August 16, 2022 | Evidence is emerging that long COVID (formally “post-acute sequelae SARS-CoV-2 infection,” or PASC) bears a striking, molecular-level resemblance to the disabling and complex illness now known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). One key difference is that long COVID has one causal agent, the SARS-CoV-2 virus, while ME/CFS has multiple potential sources, says Warren Tate, emeritus professor in the department of biochemistry at the University of Otago (New Zealand) who has been studying both post-viral disorders.
The similarities between long COVID and ME/CFS are particularly intriguing to Tate, whose daughter’s health dramatically deteriorated more than 30 years ago after a bout of glandular fever, commonly known in the United States as the Epstein-Barr virus and best known for causing mononucleosis. With every viral illness, including the flu, “a forgotten minority population” experiences lingering physical, cognitive, emotional, and neurological difficulties long after they have fought off the infection, he says.
COVID-19 has been an unexpected game-changer in that it has put post-viral syndromes on the radar of clinicians and scientists, bringing attention and resources to the study and treatment of PASC, continues Tate. Long COVID is thought to impact as much as 30% of the population infected by SARS-CoV-2, threatening to produce a secondary pandemic.
Tate says he is hopeful progress will be made in not only ameliorating the symptoms of long COVID but finding a way to reverse the condition and get the brain functioning normally again. Less certain is whether research to that end will extend to ME/CFS.
“In New Zealand, we’ve got 25,000 people with ME/CFS and at the moment the number with long COVID is probably in the low thousands,” he points out. “I am trying to get our national [health] authorities to include ME/CFS with the long COVID initiatives they all want to take [and]... there is a bit of a reluctance about that because [some] people don’t want to dilute all that attention by worrying about everything that has gone before.”
In the U.S., Tate’s position is being advocated by Solve M.E., a nonprofit organization interested in alleviating the suffering of individuals with various “long haul” diseases. The critical issue is not the disease or syndrome, he says, but people whose immune systems are engineered such that they are more sensitive to viral infections, toxic chemicals, and surgery than the rest of the population.
The body normally mounts a defense against infection that includes transient inflammation followed by healing. But people with post-viral syndrome remain in a chronic state of inflammation that causes symptoms such as loss of sleep and cognitive function, hypersensitivity to sound and light, and widely fluctuating blood sugar levels—all of which are under brain-derived homeostatic control, notes Tate.
Three years ago, in an article appearing in the International Journal of Immunopathology and Pharmacology (DOI: 10.1177/2058738418812342), Tate and his then-Ph.D. student Angus MacKay first proposed that neuroinflammation in the brain is a central feature of ME/CFS and facilitates the frequent more severe relapses of the illness in response to stress. Newly emerging evidence finds widespread neuroinflammation is also seen in patients with long COVID.
Tate and his colleagues most recently explored communication to the brain from the peripheral nervous system in both ME/CFS and long COVID and found a fluctuating pattern of inflammation that causes the brain to function abnormally, as reported in Frontiers of Neurology (DOI: 10.3389/fneur.2022.877772). Their hypothesis is that the brain effects are sustained by the initial stressor event and the systemic pathology moves to the brain via the neurovascular pathways or through a dysfunctional blood-brain barrier, sustaining illness with chronic cycles of relapse and recovery and no real healing.
The theory holds that the cluster of neurons within the paraventricular nucleus, which are responsible for processing stress, are dysfunctional because of the neuroinflammation, Tate says. In impacted individuals, otherwise mundane aggravations (e.g., driving in a rainstorm) are regarded as dangers requiring the overproduction of hormones such as serotonin that can loosen the barrier the brain has from the rest of the body.
The affected population may well extend beyond long COVID and well recognized post-viral fatigue syndromes, says Tate. Inflammatory biomarkers have been found in the cerebrospinal fluid of patients with multiple sclerosis, for example, a disease characterized by flare-ups with periods of remission that parallel what has been seen with infections with the Epstein-Barr virus.
It is likely that long COVID will also prove to have some unique features, notably the development of microclots as suggested in an article appearing recently in The Biochemical Journal, (DOI: 10.1042/BCJ20220016). The theory is that the microclots block up capillaries and that is what underpins most of the symptoms, including fatigue, “brain fog,” and inflammation.
The odyssey for Tate’s beloved daughter involved the transformation of a bright and vibrant girl into a bedridden invalid for several years. “She could only walk about five to 10 meters to the shower,” he recalls. “We just saw the life being taken out of her before our eyes.”
Being a biomedical scientist, Tate decided to apply for grant money to investigate his hunch that the enormity of her fatigue was related to energy production. He was not taken seriously—nor was her illness. The president of the Royal Psychiatric Society, highly influential in health circles in the U.K., in fact declared at the time what was soon to become known as ME/CFS a “factitious disorder.”
At the time, post-viral syndromes in general were thought to be a constellation of imagined symptoms among people who had found the stresses and strains of life so hard that they were “just sort of opting out of life,” says Tate, who could see firsthand that nothing could be further from the truth. “It was quite clear this was not a psychological illness.”
Starting about a decade ago, Tate began receiving donations from the families of victims and began his hunt for the biological basis of post-viral fatigue syndromes. Dozens of “boutique” outbreaks of these illnesses had been documented worldwide since 1930 and came to be known as myalgic encephalomyelitis (ME) in the U.K. and chronic fatigue syndrome (CFS) in the U.S.
The ME/CFS moniker is an umbrella term that crystallized at a 2016 international meeting in Florida recognizing that the names effectively describe a single debilitating illness, he says. The catalyst was a 2015 report by the Institute of Medicine affirming ME/CFS or “systemic exercise intolerance”—a proposed name flatly rejected by the global patient community—had not received proper acknowledgment and recognition from the medical and research communities as a serious illness.
As many as one in 10 people who get glandular fever go on to get ME/CFS, says Tate. Another 20% of ME/CFS cases are thought to be the result of exposure to nonviral causes like toxic chemicals or surgery. ME/CFS can also be initiated by these major stressors.
Just as the COVID-19 pandemic hit in 2020, Tate and his team published two papers (Journal of Translational Medicine, DOI: 10.1186/s12967-020-02533-3, and Clinical Epigenetics, DOI: 10.1186/s13148-020-00960-z) on molecular signatures in immune cell proteins that reflect altered energy production and DNA changes that drive ME/CFS. “We could see at the molecular level why there were such profound physiological changes in these diseases,” he says.
When COVID came along and people began describing their journeys of not recovering, Tate says, their attention shifted to comparative studies with ME/CFS. With long COVID, of course, the precipitating stress event is the SARS-CoV-2 virus itself.
The World Health Organization defines long COVID as a condition characterized by symptoms impacting everyday life (e.g., fatigue, shortness of breath, and cognitive dysfunction) that typically occur three months from the onset of acute COVID-19 symptoms, last for at least two months, and cannot be explained by an alternative diagnosis. For about 95% of people diagnosed with long COVID, it could be an ongoing lifelong disease like ME/CFS for which there is currently no therapy, Tate notes.
It takes twice as long to make a diagnosis of ME/CFS, and one-quarter of affected individuals remain housebound and some even bedbound, continues Tate. The other 75% move perhaps 2-3 years later into the chronic phase where they might “climb a couple of rungs but then fall down three,” as he describes his daughter’s eventual segue into the rotating recover-and-relapse stage.
In working with his daughter to catch up on her school studies as a young girl, Tate says, he made the discovery that “all of the information was still there in her brain; she just couldn’t access it. That was a very positive moment for me because ... [that meant] it was not a neurodegenerative disease like Alzheimer’s.”
The mission became finding the right kind of tools to “flick that switch back on” so the brain could get back its ability to have proper homeostatic control, he says.
In fact, Tate and his colleagues just finished up a molecular study on two students with ME/CFS at the University of Otago who graciously agreed to getting blood draws over a year, he says. The “DNA methylome” controlling their epigenetic code was compared to healthy controls and, lo and behold, it was found to be “much more unstable month to month... whether they were having a relapse or not.” When they went into a relapse, researchers were also able to track changes in their DNA that explained an enhanced inflammatory response by their immune system.
The two students with ME/CFS were, unsurprisingly, women. Tate’s own studies suggest females outnumber males at least four to one, and possibly as much as six to one, when it comes to disease incidence. Likewise, long COVID predominantly impacts women.
In the molecular studies done to date, the same effects have been seen in both sexes, he says. For unknown reasons, they just more often happen in females.
Interestingly, his daughter had the best year of her life with ME/CFS after getting pregnant at age 39. Short-lived excitement over the possible protective effect of pregnancy quickly gave way to a recurring rule of one-thirds with post-viral syndromes, where what helps one subpopulation of patients worsens the situation in others or elicits no change in similar proportions of diagnosed individuals.
No definitive molecular diagnostic test exists to diagnose either ME/CFS or long COVID, but efforts are underway to come up with some sort of solution. Ron Davis, famed professor of biochemistry and genetics at Stanford University whose son has spent years bedbound by the maddening disease, has been actively seeking a cure. He is currently developing a promising nanoneedle test (PNAS, DOI: 10.1073/pnas.1901274116), but it has yet to be fully tested for its disease specificity for ME/CFS, says Tate.
It is but one of a long list of research projects specific to ME/CFS that are being undertaken by Stanford’s Genome Technology Center. These include a commercially available mitochondrial function test that measures oxygen during energy production processes, which can reveal significant differences between activated T-cells of ME/CFS patients and healthy controls.
Separately, a group in Australia has developed a trio of highly sophisticated tests that could serve as useful second-line diagnostics for patients suspected of having ME/CFS based on its clinical case definition, he continues. The scientific principles were covered at length in a 2020 paper published in the International Journal of Molecular Science (DOI: 10.3390/ijms21031074).
Tate’s own group is looking at “some simple molecules that might be altered in these post-viral syndromes and could be easily detected by techniques that path labs use.”
These include creating antibodies against the phosphate group added to a stress protein kinase (PKR) when it is activated. This is indicative of a chronically activated immune system as is found in ME/CFS, Tate says. The concept is to use the phosphorylation state of a molecule as a potential diagnostic molecular biomarker by measuring the ratio of the activated phosphorylated protein to the inactive form lacking the phosphate, much like a cholesterol test measuring the ratio of high-density and low-density lipoproteins. This could then be converted into the commonly used enzyme-linked immunoassay (ELISA) format.
Healthy controls have no ongoing active form (pPKR), although anyone with a head cold might have a transient change to their immune system and test positive, he continues. Individuals with ME/CFS have had a phosphorylated state of PKR for years, making it a potentially worthwhile approach to early detection.
Longitudinal research is desperately needed. One holdup has been that it takes six months to get at an official ME/CFS diagnosis. With long COVID, a diagnosis can be made after three months.
It makes sense to launch an ongoing study enrolling people newly infected with SARS-CoV-2, knowing a proportion of them will ultimately develop the post-viral disorder, says Tate. ME/CFS could likewise be studied by enrolling individuals at the point of their initial infection, for example with the Epstein-Barr virus.
As a reviewer for European grants for ME/CFS, Tate says he sees larger clinical studies being planned to look at COVID alongside other post-viral syndromes. Oxidated stress, for example, is likely to be a shared clinical feature as the body fights off these infections.
Antioxidants in the body are designed to protect the cells from attack by oxygen and keep the body in balance, he notes, referencing coenzyme Q10 and glutathione (in a high concentration in the brain). Oxidative stress with a disease implies a person either has too many reactive oxygen species or the antioxidants in their body are depleted.
Doctors will often prescribe supplements to ME/CFS patients to replenish the antioxidants they potentially lack, says Tate. Longitudinal clinical trials are needed to ascertain whether they in fact make a difference. The same holds for therapies, such as the anti-addictive drug naltrexone, which at low doses is anti-neuroinflammatory (Frontiers in Immunology, DOI: 10.3389/fimmu.2021.687806).
At present, naltrexone appears to be adhering to the rule of one-thirds where only a portion of patients see any benefit, says Tate. But perhaps this can be remedied via personalized dosing.
Much of the research done by Tate now is beginning to look at the subtleties of effects seen in individual patients with ME/CFS by precision medicine, rather than measuring average effects in patient groups, including how they respond to exercise. Post-exertional malaise is a core symptom of both long COVID and ME/CFS, and the physical and even emotional or psychological stress can cause them to go into relapse, he says.
In one study where five young women were put on an exercise protocol under the oversight of a cardiac physiologist, each responded uniquely, says Tate. Molecular studies were then done one and two days later to look at their energy production. “They just couldn’t do as much 24 hours later whereas healthy controls... got a little boost.” But each patient had their unique physiological and molecular responses.