| Summary: | Epstein–Barr virus (EBV) reactivation in acute-phase of COVID-19 disease was recently discovered but it is not clear in terms of degree of mortality caused, and this was the aim of the current study. Six databases and three non‐databases were thoroughly searched, independently. The articles related to non‐human study (abstract, in vitro, in vivo, in silico, case study, poster, and review articles) were excluded for main analysis. Four articles related to mortality linked to EBV reactivation were systematically identified and included in the qualitative and quantitative analyses. Based on proportional meta-analysis of 4 studies, 34.3% or 0.343 (95% CI: 0.189–0.516; I2 = 74.6) mortality related to EBV reactivation was identified. To address high heterogeneity, subgroup meta-analysis was carried out. Based on subgroup analysis, 26.6% or 0.266 (95% CI: 0.191–0.348; I2 = 0) with no heterogeneity was identified. Interestingly, in comparative meta-analysis, EBV(−)/SARS-CoV-2(+) patients had statistically lesser mortality (9.9%) than EBV(+)/SARS-CoV-2(+) patients (23.6%) where RR = 2.31 (95% CI: 1.34–3.99; p=0.003; I2 = 6%). This finding is equivalent to the absolute mortality effect of 130 more per 1000 COVID-19 patients (95% CI: 34–296). Furthermore, based on statistical analysis, D-dimer was not statistically significantly different (p>0.05) between the groups although studies have shown that D-dimer was statistically significantly different (p<0.05) between these groups. Based on the inclusion and analysis of low risk of bias and high quality of articles graded with Newcastle–Ottawa Scale (NOS), when COVID-19 patients’ health state is gradually worsening, EBV reactivation needs to be suspected because EBV reactivation is a possible marker for COVID-19 disease severity.
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