Saturday evening – when Newburger and 1,800 other concerned pediatricians, including representatives from the Centers for Disease Control and Prevention and the National Institutes of Health, met in a Zoom call to discuss the phenomenon – hospitals around the world identified about 100 similar cases. About half are in the United States.
“In my lifetime, I haven’t seen anything like this happening right now,” said Newburger, medical director of the cardiac neurodevelopment program at Boston Children Hospital.
The cases appeared to have certain characteristics of a disease known as Kawasaki disease. The cardiologists, rheumatologists and critical care physicians present at the meeting were also struck by their unusual timing and location. They started three to four weeks after the big wave of adult illnesses, mainly in Europe and up and down the east coast of the United States, where Covid-19 hit hard.
The number of children affected is still tiny, relatively speaking, far lower than the number of people severely ill with the flu in a similar period. Most responded well to treatment.
“I think of it as the tip of the iceberg,” said Jane Burns, professor of pediatrics at the University of California at San Diego School of Medicine. “Fortunately, there are this very small number of patients who have this shock syndrome, while there is a large number of [covid-19] patients in the same community.
Burns, along with other doctors, said parents shouldn’t panic. The vast majority of young people under the age of 18 who are infected with coronavirus have mild or no symptoms. Researchers are not sure whether the disease is caused by covid-19 or something else. Those suffering from “pediatric multisystem inflammatory syndrome”, as doctors call the new disease, are “a small genetic subset of children who seem susceptible to this madness,” she said.
But the strange nature of the cases in most previously healthy children, and its potential connection to a virus that has sparked almost constant surprises, has put the medical community on high alert.
On Monday, New York City released a bulletin warning doctors that they had found 15 children with the disease in their hospitals, and the CDC is contacting health services about the surveillance measures. The American Heart Association is preparing to issue its own pediatric alert this week.
The global effort around inflammatory disease is part of a larger focus on children by researchers who have said that understanding their resistance to the virus could provide clues that may lead to treatment or vaccines.
For more typical respiratory viruses such as the flu, children are often the first to fall ill. Covid-19 is an anomaly, killing the elderly at a high rate while leaving the very young practically intact. Only a small fraction of American children – including an infant and a 5-year-old child who were children of first responders – died from the disease.
Scientists have questioned whether the apparent superpowers of children against the virus are due to their better resistance to infection or whether there is something protective in the biology of youth.
There is also a raging debate in the medical community over the extent to which children are susceptible to infection and can transmit the virus to others, enthusiastic about the Swiss chief of infectious diseases, who said on 27 April that children under the age of 10 could hug their grandparents and go back to school because they “don’t have the receptors to catch the disease.”
Alkis Togias of the National Institute of Allergy and Infectious Diseases), which focuses on the biology of the respiratory tract, said there is no scientific evidence to suggest that children cannot contract or transmit the virus. But there are reasons to assume that they may be less likely to be infected and less infectious to others, although this is just beginning to be studied, and he warned that the understanding of the virus changes daily.
This week, the institute announced a $ 25 million, six-month study on covid-19 in 2,000 American families hoping to answer these questions and more. It will include questionnaires on social distancing practices, interactions with people outside their homes, symptoms and swabs every two weeks for active infection, as well as blood tests to examine anti-disease antibodies.
The CDC is separately funding the creation of a registry that will track cases of covid-19 among children in more than 35 children’s hospitals in the United States to understand why some children get very sick when most don’t.
“We know that the infection rate in children is much lower than in adults,” said Togias. “What we don’t know is if, in fact, they carry the virus and spread it without getting sick or having very mild symptoms. We have so little knowledge, I can’t give you an answer on almost everything about children. So we have to understand that. ”
Over the course of four months, the world got to know the new coronavirus, its impact on children has been one of its biggest mysteries – how infected they are, how they react to the infection and their role in transmission of the virus to others.
A study published in the journal Science based on data from China estimates that children up to the age of 14 seem to be infected at one-third the rate of people aged 15 to 64 (and those over 65 years are most likely to be infected).
The issue of communicability is becoming increasingly politically charged. Some researchers have noted that there does not appear to be a single documented case of a child infecting an adult in the medical literature – a title that has been adopted by some pushing for the reopening of the economy. The claim is based on a Royal College of Pediatricians review of 78 studies which found that “the role of children in transmission is unclear, but it seems likely that they do not play an important role. “
Other research has shown that the amount of virus in the blood of children can be similar to or even greater than that of adults, making them likely to be just as contagious. A German study looked at 3,712 people, including children, and found no significant differences in viral load by age.
“Based on these results, we must warn against unlimited reopening of schools and kindergartens in the current situation,” the researchers wrote. “Children can be as contagious as adults.”
Larry Kociolek, assistant professor of pediatrics at Northwestern University and infectious disease specialist at Lurie Children’s Hospital in Chicago, and colleagues are doing similar research in the United States and have found that children under 5 who test positive have significantly more viral loads than adults. The difference between the groups therefore seems to relate more to their body’s reaction to the pathogen.
“We have observed that children generally have lighter presentations than adults, despite having a viral load equal to or even higher than that of adults,” said Kociolek.
One of the first theories about why children may be less reactive to covid-19 is based on the idea that their immune systems are less mature and may not over-react as some adult systems do. They may also be less susceptible to attack by blood vessels or other documented cardiovascular effects because they lack the comorbidities accumulated after years of bad habits and aging which 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 body. Studies have shown that the coronavirus attaches to something called ACE2 receptors, and that these receptors appear to express themselves differently in different parts of the body and in different people.
Some scientists speculate that the concentration of receptors may be different in children’s nasal cavities and lungs – where the virus seems to first invade – in a way that makes them less likely to be infected and have a serious illness. At the end of April, a study funded by the National Institutes of Health described in a letter from the Journal of Allergy and Clinical Immunology how the expression of ACE2 was reduced in the swabs of the nasal passages and throat of 11 year olds suffering from asthma. The researchers wrote that this unexpected finding could lead to “a reduced susceptibility to infection.”
“This is a grand theory and a unifying theory,” said Steven Kernie, chief of critical care medicine at the New York-Presbyterian Morgan Stanley Children Hospital and professor of pediatrics at Columbia University Irving Medical Center. Kernie said research has also shown that these receptors are highly expressed in the kidneys of adults, who have been severely damaged in a large percentage of elderly patients with coronavirus, but less concentrated in the kidneys of children.
The presentation of covid-19 also differs between adults and children in severe cases, where people end up in intensive care.
In adults, the disease has changed in form even in the way it kills: inducing cell changes that cause respiratory failure, blood clots in the legs and other means. But in children, there seems to be a little less variety in critical cases.
Many young people under the age of 18 who were in intensive care for the first few weeks were infants or adolescents who needed help with breathing, as with traditional respiratory viruses, according to intensive care doctors.
Kawasaki type cases came later.
The syndrome, first described by a Japanese pediatrician in 1967, is characterized by persistent fever, red eyes, rash, and swelling of the hands and feet, which are signs of inflammation in the blood vessels. Its cause is unknown, but some researchers believe it is a genetic susceptibility to a virus or other environmental stressor. There is no cure, but there are effective treatments, including blood thinners and an immunoglobulin serum that can be used to stabilize most children. In rare cases, children can develop heart problems for life.
Newburger, considered one of the world’s best experts on Kawasaki, said some of the children were positive for active infection with the new coronavirus, while others were not. A third group had no active infection but had antibodies showing previous exposure.
One working theory is that the condition could be a kind of post-viral syndrome occurring after infection.
This is similar to the patterns observed by researchers in some children with rashes similar to gel bites on the toes and sometimes the fingers, despite the absence of other symptoms of covid-19. The assumption is that some infected children may never know they have the virus until they have an immune response several weeks later – a small one like a rash or a large one that affects multiple internal organs.
“It is possible that the antibodies that children develop to fight the disease may cause a persistent response that causes fever and inflammation,” said Jeffrey Burns, manager of intensive care at Boston Children’s.
Craig Sable, a pediatric cardiologist at the National Children’s Hospital, described the condition as an “over-exaggerated immune inflammatory response”.
In some of these new patients, the coronary arteries, which can be around 3 millimeters in diameter in a 3-year-old child, for example, have been enlarged by 50% or even twice. Doctors also see aneurysms – a weakening of an arterial wall that leads to a bulge or bubble in the blood vessels – a condition that usually occurs in the elderly. When the 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. It was then that the global community declared that there should be an overlap between this condition and Kawasaki disease, “said Sable.
The new Kawasaki-like cases, doctors say, differ in some important respects from traditional presentations – a situation that can provide clues to the virus, its biology and its movements around the world.
The first surprising thing from the data collected on children is that most of them are between 5 and 10 years old. Most children with traditional Kawasaki disease are under the age of 5.
Almost all cases of inflammatory syndrome have occurred in Europe and the United States, about 50 in total in cities like Boston, New York, Philadelphia and Washington, DC A few were in Asia, and no one seemed to know more from a single case on the West Coast.
Some speculate that different strains of the virus may be responsible for the different incidence of these cases. Genome sequencing has shown that most of the strains circulating on the west coast appear to originate from Asia while another strain on the east coast appears to originate from Europe.
In addition, some children with covid-19 inflammatory syndrome have low blood pressure and gastrointestinal symptoms, including severe abdominal pain, vomiting and diarrhea, which are less common in Kawasaki. And while Kawasaki tends to affect Asian children disproportionately, some doctors say they see the new syndrome in children of all races, while others have noticed a high number of children of African or Caribbean.
What is worrisome, said Newburger, “is that some of these children are sicker than in average Kawasaki shock syndrome. “
The good news, she said, is that many patients have been successfully treated and fully recovered. Although it is still early, “so far, I think we can be optimistic for most patients. “