Meningitis is one of the serious clinical conditions associated with high morbidity and mortality in particularly in pediatric and immunocompromised patients [1]. Delay in diagnosis could lead to severe neurological consequences. The clinical presentation of meningitis is often complicated and confusing as the symptoms overlap and it is difficult to differentiate between bacterial, viral or fungal meningitis based on the clinical presentation alone. Differentiating the type of meningitis, bacterial, viral and tubercular is essential and a key point in management [2]. The traditional diagnostic methods used such as CSF culture, gram staining and polymerase chain reaction (PCR) are considered as reliable methods however, they have limitations which includes time required and limited accessibility in poor resource settings [3]. Therefore, there is a need to identify a cost-effective biomarker which can not only help in early diagnosis but also predict the disease severity and monitor therapeutic response. Serum Lactate dehydrogenase (LDH), a cytoplasmic enzyme released following cellular damage has garnered significant attention in recent times in the diagnosis of meningitis [4]. LDH is present in all the tissues of the body and elevated levels often indicate a cellular injury. In meningitis the disruption of blood brain barrier due to inflammatory response leads to LDH leakage into systemic circulation [5]. Few studies have explored the CSF LDH as the diagnostic tool because of its advantages such as it is less invasive and easy to measure and can correlate with systemic inflammatory burden [6, 7]. In bacterial meningitis there is intense neutrophilic infiltration and tissue necrosis as a result the LDH levels are higher compared to viral meningitis where the inflammatory response is less severe [8]. This suggest that serum LDH could serve as a rapid screening tool to distinguish between bacterial and non-bacterial meningitis particularly in settings where CSF analysis is not available of delayed. It has been shown that elevated LDH is associated with disease severity and poor outcomes in cases of meningitis. Brouwer et al. [2] have shown that CSF LDH >80 U/L was predictive of ICU admission. Ozdemir et al. [9] reported that serum LDH ≥350 IU/L correlated with septic complications in bacterial meningitis. These studies have shown that LDH has a potential to act as prognostic marker for severity of meningitis. However, the accuracy of serum LDH requires careful consideration because it may be affected by other comorbidities such as hemolysis, hepatic disease, or malignancy. This study aimed to evaluate the diagnostic and prognostic utility of serum LDH in meningitis.

This prospective study was conducted in the Department of Biochemistry, patients data was collected from the month of Aug 2023 to July 2024. Institutional Ethical approval was obtained for the study. Written consent was obtained from all the participants/ parents of the children included in the study.

Inclusion Criteria 

1. Age ≥1 year.
2. Clinical suspicion of meningitis (fever, headache, neck stiffness, altered sensorium).
3. CSF findings consistent with meningitis (pleocytosis >5 WBCs/μL).

Exclusion Criteria 

1. Traumatic lumbar puncture (RBCs >500/μL).
2. Pre-existing conditions elevating LDH (hemolysis, malignancy, hepatic disease).
3. Antibiotic pretreatment (>24 hours before CSF sampling).

Sample Size Calculation based on ROC analysis (α=0.05, power=80%), 50 patients per group (BM, VM) were required to detect an AUC difference of 0.15. 

The demographic profile of the cases was obtained including the age, sex, duration of the present illness, past history Comorbidities (immunosuppression, diabetes) and family history. Symptoms were evaluated clinically and Glasgo coma scale scores were evaluated on admission.

Classification of Meningitis: Bacterial (BM): Positive CSF culture/PCR or clinical diagnosis with CSF neutrophilia. Viral (VM): CSF lymphocytosis + PCR positivity (enterovirus/HSV). 

Laboratory Tests were performed by Semi-automated photometric systems (Erba Chem 5/7). Principle was Kinetic UV assay (NADH oxidation at 340 nm). Normal Range was from 40–280 U/L.  C-Reactive Protein (CRP) was estimated by Latex-enhanced immunoturbidimetry method. Normal range was 0.6–160 mg/L.  CSF analysis included WBC count, protein, glucose, Gram stain, culture, PCR (for HSV/enteroviruses). 

Statistical analysis

All the available results were segregated, refined and uploaded to MS Excel spreadsheet and analyzed by SPSS version 22 in Windows format. Continuous variables were represented as mean, standard deviations and percentages. LDH levels across meningitis types Kruskal-Wallis Test. Diagnostic accuracy (sensitivity, specificity, AUC via ROC curves). 

A total of n=50 cases of bacterial meningitis, n=50 cases of viral meningitis were included in the study. Table 1 shows the baseline characteristics the patients included in the study. The average age of patients in both groups is quite similar. The p-value of 0.825 indicates that there is no statistically significant difference in age between the two groups. The sex distribution is also similar between the two groups. There is a dramatic and statistically significant difference in CSF WBC count between the two groups. Bacterial meningitis patients have a much higher average WBC count in their cerebrospinal fluid compared to viral meningitis patients the p-value of 0.001 (significant). CSF protein levels are significantly higher in bacterial meningitis patients compared to viral meningitis patients the p-value of 0.012 (significant). CSF glucose levels are significantly lower in bacterial meningitis patients than in viral meningitis patients the p-value of 0.032 is statistically significant, indicating that lower glucose levels in the CSF are associated with bacterial meningitis.

Table 1: Baseline characteristics of study groups

                   * Significant

Table 2 which presents serum LDH levels in cases of meningitis and a control group. The Kruskal-Walli’s test was used to compare the groups. Patients with bacterial meningitis show significantly elevated serum LDH levels compared to the other groups. The p-value of 0.004 is less than the conventional significance level of 0.05, indicating a statistically significant difference. Patients with viral meningitis also show elevated serum LDH levels compared to the control group, although the levels are notably lower than those observed in bacterial meningitis. The p-value of 0.021 indicates a statistically significant difference from the other groups. The very small standard deviation and narrow range suggest a more homogenous LDH level within this group. The control group has the lowest serum LDH levels among the three groups. The p-value of 0.000 (or <0.001) indicates a highly statistically significant difference between the control group and the meningitis groups. Both bacterial and viral meningitis are associated with increased serum LDH levels compared to individuals without meningitis. This suggests that LDH might be a useful marker for the presence of meningitis in general. The serum LDH levels are significantly higher in bacterial meningitis compared to viral meningitis. This indicates that serum LDH could potentially be used as an adjunctive marker to help differentiate between these two types of meningitis, which is crucial for guiding treatment.

Table 2: Serum LDH levels in cases of meningitis (Kruskal-Wallis Test)

Table 3 shows the data at various serum LDH cutoff values in cases of bacterial meningitis. The cutoff ≥ 300 IU/L the sensitivity is 82.5%. The specificity of 79.8% is reasonably good. Among patients with an LDH level ≥ 300 IU/L, PPV (72.1%) actually have bacterial meningitis. NPV (51.3%) the NPV is relatively low at this cutoff. Similarly at Cutoff ≥ 350 IU/L: Sensitivity (88.2%), Specificity (82.3%), PPV (73.2%), and NPV (48.7%) LDH Cutoff ≥ 400 IU/L: Sensitivity (92.2%): The sensitivity is the highest at this cutoff (92.2%), indicating that it is good at identifying true cases of bacterial meningitis. Specificity (77.6%). PPV (74.3%) and NPV (48.2%) The NPV slightly decreases further to 48.2%, similar to the 350 IU/L cutoff. As the cutoff value for serum LDH increases, the sensitivity generally increases (better at detecting true positives), while the specificity tends to fluctuate but doesn't show a consistent upward trend across all cutoffs. Any positive result based on these cutoffs would likely require further investigation and confirmation using more definitive diagnostic methods (CSF analysis).

Table 3 Diagnostic accuracy of Serum LDH in Bacterial meningitis

Table 4: Correlation of Serum LDH with Clinical Outcomes

* Significant

A total of n=25 cases were considered as poor outcome group because of increased incidence of complications which included 21 cases of bacterial meningitis and 4 cases of viral meningitis. The other group n=75 cases were considered as good outcome based on decreased rates of complications. ICU Admission: 20 out of 25 patients in the poor outcome group required ICU admission, compared to 67 out of 75 patients in the good outcome group (p = 0.022). GCS ≤ 12 at admission: 19 patients in the poor outcome group had a Glasgow Coma Scale (GCS) score ≤ 12 at admission, compared to 6 patients in the good outcome group (p = 0.031). Neurological sequelae: 3 patients in the poor outcome group developed neurological sequelae, compared to 1 patient in the good outcome group (p = 0.320). Mortality: 3 out of 25 patients in the poor outcome group died, compared to 1 out of 75 patients in the good outcome group (p = 0.074). Table 4 indicates that higher Serum LDH levels (mean 490 IU/L in the poor outcome group) are significantly associated with a greater need for ICU admission and a more severe initial presentation (lower GCS score) in patients with meningitis (including both bacterial and viral). While there was a trend towards more neurological sequelae and higher mortality in the higher LDH group, these associations were not statistically significant in this sample. The inclusion of viral meningitis cases in the poor outcome group should be considered when interpreting these findings specifically for bacterial meningitis. Overall, the data suggests that Serum LDH levels might serve as a useful prognostic indicator in patients with meningitis.

Table 5: Proposed LDH Cutoff for clinical use

Table 5 proposes clinically relevant cutoff values for Serum LDH in the management of meningitis. An LDH level ≥ 350 IU/L is suggested as a rule-in test for bacterial etiology due to its high specificity. Using an LDH cutoff of ≥ 350 IU/L could aid clinicians in the early stages of evaluating meningitis cases. A level above this threshold would suggest a higher probability of bacterial meningitis, prompting more aggressive diagnostic and treatment approaches (e.g., early antibiotic administration). The reported specificity of 84.6% indicates a good ability to rule in bacterial etiology.  An LDH level ≥ 460 IU/L is proposed as a predictor of poor prognosis (ICU need/mortality) with a reported Relative Risk of 2.1. These proposed cutoffs offer potential tools for clinicians in differentiating meningitis types and identifying patients at higher risk for adverse outcomes, but they should be used judiciously as part of a comprehensive clinical assessment.

This study was designed to evaluate the diagnostic and prognostic utility of serum lactate dehydrogenase (LDH) as a marker for differentiating bacterial meningitis from viral meningitis. These findings of our study demonstrate that serum LDH is a valuable biomarker for bacterial meningitis. Our findings shows that differences were observed between bacterial and viral etiologies and strong association with disease severity. In this study we found that patients with bacterial meningitis exhibited significantly higher serum LDH levels (mean: 384.21 ± 60.72 IU/L) compared to viral meningitis (210.51 ± 5.8 IU/L, p = 0.004). These findings along with study of Ozdemir et al. [9] who found similar levels of LDH in bacterial meningitis. In this study at a cutoff of ≥350 IU/L, LDH showed 88.2% sensitivity and 82.3% specificity for bacterial meningitis comparable to the AUC of 0.88 in our ROC analysis. The findings of this study are in concordance with Brouwer et al. [2] who showed that LDH ≥ 300 IU/L as predictive of bacterial etiology (AUC: 0.85).  In this study the analysis of CSF parameters showed that cases of bacterial meningitis had CSF WBC counts (9950 ± 259.7 cells/µL vs. 867.38 ± 51.4 cells/µL, p = 0.001) and protein levels (259 ± 65.7 mg/dL vs. 87.6 ± 21.3 mg/dL, p = 0.012). The findings of our study were in concordance with van de Beek et al. [10] who observed similar picture in cases of bacterial and viral meningitis. The prognostic utility of serum LDH showed that patients with poor outcomes had mean Higher LDH levels (mean: 490 IU/L Higher LDH levels (mean: 490 IU/L) were associated with ICU admission (p=0.022) and lower GCS scores (p=0.031) similar findings were also reported by Kucukcongar Yavaş et al. [11] who found that LDH ≥460 IU/L to increased mortality (RR = 2.1).  The positive predictive value of this study was 85.1% at the level of ≥350 IU/L which outperforms the CRP based diagnostics (PPV: 78%) as reported by Olaciregui et al. [12] showing that LDH may be used to classify meningitis consequently reducing the use of unnecessary antibiotics. The specificity of 84.6% for bacterial meningitis at this cutoff shows that it can be used in resource limited setting where there is delay in PCR/culture reports. In this study we proposed the serum LDH levels of ≥350 IU/L for bacterial meningitis diagnosis. However, Brouwer et al. [2] in a similar study suggested that LDH of ≥300 IU/L (sensitivity: 90%). This discrepancy is like because of the differences in population in comparison to age and existing comorbidities. In a similar study Ishiguro et al. [13] emphazied that serial LDH measurements are likely to give correct values as compared to the single admission value which can still predict the outcome effectively. The overall outcome of this study shows that LDH ≥350 IU/L strongly indicates bacterial meningitis (specificity: 84.6%), warranting empiric antibiotics.  Whereas, the values of LDH <300 IU/L supports viral etiology (NPV: 80.5%), potentially avoiding overtreatment.  The values of LDH ≥460 IU/L identifies high-risk patients (ICU need: RR = 2.1), guiding intensive monitoring. 

Limitations of this study were because of single-center design may limit generalizability. Limited sample size. Confounders such as hemolysis or malignancy could elevate serum LDH independently.  Dynamic monitoring Serial LDH measurements were not assessed. 

The current study demonstrated, within the limits of the study design, that serum LDH is a reliable, easy to obtain biomarker to differentiate bacterial versus viral meningitis and predict severe outcomes. although CSF analysis is the classic and established gold standard to diagnose meningitis and its type, serum LDH levels may be adding additional valuable and possible diagnostic information, especially when CSF analysis is delayed or difficult. Our suggested cutoffs (≥350 IU/L for diagnostic purposes; ≥460 IU/L for prognostic purposes) provide clinicians, especially in resource-constrained settings, with actionable thresholds based on the relevant literature. These cutoffs should be validated in larger, multicenter cohorts in future studies.

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