The onset of ME/CFS has long been associated with viral-like illness. Although it is not currently known exactly which viruses are involved, those which cause glandular fever (Epstein-Barr virus), the mosquito-borne infection Ross River virus, and influenza have all been linked to the illness.
Prior to the COVID-19 pandemic, research interest in the viral origins of ME/CFS had diminished, with the National Institute of Health even making it clear that they weren’t interested in funding further viral studies. However, following the pandemic, and the emergence of long COVID after a clear viral infection, the interest in viruses, and how they could lead to ME/CFS and contribute to symptoms has been reignited.
A recent paper by Professor Maureen Hanson discusses how viral infections might be linked to the onset of ME/CFS, and highlights areas for further research.
What are viruses?
Viruses are very small infectious agents that cause disease by infecting living organisms (hosts) and replicating in the host cell tissue. Viruses can also lay inactive within cells of the host after an initial infection, but certain events such as another infection or physical or emotional stress can lead to reactivation of the virus.
Can any virus cause ME/CFS?
While several different viruses have been associated with the onset of ME/CFS, the evidence supporting these associations is limited both by a lack of confirmed viral infection – for example, through laboratory tests – and also by the definition of ME/CFS used.
In the paper, Hanson considers two specific studies which are often used to support the idea that different viruses can lead to ME/CFS, and clearly highlights the limitations. Her discussion of these papers is summarised below:
Study no. 1
| The study | Hickie and colleagues, Dubbo, Australia, 2006 |
| Which viruses? | Epstein Barr virus, Ross River virus |
| Who took part? | 253 people, 83 of whom, although they displayed symptoms, did not have the infection |
| Results | 9% of participants showed “post-infective syndrome” 12 months after infection |
| Limitations | While “post-infective syndrome” did include symptoms of fatigue and neurocognitive difficulties, there was no information on post-exertional malaise or unrefreshing sleep – both of which are essential for a diagnosis of ME/CFS under the IoM (NAM) ME/CFS diagnostic criteria, and the NICE guidelines for diagnosing ME/CFS. These particular viruses are unlikely to explain the number of people living with ME/CFS worldwide as Ross River virus is only common in Australia and Papua New Guinea. |
Study no. 2
| The study | Magnus and colleagues, Norway, 2009 |
| Which viruses? | Influenza virus |
| Who took part? | 4,822,337 people |
| Results | In the 3 years following suspected infection, people with influenza symptoms had an increased risk of developing ME/CFS compared with those who did not experience symptoms |
| Limitations | In this study, medical records were used to assess a diagnosis of ME/CFS rather than ensuring participants met specific diagnostic criteria for ME/CFS. Medical records were also used to assess the presence of influenza infection, and not all cases of influenza were confirmed by laboratory test, rather they were diagnosed based on symptoms. |
Enteroviruses
Hanson goes on to state that, in her opinion, enteroviruses are the “most likely culprit” in the development of ME/CFS.
What are enteroviruses?
- Enteroviruses are a specific group of viruses that usually only lead to mild illness with symptoms such as fever, runny nose, sneezing and cough. However, they can lead to more severe complications such as meningitis in infants and those with compromised immune systems.
- The diseases caused by enteroviruses include the common cold, sinusitis, hand foot and mouth disease, pancreatitis, and polio. Enteroviruses can also lead to infections that do not lead to any symptoms (asymptomatic infections).
While there is currently no evidence proving that enteroviruses can cause ME/CFS, Hanson draws on historical outbreaks of ME/CFS – such as those in Akureyri, Iceland in the 1940s, and at the Royal Free Hospital in London in the 1950s. In these outbreaks, those who developed ME/CFS often lived or worked in close proximity to those with confirmed cases of enterovirus infection.
Although more recent research has supported the connection between enteroviruses and the onset of ME/CFS – for example, stomach cell samples taken from people with ME/CFS were found to contain enteroviruses years after initial infection – these studies are limited by small sample sizes, and much more research is still needed.
It is important to note that while enteroviruses are common across the world, not everyone who contracts an enterovirus infection develops ME/CFS. Hanson suggests that enteroviruses could still be a cause of ME/CFS though two methods:
- ME/CFS is caused only by uncommon variant(s) of common enteroviruses.
- ME/CFS is caused by an uncommon reaction to a common enterovirus infection – for example due to a person’s genetics, pre-existing health condition, or other biological factor.
Human herpesviruses
Human herpesviruses (HHV) include Epstein-Barr virus (EBV), which causes glandular fever – another virus commonly reported by people with ME/CFS as the start of their illness. Despite these reports, there currently is no proof that HHV, specifically EBV, is a causal factor of ME/CFS.
What are human herpes viruses?
- HHV are another group of viruses that usually lead to significant and sometimes recurrent viral illness.
- HHV can also lie inactive (latent) in the cells they infect, and be reactivated through subsequent infection or environmental stress.
Hanson suggests that there are three possible ways HHV may lead to ME/CFS:
- HHV can directly lead to the development of ME/CFS.
- HHV infection leads to a person being more likely to develop ME/CFS following a subsequent viral infection (which may be asymptomatic).
- Initial HHV infection does not lead to ME/CFS, but reactivation of the virus could help to maintain the illness.
It is possible that methods 2 and 3 could occur together, and that method 3 may explain why some people with ME/CFS have been found to improve after they take anti-herpes viral drugs.
The concept of viral reactivation, and how it could lead to abnormal energy production in ME/CFS, is something that Dr Bupesh Prusty is investigating in a study funded by ME Research UK.
Should long COVID be called ME/CFS?
Although there are many similarities between ME/CFS and long COVID – referred to in the paper as “Post-SARS-CoV-2 infection syndrome” – Hanson highlights the importance of considering them separately in research.
One particular issue drawn upon is that the development of ME/CFS diagnostic criteria occurred before the onset of COVID-19 – meaning that they are not designed with long COVID in mind, or to capture specific long COVID symptoms. So, although many people with long COVID do meet diagnostic criteria for ME/CFS 6 months after the onset of symptoms, we cannot be sure that ME/CFS diagnostic criteria capture all symptoms specific to long COVID.
Therefore, at present, referring to long COVID as ME/CFS will only confuse the scientific literature. More research is needed to establish exactly the symptoms that characterise long COVID, and to assess the specific subgroups that exist.
Summary
The article is limited as it does not include a comprehensive review of all the evidence relating to ME/CFS and viruses. While this limits the conclusion that can be drawn, it does still demonstrate that there is evidence to support that the onset of ME/CFS could be linked to viral infection – which specific virus(es) is less clear. It also remains unclear whether it is the initial viral infection which causes ME/CFS, or whether this infection leads to a susceptibility to develop ME/CFS in the future.
Going forward, more detailed recording of both sporadic cases and outbreaks of ME/CFS is needed to enable a better understanding of the cause of illness and disease trajectory. In addition, there is a need for research which aims to identify which viruses most commonly lead to the development of ME/CFS – such as the work currently being carried out by Dr Amy Proal and her team, funded by ME Research UK.
Takeaway messages
- A number of different viruses have been linked to the onset of ME/CFS, but at present evidence is limited.
- Enteroviruses:
- A family of viruses that generally cause mild illness such as the common cold. Not all people with an enterovirus infection develop ME/CFS.
- It is possible ME/CFS is caused by a specific uncommon variant(s) of common enteroviruses or an uncommon reaction to a common enterovirus infection.
- Human herpes virus:
- Another group of viruses that usually lead to significant and sometimes recurrent viral illness.Include Epstein Barr virus which causes glandular fever and is commonly reported to be linked with ME/CFS onset.
- It is possible that HHV could directly lead to the development of ME/CFS or lead to a person being more likely to develop ME/CFS following a subsequent viral infection (which may be asymptomatic).
- SARS-CoV-2 infection:
- Although there are many similarities between ME/CFS and long COVID, the two illnesses should be considered separately in research.
- More detailed recording of both sporadic cases and outbreaks of ME/CFS is needed to enable a better understanding of cause of illness and disease trajectory.
- There is a clear need for research which aims to identify which viruses most commonly lead to the development of ME/CFS.
