What happens when you don’t recover from Epstein-Barr virus?
Epstein-Barr virus has been linked to numerous serious diseases, including the still mysterious condition chronic fatigue syndrome. Here, Gavi writer Priya Joi looks at what we know about the links between the virus and a syndrome that once left her bedridden.
- 20 April 2023
- 10 min read
- by Priya Joi
Most of my friends spent their 30th birthdays singing karaoke, or at a noisy house party, lamenting the end of their 20s. In contrast, I spent mine in a quiet restaurant at the end of my road in South London, anxiously clock-watching, as I knew I would only have a couple of hours of energy before I had to head back home to bed.
I had chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME), and most activities from socialising to running had taken a back seat, as my life was a cloudy soup of symptoms including brain fog, migraines and extreme exhaustion. Working as a journalist was often impossible. Bright light and noise were frequently overwhelming, and fibromyalgia made my muscles excruciatingly sensitive.
Suggesting that psychological interventions could help people with CFS/ME recover is not to suggest there wasn’t also a biological cause.
My symptoms had been triggered by glandular fever or mononucleosis, caused by Epstein-Barr virus (EBV), which is responsible for most cases of this infection (my blood tests showed high levels of antibodies to EBV). I happened to be one of the roughly 10% who get glandular fever and go on to develop CFS/ME.
While I was fortunate enough to recover from it within a couple of years, it nevertheless left me bedridden, and I know many people who have never recovered. It is a peculiar thing to be a science journalist who, over 20 years, has written about almost every kind of infectious disease, but never have explored CFS/ME. But that's because the condition has been fairly mysterious. There are polarised opinions in both the medical and patient communities as to what causes it and how to recover from it.
Now, however, emerging similarities with Long COVID have brought renewed interest to understanding what might cause this condition.
Echoes of Long COVID
When the COVID-19 pandemic started, data began to emerge suggesting that 10-15% of infected people continued to experience symptoms several months after the initial infection. People who, like me, have had CFS/ME had a strong sense of déjà vu.
The dominant symptoms that people with Long COVID suffer from – brain fog, fatigue, muscle pain – have been extremely familiar. So has the seeming lack of physical cause and the erratic nature of symptoms that can ease or intensify seemingly at random.
People with Long COVID have also said that their symptoms are not always linked to specific triggers. Stephanie Longet, an immunologist who is studying Long COVID, and who has the condition herself, has leg pain as one of her symptoms. Sometimes she may wake up in the morning feeling like she has run a marathon, despite having been in bed all night.
For people who have had CFS/ME that is now dormant, COVID-19 infection can reactivate their condition. Antibody levels against several herpes viruses, including EBV, have been shown to be raised in people with COVID-19 who previously had CFS/ME, compared with in people who had never had CFS/ME.
How could EBV cause CFS/ME?
EBV infects about 95% of us at some point in our life. In a few people, something happens to link this infection with a range of serious illnesses, including multiple sclerosis, Guillain-Barre syndrome and inflammatory bowel disease. A 2022 paper in Science, for instance, showed that people infected with EBV were 32% times likely to develop multiple sclerosis.
The virus mainly spreads through bodily fluids – mainly saliva, but also blood and semen. EBV can be transmitted through kissing, sharing a toothbrush, or drinking from a glass recently used by an infected person.
The link between EBV-caused glandular fever and CFS/ME has been proposed for decades. In a 1998 paper, Peter White, then at St Bartholomew's hospital in London where he led work on CFS, found that the incidence of an acute fatigue syndrome was 47% after glandular fever, compared with 20% with a different upper respiratory tract infection.
Given the ubiquity of EBV infection, studying its correlation with disease is difficult and there are still no universally accepted clinical criteria for CFS/ME, nor agreed biomarkers that could be used for diagnosis.
In an attempt to define the condition, in 2015, the US Institute of Medicine defined CFS/ME as "substantial reduction/impairment in the ability to engage in pre-illness levels of occupational, educational, social or personal activities that persists for more than six months and is accompanied by fatigue, which is new or of definite onset (not lifelong), is not the result of ongoing excessive exertion and is not substantially alleviated by rest, (ii) post-exertional malaise, (iii) unrefreshing sleep and (iv) either cognitive impairment or orthostatic intolerance."
There are multiple theories for how EBV could trigger CFS/ME. Maria Ariza at the Ohio State University Wexner Medical Center, US, and her team have proposed that EBV produces a pathogenic protein called deoxyuridine triphosphate nucleotidohydrolase (dUTPase) that causes neuroinflammation and triggers CFS/ME. This dUTPase protein altered the gene expression of proteins that influence fatigue, pain synapse structure, and function, as well as tryptophan, dopamine, and serotonin metabolism.
Madlen Loebel at Charité University Medicine Berlin, Germany, and colleagues found evidence that people with CFS/ME had immune systems that were not responding strongly enough to EBV. They had a "profound deficiency" in EBV-specific B- and T-cell memory response, suggesting the body was not equipped to clear the virus from the start.
Not all in the mind
In the 1980s, a Newsweek article described CFS/ME as "yuppie flu", referring to the burnout that wall street bankers and other high earners who worked around the clock were experiencing. Unsurprisingly, this upset many people with the condition, and mirrors similar discussions around Long COVID, with some referring to it as potentially being "all in the mind".
However, it has been suggested that there is a psychological connection with symptoms in some people with CFS/ME. Doctors like Simon Wessely, professor at the Institute of Psychiatry at King's College London, UK, who have spoken about this, have been vilified and even sent death threats as some vocal patient-support organisations and doctors deny any psychological link.
The ME Association, which was set up in 1980 to support people with CFS/ME and has now expanded to include Long COVID, maintains that "complete recovery from ME/CFS is rare" and instead encourages a focus on "convalescence and appropriate self-management".
In 2016, the organisation reprinted a piece from Nursing in Practice, in which Keith Geraghty, a doctor aligned with the association, says that CFS/ME "is sometimes presented as a psychosomatic disorder that requires psychological treatment. However, there is no compelling evidence that ME/CFS is a mental health condition and increasing evidence shows it is a biological disease with a range of complex symptoms."
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Yet there's an inherent fallacy in this statement, as a condition that requires psychological treatment is not necessarily psychosomatic – i.e. driven by worry or stress rather than a biological cause – and suggesting that psychological interventions could help people with CFS/ME recover is not to suggest there isn't also a biological cause.
Indeed, research in psychology and psychiatry has long suggested that physiological conditions can trigger psychological conditions and vice versa. Thus, suggesting that our mind and bodies are connected is not in the realm of alternative medicine.
In White's 1998 study, for instance, he found that "new episodes of major depressive disorder were triggered by infection, especially the Epstein-Barr virus", although he acknowledges they lasted an average of three weeks.
So how can a condition caused by a virus like Epstein-Barr virus be resolved by psychological treatment? The clue might be that psychological conditions may be a risk factor in developing the condition in the first place – if that's true, then it's possible that psychological interventions might help resolve symptoms for some people.
Much has been made of underlying conditions, such as obesity, as risk factors for COVID-19 or Long COVID. However, according to a 2022 study led by Siwen Wang, a researcher in the Department of Nutrition at Harvard Chan School, and colleagues, "Psychological distress was more strongly associated with developing Long COVID than physical health risk factors such as obesity, asthma, and hypertension."
In their study in JAMA Psychiatry, Wang et al describe evidence that psychological distress, including depression, anxiety and stress, puts people at a startlingly high risk (32-46%) of developing Long COVID.
'False fatigue alarms'
Paul Garner, an infectious disease expert at the UK's Liverpool School of Tropical Medicine, caught COVID-19 early in 2020, and then developed Long COVID, which he described as being "hit with a cricket bat". Speaking over the phone two years ago for an interview with Gavi, he had told me how a former CFS/ME sufferer helped him "reprogramme his mind" to counteract some of his symptoms such as brain fog.
Garner is a well-respected infectious disease researcher and I wondered what what his thinking was about using the mind to heal the body. He said: "Your body has an autonomic nervous system that is a very basic system to protect you from harm. It's the system that means you automatically pull your hand away if you touch something hot after you feel pain. And I honestly think that a lot of the chronic fatigue and ME in post-viral syndromes is to do with these systems becoming disordered.
"So in evolution, fatigue might be your body shutting you down when you are unwell to stop you using energy so your body could recover. But it just gets distorted somewhere in the disease process and faulty neural pathways set up these 'false fatigue alarms'. And when you expect them, your unconscious learns triggers for these false alarms."
The way Garner recovered through psychological techniques such as mindfulness and short bursts of exercise, is not dissimilar to the way I recovered from CFS/ME, after trying acupuncture and even swampy black potions of Chinese herbs, in a desperate attempt to heal.
Talking therapy helped me to work through the psychological distress and burnout I had been experiencing before I got sick with glandular fever, and in addressing those issues, my symptoms also lifted.
Peter White published another paper with Michael Sharpe, psychiatrist and well-known CFS expert at the University of Oxford, showing increasing evidence that cognitive behavioural therapy (CBT) can resolve symptoms in some people too.
This is not to say that everyone with CFS/ME will see their symptoms ease with the same methods, but that there is evidence that for some people, psychological interventions work.
Vaccines for EBV
Despite the number of conditions EBV is linked to, there has been a dearth of research on developing a vaccine for it – possibly because the fact that nearly everyone has been infected with the virus at some point in their life means a vaccine would have to be part of a routine immunisation programme, which is far more challenging than targeting a specific population.
In May 2022, The US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, launched an early-stage clinical trial to evaluate an investigational preventative vaccine for Epstein-Barr virus (EBV). There has only been one other study testing an investigational EBV vaccine in more than a decade.
The vaccine works by targeting EBV glycoprotein gp350, found on the surface of the virus and virus-infected cells. This glycoprotein is also the primary target for neutralising antibodies found in people who are naturally infected with EBV. The vaccine is delivered via ferritin, an iron-storing protein that works as a vaccine platform because it can display a dense array of proteins from the targeted virus on its surface.
The study won't be finished for another two years at least, and so it's too soon to say how effective it will be. So what happens in the meantime? More attention since the emergence of Long COVID has catalysed scientists into research to understand the specific mechanisms by which EBV can cause CFS/ME, although using these to develop potential treatments is likely to be a way off.
Perhaps until physiological treatments are widely available, moving away from a binary position that CFS/ME is either entirely psychosomatic or fully physiological would benefit people.
Whether or not a treatment is expected to work, and even when the mechanism of action isn't clear, the way that robust science operates is looking at the evidence to see what has an effect and what doesn't – thus, if psychological interventions improve symptoms, even if that is unexpected or seemingly unlikely, then dismissing them on the basis of assumptions that recovery from CFS/ME is near-impossible is unscientific.
Insisting that psychotherapy must help when a patient is seeing no improvement is just as unhelpful as denying the benefits of psychotherapy when there are numerous accounts of people who have recovered from CFS/ME through this approach. There is no intellectual argument to be tussled over.
Arguably, as Garner says, a "more rational, clear-headed discussion that takes into account people's lived experiences is what we need more of."