in tissue injury and repair (7). Therefore, it is reasonable to conclude that a high PLR may be associated with an increased risk of death in pediatric patients with MS-TBI.

Additionally, previous research has demonstrated that obliterated cisterns are associated with increased intracranial pressure and poor outcomes (30, 31), suggesting that the status of the cisterns can be used as an early non-invasive method for identifying patients at high risk of death or severe disability, despite the initial neurological examination indicating otherwise. Further, some studies that focused on adults explored sex differences in outcomes following moderate/severe TBIs, mainly showing an absence of differences or better outcomes in women compared to men. However, following mild TBI, most studies indicate worse psychological and global functioning outcomes in women. Biological differences, particularly sex steroids, represent another pathway that can mediate these sex differences in outcomes. Animal models suggest that the hypothalamic-pituitary-adrenal axis, which modulates the stress response, and microglia, which influence cerebral inflammation, have sex-specific responses. Indeed, these preclinical models have shown that female rodents present a stronger inflammatory response than males after TBI (32–37).

Nevertheless, this study has several limitations that are worth mentioning. First, as a single-center retrospective study, potential selection bias was inevitable, although we had performed strict inclusion criteria. Second, the cut-off values for inflammation-based indices used in this study were determined by ROC analysis based on outcome data, and further validation studies determining optimal threshold values for these inflammation indices are needed. Third, peripheral platelet and lymphocyte counts may be affected by other pathological conditions, including metabolic syndrome and renal dysfunction. Hence, the clinical significance of PLR should be cautiously explained with full consideration of any concurrent diseases.

We identified sex, admission PLR, and basal cistern status from initial CT findings as independent prognostic predictors in pediatric patients with MS-TBI, which may contribute to individualized prognosis prediction and better clinical decision making. However, a larger data set from multiple centers is still needed to confirm the findings of this research and promote its clinical implementation.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Research Ethics Committee of The Second Affiliated Hospital of Wenzhou Medical University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

PZh, NH, ZY, and XY contributed to the conception of the study. LLi, JT, YX, YW, PZo, and KS performed the data collection. PZh, NH, and GB performed the data analyses and wrote the manuscript. JT, LLin, LLi, ZY, and XY helped perform the analysis with constructive discussions. All authors contributed to the article and approved the submitted version.

This work was supported by grants from the Natural Science Foundation of Zhejiang Province (No. LY19H180003) and the National Natural Science Foundation of China (No. 82071902).

The authors declare thatthe research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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