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. 2025 Apr 29:53:101309.
doi: 10.1016/j.lanepe.2025.101309. eCollection 2025 Jun.

Validation and clinical implementation of cerebrospinal fluid C-reactive protein for the diagnosis of bacterial meningitis: a prospective diagnostic accuracy study

Sabine E Olie  1   2 , Steven L Staal  1   2 , Nina S Groeneveld  1   2 , Hans H M Schotman  3 , Jacob Bodilsen  2   4   5 , Henrik Nielsen  2   4   5 , Merijn W Bijlsma  1   6 , Diederik van de Beek  1   2 , Matthijs C Brouwer  1   2
Affiliations

Validation and clinical implementation of cerebrospinal fluid C-reactive protein for the diagnosis of bacterial meningitis: a prospective diagnostic accuracy study

Sabine E Olie et al. Lancet Reg Health Eur. .

Abstract

Background: C-reactive protein (CRP) in cerebrospinal fluid (CSF) was previously shown to be predictive for bacterial meningitis in patients with a suspected central nervous system (CNS) infection in an experimental study. We aimed to assess the diagnostic accuracy of CRP in CSF in a validation and clinical implementation study.

Methods: We validated CRP measurements in CSF for the diagnosis of bacterial meningitis in a Danish cohort of patients with acute CNS infections, and a Dutch cohort of pediatric patients suspected of a CNS infection. Subsequently, we evaluated the implementation of CRP measurements in CSF in clinical practice.

Findings: CRP in CSF was measured in 103 adult patients from Denmark, which included 34 (33%) bacterial meningitis patients. The AUC was 0.92 (95% CI: 0.85-0.99), and with a predefined cut-off of 0.3 mg/L, sensitivity was 85% (95% CI: 69-95) with a specificity of 96% (95% CI: 88-99). In 77 Dutch children, including 17 (22%) patients with bacterial meningitis, the AUC was 0.95 (95% CI: 0.87-1.00) and sensitivity and specificity were 94% (95% CI: 71-100) and 98% (95% CI: 91-100), respectively. From June 2024 to November 2024, we included 80 patients in our clinical implementation cohort, of which 15 (19%) were diagnosed with bacterial meningitis. The AUC for CRP in CSF was 0.99 (95% CI: 0.97-1.00), and sensitivity was 100% (95% CI: 78-100) with a specificity of 94% (95% CI: 85-99). Across all cohorts, the combination of CSF leukocytes and CSF CRP improved diagnostic accuracy compared to CSF leukocytes alone (p ≤ 0.001 in all cohorts).

Interpretation: CRP in CSF is a highly reliable predictor for bacterial meningitis, offering incremental value in addition to CSF leukocytes. Clinical implementation is straightforward and can be achieved at low costs in laboratories where CRP in blood is already routinely measured.

Funding: Supported by the European Research Council (ERC Consolidator grant 101001237 to MB) and the Netherlands Organisation for Health Research and Development (ZonMw; NWO-Vidi Grant [917.17.308] to MCB; NWO-Vici-Grant Grant [918.19.627] to DvdB).

Keywords: Bacterial meningitis; C-reactive protein; Cerebrospinal fluid; Diagnostic accuracy; Implementation study.

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Conflict of interest statement

MWB: grant from ItsME foundation, unrelated to the current manuscript. DvdB: grant from the Netherlands Organization for Health Research and Development, funding the current manuscript. Part of the DEX-ENCEPH trial DSMB. MCB: grant from the Netherlands Organization for Health Research and Development and the European Research Council, funding the current manuscript. Grant from Stichting de Merel, unrelated to the current manuscript. Chair of the ESGIB study group on infections of the brain until 2024. Part of the ENCEPH-UK trial steering committee.

Figures

Fig. 1
Fig. 1
CRP in CSF concentrations (mg/L) per cohort. a Danish validation cohort. b Pediatric validation cohort. c Implementation cohort.
Fig. 2
Fig. 2
Receiver operator curves for differentiating bacterial meningitis from other disorders.
See this image and copyright information in PMC

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