At first, it was just a handful of puzzling cases, Jane Newburger recalled. Other doctors had contacted her describing children with COVID-19 coming to emergency rooms in bad shape with a kind of inflammatory shock syndrome affecting multiple organs.

Some were screaming from stomach pain. Others had bubbles, or swelling, in the arteries of their hearts.

By Saturday night – when Newburger and 1,800 other worried pediatric specialists, including representatives from the Centers for Disease Control and Prevention and the National Institutes of Health, convened on a Zoom call to discuss the phenomenon – hospitals worldwide had identified about 100 similar cases. About half are in the United States.

“Not in my lifetime have I seen anything remotely similar to what’s going on right now,” said Newburger, director of the cardiac neurodevelopment program at Boston Children’s Hospital.

The cases appeared to have some characteristics of a disease known as Kawasaki disease. The cardiologists, rheumatologists and critical-care doctors in the meeting were also struck by their unusual timing and location. They started three to four weeks after the big wave of adult sickness, mostly in Europe and up and down the Eastern Seaboard of the United States, where COVID-19 had hit hard.

The number of affected children is still very small, relatively speaking, much lower than the number seriously ill from the flu during a similar time frame. And most have responded well to treatment.

“I’m thinking of it kind of like the tip of the iceberg,” said Jane Burns, a professor of pediatrics at the University of California at San Diego School of Medicine. “There’s this very small number of patients, thankfully, who are presenting with this shock syndrome, at the same time that there are a large number of [COVID-19] patients in the same community,”

Burns, along with other doctors, emphasized that parents should not panic. The vast majority of those younger than 18 who are infected with the coronavirus have only mild symptoms or none at all. And researchers aren’t certain whether the condition is caused by COVID-19 or something else. Those with “pediatric multi-system inflammatory syndrome,” as doctors call the new illness, are “a small genetic subset of children who appear to be susceptible to this crazy thing,” she said.

But the strange nature of the cases in mostly previously healthy children, and its potential link to a virus that has delivered near-constant surprises, has put the medical community on high alert.

On Monday, New York City issued a bulletin warning doctors that they had found 15 children with the condition at their hospitals and the CDC began contacting local health departments about new surveillance measures. The American Heart Association is preparing to issue its own pediatric alert later this week.

The global effort around the inflammatory condition is part of a larger focus on children in recent weeks by researchers who think that understanding their resistance to the virus may provide clues that could lead to treatments or vaccines.

For more typical respiratory viruses such as influenza, children are often the first to become sick. COVID-19 is an anomaly, killing the elderly at high rates while leaving the very young mostly untouched. Only a handful of American children – including an infant and a 5-year-old who were children of first responders – have died of the disease.

Scientists have wondered whether children’s seeming super powers against the virus are because they are more resistant to infection, or whether there is something protective in the biology of youth.

There is also raging debate in the medical community about the extent to which children are susceptible to infection and can transmit the virus to others, touched off by Switzerland’s infectious-disease chief, who made the provocative claim on April 27 that children younger than 10 could hug their grandparents and return to school, as they “don’t have the receptors to catch the disease.”

Alkis Togias of the National Institute of Allergy and Infectious Diseases, who focuses on the biology of airways, said there’s no scientific evidence to suggest that children can’t get or transmit the virus. But there is reason to speculate that they may be less infectious, although that is just beginning to be studied and he cautioned that the understanding of the virus changes daily.

This week, the NIAID announced a $25 million six-month study on COVID-19 in 2,000 U.S. families that it hopes will answer these questions and more. It will include questionnaires about social-distancing practices, interactions with people outside their households, symptoms and biweekly swabs for active infection, as well as blood tests to look at disease-fighting antibodies.

The CDC is separately financing the creation of a registry that will track COVID-19 cases among children at more than 35 U.S. children’s hospitals to understand why some children get very ill, while most do not.

“We know the rate of infection in children is way lower than in adults,” Togias said. “What we don’t know is whether, actually, they do carry the virus and transmit it without getting sick, or getting very mild symptoms. We have so little knowledge, I cannot give you an answer on almost anything related to children. So we need to figure this out.”

In the four months the world has gotten to know the novel coronavirus, its impact on children has been one of its biggest mysteries – to what extent they get infected, how they react to the infection and their role in transmitting the virus to others.

A study published in the journal Science based on data from China estimated that children through age 14 seem to be infected at a rate that is one-third that of people ages 15 to 64 (and those older than 65 were most susceptible to infection).

The question of transmissibility is increasingly politically charged. Some researchers have pointed out that there doesn’t seem to be a single, documented case of a child infecting an adult in the medical literature – a headline that has been embraced by some pushing for the reopening of the economy. The claim is based on a Royal College of Pediatricians review of 78 studies that found “the role of children in transmission is unclear, but it seems likely they do not play a significant role.”

But other research has found that the amount of virus in children’s blood can be similar to – or even higher than – that of adults, making them likely to be just as infectious. One German study looked at 3,712 people, including children, and found no significant difference in viral load based on age.

“Based on these results, we have to caution against an unlimited reopening of schools and kindergartens in the present situation,” the researchers wrote. “Children may be as infectious as adults.”

Larry Kociolek, an assistant professor of pediatrics at Northwestern University and an infectious-disease specialist at the Lurie Children’s Hospital of Chicago, and his colleagues are conducting similar research in the United States and have found that children younger than 5 who tested positive have much higher viral loads than adults. So the difference between the groups seems to be more about their bodies’ reaction to the pathogen.

“We have observed that children generally have more mild presentations than adults, despite having viral loads that are equal to or even higher than adults,” Kociolek said.

One early theory about why children may be less reactive to COVID-19 centers on the idea that their immune systems are less mature and may not overreact as adults’ do. They may also be less susceptible to an attack on the blood vessels or other documented cardiovascular effects because they do not have the co-morbidities accumulated from years of bad habits and aging that damage blood vessels and organs.

Another theory is that the difference between adults and children could be the result of how the virus binds to cells in our bodies. Studies have shown that the coronavirus attaches to something called ACE2 receptors, and that those receptors appear to be expressed differently in different parts of the body and in different people.

Some scientists hypothesize that the concentration of receptors may be different in children’s nasal cavities and lungs – where the virus seems to invade first – in a way that makes them less likely to become infected and have severe illness. In late April, a study funded by the National Institutes of Health described in a Journal of Allergy and Clinical Immunology letter how ACE2 expression was reduced in swabs of the nasal passages and throats of 11-year-olds with asthma. The researchers wrote that this unexpected finding may result in “decreased susceptibility to infection.”

“It’s a great theory and a unifying theory,” said Steven Kernie, chief of critical care medicine at New York-Presbyterian Morgan Stanley Children’s Hospital and professor of pediatrics at Columbia University Irving Medical Center. Kernie said research has also shown that these receptors are highly expressed in adults’ kidneys, which have been severely damaged in a significant percentage of older coronavirus patients, but are less concentrated in children’s kidneys.

The presentation of COVID-19 also differs between adults and children in severe cases, where people wind up in intensive care.

In adults, the disease has been a shape-shifter even in how it kills – from inducing cellular changes that lead to respiratory failure, to blood clots in the legs, to everything in between. But in children, there appears to be somewhat less variety in critical cases.

Many of those younger than 18 who were in intensive care during the first few weeks were either infants or teenagers who needed help breathing, as with traditional respiratory viruses, according to critical-care doctors.

The Kawasaki-like cases came later.

The syndrome, first described by a Japanese pediatrician in 1967, is characterized by persistent fever, red eyes, a rash, and swollen hands and feet that are signs of inflammation in the blood vessels. Its cause is unknown, but some researchers think it is a genetic susceptibility to a virus or other environmental stressor. There’s no cure but there are effective treatments, including blood thinners and an immunoglobulin serum that can be used to stabilize most children. In some rare cases, however, children may develop lifelong cardiac issues.

Newburger, considered one of the world’s leading experts on Kawasaki, said some of the children tested positive for an active infection with the novel coronavirus, while others did not. A third group did not have an active infection but had antibodies showing previous exposure.

One working theory is that the condition could be a sort of post-viral syndrome that occurs after infection.

This is similar to the patterns researchers are seeing in some children presenting with peculiar “frost-bite”-like rashes on their toes and sometimes fingers, despite having no other symptoms of COVID-19. The hypothesis is that some children who are infected may never know they had the virus until they have an immune reaction several weeks later – a small one like a rash, or a big one that affects multiple internal organs.

“It is possible that the antibodies that children develop to fight off the disease lead to a lingering response that causes fever and inflammation,” said Jeffrey Burns, head of critical care at Boston Children’s.

Craig Sable, a pediatric cardiologist at Children’s National Hospital, described the condition as a “hyper-exaggerated immune inflammatory response.”

In some of these new patients, the coronary arteries, which can be about 3 millimeters in diameter in a 3-year-old, for example, have been enlarged by 50 percent or even twofold. Doctors are also seeing aneurysms – a weakening of an artery wall that leads to a bulge or bubble in the blood vessels – a condition that typically occurs in the elderly. When those arteries leading to the heart are dilated, children are more at risk of developing clots that can burst and potentially lead to a heart attack.

“There are almost no other conditions that cause the type of coronary findings. That’s when the global community said there has to be an overlap between this condition and Kawasaki disease,” Sable said.

The new Kawasaki-like cases, doctors said, differ in important respects from traditional presentations – a situation that may provide clues about the virus, its biology and movement around the world.

The first surprising thing from the data being collected on the children is that they are mostly ages 5 to 10. In the past, those struck with the condition were mostly younger than 5.

Nearly all the inflammatory syndrome cases have been in Europe and in the United States, about 50 total in cities including Boston, New York, Philadelphia, and Washington, D.C. A few were in Asia, and no one seemed to know of more than a single case on the West Coast.

Some speculate that different strains of the virus could be responsible for the differing incidence of such cases. Genome sequencing has shown that most of the strains circulating on the West Coast appear to have originated from Asia, while a different strain on the East Coast appears to have come from Europe.

In addition, some children with the COVID-19-related inflammatory syndrome are presenting with low blood pressure and some gastrointestinal symptoms, including severe abdominal plan, vomiting and diarrhea, which are less commonly seen in Kawasaki. And while Kawasaki tends to affect Asian children disproportionately, some doctors say they are seeing the new syndrome in children of all races, while others have noticed a high number of children of African or Caribbean descent.

What’s worrisome, Newburger said, “is that some of these children are sicker than in an average Kawasaki shock syndrome.”

The good news, she said, is that many patients have been treated successfully and have fully recovered. Although it’s still early, “so far, I think we can be optimistic for most patients.”

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