Can Clinical Presentations or Hematological Indices Predict Meningitis in Febrile Children?

The aim of this study is to assess the role of clinical presentations and hematological indices in the diagnosis of meningitis in febrile children during a meningitis outbreak. A cross-sectional study, recruiting (236) febrile children underwent lumbar puncture for suspected meningitis. Participants were divided into two groups based on the results of cerebrospinal fluid (CSF) analysis: the case group included all those who carried a diagnosis of meningitis while the rest of the patients whose CSF analysis result was negative for meningitis was taken as a control group. The clinical characteristics, hematological indices were compared between both groups. Children with proved meningitis were significantly of older age and resides more in rural areas than control P value= (0.001), (0.014) respectively. The Neutrophil to lymphocyte ratio and platelet counts were the only significant hematological indices that elevated in children with meningitis P value= (0.001), (0.018) respectively. Headache and neck stiffness were documented more in children with meningitis P value = (<0.001) whilst seizure was significantly less common in children with meningitis P value = (<0.001). During a meningitis outbreak, pediatrician in low resource country can use a constellation of clinical and hematological characteristics to identify febrile children who in need of lumbar puncture to exclude meningitis.


INTRODUCTION
Meningitis is an infectious disease prevalent globally and is of major public health concern [1,2].In Arabic countries, outbreaks of meningitis frequently occurred in areas of the African meningitis belt.However, the Mediterranean region including Iraq still tackles an outbreak of meningitis every few years among several infectious diseases [3].In May 2023, Iraq encountered a meningitis outbreak, which started in the north of Iraq mainly in Sulaymaniyah City then rapidly cases were reported in increasing numbers from all over the country [4].The diagnosis of meningitis in Iraq faces several obstacles with a shortage of diagnostic kits at health care facilities [5].Physicians including pediatricians started to depend mainly on cerebrospinal fluid (CSF) analysis for the diagnosis of meningitis.Adding to this problem is that obtaining CSF analysis by lumbar puncture in children is dependent on parental approval with high refusal rates documented in Iraq [6]; this together with the lack of confirmation of cases of meningitis has led to underreporting of the cases in Iraq [5].Meningitis is prevalent in the pediatric age group and undiagnosed cases or delays in the diagnosis can lead to a high mortality rate [7][8][9].This all calls for a need to find a constellation of clinical presentations and hematological indices to serve as a diagnostic tool or at least for screening febrile children during meningitis outbreaks for early case identification and management.Our study aims to assess the role of clinical presentations, hematological indices, and routine CSF analysis in the diagnosis of meningitis in febrile children during a meningitis outbreak in Iraq an example of low low-resource country to reach a cost-effective diagnostic approach based on routine diagnostic labs.

Study design and sampling
This is a cross-sectional study, recruiting all children who underwent lumbar puncture for suspected meningitis admitted to the emergency department of Central Child Teaching Hospital, Baghdad -Iraq during the period from the 1 st of July to 31 st of November 2023.Inclusion criteria: 1.Previously healthy children who underwent lumbar puncture at the emergency department, 2. age above 1 month, 3. family gave informed consent for participation in the study.Exclusion criteria: children with underlying chronic illness or on medications that suppress immunity like steroids or immunosuppressants and those who refused to participate in the study.In addition, neonates were excluded as per hospital policy neonates are exclusively admitted to the neonatal ward and not to the emergency department.All patients in this study were examined by a pediatric neurologist and requested to have a lumbar puncture done to exclude meningitis.Glucose and protein concentrations and leukocyte count were analyzed for each CSF specimen.Meningitis is diagnosed when CSF shows leukocytes higher than 5 per microliter of CSF irrespective of CSF protein and glucose level [10].Gram stain and bacterial culture were performed by standard methods for all CSF specimens in Central Child Teaching Hospital.In addition to CSF analysis, all patients in this study had complete blood counts.Demographical and clinical characteristics were taken from patient's files at the emergency department.Participants in this study were divided into two groups based on the results of CSF analysis: the case group included all those who carried a diagnosis of meningitis while the rest of the patients whose CSF analysis result was negative for meningitis was taken as a control group.The CSF cultures for all patients were negative and PCR was not unavailable, so meningitis was diagnosed based on CSF analysis and clinical judgment [11].The ethical committee in the College of Medicine approved the study (12/2024).

Statistical analysis
Statistical analyses were performed by using SPSS software version 25.0 (SPSS, Chicago).Normality of the continuous data was tested by Shapiro Wilk test, A Student t-test was used to assess data having a normal distribution, which were given as mean and standard deviation.Non-normally distributed data were examined using the Mann-Whitney U test and provided as median and rang.The Chi-square/Fischer exact test was used to assess categorical variables, which were expressed as numbers and percentages.Any result that was deemed statistically significant had a p-value of less than 0.05.

DISCUSSION
This study showed that during the 2023 meningitis outbreak in Iraq, from febrile children who admitted to the hospital with presumptive diagnosis of meningitis, children with proved meningitis tend to be of older age and resides in rural areas.The Neutrophil to lymphocyte ratio and platelet counts were the only significant hematological indices that elevated in children with meningitis.Headache and neck stiffness were documented more in children with meningitis while seizure was surprisingly significantly less common in children with meningitis.These constellations of clinical and hematological characteristics can help pediatrician to identify febrile children who in need of lumbar puncture to exclude meningitis.The mean age of patients diagnosed with meningitis in this study was 7 years that was in line with results documented from reports in the regions from north of Iraq during the same outbreak [4] and goes with published data from meningitis outbreaks in other parts of the world, which detected a mean age of 7 years [12][13][14].While in outbreaks from other regions like Ghana, children of age range 10-14 was mostly affected in meningitis outbreak [15] .The mean age of febrile patients with proved meningitis was higher than those with negative CSF analysis.This indicates that from febrile patients in whom CSF analysis was requested based on clinical presentation, meningitis tend to affect older age patients this could be attributed to the fact that signs of meningitis in young patients is not specific which results in over requesting lumbar puncture in young age children [16][17][18].There is a robust evidence link residence in rural areas with development of meningitis during an outbreak [19][20][21] and this was evident in this study as children diagnosed with meningitis in this study during meningitis outbreak were significantly resides in rural area (P value=0.014).On the other hand, gender and the duration of the fever was not significantly related to development of meningitis Pvalue = (0.519), (0.089) respectively and this match previous published data [14,22,23] .There is an interestingly high percentage of patients in the current study received a prior antibiotic.Although patients with meningitis significantly received a prior antibiotic less than control (P value =0.004), however 70.49% of children who diagnosed as meningitis were already received a prior antibiotic.This percentage is the highest one documented till now as previous studies in children in other parts of the world showed that 11-27% of children with meningitis had pretreatment with antibiotics [24,25] .This misuse of antibiotics was previously documented in Iraq by Salim et al [26] reporting a high prevalence of antibiotic misuse among Iraqi people ranging from (45%-92%) with the highest percentage reported in pediatric population.The signs and symptom of meningitis in children is nonspecific as many cases initially carry other diagnoses [16,17,27] .In this study during 2023 meningitis outbreak in Iraq children with meningitis showed a significantly high presence of headache and neck stiffness than control.The most striking finding is lower reported seizures from children with meningitis than control.This clinical presentation match data from outbreak of meningitis in Germany [14] and Poland [28].So, the presence of headache and/or neck stiffness in febrile children during outbreak of meningitis can be regarded as an indicator of meningitis that would be useful as a screening tool in practice.Although seizure in febrile children carry fourfold increase the possibility of meningitis, however this applied only in children outside of febrile-seizure age range and mainly depend on the type of seizure as being complex seizure rather than simple seizure [17].In this study, the hematological indices were significantly different between children with meningitis and control group.Children with meningitis had significantly lower total WBC and absolute neutrophil and lymphocyte counts and this match results of previous studies as leukocytosis are nonspecific sign of inflammation (29,30).On the other hand, a significantly higher neutrophil to lymphocytes ratio and platelet count seen in children with meningitis with P value = (0.001), (0.018) respectively.The NLR and platelet count are cost-effective and readily available clinical markers of peripheral inflammation so it can be used to aid in selecting children who require lumbar puncture for CSF analysis when suspecting meningitis.The patients in the current study had diagnosed as meningitis based on CSF analysis in which the CSF showed leukocytosis >5 cells/HPF.All patients had received 7 days of antibiotics because of lack of resources to differentiate bacterial from viral meningitis.However, the CSF analysis goes with bacterial meningitis with elevated neutrophil and low CSF glucose.Although this study had multiple limitations like being single center study and lack of identification of the causative agent of meningitis however it carries a hope of opening avenues for future research.

CONCLUSION
During a meningitis outbreak, pediatrician in low resource country can use a constellation of clinical and hematological characteristics to identify febrile children who in need of lumbar puncture to exclude meningitis.

Figure 1 .
Figure 1.The study flow chart showing how patients enrolled, excluded, and divided into case and control groups.

Table 1 . Demographic characteristics of the study populations
Two symptoms (headache and neck stiffness) were more common in patients (62.3% and 49.18%, respectively) than in controls (17.54% and 5.25%, respectively) with significant differences.On the other hand, each of vomiting, seizure, and poor feeding were less common among patients (68.85%, 18.03%, and 26.23%, respectively) than controls (78.72%,59.65% and 56.14%, respectively) with significant differences.Most children in controls group (91.23%) had received prior antibiotics therapy compared with (70.49%) of patients with a highly significant difference (Table2).

Table 3 . Hematologic indices in patients and controls
PLT: platelets, N/L ratio: neutrophil to lymphocyte ratio.