Mitochondria, Post Viral Fatigue and Chronic Fatigue: Evidence and Interventions

Chronic fatigue is one of the most difficult presentations in medicine, and post viral fatigue has become far more visible since the COVID 19 pandemic. Patients have too often been disbelieved, told their symptoms are psychological, or prescribed exercise that made them worse. At the same time, some have been offered expensive tests and supplement regimens with little evidence. This article sets out what is known about myalgic encephalomyelitis or chronic fatigue syndrome and long COVID, including the role of mitochondria and energy metabolism, and what helps.

Definitions

An influential report from the United States National Academy of Medicine proposed diagnostic criteria for myalgic encephalomyelitis or chronic fatigue syndrome requiring:

• a substantial reduction in activity, persisting for more than 6 months, accompanied by profound fatigue not relieved by rest;
• post exertional malaise, a worsening of symptoms after physical, cognitive or emotional exertion, often delayed and prolonged;
• unrefreshing sleep;
• and either cognitive impairment or orthostatic intolerance.

Long COVID, or post COVID condition, describes a range of persistent symptoms after COVID 19. A subset of people with long COVID meet criteria for myalgic encephalomyelitis or chronic fatigue syndrome. Both conditions often follow infection, and many features overlap.

Post exertional malaise

Post exertional malaise is the hallmark feature. After activity that exceeds a person’s limits, symptoms worsen, often a day or more later, and may take days or weeks to recover. This distinguishes the condition from general fatigue and deconditioning and has important implications for management: pushing through activity, as encouraged in programmes of graded exercise, can cause prolonged worsening.

What research has found

Research has identified a range of abnormalities, though none is yet a validated diagnostic test.

• Immune changes, including altered immune cell function and signs of persistent immune activation.
• Autonomic dysfunction, including orthostatic intolerance and postural orthostatic tachycardia syndrome.
• Exercise physiology: some studies using repeated exercise tests on consecutive days have found reduced performance on the second day, consistent with post exertional malaise.
• Energy metabolism: studies have reported abnormalities in metabolic pathways and, in some, mitochondrial function, but findings have been inconsistent and it is unclear whether they are causes or consequences.
• Brain and nervous system: imaging and other studies have reported changes in some patients.
• Long COVID: research has identified possible roles for viral persistence, immune dysregulation, microvascular changes and autonomic dysfunction.

A detailed study of people with post infectious myalgic encephalomyelitis or chronic fatigue syndrome at the United States National Institutes of Health found differences in immune, autonomic and metabolic measures, and in how the brain regulated effort, compared with healthy volunteers. Research continues, and patients should be told honestly that mechanisms are not yet fully understood.

What current guidance recommends

NICE guidance on myalgic encephalomyelitis or chronic fatigue syndrome, updated in 2021, recommends:

• recognising the condition as a serious, complex illness;
• energy management, helping people understand their limits and plan activity to avoid post exertional malaise;
• not offering graded exercise therapy based on fixed increments, and not offering physical activity or exercise programmes derived from deconditioning models;
• considering physical activity programmes only when people feel ready, delivered by specialists and based on stabilising a baseline first;
• cognitive behavioural therapy as a supportive therapy to help people manage symptoms and distress, not as a cure;
• managing symptoms such as sleep problems, pain, orthostatic intolerance and dietary difficulties.

Practical support

Pacing and energy management

Pacing involves identifying a sustainable baseline of activity, including physical, cognitive and emotional effort, and staying within it, with planned rest. Activity diaries and, for some people, heart rate monitoring help identify limits. Increases, if any, are small and guided by symptoms.

Orthostatic intolerance

Many patients feel worse when upright. Measures include adequate fluid and, where appropriate, salt intake, compression garments, avoiding prolonged standing and, in some cases, medicines prescribed by a doctor. Assessment for postural orthostatic tachycardia syndrome may be warranted.

Sleep

Regular sleep and wake times, attention to sleep environment and treatment of coexisting sleep disorders. Standard sleep restriction techniques may not be appropriate.

Nutrition

Ensuring adequate energy, protein and micronutrients is important, as fatigue, nausea and difficulty preparing food can lead to poor intake. Small frequent meals, easy to prepare foods and help with shopping and cooking may be needed. Deficiencies such as iron, B12 and vitamin D should be checked and corrected.

Coexisting conditions

Assess for conditions that can cause or worsen fatigue, including anaemia, thyroid disease, diabetes, coeliac disease, sleep apnoea, depression and medication effects. These should be excluded before, and considered alongside, the diagnosis.

Emotional support

Living with a poorly understood, disabling condition is distressing. Validation, psychological support where wanted and connection with patient organisations can help.

Mitochondrial and other supplements

Given research interest in energy metabolism, supplements such as coenzyme Q10, NADH, D ribose, L carnitine and magnesium are widely used. A small randomised trial of coenzyme Q10 combined with NADH reported improvements in fatigue in some patients, but trials overall are small, heterogeneous and of limited quality, and no supplement has been shown to be reliably effective. Patients who wish to try a supplement should do so with a defined trial period and outcome measure, with attention to cost and interactions.

What to avoid

• Dismissing symptoms as psychological or as deconditioning.
• Graded exercise programmes that ignore post exertional malaise.
• Extensive unvalidated testing and costly protocols.
• Prolonged restrictive diets that compromise nutrition.
• Promises of cure.

An illustrative case

A 34 year old teacher has been unable to work for 8 months after a viral infection. She experiences severe fatigue, worsening a day after exertion, unrefreshing sleep, brain fog and dizziness on standing. She was advised to increase exercise gradually and became much worse. Her doctor excludes other causes; her ferritin is low. A standing test shows a large heart rate increase. With her doctor and a specialist service, she begins energy management with an activity diary and planned rest, increases fluid and salt intake with compression garments, has her iron deficiency treated and receives help with meals. Over 6 months her crashes become less frequent, her dizziness improves and she can manage short periods of work from home. Recovery is gradual, and her plan is reviewed regularly.

Belief, safety and patience

Post viral fatigue and myalgic encephalomyelitis are real, disabling conditions. The most important contributions practitioners can make are to believe patients, avoid harm, support energy management and symptom relief, address treatable coexisting conditions, and be honest about the limits of current knowledge while research continues.