超两千万美国人或患“长期新冠”，症状超200种

One Long COVID patient complains of fatigue, loss of smell, and a persistent cough weeks after his initial COVID infection.

Another experiences hallucinations and an inability to record new memories, and begins speaking unrecognizable words.

It gets stranger. Among the 200-plus symptoms identified so far are ear numbness, a sensation of “brain on fire,” erectile dysfunction, irregular menstrual periods, constipation, peeling skin, and double vision, according to a landmark July study published in British medical journal The Lancet.

The study identified symptoms involving 10 major organ systems—and the body only has 11.

With the U.S. in a sixth COVID wave and many Americans catching COVID yet again, millions are hungry to know just what they’re experiencing when it comes to persistent symptoms.

Experts say they’re working as hard as they can to find out.

“I wish I knew the full answer” as to exactly what Long COVID is, Dr. Petter Brodin—a COVID researcher, professor of pediatric immunology, and pediatrician at the Imperial College of London—tells Fortune.

But one thing is definitely certain: “Long COVID is not one thing.”

Defining an enigma

While researchers are making strides in understanding what has become a common condition, Long COVID is still poorly understood, and definitions vary.

The World Health Organization defines Long COVID as a condition that occurs in someone who had COVID, with symptoms that cannot be explained by another diagnosis, that last for two months or more. The symptoms can persist following the initial onset, or come and go over time, the organization says, adding that a diagnosis of long COVID usually wouldn't be made until three months after acute illness.

The Mayo Clinic defines long COVID as a set of symptoms stemming from COVID that persist for more than four weeks after diagnosis.

“This just shows you how uncertain the diagnosis is,” Brodin says. “Depending on whom you ask, you’ll get a different answer as to what Long COVID is.”

Whatever it is, it may already affect between 7 million and 23 million Americans who previously had the virus, or up to 7% of the U.S. population, according to the U.S. Government Accountability Office. Studies have hypothesized that between 5% and 80% of those who’ve had COVID end up with Long COVID.

A study released Tuesday by the U.S. Centers for Disease Prevention and Control found that one in five U.S. adults with a history of COVID—of the millions whose records were examined—experienced at least one medical condition potentially attributable to Long COVID in the weeks and months following infection.The rate rose to one in four among seniors.

Long COVID could potentially impact over a billion worldwide in just a few years, says Arijit Chakravarty, a COVID researcher and CEO of Fractal Therapeutics, a drug development firm. Experts say that it’s quickly growing into a major public health concern and already overwhelming primary-care physicians, who are unsure of how to define or treat it.

Of those who identify as having Long COVID, some may just have the kind of lingering fatigue you see after many viruses, while others likely have a more complex condition, Brodin says.

“We know some symptoms are more common than others—like a persistent lack of smell is pretty common, and also fatigue, to some level,” Brodin says. “I think most adults can relate to some degree of persistent fatigue after a serious infection, the flu or some other thing. If you ask people if they have Long COVID and that’s the kind of fatigue they’re describing, I can understand why 80% say yes.

“If it’s something else, it would be more rare.”

5 types of Long COVID

Those who have Long COVID can likely be divided into five categories, according to Dr. Alexandra Brugler Yonts, an infectious disease specialist at Children's National Hospital in Washington, D.C., and the head of its new Pediatric Post-COVID Program.

There are patients who simply have long-term effects of COVID, including direct lung damage. She believes the rest of the patients likely belong in one or more of four categories: inflammation, dysautonomia, ongoing viral activity, and altered immune response.

In the case of inflammation, the virus triggers the body’s release of inflammasomes that kill infected cells—but the fallout can wreak havoc in various organ systems, especially if the process continues.

In dysautonomia—also known as POTS, or Postural Orthostatic Tachycardia Syndrome—patients experience direct damage to the autonomic nervous system. Potentially autoimmune in nature, the syndrome causes disruptions in heart rate and blood pressure in response to changes in position, like sitting or standing or laying.

Ongoing viral activity could be caused by “ghost” virus cells that can linger for months after initial infection. Recent research has found that such cells, when located in the gut, can cause ongoing gastrointestinal symptoms like diarrhea that aren’t typical of a respiratory virus.

Altered immune response may be seen alone or in combination with the other categories, she says. In order to bring itself back to normal, the immune system overcorrects, resulting in susceptibility to a number of viruses the body might usually fight off. Anecdotally, she’s heard of patients in their 20s who had COVID and then came down with a slew of other illnesses in short order, like mono and strep.

Red herrings abound

Not everyone who has been diagnosed with Long COVID, or who thinks they have it, actually does, experts say.

There are those who have post-acute sequelae of COVID, or persistent symptoms like a cough or shortness of breath. Symptoms after an infection can be seen with a number of viruses, like the Epstein-Barr virus, which causes mono, and ebola.

Some patients whose COVID required hospitalization may have post-intensive care syndrome due to a traumatic and debilitating ICU stay that may have included intubation and prolonged bed confinement. Potential symptoms can include persistent muscle weakness, memory problems, and post-traumatic stress disorder.

In both cases, patients become sick with COVID and take a while to recover, but eventually do. There isn’t a break between COVID and symptoms that persist, she says.

Then there are those with late-onset sequelae, like MIS, or multisystem inflammatory syndrome. These patients fully recover from COVID, if they even had symptoms, and are fine for four to 12 weeks before developing the rare, inflammatory-based illness that can occur in those who have had COVID or been exposed. MIS-C occurs in children, MIS-A in adults. It’s fatal in some cases.

A puzzling plot twist

Brodin agrees with Brugler Yonts that some cases described as having Long COVID actually have post intensive care syndrome, MIS-C, or MIS-A.

His research has focused on those who had milder COVID initially but, in a puzzling plot twist, later developed persistent symptoms. He sees those patients as belonging in one or more of three categories: autoimmune disease triggered by COVID, metabolic disease triggered by COVID, and long-term persistence of the virus.

Brodin’s autoimmune category aligns with Brugler Yonts’ dysautonomia category, as the disorder has been hypothesized to be autoimmune. And his long-term persistence of the virus category aligns with her ongoing viral activity category. In metabolic disease triggered by COVID, the body’s metabolism adapts during infection, leading to metabolic disturbance that persists.

“We’re looking at each and every one” of the categories,” Brodin said. “As of now, there is scattered data supporting each, but nothing conclusive.”

Researchers are beginning to refine nebulous Long COVID categories. But until they can nail down the biological causes, treatments will be limited to management of symptoms.

“There are different pathologies at play,” Brugler Yonts says. “I don’t think there’s one process that is ‘Long COVID’ in every single person. There are multiple processes going on, and once we can more solidly tease that out, it will lead to better ways to manage those patients and more focused pharmaceutical treatments.”