SARS-CoV-2–associated Epstein–Barr virus reactivation and lymphomagenesis: A systematic review and meta-analysis.

Abstract

e22586 Background: SARS-CoV-2 infection induces marked immune dysregulation, a biologic milieu permissive for reactivation of latent oncogenic viruses. Epstein–Barr virus (EBV) reactivation is a recognized precursor to B-cell lymphoproliferative disease in immunocompromised states. We conducted a systematic review and meta-analysis of EBV reactivation following SARS-CoV-2 infection and contextualized these findings within epidemiologic evidence relevant to lymphoma risk. Methods: Studies evaluating EBV reactivation after SARS-CoV-2 infection were identified through systematic review. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Heterogeneity was assessed using Cochran’s Q and I² statistics. Population-based cohorts, ecological analyses, and case reports examining lymphoma occurrence in the setting of COVID-19 were reviewed qualitatively. Results: Three studies met inclusion criteria for quantitative synthesis (n = 480). Meta-analysis demonstrated a significantly increased risk of EBV reactivation among SARS-CoV-2–infected patients (pooled RR = 3.69, 95% CI 2.56–5.32), with no significant heterogeneity (Q = 1.82, I² = 0%). Population-level data further support a non-random association between COVID-19 and lymphoma. A large cohort study of hospitalized cancer patients demonstrated substantially higher odds of COVID-19 diagnosis among patients with lymphoma compared with colon cancer controls (adjusted OR 11.13). An ecological analysis identified geographic correlation between historical non-Hodgkin lymphoma incidence and COVID-19 burden. Case reports describe EBV-driven B-cell lymphoproliferative disorders emerging shortly after SARS-CoV-2 infection, though data remain insufficient for quantitative lymphoma incidence estimation. Conclusions: SARS-CoV-2 infection is associated with a nearly four-fold increased risk of EBV reactivation across available cohorts. Integrated with epidemiologic observations, these findings support biologic plausibility for COVID-19–associated immune dysregulation contributing to EBV-mediated lymphomagenesis. Establishing causality will require prospective longitudinal studies incorporating standardized viral surveillance, immune profiling, and rigorous control of confounding factors. These results underscore the importance of infectious disease control, post-infectious monitoring, and risk stratification at the interface of oncology and viral immunity. Summary of studies evaluating EBV reactivation following SARS-CoV-2 infection. Study Population EBV Reactivation Rate (COVID-19) EBV Reactivation Rate (Controls) Paolucci et al., 2021 Hospitalized adults ~50% ~10% Bernal & Whitehurst, 2023 Hospitalized adults 37.5% 10% Bernal & Whitehurst, 2023 Mixed inpatient/outpatient 33.3% 12%