When should fungal meningitis be considered in a patient with cerebrospinal fluid pleocytosis not explained by bacterial or viral infection, especially in immunocompromised hosts, and what are the recommended diagnostic tests and empiric therapy?

Fungal Meningitis: When to Suspect and How to Diagnose

When to Suspect Fungal Meningitis

Fungal meningitis should be strongly considered in any immunocompromised patient presenting with CSF lymphocytic pleocytosis, low CSF/plasma glucose ratio (<0.5), and elevated protein, particularly when bacterial cultures remain negative. 1

High-Risk Patient Populations

• Immunocompromised hosts are the primary at-risk group, including HIV-infected patients, those on immunosuppressive therapy, transplant recipients, diabetics, and elderly patients 1
• Cryptococcal meningitis can occur in apparently immunocompetent patients, though this is less common and represents an emerging clinical challenge 2
• All immunosuppressed patients with CSF pleocytosis should raise immediate suspicion for cryptococcal infection 3

Key Clinical Presentations

• Subacute presentation over days to weeks (rather than acute onset) strongly suggests fungal etiology alongside tuberculous meningitis and Listeria 1
• Endemic exposure history is critical—patients from the Southwest United States should be evaluated for Coccidioides immitis, while histoplasmosis and cryptococcosis have broader geographic distributions 1, 4
• Fungal CNS infections are increasingly recognized in both immunocompromised and immunocompetent hosts globally 5

Diagnostic CSF Profile

Characteristic Findings

• Lymphocytic predominance in CSF differential is typical of fungal meningitis 1, 4
• **CSF/plasma glucose ratio <0.5** strongly suggests fungal or tuberculous meningitis (versus viral meningitis where ratio remains >0.36) 1, 6
• Markedly elevated protein (typically >100 mg/dL) is characteristic 1, 6
• CSF lactate <2 mmol/L effectively rules out bacterial disease, helping distinguish fungal from bacterial causes 1, 7

Critical Pitfall: Pleocytosis May Be Absent

• Meningitis can occur without pleocytosis on initial CSF analysis—this is rare but documented, with fungal cases showing 56% mortality when pleocytosis is absent 8
• In one series, all immunosuppressed patients with pleocytosis were found to have cryptococcal infection, but the absence of pleocytosis does not exclude fungal meningitis 3, 8
• Never exclude fungal meningitis based solely on normal CSF cell count 7

Recommended Diagnostic Tests

Essential Fungal-Specific Studies

• Cryptococcal antigen testing on CSF is highly sensitive and should be ordered immediately in immunocompromised patients 3, 4
• India ink preparation can rapidly identify Cryptococcus, though sensitivity is lower than antigen testing 3, 4
• Fungal culture from large CSF volumes (up to 40-50 mL unless contraindicated by increased intracranial pressure) is essential for definitive diagnosis 4
• Gomori Methenamine Silver (GMS) stain highlights fungal organisms on cytology 3

Additional Testing Based on Clinical Context

• Complement-fixing antibodies to Coccidioides immitis if Southwest U.S. residence or travel history 4
• Histoplasma antigen testing for endemic areas 1
• Molecular amplification techniques (PCR) for fungal pathogens offer promise for expedited diagnosis, though availability varies 4, 5
• Antigen detection assays are more sensitive than culture and allow earlier treatment initiation 5

Concurrent Studies to Exclude Other Etiologies

• Mycobacterium tuberculosis testing (AFB smear, culture, TB PCR on 6 mL CSF) is mandatory given overlapping presentation 6
• HSV-1/2 and VZV PCR to exclude viral encephalitis 1
• Bacterial culture and Gram stain remain essential 1, 7
• Simultaneous plasma glucose measurement to calculate CSF/plasma ratio 6, 7
• Blood cultures should be obtained as they are positive in 71% of cases with meningitis, even when CSF findings are atypical 8

Empiric Therapy Recommendations

Immediate Treatment Protocol

If bacterial meningitis cannot be definitively excluded, start empiric antibiotics immediately (within one hour), including ceftriaxone + vancomycin + ampicillin if >50 years or immunocompromised, as Listeria can present with lymphocytic predominance and is resistant to cephalosporins. 1

Antifungal Coverage

• Empiric antifungal therapy should not be delayed when fungal meningitis is strongly suspected based on clinical presentation and CSF profile 4, 5
• For cryptococcal meningitis, treatment typically involves amphotericin B-based regimens, though specific dosing should follow current Infectious Diseases Society of America guidelines 5
• For histoplasmosis meningitis, amphotericin B 0.7-1 mg/kg/day for 3-4 months followed by fluconazole 800 mg daily for 9-12 months is recommended 6
• Newer antifungal agents may be required for emerging resistant pathogens 5

Critical Timing Considerations

• Institution of antibiotic/antifungal therapy should not be delayed while awaiting culture results or neuroradiologic studies 4
• Fungal cultures may take days to weeks, making empiric treatment decisions based on clinical suspicion and CSF profile essential 4, 5

Diagnostic Algorithm Summary

1. Obtain detailed history: immunosuppression status, endemic exposures, duration of symptoms (subacute >5 days favors fungal/TB) 1, 6
2. Perform lumbar puncture with opening pressure, cell count with differential, glucose, protein, lactate 7
3. Calculate CSF/plasma glucose ratio immediately—ratio <0.5 strongly suggests fungal or TB meningitis 1, 6
4. Send comprehensive CSF studies: bacterial culture/Gram stain, fungal culture/India ink/cryptococcal antigen, TB PCR/AFB/culture, viral PCR panel 1, 7, 4
5. Obtain blood cultures as adjunct diagnostic tool 8
6. Start empiric therapy immediately: broad-spectrum antibiotics (including ampicillin for Listeria) + acyclovir + antifungals based on risk stratification 1, 4
7. Brain MRI with contrast within 24 hours to evaluate for parenchymal involvement, abscess, or basal meningeal enhancement 1
8. Repeat lumbar puncture at 48-72 hours if diagnosis remains unclear and patient not improving 1

Common Pitfalls to Avoid

• Do not rely on absolute CSF glucose alone—always calculate the CSF/plasma ratio, as serum glucose abnormalities can mislead interpretation 6, 7
• Do not exclude fungal meningitis based on normal CSF cell count—meningitis without pleocytosis carries 56% mortality in fungal cases 7, 8
• Do not wait for culture results before initiating empiric antifungal therapy in high-risk patients with compatible CSF findings 4, 5
• Do not forget to add ampicillin to empiric regimens in patients >50 years or immunocompromised, as Listeria presents with lymphocytic pleocytosis mimicking fungal/TB meningitis 1
• BioFire ME panel has low sensitivity for cryptococcal infection at low fungal burdens—negative results do not exclude cryptococcal meningitis, and dedicated cryptococcal antigen testing plus fungal culture are required 1