CLEVELAND, Ohio—As scientists struggle to unpack the mystery of long COVID, it’s hard to ignore that the majority of those who suffer from it share a common symptom – debilitating fatigue.
Researchers estimate that as many as 85% of those with long COVID experience a crippling fatigue that renders them unable to work or manage even simple daily tasks. Even showering, report some patients, is simply too taxing.
What many people may not realize, is that long before COVID, some patients reported the same symptoms of persistent, debilitating fatigue, brain fog, muscle pain and intolerance to exercise, following a variety of illnesses, injuries, or infections. Those conditions are collectively referred to as infection-associated chronic diseases and include myalgic encephalomyelitis/chronic fatigue syndrome. But until recently, they had largely been dismissed by the medical community, which devoted few resources to understanding their cause.
Then came COVID, and science began paying more attention.
“Over the past decade most well-studied viral or bacterial pathogens have been connected to the development of chronic symptoms in a subset of infected patients,” said Amy Proal, a microbiologist at the PolyBio Research Foundation in a talk to the Global Interdependence Center. She cited syndromes stemming from Ebola, Zika and Dengue viruses among others, including ME/CFS. Long COVID is now believed to be the latest on that list, and patients and doctors are hoping that increased investment in understanding and treating long COVID will pay dividends for those other post-infection chronic diseases as well.
“While the development of long COVID is sometimes framed as novel or mysterious, it is actually a well-recognized phenomenon,” Proal said.
A disease largely ignored
Despite the fact that a 2015 report by the Institute of Medicine estimated between 836,000 and 2.5 million Americans suffer from myalgic encephalomyelitis/chronic fatigue syndrome, the community of doctors and researchers who study and treat the disease and the vast majority of their patients had a hard time being taken seriously prior to the pandemic. Patients were told their symptoms were all in their heads, they lacked motivation, or even that they would feel better if they just started getting more exercise.
Part of the problem has been a lack of medical education devoted to the disorder. Less than one third of medical schools include ME/CFS-specific information, and only 40% of medical textbooks include information on the condition, according to the IOM report, which goes on to state that there is a “lack of understanding of diagnosis and treatment of the condition among health care providers and skepticism about whether it is in fact a true medical condition … Many providers believe it is a psychiatric/psychological illness or at least has a psychiatric/psychological component. “
New virus, same disease?
For most of its history ME/CFS lacked a clear definition and diagnostic criteria. There simply wasn’t a unified theory of what was happening. The result was a lack of buy-in by the medical and scientific communities, which financially tied the hands of researchers and left patients struggling to validate their symptoms.
But the emergence of long COVID has begun to change all that. The waves of people suddenly reporting identical symptoms, and the enormous scope of the problem, has quickly brought the urgency for a solution into sharper focus and pushed the U.S. government to devote billions of dollars to understanding the disease and developing potential therapies.
The many parallels between long COVID and ME/CFS have caused some to ask whether long COVID is simply another form of post-infectious fatigue, but with a clear cause and millions of potential research subjects.
For those who have devoted their lives to unraveling the mystery of ME/CFS this is an enormous boon for research and an opportunity to finally reveal the biological underpinnings of a disorder that have thus far eluded them.
“The most constructive thing that could come from long COVID is that the very large investment in research will teach lessons that will apply well beyond long COVID to ME/CFS, other post-infectious and post-injury syndromes, and maybe even beyond,” said long COVID researcher Anthony Komaroff, of Harvard Medical School.
A protective brain system gone awry
According to Komaroff, there’s now strong evidence that the flu-like symptoms of fatigue, muscle aches, brain fog and loss of appetite that are shared by ME/CFS and long COVID patients are actually a reaction that is hardwired in humans with the purpose of conserving energy during periods of illness or injury.
“When you are infected or injured your immune system is called into action to fight the infection and heal the injury. That takes a lot of energy, and your body only has so many energy molecules available,” said Komaroff. Under normal circumstances, he said, this reaction is protective, but in long COVID or ME/CFS patients continue to experience symptoms months or years later, long after the infection is believed to be gone.
Five years ago, Komaroff proposed a theory that this so-called “fatigue response” was the result of the activation of a few specific, and very tiny groups of neurons “whose only purpose in life is to cause that set of symptoms when you get sick,” he said.
These groups of neurons reside in a part of the brain called the hypothalamus, and another region called the brain stem, areas that were already known to regulate sleep, mood and appetite. Komaroff said the neurons sit in the brain resting until they are stimulated by illness or injury and cause this orchestrated set of symptoms.
“It was a nice theory, but there wasn’t a shred of evidence in favor of it until a year or two ago,” Komaroff said.
But then, four separate papers were published in the journal Nature, the latest one in September, demonstrating that such clusters of neurons not only exist in the brains of mice, but when stimulated they can produce symptoms of illness.
Although he recognizes that the findings were in rodents, not humans, he is encouraged. “Most things that we find to be true of a mouse’s brain, are also true of humans,” Komaroff said. “It’s just going to be a while before we can prove it.”
The role of inflammation
But if Komaroff’s theory is correct, it also begs the question of why, once the infection has resolved, do some people continue to experience these symptoms much later. Why does the brain still think it needs to protect you if the infection is gone?
Komaroff believes inflammation has something to do with it.
“We know that if you for instance have inflammation in the lining of your gut, signals travel up the vagus nerve to your brain and activate the immune system of the brain,” he said. “It’s basically saying to the brain, there’s a threat somewhere else in the body and you’ve got to get ready for it.”
What isn’t known is the source of that inflammation; whether it is the residual effect of the COVID virus remaining hidden in various tissues of the body, whether it is the result of COVID activating other latent viruses such as Epstein-Barr or herpes, or whether the natural balance of viruses and bacteria in the body has been thrown out of whack and the immune system is generating inflammatory molecules even in the absence of a threat.
It could be any one of those things, or all of them, Komaroff said.
“It’s very unlikely that it’s exactly the same process in every person,” he said. “All of those things are not only plausible, but likely.”
And that’s what currently makes understanding long COVID and ME/CFS so challenging. Researchers have identified seven factors, none mutually exclusive, that may contribute to their development.
“They are all connected, and patients may have one or more issues occurring at the same time,” Proal said. “ … But we do not necessarily think that every patient has the exact same thing happening.”
Researchers are already looking for biomarkers that can be used to identify and diagnose patients with long COVID and ME/CFS, and various research groups are investigating different treatment options. Some are proposing antiviral treatments that target potential reservoirs of virus that may still be present in the body or brain. Others, said Komaroff, are proposing treatments that may quiet down the immune activation in the brain that triggers the fatigue response.
It remains to be seen which, if any, of these treatments actually improves symptoms. Those results are still many months or years away, but Komaroff believes the answers are coming.
“I’m a big believer in it,” he said. “I just think you have to be realistically patient.”