ABSTRACT
Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called “long COVID-19,” reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, post exertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance.
Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state.
These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics.
Concluding remarks
People with acute COVID-19 and people with ME/CFS share redox imbalance, systemic inflammation and neuroinflammation, impaired production of ATP and other abnormalities in common (Fig. 2), abnormalities that have bidirectional connections (169).
The syndrome of long COVID-19 that can develop in some COVID-19 survivors (people called “long haulers”) is very similar to ME/CFS, so it may well be that the group of abnormalities seen in acute COVID-19 and in ME/CFS also will be seen in long COVID-19. Presumably, redox abnormalities in COVID-19 are secondary to the infection with SARS-CoV-2. The same may be true among those ME/CFS patients whose illness began with an “infectious-like” illness.
Clearly, COVID-19–induced permanent damage to the lungs (chronic hypoxia), heart (congestive failure), and kidneys (fluid and acid-base abnormalities) could cause some of the persisting symptoms seen in long COVID-19. In both long COVID-19 and ME/CFS other symptoms (e.g., fatigue, brain fog) may be generated by neuroinflammation, reduced cerebral perfusion due to autonomic dysfunction, and autoantibodies directed at neural targets, as summarized elsewhere (170).
As many as 2.5 million people suffer from ME/CFS in the United States (6). The COVID-19 pandemic may generate a similar number of cases of long COVID-19 in the coming 1 to 2 y (5). It therefore is imperative that increased research be focused on both long COVID-19 and ME/CFS. Fortunately, the United States and several other countries have committed substantial funding to study chronic illnesses following COVID-19, one of which is long COVID-19. Two registries and associated biobanks of people with long COVID-19 and/or ME/CFS are available to aid research.* We suggest that the study of the connections between redox imbalance, inflammation, and energy metabolism in long COVID-19 and in ME/CFS may lead to improvements in both new diagnostics and therapies.: