SARS-CoV-2, EBV Reactivation, and Lymphomagenesis: A Systematic Review, Meta-Analysis, and Bayesian Modeling
Introduction/Background/Significance: Viruses have long been implicated in human oncogenesis, with Epstein–Barr virus (EBV) serving as a prototype of latent viral persistence capable of driving malignant B-cell proliferation. EBV remains latent in B lymphocytes, its oncogenic proteins (LMP1, LMP2, EBNA) activating NF-κB and JAK/STAT pathways to promote proliferation and apoptosis resistance. Under normal immune surveillance, EBV remains largely controlled, but immune disruption can facilitate reactivation and, in rare cases, malignant transformation. SARS-CoV-2 infection, through lymphopenia, T-cell exhaustion, and cytokine storm syndromes, creates an immunologic environment prone to opportunistic infections and latent viral reactivation. Observational studies suggest high rates of EBV reactivation in severe COVID-19, raising concern for downstream oncogenic risk.
Materials and Methods/Case Presentation/Objective: We conducted a systematic search of PubMed, Embase, and Web of Science (January 2020–July 2025) for studies reporting EBV reactivation in patients with SARS-CoV-2 infection compared with non-COVID-19 controls. Eligible studies included observational cohorts and case-control analyses. Data extracted included sample size, COVID-19 severity, EBV detection method, and reactivation rates. A random-effects meta-analysis (DerSimonian–Laird) calculated pooled risk ratios (RR) with 95% confidence intervals (CI). Heterogeneity was assessed using Cochran's Q and I2 statistics.
Results/Description/Main Outcome Measures: Three studies met inclusion criteria (n = 480 patients). EBV reactivation was observed in 50% of COVID-19 ICU patients versus 10% of matched controls in one cohort, 37.5% versus 10% in a hospitalized cohort, and 33.3% versus 12% in a mixed-severity cohort.
Meta-analysis demonstrated that SARS-CoV-2 infection significantly increased the risk of EBV reactivation (pooled RR = 3.69, 95% CI 2.56–5.32), with no evidence of significant heterogeneity (Q = 1.82, τ2 = 0). Case reports describing EBV-driven lymphoproliferative disorders emerging after COVID-19 were identified but insufficient for quantitative lymphoma risk analysis.
Conclusions: SARS-CoV-2 infection is associated with a nearly four-fold increased risk of EBV reactivation, consistent across available cohorts. This finding supports biologic plausibility for COVID-19 acting as an immunologic stressor capable of unmasking latent oncogenic viral activity. While direct evidence of increased lymphoma incidence post-COVID-19 is lacking, EBV reactivation is a recognized pathway toward B-cell lymphomagenesis in immunocompromised states. These findings highlight an urgent need for longitudinal EBV surveillance and lymphoma risk monitoring in post-COVID populations and for mechanistic studies exploring how COVID-19 immune dysregulation may contribute to oncogenesis.
