Myalgic encephalomyelitis (Chronic fatigue syndrome)

The aetiology of ME/CFS remains unknown; however, various pathogenic, environmental exposure, physical trauma, and genetic factors have been investigated as initiating triggers or precipitating events.[31] The onset of ME/CFS can be sudden, acute, or gradual.

Inflammation and infection

The acute onset of symptoms may follow an infection and emerging evidence suggests the possibility of an inflammatory component to ME/CFS.[29]

Approximately 60% to 70% of people with ME/CFS report viral and bacterial infections:[32]

Viral: Epstein-Barr virus, Ross river virus, cytomegalovirus, human herpes virus, human parvovirus, retroviruses, rubella
Bacterial: Q fever (Coxiella burnetii), Mycoplasma pneumoniae

No causal role has been established between ME/CFS and a specific infectious agent and no chronic active viral, prion, or other infections have been found in the vast majority of patients with ME/CFS.[31][33]

The Epstein-Barr virus (infectious mononucleosis) has been the most researched source of post-viral fatigue. One study found that 9% of patients developed ME/CFS 6 months post onset of Epstein-Barr.[34] Another study found that 38% of participants failed to recover from Epstein-Barr 2 months post infection, and 12% had not fully recovered at 6 months post infection.[35] A prospective study that followed 301 adolescent patients (aged 12-18 years) after developing Epstein-Barr virus found that the reported incidence of ME/CFS was 13% after 6 months.[36] The rate drops to around 4% at 24 months, indicating a high rate of remission in adolescents. Pre-existing gastrointestinal distress, autonomic symptoms, and immune markers have been implicated in the development of severe ME/CFS following infection with Epstein-Barr virus.[37]

An investigation into the severity of fatigue 5 years following Q fever, a rare infection caused by the bacteria Coxiella burnetii, found that 42.3% of participants exhibited symptoms that qualified them for a diagnosis of ME/CFS.[38] ME/CFS has been reported sporadically after cases of Q fever, parvovirus, and other infections.[39][40][41]

Approximately 31% of patients recovering from West Nile virus infection experienced chronic fatigue, of which 64% fulfilled the criteria for ME/CFS.[42] Enteroviral gastritis has been proposed as a cause of ME/CFS but has not been independently confirmed.[43][44][45] ME/CFS may also follow acute Lyme disease. The entity of chronic Lyme disease and its symptomatic overlap with ME/CFS requires more mechanistic and pathological data for comment.

In 2003, following an outbreak of SARS caused by severe acute respiratory syndrome coronavirus (SARS-CoV) researchers reported that 64% of study participants experienced fatigue at 3 months, 54% at 6 months, and 60% at 12 months post infection onset.[46] A 4-year follow-up reported that 40.3% of patients reported ongoing fatigue, of which 27.1% qualified for a diagnosis of ME/CFS.[47]

In 2009, antigenic drift of the influenza H1N1 virus resulted in a pandemic. An investigation in a Norwegian population reported an increased incidence rate of ME/CFS associated with reaction to fever and immune response during infection.[48]

People with post-coronavirus disease 2019 (COVID-19) syndrome (i.e., long COVID) have chronic disabling fatigue and other symptoms that overlap with ME/CFS.[49] Long COVID is a post-viral fatigue syndrome that shares disability, fatigue, and 'brain fog' with ME/CFS. Symptoms persist longer than 1 month in about 10% of acute COVID-19 cases, and range from mild to debilitating. Persistent shortness of breath, dyspnoea on exertion, chest pain, cough, and loss of smell may be sequelae of upper and lower respiratory infection.[50] Longitudinal studies will determine the rate of improvement of post-COVID-19 syndrome, prevalence of chronic ME/CFS in post-COVID-19 patients, and differences in their pathogenesis.[51]

Antiviral medications have not been successful in treating the broad spectrum of ME/CFS, and immunisation is not a significant precipitant.[52][53][54]

Genetic predisposition

Families with ME/CFS in several generations are known, but have not been systematically tested for genetic transmission, maternal transmission of mitochondria, penetrance in males and females, or in large enough numbers to generate useful genome-wide association studies. A study in female identical twins suggests 38% heritability (with concordance rates of 11% in non-identical twins).[55]

Patients with severe ME/CFS may be confined to bed and require home visits and in-home therapy sessions because severe pain and discomfort will prevent them from travelling. It is not known if this group represents a separate disease or aetiology, or is the extreme end of a continuous distribution of ME/CFS severity.

Future research may determine that the current diagnosis of ME/CFS is heterogeneous and encompasses multiple conditions with discrete aetiologies. It is not clear whether sudden onset of severe fatigue in <30 days versus a pattern of more chronic gradual worsening represents distinct syndromes with different aetiologies, such as microbial infections, or acute onset of autoimmune disease, as opposed to more chronic development of dysfunctional pathologies.

Viral, inflammatory, neurological, autoreactive, and metabolomics mechanisms have been proposed, but not verified, to explain the pathophysiology of ME/CFS. These mechanisms have not led to a consensus on objective biomarkers as diagnostic features, or the identification of ME/CFS phenotypes. Until these potential biomarkers have been clinically confirmed, the pathophysiology of ME/CFS will remain unclear, and diagnosis will be based entirely on self-reported symptoms and functional impairments.

Immune dysfunction and inflammation

Considering that 66% to 90% of patients with ME/CFS initially develop an acute infectious illness, exercise bradycardia might also be related to post-acute viral status, either as a direct or indirect latent effect. There is also the possibility that cellular metabolic pathways are disrupted by the viral presence or by some immunological process triggered by the acute or persistent infection.[56][57]

Immune dysregulation has been proposed based on consistent patterns of B, T, and natural killer (NK) cell dysfunction in ME/CFS.[58][59][60][61][62][63] NK cell dysfunction has been postulated as a risk factor for chronic viral infection, but again no microbes have been identified.[62][64][65][66][67] The possibility of autoimmunity is suggested by antibodies to adrenergic receptors found in ME/CFS and postural orthostatic tachycardia syndrome.[68][69] However, the potential role of autoimmunity is unsupported in other research. Alterations in cytokines, microRNA expression, epigenetic modification of DNA, and genetic polymorphisms have been reported but not confirmed.[70][71][72][73]

NK cells are a key consistent immunological finding and reduced cytotoxicity provides a viable biomarker. The cause of impaired NK cell cytotoxicity is under investigation and the current evidence suggests impaired calcium mobilisation in NK cells of people with ME/CFS, and impaired calcium-permeable channels (such as transient receptor potential [TRP]) result in impaired cellular function.[74][75]

Low-grade inflammation has been suggested through findings of increased production of nuclear factor kappa B (NFκB), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), activation markers, and interleukins. This can be further categorised through diminished levels of antioxidants, damage to proteins and DNA, in addition to mitochondrial dysfunction.

C-reactive protein may be at the upper range of normal.[76]

Neurological dysfunction

Cognitive deficits in ME/CFS affect attention, memory, and reaction time.[77] Neuroimaging studies suggest multiple regions of brain dysfunction.[78][79][80][81][82][83][84][85] Autonomic dysfunction in ME/CFS has been correlated with reduced volumes of brainstem vasomotor nuclei and limbic nuclei involved in stress responses.[86][87] Microglial activation in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons suggests neuroinflammation in ME/CFS.[88]

Other neurological abnormalities observed using neuroimaging techniques include:[89]

Reduced cerebral blood flow
Reduced white matter volume in midbrain, pons and right temporal lobe, occipital lobes, left inferior fronto-occipital fasciculus
Reduced grey matter volume in occipital lobes, right angular gyrus, posterior division of the left parahippocampal gyrus

Dysfunction of the afferent sensory (threat assessment) autonomic circuit has been postulated, resulting in heightened sensory perception, anxiety, and dysregulated sympathetic reflexes.[90][91][92] Dysregulated sensory afferent perception may contribute to photosensitivity/photophobia (migraine), vestibular dysregulation (orthostatic intolerance), chemosensitivity to irritants, and mechanosensitive stretch receptor activation (myalgia, arthralgia, systemic hyperalgesia). Autonomic responses may include palpitations, sweating, orthostasis, vasodilation followed by heat loss and chilling, and urgency of defecation/urination. Many of these magnified or disinhibited perceptual experiences have been incorporated into ME/CFS criteria.[3][4][93]

Chronic pain has been classified as nociceptive if due to peripheral or inflammatory activation of nerve endings, neuropathic if related to nerve injury, and neuroplastic if related to dysfunctional brainstem and descending antinociceptive pathways that no longer can modulate and block ascending pain signals. The authors of this topic propose a comparable 'interoplastic' mechanism in ME/CFS to explain the large number of interoceptive bodily sensations of irritation, dyspnoea, and gastrointestinal discomfort that arise from visceral and mucosal organs.

Dysfunction of the gut microbiome

The gut microbiome has a reduced diversity in ME/CFS, and, after exercise, gut microbes appear to enter the peripheral blood more readily than in control patients.[94][95] One systematic review reported limited consistency in the data observing changes in the gut microbiome.[96] While dysregulated gut-brain signalling is proposed to play a role in neurological dysfunction, there is insufficient evidence to support this hypothesis.

Mitochondrial dysfunction

A more recent development has been demonstration of abnormal metabolomics patterns in peripheral blood in ME/CFS.[97][98] Changes in mitochondrial structure, DNA, membrane potential, respiratory function, reactive oxygen species, antioxidant defence, metabolites, and coenzymes have been reported in urine, peripheral blood mononuclear cells (PBMCs), and isolated immune cells.[99] Changes in metabolite concentrations indeed suggest disturbances in cellular energy production as a consequence to the underlying pathology. For example, overexpression of Wiskott-Aldrich syndrome protein family member 3 (WASF3) in skeletal muscle and other tissues may disrupt mitochondrial respiratory supercomplex formation and induce endoplasmic reticulum stress.[100]

However, mitochondrial dysfunction and metabolomics imbalances are now being discovered in many illnesses, and so it will be critical to define the sensitivity and specificity of patterns in ME/CFS compared with other diseases in its differential diagnosis. Further, new technological innovations have suggested that PBMCs in patients with ME/CFS cannot tolerate osmotic stress compared with healthy controls.[101] While changes in mitochondria structure and function have been reported in PBMCs of ME/CFS patients, these findings are not consistent.[102]

Exertional deconditioning and cardiac output

The study of athletes and chronically immobilised patients has offered other hypotheses, and this research has contributed towards the prescription of exercise as therapy. The central fatigue hypothesis proposes that primary dysregulation of brain function leads to lethargy and loss of drive.[103] The deconditioning hypothesis proposes that ME/CFS is perpetuated by reversible physiological effects of bed rest and inactivity, and that exercise will reverse consequences of deconditioning.[104][105][106]

Deconditioning is defined as reduced oxygen uptake at maximum effort during cardiopulmonary exercise testing (VO₂ max <85% of predicted maximum).[107][108] Exercise deconditioning is present in chronically bed-bound and inactive people.[108] It is also present in up to 90% of patients with orthostatic intolerance, which frequently occurs in patients with ME/CFS.[107][108] However, ME/CFS may represent a special case because maximal exercise on 2 days leads to a significant 10% to 15% decrease in VO₂ max on the second day that is not seen in other diseases.[109][110][111]

One meta-analysis of 64 published studies showed that heart rates were significantly higher in resting patients with ME/CFS, but significantly lower at maximal exercise (HRmax) and peak exertion (HRpeak).[112] ME/CFS have lower VO₂ max, which indicates energy loss associated with the underlying pathomechanism of ME/CFS, which is exacerbated with physical activity. VO₂ max can also be used to grade cardiopulmonary disability.[113]

Submaximal exercise is a stressor in ME/CFS that induces distinct patterns of change in mRNAs for nociceptive sensor proteins, ion channels, and adrenergic and other receptors in peripheral blood leukocytes of the majority (71%) of patients with ME/CFS, but not in controls or patients with depression, prostate cancer, multiple sclerosis, or fibromyalgia.[114][115][116][117][118]

'Small heart syndrome' with small left ventricular size and low cardiac output has been proposed to lead to poor physical stamina and chronic fatiguing status in patients with ME/CFS.[119][120] The low cardiac output is a finding that overlaps with postural orthostatic tachycardia syndrome (POTS).[121] The postulated low cardiac output may also contribute to reduced performance and VO₂ max on maximal cardiopulmonary exercise stress testing.[111] Invasive cardiopulmonary testing found lower peak oxygen extraction (peak VO₂) and right atrial pressure while seated on the bicycle ergometer at maximum exercise in people with ME/CFS compared with people in the control group.[122] These findings suggest two subgroups with depressed cardiac output; one with impaired venous return, and the other with high cardiac output with peripheral left-to-right shunting and depressed peripheral oxygen extraction. Small-fibre pathology was found in 31% of ME/CFS skin biopsies, suggesting that neuropathic dysregulation and microvascular dilation may shunt oxygenated blood away from capillary beds of peripheral and exercising tissues. These mechanisms appear to be shared with long COVID.[123]

Orthostatic intolerance

Orthostatic intolerance including POTS is a common feature of ME/CFS that has been associated with decreased cerebral blood flow during upright posture and tilt-table testing.[124] Deconditioning has been proposed to be a significant contributor to orthostatic intolerance. If so, predicted peak oxygen consumption (VO₂) during maximal cardiopulmonary exercise testing should correlate with the drop in cerebral blood flow during head-up tilt testing. However, this theory is refuted by one study in which people with ME/CFS (n=199) had significantly reduced peak VO₂ indicating deconditioning, and larger reductions in cerebral blood flow during head-up tilt, indicating orthostatic intolerance compared with healthy control subjects (n=22).[125] However, the orthostatic intolerance was not related to the degree of deconditioning (cardiac output, VO₂ max). This suggests ME/CFS is associated with brainstem cardio- and baroreceptor dysregulation and cerebrovascular instability to orthostatic stressors in addition to neurovascular dysfunction and deconditioning. Similar findings have been found in long COVID.[126]

Small-fibre neuropathy

Small-fibre neuropathy has been documented in 49% of people with fibromyalgia, and it may contribute to the development of postural tachycardia/orthostatic intolerance.[127] Alternatively, people with fibromyalgia may have increased peptidergic innervation of arteriovenous anastomoses leading to peripheral arteriovenous shunts.[128] Quantitative biopsy and peripheral vascular studies are required for ME/CFS, given a potential overlap in pathophysiology.

A severity spectrum to ME/CFS has been proposed as follows:[4]

Mild ME/CFS: defined by a 50% reduction in pre-illness activity level, patients are still mobile; however, report reduced work or other activities.
Moderate ME/CFS: defined by a reduction in mobility with significant restrictions to activities of daily living and needs very frequent rest.
Severe ME/CFS: defined as housebound patients with limited activities of daily living.
Very severe ME/CFS: defined as mostly bedridden and unable to undertake activities of daily living independently.

Pathophysiology

Classification