Long COVID shares symptoms with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
NIH researcher Avindra Nath, M.D., is leading a study on long COVID similar to one he led on ME/CFS.
Long COVID might be caused by an unrelenting immune response.
For people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “fatigue” doesn’t just mean being a little tired. It means a brain like molasses, a body exhausted and weak, and legs like jelly. If you are just tired, a typical remedy is to get some exercise or move around a bit to get blood flowing. But for people with ME/CFS, exercise does just the opposite. Physical or mental exertion can debilitate them, requiring recovery time that lasts for days, months, or years. Resting does not help. This symptom, known as post-exertional malaise, is one of the defining features of the disease, and it is poorly understood.
In 2015, researchers estimated that ME/CFS affected between 900,000 and 2.5 million people in the United States, most of them undiagnosed. Other symptoms include sleeping issues, problems with memory and cognition, and muscle soreness.
If these symptoms sound familiar, it is because ME/CFS shares symptoms in common with long COVID, a group of symptoms some people who have had COVID-19 experience for weeks or months after their initial illness. Symptoms of long COVID include fatigue, post-exertional malaise, breathing problems, and heart palpitations.
Researchers do not know a lot about what causes ME/CFS or long COVID, but both conditions appear to follow an infection, among other similarities. Members of the ME/CFS community are hopeful that research into long COVID will help shed light on their own struggles, which currently have no known cause or treatment.
Avindra Nath, M.D., the clinical director of the National Institute of Neurological Disorders and Stroke, studies ME/CFS and has recently turned his attention to long COVID. He is preparing for a clinical study that will bring people into the lab for several days at a time to look for underlying causes of long COVID, similar to a study he leads for ME/CFS. We spoke to Nath about long COVID and ME/CFS and how research into one disease may help people with the other.
What is long COVID?
NATH: There is no good definition of long COVID, and people define it differently. Some patients are so sick, they were admitted into the intensive care unit (ICU). When they come out, they’re better, but they haven’t gotten back to baseline. If you are really sick, it’s going to take you a while to get better because you have damage to so many different organ systems.
There’s also a second group of patients that tell you that when they had COVID-19, they might have seen a doctor, but maybe they didn’t. And they tested themselves, they were positive, and after a few days, the symptoms got better. And then they started experiencing other symptoms. They realize, “Oh, I can’t think properly. When I stand up, I get dizzy. I’m getting depressed, or my hands and feet are tingling.” Some patients can’t sleep well at night; others complain of fatigue or palpitations. These are the types of patients we’re going to be studying.
What happens to the body in people with long COVID following mild infection is going to be very different compared to those who have long-term symptoms after being very sick. There’s a sizable population of people who have these new symptoms.
Why are people with ME/CFS hopeful that research into long COVID will help them?
People with ME/CFS have been saying for decades that they develop a constellation of persistent new symptoms following some kind of infection. They go to doctors, and they often cannot find anything abnormal. Every test comes back normal. The patients are very frustrated and often say, “You think that this is all in my head? This is real. I was perfectly fine before this happened. And now my life is devastated.”
So you have both sides frustrated: The doctors are frustrated because they don’t know what is wrong with the patient, and the patients are frustrated because they think the doctor doesn’t believe their symptoms. So ME/CFS kind of lingers out there in no man’s land.
And now we’ve got COVID-19 infection affecting hundreds of millions of people. If other infections trigger ME/CFS, then you would think that COVID-19 would surely do it too. And it is true that many of the symptoms that we see in long COVID patients are similar to what we see in ME/CFS patients as well. There is substantial overlap between the two conditions. All clinical studies of long COVID patients would be relevant to ME/CFS.
“We believe your disease. We know that you’re suffering. And we’re doing something about it.” —Avindra Nath, M.D.
What is difficult about studying long COVID and ME/CFS?
It’s difficult studying a disease which is subjective in nature. Without a specific test, you’re left with the ability of people to express themselves and describe their symptoms. People use language in different ways. That makes it very challenging.
The pressing question is, can you find a biological reason for the condition? That’s what everybody’s after: to find a biological marker, like a blood test or something, that will describe it. We probably won’t find one thing, but we might find a few things that will point to some biological cause. And that will give us some indication of what part of the body’s systems aren’t working right.
What have you done to find a biological cause for long COVID?
We studied brain tissue from patients who had died from COVID-19 at home. COVID-19 came on so fast, they died suddenly. They didn’t go to the hospital. They didn’t spend time in ICU. When we looked at the lungs and other organs, we saw only a little damage — not enough to cause secondary damage to the brain. We knew that damage we saw in the brain was directly related to the infection.
When we looked at the brains, to our surprise, we did not see SARS-CoV-2. Instead, we found the brains had extensive injury to the blood vessels. We saw inflammatory cells — a kind of immune cell — around the blood vessels in the brain. Since these patients were functional until the time of death, we reasoned that if they had survived, they may have developed long-term neurological symptoms. It’s possible that long COVID might be similar.
What are you looking for?
I want to understand what’s happening with the immune system and what it is doing to the brain. The immune system has a lot of different parts to it. It can affect every organ in the body. And I want to understand which parts of the immune system are normal and which parts are acting up. If I can find the parts that are acting up, then I can figure out how to shut them down.
So we’re going to test their spinal fluid, blood, and serum. We’re going to do a neuropsychological battery of tests. We’re going to test their nerve conduction, their heart function, their autonomic function, neurotransmitters — there’s a lot of things we’re going to try, depending on the types of symptoms the patients have.
We will look for SARS-CoV-2, too. We’re looking at stool samples, saliva, and spinal fluid. Biological fluids are better than biopsies for finding the virus. Even if there’s a small amount of virus in a fluid, you can concentrate it and pull it out.
NIH Intramural Study on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Dr. Nath explores the clinical and biological characteristics of ME/CFS.
So what is causing long COVID?
That’s the question. Is the virus persisting in the body somewhere? Or is long COVID some kind of an immune reaction that continues on after SARS-CoV-2 is gone? There’s probably evidence for both. There’s no doubt that the immune system continues to be activated. But we aren’t sure what is driving that persistent immune activation. It’s possible that there’s some residual virus sitting someplace that’s driving it.
Or long COVID might have nothing to do with the virus. It might be that once the immune system gets stimulated, it just self-perpetuates — there are a lot of other autoimmune diseases like that. In lupus or multiple sclerosis, you never find any infection. The immune system just kind of activates. It might be triggered by something at first, but then that trigger is gone, and the activation persists.
Now, what if SARS-CoV-2 is driving long COVID? The problem is, we’re not finding the virus in patients, so if it’s there, it’s in very small amounts. And we don’t even know where to look — the blood, the tissues? You can’t biopsy people’s brains. Or let’s say it’s in the gut — which part of the gut do you biopsy? We have 23 feet of gut; where do we take a little snip from? There are so many places that the virus can hide.
What should people with long COVID or ME/CFS know about ongoing research?
They should know that we believe your disease. We know that you’re suffering. And we’re doing something about it. We may not have all the answers for you today, but it’s not from a lack of trying.
If you talk to anybody in United States right now, everybody knows of someone who’s suffering from something related to COVID-19. So the motivation level for everyone who can do anything about it is extremely high. The desperation is shared by all of us.
- Spudich, S., & Nath, A. (2022). Nervous system consequences of COVID-19. Science, 375(6578), 267-269. https://doi.org/10.1126/science.abm2052