Infections and ME/CFS

Although the exact reason ME/CFS develops remains unclear, infections from microorganisms that cause disease – pathogens such as bacteria, viruses and fungi – may provide a possible explanation.

Recently, ME Research UK summarised two articles relating to viruses and ME/CFS: one which discussed the viral origins of ME/CFS, and another which considered what existing research tells us about whether viruses may be a potential cause of ME/CFS. These papers highlight that viruses are commonly linked to ME/CFS – most often, enteroviruses which usually cause mild symptoms such as those you would get with the common cold, and human herpes viruses which cause a number of diseases including glandular fever.

Certain bacteria such as Coxiella burnetii which causes Q fever, Mycobacterium tuberculosis infection which causes tuberculosis, and Mycoplasma pneumoniae which causes pneumonia have also been associated with ME/CFS, as have fungal infections such as overgrowth of the fungus Candidia albicans in the intestine.

While existing evidence does provide a link between ME/CFS and a number of different pathogens, more research is still needed to understand whether they can actually cause the disease, and, if so, exactly which pathogens can cause ME/CFS, the mechanisms involved, and why some people are more likely to develop ME/CFS than others.

A recent study of 791,622 people in Taiwan explored whether having a history of infection with one of 14 different pathogens (5 viruses, 8 bacteria and 1 fungus) could be linked to the development of ME/CFS.

What did the study do?

The researchers used information from a large electronic database of health records for over 2 million people in Taiwan.

From this database, two groups of people were identified:

One group of 395,811 people who had a record of infection with one of 14 different pathogens.
Another group of 395,811 people with no record of infection.

These pathogens are described in more detail below.

Viruses

Varicella-zoster virus (Human herpes virus 3). Causes chicken pox: an itchy, blister-like rash on the chest, back, and face which can then spread to the entire body. Reactivation of the Varicella-zoster virus causes shingles – a painful rash that develops around a nerve.
Epstein-Barr virus. This can cause glandular fever (mononucleosis, or mono). Common symptoms include a fever, sore throat, swollen glands and fatigue (although infection does not always cause symptoms).
Enterovirus. These are a group of viruses that lead to illnesses that spread easily. Most infections caused are mild, such as the common cold, but enteroviruses can also cause polio and meningitis. Symptoms vary depending on the type of enterovirus infection. Sometimes there are no symptoms of infection.
Influenza virus. This causes the flu (Influenza), symptoms of which include fever, chills, a dry cough, muscle aches, sickness, and loss of appetite.
Dengue virus. Spread by mosquitos and causes Dengue. Dengue is common in parts of Africa and Asia, Central and South America, the Caribbean, the Pacific islands, and some southern areas of North America. Symptoms can include fever, severe headache, pain behind the eyes, sickness, swollen glands and a rash.

Bacteria

Mycobacterium tuberculosis. Causes tuberculosis. When these bacteria survive and multiply in the lungs, a TB infection is established which can be in one of three stages: primary infection – no symptoms or low fever, cough and fatigue; latent infection – no symptoms; active disease – symptoms begin in the lungs and include cough, coughing up blood, and chest pain. May also spread to the rest of the body with symptoms varying depending where the infection is.
Escherichia coli (E. coli). Some specific types of E. coli cause symptoms including diarrhoea, stomach cramping and pain, and nausea and vomiting.
Salmonella. A group of bacteria that cause food poisoning. Usually spread through cross-contamination and inadequate cooking. Symptoms include diarrhoea, stomach cramps, fever, sickness and vomiting, and headache.
Staphylococcus aureus. Causes “Staph infection”. Symptoms include a painful red lump on the skin, hot, red and sore skin, and sores, crusts and blisters.
Chlamydia pneumoniae. Causes sinusitis, bronchitis, inflammation of the throat, and pneumonia. Symptoms include fatigue, fever, headache, a runny nose and sore throat.
Orientia tsutsugamushi. The cause of Scrub typhus, a disease spread through bites of infected larval mites. The disease most often occurs in rural areas of Southeast Asia, Indonesia, China, Japan, India, and northern Australia. Symptoms include fever and chills, headache, muscle pains, a dark region at the site of the bite, enlarged glands and a rash.
Mycoplasma. Infects different parts of the body depending on the type of mycoplasma bacteria causing the infection. One example is Mycoplasma pneumoniae which causes a mild form of pneumonia. Symptoms include sore throat, fatigue, fever and headache.
Borrelia burgdorferi. Spread by infected ticks and causes Lyme disease. Most common in central Europe, eastern Asia, and western Europe. Symptoms include a circular shaped rash around the bite, while some people also experience a fever, headache, muscle aches and fatigue.

Fungi

Candida. Present normally in our bodies and on our skin. Usually kept under control by bacteria, but when it overgrows can cause infection. Symptoms include mouth sores, pain when urinating, vaginal discharge, and digestive problems depending on the location of infection.

Once the groups with and without a history of infection had been established, the researchers looked at whether or not participants went on to receive a diagnosis of ME/CFS in the 17 years between 1 January 2000 and 31 December 2017.

Both infections and ME/CFS were identified using International Classification of Disease (ICD) codes, which allow the systematic recording and comparison of illness, but do not provide detail about how a diagnosis of ME/CFS or infection was made.

The researchers excluded people from the study for a number of reasons:

Age less than 20 years.
Diagnosis of ME/CFS occurred before date of infection.
A record of more than one infection.
A diagnosis of any of a number of health conditions during the study period, including rheumatoid arthritis, sleep apnoea, systemic lupus erythematosus, and multiple sclerosis.

The statistical analysis took into account age, sex, any use of antibiotics, and pre-existing conditions such as hypothyroidism, diabetes mellitus, insomnia, depression, anxiety, dementia, irritable bowel syndrome and fibromyalgia.

What did the study find?

The results showed that, overall, those with a history of infection were more likely to have ME/CFS diagnoses than the group without a history of infection.

When considering the pathogens separately, 9 of the 14 investigated were significantly associated with an increased chance of developing ME/CFS. The highest chance of ME/CFS was observed for those with a history of infection with Borrelia burgdorferi (a bacteria), followed by Enterovirus, and Influenza virus.

The ranking of the other associated pathogens is shown in the table below.

Ranking	Pathogen	Type
1	Borrelia burgdorferi	Bacteria
2	Enterovirus	Virus
3	Influenza virus	Virus
4	Mycobacterium tuberculosis	Bacteria
5	Candida	Fungus
6	Salmonella	Bacteria
7	Staphylococcus aureus	Bacteria
8	Escherichia coli (E. coli)	Bacteria
9	Varicella-zoster virus (Human herpes virus 3)	Virus

For all other pathogens investigated, the results were not significant. It is important to note here that the numbers of those with ME/CFS were small for these groups – for example, only 3 people were diagnosed with ME/CFS in the group who had a record of Epstein-Barr virus infection – and the lack of significance may therefore be due to the small number of participants.

What do the results mean?

This study found that people with a history of infection with one of 14 different pathogens had a higher chance of developing ME/CFS over the 17-year study period, compared with those without a record of infection – this was irrespective of sex, age, other heath conditions and medications used. Interestingly, when pathogens were considered separately, an increased chance of developing ME/CFS following infection was observed across bacteria, viruses and fungi.

A history of infection with Borrelia burgdorferi – a bacteria that causes Lyme disease – was found to be associated with the highest chance of developing ME/CFS. Research has shown that in Eastern Asia (which includes Taiwan), the proportion of people bitten by ticks who test positive for a Borrelia burgdorferi infection (71.4%) is higher than that reported Europe (23.2% in Western Europe) or America (30.4% in North America).

These differences may play a role in explaining the results observed in this study. However, it is also important to note that there is an overlap in the symptoms of ongoing Lyme disease and ME/CFS, with some research also suggesting that the mechanisms of the two diseases may overlap. The similarity between the two diseases may lead to misdiagnosis of ongoing Lyme disease as ME/CFS, which could also explain why Borrelia burgdorferi was associated with the highest chance of developing ME/CFS in this study.

Limitations

The study had several limitations, which must be taken into consideration.

Although the study used a large number of participants (which is beneficial as it reduces the chance of missing a significant result), multiple questions were asked of the same dataset. This is something that increases the chance of finding a significant result where there is none. Statistical techniques can be applied to reduce the risk of a “chance finding”, but do not appear to have been used in this study.

While the population included in the study was large overall, within some of the infection groups the numbers of people with a record of ME/CFS were very small. For most infections where this was the case, such as EBV, the groups had insignificant results. However, the group with the highest chance of ME/CFS – those with a history of infection with the bacteria Borrelia burgdorferi – also only had three people with a diagnosis of ME/CFS. Therefore, the researchers state that they are not confident in this result, and it should be interpreted with caution.

The researchers used pre-exiting health records to identify participants. This is beneficial as it allowed the researchers to access detailed information on a large number of people without collecting new data – which is more costly and takes a lot more time. However, it also comes with its own potential limitations.

While records of diagnosis for both ME/CFS and infection were available to researchers, the actual method used to make the diagnosis was not. For ME/CFS this means that it not clear which symptoms were required for diagnosis; for example, whether post exertional malaise (PEM) was included, or even whether the requirements for a diagnosis were consistent between participants.
As the study relied on information in medical records, it is impossible for the researchers to accurately capture participants who were unwell but did not seek medical treatment, meaning there was no record of the infection causing the illness, or those who had symptoms of ME/CFS who either did not seek medical treatment or received the wrong diagnosis.

Overall, this study adds to the existing evidence that a number of different pathogens are linked to ME/CFS. However, much more research is needed to establish whether and how pathogens may be involved in the development of ME/CFS, ensuring not only that there are enough participants for each pathogen investigated, but also that standardised criteria (include PEM as a required symptom) are used to diagnose ME/CFS.

Takeaway messages

A recent study of 791,622 people in Taiwan explored whether having a history of infection with one of 14 different pathogens (5 viruses, 8 bacteria and 1 fungus) could be linked to the development of ME/CFS.
Although the exact reason ME/CFS develops remains unclear, infections from microorganisms that cause disease may provide a possible explanation.
The results showed that, overall, people with a history of infection had a higher number of ME/CFS diagnoses than the group without any history of infection.
When considering the pathogens separately, 9 of the 14 investigated were significantly associated with an increased chance of receiving an ME/CFS diagnosis.
The highest chance of ME/CFS diagnosis was observed for those with a history of infection with the bacteria Borrelia burgdorferi, followed by Enterovirus and Influenza virus.
Overall, this study adds to the existing evidence that a number of different pathogens are linked to ME/CFS. However, the results cannot tell us whether these pathogens actually cause the disease.