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What you need to know about ME/CFS

What you need to know about ME/CFS

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Evidence-based knowledge and expert medical opinion

What you need to know about ME/ CFS was written by Dr Katrina Pears, Research Correspondent for The ME Association.

Medical Disclaimer

This leaflet is not intended to be a substitute for personalised medical advice or treatment. You should consult your doctor whenever a new symptom arises, or an existing symptom worsens. It is important to obtain medical advice that considers other causes and possible treatments. Do not assume that new or worsened symptoms are solely because of ME/CFS or Long Covid.

Contents

Introduction
Background
Context
The NICE Guideline on ME/CFS
Research Evidence: Disease Pathology
Conclusion
Advancing ME/CFS Research
How You Can Help

Introduction

This booklet provides a summary of what you need to know about ME/CFS and is based on the evidence-based NICE Guideline, expert medical opinion, and the result of medical research. It considers key symptoms, diagnosis, multidisciplinary care, what might cause the disease, predisposing, precipitating and perpetuating factors, and explains what the research has been telling us about the underlying disease process.

Background

  • ME/CFS is a complex, chronic medical condition affecting multiple body systems and its pathophysiology is still being investigated.
  • It can cause many different symptoms, which can be triggered or worsened by any kind of effort or activity.
  • It affects everyone differently and its impact varies widely – for some people symptoms still allow them to carry out some activities, whereas for others they cause substantial incapacity.
  • It is a fluctuating condition in which a person’s symptoms can change unpredictably in nature and severity over a day, week or longer.
  • It can affect different aspects of the lives of both people with ME/CFS and their families and carers, including activities of daily living, family life, social life, emotional wellbeing, work and education.
  • People with ME/CFS may have experienced prejudice and disbelief and could feel stigmatised by others ( including family, friends, health and social care professionals, and teachers) who do not understand their illness.
  • Because it can look like many other illnesses, people often face uncertainty and delays in diagnosis.
  • Symptoms include flu-like malaise, sleep difficulties, brain fog and a profound fatigue that is unlike normal tiredness.
  • People may also experience chronic pain, headaches, nausea, digestive problems, and sensitivity to light, sound and other stimuli.
  • Symptoms come and go and can change or worsen with little warning, causing distress and disrupting people’s lives.
  • There are options that can help people manage their ME/CFS, but a therapy that helps one person may cause harm to another, so a carefully tailored plan and specialist advice is always needed.

Context

  • Over 402,000 people in the UK have ME/CFS, however, the exact prevalence in the UK is unknown, especially given the rise in incidence after the Covid-19 pandemic.
  • About 2.4 times as many women affected as men.
  • ME/CFS can affect people of all ages. It is a complex, multi-system, chronic medical condition that has considerable personal, social and economic consequences and a significant impact on a person’s quality of life, including their psychological, emotional and social wellbeing.
  • Everyday life for people with ME/CFS, their family and carers is disrupted and unpredictable. Many people with the condition are unemployed, and less than a fifth work full-time.
  • Approximately 25% have severe or very severe disease and are housebound or bedbound.
  • The quality of life of people with ME/CFS is lower than that of many people with other severe chronic conditions, including multiple sclerosis and some forms of cancer.
  • It is not clear what causes ME/CFS. In many cases, symptoms are thought to have been triggered by an infection, but it is not simply post-illness fatigue. It lasts longer and even minimal mental or physical activity can make symptoms worse.
  • There is no diagnostic test or universally-accepted definition for ME/CFS. People with the condition report delays in diagnosis, and many healthcare professionals lack the confidence and knowledge to recognise, diagnose and manage it.
  • The terms myalgic encephalomyelitis (ME; or encephalopathy), chronic fatigue syndrome (CFS), CFS/ME and ME/CFS have all been used for this condition and there are different clinical and research definitions for each name.
  • There is no sound pathological evidence of widespread inflammation involving the brain and spinal cord, which makes the term ‘encephalomyelitis’ problematic.
  • Myalgic encephalomyelitis is classified under diseases of the nervous system in the SNOMED CT and ICD10 (G93.3), ICD11 (8E49).
  • Many people with ME/CFS consider the name ‘chronic fatigue syndrome’ too broad, simplistic and judgemental.
  • For consistency, the abbreviation ME/CFS is used by the ME Association and by the National Institute for Health and Care Excellence (NICE) in its guideline.
  • Fatigue associated with another chronic disease may be confused with ME/CFS and some practitioners are reluctant to positively diagnose ME/CFS when no other causes are found.
  • People with ME/CFS report a lack of belief and acknowledgement from health and social care professionals about their condition and related problems, which may lead them to be dissatisfied with care and to disengage from services.
  • There are added issues for children and young people if illness makes school attendance difficult, bringing families to the attention of educational and social care services.

The NICE Guideline ME/CFS

The National Institute for Health and Care Excellence (NICE) provides evidence-based clinical recommendations to healthcare professionals in England which are also recognised by Northern Ireland, Scotland and Wales.

In October 2021, NICE produced a new guideline on ME/CFS following extensive stakeholder consultation, and we recommend that any patient, carer or family member takes the time to read the recommendations and learn what can be expected from the NHS and social care services.

We fully endorse the recommendations and will continue to work with national and local healthcare providers to ensure the guideline is implemented effectively as it offers the best chance of improving health outcomes for people with ME/CFS.

Key Symptoms

  • There currently is no diagnostic test for ME/CFS, and it is recognised on clinical grounds alone.
  • Suspect ME/CFS if:
    • the person has had all of the persistent symptoms in Box A: Symptoms for suspecting ME/CFS for a minimum of six weeks in adults and four weeks in children and young people and,
    • the person’s ability to engage in occupational, educational,
    • social or personal activities is significantly reduced from preillness levels and,
    • symptoms are not explained by another condition.

Box A: Symptoms for Suspecting ME/CFS

All of these symptoms should be present:
  1. Debilitating fatigue that is worsened by activity, is not caused by excessive cognitive, physical, emotional or social exertion, and is not significantly relieved by rest.
  2. Post-exertional malaise after activity in which the worsening of symptoms:
    • is often delayed in onset by hours or days
    • is disproportionate to the activity
    • has a prolonged recovery time that may last hours, days, weeks or longer.
  3. Unrefreshing sleep or sleep disturbance (or both), which may include:
    • feeling exhausted, feeling flu-like and stiff on waking.
    • broken or shallow sleep, altered sleep pattern or hypersomnia.
  4. Cognitive difficulties (sometimes described as ‘brain fog’), which may include problems
    finding words or numbers, difficulty in speaking, slowed responsiveness, short-term memory problems, and difficulty concentrating or multi-tasking.

Other common symptoms

Be aware that the following symptoms may also be associated with, but are not exclusive to, ME/CFS:

  • Pain which can affect muscles (myalgia), joints (arthralgia) and nerves (neuropathic) but is minimal or not present at all in a minority of people. Pain is often difficult to alleviate with simple analgesics and may be accompanied by sensory disturbances/ paraesthesia.
  • Poor temperature control/thermoregulation including increased sensitivity to hot and cold environments, sweating episodes, feeling feverish.
  • On-going flu-like symptoms including sore throats and tender glands without pathological enlargement.
  • Intolerance or increased sensitivity to alcohol, chemicals and medications – especially psychotropic (antidepressant) drugs.
  • Headaches of a new type or severity that may have a migrainous quality
  • Sensory disturbances including paraesthesiae (‘pins and needles’) and increased sensitivity to touch, noise (hyperacusis) and bright light (photophobia)
  • Digestive disturbances consistent with irritable bowel syndrome ( i.e. abdominal pain, bloating, change in bowel habit) which may develop following the onset of ME/CFS and can be exacerbated by certain foods

Diagnosis

  • Diagnose ME/CFS in a child, young person or adult who has key symptoms that have persisted for a minimum of six weeks in adults and four weeks in children and young people, and are not explained by another condition.
    • Primary healthcare professionals should consider seeking advice from an appropriate specialist if there is uncertainty about interpreting signs and symptoms at 3 months and whether further investigations are needed.
  • Refer adults directly to an ME/CFS specialist team (see Box B) to confirm their diagnosis and develop a care and support plan.
  • Refer children and young people who have been diagnosed with ME/ CFS after assessment by a paediatrician directly to a paediatric ME/CFS specialist team (see Box B: ME/CFS Specialist Team) to confirm their diagnosis and develop a care and support plan.

Box B: ME/CFS Specialist Teams

  • Specialist teams consist of a range of healthcare professionals with training and experience in assessing, diagnosing, treating and managing ME/CFS.
  • They commonly have medically-trained clinicians from a variety of specialisms ( including rheumatology, rehabilitation medicine, endocrinology, infectious diseases, neurology, immunology, general practice and paediatrics) as well as access to other healthcare professionals specialising in ME/CFS.
  • These may include physiotherapists, exercise physiologists, occupational therapists, dietitians, and clinical or counselling psychologists.
  • Children and young people are likely to be cared for under local or regional paediatric teams that have experience of working with children and young people with ME/CFS in collaboration with ME/CFS specialist centres.

Severity of ME/CFS

Definitions of severity are not clear cut because individual symptoms vary widely in severity and people may have some symptoms more severely than others. The definitions below provide a guide to the level of impact of symptoms on everyday functioning.

Mild ME/CFS

People with mild ME/CFS care for themselves and do some light domestic tasks (sometimes needing support) but may have difficulties with mobility. Most are still working or in education, but to do this they have probably stopped all leisure and social pursuits. They often have reduced hours, take days off and use the weekend to cope with the rest of the week.

Moderate ME/CFS

People with moderate ME/CFS have reduced mobility and are restricted in all activities of daily living, although they may have peaks and troughs in their level of symptoms and ability to do activities. They have usually stopped work or education, and need rest periods, often resting in the afternoon for 1 or 2 hours. Their sleep at night is generally poor quality
and disturbed.

Severe ME/CFS

People with severe ME/CFS are unable to do any activity for themselves or can carry out minimal daily tasks only (such as face washing or cleaning teeth). They have severe cognitive difficulties and may depend on a wheelchair for mobility. They are often unable to leave the house or have a severe and prolonged after-effect if they do so. They may also spend most of their time in bed and are often extremely sensitive to light and sound.

Very severe ME/CFS

People with very severe ME/CFS are in bed all day and dependent on care. They need help with personal hygiene and eating and are very sensitive to sensory stimuli. Some people may not be able to swallow and may need to be tube fed.

Multidisciplinary care

  • Provide care for people with ME/CFS using a coordinated multidisciplinary approach. Based on the person’s needs, include access to health and social care professionals with expertise in the following as a minimum, with additional expertise depending on symptoms:
    • medical assessment and diagnosis
    • developing personalised care and support plans
    • self-management strategies, including energy management
    • symptom management, including prescribing and medicines management
    • managing flare-ups and relapses
    • activities of daily living, including dental health
    • psychological, emotional and social wellbeing, including family and sexual relationships
    • diet and nutrition mobility, avoiding falls and problems from loss of dexterity, including access to aids and rehabilitation services
    • social care and support
    • support to engage in work, education, social activities and hobbies.
  • Care for people whose ME/CFS is managed in primary care should be supported by advice and direct clinical consultation from an ME/CFS specialist team.
  • Give adults, children and young people with ME/CFS and their family or carers (as appropriate) a named contact in their primary care and/or ME/ CFS specialist team to coordinate their care and support plan, help them access services and support them during periods of relapse.
  • Provide children and young people with ME/CFS and their family or carers (as appropriate) with details of a named professional in the ME/CFS specialist team who they can contact with any concerns about the child or young person’s health, education or social life.

Source:
The 2021 NICE Guideline on ME/CFS: diagnosis and management. https://www.nice.org.uk/guidance/ng206

More Information

  • The ME Association has produced a wide range of FREE literature about ME/CFS and Long Covid written by topic experts for you to download, on topics of: Diagnosis, Management, Long Covid & ME/CFS, Benefits, Employment, Education and more.
  • You can also find the NICE Guideline on ME/CFS (and the NICE Rapid Guideline on Long Covid) on the website.
  • We hope to hear more from the Department of Health and Social Care (DHSC) about the Delivery Plan on ME/CFS in Spring 2025 when it should be published. https://tinyurl.com/y9hn6wm3

Causation

The underlying cause of ME/CFS is still subject to medical debate. This is one of the reasons why doctors can hold differing views on how
people with the condition should be managed.

However, with the NICE Guideline on ME/CFS, the DHSC Delivery Plan and renewed interest in this field as a result of Long Covid, there is now
a widely-held consensus view that ME/CFS is perpetuated by a physical disease process.

Traditionally there were three main views held by the medical profession:

  1. That ME/CFS is most often triggered by an infection leading to a chronic disease state in susceptible individuals resulting in key
    symptoms that cause functional impairments and a reduced quality of life.
    • This is the view that has been held by the ME Association since we were established in 1980 and is one that is gaining much wider acceptance.
    • An increasing number of research studies have shown that the disease process involves, for example, the brain and nervous systems, the
      immune system, the endocrine (hormone producing) system, muscle, and mitochondria (energy-producing cells).
    • However, while these studies have produced interesting results, they are often small and in need of replication. But the recent interest in Long Covid is having a positive effect as studies are revealing similar results on a larger scale.
    • In regard to emotional and behavioural issues, we believe they are a perfectly understandable result of living with – and not a cause of – ME/CFS and should be treated, where appropriate, by mental health professionals who form part of multidisciplinary ME/CFS specialist services.
  1. That ME/CFS involves a combination of physical, psychological and social factors: the biopsychosocial (BPS) model.
    • This model assumed that, while ME/CFS is often triggered by a physical stressor such as an infection, persisting ill health is largely maintained by maladjusted behaviour, unhelpful illness beliefs and inactivity causing physical deconditioning.
  2. That ME/CFS is a psychiatric disorder with no physical disease process.
    • A few doctors still take the view that ME/CFS does not exist or is just a form of atypical depression or hysteria, despite evidence to the contrary.

With the NICE Guideline on ME/CFS and other more recent developments, the NHS and social care providers should have an improved awareness and an increased understanding of ME/CFS. We hope that people with this very real disease will now feel believed, have their experiences validated and receive a much better standard of care and support from healthcare providers.

Is ME/CFS a three-stage illness?

There is a considerable degree of agreement emerging that we are dealing with a three-stage process in ME/CFS. This involves specific factors that predispose, precipitate and perpetuate the various symptoms.

  • Predisposing factors:
    • As with many chronic diseases – arthritis, cancer, heart disease etc. – it appears that genetic factors may play a role.
    • While ME/CFS is not a genetic disorder in the sense that it can be passed from parent to child, there is growing evidence that some people have a genetic make-up that increases the risk of ME/CFS developing when a trigger factor, such as an infection, occurs at a particular time in their life.
    • This genetic predisposition may also help to explain why there are families with more than one member who has ME/CFS.
    • New research on brain structure and function suggests that infections, or events prior to the onset of ME/CFS, may help to prime or activate immune-system cells in the brain called microglia. When faced with another infection, this priming of the microglia may then make some people more vulnerable to developing ME/CFS.
  • Precipitating factors:
    • One area where there is a considerable degree of medical agreement relates to what triggers or precipitates ME/CFS.
    • Most people with this illness pre-date the onset of their symptoms to an infection – normally viral but sometimes bacterial – from which they ‘fail to recover’ and continue to have ‘flu-like symptoms’, along with the very characteristic muscle and brain symptoms that are associated with ME/CFS.
    • Evidence suggests that the Epstein Barr virus (EBV) which can cause glandular fever, and the influenza viruses which can cause the Flu, are two of the most common viral triggers, but anecdotal and research evidence indicates that a wide range of viral or bacterial infection has the potential to trigger ME/CFS in susceptible individuals.
    • Other types of immune-system stressors – vaccinations, trauma, pregnancy, surgery – can also occasionally trigger ME/CFS.
    • Stress – physical, mental, emotional, or a combination of all three – around the time of a triggering event, or during the period of convalescence, can be an important co-factor in determining whether someone develops ME/CFS and whether the individual is able to return to pre-illness levels of functional ability.
  • Perpetuating factors:
    • This is where the situation becomes far more uncertain, and where disagreements emerge in relation to what then perpetuates or keeps the illness going.
    • Those who – like the ME Association – adhere to the physical model of causation believe that ME/CFS is perpetuated by a complex interaction involving changes to the way in which the brain, nervous system, muscle, immune and endocrine systems respond to the triggering viral infection, or other immune system stressor. When the infection or other event has passed, the body fails to return to its normal state, symptoms persist and new symptoms develop, and functional incapacity continues or worsens.
  • Those who believe that ME/CFS is a mental health or somatoform disorder argue that symptoms are largely prolonged by what are called abnormal illness beliefs and behaviours, along with physical deconditioning. And that any physical abnormalities are caused by factors such as sleep disturbance and inactivity.

Research Evidence: Disease Pathology

GENETICS

  • Gene polymorphisms (variations in DNA sequences) have been identified, which are involved in various processes such as immune modulation, oxidative stress and energy metabolism.
  • Gene expression
    • Under and over-expression of certain genes and miRNAs (small molecules that regulate gene expression) may explain some symptoms and also account for an increased susceptibility to developing ME/CFS.
    • They also represent potential biomarkers for diagnosis and drug treatment targets. miRNAs might be used to place patients into subgroups.
  • The ME Association has supported the world’s largest study into ME/ CFS, the £3.2m DecodeME project, which will hopefully shed more light on the role of genetics when its results are published in 2025/26. DecodeME: https://www.decodeme.org.uk

IMMUNE SYSTEM

  • Activated immune system
    • Studies have shown cytokine mediated, low-level immune system activation, in the blood and cerebrospinal fluid (cytokines are produced in response to any type of infection).
    • This results in low-grade inflammation and a general ‘sickness response’, involving decreased appetite, wanting to sleep a lot and flu-like malaise and pain.
    • Several studies have demonstrated altered levels of inflammatory markers, called cytokines, and activated immune cells, such as lymphocytes. Prolonged higher levels of cytokines effect the body’s ability to respond to stress, which may result in the development of disease, like ME/CFS.
    • UK ME/CFS Biobank researchers have found highly increased levels of a type of immune cell called MAIT (Mucosal Associated Invariant T-cell) cells in severely affected patients. The study was the feature of a research review: Cliff et al. (2019) Cellular Immune Function in ME/CFS: https://tinyurl.com/3ztrmpnh
  • Natural killer cells (NK)
    • Reduced NK-cell activity is common research finding.
    • NK-cells are a type of white blood cell that comprise part of the immune system and act like security guards, circulating round the body looking for potential threats.
    • However, UK ME/CFS Biobank researchers have reported no differences in NK-cell number and function in patients compared to controls. This study was the feature of a research review: https://meassociation.org.uk/4e59
  • T-cell dysfunction
    • Studies have shown that there are problems in the way the immune T-cells produce energy, with ME/CFS having decreased levels of glycolysis at rest.
    • Some patients have also shown difference in markers of T-cell activation, which suppress or activate an immune response.
  • Autoimmunity
    • Some studies have found activated T- and B-cells, as well as an increased incidence of autoantibodies ( immune cells, that attack tissues of your own body, instead of targeting foreign cells, such as bacteria).
    • Although whether ME/CFS is an autoimmune disease – like multiple sclerosis (MS) for example – is still being debated.
  • Viral reactivation
    • There has been conflicting evidence over the role of human herpes viruses (HHV) in ME/CFS.
    • A common HHV is the Epstein Barr virus (EBV) which often results in glandular fever and is among the top recognised triggers that lead to the development on ME/CFS in susceptible individuals.
    • HHVs can remain dormant in the body after the initial infection has passed and can be reactivated because of an immune-system stressor-which might be a cause of continuing or worsening symptoms and disability.
    • Evidence for this has been found in ME/CFS and Long Covid, and the topic was subject to a research review: https://meassociation.org.uk/hhml

BRAIN AND NEUROLOGY

There is growing evidence of significant abnormalities involving the brain and central nervous system in ME/CFS and similar findings have been made in Long Covid.

  • Endocrine involvement: hormone producing glands
    • This is one of the most consistent findings in research, involving the down regulation of the hypothalamic-pituitary-adrenal (HPA) axis.
    • The hypothalamus and pituitary are small glands inside the brain that play a key role in the control and production of hormones.
    • Studies have found disturbances involving the HPA axis, mainly demonstrating defects in the output of the hormone cortisol from the adrenal glands, which sit above the kidneys (lower level of cortisol = hypocortisolaemia).
    • This could explain key symptoms such as fatigue, sleep dysfunction and temperature regulation.
  • Neuroinflammation
    • Several studies support the presence of neurobiological and spinal fluid abnormalities, some of which are consistent with low-level neuroinflammation. Studies from America found increased temperature inside the brains of ME/ CFS patients, as well as increased levels of metabolites, including lactate and choline.
    • bladder symptoms are very common.
  • Central Nervous System
    • Defects have been found in the basal ganglia pathways (areas of the brain which are extremely sensitive to cytokines). Post-mortem research has also found dorsal root ganglionitis ( inflammation in a part of the peripheral nervous system). Abnormal microglia activation ( immune cells in the brain) has been found in ME/CFS, a marker of inflammation.
  • Cerebrospinal fluid
    • Studies have shown abnormalities in proteins and white blood cells.
  • Autonomic nervous system (ANS) dysfunction
    • Abnormalities have been consistently reported in the ANS, this part of the brain is not under conscious control and sends messages to “speed up” or “slow down” to vital organs, such as the heart, bowel and bladder.
    • Studies have shown disturbances in the autonomic regulation of cardiovascular reflexes in a subgroup of patients.
    • POTS (Postural orthostatic tachycardia syndrome – represented by an abnormal increase in heart rate upon sitting or standing) is often also diagnosed or Neurally-mediated hypotension.
    • The ANS also controls circulation, which may help to explain why people with ME/CFS experience problems with cold extremities, and temperature regulation. ANS dysfunction may also explain why irritable bowel and bladder symptoms are very common.
  • Neuroimaging
    • Studies have demonstrated a number of structural and functional abnormalities compared to controls, including differences in the volume of white and grey matter in the brain, reduced cerebral blood flow, neuroinflammation, larger brainstem volumes, altered cortical volume and thickness, volumetric difference in the hippocampal subfields and neuronal-microstructural changes. This could help to explain symptoms of cognitive dysfunction, as well as pain.

MUSCLE AND METABOLIC ACTIVITY

Energy, or lack thereof, is a significant concern in ME/CFS and in Long Covid. There is growing evidence of dysfunction in mitochondria, which are often called the powerhouse of the cell, and are specialised structures that produce most of our cellular energy.

  • Energy metabolism pathways
    • Research suggests problems in the energy metabolism pathways, such as functional impairments involving an enzyme (a type of protein that acts as a catalyst for chemical reactions in the body) called pyruvate dehydrogenase and impairments in the activation of another enzyme called AMPK, leading to impaired glucose uptake.
  • Bioenergetic abnormalities
    • Researchers from Newcastle University reported cellular bioenergetic abnormalities. Several measures of mitochondrial function were found to be affected, but maximal respiration was found to be lower.
  • This suggests that, when the cells experience physiological stress, they are less able to elevate their respiration rate to fulfil cellular energy demands. However, the same research group in 2019 demonstrated that the activity of the enzyme complexes within the mitochondria are functioning normally.
  • This then suggests the abnormalities in energy production previously observed might be caused by something upstream of the mitochondria and not represent problems with the mitochondria themselves. This topic was the subject of a research review on the role of mitochondria in ME/CFS: https://meassociation.org.uk/34hb
  • Mitochondrial dysfunction
    • Muscle biopsies have shown evidence of mitochondrial degeneration, deletions of mitochondrial DNA (DNA, located inside the mitochondria, which is inherited from your mother) and reduction of mitochondrial activity.
  • Muscle abnormalities
    • Several muscle abnormalities have been reported, including defects in muscle energy metabolism, changes in muscle fibre types, prolonged production of lactic acid (following exercise) and demonstrating PEM using repetitive isometric quadriceps exercise testing. These findings demonstrate that muscle symptoms cannot be due to inactivity/deconditioning.
  • Exercise pathology: Post-Exertional Malaise (PEM)
    • Exercise physiology research has demonstrated that a 2-day cardiopulmonary exercise test (CPET) can objectively confirm the presence of PEM and could be used as a diagnostic test.
    • This testing method has determined that PEM cannot be due to inactivity or deconditioning.
    • Recent research using metabolomics has shown that ME/CFS patients have a different response to exercise which effects their ability to recover previous functional ability. This has been subject to one of our research reviews: https://meassociation.org.uk/3h01

BLOOD AND PLASMA

  • Red blood cell morphology
    • Research has shown that red blood cells from ME/CFS patients are ‘stiffer’ and less able to change shape (called deformability) to squeeze through small capillaries. This suggests blood flow and oxygen supply to cells may be reduced in ME/CFS. This study was the subject of a research review: https://meassociation.org.uk/dpvn
  • Plasma factor
    • Preliminary, unpublished studies from several independent groups have now found that a factor in the blood plasma (a component of the blood that doesn’t include red blood cells) can affect cell metabolism in ME/CFS and that the effect can be transferred to healthy cells.
    • They found that adding plasma from ME/CFS patients to healthy control cells made them increase their oxygen consumption, indicating the mitochondria were working harder. The factor in the blood responsible for these changes is yet to be identified.
  • ‘Nano-needle’ test
    • Results from a pilot-study testing electrical impedance (ability of a current to pass through cells) in ME/ CFS and healthy cells in plasma show that putting the cells under ‘stress’ and making them work harder resulted in a dramatic change in signal. It’s as though the cells were unable to keep up with the added demand put on them.
    • Interestingly, when plasma from ME/CFS patients was applied to healthy-control cells, the same signal occurred. Suggesting a factor in the plasma was affecting the cells functioning.
  • Endothelial dysfunction
    • The endothelium is a thin layer of cells lining the heart and blood vessels. Endothelial cells release substances that control vascular relaxation and contraction (by nitric oxide gas) as well as enzymes that control blood clotting, immune function and platelet (a colourless substance in the blood) adhesion.
    • Impaired endothelial function could cause symptoms of chronic fatigue, and post-exertional malaise. This has been subject to a research review: https://meassociation.org.uk/04he

CARDIOVASCULAR / HEART

  • Cardiac output – Some studies have found results suggesting low cardiac output as an explanation for poor physical stamina and chronic fatigue (as a symptom).
  • Hypotension – There is also some evidence of hypotension (low blood pressure), especially on standing, which could explain symptoms such as fatigue, dizziness, cognitive issues, tremors and nausea.

GASTROINTESTINAL (GI) TRACT

  • Gut Dysbiosis
    • Gut dysbiosis means an imbalance of gut flora diversity – not enough beneficial bacteria and an overgrowth of bad bacteria.
    • Researchers are currently investigating the role of the microbiome (the collection of different types of microbes, such as bacteria in the gut), with findings that indicate gut dysbiosis with altered composition and greater heterogeneity of microbes.
    • This might contribute to general inflammation and to symptoms like fatigue and gastrointestinal symptoms.
    • Other gastrointestinal findings show altered gut-brain activity, increased gut permeability, gut dysmotility and altered gut microbiome, which also vary depending on the duration of illness.
    • However, studies in this area haven’t established whether microbiome changes cause or contribute to the development of ME/CFS and resulting symptoms or whether these changes are in fact caused by patients being ill and unable to maintain a healthy balanced diet, for example.
    • Similar findings have also been established in Long Covid.

METABOLISM

  • Metabolic pathways
    • Recent studies have found abnormalities in several metabolic (chemical) pathways, particularly those involved in the glucose metabolism suggesting that there may be problems in converting glucose to energy.
    • Other findings point towards a redox imbalance (where there are too many oxidising molecules compared to antioxidant molecules) and oxidative stress (where cells are overburdened with toxic by-products from metabolic reactions and don’t have enough antioxidants to clear them), which may lead to a lack of oxygen in cells.
    • Metabolic studies looking at chemical reactions at a cellular level are high output studies, meaning a lot of data is produced, which provide a high chance of finding significant results. More about metabolomics can be read in our Medical Matters on the website.

Conclusion

The most widely accepted model for ME/CFS is that it is a complex, multisystem disease that is triggered by an immune-system stressor, commonly an infection, in a genetically predisposed individual. The disease is then perpetuated by interaction of various changes in the brain, muscles, immune and endocrine (hormone-producing) systems.

We need a better understanding of the underlying disease pathways, and the various clinical and pathological sub-groups, and are pushing for new research investment. However, important clues have emerged, and new types of drug treatment are being assessed on the basis of these abnormalities.

The Covid-19 pandemic has served to highlight ME/CFS and the ME Association were the first to draw attention to the similarities with Long Covid back in May 2020. The seriousness of the pandemic and the much larger number of people affected initially led to a fairly quick response from governments around the world.

We are now in a situation where increasing numbers of scientists and clinicians are viewing ME/CFS and Long Covid as similar ‘post-infectious syndromes’ and we are now seeing more people whose trigger was Covid-19 being diagnosed with ME/CFS rather than Long Covid.

Research provides the best chance we have of really improving the lives of people affected by these debilitating diseases and of preventing them from developing in the future. The need for better research is being taken seriously in the UK and we hope that effective forms of treatment will eventually emerge.

MORE INFORMATION

We produce detailed explanations and references for research published on ME/CFS and Long Covid in several formats:

Advancing ME/CFS Research

We need:

  • Much larger studies in order to see more definitive research and the removal of any false positives.
  • Well-defined patient cohorts and greater use of sedentary and other relevant controls.
  • To have a great representation of all ME severities.
  • To identify subgroups. There is a general consensus amongst researchers that there are several subgroups of patients which present with slightly different symptoms and pathologies. These need to be defined in order to study them separately.
  • To use new investigative techniques – including genomics, metabolomics and proteomics to find out what is happening at a cellular level.
  • Collaboration between different areas of research in order to see the ‘whole picture’.
  • More funding!
    • The Medical Research Council (MRC) regards ME/CFS as a research priority and issued a highlight notice in 2011 to encourage research applications, but very little has happened despite this central encouragement.
    • In 2024, the Department of Health and Social Care (DHSC) will issue a Delivery Plan on ME/CFS that will also serve to highlight opportunities for research in association with the MRC, National Institute for Health Research (NIHR), and research-funding charities like the ME Association.

The Ramsay Research Fund

The ME Association supports biomedical research by issuing grants to suitable applicants via The MEA Ramsay Research Fund. In the last 40 years, thanks to the generosity of our supporters and our commitment to biomedical research, we will have invested over £4,000,000 in research studies and infrastructure projects.

In 2025, we will be announcing investment in the largest single study we have ever funded before. This marks a recognition that in order to advance this field, we need to support bigger and better research.

We cannot rely on the government and UKRI to fund the research we need. To a great extent we have to increase our own efforts to raise funds. But we hope that with the DHSC Delivery Plan and its research focus, we will be able to work on more projects in collaboration with the MRC and NIHR, to benefit from their expertise and help spread the risk of large and necessary investments.

We continue to seek good quality research investments that will advance our knowledge of ME/CFS and Long Covid and bring us closer to
effective treatments. MEA Research

Some of our currently funded projects include:

  • The UK ME/CFS Biobank (UKMEB) was launched in August 2011 with funding and input from the ME Association. The Biobank has an international reputation for quality and efficiency, providing samples to researchers across the globe which allows that research to focuss on improving recognition, diagnosis and treatment of ME/CFS.
    • The UKMEB contains samples from mild to severely affected people aged 18-60, as well as healthy controls and people with multiple sclerosis (MS). Blood samples have been aliquoted into serum, plasma, peripheral blood mononuclear cells (PBMC), red blood cells/granulocyte pellet, whole blood, and RNA.
    • The MEA Ramsay Research Fund has continued to provide annual grants since 2011 as we believe it to be a vital infrastructure project. The Ramsay Research Fund now covers all the basic running costs of this vital and unique project. We have confirmed this funding arrangement for a further two years. This will bring the total investment since 2011 in this worthwhile investment to £962,000. The UK ME/CFS Biobank: https://meassociation.org.uk/CMEB
  • Since 2016, The MEA Ramsay Research Fund has provided grants of over £300,000 to the Morten Group, Oxford who have been investigating the role of the mitochondria (the powerhouses of the cell) in health and disease. The research group, led by Dr Karl Morten has become a hub for ME/CFS research starting out with the Acumen mitochondrial test to access cellular-energy dysfunction to new approaches to finding biomarkers using single-cell Raman micro-spectroscopy. The Morten Group Oxford: https://www.mortengroup.org.uk
  • In 2023, we set up an arrangement with the Manchester Brain Bank which allows us to continue the study of tissue from post-mortem examinations. Hopefully, this study will shed further light on the role of the brain and nervous systems in ME/CFS.
    • The MEA Ramsay Research Fund will be funding detailed examinations of the brain, spinal cord and dorsal root ganglion in at least five people with a firm diagnosis ME/CFS who are aged between 18 and 50 at the time of death. We will then review the results and decide whether to proceed with funding further examinations.
    • The upper age limit of 50 is in place to try and ensure that any abnormalities that are found in the brain and spinal cord are not age-related and are more likely to be relevant to ME/CFS.
    • If you wish to donate your brain and spinal cord to post-mortem medical research into ME/CFS you must have had a firm diagnosis of ME/CFS from a doctor and understand that we can only proceed if you are aged 18 to 50 at the time of death.
    • If you wish to register your interest:
      1. Complete the MEA Statement of Intent and make sure that your next of kin and solicitor (if you have one) is aware of it. https://meassociation.org.uk/fcik
      2. Include this information if you are making a Power of Attorney for Health and Welfare.
      3. Send a copy of the completed MEA Statement of Intent by email to the Manchester Brain Bank – contact details are on the Statement of Intent: phillip.tinkler@manchester.ac.uk Manchester Brain Bank: https://meassociation.org.uk/s96p

How You Can Help

Please help us to build on the success of The MEA Ramsay Research Fund and join us in expanding its vital work. We will learn why only certain people develop these diseases, the cause of symptoms and ongoing disability, and develop effective forms of treatment and prevention. With your support, these goals will be achieved much sooner.

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