Abstract

Background: Traumatic brain injury (TBI) remains the predominant cause of mortality and disability among the pediatric population. At present, there are no radiation-free, simple, and cost-effective tools available to assess the severity and prognosis of pediatric TBI. The systemic immune-inflammation index (SII), neutrophilto-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) serve as inflammatory biomarkers that may assist in predicting the outcome of pediatric TBI. This research aims to assess the utility of SII, NLR, and PLR as a predictive biomarker in children with TBI.

Methods: A retrospective analysis was conducted on SII, NLR, and PLR by reviewing the medical records of all pediatric (age ≤18 years) TBI cases who came to the emergency department in the period from January 2023 to August 2024. Patients were categorized according to 28-day mortality and the severity of TBI. The correlation between the biomarkers and outcomes was analyzed.

Results: A total of 206 patients were included in this study. The mean age was 13.81 (1–18). The 28-day mortality rate was 5.3% (n = 11). There were no significant differences in SII, NLR, and PLR between the survivor and mortality groups (P = 0.317, P = 0.288, and P = 0.200, respectively). Based on the TBI severity, there was a significant difference in the SII, NLR, and PLR across mild, moderate, and severe TBI (P = 0.006, P = 0.002, P = 0.001, respectively).

Conclusion: The findings of our study did not reveal a significant predictive relationship between SII, NLR, and PLR to 28-day mortality. Nonetheless, there were significant differences in SII, NLR, and PLR among mild, moderate, and severe TBI groups. Further research under more controlled conditions is essential to facilitate the use of SII, NLR, and PLR as predictive biomarkers in pediatric TBI.

Keywords: Biomarker, Neuroinflammation, Neutrophil-to-lymphocyte ratio, Pediatric traumatic brain injury (TBI), Platelet-to-lymphocyte ratio, Systemic immune-inflammation index

INTRODUCTION

Traumatic brain injury (TBI) remains a major health problem worldwide, both in adults and children. TBI is the predominant cause of mortality and disability among the pediatric population.[ 3 ] The global incidence of pediatric TBI ranges from 12 to 486 cases/100,000 children or approximately more than 3 million cases annually.[ 7 ] The incidence of pediatric TBI is believed to be higher in developing countries such as Indonesia, where the number of traffic accidents is still very high. Nevertheless, there remains an insufficient amount of research data from developing countries.[ 10 , 38 ] Despite causing high disability and mortality, research on pediatric TBI is not as extensive as that on TBI in adults.

The pathophysiology of pediatric TBI can be categorized into primary and secondary injury based on its directness. The primary or direct injury occurs as a result of initial mechanical forces at the time of injury, resulting in damage to the brain tissue and disruption of its normal function.[ 23 , 25 ] The secondary or indirect injury occurs after the primary injury is triggered by conditions such as hypoxia, ischemia, and cerebral edema. Secondary injury cascades include excitotoxicity, oxidative stress, and neuroinflammation. Improperly treated secondary damage will lead to long-term brain damage and neurodegenerative disorders.[ 17 , 33 ]

TBI-induced neuroinflammation is a complex physiological reaction between central nervous system (CNS) cells, cytokines, chemokines, and the subsequent infiltration of peripheral immune cells and occurs over hours to days following the initial trauma. During the acute phase, regulated neuroinflammation is beneficial for eliminating debris and pathogens and promoting regeneration. However, excessive and unregulated neuroinflammation may exacerbate secondary brain injury by inducing cerebral edema, increasing intracranial pressure, disrupting oxygen delivery and cerebral blood flow, and resulting in neuronal death or neurodegenerative disorders.[ 23 , 39 , 40 ] Due to the nature of a child’s brain development which is still in a rapid development period, damage due to excessive neuroinflammation will result in brain development abnormalities and result in disorders in the child’s normal development.[ 7 , 10 ]

The management of pediatric TBI is complex, including explaining the patient’s expected outcome to their family. Prognostic models such as international mission on prognosis and analysis of clinical trials and corticoid randomization after significant head injury are extensively used to predict outcomes in the adult TBI population [ 8 , 31 , 37 ]; however, these models are inapplicable in pediatric TBI patients. Other common instruments to predict TBI patient outcomes are computed tomography (CT)-based scoring systems such as the Marshall Classification System and the Rotterdam CT Score.[ 4 , 9 , 28 ] However, excessive use of head CT scans may elicit concerns about radiation exposure in pediatric patients.

Numerous studies have investigated the application of blood biomarkers in assessing TBI-related neuronal damage and predicting outcomes. The most common biomarkers used are S100B, tau, neurofilament light chain, ubiquitin carboxy-terminal hydrolase-L1, and glial acidic fibrillary protein.[ 12 , 14 , 20 , 34 ] However, these examinations are still not yet established as a standard treatment and require a significant additional cost. Therefore, a simple examination that is easy, affordable, and routinely performed is needed to help assess the outcome of pediatric TBI.

The systemic immune-inflammation index (SII), neutrophilto-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are hematological component calculations that are widely available and low-cost blood biomarkers. These calculations reflect the balance between immune status and the host’s systemic inflammatory response. SII, NLR, and PLR also could be used to predict unfavorable outcomes in certain adult trauma cases.[ 1 , 2 , 6 , 11 , 16 , 26 ] However, so far, there have been no studies that specifically investigate these three parameters for pediatric TBI cases. This study aims to evaluate and compare the value of SII, NLR, and PLR in determining the 28-day mortality outcomes in pediatric TBI patients at a tertiary referral hospital in Surabaya, Indonesia.

MATERIALS AND METHODS

Study design

This is a retrospective analytical cross-sectional study in a single tertiary referral hospital, Dr. Soetomo General Academic Hospital in Surabaya, Indonesia. All pediatric patients (≤ 18 years old) who had come to the emergency department and were diagnosed with TBI in the period from January 2023 to August 2024 were identified in the hospital database and reviewed. The Health Research Ethics Committee of the Dr. Soetomo General Academic Hospital, Surabaya, reviewed and approved this study (No. 3156/111/4/ IX/2024).

The inclusion criteria used were all TBI patients under 18 years old, admitted within 24 hours after the incident, had a head CT scan and complete blood count laboratory results at the time of admission, and had a minimum follow-up period of 28 days. The exclusion criteria were patients who did not undergo a CT scan and complete blood count, had initial conditions such as active infection, hematological, autoimmune, and malignancy diseases, and incomplete or inaccessible data.

Data collection

The medical records of pediatric patients with TBI admitted to the emergency department were compared to the surgical registry and inpatient and outpatient clinic records to minimize data loss. The variables collected were demographic data (age and sex), etiologies of TBI, the severity of TBI (Glasgow Coma Scale [GCS] score), multitrauma event, head CT scan results, neurosurgical procedures, complete blood count results, and 28-day mortality.

The SII, NLR, and PLR values were calculated from the patient’s initial complete blood count during admission to the emergency department. NLR values were obtained by dividing the neutrophil number by the lymphocyte number, PLR by dividing the platelet number by the lymphocyte number, and SII by multiplying the platelet and neutrophil number and dividing by the lymphocyte number. Initial hemoglobin was also used as a measured variable.

Head CT scan results were obtained from radiologist expertise in the medical records and described as epidural hematoma (EDH), subdural hematoma (SDH), traumatic intracerebral hematoma (tICH), traumatic subarachnoid hemorrhage, a combination of more than one lesion, or normal finding. Patients were classified as survivor and mortality groups according to 28-day mortality.

Statistical analysis

The numeric data analysis was presented as mean ± standard deviation, along with number (n) and percentage for categorical data. The Shapiro–Wilk test was used to analyze data for normality. Statistical analysis for group comparison was performed using analysis of variance for normally distributed data. For non-normal distribution data, the Mann–Whitney test was performed.

To find any significant differences between the groups, a post hoc test was conducted. For the correlation test analysis, the Pearson test was used for categoric data and the Spearman correlation for numeric data. Statistical significance was considered for P = 0.05 or less with a 95% confidence interval. The data analysis was conducted using the Statistical Package for the Social Sciences statistical software version 25 (IBM Corp., Armonk, NY, USA).

RESULTS

From January 2023 to August 2024, we identified 278 pediatric patients with TBI that admitted to our emergency department. Seventy-two patients were excluded due to preexisting medical conditions, no laboratory tests or CT scans were performed, and/or incomplete data. A total of 206 patients met the inclusion criteria and were included in the study [ Table 1 ].

Table 1:

Demographic data and the studied variables.

The study’s mean age was 13.81, with a range of 1–18 years. The male gender dominates with a figure of 72.3% (n = 149). The main etiologies of TBI were traffic accidents with 84.5% (n = 174), followed by falls from height with 9.2% (n = 19), and assaults with 2.9% (n = 6). The mean number of TBI severity levels determined by the GCS score is 13.25 ± 2.66. There is a statistically significant association between GCS and 28-day mortality. The GCS in the survivor group (13.53 ± 2.28) was significantly higher than the mortality group (8.27 ± 3.93; P ≤ 0.001). The mortality rate at 28 days was 5.3% (n = 11).

Multitrauma occurred in 43.2% of the cases (n = 89). Neurosurgical procedures were conducted in 27.7% (n = 57) patients. The main diagnoses identified by the head CT scan were EDH (26.7%), SDH (14.1%), and tICH (11.7%). Combined lesions (≥2 lesions) occurred in 25.2% of cases (n = 52). Normal findings on head CT are observed in 49.5% of patients (n = 102). From the head CT result, SDH was found significantly higher in the mortality group than in the survivor group (72.7% vs. 10.8%; P ≤ 0.001).

In the comparison of hematological data between survivor and mortality groups, SII was elevated in the survivor group (2453.01 ± 1825.39 vs. 2016.84 ± 1868.52). NLR was higher in the survivor group (8.58 ± 5.95 vs. 7.52 ± 7.39). The PLR result was also higher in the survivor group than in the mortality group (185.04 ± 115.40 vs. 139.79 ± 102.78). In addition, hemoglobin level was found to be significantly higher (12.18 ± 2.11 vs 11.59 ± 3.41, P = 0.003) in the survivor group.

Based on the TBI severity classification, there was a significant difference in the SII across mild, moderate, and severe TBI (1311.64 ± 873.04; 2434.02 ± 1843.02; 2889 ± 1874, P = 0.006). There was also a significant difference in the NLR result (5.14 ± 4.02; 8.26 ± 5.62; 11.14 ± 7.46, P = 0.002). The PLR result was also significantly different in these groups (193.70 ± 115.75; 172.07 ± 110.72; 92.15 ± 71.33, P = 0.001) [ Table 2 ].

Table 2:

Comparison between SII, NLR, and PLR regarding TBI severity.

DISCUSSION

The SII, NLR, and PLR are biomarkers derivable from the routine differential blood count. These inflammation biomarkers have been extensively studied and tested for their usefulness in recent years; nevertheless, there are not many studies that use them in pediatric TBI. Under normal conditions, neutrophils are unable to enter CNS due to the integrity of the blood–brain barrier (BBB) formed by tight junctions between endothelial cells. Injuries to the CNS cells following TBI will initiate neuroinflammation. TBI-induced neuroinflammation cascade will further release proinflammatory cytokines, chemokines, and angiogenic factors and could impair the integrity of BBB, leading to significant leukocyte infiltration. Neutrophils are among the initial immune cells recruited to and infiltrate the injury site within the 1^st h after injury. The primary function of neutrophils in the injured CNS is phagocytosis, which is to clear the damaged tissue by engulfing debris and dead cells by releasing reactive oxygen species and proteolytic enzymes in conjunction with microglia and macrophages derived from peripheral monocytes.[ 19 , 26 , 32 , 35 , 36 ]

Neutrophils also could release proinflammatory cytokines by themselves, causing further disruption to the BBB, leading to excessive neuroinflammation and cerebral edema. The accumulation of neutrophils and their released substances may exacerbate damage to CNS cells, potentially resulting in neurodegenerative conditions.[ 19 , 26 , 32 , 35 , 36 ] The peak number of neutrophils that infiltrate the brain occurs 24 hours postinjury.[ 15 ]

Lymphocytes, a type of white blood cell, play a complex and protracted role in the immune response after TBI. In contrast to neutrophils, which respond rapidly, lymphocytes play a significant role in the adaptive immune response and contribute to the long-term outcomes of brain injury. Lymphocyte infiltration peaks within days to weeks postinjury, and previous studies indicate that lymphocytes have no significant impact in the early stages of TBI.[ 30 , 32 , 35 ]

Contrary to the damaging effects of neutrophils, studies showed that autoreactive lymphocytes promote healing in the CNS tissue following TBI. They are regarded as possessing neuroprotective effects and improve neurological function.[ 13 , 32 ] Another study also emphasized the importance of lymphocyte count for the survival of trauma patients.[ 15 ]

Under normal circumstances, platelets circulate within the bloodstream in an inactive state. During the acute phase following primary TBI, blood vessels rupture, and BBB disruption will make platelets migrate to the injured vessels to prevent further bleeding by forming blood clots. Perilesional microthrombosis and platelet hyperactivity will result in significant platelet consumption and depletion. In moderate and severe TBI, the equilibrium between coagulation and anticoagulation is disrupted, resulting in a diminished platelet count in the bloodstream. The low platelet count may lead to a coagulopathy state after TBI and increase the risk of secondary bleeding.[ 1 , 16 , 21 , 22 ] Trauma-induced coagulopathy (thrombocytopenia) occurs in 10–35% of patients within 48 hours postinjury, correlating with the occurrence of more severe trauma, multiorgan failure, and higher mortality rates.[ 1 , 18 , 22 ] In addition to its function to form blood clots, platelets also contribute to immune responses and stimulate neuroinflammation mediator releases. Platelets also exacerbate inflammatory responses by interacting with immune cells such as macrophages and neutrophils.[ 16 , 18 ]

This study investigates the prognostic value of SII, NLR, and PLR in pediatric TBI patients. In grouping based on the severity of trauma (mild, moderate, and severe TBI), there were significant differences in the SII, NLR, and PLR values. SII and NLR were significantly higher in severe TBI (P = 0.006 and P = 0.002), but PLR was significantly higher in mild TBI (P = 0.001).

In groups based on 28-day mortality, our results showed that both NLR and SII were higher in the survivor group compared to the mortality group, whereas PLR was higher in the survivor group. This study showed that PLR was higher in the survivor group. This result is consistent with prior research.[ 1 , 16 , 21 , 41 ] Excessive platelet consumption in severe trauma will diminish circulating platelets. A reduced PLR is expected in patients with severe TBI and correlates with higher mortality rates.

Our study presents findings on NLR and SII that differ from earlier studies, which indicated that higher NLR and SII were associated with poorer outcomes.[ 2 , 5 , 19 , 24 , 27 ] Several factors may affect these findings. First, there was a huge discrepancy in sample size between the survivor group (n = 195) and mortality group (n = 11) which may impact the statistical analysis. The second factor is the diversity in age among the pediatric population in this study (1–18 years). Pediatric is a special population that differs from the adult population. The SII, NLR, and PLR may vary across different ages or sexes within the pediatric population. A recent study revealed the significant variation of these inflammatory biomarkers among various age groups, highlighting the necessity for tailored reference values for children.[ 29 ] The final factor that could potentially impact the findings is that this study was conducted in a tertiary referral hospital located in a developing country, Indonesia. In areas where prehospital services or referral systems have yet to reach optimal effectiveness. In some cases, trauma patients may require several hours to receive medical attention. Frequently, traffic accident patients arrive at our hospital without using an ambulance or without being accompanied by medical staff. Patients referred from other cities or hospitals frequently did not receive optimal treatment at the referring facility or during transport in the ambulance.

Limitations and considerations

This study retrospectively compares patient survivor and mortality groups according to 28-day mortality. However, there was a limitation caused by the disparity in these two groups’ sample sizes. The number in the mortality groups (n = 11) is much smaller than in the survivor group (n = 195). The large discrepancy in these two groups’ sample sizes may have reduced the power of the analysis, contributing to the non-significant result.

Aside from medical treatment considerations, the limited sample size in the mortality group may be attributed to the study design, which includes all pediatric TBI patients, including those with mild TBI. Future research should focus on obtaining a more balanced sample that is specific to age and severity to provide more conclusive results.

CONCLUSION

This study did not identify a significant predictive relationship between SII, NLR, and PLR and 28-day mortality, which can be attributed to the disparity in sample sizes. The findings of this study indicated significant differences in SII, NLR, and PLR across mild, moderate, and severe TBI groups. The observed trends suggest SII, NLR, and PLR may serve as promising neuroinflammation biomarkers for pediatric TBI, particularly due to their ease of use, affordable, and routinely conducted in an emergency hospital setting. The SII, NLR, and PLR may serve as valuable indicators for predicting the severity and the outcome of pediatric TBI patients. Nonetheless, considering the special characteristics of the pediatric population, further research is needed with more standardized, uniform, and homogenous factors (such as age, sex, and posttraumatic blood sampling interval) to enable SII, NLR, and PLR to be used broadly in clinical settings.

Availability of data and materials

Further inquiries about data generated or analyzed for this study can be directed to the corresponding author at a reasonable request.

Authors’ contributions

MAP:Contributed to the conceptualization, investigation, methodology, supervision, writing, and finalizing of the manuscript of the study; WS :Contributed to reviewing and editing the manuscript of the study;ADD :Contributed to the data collection, writing, and editing of the study;BU contributed to data analysis; GOT, CK, and SPB : Contributed to data collection and analysis.

Ethical approval

This study was evaluated and approved by the Health Research Ethics Committee of the Dr. Soetomo General Academic Hospital, Surabaya, where the research was conducted (No. 3156/111/4/IX/2024).

Declaration of patient consent

Patient’s consent not required as patients identity is not disclosed or compromised.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

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