Blood-Based Immune Biomarkers Urgently Needed to Diagnose Bacterial Meningitis Faster

Bacterial meningitis is one of the most dangerous infections a person can develop, and clinicians still lack a fast, reliable way to confirm it from a simple blood sample. In a review published in Discover Immunity, researchers Yongwen Pan, Zheng Nie, Hexiang Jiang and Yang Yang argue that the field must urgently begin screening peripheral blood-based immunologic biomarkers for diagnosing bacterial meningitis. The authors, writing from a perspective grounded in a systematic PubMed search that retrieved 1,987 studies published in English up to March 26, 2025, lay out why current diagnostic pathways fall short and why the host immune response visible in blood may hold the key to earlier detection.

The stakes are high. According to the review, bacterial meningitis causes roughly 318,000 deaths each year and accounts for the loss of more than 20,000 disability-adjusted life years, making it a major public health challenge worldwide. Even with treatment, about half of survivors may experience long-term neurological sequelae, including seizures, cognitive decline and sensory impairments. The disease carries the highest burden among meningitis causes and is particularly threatening to preterm infants and neonates with compromised immune function. Vaccination against Haemophilus influenzae type B, Streptococcus pneumoniae and Neisseria meningitidis, together with perinatal antibiotic prophylaxis against Streptococcus agalactiae, has driven a general decline in incidence, but the emergence of non-vaccine serotypes and resistant strains, including a rising number of penicillin-resistant Streptococcus pneumoniae isolates, continues to complicate clinical management.

Early diagnosis and prompt antibiotic treatment are critical for improving outcomes, yet the clinical presentation of bacterial meningitis frequently overlaps with that of viral meningitis. Symptoms often lack specificity, especially in infants, young children, the elderly and immunocompromised patients, where atypical presentations can lead to missed diagnoses. Because distinguishing bacterial from viral disease at the bedside is so difficult, clinicians frequently initiate empirical combination therapy with both antivirals and antibiotics, which the review notes increases the risk of drug resistance and adds to the healthcare burden. Delayed treatment, meanwhile, is associated with increased in-hospital mortality and adverse health outcomes.

The diagnostic gold standard remains direct detection of bacteria, most often through cerebrospinal fluid obtained by lumbar puncture. But this approach has well-documented weaknesses. The sensitivity of Gram stain and culture varies widely with age group and pathogen, from roughly 60 percent in neonates and 50 to 63 percent in children down to 50 percent for Gram-negative bacilli, and prior antibiotic treatment significantly reduces the sensitivity of CSF culture. One study cited in the review found that only 34 of 1,898 CSF enrichment broth cultures were positive, with 30 of those patients clinically classified as having aseptic meningitis, suggesting most were contaminants. Multiplex PCR point-of-care panels in cerebrospinal fluid show diagnostic promise for accelerating pathogen identification, but the review concludes that their translation into routine practice is not yet justified by high-quality evidence, given the paucity of diagnostic accuracy studies and the absence of randomized controlled trials.

Newer sequencing technologies have produced mixed results. Metagenomic next-generation sequencing provided superior diagnostic results for tuberculous meningitis in CSF samples compared with GeneXpert, modified Ziehl-Neelsen staining and CSF culture in a multicenter retrospective study in China, and a case report documented the diagnosis of Listeria monocytogenes meningoencephalitis by the same technique. Yet second-generation sequencing detected Streptococcus suis infections in blood samples at significantly lower rates than in CSF samples, and targeted next-generation sequencing applied to CSF from 72 adults with microbiologically confirmed tuberculous meningitis, while rapidly and accurately detecting resistant strains, was limited to cases with high bacterial loads. These constraints reinforce the authors’ argument that complementary biomarkers are needed.

CSF analysis itself is far from definitive. In untreated, immunocompetent patients with acute bacterial meningitis, CSF is typically purulent and turbid, with polymorphonuclear cell counts often exceeding 1,000 cells per microliter, severe blood-CSF barrier dysfunction with total protein above 1,000 mg/dL, reduced glucose often below 30 mg/dL, a CSF-to-blood glucose ratio under 0.3, or elevated lactate above 3.5 mmol/L. However, up to one-third of cases may show atypical presentations, including patients with normal CSF white cell counts. In a study of 1,816 pneumococcal meningitis patients, 33 percent had cell counts below 1,000 per microliter, and a French nationwide prospective surveillance study of children aged 3 months to 15 years found that 173 of 4,754 acute bacterial meningitis cases did not exhibit pleocytosis. Antibiotic pretreatment can also alter CSF parameters, raising glucose levels and lowering protein levels, and no single CSF parameter reliably diagnosed bacterial meningitis in an assessment of 538 meningitis cases, of which 39 were bacterial and 499 viral.

CSF biomarkers perform better but depend on obtaining spinal fluid in the first place. CSF procalcitonin distinguished bacterial from viral meningitis with an area under the curve of 0.76 versus 0.67 for serum procalcitonin in one comparison of 29 bacterial, 25 viral and 47 non-meningitis patients, achieving 55.17 percent sensitivity and 95.83 percent specificity at a cutoff of 0.085 ng/mL, and another study of patients after empirical antibiotic treatment reported an AUC of 0.881 with 69.39 percent sensitivity and 91.49 percent specificity. Combined cytokine and protein markers have shown even stronger discrimination, with CSF interleukin-12 plus serum C-reactive protein reaching an AUC of 0.995, 100 percent sensitivity and 90.9 percent specificity in one analysis. But lumbar puncture is not always feasible. In a nationwide prospective cohort study of 1,533 adults with community-acquired bacterial meningitis, 3.1 percent experienced potential clinical deterioration following the procedure, and although cranial CT is commonly used to assess contraindications, its inter-rater reliability is only moderate, normal CT results do not guarantee safety, and the scanning process may delay timely antibiotic administration.

This is where blood comes in. The authors emphasize that host immune responses occur before the onset of clinical symptoms, providing a theoretical basis for screening early diagnostic biomarkers from an immunological perspective. Pathogen invasion activates pattern recognition receptors and triggers an immune cascade, and cytokines released by the peripheral immune system cross the blood-CSF barrier into the CSF. Notably, a large genome-wide association study of pneumococcal meningitis patients and pathogen samples indicated that host genetic variations could explain 50 percent of disease severity, whereas the impact of the pathogen genome was not significant. Existing serum markers have limits: serum procalcitonin’s diagnostic capability is significantly lower than that of CSF procalcitonin, and serum C-reactive protein poorly distinguished subjects with and without meningitis among symptomatic early-onset sepsis patients. Both markers can also be elevated in enterovirus, respiratory syncytial virus or severe SARS-CoV-2 infections.

Multi-omics technologies offer a way forward. RNA sequencing of peripheral blood interrogates host immune responses and aids etiological differentiation; in febrile infants 60 days old or younger, researchers built a 66-gene classifier for serious bacterial infection with 87 percent sensitivity and 89 percent specificity, and a 10-gene classifier for bacteremia with 94 percent sensitivity and 95 percent specificity. Peripheral blood transcriptome analysis of bacterial meningitis has revealed dynamic immune changes, with early stages showing increased neutrophil infiltration and RNF144B gene expression positively correlated with it, while during remission neutrophil proportions fall, NKT cell proportions rise and FYN gene expression correlates with NKT cell infiltration. The expression signatures of RNF144B and FYN were significantly distinct in the peripheral blood of bacterial meningitis patients compared with those with viral meningitis, and Mendelian randomization identified RNF144B as a risk factor and FYN as a protective factor for the disease. The authors caution, however, that these findings require further confirmation and that the diagnostic accuracy of candidate biomarkers reported so far remains unvalidated.

The review concludes that integrating transcriptomics, proteomics, metabolomics and genetic analysis, potentially combined with machine learning, holds great potential for characterizing the molecular landscape of bacterial meningitis and identifying disease-specific biomarkers that could enable early diagnosis, risk assessment and personalized treatment strategies. Relevant studies are currently lacking, and the authors recommend that future work focus on discovering and rigorously validating these critical immunologic biomarkers. Until such validation is complete, cerebrospinal fluid analysis and microbial culture will remain the diagnostic mainstays, but the case for looking to the blood, where the immune response declares itself before symptoms appear, has rarely been made so systematically.

Subject of Research: Peripheral blood immune biomarkers for diagnosing bacterial meningitis

Article Title: Urgent need for screening of peripheral blood-based immunologic biomarkers for the diagnosis of bacterial meningitis

Article References: Pan, Y., Nie, Z., Jiang, H., & Yang, Y. (2026). Urgent need for screening of peripheral blood-based immunologic biomarkers for the diagnosis of bacterial meningitis. Discover Immunity, 3(1), Article 1. https://doi.org/10.1007/s44368-025-00017-4

Image Credits: AI Generated

DOI: 10.1007/s44368-025-00017-4

Keywords: bacterial meningitis, biomarkers, peripheral blood, host immune response, cerebrospinal fluid, lumbar puncture, multi-omics, RNA sequencing, Mendelian randomization, procalcitonin, C-reactive protein, diagnosis