Epstein-Barr virus can be reactivated in long COVID

In a recently published study medRxiv* Preprint servers, researchers from the University of California, San Francisco, and Monogram Biosciences examined the associations between the post-acute consequences of coronavirus disease 2019 (COVID-19) (PASC) and Epstein-Barr virus (EBV) reactivation.

Study: Evidence of Recent Epstein-Barr Virus Reactivation in Individuals With Long COVID. Credit: Kateryna Kon/Shutterstock


The biological processes underlying Long COVID (LC), a type of PASC defined by recurrent or chronic infectious symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affecting quality of life, are currently the subject of intense research.

Latent Epstein-Barr virus (EBV), a common human herpesvirus, is present in 90 to 95% of adults in high-income settings. Recent reports have suggested reactivation of EBV as the cause of LC. However, there are few such investigations in well-defined post-acute SARS-CoV-2 cohorts of individuals with and without PASC symptoms over a time course compatible with existing case definitions of LC.

About the study

The aim of the present investigation was to determine the frequency of virological and serologic evidence of EBV reactivation in a well-defined post-acute SARS-CoV-2 cohort of individuals with and without LC symptoms approximately four months after the first COVID-19 Appear. This allowed researchers to assess the independent impact of EBV reactivation on multiple LC symptom categories while controlling for a range of demographic and clinical parameters, including information about acute infections. The team hypothesized that the cohort with PASC symptoms would be enriched for signs of EBV reactivation, in contrast to those who documented full recovery from COVID-19.

The EBV serological assessment includes an estimate of various antibody responses that provide information about previous viral infections and recent viral reactivations. The authors used covariate-fitted binary logistic regression models to assess the independent relationships between comorbidities, demographic variables, and early EBV antigen D (EA-D) and nuclear antigen (NA) immunoglobulin G (IgG) outcomes with LC and between individuals with certain identify symptoms.

The team used plasma samples from a randomly selected subset of 50 subjects who had undergone EBV serological screening categorized by EA-D positivity for quantitative EBV polymerase chain reaction (PCR). This was to assess whether circulating EBV deoxyribonucleic acid (DNA) could be detected in the COVID-19 recovery period and whether there was a correlation between PASC and EBV DNA retention.

In 294 subjects with accessible serologic measurements during a convalescence visit, researchers analyzed the relationships between participant demographics, acute COVID-19 severity, and comorbidities. They also examined the correlation between EBV antibody findings in a group of 143 individuals with available circulating biomarker information.

Life cycle of the Epstein-Barr virus.  Image credit: Designua/ShutterstockLife cycle of the Epstein-Barr virus. Image credit: Designua/Shutterstock


The authors found that PASC symptoms such as neurocognitive impairment and fatigue were associated with serological evidence of recent EBV reactivation in a group of several hundred people with a history of COVID-19 an average of four months after initial diagnosis of COVID-19. These participants had either EBV-NA IgG titers greater than 600 U/mL or EA-D IgG positivity. The researchers also obtained these results after controlling for sample timing, various participant variables, underlying medical conditions, and previous hospitalizations. However, these individuals did not show persistent EBV viraemia.

The team discovered an association between serological correlates of recent EBV reactivation and hospitalization, suggesting that EBV reactivation may be particularly significant in severe SARS-CoV-2 infection, which is regularly associated with a higher prevalence of PASC could. Specifically, the researchers reported that PASC was also found in a tiny percentage of patients with no evidence of recent or past EBV infection, indicating that EBV reactivation was not a prerequisite for LC.

The authors found that serological evidence of recent EBV reactivation was independent of other inflammatory correlates. This conclusion again confirmed the hypothesis that EBV may have an etiological function in PASC. In addition, they discovered independent relationships between EBV-EA-D-IgG positivity, fatigue and pre-existing autoimmune disease.

The scientists explained that it is unclear which biological processes are responsible for the elevated EBV-NA IgG levels observed in connection with PASC symptoms. They discovered that high EBV viral capsid antigen (VCA) IgG levels and not high NA IgG levels were negatively associated with highly symptomatic acute infection, defined as more than 10 symptoms. High levels of VCA-IgG present prior to acute SARS-CoV-2 infection could be protective and minimize the likelihood of EBV reactivation.


Overall, the present work demonstrated that LC symptoms in a post-acute SARS-CoV-2 cohort were associated, but not associated, with serological evidence of recent EBV reactivation after controlling for sample timing, participant variables, prior hospitalization, and comorbidities with persistence of EBV viremia. The team showed that serologic evidence of recent EBV activity could result, at least in part, in some features of PASC.

Nonetheless, this study also emphasized that not all LC were associated with EBV. Other processes, such as persistent SARS-CoV-2 infection in different tissues, might have even more relevant functions in LC, illustrated by the increasing case-series level evidence that PASC symptoms are associated with SARS-CoV-2-targeted antivirals Means drastically disappear therapies.

The current results contribute to the understanding of the connections between EBV reactivation and PASC and suggest that further investigations in the acute stage of SARS-CoV-2 infection were needed. The authors mentioned that additional research on SARS-CoV-2 and other viruses in acute infection and recovery is needed to understand the underlying mechanisms of LC and to develop potential treatments that could slow or stop these processes.

*Important NOTE

medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be relied upon as conclusive, guide clinical practice/health behavior, or be treated as established information.

Magazine reference:

  • Evidence of Recent Epstein-Barr Virus Reactivation in Individuals With Long COVID; Michael J Peluso, Tyler-Marie Deveau, Sadie E Munter, Dylan Ryder, Amanda Buck, Scott Lu, Sarah A Goldberg, Rebecca Hoh, Viva Tai, Leonel Torres, Nikita S Iyer, Monika Deswal, Lynn H Ngo , Melissa Buitrago, Antonio Rodriguez, Jessica Y Chenna, Brandon C Yee, Ahmed Chenna, John W Winslow, Christos J Petropoulos, Amelia N Deitchman, Peter W Hunt, Matthew S Durstenfeld, Priscilla Y Hsue, J Daniel Kelly, Jeffrey N Martin, Steven G Deeks, Timothy J Henrich. medRxiv Preprint 2022, DOI: https://doi.org/10.1101/2022.06.21.22276660, https://www.medrxiv.org/content/10.1101/2022.06.21.22276660v1

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