The list of things that Covid-19 does to the body keeps getting longer. Between the cytokine storms, the neurological ailments, the swollen-up toes, it’s all rather confusing, frightening, and yes, decidedly weird—though, as virology Twitter will happily remind you, “all viruses are weird.”
The latest twist concerns how Covid-19 affects kids. The earliest reports showed that while kids are just as likely as adults to catch the virus, their symptoms are generally milder—except for infants and children with preexisting conditions. Now, starting in Europe and then in New York and other cities on the East Coast, reports have emerged of a “mysterious ailment” that trails in the wake of Covid-19 infections. Kids have been showing up in hospitals with nagging fevers, rashes, bloodshot eyes, and other signs of an immune system going haywire. Many of the cases have evoked a rare, but treatable, ailment called Kawasaki disease, an inflammatory illness that affects young children. Other patients have had more severe symptoms, such as low blood pressure and abdominal pain, sometimes requiring intensive care. Those cases are being called by a different name: pediatric inflammatory multisystem syndrome, or PIMS.
The scale of those complications is still emerging. At last count, these immune conditions have been reported in more than 100 kids in the New York area, three of whom have died. France and the United Kingdom each reported a single death late this week. In The Lancet, Wednesday, researchers at hospitals in northern Italy identified the strongest link yet between the syndrome and Covid-19 infection, reporting 10 cases of Kawasaki-like illness over a two-week period, a 30-fold increase over the norm, with most patients testing positive for a current or past SARS-CoV-2 viral infection. Just as many states are debating whether to reopen schools and summer camps, the mounting reports have given a sense of a secondary pandemic unfolding, equally terrifying as the first. Earlier this week, testifying before Congress, Anthony Fauci, director of the National Institute of Allergy and Infectious Disease, suggested policymakers stay “humble” about what we don’t know about Covid-19 and kids.
He didn’t say to panic.
“I think there’s generalized fear and anxiety, because we told people the good news is that this virus doesn’t do anything to children. And now we’re saying, ‘Actually, here’s a new thing,’” says Jane Burns, director of the Kawasaki Disease Research Center at the University of California, San Diego. While she calls it “an ugly twist,” she notes that the original mantra still holds true: Very few kids are getting severely sick from Covid-19. “It’s a very rare phenomenon,” she says. And among those who develop this new condition, even in its more severe form, most are doing just fine with treatment. For most kids, she says, Covid-19 symptoms are still mild—undetectable even. (Though that raises plenty of other questions about the role of kids in the virus’s transmission.)
Still, Burns says the cluster of cases is unusual—unprecedented, even, in her 30 years studying Kawasaki disease and other immune conditions in kids. “Nobody saw this coming,” she says. “I mean, how could we?” Luckily, she says, doctors appear well equipped to handle it—and might have a lot to learn about the mysteries of rare immune diseases thanks to this surge in cases.
Kawasaki disease, with its telltale nagging fever and bouts of inflammation, is easily spotted by doctors. But that wasn’t always so. For a long time, doctors didn’t bother to distinguish it from other mystery inflammatory conditions linked to the developing immune system, says Susan Kim, a pediatric rheumatologist at the University of California, San Francisco. But then, in the 1960s, a Japanese doctor named Tomisaku Kawasaki identified a startling pattern: In some cases, if the inflammation was left untreated, kids would develop aneurysms in arteries around the heart that could result in long-term cardiac damage. So he developed a range of symptom criteria associated with the heart condition, including fever and various forms of inflammation, for the disease that came to bear his name.
If caught early, most kids avoid any long-term heart issues. “Run-of-the-mill Kawasaki disease is and can be treated by a general pediatrician,” Kim says. Kids are treated with aspirin and intravenous immunoglobulin, or IVIG—an antibody solution that helps the body calm its overactive immune response. They usually feel better within a few days.
The mystery is what causes the immune system to go haywire in the first place. “No one knows what causes Kawasaki disease, but in genetically predisposed individuals, some kind of immune trigger turns on that cascade of symptoms,” Kim says. Over the decades, there have been lots of theories about that trigger, from fungi to aerosol pollutants to bacterial infections. In the 1980s, a theory about carpet cleaning chemicals prevailed, though it turned out to be bogus. Viruses have also been suspected. In 2005, a cluster of cases in Connecticut was associated with a coronavirus that causes the common cold, but subsequent studies failed to establish a firm link. Other researchers have found associations with other common viruses, looking at trends in seasonal illness and in the incidence of Kawasaki disease around the globe.
“It has to be more than one type of trigger,” says Kevin Friedman, a pediatric cardiologist at Boston Children’s Hospital, which has seen about 15 cases of Kawasaki-like illness with apparent ties to Covid-19, all of whom have done well so far. “It’s too ubiquitous across the world for us to find a single thing.” Different triggers may be associated with different populations of kids, he adds, and could be the result of different genetic predispositions.
With all of this uncertainty about triggers, Kim says she wasn’t particularly surprised to see a mystery inflammatory ailment coming on the heels of a novel disease outbreak. While the number of cases—and some of the symptoms—are unusual, she points out, it’s also unusual to see millions of people infected over a few weeks by a single virus.
Given those distinct symptoms, it’s still too early to know for sure how closely related the Covid-linked syndrome is to typical Kawasaki disease. There are also differences in which children the illness appears to affect. Ordinarily, Kawasaki disease is most prevalent in Japan and Korea, and it typically affects children younger than age 5. Researchers don’t know why that is, exactly, but the geographic disparity lends weight to a theory that a genetic predisposition to certain triggers is involved. But when Burns recently turned to her collaborators at hospitals in Asia, they reviewed their case data and found nothing similar to the PIMS cases. In Japan, there were actually fewer cases of mild Kawasaki disease than is the norm. The surge of cases tied to Covid-19 is instead being seen in the US and Europe. Most of the children are black, and they tend to be older—teenagers, even.
Those differences have led some to suggest that the conditions are entirely distinct. But Burns notes that in the US and Europe the severe PIMS cases have been accompanied by a surge of cases that look like normal Kawasaki disease. “From what we’re seeing now, I think you’d be hard pressed to deny that SARS-CoV-2 is a trigger,” she says.
In that sense, the surge of cases may present researchers with a unique opportunity to understand how these kinds of immune ailments work. “People who do the basic science are looking at this as a potentially once-in-a-lifetime opportunity to figure out the causes of Kawasaki disease,” Friedman says. Usually, researchers struggle to study the disease on a population level, since the condition is rare, affecting only about 5,000 children in the United States each year, and because the triggers are unknown and potentially varied. With Covid-19, researchers are in the rare position of identifying a single immune trigger and having a large cohort of patients whose genes can be plumbed for potential links.
But that’s all in the future, Burns says. For now, the immediate concern is getting cases identified and treated. Researchers want to know whether the conditions seen in kids are directly related to the cytokine storms seen in adults with Covid-19—an often fatal condition in which the immune system suddenly overreacts, often after a period of respite from the virus. The good news is that for kids, unlike those adults, this condition is usually treated with relative ease—using the same antibody treatment for mild Kawasaki disease cases, plus additional steroids. “It does seem they respond to IVIG and that their heart function returns,” Burns says. She hopes to get a clinical trial of different steroid treatments off the ground soon that will help researchers to fine-tune their treatments for the more severe cases. “We’re already getting very good at treating it,” she says.
And even then, the overall number of cases remains small, Kim points out, despite the daily headlines. “The news makes it sound quite frightening, but it’s not like any single medical center has even tens of patients at this point,” she says. Does your kid have a fever that’s lasting more than a few days? Then do what you’d normally do in that situation: Call their doctor. But don’t worry too much about it, either. “Parents should not be freaking out about this,” Friedman says.
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