Explore the Top 10+ priorities

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Priority 1

What is the biological mechanism that causes post-exertional malaise (symptoms caused or made worse by physical, mental or emotional effort, which can be delayed) in people with ME/CFS? How is this best treated and managed?

This question was unanimously ranked as the top priority by every group at the workshop, and by respondents overall in the second questionnaire. Post-exertional malaise (PEM) is considered the hallmark symptom of ME/CFS, with evidence from two-day cardiopulmonary exercise testing (CPET) demonstrating an indicative drop in functioning 24 hours after exertion. It is a highly restrictive and debilitating aspect of ME/CFS. Understanding the biological mechanism behind post-exertional malaise would likely unlock major clues to the cause of ME/CFS, and how to manage and treat it.

Workshop participants noted that PEM triggers symptoms of ME/CFS. If PEM is understood, then the mechanisms behind other symptoms such as cognitive dysfunction, fatigue, pain and sleep problems may also be understood.

Priority 2

Which existing drugs used to treat other conditions might be useful for treating ME/CFS, such as low dose naltrexone, or drugs used to treat Postural Orthostatic Tachycardia Syndrome (POTS)?​

This question was unanimously ranked second by all small groups at the workshops. People with ME/CFS in the UK are sometimes prescribed off-label drugs, or are prescribed drugs for other conditions they live with, that appear to significantly improve their ME/CFS. However anecdotal reports do not give the evidence needed for these drugs to be used in everyday clinical practice.
Symptoms common to other diseases, such as pain, nausea, orthostatic intolerance, fatigue, migraines, cognitive dysfunction and many more are all potential targets for drug trials in ME/CFS.
Workshop participants were clear that answering this question could be the fastest route to improving the quality of life of people with ME/CFS.

Workshop participants noted that PEM triggers symptoms of ME/CFS. If PEM is understood, then the mechanisms behind other symptoms such as cognitive dysfunction, fatigue, pain and sleep problems may also be understood.

Priority 3

How can an accurate and reliable diagnostic test be developed for ME/CFS?

Despite its prevalence and the impact ME/CFS has on people’s lives, no diagnostic test is available. An accurate and reliable diagnostic test could carry huge benefits, including:

  • Speeding up diagnosis to ensure early and accurate advice on managing the disease
  • Preventing misdiagnosis and inappropriate treatment
  • Ruling out other possible causes for symptoms
  • Providing clues about the underlying biology of this disease – a recurring theme through this priority setting process
  • Enabling accurate identification of subjects for future research studies.

There was strong consensus throughout the workshops that this was a high priority with practical importance for people with ME/CFS, carers and health care professionals.

Priority 4

Is ME/CFS caused by a faulty immune system? Is ME/CFS an autoimmune condition?​

This question speaks to a strong desire to understand the biological causes of the disease. There are similarities between ME/CFS and some other autoimmune conditions. Indicators, such as high prevalence among women, increased autoantibody levels, and altered cytokine expression, all suggest immune dysfunction. Understanding this would provide direction to the search for treatments and a cure.

During the prioritisation survey another question on the immune system was highly ranked, but not taken through to the workshop due to overlap with this one. Instead, we highlight it here: Does the immune system continue to over-function or under-function in some people with ME/CFS to cause symptoms? What does this mean for treatment and risks from infections and vaccinations, including COVID-19?

Priority 5

Are there different types of ME/CFS linked to different causes and how severe it becomes? Do different types of ME/CFS need different treatments or have different chances of recovery?

People with ME/CFS present with a wide range of symptoms and there is huge variation in the symptoms that individuals find the most debilitating. We have no way of predicting if someone will become severely ill, or if they will recover. Anecdotally, treatments or strategies that help one person often do not help another.
During workshop discussions, participants in different groups repeatedly mentioned their hope that this question would lead to more research into severe ME/CFS.

Future research and disease management would hugely benefit from the ability to categorise ME/CFS into more specific groups of people with similar symptoms, underlying biology or prognosis.

Across health care, we are discovering that we can, and should, tailor treatments to the individual. Reaching this point in our understanding of ME/CFS would be an important leap forward.

Priority 6

Why do some people develop ME/CFS following an infection? Is there a link with long-COVID? ​

Up to 80% of people with ME/CFS first develop symptoms after a viral infection and there are many similarities between ME/CFS and long-COVID. The response to the COVID-19 pandemic, and corresponding research interest into the long-term effects of viral infection, is an important opportunity to understand the role of infectious agents in causing ME/CFS. Workshop participants commented on the need for people with ME/CFS to be included in long-COVID research studies and vice versa.

Future research and disease management would hugely benefit from the ability to categorise ME/CFS into more specific groups of people with similar symptoms, underlying biology or prognosis.

Across health care, we are discovering that we can, and should, tailor treatments to the individual. Reaching this point in our understanding of ME/CFS would be an important leap forward.

Priority 7

What causes the central and peripheral nervous systems (brain, spinal cord and nerves in the body) to malfunction in people with ME/CFS? Could this understanding lead to new treatments?

Many of the symptoms seen in ME/CFS indicate probable involvement or malfunction of the nervous systems, including orthostatic intolerance, dysregulated body temperature, exercise intolerance, some gut symptoms, and sensory sensitivities. Understanding the underlying mechanisms would direct the search for diagnostic tests, treatments, and a cure.

Workshop participants prioritised this over questions about individual symptoms as they felt it would incorporate investigation of the mechanisms underlying cognitive dysfunction, fatigue, pain and sleep problems. Cognitive dysfunction was noted as having a distinct impact on children and young people’s education, as well as being a primary reason some people with ME/CFS cannot work.

Priority 8

Is there a genetic link to ME/CFS? If yes, how does this affect the risk of ME/CFS in families? Could this lead to new treatments?

Many people with ME/CFS report that other members of their immediate or extended families also have the disease. This has led to speculation about genetic causes. At the time of this report, the first large-scale genome-wide association study (GWAS) of 25,000 people with ME/CFS, called the DecodeME study, is underway. Workshop participants ranked this question lower than it otherwise might have been because of DecodeME, but they noted that its results should be considered a starting point for further research. If genetic links to ME/CFS are found, further research will be needed to understand this, and in particular to transfer this knowledge into understanding underlying mechanisms, developing or assessing treatments, and hopefully a cure. This information could also impact on family planning

Priority 9

What causes ME/CFS to become severe?

Quality of life for people with ME/CFS is generally lower than other disabling diseases with which it has been compared. People with severe ME/CFS live with extreme disability: housebound or bedbound, they experience constant, severely debilitating symptoms, limiting all activities of daily living. For those with very severe ME/CFS, tube-feeding can become necessary, light and sound are usually intolerable, pain is often unmanageable, and speech may not be possible. Some describe it as a living death. Historically, research has neglected and excluded this population.

Understanding what causes ME/CFS to become severe could prevent others suffering the same fate, and give us clues on how to best to support and treat this under-served population.

Severe ME/CFS was discussed as a high priority by all small groups at the workshops. It was highlighted that normal research methods need adapting to include people with severe ME/CFS, for example by conducting home visits.

Priority 10

How are mitochondria, responsible for the body's energy production, affected in ME/CFS? Could this understanding lead to new treatments?

Many small-scale studies have shown that people with ME/CFS have dysfunctional mitochondria, or the under- or over-expression of related proteins.22 Mitochondrial research is a promising area which needs to be taken forward on a larger scale, with studies designed to replicate and progress current findings in well-defined cohorts. New drugs could be developed, or existing drugs repurposed, to target this dysfunction once there is a better understanding of the pathology.

Priority 10+

Does poor delivery or use of oxygen within the body cause ME/CFS symptoms? If so, how is this best treated?

Initial research suggests peak oxygen uptake is lower in people with ME/CFS than healthy controls. “Air hunger” is sometimes reported as a symptom, and this question was a high priority for those with very severe ME/CFS in the second survey. Investigating delivery and use of oxygen could incorporate research into impaired blood flow, clotting, movement of molecules within cells, and whether cardiac function is impacted in ME/CFS. Workshops participants prioritised this question in order to further explore underlying mechanisms of this disease.

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