Mysterious wave of COVID toes still has scientists stumped

Puffy, red-purple, and sometimes painful toes were one of the odder symptoms seen early in the pandemic. But experts are debating their cause—and whether COVID-19 is even to blame.

Lisa Arkin saw more swollen, discolored toes during the early months of the pandemic than she had during her entire career.

Arkin, a pediatric dermatologist at the University of Wisconsin-Madison, treated just a couple of patients with temporary skin lesions called pernio, or chilblains, each year. But in April 2020, when COVID-19 cases first surged, she saw 30 chilblain patients. “My urgent clinics—either telemedicine or in-person—were suddenly filled with patients with purple toes, complaining about swelling, blistering, discomfort, and pain,” Arkin says. “I was completely shocked.”

Dermatologists in other parts of the U.S., and around the world where COVID-19 cases were rising, were also reporting cases of people with red-purple lesions often on their toes. So-called chilblains typically started out with a burning itching sensation on the toes followed by the discoloration, which often resolves without treatment within a few weeks. In some unusual cases, however, the condition lasted for months and even up to a year or more.

“At its most mild, people complain of it being like a mild itch,” says Esther Freeman, a dermatologist and epidemiologist at Harvard Medical School. “At its most severe, it’s so painful that some patients can’t put their shoes on for a couple of weeks.”

Physicians began wondering if the chilblains were due to SARS-CoV-2, the virus that causes COVID-19. In the last two years, scientists have studied thousands of pandemic chilblains or ‘COVID toe’ cases around the world, examining blood and skin biopsies to answer that question. Here’s what we know so far.

What are COVID toes?

It isn’t uncommon for viral infections, including measles, chickenpox, and mononucleosis, to cause a rash of blisters, small bumps, or patches on different parts of the body. These symptoms arise as the body’s immune system responds to the virus or to virus-damaged skin cells.

Similarly, dermatologists have now identified an array of skin conditions, including chilblains, associated with COVID-19. “If you had asked, say, 100 dermatologists before the pandemic what rashes would you expect to see with a virus, pernio chilblains would not have made the list—it would not have made the top 50,” says Freeman. "Chilblains have only rarely been associated with viruses," she says.

Many of the affected patients—often children and young adults—never developed typical COVID-19 symptoms such as cough, fever, and muscle pain. If they did, their symptoms were mild. The lesions—which typically develop after repeated exposure to cold and damp conditions and can also affect fingers, heels, ears, and nose—usually appeared between one and four weeks after a positive COVID-19 test. However, many COVID toe patients, including several of Arkin’s young patients, had a negative PCR test and lacked antibodies against SARS-CoV-2, suggesting that they probably never had COVID-19.

Similarly, a study conducted in Northern California found that only 17 of 456 patients diagnosed with chilblains between April and December 2020 tested positive for COVID-19 using a PCR test, and only one of 97 who had their blood sampled for SARS-CoV-2-specific antibodies tested positive. This despite a spike in chilblain cases in 2020 compared to those recorded in the region between 2016 and 2019.

“That's what has made it so hard and confusing to be able to say if it is COVID associated,” Arkin says.

What causes COVID toes?

In some studies, researchers detected the presence of virus particles in the skin biopsies of COVID toe patients, suggesting a SARS-CoV-2 role, but experts aren’t convinced by those findings.

A study published in October last year in the British Journal of Dermatology was among those suggesting an aggressive immune response to a SARS-CoV-2 exposure may be responsible for COVID toes. The researchers studied the blood and skin samples of 50 patients—several of whom had COVID-19 symptoms like cough, fatigue, and fever—who had such chilblains for the first time in April 2020 and tested negative on a PCR test.

The study showed that compared to healthy individuals, COVID toe patients had high levels of immune proteins called autoantibodies in their blood that erroneously damaged their own healthy tissues. They also carried high levels of proteins called type I interferons that are a first line of defense against viral infections.

“The way I explained it to my patients is COVID toes are almost too much of a good thing,” Freeman says. “Your body did a pretty good job of fighting off the virus, and in fact it had a pretty appropriate immune response in that there was a lot of this interferon around. And a side effect of having all this interferon around is that your toes turn purple.”

This potent interferon production may be helping COVID toe patients clear the SARS-CoV-2 infection before COVID-19-specific antibodies form, which could explain why many such patients are negative on antibody tests. Also, the production of certain type I interferons is higher in children and young adults and declines with age, which might explain why COVID toes are more common in that demographic.

Also, “we know people who have interferonopathy, which are genetic diseases where there is too much interferon production, get pernio [chilblain]-like lesions,” says Lindy Fox, a dermatologist at the University of California, San Francisco.

Last year, some individuals also developed such chilblain-like lesions shortly after getting their mRNA COVID-19 vaccine. “Thankfully, it’s not very common,” Freeman says. “But it does seem possible that some patients are mounting a similar interferon response after vaccination, as people do to the virus itself.”

But increased type I interferon levels alone may not explain pandemic chilblains. For instance, patients with viral hepatitis and cancer are treated with interferons to clear the virus or arrest and destroy the growth of cancer cells, yet the interferons don’t induce chilblain-like skin conditions.

Some experts suggest that there may be COVID toe cases that have nothing to do with the virus but something to do with pandemic behavior. People weren’t wearing shoes and socks as much while staying at home, which could have induced pandemic chilblains in some people, says Akiko Iwasaki, an immunologist at Yale University. Though “this would require more analysis,” she says. Until experts are able to trace back a definitive SARS-CoV-2 footprint in COVID toes patients, that association will continue to be subject to speculation. “There’s lots of open questions,” Arkin says, “and may be more mysteries still than answers.”

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