One study found that in people with neurological COVID symptoms, the immune system seems to be activated specifically in the central nervous system, creating inflammation. But brain inflammation is probably not caused by the virus infecting that organ directly. Avindra Nath, who has long studied postviral neurological syndromes at the National Institutes of Health, found something similar in an autopsy study of people who died of COVID. “When you look at the COVID brain, you don't actually find [huge amounts of virus, but] we found a lot of immune activation,” he says, particularly around blood vessels. The examinations suggested that immune cells called macrophages had been stirred up. “Macrophages are not that precise in their attack,” Nath says. “They come and start chewing things up; they produce all kinds of free radicals, cytokines. It's almost like blanket bombing—it ends up causing a lot of damage. And they're very hard to shut down, so they persist for a long time. These are the unwelcome guests” that may be causing persistent inflammation in the brain.
Determining which patients have ongoing inflammation could help inform treatments. Early research identified markers that often are elevated in people with the condition, says Troy Torgerson, an immunologist at the Allen Institute in Seattle. Three cell-signaling molecules—tumor necrosis factor alpha, interleukin 6 and interferon beta—stood out in long COVID patients. But this pattern wasn't found in absolutely everyone. “We're trying to sort through long COVID patients and say, ‘This would be a good group to take to trials of an anti-inflammatory drug, whereas this group may need to focus more on rehabilitation,’” Torgerson says. He led a study (currently released as a preprint, without formal scientific review by a journal) in which his team measured proteins from the blood of 55 patients. The researchers found that a subset had persistent inflammation. Among those people, they saw a distinct immune pathway linked to a lasting response to infection. “One subset of patients does appear to have an ongoing response to some virus,” Torgerson says.
Isolated pockets of SARS-CoV-2 or even pieces of viral proteins may remain in the body well after the initial infection and continue to elicit an immune attack. The first solid evidence for “viral persistence” outside the lungs came in 2021 from researchers in Singapore who found viral proteins throughout the gut in five patients who had recovered from COVID as much as six months earlier. A study conducted at the University of California, San Francisco, found evidence for viral particles in the brains of people with long COVID. Scientists collected exosomes, or tiny packets of cellular material, released specifically from cells of the central nervous system. The exosomes contained pieces of viral proteins as well as mitochondrial proteins, which may indicate an immune attack on those vital cellular organelles. Amounts of such suspicious proteins were higher in patients with neuropsychiatric symptoms than in those without them.
The virus could linger in the brain for months, according to research conducted at the NIH and reported in Nature in December 2022. The autopsy study of 44 people who died of COVID found rampant inflammation mainly in the respiratory tract, but viral RNA was detected throughout the body, even in the brain, as long as 230 days after infection. Two other studies, both published last year in the Proceedings of the National Academy of Sciences USA, showed evidence that SARS-CoV-2 may infect astrocytes, a type of neural support cell, gaining entrance via neurons in the skin lining the nose.
Researchers are examining inflammatory signals in patients with long COVID in increasingly fine detail. A small study led by Joanna Hellmuth, a neurologist at U.C.S.F., found that patients with cognitive symptoms had immune-related abnormalities in their cerebrospinal fluid, whereas none of the patients without cognitive symptoms did. At the 2022 meeting of the Society for Neuroscience, Hellmuth reported that she had looked at more specific immune markers in people with cognitive symptoms and found that some patients had an elevated level of VEGF-C, a marker of endothelial dysfunction. Higher VEGF-C concentrations are associated with higher levels of immune cells getting into the brain, she says, and “they're not doing their normal function of maintaining the blood-brain barrier; they're distracted and perhaps activated.” Although the studies are small, Hellmuth adds, they reveal “real biological distinctions and inflammation in the brain. This is not a psychological or psychosomatic disorder; this is a neuroimmune disorder.”
What keeps the immune system in attack mode? According to Torgerson, “one option is that you've developed autoimmunity,” in which antibodies produced by the immune system to fight the virus also mark a person's own cells for immune attack. The response to the virus “turns the autoimmunity on, and that doesn't get better even when the virus goes away,” he says. Several studies have found evidence of autoimmune components called autoantibodies that interact with nerve cells in people with long COVID.
Clues about the inflammatory processes at work could point toward treatments for neurological symptoms. “If it's a macrophage-mediated inflammatory process ... intravenous immunoglobulin could make a difference [to] dampen the macrophages,” Nath says. The treatment, referred to as IVIg, contains a cocktail of proteins and antibodies that can mitigate an overactive immune response.
IVIg can also be used to block autoantibodies. And a therapy called rituximab that targets antibody-producing B cells provides “a time-tested therapy for a lot of autoantibody-mediated syndromes,” Nath says. Another strategy is to use corticosteroids to dampen immune activity altogether, although those drugs can be used for only a limited time. “That's a sledgehammer approach, and you can see if it makes a difference. At least it gives you an idea that, yes, it's an immune-mediated phenomenon, and now we need to find a better way to target it,” Nath says.
If the virus does hang around in some form, antiviral medications could potentially clear it, which might help resolve neurological symptoms. That's the hope of scientists running a clinical trial of Paxlovid, Pfizer's antiviral drug for acute COVID.
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