New clues to the biology of long COVID are starting to emerge

Kelly LaDue thought she was done with COVID-19 in the fall of 2020 after being tormented by the virus for a miserable couple of weeks.

"And then I started with really bad heart-racing with any exertion. It was weird," says LaDue, 54, of Ontario, N.Y. "Walking up the stairs, I'd have to sit down and rest. And I was short of breath. I had to rest after everything I did."

A year later, LaDue still feels like a wreck. She gets bad headaches and wakes up with pain all over her body on more days than not. She also experiences a sudden high-pitched whistling in her ears, bizarre phantom smells and vibrations in her legs. Her brain is so foggy most of the time that she had to quit her job as a nurse and is afraid to drive.

"These symptoms, they come and go," she says. "You think: 'It's gone.' You think: 'This is it. I'm getting better.' And then it'll just rear back up again."

Patients like LaDue have researchers scrambling to figure out why some people experience persistent, often debilitating symptoms after catching SARS-CoV-2. It remains unclear how often it occurs. But if only a small fraction of the hundreds of millions of people who've had COVID-19 are left struggling with long-term health problems, it's a major public health problem.

"I think it's the post-pandemic pandemic," says Dr. Angela Cheung, who's studying long COVID-19 at the University of Toronto. "If we are conservative and think that only 10% of patients who develop COVID-19 would get long COVID, that's a huge number."

"Not caused by one thing"

So far there are more theories than clear answers for what's going on, and there is good reason to think the varied constellation of symptoms could have different causes in different people. Maybe, in some, the virus is still hiding in the body somewhere, directly damaging nerves or other parts of the body. Maybe the chronic presence of the virus, or remnants of the virus, keeps the immune system kind of simmering at a low boil, causing the symptoms. Maybe the virus is gone but left the immune system out of whack, so it's now attacking the body. Or maybe there's another cause.

"It's still early days. But we believe that long COVID is not caused by one thing. That there are multiple diseases that are happening," says Akiko Iwasaki, a professor of immunobiology at Yale University who is also studying long COVID-19.

But Iwasaki and others have started finding some tantalizing clues in the blood of some patients. Those include unusual levels of cytokines, which are chemical messengers that the immune system uses to communicate, as well as proteins produced by the immune system known as autoantibodies, which attack cells and tissues in the body instead of the virus.

"We are finding elevated cytokines in long-COVID patients and we're trying to decode what those cytokines mean. We're also seeing some distinct autoantibody reactivity and are trying to find out what those antibodies are doing and whether they are causing harm," Iwasaki says.

Other researchers have produced similar findings. Dr. Steven Deeks at the University of California, San Francisco, found long-COVID-19 patients appear to have elevated levels of a cytokine called interleukin-6, suggesting they may be suffering from a state of chronic inflammation.

"The first couple of weeks of the infection is associated with a massive amount of inflammation. The virus just blows up the immune system," Deeks says. "So it's reasonable to think that, in some people, the acute COVID results in an inflammatory state that can contribute to long COVID over time."

Yet another clue found in one subgroup of patients is an unusual pattern of activity by key immune system cells, such as as T-cells, which may support the idea that the virus is hiding in the body.

"That's a signature or pattern which could be consistent with a low-level, but persistent, infection in the long-COVID syndrome patient," says Dr. Igor Koralnik at Northwestern Feinberg School of Medicine.

While much more research is needed, the researchers hope these findings could eventually lead to ways to help long-COVID patients. One possible therapy for some patients might turn out to be anti-viral drugs that target a virus hiding in the body. Another possibility might be clearing the virus with a vaccine, which does seem to help some long-COVID patients. Researchers think drugs that dampen down the immune system may also help.

"We need to understand what's going on in each patient — because the treatment option will be very different depending on what they actually have," Iwasaki says.

Still more questions than answers

But others are not so sure that any of the evidence produced so far linking subtle changes in lab tests to physical problems in long-COVID-19 patients is very convincing. That includes any signs that the immune system is the problem — what's known as an autoimmune disease.

"The thing that has struck me most now in a year and a half of seeing these patients and extensively testing them is that we are finding little to no abnormalities," says Dr. Michael Sneller, who has been conducting a battery of detailed tests on hundreds of long-COVID-19 patients at the National Institutes of Health.

"Echocardiogram, pulmonary function tests, X-rays, brain MRIs. You name it. Laboratory markers of organ dysfunction. We're not seeing any of that," Sneller says of the patients in his study. "And precious little evidence of immune activation, looking just at the sort of standard markers of inflammation. I'm running out of tests to do basically."

But Sneller says his team hasn't ruled out anything and is continuing to analyze data about the immune system. His team is also conducting psychological testing on their study's subjects — though not because he doubts their symptoms.

"It's 100% real. These people have these symptoms. Absolutely. The question is what's causing them," he says. "Anxiety can produce real symptoms."

For her part, LaDue hopes researchers eventually figure out what's going with her and other patients.

"I want to feel normal, and I hope to be back to normal again someday," she says. "The hardest part, definitely, is trying to look and be normal — but not feeling normal."

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