Clinical Overview of ME/CFS

Key points

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, life-altering disease affecting many organ systems. It goes well beyond "being tired" and profoundly impacts patients' quality of life and abilities. Patients frequently experience a substantial impairment in physical and mental function at some point in their illness. It's estimated that as many as 3.3 million people in the United States have ME/CFS. The vast majority are undiagnosed.

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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic, debilitating disease. The disease is identified by three required symptoms and at least one of two additional symptoms.

  1. The reduced ability to perform pre-illness activities that lasts for more than 6 months. This reduced ability is accompanied by profound fatigue not improved by rest.
  2. Post-exertional malaise (PEM). PEM is a hallmark of ME/CFS with symptoms that worsen after physical, mental, or emotional effort.
  3. Unrefreshing sleep.

Orthostatic intolerance and/or cognitive impairment must also be present. Symptoms are present for half the time, with moderate to severe intensity and functional impairment.

Many patients have multiple symptoms, in different systems. Long COVID brings greater attention to ME/CFS, as both illnesses share many of the same symptoms.


The cause or causes of ME/CFS are still unknown. However, ME/CFS is increasingly viewed as an infection-associated chronic illness. This is because of the frequency of its association with infection and the symptom overlap with illnesses following known infections. Other factors may also contribute to development of ME/CFS.

ME/CFS-like illness has been described following infections with a wide variety of diseases. These include:

  • Epstein-Barr
  • Ross River
  • Coxiella burnetti (the cause of Q fever)
  • Herpesviruses
  • Enterovirus
  • Rubella
  • Candida albicans
  • Bornaviruses
  • Mycoplasma
  • Retroviruses, and
  • SARS-CoV-2 (the cause of COVID-19)

People who had severe symptoms with these illnesses were more likely than those with mild symptoms to later develop ME/CFS-like illness.

No single infectious agent has been established as a cause of ME/CFS. However, up to 80% of patients develop ME/CFS following an acute viral-like illness. In most cases, the cause of the infection is unknown. It is possible that, in some people, an infection may lead to immune system changes that contribute to development of ME/CFS.

Some patients report experiencing an accident, trauma, immobilization, surgery, or significant physical or emotional stress prior to onset of ME/CFS symptoms.

ME/CFS has been observed within some families. This suggests either a possible genetic link or a common environmental exposure (infectious or toxic). Twin studies show higher rates of ME/CFS in identical twins than in fraternal twins. However, specific genetic associations have not been established.

Exposure to mold or toxins has been suspected as a trigger for ME/CFS. However, associations of specific environmental factors with ME/CFS have not been established.

Onset and severity

ME/CFS onset can be acute or gradual. Gradual onset can occur over months or years. Acute onset may follow:

  • A flu-like syndrome (fever, malaise, aches, respiratory symptoms).
  • Acute infection (e.g. Epstein-Barr infection).
  • Trauma such as a car accident or surgery.

The severity and frequency of symptoms varies among patients and by individual patient. Symptoms can fluctuate during the day, from day to day, and throughout the illness.

ME/CFS ranges from mild to severe. Some patients may not appear obviously ill during clinical evaluations. Others with severe ME/CFS or exacerbated symptoms may not be able to visit the clinic. Healthcare providers may not see patients when their symptoms are at worst. Levels of illness severity are based on the patient's degree of impairment:


Patients may be able with careful planning and activity management to keep a job or continue education. Patients may be able to participate in social and family activities and attend to daily life.


Patients might have trouble maintaining a regular work schedule. They may have difficulty standing and sitting for prolonged periods. Patients have limited ability to participate in social and family activities.

Severe or very severe

Patients may be wheelchair-dependent, house- or bed-bound for months or even years. Symptoms may increase after daily tasks or trips to healthcare providers. For example, bathing and cooking meals may require significant assistance. They may also need to adjust or interrupt their employment or education. Read more about the care of severely ill patients.

Clinical features

ME/CFS is a biological illness, not a psychologic disorder. Patients are neither malingering nor seeking secondary gain. Patients have multiple pathophysiological changes that affect multiple organ systems. To date, none are sensitive or specific enough for diagnosis. Changes have been reported in:

Some people with ME/CFS have impaired natural killer cell function and/or T cell function. They may have chronic higher production of inflammatory cytokines. In some cases, there may be a slight increase in autoantibodies. These include rheumatic factor, anti-thyroid antibodies, anti-gliadin, anti-smooth muscle antibodies, and cold agglutinins. Mast-cell activation syndrome has been reported.

Some people with ME/CFS may not efficiently produce or use energy from the usual "fuel" cells. These include oxygen, glucose, fatty acids, and amino acids. Exercise studies in adults show impaired oxygen consumption and activation of anaerobic metabolic pathways in the early exercise stages.

Some people with ME/CFS may have dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis). Some patients with ME/CFS have flattened diurnal cortisol profiles. However, their cortisol levels are still within the normal range.

Some people with ME/CFS, particularly adolescents, experience orthostatic intolerance (OI). These patients develop worsening of symptoms with quiet upright posture. Symptoms may improve (though not necessarily fully resolve) when lying down or reclining. Two common forms of OI experienced by patients with ME/CFS are:

Neurally-mediated hypotension (NMH): an abnormality in the regulation of blood pressure during upright posture. NMH is sometimes referred to as neurocardiogenic syncope, vasodepressor syncope, vaso-vagal syncope, "the fainting reflex", and delayed orthostatic hypotension.

Postural orthostatic tachycardia syndrome (POTS): an abnormality where change from lying to standing causes an abnormal increase in heart rate. The heart is usually structurally normal.

These two conditions can occur together. Notably, not all patients with NMH or POTS have ME/CFS, and not all patients with ME/CFS have NMH or POTS.

Other symptoms of autonomic dysfunction include difficulty regulating body temperature, sweating abnormalities and bloating.

Some people with ME/CFS have irritable bowel syndrome, leaky gut, or changes in the microbiome of the intestines.

While joints and muscles are not damaged, musculoskeletal pain, often widespread, is a frequent problem.

Endometriosis, early menopause and other menstrual irregularities are more common in women with ME/CFS than those without ME/CFS.


The percentage of ME/CFS patients who recover is not well-studied. However, there is evidence and experience that early diagnosis and timely and appropriate management may play a role.

Some patients return to full function. Many who improve continue to have symptoms but do not achieve pre-illness levels of function. Others who improve continue to modify their activities to remain improved or free of symptoms. Remissions occur but can be followed by relapses. Some symptoms do not improve or, in fact, worsen over time.

More studies are needed. However, most experts agree that children and teenagers have a better chance of full or partial recovery from ME/CFS than adults.