The Epstein-Barr virus (EBV) is back again and it doesn’t look like it’s going to go away anytime soon. In fact, we’ll likely be seeing more and more of this complex virus as time goes on – and hopefully, finally, learn not just what it’s doing in long COVID but in chronic fatigue syndrome (ME/CFS) as well.
“LIINCING” the Epstein-Barr Virus and Long COVID
The “Chronic viral coinfections differentially affect the likelihood of developing long COVID” study came out of a very active group of long-COVID researchers at one of the top medical universities in the country – the University of California at San Francisco. Early on in the pandemic, they formed the “Long Term Impact of Long COVID”, or LIINC group, and started studying long-COVID patients. They are all in on long COVID.
They’ve been responsible for a number of findings, including that gut microbes are leaking into the blood, that systemic inflammation and profound immune dysregulation is present, that Paxlovid may be helpful, that exercise capacity is reduced, and that persistent immune activation is present. LIINC is an independent group that is also working within the RECOVER Initiative.
This study was focused on finding patterns of EBV activation in long-COVID patients vs people who had recovered from COVID-19. Did people with long COVID have an active EBV infection? Was their immune response to the virus different?
The group assessed 5 different antibodies the body produces to tamp down EBV infections:
- EBV-VCA IgG antibodies – high levels indicate a recent infection.
- EBV-IgM antibodies – high levels indicate a recent infection.
- EBV – c VCA IgG antibodies – indicate an infection sometime in the past (95% of people have been exposed to EBV).
- Anti-EA-D IgG antibodies – indicate that an active infection is present or that a recent infectious event occurred.
- EBV nuclear antigen [EBNA]) IgG – The levels of this antibody usually increase as the virus transitions to latency. EBNA antibodies can be involved in mimicry (i.e. they can attack the body tissues) and have been associated with an autoimmune response.
They also directly looked for evidence of EBV in the blood using PCR in 50 participants and assessed whether the participants had been exposed to another herpesvirus called cytomegalovirus (CMV) at some point (CMV IgG test).
Plus, they also assessed several neuronal and immune markers:
- markers of neuronal injury, inflammation, and immune activation (glial fibrillary acidic protein [GFAP, a marker of astrocyte activation] and neurofilament light chain [NFL, a marker of neuronal injury],
- cytokines – monocyte chemoattractant protein-1 [MCP-1], IFN-γ, IL-6, IL-10, TNF-α, and IP-10).
They also took a deep dive into symptoms. They used two different symptom assessments to assess new symptoms: the CDC’s 32 COVID-19 symptom list and the Patient Health Questionnaire (PHQ) somatic symptom scale. Because neither assesses the frequency of symptoms, and only the PHQ assesses the severity of symptoms, none would be considered an adequate symptom assessment in an ME/CFS study. (If you want to do really good symptom assessments you have to go to the field that needed to develop them (ME/CFS) and use Lenny Jason’s DePaul Symptom Questionnaire which assesses both frequency and severity.) The authors also used a visual analog scale to assess general health pre- and post-infection.
They created different symptom groups – fatigue, neurocognitive, gastrointestinal, and cardiopulmonary – and then assessed whether the different results (EBV antibodies, CMV antibody, cytokine, and neuronal panel) were associated with them; i.e. whether an EBV antibody was associated with increased levels of neurocognitive symptoms, etc.
This research group had been concentrating on HIV. Because some studies suggested that people carrying the HIV retrovirus were more likely to come down with long COVID, the study included about 55 people living with HIV, which apparently left the study cohort a bit male-heavy. Fifty-six percent of the 280-person cohort were males, 19% were living with HIV, and 18% had been hospitalized during their COVID-19 infection. The participants were assessed about 4 months post-infection.
The Fatigue and Nervous System Virus?
“The study confirmed that a connection between EBV reactivation and long COVID exists”. The authors
The tests did not indicate that the long-COVID patients had an active EBV infection. EBV was detected in the blood by PCR in only 1 of the 50 people tested, and it was at low levels.
Higher levels of EBV NA IgG – the antibody that gets produced as the virus is settling into its latent state – were, however, associated with neurocognitive symptoms and with having long COVID.
Increased levels of EBV EAD IgG – the antibody that suggests that a recent infectious event has occurred – were strongly associated with new-onset fatigue. Being hospitalized, having a prior autoimmune diagnosis (thyroiditis), and having a high basal metabolic index were also associated with more new-onset fatigue.
Note that his paper found that the long-COVID group did not have an active EBV infection. Long COVID was associated with: a) the immune response to the reactivation of the virus that occurred during the COVID-19 infection; and/or b) an immune response to the virus settling into a latent state. In either case, this paper suggests that it’s the immune response to the reactivation of the virus that was causing problems.
- The “Long-term Impact of Infection with Novel Coronavirus”, or LIINC group, at the University of California at San Francisco started studying long-COVID patients early.
- They’ve produced several findings in long COVID. In this study, they assessed the levels of 5 EBV antibodies, used PCR to see if EBV was in the blood, assessed several immune and nervous system factors, and used symptoms to put long-COVID patients into different categories: fatigue-long COVID, neurocognitive long COVID, gastrointestinal long COVID, and cardiopulmonary long COVID.
- Nothing in the results suggested that EBV was “active”; that is, it was not producing more virions. Instead, the results suggested that an active EBV infection triggered at the time of the coronavirus infection (but which was no longer present) had produced an immune response that was causing problems in long COVID. In other words, the virus has gone into hiding, but the immune response lingers on.
- This showed up in the increased levels of 2 antibodies to EBV in the long-COVID patients that were associated with increased fatigue and neurocognitive symptoms. Since they were not associated with gastrointestinal or cardiopulmonary long COVID it does not appear that EBV reactivation is having much of an effect on them.
- The fact that antibodies to EBV were associated with fatigue wasn’t entirely surprising as EBV reactivation has been associated with fatiguing illnesses like infectious mononucleosis, multiple sclerosis, and ME/CFS.
- At least five studies have found evidence of EBV reactivation in long COVID, and EBV has been found reactivated in autoimmune diseases, in immunocompromised patients, during times of hormonal changes, in ME/CFS, and during stressful situations.
- Stress is an interesting reactivator given that both of the major stress response axes (HPA axis, autonomic nervous system (ANS)) are impaired in ME/CFS.
- Despite EBV’s connection to infectious mononucleosis, cancer, autoimmune diseases, ME/CFS and now long COVID, the antivirals used to treat it are not very effective and better ones are needed.
- The findings – some from very good studies – that an EBV subset exists in long COVID should be catnip for the NIH RECOVER program. RECOVER was designed to methodically and rigorously chase down leads, and come to definitive conclusions.
- If RECOVER really takes EBV on, we should rather quickly learn much about the impact EBV is doing, why people with long COVID – and likely people with ME/CFS – are so susceptible to it, and ultimately learn how to effectively treat it. That could be a huge benefit for long COVID and ME/CFS.
The fact that the EBV findings were associated with fatigue and neurocognitive symptoms was not surprising given that these symptoms are common in infectious mononucleosis (usually associated with an EBV infection) and in ME/CFS. The authors also noted the now very strong EBV connection with another very fatiguing illness – multiple sclerosis.
While two EBV antibodies were associated with neurocognitive and fatigue in long COVID, none of the EBV antibodies were associated with gastrointestinal-long COVID. Instead, gut symptoms were more prominent in people who had been hospitalized or had a high basal metabolic index (BMI – were overweight).
The only factor that was associated with cardiopulmonary symptoms was being hospitalized. Those symptoms were clearly fading over time as they were the only symptom that was being reduced after 100 days.
The biggest shocker was that having a prior CMV infection was associated with not having neurocognitive long COVID, and was almost associated with not having long COVID (>5 symptoms) (p<.057).
The authors noted that past studies had found high amounts of EBV reactivation in the acute stages of long COVID in hospitalized patients. Their results showed that EBV reactivation was causing problems even in non-hospitalized long-COVID patients. They stated that “the study confirmed that a connection between EBV reactivation and long COVID exists”.
EBV has become quite a thing in long COVID. It took less than a year for it to start popping up in long-COVID studies. A major March 2022 study that pegged an EBV reactivation subset was followed by a June 2022 study that found 2/3rds of long-COVID patients showed signs of EBV reactivation. Iwasaki’s major August 2022 study was the next to uncover a significant EBV subset. Not long afterward, an Australian group linked EBV reactivation in the throat to long-COVID fatigue.
EBV reactivation is a major concern in diseases with states of severe immunodeficiency and it can be triggered in many ways. Immunosuppressants, cancer treatments, autoimmune diseases, hormonal changes, and a coronavirus infection can all prompt EBV to emerge from slumber, rev its engines up, and start producing new virions. A recent study seemed to nail down EBV as the cause of multiple sclerosis, but evidence is emerging that EBV may be implicated in other autoimmune diseases. A recent paper, for instance, suggests that EBV may trigger rheumatoid arthritis.
Because EBV reactivates in response to stress, it seems like the perfect virus for a disease with impairments in both of the major stress responses (HPA axis, autonomic nervous system (ANS)) like ME/CFS. Given the recent focus on early or innate immune system findings (monocytes/macrophages) in ME/CFS and long COVID, it’s interesting that failures of the innate immune system may pave the way for EBV reactivation.
Even without the long-COVID and ME/CFS connection, EBV is a big deal. It was the first virus to get its complete genome sequenced (congratulations!) and is purportedly responsible for hundreds of thousands of cancer deaths every year. The available antivirals were not developed to stop EBV, though, and are not particularly effective at doing so. Nor have EBV vaccines been developed. I was told that at least one newer, more effective EBV drug has been developed but hadn’t received much interest until EBV showed up in long COVID.
One would think that the Epstein-Barr virus has shown up enough in enough really good studies for the RECOVER Initiative to take note. RECOVER, thus far, has pretty much failed miserably with its initial set of clinical trials, but the EBV situation is different. Theoretically, RECOVER should excel here.
As Dr. Koroshetz explained, RECOVER was designed to methodically and rigorously chase down leads, and come to definitive conclusions. That’s a recipe for efficiency and movement and it’s the antidote to the situation we have in ME/CFS: lots of small intriguing studies that leave the field interested but unclear about the impact EBV is having. If RECOVER really takes EBV on, we should rather quickly learn much about the impact EBV is having, why people with long COVID and likely people with ME/CFS are so susceptible to it, and ultimately learn how to effectively treat it.
Keep the Information Flowing!
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