An Unexpected Virus Culprit is Found in Long COVID
Epstein-Barr virus (EBV) is a bigger threat than we thought, and we still don’t know how to treat it.
This article was originally published at Microbial Instincts on August 23, 2022.
When it comes to herpesviruses, once infected, you stay infected.
One unique trait of herpesviruses is the ability to stay latent (i.e., dormant) in the infected host for life. In this latent state, the herpesvirus is inactive, and no virus replication occurs. But in times of stress or immunosuppression, latent herpesvirus can reactivate, start replicating and cause problems.
Is long COVID one of the symptoms of herpesvirus reactivation?
Studies have now found that might actually be the case in some but not all long-Covid cases —with the culprit being Epstein-Barr virus (EBV), also known as human herpesvirus 4.
Evidence of EBV reactivation found in long COVID
In a recent study conducted at Yale School of Medicine, Connecticut, U.S., Klein et al. performed sophisticated blood immune profiling and machine learning techniques to pinpoint what characterizes long-Covid — i.e., what biomarkers distinguish long-Covid from non-long Covid patients.
Klein et al. recruited 178 participants, consisting of 99 individuals with long COVID, 40 uninfected healthy controls, and 39 convalescent controls. (Convalescent: previously infected with SARS-CoV-2 but recovered.)
Among individuals with prior Covid (long COVID and convalescent groups), most were not hospitalized during their Covid period over a year ago.
And blood immune profiling revealed that:
Long COVID group had dysregulated immunological activities involving monocytes, dendritic cells, activated B-cells and T-cells, exhausted T-cells, and certain interleukins compared to other groups.
Long COVID group had lower cortisol levels compared to other groups, which, according to machine learning analyses, is the most significant predictor of long COVID.
No differences in levels of over 6000 autoantibodies between groups.
Long COVID group had higher antibody reactivities against 4 out of 225 virus proteins: EBV capsid protein gp23, EBV early D antigen, EBV glycoprotein gp42, and varicella-zoster virus (VZV) glycoprotein E:
Notably, in the long COVID group, antibody reactivity against EBV proteins correlated with markers of T-cell exhaustion and activation.
This indicates that latent EBV reactivation may drive T-cell dysregulation (or vice versa) and that “the bodies of people with Long Covid are actively fighting something,” said David Putrino, Ph.D., a neurophysiologist, one of the two directors of the Klein et al. study.
“Our data suggest the involvement of persistent antigen, reactivation of latent herpesviruses, and chronic inflammation, and are less consistent with the autoantibodies to extracellular antigens,” Klein et al. wrote. “In aggregate, these findings are consistent with chronic immune engagement against reservoirs of viral antigen among participants with Long COVID.”
Klein et al. aren’t the first to discover the link between EBV reactivation and long COVID. Several other studies have also reported similar findings:
Peluso et al. (2022) demonstrated that increased antibody reactivity against EBV proteins — which correlated with markers of inflammatory cytokines — predicted the development of long-Covid.
Su et al. (2022) showed that increased plasma levels of EBV gene fragments— which correlated with markers of activated and exhausted T-cells — in Covid-19 patients predicted the development of long COVID.
Rohrhofer et al. (2022) reported a higher rate of EBV DNA positivity in throat samples of long-Covid patients compared to non-long-Covid controls (50% vs. 20%).
Gold et al. (2021) found a higher rate of antibody reactivity against EBV proteins in long COVID patients compared to non-long COVID controls who recovered from Covid (67% vs. 10%).
In sum, several studies have found evidence of EBV reactivation and EBV-related immune abnormalities in some but not all long COVID patients.
Indeed, it’s important to note that not all long COVID patients have EBV reactivation, and not all EBV reactivation will lead to long COVID.
In figure 1 above, for example, each dot denotes the data point of an individual case. Some dots between the long COVID and control groups overlap, indicating no differences in EBV reactivation markers in those cases. In essence, not every long COVID case is explainable by EBV reactivation.
Based on the findings of Rohrhofer et al. and Gold et al., EBV likely contributes to long COVID development in 30–50% of cases. And Klein et al. only noted that 20–30% of long COVID patients had markers of T-cell exhaustion correlated with EBV reactivation.
Therefore, it’s unlikely that one true cause of long COVID exists. Long COVID is a multifactorial syndrome stemming from multiple disease-related biological factors, one of which is EBV reactivation.
Further analyses by Peluso et al. revealed that antibody reactivity against EBV proteins predicted the development of fatigue and neurological symptoms of long COVID but, intriguingly, not the cardiopulmonary and gastrointestinal symptoms. This finding suggests that EBV may be responsible for certain subtypes or symptomatic patterns of long COVID.
EBV may also trigger other diseases
At the same time, because EBV is also closely tied to many other diseases — such as B-cell-related cancers, multiple sclerosis, and other autoimmune diseases — it’s possible that long COVID patients may develop these EBV-related diseases later. But this hypothesis has not yet been studied.
As Klein et al. noted, “Whether EBV reactivation may also predispose people with Long COVID to the development or exacerbation of autoimmune pathologies, as has been recently reported for people with multiple sclerosis, will require extensive longitudinal monitoring and surveillance…”
Now, aside from long COVID, what are the broader implications of EBV?
Over 90% of the population worldwide has been infected with EBV at some point in their lives, especially during childhood, mainly via the oral route such as kissing and sharing eating utensils or food and drinks.
The first EBV infection can either cause disease indistinguishable from common childhood illnesses or no disease. In either case, EBV will enter a latent state in B-cells in the body forever. In this state, EBV may occasionally reactivate and re-infect cells, which may or may not cause disease again.
The disease caused by EBV is infectious mononucleosis; possible symptoms are fatigue, body aches, fever, sore throat, swollen lymph nodes, or rash.
Most people recover in 2–4 weeks. However, some may still have fatigue for several more weeks to months, possibly leading to chronic fatigue syndrome, which is also one of the possible diagnoses of long COVID.
Repeated cycles of EBV latency and reactivation/re-infection put the immune system on high alert. As a result, T-cells — which kill abnormal cells like virus-infected or cancerous cells — are continually activated but unsuccessful at eliminating the threat, ultimately leading to a perpetual state of T-cell exhaustion and chronic inflammation.
Thus, markers of EBV-related T-cell exhaustion and chronic inflammation are commonly seen in chronic diseases like cancer, multiple sclerosis, chronic fatigue syndrome, and, now, long COVID.
Particularly in cancer and multiple sclerosis, EBV infection or reactivation has been postulated as one of their leading causes or causative agents.
Because EBV could prime B-cells to undergo abnormal growth rate and morphology changes, EBV is suspected to cause about 1% of cancers worldwide, especially B-cell-related cancers.
Because EBV could prime B-cells to produce auto-antibodies that attack the neuronal myelin sheath, EBV can cause multiple sclerosis in some cases. A 20-year longitudinal study, for instance, has shown conclusively that EBV can trigger the development and is the leading cause of multiple sclerosis.
EBV, therefore, is a bigger microbial foe than we thought.
We still don’t know how to treat EBV
At this point, no specific vaccines or antivirals exist against EBV. Only general anti-pain or anti-fever medications, as well as adequate rest and hydration, are recommended to treat EBV infection.
But by realizing the threat of EBV in instigating or facilitating chronic diseases, including long COVID, new treatments can be pursued and developed. Current promising EBV antivirals in pre-clinical and clinical testing — but not officially approved for public use — include acyclovir, ganciclovir, omaciclovir, valomaciclovir, and maribavir.
By now, we should have one or two approved EBV antivirals. But judging from the lack of it, it’s fair to say we have neglected the threat of EBV for too long. With the rise of the highly prevalent and debilitating long COVID syndrome, we should begin to take EBV more seriously.
By paving new treatments for EBV, we might also be able to treat EBV-related chronic diseases other than long COVID, such as multiple sclerosis, B-cell cancers, chronic fatigue syndrome, and whatever EBV-related diseases we haven’t yet unearthed.
Thank you I have had this exact issue over three years now. It is beyond frustrating. Exhausted all the time. Wake up that way. Luckily for me I had a “friend” tell me it’s because I got “the shot” and that I don’t know what my brother died from. The week of the anniversary of his death. It was COVID. Not sure how the helps me at all, but I guess it made her feel powerful. We are no longer friends.
Very interesting, thanks for writing this. Is EBV infection found "everywhere"? Meaning, are there parts of the world where EBV infection is uncommon? (Thinking of places like highland New Guinea which have had less contact with the outside world until recently)...