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Inflamed Brains, Toe Rashes, Strokes: Why COVID-19’s Weirdest Symptoms Are Only Emerging Now

These symptoms sound scary, but they should be expected. Here’s what scientists know about the “new” effects of the coronavirus.

An infection can inflict serious damage inside your body in many different ways, and COVID-19 seems to use just about all of them. The coronavirus primarily attacks the lungs, which can cause pneumonia or even respiratory failure, and in one of every five patients, it also leads to multiple organ failure.

Yet, as the pandemic continues to ravage the world, case reports have emerged of more unusual damage ranging from hundreds of tiny blood clots to strokes in young people, and even mysterious inflammatory responses, such as full-body rashes in children and the red lesions that have come to be known unofficially as COVID toe.

Although these conditions seem strange and scary, they have been seen in viral medicine even before the advent of COVID-19, and, to some degree, they are to be expected. Every human body is unique, so a disease that strikes millions of people will yield some oddities. What exactly is going on in these cases, and how common are they? Here’s what we know—and what the scientific community still needs to find out to treat these unusual cases.

COVID-19 and the body: The basics

COVID-19 starts as a respiratory disease. The virus invades cells in the nose, throat, and lungs and starts to replicate, causing flu-like symptoms that can progress to pneumonia and even punch holes in your lungs, leaving permanent scars. For many patients, that’s the worst of it.

But for others, the immune system inexplicably goes haywire and their bodies release proteins called cytokines—alarm beacons that help recruit immune cells to the site of an infection. If too many cytokines leak into the bloodstream and fill the body, immune cells start killing anything they encounter. This response, called a cytokine storm, creates massive inflammation that weakens the blood vessels, causing fluid to seep into the lungs’ air sacs, triggering respiratory failure. A cytokine storm can damage the liver or kidneys and result in multi-organ failure.

Possible heart infections

Beyond the lungs, the new coronavirus seems to wreak havoc in the heart, with one in five COVID-19 patients experiencing some cardiac injury, according to a recent study out of China.

The heart pumps blood throughout the body, supplying the organs with oxygen from the lungs. Respiratory viruses such as coronaviruses and influenza can interfere with that balance of supply and demand. If a virus attacks the lungs, they become less efficient at supplying oxygen to the bloodstream. An infection can also inflame the arteries, causing them to narrow and supply less blood to the organs, including the heart. The heart then responds by working harder to compensate, which can lead to cardiovascular distress.

One unusual and as-yet unexplained symptom—even among young and otherwise healthy people—is myocarditis, a relatively rare condition in which inflammation weakens the heart muscle.

New reports have raised the possibility that the coronavirus may embed itself directly in the heart. Viruses enter cells by looking for their favorite doorways—proteins called receptors. In the case of the coronavirus, scientists have noted that the heart possesses the same protein gateway of choice, called ACE-2, that SARS-CoV-2 uses to attack the lungs.

“No one convincingly has shown with a biopsy that there’s actually viral particles inside the heart muscle cells,” says Robert Bonow, a professor of cardiology at the Northwestern University Feinberg School of Medicine and past president of the American Heart Association. He notes that these signs of myocarditis could also be brought on by a cytokine storm that’s inflaming the rest of the body. However, viruses such as chickenpox and HIV have been known to directly infect heart muscle, and research suggests that the coronavirus can invade the blood vessel lining.

This growing evidence of the significant role the heart is playing has raised the question of whether COVID-19 should also be classified as a cardiovascular disease. “It’s led to lots of questions about how we treat patients these days,” Bonow says. “When a 75-year-old man comes in with chest pain, is it a heart attack or COVID?”

Mysterious blood clotting

For many patients, COVID-19 is causing a lot of clotting and in an unusual number of ways.

More than 160 years ago, a German physician named Rudolf Virchow detailed three reasons abnormal blood clots can occur. First, if the inner lining of blood vessels becomes injured, perhaps due to an infection, it can release proteins that promote clotting. Second, clots can form if the blood flow becomes stagnant, which sometimes happens when people in hospital beds are immobile for too long. Finally, vessels can develop a tendency to become cluttered with platelets or other circulating proteins that repair wounds—which typically happens with inherited diseases but can also be triggered by systemic inflammation.

“I think we have evidence that all three of those are playing a role in COVID,” says Adam Cuker, an associate professor of medicine at the Hospital of the University of Pennsylvania who specializes in clotting disorders.

Cytokine storms can also exacerbate inflammatory conditions that clog arteries, such as the fatty plaques behind atherosclerosis—hence why pre-existing cardiovascular disease correlates with severe COVID-19.

Doctors are puzzled by the extent of blood clotting caused by COVID-19. In late April, the Washington Post reported that clotting is manifesting itself in some pretty abnormal ways—including hundreds of microclots that form in the bloodstream, collect in lungs, and clog dialysis machines used to treat kidney disorders.

At the Hospital of the University of Pennsylvania, the intensive care unit is seeing up to three times as many clots in patients with COVID-19 than they’re used to seeing in ICU patients without the disease, Cuker says. So far, trying to address the problem has involved increasing the dose of blood thinners given to patients with COVID-19, even as clinical trials are examining whether these medications actually reduce the risk of coronavirus-induced clots.

It’s not clear why COVID-19’s clots are so tiny and are filling organs by the hundreds, Cuker says, but it might be due to a part of the immune system called the complement pathway, which involves normally inactive proteins that circulate in the blood. In other disorders, inappropriate activation of this pathway can manifest as tiny clots.

Cuker, who is helping to develop guidelines on how to treat COVID-related clotting for the American Society of Hematology, says scientists are taking a broad view in their search for the answers. “All of these systems may be playing a role, and we need to understand that.”

Unexpected strokes

This uptick in clotting may explain why young COVID-19 patients without any cardiac risk factors are suffering from strokes, which typically afflict the brains of the elderly. Although it’s surprising to see strokes in young people, strokes should perhaps be expected given that the connection was also observed during the 2002-2003 outbreak of SARS, a related coronavirus.

“Almost all the [neurological] things we’re seeing now with COVID-19 are things you might have predicted would have happened,” says Kenneth Tyler, chairman of the department of neurology at the University of Colorado School of Medicine and a fellow of the American Academy of Neurology.

Most of the strokes reported with COVID-19 have been “ischemic,” meaning a clot plugs one of the vessels supplying blood to the brain. Ischemic strokes are already common in general—with 690,000 cases in the U.S. per year—due to their tight correlation with cardiovascular conditions like atherosclerosis. If an ischemic stroke blocks the supply of oxygenated blood for too long, it can impair the area of the brain that lies downstream. That’s why the manifestations caused by the coronavirus can seem random—such as trouble speaking or seeing or walking. Some COVID-19 cases have also involved hemorrhagic stroke, which occurs when a weakened blood vessel ruptures and bleeds into the brain, compressing the surrounding brain tissue.

Cuker says it’s not known how common strokes and clotting might be among COVID-19 patients because most of the observations have been confined to the ICU. That means the record is missing patients who were discharged from the hospital and later developed a COVID-related clot, or people whose infections had mild or no symptoms before the clot.

“Is this just a small number of cases getting a lot of attention, or is this actually a more common problem that rises to the level of a public health issue?” Cuker asks.

Brain inflamed

Reports have also linked COVID-19 to patients suffering from encephalitis, or inflammation of the brain, as well as a much rarer syndrome called Guillain–Barré, in which the body’s immune system attacks the nerves. In milder cases, encephalitis can cause flu-like symptoms; in more severe cases, it might bring seizures, paralysis, and confusion.

COVID-19 isn’t a trailblazer in this regard, as many different viruses—herpes, tick-borne viruses, rabies, and the original SARS—can cause encephalitis. When one of these viruses invades the nervous system, it can injure and inflame the brain either by directly killing cells or by inviting the immune system to do the job, akin to a cytokine storm. In the case of COVID-19, Tyler says the cause is not known.

With Guillain–Barré, the immune system attacks the network of nerves and ganglia that run throughout your body. This disorder tends to show up weeks after a germ has cleared the body and can cause weakness and tingling in your extremities that can eventually lead to paralysis. Although this disorder has only been observed in a handful of COVID-19 case reports, Tyler thinks its connection is more than just coincidence.

Scientists don’t really know the exact mechanisms of Guillain–Barré, but it appears to be associated with what’s known as the body’s acquired immune system, which responds to a pathogen by developing specific antibodies to fight it. These antibodies take weeks to develop and are normally protective—but they are thought to occasionally go haywire as well, attacking the nerves and their coating.

Skin deep?

One of the most recently discovered—and most inexplicable—signs of COVID-19 is a broad range of inflammatory symptoms that it seems to be provoking in the skin, including rashes, the painful red lesions that have come to be known as COVID toe, and the collection of symptoms in children that’s been labeled a “Kawasaki-like” syndrome.

“It’s like reading a dermatology textbook, because it really spans the full gamut,” says Kanade Shinkai, a professor of dermatology at the University of California, San Francisco.

A virus can cause a rash in two ways. It can spread across the body and deposit itself directly in the skin, which is how chickenpox works. Alternatively, a virus can activate the immune system, producing rashes in nonspecific patterns all over the skin both as part of its normal response to infection or as an overreaction associated with a cytokine storm. Shinkai says viral rashes typically occur in less than 2 percent of patients with other common viruses.

However, with COVID-19, rashes take on so many different patterns that it’s hard to tell if any of them are unique to SARS-CoV-2 in the same way that itchy red bumps and blisters are a telltale sign of chickenpox. The situation is so mystifying that some experts wonder if the rashes seen in COVID-19 patients are just a coincidence.

“Some people have even argued that what we’re seeing is rashes during the time of COVID-19, but not necessarily rashes associated with COVID-19,” Shinkai says. “That’s a big mystery and a big scientific question that still needs to be answered.”

That’s also the case with COVID toes. Dermatologists are seeing a rise in patients complaining of painful red or purple lesions on their toes and fingers, which might be caused by microclots or inflammation in the blood vessels in those places. But while some patients with COVID toe have tested positive for the virus, this symptom is also present in people who test negative for both the virus itself and the antibodies generated in response, Shinkai says.

To better understand these skin manifestations, Shinkai says, we need more studies that describe them comprehensively. Although one Italian study identified rashes in 20 percent of patients, another study out of Wuhan found them in only 0.2 percent of patients. Shinkai wants to know whether that disparity reveals a difference in patients or in the researchers’ attention to the details.

Similarly, scientists are baffled by the diseases in children that have been grouped together as a Kawasaki-like syndrome. Kawasaki disease is a rare condition that causes inflammation in blood vessels throughout the body, particularly in Japanese children. While the cause remains unknown, its symptoms include full-body rashes, swelling, bloodshot eyes, abdominal pain, and diarrhea. Though Kawasaki disease normally resolves on its own without long-term consequences, it can cause severe heart complications.

Recently, a spate of reports has identified children diagnosed with COVID-19 who share some or all of the symptoms of Kawasaki disease. Michael Agus, chief of medical critical care at Boston Children’s Hospital, says physicians are only just beginning to describe the connection.

So far, COVID-19 doctors have spotted two forms of Kawasaki-like disease. One centers on viral sepsis—a severe inflammatory response to an infection that causes depressed heart function and low blood pressure. The other variety emerges in the weeks after COVID-19 infection or exposure, with some of the more classic Kawasaki symptoms listed above, including changes in the shape of the heart’s arteries.

Although this condition sounds scary, Agus says it’s very rare. It has been observed only in clusters of children in Europe and North America, and it’s hard to tell whether all the cases are even linked to COVID-19, given that some Kawasaki-like children test negative for the virus and have no signs of antibodies from past infection. Agus says finding the answers will depend on more comprehensive patient descriptions, but also on better access to testing and clinical trials.

In the meantime, researchers say, we should stay focused on maintaining the now standard practices to protect ourselves from COVID-19, including wearing masks outside, meticulous handwashing, and careful social distancing. “That’s going to be the answer,” Agus says, “whether this turns into one syndrome or four syndromes.”


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