Cerebrospinal Fluid Protein as a Prognostic Marker in Neonatal Meningitis: A Prospective Study from Nepal

Cerebrospinal Fluid Protein as a Prognostic Marker in Neonatal Meningitis: A Prospective Study from Nepal | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cerebrospinal Fluid Protein as a Prognostic Marker in Neonatal Meningitis: A Prospective Study from Nepal Prakriti Mishra, Depeshwara Nepal, Bulu Wagley, Prakash Sharma This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8611132/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Acute meningitis is a major contributor to neurodevelopmental morbidity and death among newborns. In a resource limited setting, where cerebrospinal fluid (CSF) culture yield is often low, early identification of neonates at risk of poor neurological outcomes is challenging. This study aimed to evaluate the prognostic utility of routinely sent CSF marker in predicting short term neurological outcome among neonates who are being treated as meningitis in such settings. Methods This prospective study included 54 neonates being treated for meningitis at a tertiary level pediatric referral center in Nepal. Neonatal meningitis was defined as either a positive CSF culture, or the presence of CSF pleocytosis (≥ 20 WBCs/µL) accompanied by elevated protein (≥ 150 mg/dL preterm; ≥100 mg/dL term) or low glucose (< 30 mg/dL). CSF protein level at diagnosis was the primary exposure. The primary outcome was poor short-term neurological status (defined by residual sequelae or death) at discharge. Statistical analysis included the Mann-Whitney U test, Fisher’s exact test for the ≥ 200 mg/dL cutoff, and logistic regression adjusted for gestational age. Results Among the 54 neonates, most neonates were term (70.4%) and males predominated (59.3%). Fever or hypothermia and refusal to suck were the most common presenting features, each observed in 55.6% of cases. Cerebrospinal fluid culture was positive in 5.6% of neonates, predominant yield being Klebsiella species. At discharge, 12 (22.2%) neonates had a poor neurological outcome. Median CSF protein was 239mg/dL (IQR 253.3) in the poor outcome group vs. 120mg/dL (IQR 44.0) in the good outcome group (p < 0.001). CSF protein ≥ 200 mg/dL had a sensitivity of 91.7% and specificity of 92.9% for predicting poor outcome. The adjusted odds ratio for poor outcome with CSF protein ≥ 200 mg/dL was 141.9 (95% CI: 13.0–1545.8). Conclusion Elevated CSF protein is a strong predictor of adverse short-term outcomes in neonates being treated as meningitis in resource limited settings. meningitis neonate outcome prognosis protein Background Acute meningitis is a devastating disease with deaths and significant long-term sequelae in survivors. 1 It remains a major cause of neonatal deaths in developing countries, with mortality rates reported as high as 40–58%. 2 In Nepal, 16.8% of neonates with late-onset sepsis have meningitis, which shows a substantial burden of meningitis among septic newborns in our part of the world. 3 Definitive diagnosis of meningitis is made through isolation of causative organism in the CSF. 4 However, in many low resource settings CSF culture yield is low due to prior antibiotics; and lack of access to advanced diagnostic tests hinder isolation of causative agent. 5 , 6 This necessitates the use of other CSF parameters like WBC count, sugar and protein to diagnose the condition. 7 , 8 CSF protein is known to reflect inflammation and thus regarded as a biologically plausible prognostic factor in meningitis. 9 , 10 But its specific prognostic utility is not well-established in our regional context. Therefore, this prospective study aimed to evaluate the association between CSF protein levels at diagnosis and short-term neurological outcomes at discharge in neonates being treated as meningitis at a tertiary care center in Nepal. Methods Study Design and Setting A single-center, prospective observational study was conducted in the Neonatal Intensive Care Unit (NICU) and Neonatal Intermediate Care Unit (NIMCU) of Kanti Children’s Hospital (KCH), a national-level tertiary care referral center from November 2022 to August 2023. Ethical Approval and Consent to Participate Ethical approval was granted by the Institutional Review Board (IRB) of NAMS (Reference number: 50312079180). Written informed consent was obtained from a parent or legal guardian of each participant prior to enrolment. Study Participants Neonates with clinical suspicion of sepsis or meningitis who underwent lumbar puncture and met the predefined diagnostic criteria for neonatal meningitis were eligible for inclusion. Participants were recruited consecutively from both NICU and NIMCU. The exclusion criteria were: perinatal asphyxia (HIE Grade II or III), major congenital anomalies, chromosomal abnormalities, inborn errors of metabolism, extreme preterm ( < 28 weeks), extreme low birth weight (< 1000g), or refusal of parental consent. Study Definitions Neonatal Meningitis: In our clinical setting, a practical challenge exists. Many neonates suspected of meningitis have already received antibiotic treatment before a diagnostic lumbar puncture is performed. This pretreatment significantly reduces the chance of obtaining a positive CSF culture. Additionally, we lack access to advanced laboratory equipment that can rapidly differentiate between bacterial and other types of meningitis, such as viral. Given these constraints, clinicians must make urgent treatment decisions based on the best available evidence. Therefore, for this study, we defined a case of neonatal meningitis using a composite set of criteria, aiming to capture both confirmed and highly probable cases. A neonate was considered to have meningitis if they met any one of the following conditions: Culture-proven meningitis: A positive bacterial culture from the CSF. CSF pleocytosis with supporting biochemical evidence: CSF white blood cell count of ≥ 20 cells/µL, accompanied by at least one of the following: an elevated CSF protein level (≥ 150 mg/dL for preterm neonates; ≥100 mg/dL for term neonates) or low CSF glucose level (< 30 mg/dL). This definition is both pragmatic and aligned with established clinical reasoning. First, it adopts the CSF pleocytosis threshold (≥ 20 cells/µL) recommended by the UK's National Institute for Health and Care Excellence (NICE) guidelines for initiating treatment in suspected neonatal meningitis. 11 Second, it incorporates well-recognized biochemical markers of bacterial meningitis i.e elevated protein and low glucose, to increase diagnostic specificity when culture results are negative or unavailable. Good outcome: Neonates who have completely recovered and have normal physical examination by the day of discharge. Poor outcome: Neonates with residual spasticity, muscle weakness, immobility in one or more limbs, hydrocephalus, seizure disorder, or any other complications and death as a result of neonatal meningitis. Sample Size Calculation Given the relatively low incidence of neonatal meningitis and the single-center design of this preliminary study, a formal sample size calculation for diagnostic accuracy was not performed. The study used a feasibility design enrolling all consecutive neonates meeting the inclusion criteria over an eight-month study period (November 2022 to August 2023). This resulted in a final cohort of 54 neonates. Data Collection and Procedures Following informed consent, detailed clinical history was obtained and examination conducted. Relevant investigations including complete blood count, random blood sugar, renal function tests, c-reactive protein, blood and urine cultures, chest X-ray, and CSF analysis were performed according to hospital protocol. Lumbar puncture (LP) was performed under aseptic conditions. CSF samples were sent for Gram stain, culture, cell count, glucose, and protein estimation. CSF glucose was measured using the glucose oxidase/peroxidase method, and protein was measured using reagents in a semi-automated Stat Fax 3300 analyzer. Neonates were monitored daily until discharge or death. Data was recorded in a structured proforma. Outcome Measures At discharge, neurological and general status was reassessed to categorize outcomes as Good or Poor. Neonates who demonstrated complete clinical recovery with normal physical and neurological examination findings at the time of discharge were categorized as having a good outcome. Neonates presenting with residual neurological sequelae such as spasticity, muscle weakness, limb immobility, hydrocephalus, seizure disorder, or death as a result of neonatal meningitis were classified as having a poor outcome. Statistical Analysis Data were entered in MS Excel version 10. Proper data cleaning was done. All the data was password protected with access only to investigator. Patient identity was kept confidential. Data analysis was done using IBM SPSS version 23. Categorical variables are presented as frequencies and percentages. Continuous variables are presented as median and interquartile range (IQR). The primary outcome was poor neurological status at discharge. The Mann-Whitney U test was used to compare CSF protein levels between outcome groups. For evaluating the prognostic utility of CSF protein, a pre-specified, rounded threshold of 200 mg/dL was chosen for primary analysis. This value facilitates memorization and application at the bedside. The association between the pre-specified CSF protein cutoff (≥ 200 mg/dL) and poor outcome was assessed using Fisher’s Exact Test. The diagnostic accuracy (sensitivity, specificity, predictive values) of this cutoff was calculated. To adjust for the potential confounding effect of gestational age, a binary logistic regression model was fitted with poor outcome as the dependent variable and CSF protein category (≥ 200 mg/dL vs. <200 mg/dL) and gestational age category (preterm vs. term) as independent variables, yielding an adjusted odds ratio (aOR) with 95% confidence interval (CI). Statistical significance was set at a two-tailed p-value < 0.05. Trial Registration This was an observational study and was not registered as a clinical trial. Results During the study period, 384 cases of neonatal sepsis were admitted in NICU and NIMCU. Of them, 54 (14%) were diagnosed as case of neonatal meningitis. Majority of the population were term neonates, giving a term-to-preterm ratio of 2.3:1. There were 32 (59.26%) males with male-to-female ratio of 1.4:1. The baseline demographic, clinical, and laboratory characteristics of the cohort are summarized in Table 1 . Table 1 Baseline Characteristics of the Study Cohort (N = 54) Variable Values N (%) Demographic Characteristics Gender Male Female 32(59.26) 22(40.74) Gestational age Term Preterm 38(70.37) 16(29.63) Clinical Features at Presentation Fever/ Hypothermia 30(55.6) Refusal to suck 30(55.6) Poor Cry 19(35.2) Respiratory Distress 17(31.5) Seizures 17(31.5) Lethargy 14(25.9) Irritability 14(25.9) Vomiting 13(24.1) Hypotonia 8(14.8) High-Pitched Cry 7(13.0) Vacant Stare 5(9.3) Bulging anterior fontanelle 4(7.4) Stupor 4(7.4) Tachypnea 4(7.4) Poor perfusion 3(5.6) Cerebrospinal fluid culture was positive in 3 (5.56%) neonates, of which Klebsiella species were isolated in 2 (3.70%) cases while methicillin-resistant Staphylococcus aureus was isolated in 1 (1.85%) case. At discharge, 12 (22.22%) cases had a poor clinical outcome (Table 2 ). Table 2 Distribution of Study Population by Clinical Outcome Outcome Values N (%) Good Outcome 42(77.8) Poor Outcome Seizure disorder Hypertonia Hypotonia 12(22.2) 7(58.33) 4(33.33) 1(8.33) Total 54 The median CSF protein level was significantly higher in neonates with a poor outcome (239.0 mg/dL, IQR 253.3) compared to those with a good outcome (120.0 mg/dL, IQR 44.0) (Mann-Whitney U = 45.5, p < 0.001) (Table 3 ) Table 3 Comparison of CSF Protein Levels by Neurological Outcome at Discharge Outcome Group N Median CSF Protein (IQR), mg/dL Good Outcome 42 120.0 (44.0) Poor Outcome 12 239.0 (253.3) *Mann-Whitney U = 45.5, p < 0.001* Using the pre-specified cutoff of ≥ 200 mg/dL, elevated CSF protein showed a strong association with poor outcome (Fisher’s exact test, p < 0.001) (Table 4 ) Table 4 Association Between CSF Protein ≥ 200 mg/dL and Poor Neurological Outcome CSF Protein Good Outcome (n = 42) Poor Outcome (n = 12) Total < 200 mg/dL 39 1 40 ≥ 200 mg/dL 3 11 14 *P-value (Fisher’s Exact Test) < 0.001* In a logistic regression model adjusted for gestational age, CSF protein ≥ 200 mg/dL remained a strong, independent predictor of poor outcome (adjusted odds ratio [aOR] = 141.86, 95% CI: 13.02 to 1545.77, p < 0.001) (Table 5 ) Table 5 Logistic Regression Analysis of Predictors for Poor Neurological Outcome Predictor aOR (Adjusted Odds Ratio) 95% Confidence Interval p-value CSF Protein ≥ 200 mg/dL (vs. <200 mg/dL) 141.86 13.0–1545.8 < 0.001 Gestational Age (Preterm vs. Term) 1.05 0.11–9.99 0.967 *Model adjusted for gestational age. Reference categories: CSF Protein < 200 mg/dL; Term gestation.* CSF protein ≥ 200 mg/dL had a sensitivity of 91.7% and specificity of 92.9% for predicting poor outcome. (Table 6 ) Table 6 Diagnostic Accuracy of CSF Protein ≥ 200 mg/dL for Predicting Poor Outcome Metric Value (95% Confidence Interval)* Sensitivity 91.7% (61.5% – 99.8%) Specificity 92.9% (80.5% – 98.5%) Positive Predictive Value (PPV) 78.6% (49.2% – 95.3%) Negative Predictive Value (NPV) 97.5% (86.8% – 99.9%) Accuracy 92.6% (82.1% – 97.9%) Confidence intervals calculated using the Wilson score method. Discussion This prospective study evaluated the utility of cerebrospinal fluid protein, a routinely available investigation, in predicting short-term neurological outcomes among neonates treated for meningitis in a resource-limited setting. Higher CSF protein levels clearly distinguished infants with poor outcomes from those who recovered well. Furthermore, a cutoff value of 200 mg/dL showed high sensitivity and specificity in identifying neonates at increased risk of adverse neurological outcomes. These findings are biologically possible. Cerebrospinal fluid protein reflects the intensity of neuroinflammation and disruption of the blood–brain barrier. 12 Higher CSF protein levels indicate more severe meningeal inflammation and neuronal injury, which reasonably explains their association with an increased risk of residual neurological deficits. 13 The prognostic threshold of CSF protein ≥ 200 mg/dL observed in our cohort supports the established role of this biomarker in neonatal meningitis. Previous systematic reviews have identified elevated CSF protein as a Level I evidence predictor of adverse outcomes. 9 , 14 In our study, the strong association (adjusted odds ratio > 140) is consistent with this high-level evidence, though the exact value is influenced by the modest sample size. Mechanistically, higher CSF protein likely reflects a more intense inflammatory response, which has been linked to neurological complications in previous studies. 15 , 16 A notable feature of the present study was the low CSF culture positivity rate (5.6%), which aligns with other studies conducted in similar resource-limited settings. Multiple factors likely contribute to this, including early empirical antibiotic use before lumbar puncture, low organism load, and technical limitations of conventional culture methods. The pathogens isolated i.e. Klebsiella pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) are consistent with global data indicating the predominance of gram-negative and resistant gram-positive organisms in neonatal intensive care units. 17 , 18 The low rate of microbiological confirmation underscores the need to rely on CSF biochemical markers such as protein, glucose and cell count for both diagnosis and prognostication in neonatal meningitis. In our cohort, 22.2% of neonates experienced poor outcomes which included neurological sequelae such as seizures, hypertonia and hypotonia. These complications are in line with those described in several other regional and international studies. 19 , 20 Interestingly, no deaths occurred in this study population in contrast to the higher mortality rates reported elsewhere. This discrepancy may be attributed to improved neonatal care practices, timely administration of empirical antibiotics, exclusive breastfeeding, and enhanced NICU monitoring at our tertiary care center. This study has several important strengths. The prospective design allowed for standardized data collection and reduced the risk of recall bias. Inclusion of a pragmatic, treatment-based clinical cohort improves the applicability of the findings to routine practice, particularly in comparable resource-limited settings. In addition, the use of non-parametric statistical methods was appropriate for the data distribution. Adjustment for gestational age, which is a key clinical confounder, further enhances the robustness of the observed associations. However, several limitations must be acknowledged. The main limitation of this study is uncertainty regarding the underlying etiology of meningitis in our cohort. Although the case definition reflects the realities of urgent clinical decision-making, microbiological confirmation was achieved in only 5.6% of cases. As a result, the cohort likely included a heterogeneous mix of bacterial, viral, and other causes of meningeal inflammation. Accordingly, our findings should be interpreted as reflecting the prognostic value of CSF protein in clinically diagnosed meningitis, rather than in microbiologically confirmed bacterial disease alone. Second, neurological outcome was assessed at the time of hospital discharge, which represents a short-term endpoint. While this approach is appropriate for identifying early morbidity, it does not capture neurodevelopmental impairments that may emerge later in infancy or childhood. Thus, the findings reflect early neurological risk rather than long-term developmental prognosis. Finally, the sample size was modest and drawn from a single center, limiting the precision of the estimates and potentially affecting how well the 200 mg/dL CSF protein cutoff applies to other populations or clinical settings. Despite these limitations, the findings have clear practical relevance. In settings where advanced microbiological or neuroimaging facilities are limited, CSF protein remains an inexpensive and widely available test. A CSF protein level of ≥ 200 mg/dL should prompt clinicians to recognize a higher risk of poor early neurological outcomes. This information can support closer clinical monitoring, guide clear and realistic counseling of families, and allow earlier planning for rehabilitation and follow-up services. Conclusion The results from this study should be considered as hypothesis-generating rather than definitive. They highlight the need for larger, multicenter studies that use advanced diagnostics to better identify the causes of meningitis. Long-term, standardized follow-up into childhood would help capture delayed neurodevelopmental outcomes. Such studies could refine the prognostic thresholds for CSF protein and potentially allow the development of models that combine protein levels with other clinical markers to improve risk prediction. This study provides preliminary evidence that CSF protein level at the time of diagnosis is a strong and independent predictor of short-term neurological outcomes in neonates being treated as meningitis in low resource settings. As a simple and widely available test, it offers a practical way to identify infants at higher risk. This information can help clinicians working in such settings prioritize care, guide family counseling, and plan early interventions to improve outcomes. Abbreviations aOR Adjusted Odd’s Ratio CI Confidence Interval CSF Cerebrospinal Fluid HIE Hypoxic Ischemic Encephalopathy IRB Institutional Review Board IQR Inter Quartile Range KCH Kanti Children’s Hospital LP Lumbar Puncture NAMS National Academy of Medical Sciences NICU Neonatal Intensive Care Unit NIMCU Neonatal Intermediate Care Unit WBC White Blood Cell Declarations Ethics approval and consent to participate The study was approved by the Institutional Review Committee of National Academy of Medical Sciences (Reference number: 50312079180). Written informed consent was obtained from the parents or legal guardians of all participants. Consent for publication Not applicable as this study doesn’t include any identifiable data of the patient’s involved in the study. Competing interests The authors declare that they have no financial or non-financial competing interests. Artificial Intelligence (AI) statement Any AI-assisted technologies were not used while preparing the manuscript. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author Contribution All authors meet the ICMJE criteria for authorship and have approved the final manuscript. PM conceived the study. PM and DN participated in its design and coordination. PM, BW and PS collected the data. All authors have their contribution in interpretation of data. PM and DN performed the statistical analysis. PN drafted the initial manuscript. DN, BW and PS revised the manuscript and contributed in its final preparation. All authors have approved the final manuscript for submission. All the authors agree to be accountable for all aspects of the work and to ensure that questions related to accuracy of the work are appropriately investigated and resolved. Acknowledgements The authors would like to thank Department of Pediatrics of KCH, Kathmandu for their support during the study and wish to thank the patients and their families for their participation in this study. Data Availability The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. References Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. The Lancet [Internet]. 2012 June [cited 2022 Mar 15];379(9832):2151–61. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0140673612605601 Furyk JS, Swann O, Molyneux E. Systematic review: neonatal meningitis in the developing world. Trop Med Int Health. 2011 June;16(6):672–9. Das AK, Mishra D, Jha NK, Mishra R, Jha S. Role of Lumbar Puncture in Late Onset Neonatal Sepsis. J Nepal Paedtr Soc [Internet]. 2019 Dec 31 [cited 2026 Jan 14];39(3):155–61. Available from: https://www.nepjol.info/index.php/JNPS/article/view/28459 Bundy LM, Noor A. Neonatal Meningitis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 [cited 2022 Mar 15]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK532264/ Gordon SM, Srinivasan L, Harris MC. Neonatal Meningitis: Overcoming Challenges in Diagnosis, Prognosis, and Treatment with Omics. Front Pediatr. 2017;5:139. Nga Nguyen TQ, Nguyen TV, Tran MD, Skinner A, Narchi H. Cerebrospinal Fluid Polymerase Chain Reaction in the Diagnosis of Neonatal Bacterial Meningitis: A Single-Center Experience From Vietnam. Indian Pediatr. 2022;59(12):943–5. Rajesh NT, Dutta S, Prasad R, Narang A. Effect of delay in analysis on neonatal cerebrospinal fluid parameters. Arch Dis Child Fetal Neonatal Ed. 2010;95(1):F25–29. Garges HP, Moody MA, Cotten CM, Smith PB, Tiffany KF, Lenfestey R, et al. Neonatal meningitis: what is the correlation among cerebrospinal fluid cultures, blood cultures, and cerebrospinal fluid parameters? Pediatrics. 2006;117(4):1094–100. Mao DH, Miao JK, Zou X, Chen N, Yu LC, Lai X et al. Risk Factors in Predicting Prognosis of Neonatal Bacterial Meningitis—A Systematic Review. Front Neurol [Internet]. 2018 Nov 20 [cited 2023 Aug 26];9:929. Available from: https://www.frontiersin.org/article/ 10.3389/fneur.2018.00929/full Pelkonen T, Urtti S, Cardoso O, Kyaw MH, Roine I, Peltola H. Risk factors for death in suspected severe bacterial infection in infants aged < 90 days in Luanda, Angola. International Journal of Infectious Diseases [Internet]. 2021 May [cited 2023 Sept 14];106:223–7. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1201971221002885 Meningitis. (bacterial) and meningococcal septicaemia in under 16s: recognition, diagnosis and management. 2015;42. Barichello T, Fagundes GD, Generoso JS, Elias SG, Simões LR, Teixeira AL. Pathophysiology of neonatal acute bacterial meningitis. Journal of Medical Microbiology [Internet]. 2013 Dec 1 [cited 2023 Aug 30];62(12):1781–9. Available from: https://www.microbiologyresearch.org/content/journal/jmm/ 10.1099/jmm.0.059840-0 Tan J, Kan J, Qiu G, Zhao D, Ren F, Luo Z et al. Clinical Prognosis in Neonatal Bacterial Meningitis: The Role of Cerebrospinal Fluid Protein. Murthy AK, editor. PLoS ONE [Internet]. 2015 Oct 28 [cited 2022 Mar 19];10(10):e0141620. Available from: https://dx.plos.org/10.1371/journal.pone.0141620 Liu Y, Feng Y, Guo Y, Chen J, Liu C, Liang J. Clinical predictors of poor outcome of bacterial meningitis in infants less than 90 days: a systematic review. Front Pediatr [Internet]. 2024 Sept 19 [cited 2026 Jan 15];12:1414778. Available from: https://www.frontiersin.org/articles/ 10.3389/fped.2024.1414778/full Liu MD, Xu FL, Duan WL, Liu JX, Li XN, Liu YX, et al. [Risk factors for poor prognosis of neonatal bacterial meningitis]. Zhongguo Dang Dai Er Ke Za Zhi. 2019;21(11):1064–8. Huo L, Fan Y, Jiang C, Gao J, Yin M, Wang H et al. Clinical Features of and Risk Factors for Hydrocephalus in Childhood Bacterial Meningitis. J Child Neurol [Internet]. 2019 Jan [cited 2023 Aug 26];34(1):11–6. Available from: http://journals.sagepub.com/doi/ 10.1177/0883073818799155 Hallmaier-Wacker LK, Andrews A, Nsonwu O, Demirjian A, Hope RJ, Lamagni T, et al. Incidence and aetiology of infant Gram-negative bacteraemia and meningitis: systematic review and meta-analysis. Arch Dis Child. 2022;107(11):988–94. Ou-Yang MC, Tsai MH, Chu SM, Chen CC, Yang PH, Huang HR et al. The Clinical Characteristics, Microbiology and Risk Factors for Adverse Outcomes in Neonates with Gram-Negative Bacillary Meningitis. Antibiotics [Internet]. 2023 June 30 [cited 2026 Jan 14];12(7):1131. Available from: https://www.mdpi.com/2079-6382/12/7/1131 Hsu MH, Hsu JF, Kuo HC, Lai MY, Chiang MC, Lin YJ et al. Neurological Complications in Young Infants With Acute Bacterial Meningitis. Front Neurol [Internet]. 2018 Oct 24 [cited 2026 Jan 14];9:903. Available from: https://www.frontiersin.org/article/ 10.3389/fneur.2018.00903/full Haffner DN, Machie M, Hone E, Said RR, Maitre NL. Predictors of Neurodevelopmental Impairment After Neonatal Bacterial Meningitis. J Child Neurol. 2021;36(11):968–73. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8611132","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":586882983,"identity":"4ceea10a-75b1-46ff-94aa-e7b4d6e31d89","order_by":0,"name":"Prakriti Mishra","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYHACZgYGAwYe++ONjQ+APB4+IrUY8DCcOXzYAKSFjTgtQGsYbqSlSYC4BLWYSx9+bFxR8EeGcUaOWeXXHDsZNgbmh49u4NFi2ZdmnHgG6DBmnjdmt2W3JQMdxmZsnINHi8EZBuODDUAtbOw5ZrcltzEDtfCwSePXwv4ZrIWHIcesWHJbPTFaeIwTQVokONLSGD9uO0xYi2UPT7Fhg4ExjwHP4cPSjNuO87AxE/CLOQ/7ZsmGP3L2BuyNjR9/bqu252dvfvgYr8OQOcw8YBKPcgwtjD8IqB4Fo2AUjIKRCQAYxj8pUruocQAAAABJRU5ErkJggg==","orcid":"","institution":"Kanti Children’s Hospital","correspondingAuthor":true,"prefix":"","firstName":"Prakriti","middleName":"","lastName":"Mishra","suffix":""},{"id":586882984,"identity":"ac243457-ea8f-4e34-ae84-af90ae2029d0","order_by":1,"name":"Depeshwara Nepal","email":"","orcid":"","institution":"National Academy of Medical Sciences (NAMS)","correspondingAuthor":false,"prefix":"","firstName":"Depeshwara","middleName":"","lastName":"Nepal","suffix":""},{"id":586882985,"identity":"e0225afd-f46e-4abd-abcb-e64399bb2356","order_by":2,"name":"Bulu Wagley","email":"","orcid":"","institution":"National Academy of Medical Sciences (NAMS)","correspondingAuthor":false,"prefix":"","firstName":"Bulu","middleName":"","lastName":"Wagley","suffix":""},{"id":586882986,"identity":"2617bb00-04b0-4936-87eb-4f7bc9deecbc","order_by":3,"name":"Prakash Sharma","email":"","orcid":"","institution":"Province Hospital","correspondingAuthor":false,"prefix":"","firstName":"Prakash","middleName":"","lastName":"Sharma","suffix":""}],"badges":[],"createdAt":"2026-01-15 13:53:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8611132/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8611132/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102745440,"identity":"64b1ef01-334e-4e9b-94ed-8b966867b6f0","added_by":"auto","created_at":"2026-02-16 08:50:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":685430,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8611132/v1/53005448-2c36-4ba0-bb3b-28a503eca2f7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cerebrospinal Fluid Protein as a Prognostic Marker in Neonatal Meningitis: A Prospective Study from Nepal","fulltext":[{"header":"Background","content":"\u003cp\u003eAcute meningitis is a devastating disease with deaths and significant long-term sequelae in survivors.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e It remains a major cause of neonatal deaths in developing countries, with mortality rates reported as high as 40\u0026ndash;58%.\u003csup\u003e2\u003c/sup\u003e In Nepal, 16.8% of neonates with late-onset sepsis have meningitis, which shows a substantial burden of meningitis among septic newborns in our part of the world.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDefinitive diagnosis of meningitis is made through isolation of causative organism in the CSF.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e However, in many low resource settings CSF culture yield is low due to prior antibiotics; and lack of access to advanced diagnostic tests hinder isolation of causative agent.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e This necessitates the use of other CSF parameters like WBC count, sugar and protein to diagnose the condition.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCSF protein is known to reflect inflammation and thus regarded as a biologically plausible prognostic factor in meningitis.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e But its specific prognostic utility is not well-established in our regional context. Therefore, this prospective study aimed to evaluate the association between CSF protein levels at diagnosis and short-term neurological outcomes at discharge in neonates being treated as meningitis at a tertiary care center in Nepal.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Setting\u003c/h2\u003e \u003cp\u003eA single-center, prospective observational study was conducted in the Neonatal Intensive Care Unit (NICU) and Neonatal Intermediate Care Unit (NIMCU) of Kanti Children\u0026rsquo;s Hospital (KCH), a national-level tertiary care referral center from November 2022 to August 2023.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthical Approval and Consent to Participate\u003c/strong\u003e \u003cp\u003eEthical approval was granted by the Institutional Review Board (IRB) of NAMS (Reference number: 50312079180). Written informed consent was obtained from a parent or legal guardian of each participant prior to enrolment.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Participants\u003c/h3\u003e\n\u003cp\u003eNeonates with clinical suspicion of sepsis or meningitis who underwent lumbar puncture and met the predefined diagnostic criteria for neonatal meningitis were eligible for inclusion. Participants were recruited consecutively from both NICU and NIMCU.\u003c/p\u003e \u003cp\u003eThe exclusion criteria were: perinatal asphyxia (HIE Grade II or III), major congenital anomalies, chromosomal abnormalities, inborn errors of metabolism, extreme preterm (\u003cb\u003e\u0026lt;\u003c/b\u003e\u0026thinsp;28 weeks), extreme low birth weight (\u0026lt;\u0026thinsp;1000g), or refusal of parental consent.\u003c/p\u003e\n\u003ch3\u003eStudy Definitions\u003c/h3\u003e\n\u003cp\u003eNeonatal Meningitis: In our clinical setting, a practical challenge exists. Many neonates suspected of meningitis have already received antibiotic treatment before a diagnostic lumbar puncture is performed. This pretreatment significantly reduces the chance of obtaining a positive CSF culture. Additionally, we lack access to advanced laboratory equipment that can rapidly differentiate between bacterial and other types of meningitis, such as viral. Given these constraints, clinicians must make urgent treatment decisions based on the best available evidence. Therefore, for this study, we defined a case of neonatal meningitis using a composite set of criteria, aiming to capture both confirmed and highly probable cases. A neonate was considered to have meningitis if they met any one of the following conditions:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCulture-proven meningitis: A positive bacterial culture from the CSF.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCSF pleocytosis with supporting biochemical evidence: CSF white blood cell count of \u0026ge;\u0026thinsp;20 cells/\u0026micro;L, accompanied by at least one of the following: an elevated CSF protein level (\u0026ge;\u0026thinsp;150 mg/dL for preterm neonates; \u0026ge;100 mg/dL for term neonates) or low CSF glucose level (\u0026lt;\u0026thinsp;30 mg/dL).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eThis definition is both pragmatic and aligned with established clinical reasoning. First, it adopts the CSF pleocytosis threshold (\u0026ge;\u0026thinsp;20 cells/\u0026micro;L) recommended by the UK's National Institute for Health and Care Excellence (NICE) guidelines for initiating treatment in suspected neonatal meningitis.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Second, it incorporates well-recognized biochemical markers of bacterial meningitis i.e elevated protein and low glucose, to increase diagnostic specificity when culture results are negative or unavailable.\u003c/p\u003e \u003cp\u003eGood outcome: Neonates who have completely recovered and have normal physical examination by the day of discharge.\u003c/p\u003e \u003cp\u003ePoor outcome: Neonates with residual spasticity, muscle weakness, immobility in one or more limbs, hydrocephalus, seizure disorder, or any other complications and death as a result of neonatal meningitis.\u003c/p\u003e\n\u003ch3\u003eSample Size Calculation\u003c/h3\u003e\n\u003cp\u003eGiven the relatively low incidence of neonatal meningitis and the single-center design of this preliminary study, a formal sample size calculation for diagnostic accuracy was not performed. The study used a feasibility design enrolling all consecutive neonates meeting the inclusion criteria over an eight-month study period (November 2022 to August 2023). This resulted in a final cohort of 54 neonates.\u003c/p\u003e\n\u003ch3\u003eData Collection and Procedures\u003c/h3\u003e\n\u003cp\u003e Following informed consent, detailed clinical history was obtained and examination conducted. Relevant investigations including complete blood count, random blood sugar, renal function tests, c-reactive protein, blood and urine cultures, chest X-ray, and CSF analysis were performed according to hospital protocol. Lumbar puncture (LP) was performed under aseptic conditions. CSF samples were sent for Gram stain, culture, cell count, glucose, and protein estimation. CSF glucose was measured using the glucose oxidase/peroxidase method, and protein was measured using reagents in a semi-automated Stat Fax 3300 analyzer. Neonates were monitored daily until discharge or death. Data was recorded in a structured proforma.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOutcome Measures\u003c/h2\u003e \u003cp\u003eAt discharge, neurological and general status was reassessed to categorize outcomes as Good or Poor. Neonates who demonstrated complete clinical recovery with normal physical and neurological examination findings at the time of discharge were categorized as having a good outcome. Neonates presenting with residual neurological sequelae such as spasticity, muscle weakness, limb immobility, hydrocephalus, seizure disorder, or death as a result of neonatal meningitis were classified as having a poor outcome.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData were entered in MS Excel version 10. Proper data cleaning was done. All the data was password protected with access only to investigator. Patient identity was kept confidential. Data analysis was done using IBM SPSS version 23. Categorical variables are presented as frequencies and percentages. Continuous variables are presented as median and interquartile range (IQR). The primary outcome was poor neurological status at discharge. The Mann-Whitney U test was used to compare CSF protein levels between outcome groups. For evaluating the prognostic utility of CSF protein, a pre-specified, rounded threshold of 200 mg/dL was chosen for primary analysis. This value facilitates memorization and application at the bedside. The association between the pre-specified CSF protein cutoff (\u0026ge;\u0026thinsp;200 mg/dL) and poor outcome was assessed using Fisher\u0026rsquo;s Exact Test. The diagnostic accuracy (sensitivity, specificity, predictive values) of this cutoff was calculated. To adjust for the potential confounding effect of gestational age, a binary logistic regression model was fitted with poor outcome as the dependent variable and CSF protein category (\u0026ge;\u0026thinsp;200 mg/dL vs. \u0026lt;200 mg/dL) and gestational age category (preterm vs. term) as independent variables, yielding an adjusted odds ratio (aOR) with 95% confidence interval (CI). Statistical significance was set at a two-tailed p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTrial Registration\u003c/h3\u003e\n\u003cp\u003eThis was an observational study and was not registered as a clinical trial.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eDuring the study period, 384 cases of neonatal sepsis were admitted in NICU and NIMCU. Of them, 54 (14%) were diagnosed as case of neonatal meningitis. Majority of the population were term neonates, giving a term-to-preterm ratio of 2.3:1. There were 32 (59.26%) males with male-to-female ratio of 1.4:1. The baseline demographic, clinical, and laboratory characteristics of the cohort are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics of the Study Cohort (N\u0026thinsp;=\u0026thinsp;54)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValues N (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographic Characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003cp\u003eMale\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32(59.26)\u003c/p\u003e \u003cp\u003e22(40.74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age\u003c/p\u003e \u003cp\u003eTerm\u003c/p\u003e \u003cp\u003ePreterm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38(70.37)\u003c/p\u003e \u003cp\u003e16(29.63)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical Features at Presentation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever/ Hypothermia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30(55.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRefusal to suck\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30(55.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoor Cry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19(35.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory Distress\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17(31.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeizures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17(31.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLethargy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14(25.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIrritability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14(25.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13(24.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypotonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(14.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-Pitched Cry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7(13.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVacant Stare\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5(9.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBulging anterior fontanelle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(7.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStupor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(7.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTachypnea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(7.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoor perfusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3(5.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCerebrospinal fluid culture was positive in 3 (5.56%) neonates, of which Klebsiella species were isolated in 2 (3.70%) cases while methicillin-resistant Staphylococcus aureus was isolated in 1 (1.85%) case. At discharge, 12 (22.22%) cases had a poor clinical outcome (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of Study Population by Clinical Outcome\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValues N (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGood Outcome\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42(77.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePoor Outcome\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSeizure disorder\u003c/p\u003e \u003cp\u003eHypertonia\u003c/p\u003e \u003cp\u003eHypotonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12(22.2)\u003c/p\u003e \u003cp\u003e7(58.33)\u003c/p\u003e \u003cp\u003e4(33.33)\u003c/p\u003e \u003cp\u003e1(8.33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe median CSF protein level was significantly higher in neonates with a poor outcome (239.0 mg/dL, IQR 253.3) compared to those with a good outcome (120.0 mg/dL, IQR 44.0) (Mann-Whitney U\u0026thinsp;=\u0026thinsp;45.5, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of CSF Protein Levels by Neurological Outcome at Discharge\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome Group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian CSF Protein (IQR), mg/dL\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGood Outcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e120.0 (44.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoor Outcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e239.0 (253.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e*Mann-Whitney U\u0026thinsp;=\u0026thinsp;45.5, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001*\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eUsing the pre-specified cutoff of \u0026ge;\u0026thinsp;200 mg/dL, elevated CSF protein showed a strong association with poor outcome (Fisher\u0026rsquo;s exact test, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAssociation Between CSF Protein\u0026thinsp;\u0026ge;\u0026thinsp;200 mg/dL and Poor Neurological Outcome\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSF Protein\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGood Outcome (n\u0026thinsp;=\u0026thinsp;42)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePoor Outcome (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;200 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;200 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e*P-value (Fisher\u0026rsquo;s Exact Test)\u0026thinsp;\u0026lt;\u0026thinsp;0.001*\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eIn a logistic regression model adjusted for gestational age, CSF protein\u0026thinsp;\u0026ge;\u0026thinsp;200 mg/dL remained a strong, independent predictor of poor outcome (adjusted odds ratio [aOR]\u0026thinsp;=\u0026thinsp;141.86, 95% CI: 13.02 to 1545.77, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLogistic Regression Analysis of Predictors for Poor Neurological Outcome\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePredictor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eaOR (Adjusted Odds Ratio)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e95% Confidence Interval\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSF Protein\u0026thinsp;\u0026ge;\u0026thinsp;200 mg/dL\u0026nbsp;(vs. \u0026lt;200 mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e141.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e13.0\u0026ndash;1545.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational Age\u0026nbsp;(Preterm vs. Term)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.11\u0026ndash;9.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.967\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e*Model adjusted for gestational age. Reference categories: CSF Protein\u0026thinsp;\u0026lt;\u0026thinsp;200 mg/dL; Term gestation.*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCSF protein\u0026thinsp;\u0026ge;\u0026thinsp;200 mg/dL had a sensitivity of 91.7% and specificity of 92.9% for predicting poor outcome. (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDiagnostic Accuracy of CSF Protein\u0026thinsp;\u0026ge;\u0026thinsp;200 mg/dL for Predicting Poor Outcome\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetric\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue (95% Confidence Interval)*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSensitivity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91.7% (61.5% \u0026ndash; 99.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpecificity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92.9% (80.5% \u0026ndash; 98.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive Predictive Value (PPV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78.6% (49.2% \u0026ndash; 95.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative Predictive Value (NPV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97.5% (86.8% \u0026ndash; 99.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccuracy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92.6% (82.1% \u0026ndash; 97.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eConfidence intervals calculated using the Wilson score method.\u003c/em\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis prospective study evaluated the utility of cerebrospinal fluid protein, a routinely available investigation, in predicting short-term neurological outcomes among neonates treated for meningitis in a resource-limited setting. Higher CSF protein levels clearly distinguished infants with poor outcomes from those who recovered well. Furthermore, a cutoff value of 200 mg/dL showed high sensitivity and specificity in identifying neonates at increased risk of adverse neurological outcomes.\u003c/p\u003e \u003cp\u003eThese findings are biologically possible. Cerebrospinal fluid protein reflects the intensity of neuroinflammation and disruption of the blood\u0026ndash;brain barrier.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Higher CSF protein levels indicate more severe meningeal inflammation and neuronal injury, which reasonably explains their association with an increased risk of residual neurological deficits.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe prognostic threshold of CSF protein\u0026thinsp;\u0026ge;\u0026thinsp;200 mg/dL observed in our cohort supports the established role of this biomarker in neonatal meningitis. Previous systematic reviews have identified elevated CSF protein as a Level I evidence predictor of adverse outcomes.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e In our study, the strong association (adjusted odds ratio\u0026thinsp;\u0026gt;\u0026thinsp;140) is consistent with this high-level evidence, though the exact value is influenced by the modest sample size. Mechanistically, higher CSF protein likely reflects a more intense inflammatory response, which has been linked to neurological complications in previous studies.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eA notable feature of the present study was the low CSF culture positivity rate (5.6%), which aligns with other studies conducted in similar resource-limited settings. Multiple factors likely contribute to this, including early empirical antibiotic use before lumbar puncture, low organism load, and technical limitations of conventional culture methods. The pathogens isolated i.e. Klebsiella pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) are consistent with global data indicating the predominance of gram-negative and resistant gram-positive organisms in neonatal intensive care units.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e The low rate of microbiological confirmation underscores the need to rely on CSF biochemical markers such as protein, glucose and cell count for both diagnosis and prognostication in neonatal meningitis.\u003c/p\u003e \u003cp\u003eIn our cohort, 22.2% of neonates experienced poor outcomes which included neurological sequelae such as seizures, hypertonia and hypotonia. These complications are in line with those described in several other regional and international studies.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Interestingly, no deaths occurred in this study population in contrast to the higher mortality rates reported elsewhere. This discrepancy may be attributed to improved neonatal care practices, timely administration of empirical antibiotics, exclusive breastfeeding, and enhanced NICU monitoring at our tertiary care center.\u003c/p\u003e \u003cp\u003eThis study has several important strengths. The prospective design allowed for standardized data collection and reduced the risk of recall bias. Inclusion of a pragmatic, treatment-based clinical cohort improves the applicability of the findings to routine practice, particularly in comparable resource-limited settings. In addition, the use of non-parametric statistical methods was appropriate for the data distribution. Adjustment for gestational age, which is a key clinical confounder, further enhances the robustness of the observed associations.\u003c/p\u003e \u003cp\u003eHowever, several limitations must be acknowledged. The main limitation of this study is uncertainty regarding the underlying etiology of meningitis in our cohort. Although the case definition reflects the realities of urgent clinical decision-making, microbiological confirmation was achieved in only 5.6% of cases. As a result, the cohort likely included a heterogeneous mix of bacterial, viral, and other causes of meningeal inflammation. Accordingly, our findings should be interpreted as reflecting the prognostic value of CSF protein in clinically diagnosed meningitis, rather than in microbiologically confirmed bacterial disease alone. Second, neurological outcome was assessed at the time of hospital discharge, which represents a short-term endpoint. While this approach is appropriate for identifying early morbidity, it does not capture neurodevelopmental impairments that may emerge later in infancy or childhood. Thus, the findings reflect early neurological risk rather than long-term developmental prognosis. Finally, the sample size was modest and drawn from a single center, limiting the precision of the estimates and potentially affecting how well the 200 mg/dL CSF protein cutoff applies to other populations or clinical settings.\u003c/p\u003e \u003cp\u003eDespite these limitations, the findings have clear practical relevance. In settings where advanced microbiological or neuroimaging facilities are limited, CSF protein remains an inexpensive and widely available test. A CSF protein level of \u0026ge;\u0026thinsp;200 mg/dL should prompt clinicians to recognize a higher risk of poor early neurological outcomes. This information can support closer clinical monitoring, guide clear and realistic counseling of families, and allow earlier planning for rehabilitation and follow-up services.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe results from this study should be considered as hypothesis-generating rather than definitive. They highlight the need for larger, multicenter studies that use advanced diagnostics to better identify the causes of meningitis. Long-term, standardized follow-up into childhood would help capture delayed neurodevelopmental outcomes. Such studies could refine the prognostic thresholds for CSF protein and potentially allow the development of models that combine protein levels with other clinical markers to improve risk prediction.\u003c/p\u003e \u003cp\u003eThis study provides preliminary evidence that CSF protein level at the time of diagnosis is a strong and independent predictor of short-term neurological outcomes in neonates being treated as meningitis in low resource settings. As a simple and widely available test, it offers a practical way to identify infants at higher risk. This information can help clinicians working in such settings prioritize care, guide family counseling, and plan early interventions to improve outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eaOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAdjusted Odd\u0026rsquo;s Ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence Interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCSF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebrospinal Fluid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHIE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHypoxic Ischemic Encephalopathy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIRB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInstitutional Review Board\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInter Quartile Range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eKCH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eKanti Children\u0026rsquo;s Hospital\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLumbar Puncture\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNAMS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNational Academy of Medical Sciences\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNICU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNeonatal Intensive Care Unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNIMCU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNeonatal Intermediate Care Unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWBC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWhite Blood Cell\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003e The study was approved by the Institutional Review Committee of National Academy of Medical Sciences (Reference number: 50312079180). Written informed consent was obtained from the parents or legal guardians of all participants.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable as this study doesn\u0026rsquo;t include any identifiable data of the patient\u0026rsquo;s involved in the study.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no financial or non-financial competing interests.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eArtificial Intelligence (AI) statement\u003c/h2\u003e \u003cp\u003eAny AI-assisted technologies were not used while preparing the manuscript.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors meet the ICMJE criteria for authorship and have approved the final manuscript. PM conceived the study. PM and DN participated in its design and coordination. PM, BW and PS collected the data. All authors have their contribution in interpretation of data. PM and DN performed the statistical analysis. PN drafted the initial manuscript. DN, BW and PS revised the manuscript and contributed in its final preparation. All authors have approved the final manuscript for submission. All the authors agree to be accountable for all aspects of the work and to ensure that questions related to accuracy of the work are appropriately investigated and resolved.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe authors would like to thank Department of Pediatrics of KCH, Kathmandu for their support during the study and wish to thank the patients and their families for their participation in this study.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLiu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. The Lancet [Internet]. 2012 June [cited 2022 Mar 15];379(9832):2151\u0026ndash;61. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://linkinghub.elsevier.com/retrieve/pii/S0140673612605601\u003c/span\u003e\u003cspan address=\"https://linkinghub.elsevier.com/retrieve/pii/S0140673612605601\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuryk JS, Swann O, Molyneux E. Systematic review: neonatal meningitis in the developing world. Trop Med Int Health. 2011 June;16(6):672\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDas AK, Mishra D, Jha NK, Mishra R, Jha S. Role of Lumbar Puncture in Late Onset Neonatal Sepsis. J Nepal Paedtr Soc [Internet]. 2019 Dec 31 [cited 2026 Jan 14];39(3):155\u0026ndash;61. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nepjol.info/index.php/JNPS/article/view/28459\u003c/span\u003e\u003cspan address=\"https://www.nepjol.info/index.php/JNPS/article/view/28459\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBundy LM, Noor A. Neonatal Meningitis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 [cited 2022 Mar 15]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/books/NBK532264/\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.nih.gov/books/NBK532264/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGordon SM, Srinivasan L, Harris MC. Neonatal Meningitis: Overcoming Challenges in Diagnosis, Prognosis, and Treatment with Omics. Front Pediatr. 2017;5:139.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNga Nguyen TQ, Nguyen TV, Tran MD, Skinner A, Narchi H. Cerebrospinal Fluid Polymerase Chain Reaction in the Diagnosis of Neonatal Bacterial Meningitis: A Single-Center Experience From Vietnam. Indian Pediatr. 2022;59(12):943\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRajesh NT, Dutta S, Prasad R, Narang A. Effect of delay in analysis on neonatal cerebrospinal fluid parameters. Arch Dis Child Fetal Neonatal Ed. 2010;95(1):F25\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarges HP, Moody MA, Cotten CM, Smith PB, Tiffany KF, Lenfestey R, et al. Neonatal meningitis: what is the correlation among cerebrospinal fluid cultures, blood cultures, and cerebrospinal fluid parameters? Pediatrics. 2006;117(4):1094\u0026ndash;100.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMao DH, Miao JK, Zou X, Chen N, Yu LC, Lai X et al. Risk Factors in Predicting Prognosis of Neonatal Bacterial Meningitis\u0026mdash;A Systematic Review. Front Neurol [Internet]. 2018 Nov 20 [cited 2023 Aug 26];9:929. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.frontiersin.org/article/\u003c/span\u003e\u003cspan address=\"https://www.frontiersin.org/article/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fneur.2018.00929/full\u003c/span\u003e\u003cspan address=\"10.3389/fneur.2018.00929/full\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePelkonen T, Urtti S, Cardoso O, Kyaw MH, Roine I, Peltola H. Risk factors for death in suspected severe bacterial infection in infants aged\u0026thinsp;\u0026lt;\u0026thinsp;90 days in Luanda, Angola. International Journal of Infectious Diseases [Internet]. 2021 May [cited 2023 Sept 14];106:223\u0026ndash;7. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://linkinghub.elsevier.com/retrieve/pii/S1201971221002885\u003c/span\u003e\u003cspan address=\"https://linkinghub.elsevier.com/retrieve/pii/S1201971221002885\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeningitis. (bacterial) and meningococcal septicaemia in under 16s: recognition, diagnosis and management. 2015;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarichello T, Fagundes GD, Generoso JS, Elias SG, Sim\u0026otilde;es LR, Teixeira AL. Pathophysiology of neonatal acute bacterial meningitis. Journal of Medical Microbiology [Internet]. 2013 Dec 1 [cited 2023 Aug 30];62(12):1781\u0026ndash;9. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.microbiologyresearch.org/content/journal/jmm/\u003c/span\u003e\u003cspan address=\"https://www.microbiologyresearch.org/content/journal/jmm/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1099/jmm.0.059840-0\u003c/span\u003e\u003cspan address=\"10.1099/jmm.0.059840-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan J, Kan J, Qiu G, Zhao D, Ren F, Luo Z et al. Clinical Prognosis in Neonatal Bacterial Meningitis: The Role of Cerebrospinal Fluid Protein. Murthy AK, editor. PLoS ONE [Internet]. 2015 Oct 28 [cited 2022 Mar 19];10(10):e0141620. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://dx.plos.org/10.1371/journal.pone.0141620\u003c/span\u003e\u003cspan address=\"https://dx.plos.10.1371/journal.pone.0141620\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Feng Y, Guo Y, Chen J, Liu C, Liang J. Clinical predictors of poor outcome of bacterial meningitis in infants less than 90 days: a systematic review. Front Pediatr [Internet]. 2024 Sept 19 [cited 2026 Jan 15];12:1414778. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.frontiersin.org/articles/\u003c/span\u003e\u003cspan address=\"https://www.frontiersin.org/articles/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fped.2024.1414778/full\u003c/span\u003e\u003cspan address=\"10.3389/fped.2024.1414778/full\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu MD, Xu FL, Duan WL, Liu JX, Li XN, Liu YX, et al. [Risk factors for poor prognosis of neonatal bacterial meningitis]. Zhongguo Dang Dai Er Ke Za Zhi. 2019;21(11):1064\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuo L, Fan Y, Jiang C, Gao J, Yin M, Wang H et al. Clinical Features of and Risk Factors for Hydrocephalus in Childhood Bacterial Meningitis. J Child Neurol [Internet]. 2019 Jan [cited 2023 Aug 26];34(1):11\u0026ndash;6. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://journals.sagepub.com/doi/\u003c/span\u003e\u003cspan address=\"http://journals.sagepub.com/doi/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/0883073818799155\u003c/span\u003e\u003cspan address=\"10.1177/0883073818799155\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHallmaier-Wacker LK, Andrews A, Nsonwu O, Demirjian A, Hope RJ, Lamagni T, et al. Incidence and aetiology of infant Gram-negative bacteraemia and meningitis: systematic review and meta-analysis. Arch Dis Child. 2022;107(11):988\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOu-Yang MC, Tsai MH, Chu SM, Chen CC, Yang PH, Huang HR et al. The Clinical Characteristics, Microbiology and Risk Factors for Adverse Outcomes in Neonates with Gram-Negative Bacillary Meningitis. Antibiotics [Internet]. 2023 June 30 [cited 2026 Jan 14];12(7):1131. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.mdpi.com/2079-6382/12/7/1131\u003c/span\u003e\u003cspan address=\"https://www.mdpi.com/2079-6382/12/7/1131\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsu MH, Hsu JF, Kuo HC, Lai MY, Chiang MC, Lin YJ et al. Neurological Complications in Young Infants With Acute Bacterial Meningitis. Front Neurol [Internet]. 2018 Oct 24 [cited 2026 Jan 14];9:903. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.frontiersin.org/article/\u003c/span\u003e\u003cspan address=\"https://www.frontiersin.org/article/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fneur.2018.00903/full\u003c/span\u003e\u003cspan address=\"10.3389/fneur.2018.00903/full\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaffner DN, Machie M, Hone E, Said RR, Maitre NL. Predictors of Neurodevelopmental Impairment After Neonatal Bacterial Meningitis. J Child Neurol. 2021;36(11):968\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"meningitis, neonate, outcome, prognosis, protein","lastPublishedDoi":"10.21203/rs.3.rs-8611132/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8611132/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAcute meningitis is a major contributor to neurodevelopmental morbidity and death among newborns. In a resource limited setting, where cerebrospinal fluid (CSF) culture yield is often low, early identification of neonates at risk of poor neurological outcomes is challenging. This study aimed to evaluate the prognostic utility of routinely sent CSF marker in predicting short term neurological outcome among neonates who are being treated as meningitis in such settings.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis prospective study included 54 neonates being treated for meningitis at a tertiary level pediatric referral center in Nepal. Neonatal meningitis was defined as either a positive CSF culture, or the presence of CSF pleocytosis (\u0026ge;\u0026thinsp;20 WBCs/\u0026micro;L) accompanied by elevated protein (\u0026ge;\u0026thinsp;150 mg/dL preterm; \u0026ge;100 mg/dL term) or low glucose (\u0026lt;\u0026thinsp;30 mg/dL). CSF protein level at diagnosis was the primary exposure. The primary outcome was poor short-term neurological status (defined by residual sequelae or death) at discharge. Statistical analysis included the Mann-Whitney U test, Fisher\u0026rsquo;s exact test for the \u0026ge;\u0026thinsp;200 mg/dL cutoff, and logistic regression adjusted for gestational age.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong the 54 neonates, most neonates were term (70.4%) and males predominated (59.3%). Fever or hypothermia and refusal to suck were the most common presenting features, each observed in 55.6% of cases. Cerebrospinal fluid culture was positive in 5.6% of neonates, predominant yield being \u003cem\u003eKlebsiella\u003c/em\u003e species. At discharge, 12 (22.2%) neonates had a poor neurological outcome. Median CSF protein was 239mg/dL (IQR 253.3) in the poor outcome group vs. 120mg/dL (IQR 44.0) in the good outcome group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). CSF protein\u0026thinsp;\u0026ge;\u0026thinsp;200 mg/dL had a sensitivity of 91.7% and specificity of 92.9% for predicting poor outcome. The adjusted odds ratio for poor outcome with CSF protein\u0026thinsp;\u0026ge;\u0026thinsp;200 mg/dL was 141.9 (95% CI: 13.0\u0026ndash;1545.8).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eElevated CSF protein is a strong predictor of adverse short-term outcomes in neonates being treated as meningitis in resource limited settings.\u003c/p\u003e","manuscriptTitle":"Cerebrospinal Fluid Protein as a Prognostic Marker in Neonatal Meningitis: A Prospective Study from Nepal","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-11 12:33:05","doi":"10.21203/rs.3.rs-8611132/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-02-20T09:10:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5256053271468033803216745000399002757","date":"2026-02-20T06:29:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-19T20:56:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"17424691199916280216620147433637460559","date":"2026-02-13T18:38:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-06T10:00:42+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-19T12:52:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-19T03:46:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-19T03:46:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2026-01-15T13:40:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"383e093b-c5c2-47e7-968f-3cc742cc067c","owner":[],"postedDate":"February 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-11T12:33:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-11 12:33:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8611132","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8611132","identity":"rs-8611132","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}