Abstract
Objectives
Given the difficulty in the differential diagnosis of acute bacterial meningitis (BM) and viral meningitis (VM), we aimed to compare the ability of cerebrospinal fluid (CSF) biomarkers, such as lactate, glucose, lactate dehydrogenase (LDH), C-reactive protein (CRP), total white blood cell count, and predominance of neutrophils, as single tests to differentiate microbiologically defined acute BM and VM.
Methods
CSF samples were divided into three groups: BM (n=17), VM (n=14) (both with the etiological agent identified), and normal control groups (n=26).
Results
All the biomarkers studied were significantly higher in the BM group than in the VM or control groups (p>0.05). CSF lactate showed the best diagnostic clinical performance characteristics: sensitivity (94.12%), specificity (100%), positive and negative predictive value (100 and 97.56%, respectively), positive and negative likelihood ratio (38.59 and 0.06, respectively), accuracy (98.25%), and AUC (0.97). CSF CRP is excellent for screening BM and VM, as its best feature is its specificity (100%). CSF LDH is not recommended for screening or case-finding. LDH levels were higher in Gram-negative diplococcus than in Gram-positive diplococcus. Other biomarkers were not different between Gram-positive and negative bacteria. The highest level of agreement between the CSF biomarkers was between CSF lactate and CRP [kappa coefficient, 0.91 (0.79; 1.00)].
Conclusions
All markers showed significant differences between the studied groups and were increased in acute BM. CSF lactate is better than the other biomarkers studied for screening acute BM due to its high specificity.
Funding source: no funding
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Research funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. Sérgio Monteiro de Almeida: data collection and analysis, article preparation, writing, and revision. Juliane Rosa Castoldi and Salomão Cury Riechi: data collection and article revision.
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Competing interests statement: Authors state no conflict of interest.
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Informed consent: Not applicable.
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Ethical approval: This study was approved by the Institutional Research Review Board of the Hospital de Clínicas, Universidade Federal do Paraná (HC-UFPR), Brazil (CAAE n 40364714.7.0000.0096).
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Data availability: Prof. Sergio Monteiro de Almeida declares that he has full access to all of the data, which is available after Institutional Review Board approval.
References
1. Nauclér, P, Huttner, A, van Werkhoven, CH, Singer, M, Tattevin, P, Einav, S, et al.. Impact of time to antibiotic therapy on clinical outcome in patients with bacterial infections in the emergency department: implications for antimicrobial stewardship. Clin Microbiol Infect 2021;27:175–81. https://doi.org/10.1016/j.cmi.2020.02.032.Search in Google Scholar PubMed
2. de Almeida, SM, Faria, FL, de Goes Fontes, K, Buczenko, GM, Berto, DB, Raboni, SM, et al.. Quantitation of cerebrospinal fluid lactic acid in infectious and non-infectious neurological diseases. Clin Chem Lab Med 2009;47:755–61. https://doi.org/10.1515/cclm.2009.160.Search in Google Scholar
3. de Almeida, SM, Furlan, SMP, Cretella, AMM, Lapinski, B, Nogueira, K, Cogo, LL, et al.. Comparison of cerebrospinal fluid biomarkers for differential diagnosis of acute bacterial and viral meningitis with atypical cerebrospinal fluid characteristics. Med Princ Pract 2020;29:244–54. https://doi.org/10.1159/000501925.Search in Google Scholar PubMed PubMed Central
4. Goodlet, KJ, Tan, E, Knutson, L, Nailor, MD. Impact of the Film Array meningitis/encephalitis panel on antimicrobial duration among patients with suspected central nervous system infection. Diagn Microbiol Infect Dis 2021;100:115394. https://doi.org/10.1016/j.diagmicrobio.2021.115394.Search in Google Scholar PubMed
5. McGill, F, Heyderman, RS, Panagiotou, S, Tunkel, AR, Solomon, T. Acute bacterial meningitis in adults. Lancet 2016;388:3036–47. https://doi.org/10.1016/s0140-6736(16)30654-7.Search in Google Scholar
6. Sulaiman, T, Salazar, L, Hasbun, R. Acute versus subacute community-acquired meningitis: analysis of 611 patients. Medicine 2017;96:e7984. https://doi.org/10.1097/md.0000000000007984.Search in Google Scholar PubMed PubMed Central
7. Fellner, A, Goldstein, L, Lotan, I, Keret, O, Steiner, I. Meningitis without meningeal irritation signs: what are the alerting clinical markers? J Neurol Sci 2020;410:116663. https://doi.org/10.1016/j.jns.2019.116663.Search in Google Scholar PubMed
8. Kyriazopoulou, E, Giamarellos-Bourboulis, EJ. Antimicrobial stewardship using biomarkers: accumulating evidence for the critically ill. Antibiotics 2022;11:367. https://doi.org/10.3390/antibiotics11030367.Search in Google Scholar PubMed PubMed Central
9. Vidal, LR, Almeida, SM, Messias-Reason, IJ, Nogueira, MB, Debur, Mdo C, Pessa, LF, et al.. Enterovirus and herpesviridae family as etiologic agents of lymphomonocytary meningitis, Southern Brazil. Arq Neuropsiquiatr 2011;69:475–81. https://doi.org/10.1590/s0004-282x2011000400013.Search in Google Scholar PubMed
10. de Almeida, SM, Barros, N, Fernandes Dos Santos, A, Custodio, G, Petterle, RR, Nogueira, K, et al.. Clinical performance of amperometry compared with enzymatic ultra violet method for lactate quantification in cerebrospinal fluid. Diagnosis 2020;8:510–4. https://doi.org/10.1515/dx-2020-0065.Search in Google Scholar PubMed
11. Deisenhammer, F, Bartos, A, Egg, R, Gilhus, NE, Giovannoni, G, Rauer, S, et al.. Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force. Eur J Neurol 2006;13:913–22. https://doi.org/10.1111/j.1468-1331.2006.01493.x.Search in Google Scholar PubMed
12. Sim, J, Wright, CC. The kappa statistic in reliability studies: use, interpretation, and sample size requirements. Phys Ther 2005;85:257–68. https://doi.org/10.1093/ptj/85.3.257.Search in Google Scholar
13. Mitchell, AJ. The clinical significance of subjective memory complaints in the diagnosis of mild cognitive impairment and dementia: a meta-analysis. Int J Geriatr Psychiatry 2008;23:1191–202. https://doi.org/10.1002/gps.2053.Search in Google Scholar PubMed
14. Mitchell, AJ. Sensitivity × PPV is a recognized test called the clinical utility index (CUI+). Eur J Epidemiol 2011;26:251–2. https://doi.org/10.1007/s10654-011-9561-x.Search in Google Scholar PubMed
15. Galen, RS, Gambino, SR. Beyond normality-the predictive value and efficiency of medical diagnosis. New York, NY: Wiley; 1975.Search in Google Scholar
16. Akobeng, AK. Understanding diagnostic tests 2: likelihood ratios, pre- and post-test probabilities and their use in clinical practice. Acta Paediatr 2007;96:487–91. https://doi.org/10.1111/j.1651-2227.2006.00179.x.Search in Google Scholar PubMed
17. Glas, AS, Lijmer, JG, Prins, MH, Bonsel, GJ, Bossuyt, PMM. The diagnostic odds ratio: a single indicator of test performance. J Clin Epidemiol 2003;56:1129–35. https://doi.org/10.1016/s0895-4356(03)00177-x.Search in Google Scholar PubMed
18. McGee, S. Simplifying likelihood ratios. J Gen Intern Med 2002;17:647–50. https://doi.org/10.1046/j.1525-1497.2002.10750.x.Search in Google Scholar PubMed PubMed Central
19. Matthews, BW. Comparison of the predicted and observed secondary structure of T4 phage lysozyme. Biochim Biophys Acta 1975;405:442–51. https://doi.org/10.1016/0005-2795(75)90109-9.Search in Google Scholar PubMed
20. Fagan, TJ. Letter: nomogram for Bayes theorem. N Engl J Med 1975;293:257. https://doi.org/10.1056/NEJM197507312930513.Search in Google Scholar PubMed
21. Sackett, DL, Haynes, RB. Evidence base of clinical diagnosis: the architecture of diagnostic research. Br Med J 2002;324:539–41. https://doi.org/10.1136/bmj.324.7336.539.Search in Google Scholar PubMed PubMed Central
22. Akobeng, AK. Understanding diagnostic tests 3: receiver operating characteristic curves. Acta Paediatr 2007;96:644–7. https://doi.org/10.1111/j.1651-2227.2006.00178.x.Search in Google Scholar PubMed
23. Kleine, TO, Zwerenz, P, Zöfel, P, Shiratori, K. New and old diagnostic markers of meningitis in cerebrospinal fluid (CSF). Brain Res Bull 2003;61:287–97. https://doi.org/10.1016/s0361-9230(03)00092-3.Search in Google Scholar PubMed
24. Fishman, RA. Cerebrospinal fluid in diseases of the nervous system, 2nd ed. Philadelphia: Saunders; 1992:384 p.Search in Google Scholar
25. Huy, NT, Thao, NT, Diep, DT, Kikuchi, M, Zamora, J, Hirayama, K. Cerebrospinal fluid lactate concentration to distinguish bacterial from aseptic meningitis: a systemic review and meta-analysis. Crit Care 2010;14:R240. https://doi.org/10.1186/cc9395.Search in Google Scholar PubMed PubMed Central
26. Briem, H. Comparison between cerebrospinal fluid concentrations of glucose, total protein, chloride, lactate, and total amino acids for the differential diagnosis of patients with meningitis. Scand J Infect Dis 1983;15:277–84. https://doi.org/10.3109/inf.1983.15.issue-3.08.Search in Google Scholar PubMed
27. Leib, SL, Boscacci, R, Gratzl, O, Zimmerli, W. Predictive value of cerebrospinal fluid (CSF) lactate level versus CSF/blood glucose ratio for the diagnosis of bacterial meningitis following neurosurgery. Clin Infect Dis 1999;29:69–74. https://doi.org/10.1086/520184.Search in Google Scholar PubMed
28. Wong, GK, Poon, WS, Ip, M. Use of ventricular cerebrospinal fluid lactate measurement to diagnose cerebrospinal fluid infection in patients with intraventricular haemorrhage. J Clin Neurosci 2008;15:654–5. https://doi.org/10.1016/j.jocn.2007.03.011.Search in Google Scholar PubMed
29. Tunkel, AR, Hartman, BJ, Kaplan, SL, Kaufman, BA, Roos, KL, Scheld, WM, et al.. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39:1267–84. https://doi.org/10.1086/425368.Search in Google Scholar PubMed
30. Sakushima, K, Hayashino, Y, Kawaguchi, T, Jackson, JL, Fukuhara, S. Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial meningitis from aseptic meningitis: a meta-analysis. J Infect 2011;62:255–62. https://doi.org/10.1016/j.jinf.2011.02.010.Search in Google Scholar PubMed
31. Chicco, D, Jurman, G. The advantages of the Matthews Correlation Coefficient (MCC) over F1 score and accuracy in binary classification evaluation. BMC Genom 2020;21:6. https://doi.org/10.1186/s12864-019-6413-7.Search in Google Scholar PubMed PubMed Central
32. Lindquist, L, Linné, T, Hansson, LO, Kalin, M, Axelsson, G. Value of cerebrospinal fluid analysis in the differential diagnosis of meningitis: a study in 710 patients with suspected central nervous system infection. Eur J Clin Microbiol Infect Dis 1988;7:374–80. https://doi.org/10.1007/bf01962340.Search in Google Scholar
33. Negrini, B, Kelleher, KJ, Wald, ER. Cerebrospinal fluid findings in aseptic versus bacterial meningitis. Pediatrics 2000;105:316–9. https://doi.org/10.1542/peds.105.2.316.Search in Google Scholar PubMed
34. de Almeida, SM, Barros, NC, Petterle, R, Nogueira, K. Comparison of cerebrospinal fluid lactate with physical, cytological, and other biochemical characteristics as prognostic factors in acute bacterial meningitis. Arq Neuropsiquiatr 2019;77:871–80. https://doi.org/10.1590/0004-282x20190185.Search in Google Scholar PubMed
35. Sumanth Kumar, AS, Sahu, BP, Kumar, A. Prognostic value of cerebrospinal fluid lactate in meningitis in postoperative neurosurgical patients. Neurol India 2018;66:722–5. https://doi.org/10.4103/0028-3886.232330.Search in Google Scholar PubMed
36. Abramson, JS, Hampton, KD, Babu, S, Wasilauskas, BL, Marcon, MJ. The use of C-reactive protein from cerebrospinal fluid for differentiating meningitis from other central nervous system diseases. J Infect Dis 1985;151:854–8. https://doi.org/10.1093/infdis/151.5.854.Search in Google Scholar PubMed
37. Javadinia, S, Tabasi, M, Naghdalipour, M, Atefi, N, Asgarian, R, Khezerloo, JK, et al.. C - reactive protein of cerebrospinal fluid, as a sensitive approach for diagnosis of neonatal meningitis. Afr Health Sci 2019;19:2372–7. https://doi.org/10.4314/ahs.v19i3.10.Search in Google Scholar PubMed PubMed Central
38. Bansal, S, Gupta, R, Gupta, P, Kakkar, M, Malhotra, A, Bansal, S. Quantitative levels of C-reactive protein in cerebrospinal fluid in children with bacterial and other meningitis. J Evol Med Dent Sci 2013;2:4594–8. https://doi.org/10.14260/jemds/884.Search in Google Scholar
39. Nagarathna, S, Veenakumari, H, Chandramuki, A. Laboratory diagnosis of meningitis. Meningitis: In Tech 2012. Available from: https://doi.org/10.5772/29081.Search in Google Scholar
40. Kawamura, M, Nishida, H. The usefulness of serial C-reactive protein measurement in managing neonatal infection. Acta Paed 1995;84:10–3. https://doi.org/10.1111/j.1651-2227.1995.tb13475.x.Search in Google Scholar PubMed
41. Malla, KK, Malla, T, Rao, KS, Basnet, S, Shah, R. Is cerebrospinal fluid C-reactive protein a better tool than blood C-reactive protein in laboratory diagnosis of meningitis in children? Sultan Qaboos Univ Med J 2013;13:93. https://doi.org/10.12816/0003201.Search in Google Scholar PubMed PubMed Central
42. Peltola, H. C-reactive protein for rapid monitoring of infections of the central nervous system. Lancet 1982;319:980–3. https://doi.org/10.1016/s0140-6736(82)91989-4.Search in Google Scholar PubMed
43. Gershom, EB, Briggeman-Mol, G, de Zegher, F. Cerebrospinal fluid C-reactive protein in meningitis: diagnostic value and pathophysiology. Eu J Ped 1986;145:246–9. https://doi.org/10.1007/bf00439393.Search in Google Scholar
44. Singh, N, Arora, S, Kahlon, PS. Cerebrospinal fluid C-reactive protein in meningitis. Indian Pediatr 1995;32:687–8.Search in Google Scholar
45. Nand, N, Sharma, M, Saini, DS. Evaluation of lactic dehydrogenase in cases of meningitis. Indian J Med Sci 1993;47:96–100.Search in Google Scholar
46. Nayak, BS, Bhat, R. Cerebrospinal fluid lactate dehydrogenase and glutamine in meningitis. Indian J Physiol Pharmacol 2005;49:108–10.Search in Google Scholar
47. Therrien, G, Butterworth, RF. Cerebrospinal fluid amino acids in relation to neurological status in experimental portal-systemic encephalopathy. Metab Brain Dis 1991;6:65–74. https://doi.org/10.1007/bf00999904.Search in Google Scholar PubMed
48. Schumann, G, Bonora, R, Ceriotti, F, Clerc-Renaud, P, Ferrero, CA, Férard, G, et al.. IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 degrees C. Part 3. Reference procedure for the measurement of catalytic concentration of lactate dehydrogenase. Clin Chem Lab Med 2002;40:643–8. https://doi.org/10.1515/CCLM.2002.111.Search in Google Scholar PubMed
49. Tamune, H, Takeya, H, Suzuki, W, Tagashira, Y, Kuki, T, Honda, H, et al.. Cerebrospinal fluid/blood glucose ratio as an indicator for bacterial meningitis. Am J Emerg Med 2014;32:263–6. https://doi.org/10.1016/j.ajem.2013.11.030.Search in Google Scholar PubMed
50. Talukdar, B, Khalil, A, Sarkar, R, Saini, L. Meningococcal meningitis. Clinical observations during an epidemic. Indian Pediatr 1988;25:329–34.Search in Google Scholar
51. Kanegaye, JT, Soliemanzadeh, P, Bradley, JS. Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment. Pediatrics 2001;108:1169–74. https://doi.org/10.1542/peds.108.5.1169.Search in Google Scholar
52. Blazer, S, Berant, M, Alon, U. Bacterial meningitis. Effect of antibiotic treatment on cerebrospinal fluid. Am J Clin Pathol 1983;80:386–7. https://doi.org/10.1093/ajcp/80.3.386.Search in Google Scholar PubMed
© 2023 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Review
- Cognitive biases in internal medicine: a scoping review
- Opinion Papers
- “Pivot and Cluster Strategy” in the light of Kahneman’s “Decision Hygiene” template
- Developing a European longitudinal and interprofessional curriculum for clinical reasoning
- Optimizing measurement of misdiagnosis-related harms using symptom-disease pair analysis of diagnostic error (SPADE): comparison groups to maximize SPADE validity
- Reframing context specificity in team diagnosis using the theory of distributed cognition
- Original Articles
- Promoting clinical reasoning with meta-memory techniques to teach broad differential diagnosis generation in a pediatric core clerkship
- Semantic competence and prototypical verbalizations are associated with higher OSCE and global medical degree scores: a multi-theory pilot study on year 6 medical student verbalizations
- Influence of comorbid depression and diagnostic workup on diagnosis of physical illness: a randomized experiment
- Recognition, diagnostic practices, and cancer outcomes among patients with unintentional weight loss (UWL) in primary care
- Quantitation of neurofilament light chain protein in serum and cerebrospinal fluid from patients with multiple sclerosis using the MSD R-PLEX NfL assay
- Analysis of common biomarkers in capillary blood in routine clinical laboratory. Preanalytical and analytical comparison with venous blood
- Comparison between cerebrospinal fluid biomarkers for differential diagnosis of acute meningitis
- Short Communications
- Exploring relationships between physician stress, burnout, and diagnostic elements in clinician notes
- Development of a student-created internal medicine frameworks website for healthcare trainees
- Case Report - Lessons in Clinical Reasoning
- Lessons in clinical reasoning – pitfalls, myths, and pearls: a case of crushing, substernal chest pain
- Letters to the Editor
- Ample room for cognitive bias in diagnosing accidental hypothermia
- Auscultation order of lung and heart sounds and autonomous noise cancellation
- Reliability of a single-nostril nasopharyngeal swab for diagnosing SARS-CoV-2 infection
Articles in the same Issue
- Frontmatter
- Review
- Cognitive biases in internal medicine: a scoping review
- Opinion Papers
- “Pivot and Cluster Strategy” in the light of Kahneman’s “Decision Hygiene” template
- Developing a European longitudinal and interprofessional curriculum for clinical reasoning
- Optimizing measurement of misdiagnosis-related harms using symptom-disease pair analysis of diagnostic error (SPADE): comparison groups to maximize SPADE validity
- Reframing context specificity in team diagnosis using the theory of distributed cognition
- Original Articles
- Promoting clinical reasoning with meta-memory techniques to teach broad differential diagnosis generation in a pediatric core clerkship
- Semantic competence and prototypical verbalizations are associated with higher OSCE and global medical degree scores: a multi-theory pilot study on year 6 medical student verbalizations
- Influence of comorbid depression and diagnostic workup on diagnosis of physical illness: a randomized experiment
- Recognition, diagnostic practices, and cancer outcomes among patients with unintentional weight loss (UWL) in primary care
- Quantitation of neurofilament light chain protein in serum and cerebrospinal fluid from patients with multiple sclerosis using the MSD R-PLEX NfL assay
- Analysis of common biomarkers in capillary blood in routine clinical laboratory. Preanalytical and analytical comparison with venous blood
- Comparison between cerebrospinal fluid biomarkers for differential diagnosis of acute meningitis
- Short Communications
- Exploring relationships between physician stress, burnout, and diagnostic elements in clinician notes
- Development of a student-created internal medicine frameworks website for healthcare trainees
- Case Report - Lessons in Clinical Reasoning
- Lessons in clinical reasoning – pitfalls, myths, and pearls: a case of crushing, substernal chest pain
- Letters to the Editor
- Ample room for cognitive bias in diagnosing accidental hypothermia
- Auscultation order of lung and heart sounds and autonomous noise cancellation
- Reliability of a single-nostril nasopharyngeal swab for diagnosing SARS-CoV-2 infection