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

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).