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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) — the illness originally called just “chronic fatigue syndrome” — often begins suddenly in young, healthy adults following what seems, at first, to be a transient “flu-like” illness. However, patients are left with symptoms that persist for years (Mayo Clin Proc 2021; 96:2861).
When interest in ME/CFS surged in the mid-1980s, it was uncertain if any underlying biological abnormalities existed that could explain the patients' symptoms. Indeed, most standard clinical laboratory test results were normal. This led skeptics to suspect that patients were suffering from depression or somatization or even that they were fabricating their symptoms to achieve some secondary goal. By 2020, however, thousands of published scientific studies had identified multiple abnormalities, many National Institutes of Health (NIH) conferences had been dedicated to ME/CFS, and research on the illness was underway at laboratories around the world.
Then came the COVID-19 pandemic. Within a few months, it became clear that following recovery from acute COVID-19, some patients were left with a group of persisting symptoms that were similar to those of people with ME/CFS: fatigue, cognitive problems, postexertional malaise, disrupted sleep, orthostatic intolerance, myalgias and arthralgias, tachyarrhythmias, and gastrointestinal complaints. The most commonly used name for this illness is “long COVID.”
Not only do ME/CFS and long COVID share symptoms. As summarized in detail in two recent reviews, one of which I coauthored, similar underlying biological abnormalities have been reported by multiple laboratories (Front Med 2023; 10:1187163; Nat Rev Microbiol 2023; 21:133). The most robust findings are briefly summarized here.
Neurological: Abnormalities noted in both illnesses include cognitive deficits, primarily in attention and reaction time; reduced cerebral blood flow; down-regulation of the hypothalamic-pituitary-adrenal axis; white matter abnormalities on magnetic resonance imaging; reduced sleep efficiency; and autonomic dysfunction.
Immunological and Infectious: Both illnesses involve increased levels of cytokines, particularly proinflammatory cytokines; high levels of autoantibodies, including antibodies that target the nervous system; reactivation of latent herpesviruses, particularly Epstein-Barr virus (EBV), human herpesvirus-6 and cytomegalovirus; and a proinflammatory gut microbiome. In people with long COVID, we have growing evidence that one trigger of the illness can be residual reservoirs of SARS-CoV-2 RNA and antigen which elicit a chronic, low-grade inflammatory response.
Metabolic: Abnormalities noted in both illnesses include reduced ability to generate ATP from glucose, fatty acids, amino acids and possibly oxygen; and increased oxidative stress.
Cardiovascular/Cardiopulmonary: In each illness, exercise capacity is diminished; ventilatory efficiency is reduced; endothelial dysfunction occurs; and platelets are hyperactivated, forming microclots.
Among people with long COVID, these underlying abnormalities — like the symptoms — are most likely to develop in people who were most gravely ill with acute COVID-19. However, the abnormalities, like the symptoms, also can occur in some people who were only mildly ill.
Not only are the symptoms of ME/CFS similar to those of long COVID, they also are similar to the persisting symptoms reported in some patients following “recovery” from acute infection with a variety of viral, bacterial and protozoal agents, including EBV, West Nile virus, Borrelia burgdorferi, and Giardia lamblia. A similar syndrome of persisting symptoms has been reported following “recovery” from major physical trauma, sometimes called “SICU syndrome” (Nat Med 2022; 28:911).
Why would multiple different infectious agents and major physical trauma produce a similar syndrome? One hypothesis is that this syndrome is driven by an evolutionarily preserved protective response, the goal of which is to change an animal's behavior. The symptoms — fatigue, “brain fog,” and anorexia — discourage activities that consume energy (ATP), like movement, thinking, and digesting. This frees up available supplies of ATP for the fight against infection or injury. For some reason, in some patients, either this protective response is not turned off when the infection is eradicated and the injury is healed, or some ongoing inflammation in the body continually signals the brain that the battle is not over.
NIH has invested more than $1 billion to understand the biology of post–COVID-19 illnesses, including long COVID. Given the similarity in the symptoms and underlying biology between long COVID and ME/CFS, this investment hopefully also will provide some answers for people suffering from ME/CFS.
