Chronic Fatigue

As a symptom, chronic fatigue (fatigue lasting more than 6 months) affected 10.1% of adults in a global meta-analysis of general-population studies. ^[1] In the same meta-analysis, fatigue with no underlying medical condition to explain it was about 2.7-fold as common as fatigue explained by a medical condition. ^[1] Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a distinct illness, characterised by severe fatigue limiting normal daily activities for at least 6 months, together with unrefreshing sleep, worsening of symptoms after physical or mental effort (post-exertional malaise, PEM), and either cognitive problems or orthostatic intolerance. ^[2] The fatigue of ME/CFS is not alleviated by rest, and patients also report cognitive impairment, muscle and joint pain, sleep disturbances and immune dysfunction. ^[3] In 2015 the US National Academy of Medicine published evidence-based clinical diagnostic criteria for ME/CFS, which the US Centers for Disease Control and Prevention adopted. ^[4] Terminology is itself debated: the Institute of Medicine proposed the name Systemic Exertion Intolerance Disease (SEID), whereas the International Consensus Criteria favour myalgic encephalomyelitis, consistent with its neurological classification in the WHO International Classification of Diseases. ^{[5] [6]} A meta-analysis of prevalence studies estimated ME/CFS prevalence at 0.89% under the most commonly used case definition (CDC-1994), with rates in women approximately 1.5 to 2 times those in men. ^[7]

ME/CFS is described as a chronic neurologic disease that is often preceded by infection. ^[8] One integrative model proposes that ME/CFS arises from genetic vulnerabilities combined with environmental triggers, notably viral infections, leading to immune dysregulation, chronic inflammation, gut dysbiosis and metabolic disturbances. ^[9] A growing literature links mitochondrial dysfunction with low-grade systemic inflammation in ME/CFS, fibromyalgia and long COVID. ^[10] Newer studies indicate that specific proteins encoded by Epstein-Barr virus could contribute to the immune and neurological abnormalities seen in a subgroup of patients with ME/CFS. ^[11] Post-acute infection syndromes, including post-acute sequelae of SARS-CoV-2, share symptom profiles that overlap with ME/CFS, suggesting a possible common etiopathogenesis, and several studies estimate that half of patients with post-COVID syndrome fulfil ME/CFS criteria. ^{[12] [8]}

Fatigue is a common symptom in primary care with causes ranging from benign to life threatening, and the patient's history guides a rational evaluation, although for many patients no diagnosis is ultimately identified. ^[14] Persistent fatigue is also prominent in other conditions, for example a pooled prevalence of 41% among COVID-19 survivors more than 30 days after infection, and an overall prevalence of 61.0% for post-dialysis fatigue in haemodialysis patients. ^{[15] [16]} Fibromyalgia, irritable bowel syndrome and chronic fatigue syndrome often overlap as central sensitivity syndromes, and fibromyalgia is diagnosed clinically after excluding important differential diagnoses. ^[17] There is no specific diagnostic test or definitive biomarker for ME/CFS, so diagnosis relies on clinical criteria, which vary across guidelines. ^{[18] [3] [9]} Case definition and method strongly shape estimates: in a prevalence meta-analysis, rates were 0.89% with CDC-1994 versus 0.17% with the Holmes criteria, and 1.14% with interviews versus 0.09% with physician diagnosis.

There are currently no effective, FDA-approved pharmacological treatments for ME/CFS and related post-viral fatigue syndromes. ^{[9] [10]} Management is supportive and symptom-directed with a patient-centred approach, and one clinical review considers pacing of activities with strategic rest periods the most important coping strategy for limiting post-exertional malaise. ^[5] The United States and other governments, as well as major health care organizations, have withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for ME/CFS. ^[4] In contrast, a Cochrane review that included randomised trials with data from 1518 participants concluded that exercise therapy probably reduces fatigue at the end of treatment compared with passive control, while long-term benefit and the risk of serious adverse reactions remain uncertain. ^[18] That Cochrane review searched trials only up to May 2014, included patients diagnosed with the CDC-1994 or Oxford criteria, notes that patients diagnosed with other criteria may experience different effects, and its planned update has been discontinued.