The causes of long COVID, which disables millions, may come together in the brain and nervous system
BY STEPHANI SUTHERLAND Scientific American, 2023 Issue Neuroscience
Tara Ghormley has always been an overachiever. She finished at the top of her class in high school, graduated summa cum laude from college and earned top honors in veterinary school. She went on to complete a rigorous training program and build a successful career as a veterinary internal medicine specialist. But in March 2020 she got infected with the SARS-CoV-2 virus—just the 24th case in the small, coastal central California town she lived in at the time, near the site of an early outbreak in the COVID pandemic. “I could have done without being first at this,” she says.
Almost three years after apparently clearing the virus from her body, Ghormley is still suffering. She gets exhausted quickly, her heartbeat suddenly races, and she goes through periods where she can’t concentrate or think clearly. Ghormley and her husband, who have relocated to a Los Angeles suburb, once spent their free time visiting their “happiest place on Earth”—Disneyland—but her health prevented that for more than a year. She still spends most of her days off resting in the dark or going to her many doctors’ appointments. Her early infection and ongoing symptoms make her one of the first people in the country with “long COVID,” a condition where symptoms persist for at least three months after the infection and can last for years. The syndrome is known by medical professionals as postacute sequelae of COVID-19, or PASC.
People with long COVID have symptoms such as pain, extreme fatigue and “brain fog,” or difficulty concentrating or remembering things. As of March 2023, the syndrome was estimated to affect more than 15 million adults in the U.S., and a 2022 report found that it had forced between two million and four million Americans out of the workforce. Long COVID often arises in otherwise healthy young people, and it can follow even a mild initial infection. The risk appears at least slightly higher in people who were hospitalized for COVID and in older adults (who end up in the hospital more often). Women and those at socioeconomic disadvantage also face higher risk, as do people who smoke, are obese, or have any of an array of health conditions, particularly autoimmune disease. Vaccination appears to reduce the danger but does not entirely prevent long COVID.
The most common, persistent and disabling symptoms of long COVID are neurological. Some are easily recognized as brain- or nerve-related: many people experience cognitive dysfunction in the form of difficulty with memory, attention, sleep and mood. Others may seem rooted more in the body than the brain, such as pain and postexertional malaise (PEM), a kind of “energy crash” that people experience after even mild exercise. But those, too, result from nerve dysfunction, often in the autonomic nervous system, which directs our bodies to breathe and digest food and generally runs our organs on autopilot. This so-called dysautonomia can lead to dizziness, a racing heart, high or low blood pressure, and gut disturbances, sometimes leaving people unable to work or even function independently.
The SARS-CoV-2 virus is new, but postviral syndromes are not. Research on other viruses, and on neurological damage from the human immunodeficiency virus (HIV) in particular, is guiding work on long COVID. And the recognition that the syndrome may cause its many effects through the brain and the nervous system is beginning to shape approaches to medical treatment. “I now think of COVID as a neurological disease as much as I think of it as a pulmonary disease, and that’s definitely true in long COVID,” says William Pittman, a physician at UCLA Health in Los Angeles, who treats Ghormley and many similar patients.
Although 15 million current U.S. sufferers is a reasonable estimate of the condition’s toll, there are other, more dire assessments. A meta-analysis of 41 studies conducted in 2021 concluded that worldwide, 43 percent of people infected with SARS-CoV-2 may develop long COVID, with about 30 percent—translating to approximately 30 million people—affected in the U.S. Some studies have offered more conservative numbers. A June 2022 survey reported by the U.S. National Center for Health Statistics found that among adults who had had COVID, one in five was experiencing long COVID three months later; the U.K. Office for National Statistics put the estimate at one in 10. Even if only a small share of infections result in long COVID, experts say, they will add up to millions more people affected—and potentially disabled.
Most of the first recognized cases of long COVID were in patients who needed extended respiratory therapy or who had obvious organ damage that caused lasting symptoms. People reporting neurological symptoms were often overlooked or dismissed as traumatized by their initial illness and hospitalization. But as 2020 came to an end, says Helen Lavretsky, a psychiatrist at the University of California, Los Angeles, “we started getting to a place of sorting through what was really going on … and it became very evident at that time that neuropsychiatric symptoms were quite prevalent,” most commonly fatigue, malaise, brain fog, smell loss and post-traumatic stress disorder, as well as cognitive problems and even psychosis.
Ghormley was in her late 30s and relatively healthy when she caught the virus, but she had underlying conditions—including rheumatoid arthritis and asthma—that put her at risk for severe COVID. She spent several days at home, struggling to breathe, and then she went to the hospital, where her blood pressure soared and her blood glucose dropped precipitously. She mostly recovered from this acute phase within a few weeks, but, she says, “I never really got better.”
Soon after coming home from the hospital, Ghormley developed what her husband called “goldfish brain.” “I’d put something down and have no idea where I put it,” she recalls. “It kept happening over and over. I was thinking, ‘This is getting weird.’ My husband said I was not remembering anything. I’d try to talk, and I knew what I wanted to say, but I couldn’t think of the word.”
She also experienced tremors, dramatic mood swings and painful hypersensitivity to sounds. “My husband opening a paper bag felt like knives stabbing me in the ear,” she recounts. Any exertion—physical or mental—left her exhausted and in pain. The changes were jarring to Ghormley, who prided herself on her sharp mind. “The thing that bothered me the most was that I was really having trouble thinking, speaking, remembering—trying to complete a task and having no idea what it was. Suddenly I had quite profound neurological deficits. Everything fell apart for me at that time. That was horribly traumatic … it kind of broke me. I didn’t feel like me.”
ROOTS OF DYSFUNCTION
As a veterinary internist, Ghormley says, it’s her job to problem solve when mysterious symptoms arise, including her own. “I was actively trying to find reasons and find what I could do.” She theorized that some of her neurological symptoms might be the result of thrombotic events, blood clots that can cause ministrokes. Several early studies showed that COVID attacks endothelial cells, which line blood vessels. That can lead to clotting and oxygen deprivation in multiple organs, including the brain. Even subtle disruption of endothelial cells in the brain could contribute to cognitive dysfunction.
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.