EBV infection is an aetiologic factor in the carcinogenesis of NPC [19]. Studies have shown that the presence of EBV DNA is a promising indicator for posttreatment surveillance [15, 20]. Currently, EBV DNA monitoring is recommended by the National Comprehensive Cancer Network (NCCN), with Category 2B of Evidence and Consensus in NPC [21]. However, whether plasma EBV DNA measurements are reliable, and how to arrange EBV DNA tests during the COVID-19 pandemic remain unknown.

In this article, we found that plasma EBV DNA was a valuable tool for predicting recurrence or metastasis using an appropriate cut-off value after radical treatment in NPC patients infected with the Omicron strain of SARS-CoV-2. However, EBV DNA alone was not a reliable factor for the confirmation of relapse since some patients had false-negative results [22,23,24]. Studies have reported that 51%-67% of NPC patients with local or locoregional failure have elevated EBV DNA, and 86%-96% of patients with distant metastases have detectable EBV DNA [20]. Therefore, during the COVID-19 pandemic, the diagnosis of relapse should be made by combining EBV DNA with other tools, including CT, MRI, bone ECT, PET-CT, nasendoscopy, and biopsy. Our findings support the consensus that EBV DNA should not be the only surveillance test available, and it can not replace clinical consultations, nasendoscopy, biopsy, and other imaging or diagnostic tools for predicting the relapse of NPC after radical treatment [25]. Simple, reliable, and economical approaches are needed to improve the accuracy of EBV DNA monitoring. Notably, we speculated that the fluctuations in EBV DNA levels might be due to SARS-CoV-2 infection, since we rarely found so many patients with abnormal fluctuations in EBV DNA when no signs of cancer recurrence or metastasis existed in NPC patients before the COVID-19 epidemic. Therefore, explorations are needed to study the difference in EBV DNA between NPC patients with or without COVID-19 and to confirm whether there is any relationship between EBV DNA levels and SARS-CoV-2 infection. In addition, the underlying mechanisms are wanted to explain why EBV DNA fluctuates after SARS-CoV-2 infection, which could help to provide a valuable reference for the future for the COVID-19 epidemic.

In addition, the optimal timing and frequency of EBV DNA tests needed to determined. Chen et al. showed that 63.8% of patients with detectable cell-free EBV DNA developed recurrence. For EBV DNA-detectable patients who did not develop recurrence, 81.7% had transiently detectable EBV DNA that decreased undetectable levels after long-term follow-up [26]. Thus, dynamic and regular EBV DNA tests are recommended after the completion of radical treatment in non-disseminated NPC patients. In our study, the average time for EBV DNA to recover to undetectable levels was 63 days in no-relapse NPC patients whose EBV DNA level increased from undetectable to detectable during follow-up. Thus, we suggest every 2-month interval test for EBV DNA for patients infected with the Omicron strain of SARS-CoV-2. However, for patients whose EBV DNA is always detectable, whose level is higher than the cut-off value (62.3 copies/mL) or whose level is persistently elevated, we should be aware of the potential for recurrence or metastasis. For patients whose EBV DNA was transiently elevated, transient lytic and latent cycles of EBV could not be completely ruled out. Despite all these possibilities, closer monitoring of EBV DNA was suggested for NPC patients with abnormal EBV DNA levels. In addition, other specific examinations, such as the COVID-19 pandemic, are still wanted even if a prolonged interval is allowed in severely resource-constrained circumstances. Imaging and histological tools provided a clear and integrated representation of the appearance and properties of the tumor. Therefore, imaging and endoscopic assessments are essential for the surveillance of NPC patients with increased or progressively increasing levels of EBV DNA or symptoms highly suggestive of NPC recurrence and metastasis. Further validation is needed in prospective and multicentre clinical trials to determine the frequency of EBV DNA monitoring.

To our knowledge, our study is the first to explore the utilization of EBV DNA in patients with non-metastatic NPC after radical treatment during the COVID-19 pandemic. Our study had several limitations. First, our study was conducted in a high-incidence area of NPC in the Asian population, which may not be applicable to non-endemic areas or other ethnic groups. Second, this article was a retrospective study in a single centre. Third, since SARS-CoV-2 is highly variable, it is unclear whether our findings could be applied to other variants of SARS-CoV-2 and second infections caused by COVID-19 [27, 28]. Fourth, the time of EBV DNA detection is irregular due to resource limitations during the COVID-19 pandemic and personal factors, and the follow-up time is relatively short. However, further studies are needed to explore the utilization of EBV DNA during the COVID-19 pandemic.