Is the Epstein-Barr Virus Associated With COVID-19?

Paul G. Auwaerter, MD


March 17, 2022

This transcript has been edited for clarity.

Hello. I'm Paul Auwaerter with Medscape Infectious Diseases, speaking from the Johns Hopkins University School of Medicine.

There have been two recent papers that have brought Epstein-Barr virus, otherwise known as EBV, into an interesting mix of whether it may be a cause of autoimmune illnesses or prolonged fatigue after COVID-19.

As a long-time student of infectious mononucleosis, which for decades was unexplained, it's interesting looking back at history that the link to EBV was due to an accidental lab-based infection where a lab worker became infected and subsequently developed an infectious mononucleosis–type illness. That link was solidly established in 1967.

Through the 1970s and 1980s, EBV was often thought of as a cause of fatigue and other subjective symptoms, so-called chronic EBV. To this day, in my infectious diseases practice, it's not uncommon that serologic profiles of EBV are checked and patients are referred with a request of whether their EBV is a cause of their symptoms of pain, fatigue, poor sleep, or brain fog, and if there are any interventions worth of note.

Over the years, there hadn't been much credible evidence to link other than the general serologic evidence that most adults (historically, it's always been thought 95% of people) by the time they're 40, are infected with EBV.

However, the two papers that I think are interesting follow on the heels of large amounts of epidemiologic evidence over the years that have tried to link EBV as an association and perhaps a cause of things such as Hodgkin lymphoma from a large Danish epidemiologic study and then also autoimmune diseases, such as rheumatoid arthritis, Sjögren syndrome or lupus, from a variety of studies that suggested that incidences of these diseases are more frequent after someone has recovered from infectious mononucleosis.

A recent paper in Science about multiple sclerosis (MS) in the US military demonstrated that there was a 32-fold increased risk for MS among 955 members of the military, who unfortunately developed MS. Almost all who developed MS had evidence in their smaller cohort, where they had samples longitudinally to assess for EBV, that they developed MS only after EBV infection. This was, on average, 10 years after acquiring the virus.

The other paper deals with so-called PASC, or post-acute sequelae of COVID-19, so-called long COVID-19, in 309 patients that was published recently in Cell in January 2022. The authors identified four risk factors for this condition, including type 2 diabetes, the extent of SARS-CoV-2 viremia-specific antibodies, and they also noted EBV viremia.

As I sit back and wonder whether EBV is a linchpin in all of this, we still have no clear understanding of mechanisms and we merely have descriptions and perhaps increasing evidence that there may be some role.

Unfortunately, there are no antiviral agents that clearly control EBV, and in fact, it is unclear whether control of EBV reactivation would play any role in prevention. I think this becomes a fundamentally more difficult question. One has always wondered if herpes reactivation contributes to disease states or symptoms such as fatigue.

I'm always reminded of the studies of cytomegalovirus (CMV) in acute illness, especially in the intensive care unit (ICU). There, anti-CMV therapy really did not appear to have any impact on the extent of critical illness, so the CMV reactivation was merely a reflection of the disease rather than contributing to the severity of illness.

Unless there are some fundamental discoveries in mechanisms, we're really waiting to see whether something like an effective EBV vaccine might, therefore, prevent autoimmune illness or MS. There have been some candidate vaccines, but they've unfortunately languished a bit.

I think there is maybe an increasing role to look at EBV, which is something that may be a significant challenge. There have been attempts at herpes simplex virus (HSV) vaccines and so on, but this probably is going to be one of the few ways to truly get at whether abolishing EBV vaccine plays some role in staunching the emergence of autoimmune diseases, such as lupus, possibly cancers, and even conditions such as long COVID-19 or potentially MS.

Thanks very much for listening.

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