Epstein-Barr Virus Central Nervous System Infections and Mortality Risk in Patients Presenting With Suspected Meningitis: Results From the Botswana National Meningitis Survey and the Harare Meningitis Aetiology Study

By
Jayne Ellis
James Milburn
Kebatshabile Ngoni
Christopher G Williams
Charles Muthoga
Taddy Mwarumba
Ezekiel Gwakuba
George Manenji
Rachita Suresh
Tichoaya Machiya
Janet Thubuka
Cassie Northcott
James Penney
Matthew Kinsella
Imogen Mechie
Samuel Ensor
Tshepo Leeme
Leah Owen
Hannah Barton
Keatlaretse Siamisang
Mark W Tenforde
William Hurt
Ronan Doyle
Daniel Grint
Síle F Molloy
Thomas S Harrison
David M Goldfarb
Madisa Mine
Margaret Mokomane
Gift Ngwende
Lenon Gwaunza
Tiny Mazhani
Chiratidzo Ndhlovu
Joseph N Jarvis
October 23, 2025
0 min

Open Forum Infectious Diseases

Overview

Epstein-Barr virus (EBV) CNS infection was detected in 26% of patients with suspected meningitis in Botswana and Zimbabwe cohorts, predominantly among HIV-positive individuals. While EBV CNS infection correlated with increased in-hospital mortality in unadjusted analysis, this association was not significant after adjusting for age, sex, and HIV status, suggesting EBV acts mainly as a bystander virus reflecting CNS inflammation.

Background

Meningitis remains a leading cause of morbidity and mortality worldwide, especially in sub-Saharan Africa where HIV-associated cryptococcal and tuberculous meningitis predominate. EBV is a common herpesvirus that can infect the CNS, but its clinical significance in meningitis patients is unclear. Prior studies have shown high rates of EBV detection in cerebrospinal fluid (CSF) of HIV-positive patients with CNS infections, yet whether EBV contributes to worse outcomes or is merely a marker of immune activation is uncertain.

Data Highlights

Characteristic	Value
Total participants	581
Male participants	54%
Median age (IQR)	38 (29–46) years
HIV positive	76%
Cryptococcal meningitis	12.0%
Tuberculous meningitis	6.4%
EBV CNS infection prevalence	26% (152 of 581)
Unadjusted odds ratio for mortality with EBV CNS infection	1.64 (95% CI, 1.10–2.43; P = .01)
Adjusted odds ratio for mortality with EBV CNS infection	1.29 (95% CI, 0.84–1.98; P = .25)

Key Findings

EBV DNA was detected in the CSF of 26% of patients with suspected meningitis.
EBV CNS infection was significantly associated with older age, HIV positivity, and CSF pleocytosis (P < .001).
Unadjusted analysis showed EBV CNS infection increased in-hospital mortality risk (OR 1.64; P = .01).
After adjusting for sex, age, and HIV status, EBV CNS infection was not significantly associated with mortality (adjusted OR 1.29; P = .25).
Subgroup analyses suggested the mortality association may vary by meningitis diagnostic category.
EBV CNS infection likely represents a bystander virus reflecting heightened CNS inflammation rather than a direct cause of increased mortality.

Clinical Implications

Detection of EBV DNA in CSF among patients with suspected meningitis, especially those living with HIV, should be interpreted cautiously as it may not indicate a direct pathogenic role. Clinicians should consider EBV CNS infection as a marker of CNS inflammation rather than a primary target for antiviral therapy. Focus should remain on diagnosing and treating the primary meningitis etiology to improve patient outcomes.

Conclusion

EBV CNS infection is common in patients with suspected meningitis in sub-Saharan Africa and correlates with markers of CNS inflammation. However, it does not independently increase in-hospital mortality after adjustment for confounders, supporting its role as a bystander virus in this context.

References

Botswana National Meningitis Survey and Harare Meningitis Aetiology Study 2024 -- Risk of Mortality Associated with Epstein-Barr Virus Infections in the Central Nervous System Among Patients with Suspected Meningitis