
==== Front
Ann Indian Acad Neurol
Ann Indian Acad Neurol
AIAN
Ann Indian Acad Neurol
Annals of Indian Academy of Neurology
0972-2327
1998-3549
Wolters Kluwer - Medknow India

39150475
AIAN-27-371
10.4103/aian.aian_384_24
Original Article
Diagnostic Value of Serum Procalcitonin, CSF Neutrophil-to-lymphocyte Ratio, and CSF Lactate in Pediatric Bacterial Meningoencephalitis
Nugrahanto Andika Priamas
Triono Agung
Damroni Rais Aliffandy
Herini Elisabeth Siti
Division of Paediatric Neurology, Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
Address for correspondence: Agung Triono, Division of Paediatric Neurology, Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Jl. Farmako, Senolowo, Sekip Utara, Depok, Sleman, Daerah Istimewa Yogyakarta - 55281, Indonesia. E-mail: agung.triono@ugm.ac.id
Jul-Aug 2024
16 8 2024
27 4 371377
12 5 2024
13 6 2024
30 6 2024
Copyright: © 2024 Annals of Indian Academy of Neurology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Background:

Bacterial meningoencephalitis presents significant diagnostic and therapeutic challenges with high morbidity and mortality in pediatric populations worldwide. The early and precise identification of the etiology of these infections is essential for effective treatment and better patient results. Traditional diagnostic methods, while effective, can be time-consuming. This manuscript aims to evaluate the accuracy of serum procalcitonin (PCT), cerebrospinal fluid (CSF) neutrophil-to-lymphocyte ratio (NLR), and CSF lactate as biomarkers in pediatric bacterial meningoencephalitis.

Methods:

From March 2021 to November 2023, a cross-sectional study was conducted at Dr. Sardjito General Hospital, a tertiary referral hospital in Yogyakarta, Indonesia. One hundred ninety-seven patients underwent complete clinical and laboratory examinations before being divided into bacterial and non-bacterial groups based on CSF culture results and cytochemical profiles. The diagnostic accuracy was evaluated by the receiver operating characteristic curve using Statistical Package for the Social Sciences.

Results:

Serum PCT, CSF NLR, and CSF lactate levels showed a notable increase in the bacterial meningoencephalitis group (mean = 4.63 ± 5.52 ng/ml, 4.39 ± 6.68, and 3.59 ± 2.38 mmol/l, respectively) compared to the viral/aseptic group (mean = 0.51 ± 0.88 ng/ml, 0.33 ± 0.95, and 2.25 ± 2.33 mmol/l, respectively) (P < 0.001). Serum PCT and CSF NLR combined measurement had high sensitivity (86.4%) and specificity (88.6%), with an area under the curve of 0.929 (95% confidence interval, 0.873–0.985), surpassing other tested biomarkers.

Conclusion:

The findings suggest that combining serum PCT and CSF NLR could be beneficial for early diagnosis, potentially allowing timely, targeted treatment and differentiating between bacterial and non-bacterial infections, ultimately improving patient outcomes.

Bacterial meningoencephalitis
biomarker
lactate
neutrophil–lymphocyte ratio
procalcitonin
==== Body
pmcBACKGROUND

Bacterial intracranial infections, such as meningitis and encephalitis, have a notable impact on illness and death rates among children globally. The early and precise identification of the etiology of these infections is essential for effective treatment and better patient results. However, the clinical presentation in children can be nonspecific, and conventional diagnostic methods such as culture and Gram staining of cerebrospinal fluid (CSF) are time-consuming and not always definitive.[1]

The prognosis of bacterial intracranial infections in children largely depends on the timeliness of diagnosis and initiation of appropriate therapy. Delayed or inaccurate diagnosis can lead to severe complications, including neurologic damage and death. It is difficult to differentiate the etiology of meningoencephalitis in children because most cases present the same clinical picture, especially in the acute phase.[2] Moreover, overuse of empirical antibiotics increases resistance.[3] Therefore, there is a pressing need for reliable biomarkers that can provide rapid and accurate diagnostic information.

Current diagnostic methods rely heavily on clinical presentation, CSF analysis, and imaging. The gold standard for diagnosis is CSF culture and polymerase chain reaction (PCR) of a CSF sample. However, these methods have limitations: results may take time, and they may not always be conclusive or available in all healthcare settings. In addition, distinguishing bacterial from viral infections is crucial as their treatments differ significantly, but this distinction can be challenging with traditional methods.[4]

Serum procalcitonin (PCT) is a promising biomarker for bacterial infections as it is the precursor of calcitonin, a hormone produced by the thyroid gland. PCT levels are typically low in healthy individuals, but increase significantly in response to bacterial infections. This increase is thought to result from the proinflammatory response to bacterial endotoxins.[5] The “neutrophil-to-lymphocyte ratio” (NLR) is a leukocyte-produced biomarker that has been newly recognized as an inflammation indicator. NLR is considered to be more reliable for detecting bacterial infections due to incorporation of both neutrophils and lymphocytes in its calculation, as opposed to relying solely on absolute neutrophil counts. Elevated NLR levels, specifically in CSF, may indicate the host’s immune response to bacterial clusters initially localized in the meninges.[6] CSF lactate is considered a potential diagnostic marker for bacterial meningoencephalitis. It is produced in higher amounts during anaerobic metabolism, which increases in bacterial meningitis due to the presence and activity of bacteria and the host’s immune response.[7]

In low- and middle-income countries, diagnosing and managing meningoencephalitis can be particularly challenging due to limited access to advanced laboratory facilities and rapid diagnostic tests. Recent studies indicate that serum PCT, CSF NLR, and CSF lactate levels are promising biomarkers for early detection of bacterial infections. Our study aimed to evaluate the diagnostic accuracy of these biomarkers and their combination in promptly diagnosing bacterial meningoencephalitis.

METHODS

This study was conducted prospectively from March 2021 to November 2023 using a cross-sectional design at Dr. Sardjito General Hospital, a tertiary referral hospital in Yogyakarta, Indonesia. The Medical and Health Research Ethics Committee Faculty of Medicine, Public Health, and Nursing of Universitas Gadjah Mada approved this study (KE/0214/02/2023). The patients were ascertained for this study after their parents signed a written informed consent form. A total of 245 children with suspected meningoencephalitis were enrolled and underwent thorough examinations, including gathering primary demographic information. Information on clinical symptoms such as loss of consciousness, fever, seizure, focal neurologic deficit, vomiting, and meningeal signs were also collected. Biochemical, cytological, and culture examinations of CSF samples included leukocyte counts, neutrophil counts, glucose levels, and protein concentrations. GeneXpert testing for Mycobacterium tuberculosis with CSF sample was also performed to diagnose tuberculous meningitis. Simultaneously, blood samples were also taken to analyze serum leukocyte count, PCT levels, and blood culture results. Serology testing for Japanese encephalitis, herpes simplex virus (HSV) 1, and HSV 2 was also conducted. NLR was determined by dividing the absolute neutrophil counts by the absolute lymphocyte counts using the available CSF analysis result. In addition, imaging studies such as a computed tomographic scan or magnetic resonance imaging were performed to provide valuable information about the presence of intracranial lesions and swelling in the brain. The measurement of serum PCT was conducted using the PCT-Q assay developed by Brahms in Berlin. This is a diagnostic test that uses immunochromatography to identify and measure the levels of serum PCT in a semi-quantitative manner. The test has a short incubation period of just 30 min, and it does not rely on any specific equipment and does not need calibration.

Children aged 6 months to 17 years old were eligible for inclusion if they met the clinical criteria for meningoencephalitis, provided a complete set of clinical data, and submitted the necessary blood and CSF samples for laboratory testing. The exclusion criteria were the subjects rejected by parents, subjects having secondary infections apart from intracranial infections, those who had taken antibiotics for more than 3 days, and renal insufficiency. We excluded children under 6 months of age due to ethical considerations and physiologic differences. Younger children do not have fully developed blood–brain barrier and have an immature immune response, which could lead to variations in CSF parameters compared to older children. We excluded patients above 17 years old due to the hospital’s policy to treat such individuals in the adult neurology department. The patients were divided into two groups based on bacterial and nonbacterial categorization, as shown in Figure 1. Patients with bacterial meningoencephalitis were further divided into two subgroups: (1) a definite bacterial group, comprising samples with either a positive Gram staining, culture, or PCR for mycobacterium tuberculosis (MTB) and (2) a presumed bacterial group, indicating presence of a clinical picture of meningitis with at least one of the following criteria: protein ≥80 mg/dl, glucose <40 mg/dl, white blood cell count ≥300 cells, and polymorph nuclear cell predominance. However, nonbacterial (viral/aseptic) meningoencephalitis can be divided into two subgroups: definite viral/aseptic group, which includes samples with positive serology for viral infections, and presumed viral/aseptic group, where there is presence of clinical symptoms of meningoencephalitis, with CSF lacking the previously mentioned bacterial characteristics.

Figure 1 Sample selection flow chart CSF = cerebrospinal fluid, PCR = polymerase chain reaction, PMN = polymorphonuclear neutrophils, WBC = white blood cells

Data analysis was conducted using Statistical Package for the Social Sciences version 27. The results were displayed through frequency tables, graphs, and charts. Mean, median, and standard deviation values were calculated for both sets of patients. The Mann–Whitney U test was employed for non-normally distributed data, while the independent t-test was used for normally distributed data to compare the findings between the two groups. Receiver operating characteristic curves were used to assess biomarker accuracy; this included calculating measures such as area under the curve, optimal cut-off value, sensitivity, and specificity. Statistical significance was set at a threshold of P < 0.05.

RESULTS

This study involved 197 children, with males accounting for 52.8% (n = 104) of the total. Based on the CSF culture results and cytochemical profiles, the cases were categorized into two groups based on the etiology – bacterial (n = 80) and non-bacterial (n = 117) groups. The mean age was 6.54 ± 5.98 and 5.23 ± 5.14 years for bacterial and non-bacterial groups, respectively. Altered mental status was the most common clinical manifestation in the bacterial group, reported by 89.9% of patients, followed by fever (86.1%) and seizure (68.4%). In contrast, fever was the most frequent clinical manifestation in the non-bacterial category at 88.1%, followed by changes in mental status (78.8%) and seizures (69.5%). The bacterial group had a longer hospitalization than the non-bacterial group (P < 0.05). A total of 19 patients died – 14 from the bacterial group and five from the non-bacterial group (P < 0.05). The baseline characteristics were comprehensively presented in Table 1.

Table 1 Baseline characteristics

	Bacterial group (n=80)	Non-bacterial group (n=117)	P	
Age (years), mean±SD	6.54±5.98	5.23±5.14	0.103	
Sex	
    Male (%)	51.9	53.4	0.837	
    Female (%)	48.1	46.6		
Altered mental status n (%)	71 (89.9)	93 (78.8)	0.042*	
Fever n (%)	68 (86.1)	104 (88.1)	0.670	
Seizure n (%)	54 (68.4)	82 (69.5)	0.866	
Focal neurologic deficit n (%)	18 (22.8)	16 (13.6)	0.093	
Vomiting n (%)	31 (39.2)	18 (15.3)	0.000*	
Meningeal sign n (%)	32 (40.5)	16 (13.6)	0.000*	
Hospitalization (days), mean±SD	28.61±44.64	17.21±11.91	0.009*	
Death n (%)	14 (17.5)	5 (4.27)	0.002*	
*Bold values denote statistical significance at the P < 0.05 level. SD=Standard deviation

On comparing the two groups, statistically significant differences were observed in various laboratory parameters. Serum PCT concentrations were 4.63 ± 0.51 and 0.51 ± 0.88 ng/ml, total leukocyte count (per cubic millimeter) was 16.76 ± 4.32 and 10.88 ± 6.85, NLR in CSF was 4.92 ± 4.89 and 4.89 ± 5.43, lactate concentrations in CSF were 3.59 ± 2.25 and 2.38 ± 2.33, glucose concentrations in CSF were 50.31 ± 24.65 and 67.43 ± 23.09, and CSF protein levels were 0.49 ± 0.11 and 0.11 ± 0.33 for the bacterial and non-bacterial groups, respectively (P < 0.05). However, NLR serum ratios did not show statistical significance (P = 0.333) between the bacterial group (4.39 ± 6.68) and the non-bacterial group (4.89 ± 5.43). The laboratory results for blood and CSF samples are shown in Table 2.

Table 2 Laboratory findings of blood and cerebrospinal fluid

	Bacterial group (n=80)	Non-bacterial group (n=117)	P	
Procalcitonin (ng/ml)	4.63±0.51	0.51±0.88	0.000*	
Total leukocyte count (per cubic millimeter)	16,764.32±28,468.91	10,886.85±5,650.42	0.003*	
NLR serum ratio	4.92±4.89	4.89±5.43	0.333	
NLR CSF ratio	4.39±6.68	0.33±0.95	0.000*	
Lactate CSF (mmol/l)	3.59±2.25	2.38±2.33	0.000*	
Glucose CSF (mg/dl)	50.31±24.65	67.43±23.09	0.000*	
Protein CSF (g/dl)	0.49±0.11	0.11±0.33	0.007*	
All values are represented as mean±SD. *Bold values denote statistical significance at the P < 0.05 level. CSF=Cerebrospinal fluid, NLR=Neutrophil-to-lymphocyte ratio

For pathogenic bacterial analysis, a total of 197 CSF specimens were examined in CSF culture and GeneXpert for MTB; only 60 were positive for bacterial growth. Five bacterial species that were most commonly found included M. tuberculosis (n = 13), Escherichia coli (n = 5), Staphylococcus aureus (n = 5), Staphylococcus warneri (n = 5), and Moraxella group (n = 5). Distribution of pathogenic bacteria is shown in Figure 2. Serological testing of the CSF samples confirmed Japanese encephalitis infection in one patient, and seven patients were diagnosed with presumed HSV meningitis based on clinical features, electroencephalography, and imaging results and positive serology in the serum (IgM). Children with Gram-negative infection showed a notable rise in CSF NLR compared to those with Gram-positive infection (P < 0.05). The CSF NLR levels were 0.37 ± 0.08 and 12.25 ± 24.59 for the gram-positive and gram-negative groups, respectively [Table 3].

Figure 2 Pathogenic bacterial distribution

Table 3 Comparison of biomarkers in Gram-positive and -negative groups

	Gram positive (n=35)	Gram negative (n=25)	P	
Procalcitonin (ng/ml)	9.96±25.05	12.25±24.59	0.581	
NLR CSF ratio	0.37±0.08	7.73±20.42	0.000*	
Lactate CSF (mmol/l)	14.99±81.10	4.36±2.89	0.177	
All values are represented as mean±SD. *Bold values denote statistical significance at the P < 0.05 level. CSF=Cerebrospinal fluid, NLR=Neutrophil-to-lymphocyte ratio

We analyzed the ability of PCT, CSF NLR, and lactate CSF to diagnose bacterial meningoencephalitis in children. The diagnostic sensitivity, specificity, and area under the curve (AUC) were 86.4%, 81.4%, and 0.921 (0.867–0.974), respectively, for PCT; 77.3%, 82.9%, and 0.869 (0.754–0.965), respectively, for CSF NLR; and 68.2%, 81.4%, and 0.775 (0.652–0.898), respectively, for lactate CSF. Interestingly, serum PCT and CSF NLR combined measurement had high sensitivity (86.4%) and specificity (88.6%), with an AUC of 0.929 (95% confidence interval, 0.873–0.985), surpassing the performance of other biomarkers tested in the study. The performance of the evaluated biomarkers for diagnosing bacterial meningoencephalitis, including their receiver operating characteristic curves, was shown in Figure 3 and Table 4.

Figure 3 ROC curves of combined biomarker in the diagnosis of bacterial meningoencephalitis. ROC = receiver operating characteristic

Table 4 Efficacy of tested biomarkers in diagnosis of bacterial meningoencephalitis

	Sensitivity	Specificity	AUC	P	95% CI	Cut-off	
Procalcitonin	86.4%	81.4%	0.921	0.000	0.867-0.974	0.65	
NLR CSF ratio	77.3%	82.9%	0.869	0.000	0.754-0.965	0.7	
Lactate CSF	68.2%	81.4%	0.775	0.000	0.652-0.898	2.8	
Procalcitonin and NLR CSF	86.4%	88.6%	0.929	0.000	0.873-0.985		
Procalcitonin and lactate CSF	81.8%	81.4%	0.909	0.000	0.841-0.978		
NLR and lactate CSF	77.3%	85.7%	0.863	0.000	0.760-0.965		
All biomarkers	86.4%	84.3%	0.924	0.000	0.857-0.991		
AUC=Area under the curve, CI=Confidence interval, CSF=Cerebrospinal fluid, NLR=neutrophil-lymphocyte ratio

DISCUSSION

The study revealed a notable elevation in serum PCT levels in children with bacterial infections compared to non-bacterial ones. The mean serum PCT concentration among the bacterial group was 4.63 ± 0.51 ng/ml, whereas in the non-bacterial group, it was 0.51 ± 0.88 ng/ml (P < 0.001). This finding is consistent with a previous study comparing serum PCT levels between bacterial meningoencephalitis and viral and unidentified infections.[8] PCT is mainly produced by the C-cells of the thyroid gland and acts as a precursor protein that is cleaved to produce calcitonin. Bacterial infections induce the upregulation of PCT and its subsequent release into the circulation.[9] Bacterial infections may increase the expression of the CALC-1 gene either by directly interacting with their antigens or indirectly by stimulating the production of interleukin (IL)-6 and IL-1.[10] This protein can be produced by organs outside the thyroid in response to bacterial antigens or cytokines from macrophage activation. However, these additional sources are unable to convert PCT into calcitonin, leading to a rapid increase in PCT levels in the bloodstream. Pure viral infections do not cause a significant rise in PCT levels compared to other types of viral infections due to the decrease in tumor necrosis factor-α and the inhibition of PCT expression by viral interferon-ɣ. This explains the cause of the increased levels of PCT in patients with bacterial infections.[1011] Moreover, the sensitivity, specificity, and AUC of serum PCT were 86.4%, 81.4%, and 0.921 (0.867–0.974), respectively. This result was consistent with previous studies that showed serum PCT is a reliable and impactful diagnostic for differentiating the etiology of meningitis in children with a sensitivity and specificity of 95.45% and 84.61%, respectively.[12] In instances of mycobacterial central nervous system (CNS) infections, such as tuberculous meningitis, PCT levels can be elevated, although not to the extent seen in cases caused by other bacterial pathogens. Elevated PCT (>0.4 ng/ml) was found to be indicative of an unfavorable prognosis, and its level showed a negative correlation with the glasgow coma scale (GCS) score at discharge[1314]

Although the use of PCT as a biomarker for meningoencephalitis shows potential, it is not devoid of constraints. One disadvantage of serum PCT is its lack of specificity for bacterial meningitis since it can also be increased in bacterial infections in other organs and noninfectious inflammatory processes.[1516] Individuals might exhibit substantial variation in PCT levels, which can be influenced by factors such as age, comorbidities, and the presence of other illnesses. The diversity of this condition poses a challenge in determining universally applicable thresholds for identifying bacterial meningoencephalitis. The PCT response latency can hinder its efficacy during the initial phases of illness when prompt detection and care are crucial. When individuals have mixed infections that involve both bacteria and viruses, PCT may not effectively distinguish between the two types of infections. The absence of specificity can confound the clinical interpretation of PCT levels when there are several infections present. Administering antibiotics or other therapeutic measures may generate false-negative results or impede the monitoring of treatment success due to the rapid drop of serum PCT concentrations during antibiotic therapy.[15] In the previous study conducted by Kalchev et al.[8] in 2020, the sensitivity of PCT was found to be 83.3% and the specificity was 72.7%.

CSF NLR may serve as an alternative biomarker for differentiating between bacterial and viral meningitis according to a previous study. There was a notable statistical difference in the mean CSF NLR value between the bacterial and non-bacterial groups.[617] The bacterial group in this study demonstrated higher CSF NLR compared to the non-bacterial group, with mean values of 4.39 ± 6.68 and 0.33 ± 0.95, respectively. This discovery aligns with a previous study that identified a statistically significant increase in NLR among individuals with bacterial causes.[17] The new inflammation marker, NLR, has shown promise in differentiating between bacterial and viral infections.[18] The reason behind the increase in NLR among individuals with bacterial infection is not fully understood, but it has been associated with the body’s innate (neutrophils) and adaptive (lymphocytes) immune responses.[17] Elevated NLR levels, specifically in CSF, may indicate the host’s immune response to bacterial clusters initially localized in the meninges.[6] Another study further validates our findings, indicating that individuals with a Gram-negative infection exhibited notably increased NLR levels compared to those with a Gram-positive infection. Gram-negative bacteria can be differentiated from Gram-positive bacteria by the existence of endotoxin or lipopolysaccharide (LPS) in their outer membrane. Upon release, LPS engages with Toll-like receptor 4 to stimulate the nuclear factor-kappaB (NF-κB) pathway, leading to an inflammatory feedback. It is commonly understood that tumor necrosis factor-alpha (TNF-α) and IL-6 act as downstream components in the NF-κB pathway. Research conducted by Turkmen et al. established a connection between NLR and the levels of TNF-α and IL-6.[1718] However, the restriction of CSF NLR depends on the reactions elicited by the growing immune system and the exposure to various pathogens in different age groups.[1920] Patients above the age of 14 exhibited notably elevated neutrophil counts and NLRs. The CSF neutrophil count and NLR were found to be more efficient in differentiating a bacterial cause of intracranial infection in patients over 14 years old, as opposed to those aged 0–14 years.[21]

A previous investigation emphasized the importance of CSF lactate in differentiating bacterial from aseptic meningitis, indicating that measuring CSF lactate was more efficient than other commonly used biomarkers.[22] Another study states that antibiotic therapy before a lumbar puncture did not have a significant impact on the AUC of CSF lactate.[1] Another previous study also concluded that elevated CSF lactate levels primarily signify the existence of an infection and are not associated with the number of red blood cells present in CSF. As a result, measuring CSF lactate concentration is a dependable method for identifying bacterial meningitis.[2] The cause of elevated lactate levels in the CSF of people with bacterial meningitis is not fully understood. However, it has been associated with the anaerobic breakdown of glucose in the brain tissue due to decreased cerebral blood flow and oxygen consumption. Our study revealed notably elevated lactate concentrations in the CSF of individuals with bacterial infections in comparison to those afflicted by viral or aseptic infections. However, our study did not demonstrate high sensitivity and specificity as a diagnostic tool. Elevated CSF lactate can be found in several conditions other than bacterial meningitis, including viral meningitis, CNS involvement by systemic diseases, brain injury, seizures, and hypoxia, which can lead to false-positive results. The stage of the disease when the lumbar puncture is performed can affect lactate levels. If the lumbar puncture is done very early in the course of bacterial meningitis, lactate might not yet be elevated. Hence, it is not advisable to rely on CSF lactate, but to integrate it with another clinical prediction model like the Bacterial Meningitis Score.[2324]

The use of serum PCT in combination with NLR in CSF offers enhanced diagnostic utility for distinguishing bacterial from non-bacterial intracranial infections, as these two biomarkers supply complementary data. Serum PCT is a systemic biomarker that becomes elevated in response to bacterial infections. It reflects the body’s overall inflammatory response to a bacterial pathogen. In a bacterial infection, especially of severe nature, PCT levels tend to be higher compared to viral or other non-bacterial infections.[89] CSF NLR is calculated from the CSF cell count and gives an indication of the inflammatory response within CNS. An elevated NLR in CSF may point toward a stronger neutrophilic response, which is more typical in bacterial meningitis. However, lymphocytosis is more common in viral or non-bacterial infections.[1719] Using both biomarkers together provides a more comprehensive understanding of systemic and CNS-specific responses to an infection. The combined approach enhances sensitivity and specificity, as it is less probable for both biomarkers to be elevated in non-bacterial infections. This combination offers a more precise and dependable diagnostic approach, reducing the risk of false positives or negatives that can occur when relying on a single biomarker.

Streptococcus pneumoniae and Neisseria meningitidis are typically the most common causes of community-acquired bacterial meningitis. However, the finding that E. coli and Staphylococcus are major players suggests that specific factors might be at play in the population being studied. Bacterial prevalence can vary geographically, and the study’s location might have a higher prevalence of E. coli and Staphylococcus strains capable of causing meningitis. The age range and overall health of the study participants could also be influencing the results. For example, E. coli meningitis is more common in younger individuals, while Staphylococcus infections might be more prevalent in people with certain underlying medical conditions. E. coli meningitis can occur in children beyond the neonatal period and is not limited to just that age group. Previous research has demonstrated that more than a quarter of meningitis cases transpire in children older than 28 days and nearly 9% in those older than 89 days.[25] Sta. aureus meningitis commonly occurs in patients who have undergone neurosurgical procedures. However, it can also develop as a community-acquired infection in individuals without predisposing factors, indicating hematogenous spread as a potential route of infection.[26]

In low- and middle-income countries (LMICs), the diagnosis and management of meningoencephalitis can be particularly challenging due to resource constraints, including limited access to advanced laboratory facilities and rapid diagnostic tests. Serum PCT tests and CSF NLR calculations can be relatively cost-effective compared to more sophisticated testing methods, such as PCR and culture, which might not be readily available or affordable in LMICs. PCT levels and NLR can typically be obtained faster than culture results, enabling quicker decision-making for initiating treatment, which is crucial for outcomes in meningitis. These biomarkers can also be used for monitoring the progression of the disease or the response to treatment over time. For accurate and reliable identification of the etiology of meningoencephalitis, clinicians should interpret these marker values, alongside a thorough clinical evaluation and other diagnostic techniques. In LMICs with a high frequency of various etiology of meningitis, limited technical expertise, and high incidence of antibiotic resistance, the need for new markers to differentiate between different diseases is further emphasized. Furthermore, continuous study is necessary to investigate novel biomarkers for bacterial meningoencephalitis.

Limitation

Due to resource constraints, we were unable to perform serological testing or PCR analysis of the CSF samples to definitively establish the etiology of viral infections.

CONCLUSION

The findings suggest that combining serum PCT and CSF NLR could be beneficial for early diagnosis, potentially allowing timely, targeted treatment and differentiating between bacterial and non-bacterial infections, ultimately improving patient outcomes. Due to the limitation of these biomarkers, further study is necessary to investigate novel biomarkers for meningoencephalitis.

Financial support and sponsorship

Faculty of Medicine, Public Health, and Nursing of Universitas Gadjah Mada funded this research.

Conflicts of interest

There are no conflicts of interest.

Acknowledgement

We are grateful to the patients and their parents for their collaboration.
==== Refs
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