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Two small studies hint at an association between the Epstein-Barr virus and long COVID. Mario Tama/Getty Images
  • More than 95% of healthy adults have a “latent” or dormant infection of the Epstein-Barr virus (EBV), a type of herpes virus.
  • Illness and other stressors can reactivate the infection.
  • Two very small recent studies have suggested reasons to explore the relationship between reactivation of the infection and the severity of both long COVID and COVID-19.
  • If more extensive studies support the role of EBV reactivation in long COVID, antiviral drugs that work against herpes viruses may help prevent or treat the condition.

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Around a third of people who have had COVID-19 experience symptoms lasting 12 weeks or more, including fatigue, “brain fog,” and skin rashes, collectively known as long COVID.

Other symptoms include difficulty sleeping, joint and muscle pain, sore throat, headaches, and fever.

Individuals can develop long COVID regardless of whether their initial infection with SARS-CoV-2 — the virus that causes COVID-19 — was symptom-free, mild, or severe.

Two small studies examined the role of the reactivation of another virus in long COVID and more severe cases of COVID-19.

This other infection is EBV, a type of herpes virus that can cause glandular fever, which shares many symptoms with long COVID. At least 95% of adults have a “latent” or dormant EBV infection that causes no symptoms.

As below, the results of the two studies are limited, but further investigation is warranted.

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In the first study, doctors at Renmin Hospital of Wuhan University in Wuhan, China, looked at 67 hospitalized people who had both confirmed COVID-19 and an EBV test that their doctor ordered.

It is important to note that most of the patients initially eligible for the study did not undergo an ordered EBV test, so it might be that there was something different about these 67 individuals that led to this recommended screening.

Nevertheless, of those 67 people, around 55% were confirmed as having a reactivated EBV infection.

They found that these patients were more likely to report having experienced fever, although neither group of patients had a measured elevated temperature in the hospital. No other symptoms or vital signs differed between the groups.

The authors did find a higher level of an inflammatory marker called CRP in the EBV group, but in both groups, the levels were within the normal healthy range. The cases were mostly mild in both groups, and the EBV group did not need more oxygen, increased access to ICU care, or longer recovery time.

Their study appears in the journal Scientific Reports.

In the second small study, researchers at universities in the United States and Turkey found that around a third of 185 randomly surveyed COVID-19 patients had symptoms at least 30 days after testing positive.

When the scientists tested blood samples from some participants, they discovered that 66.7% (20 out of 30) of those with long COVID had a reactivated EBV infection.

By contrast, only 10% (2 out of 20) of those who did not develop long COVID were positive for EBV reactivation.

All 185 people in this group tested positive for COVID-19 more than 90 days before undergoing blood tests.

The scientists also analyzed the blood of a second group of 18 patients 21–90 days after testing positive for SARS-CoV-2. This revealed a similar ratio between those with long COVID who had a reactivated EBV infection and those who did not.

The researchers say this suggests that reactivation occurred soon after or concurrently with contraction of the SARS-CoV-2 infection.

They conclude that infection with SARS-CoV-2 may reactivate EBV, which in turn may cause many long COVID symptoms.

This study, led by the research charity World Organization, appears in the journal Pathogens.

The authors write:

“These findings suggest that many long COVID symptoms may not be a direct result of the SARS-CoV-2 virus but may be the result of COVID-19 inflammation-induced EBV reactivation.”

“Over 95% of the world’s population [has an infection] with EBV, and this remains as a largely asymptomatic infection for our lives,” explained Lawrence Young, Ph.D., a virologist and professor of molecular oncology at the University of Warwick in the United Kingdom, who was not involved in either study.

“The virus continues to replicate at a low level in our mouths, noses, and throats, and maintains lifelong latent (dormant) infection in our B lymphocytes,” he told Medical News Today.

“The hypothesis is that primary infection with SARS-CoV-2 targets cells in our mouths and [throat] in which EBV is already present and that this induces high levels of EBV replication,” he added.

If future studies confirm the role of EBV reactivation in long COVID, he believes this will provide opportunities to improve diagnosis of the condition.

He added that anti-herpesvirus drugs, such as ganciclovir, might be effective, though researchers have yet to investigate this.

However, because the study in Pathogens was retrospective, it could not rule out the possibility that EBV reactivation occurred before SARS-CoV-2 infection.

It recruited patients online after they had recovered from the initial infection.

“We had no access to them prior to COVID-19 diagnosis or during their treatment for COVID-19. That was all in the hands of their personal physicians,” said Prof. David Hurley, Ph.D., of the College of Veterinary Medicine at the University of Georgia, Athens, GA, one of the authors of the study in Pathogens.

Prof. Young said that in most people, EBV becomes dormant again following a reactivation. However, in rare cases, it can cause long-term health problems.

A phase 1 clinical trial of an EBV vaccine recently started to test its safety and immune responses in volunteers.

In theory, such a vaccine could protect people against severe illness and long-term health effects of EBV reactivation.

Prof. Hurley remains skeptical, however. He told MNT that there are no effective vaccines against the closely related herpes simplex viruses 1 or 2, despite decades of research.

“No vaccine for EBV is available,” he said. “This is a sad situation as the worst long-term reactivation consequences of EBV are lymphomas, epithelial cancers in the nose and sinuses, and tumors found in muscle tissues.”

This virus lies dormant in immune cells, nerve cells, and epithelial cells, but stressors can reactivate it. In rare cases, this can cause cancer.

“The right combination of stress and inflammation can promote cancer,” said Prof. Hurley.

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