Recently, ME Research UK summarised an article by Professor Maureen Hanson about the viral origins of ME/CFS.
Viruses are tiny non-living microbes made up of genetic material – either two strands (deoxyribonucleic acid [DNA]) or a single strand (ribonucleic acid [RNA]) – inside a protein shell. Sometimes they also have an outer layer of fat molecules; those with this outer layer are called “enveloped viruses”, and those without are called “non-enveloped viruses”. For viruses to cause an infection in the body, they must enter a cell and replicate, using their genetic material.
In her article, Prof. Hanson states that a number of different viruses can be linked to the onset of ME/CFS. These are:
- Enteroviruses: non-enveloped RNA viruses which usually only lead to mild illness with symptoms such as fever, runny nose, sneezing and cough.
- Human herpes viruses (HHV): enveloped DNA viruses which lead to illnesses including glandular fever.
- Ross River Virus and the Influenza virus: enveloped RNA viruses which were also both mentioned, but it was noted that the evidence for the association of these with ME/CFS is extremely limited.
At the recent Immunology webinar for the NIH ME/CFS Research roadmap series, Dr Nancy Klimas highlighted the association between viruses and inflammation in the body. Inflammation, particularly in the brain, is thought to play an important role in ME/CFS.
Dr Klimas explained that viruses can lead to inflammation in two ways: firstly upon initial infection, and secondly through viruses which persist in cells of the body. This second mechanism is thought to induce a constant state of immune overactivation and ongoing low grade inflammation, something which has been observed in people with ME/CFS, and a mechanism through which HHV in particular have been related to ME/CFS.
Despite these links, it remains unclear whether viruses cause the disease, and prior to the COVID-19 pandemic, research into viruses as a potential cause of ME/CFS had decreased.
However, the emergence of long COVID rekindled interest in the area due to:
- The observed similarity in symptoms between long COVID and ME/CFS.
- The emergence of long COVID symptoms following a coronavirus infection.
- The observation that not everyone who catches COVID develops long COVID (interestingly, there is evidence to suggest that the development of long-term symptoms may be due to reactivation of an Epstein Barr Virus infection – although this research is not conclusive).
Much of the detailed research investigating viruses and ME/CFS that started following the emergence of long COVID is likely to be ongoing – for example, two projects funded through a call for “researchers wishing to investigate the viral causes of ME/CFS” released by ME Research UK in 2021. One investigating infectious triggers and mitochondrial dysfunction in ME/CFS, led by Dr Bupesh Prusty, and the other which aims to identify viruses in tissue and nerve samples from ME/CFS patients, led by Dr Amy Proal.
While this work is ongoing, and future research planned, it is also important to consider what is already known about viruses as a cause of ME/CFS. Therefore, in a recently published paper, a research team in Korea set out to review existing studies and explore the extent to which viral infections may contribute to the development of ME/CFS.
What did the study do?
The review aimed to identify and summarise all existing, peer-reviewed, published studies relating to viral infections and the development of ME/CFS.
The research team used specific terms including “virus”, “myalgic encephalomyelitis” and “chronic fatigue syndrome” to search two online databases of published biomedical studies.
There were 1,999 studies identified which contained the search terms used. These studies were then screened against the inclusion and exclusion criteria below:
| Inclusion criteria | Exclusion criteria |
| Investigated viral infection. Included both people with ME/CFS and a control group – this could be either a healthy control group, or those a disease other than ME/CFS. Had information on the number of people with ME/CFS, and the number of controls with a viral infection. | Not published in English. Duplicate of an article already considered. No full text available (for example, if there was only a published abstract). |
There were 64 studies that met the inclusion criteria for the review. From these, detailed information was collected including: the number of participants (both overall, and those with the virus(es) of interest), the virus(es) that had been investigated, and the case definition for ME/CFS used.
The information from the separate studies was then pooled together, and used to consider whether there were higher numbers of people with ME/CFS who had evidence of specific viral infections compared with those in the control groups – both healthy controls and those with other diseases.
What did the study find?
In the 64 studies that met the inclusion criteria, there were 4,971 people with ME/CFS, and 5,565 controls (either healthy or with a disease other than ME/CFS).
The studies included in this review used a range of criteria to diagnose ME/CFS (see below) – the Fukuda criteria for CFS was the most commonly used (63% of participants), followed by the Canadian Consensus Criteria for ME/CFS (13% of participants).
A total of 18 different viruses were considered in the review. The table below provides a summary of results for viruses which were found to be more common in people with ME/CFS compared with some controls.
| Virus | Virus type | Symptoms or illness caused slapped cheek syndrome | More common in those with ME/CFS than healthy controls | More common in those with ME/CFS than controls with another disease |
| HHV-7 | Enveloped DNA virus | Often acts together with HHV-6 and can cause roseola – a red spotty rash and high temperature | Yes | No |
| HHV-6 | Enveloped DNA virus | Often acts together with HHV-7 and can cause roseola – a red spotty rash and high temperature | Yes | No |
| Parvovirus B19 | Non-enveloped DNA virus | Slapped cheek syndrome or “Fifth disease” | Yes | No evidence |
| Borna Disease Virus | Enveloped RNA virus | Inflammation of the brain | Yes | No |
| Coxsakie B virus (an enterovirus) | Non-enveloped RNA virus | Fever, headache, sore throat, gastrointestinal distress, extreme fatigue as well as chest and muscle pain | Yes | No evidence |
Note: Infection with any of the above viruses may also not cause any symptoms at all – asymptomatic infection.
Results also indicated that the numbers of infections with more than one virus (co-infections) in those with ME/CFS (specifically HHV-6 and HHV-7, and HHV-7 and Parvovirus B19) were higher than in healthy controls – however these results showed a high degree of uncertainty.
Summary
The results of this review indicate that evidence of infection from certain viruses (specifically, HHV-7, HHV-7, Parvovirus B19, Borna Disease Virus, and Coxsakie B virus [an enterovirus]) were more common in people with ME/CFS compared with healthy controls. Despite this, it remains unclear whether one particular group of viruses cause ME/CFS. Additionally, there was not enough evidence to enable the researchers to draw conclusions when comparing people with ME/CFS to controls who had another disease, or when considering co-infections.
This review has several limitations which must be taken into consideration:
- Although the studies used a range of criteria to diagnose ME/CFS, the information extracted from them was all grouped together for analysis. Combining data from studies using different diagnostic criteria may not be appropriate as the criteria do not all require the same symptoms for a diagnosis of ME/CFS; for example, the Fukuda (for CFS) criteria do not require post exertional malaise – often referred to as the main symptom of ME/CFS for a diagnosis – while the Canadian Consensus Criteria (for ME/CFS) does.
- The researchers only searched a small number of databases for articles, and appear to miss other commonly used methods of identifying articles in a systematic review such as searching the reference lists of included papers.
- Seven studies that were potentially relevant to the review but not published in English were excluded.
- Importantly, there was no consideration of whether the studies included in the review had accounted for participant characteristics such as age and ethnicity, which may impact on the association between viral infection and the onset of ME/CFS.
The findings from this review show that much more research is required to better understand whether viruses may be involved in the development of ME/CFS, and if so, which viruses, and how they lead to the development of symptoms – such as projects recently funded by ME Research UK including the aforementioned work led by Dr Amy Proal and Dr Bupesh Prusty, and more recently, another project, led by Prof. Simon Carding, which aims to investigate whether gut viruses have a role in the development of ME/CFS.
Takeaway messages
- Although viruses have been linked to the onset of ME/CFS, it is still unclear whether they could be a cause of the disease.
- A recent study set out to review existing research, and explore what it can can tell us about the extent to which viral infections may contribute to the development of ME/CFS.
- 64 studies were identified for inclusion in the review, within which were 4,971 people with ME/CFS, and 5,565 controls (either healthy or with a disease other than ME/CFS).
- The studies included in this review used 7 different criteria to diagnose ME/CFS, of which the Fukuda criteria for CFS was the most commonly used.
- 18 different viruses were considered, of which only Human Herpes Virus-7, Parvovirus B19, Borna Disease Virus, and Coxsakie B virus (an enterovirus) were found to be more common in those with ME/CFS compared with healthy controls.
- There was not enough evidence to draw conclusions when comparing people with ME/CFS with controls who had another disease, or when considering co-infections.
- This review has several limitations which must be taken into consideration including:
- Researchers grouped participants diagnosed with different ME/CFS criteria together in analysis.
- There was a lack of consideration for whether studies had accounted for participant characteristics such as age and ethnicity.
- Much more research is required to better understand whether viruses may be involved in the development of ME/CFS, and, if so, which viruses, and how they lead to the development of symptoms.
