Doctors can’t reliably predict whether an adult newly diagnosed with COVID-19 will recover quickly or battle life-threatening complications. The same is true for children.
Thankfully, the vast majority of kids with COVID-19 don’t get sick or show only mild flu-like symptoms. But a small percentage develop a delayed, but extremely troubling, syndrome called multisystem inflammatory syndrome in children (MIS-C). This can cause severe inflammation of the heart, lungs, kidneys, brain, and other parts of the body, coming on weeks after recovering from COVID-19. Fortunately, most kids respond to treatment and make rapid recoveries.
COVID-19’s sometimes different effects on kids likely stem not from the severity of the infection itself, but from differences in the immune response or its aftermath. Additional support for this notion comes from a new study, published in the journal Nature Medicine, that compared immune responses among children and adults with COVID-19 . The study shows that the antibody responses in kids and adults with mild COVID-19 are quite similar. However, the complications seen in kids with MIS-C and adults with severe COVID-19 appear to be driven by two distinctly different types of antibodies involved in different aspects of the immune response.
The new findings come from pediatric pulmonologist Lael Yonker, Massachusetts General Hospital (MGH) Cystic Fibrosis Center, Boston, and immunologist Galit Alter, the Ragon Institute of MGH, Massachusetts Institute of Technology, and Harvard, Cambridge. Yonker runs a biorepository that collects samples from kids with cystic fibrosis. When the pandemic began, she started collecting plasma samples from children with mild COVID-19. Then, when Yonker and others began to see children hospitalized with MIS-C, she collected some plasma samples from them, too.
Using these plasma samples as windows into a child’s immune response, the research teams of Yonker and Alter detailed antibodies generated in 17 kids with MIS-C and 25 kids with mild COVID-19. They also profiled antibody responses of 60 adults with COVID-19, including 26 with severe disease.
Comparing antibody profiles among the four different groups, the researchers had expected children’s antibody responses to look quite different from those in adults. But they were in for a surprise. Adults and kids with mild COVID-19 showed no notable differences in their antibody profiles. The differences only came into focus when they compared antibodies in kids with MIS-C to adults with severe COVID-19.
In kids who develop MIS-C after COVID-19, they saw high levels of long-lasting immunoglobulin G (IgG) antibodies, which normally help to control an acute infection. Those high levels of IgG antibodies weren’t seen in adults or in kids with mild COVID-19. The findings suggest that in kids with MIS-C, those antibodies may activate scavenging immune cells, called macrophages, to drive inflammation and more severe illness.
In adults with severe COVID-19, the pattern differed. Instead of high levels of IgG antibodies, adults showed increased levels of another type of antibody, called immunoglobulin A (IgA). These IgA antibodies apparently were interacting with immune cells called neutrophils, which in turn led to the release of cytokines. That’s notable because the release of too many cytokines can cause what’s known as a “cytokine storm,” a severe symptom of COVID-19 that’s associated with respiratory distress syndrome, multiple organ failure, and other life-threatening complications.
To understand how a single virus can cause such different outcomes, studies like this one help to tease out their underlying immune mechanisms. While more study is needed to understand the immune response over time in both kids and adults, the hope is that these findings and others will help put us on the right path to discover better ways to help protect people of all ages from the most severe complications of COVID-19.
Most children infected with SARS-CoV-2, the virus that causes COVID-19, develop only a mild illness. But, days or weeks later, a small percentage of kids go on to develop a puzzling syndrome known as multisystem inflammatory syndrome in children (MIS-C). This severe inflammation of organs and tissues can affect the heart, lungs, kidneys, brain, skin, and eyes.
Thankfully, most kids with MIS-C respond to treatment and make rapid recoveries. But, tragically, MIS-C can sometimes be fatal.
With COVID-19 cases in children having increased by 21 percent in the United States since early August , NIH and others are continuing to work hard on getting a handle on this poorly understood complication. Many think that MIS-C isn’t a direct result of the virus, but seems more likely to be due to an intense autoimmune response. Indeed, a recent study in Nature Medicine  offers some of the first evidence that MIS-C is connected to specific changes in the immune system that, for reasons that remain mysterious, sometimes follow COVID-19.
These findings come from Shane Tibby, a researcher at Evelina London Children’s Hospital, London. United Kingdom; Manu Shankar-Hari, a scientist at Guy’s and St Thomas’ NHS Foundation Trust, London; and colleagues. The researchers enlisted 25 children, ages 7 to 14, who developed MIS-C in connection with COVID-19. In search of clues, they examined blood samples collected from the children during different stages of their care, starting when they were most ill through recovery and follow-up. They then compared the samples to those of healthy children of the same ages.
What they found was a complex array of immune disruptions. The children had increased levels of various inflammatory molecules known as cytokines, alongside raised levels of other markers suggesting tissue damage—such as troponin, which indicates heart muscle injury.
The neutrophils, monocytes, and other white blood cells that rapidly respond to infections were activated as expected. But the levels of certain white blood cells called T lymphocytes were paradoxically reduced. Interestingly, despite the low overall numbers of T lymphocytes, particular subsets of them appeared activated as though fighting an infection. While the children recovered, those differences gradually disappeared as the immune system returned to normal.
It has been noted that MIS-C bears some resemblance to an inflammatory condition known as Kawasaki disease, which also primarily affects children. While there are similarities, this new work shows that MIS-C is a distinct illness associated with COVID-19. In fact, only two children in the study met the full criteria for Kawasaki disease based on the clinical features and symptoms of their illness.
Another recent study from the United Kingdom, reported several new symptoms of MIS-C . They include headaches, tiredness, muscle aches, and sore throat. Researchers also determined that the number of platelets was much lower in the blood of children with MIS-C than in those without the condition. They proposed that evaluating a child’s symptoms along with his or her platelet level could help to diagnose MIS-C.
It will now be important to learn much more about the precise mechanisms underlying these observed changes in the immune system and how best to treat or prevent them. In support of this effort, NIH recently announced $20 million in research funding dedicated to the development of approaches that identify children at high risk for developing MIS-C .
The hope is that this new NIH effort, along with other continued efforts around the world, will elucidate the factors influencing the likelihood that a child with COVID-19 will develop MIS-C. Such insights are essential to allow doctors to intervene as early as possible and improve outcomes for this potentially serious condition.
NIH Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of the Director; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute on Drug Abuse; National Institute of Minority Health and Health Disparities; Fogarty International Center
There’s been a lot of focus, and rightly so, on why older adults and adults with chronic disease appear to be at increased risk for coronavirus disease 2019 (COVID-19). Not nearly as much seems to be known about children and COVID-19.
For example, why does SARS-CoV-2, the novel coronavirus that causes COVID-19, seem to affect children differently than adults? What is the psychosocial impact of the pandemic on our youngsters? Are kids as infectious as adults?
A lot of interesting research in this area has been published recently. That includes the results of a large study in South Korea in which researchers traced the person-to-person spread of SARS-CoV-2 in the early days of the pandemic. The researchers found children younger than age 10 spread the virus to others much less often than adults do, though the risk is not zero. But children age 10 to 19 were found to be just as infectious as adults. That obviously has consequences for the current debate about opening the schools.
To get some science-based answers to these and other questions, I recently turned to one of the world’s leading child health researchers: Dr. Diana Bianchi, Director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Dr. Bianchi is a pediatrician with expertise in newborn medicine, neonatology, and reproductive genetics. Here’s a condensed transcript of our chat, which took place via videoconference, with Diana linking in from Boston and me from my home in Chevy Chase, MD:
Collins: What is the overall risk of children getting COVID-19? We initially heard they’re at very low risk. [NOTE: Since the recording of this interview, new data has emerged from state health departments that suggest that as much as 10 percent of new cases of COVID-19 occur in children.]
Bianchi: Biological factors certainly play some role. We know that the virus often enters the body via cells in the nasal passage. A recent study showed that, compared to adults, children’s nasal cells have less of the ACE2 receptor, which the virus attaches to and uses to infect cells. In children, the virus probably has less of an opportunity to grab onto cells and get into the upper respiratory tract.
Importantly, social reasons also play a role in that low percentage. Children have largely been socially isolated since March, when many schools shut down. By and large, young kids have been either home or playing in their backyards.
Collins: If kids do get infected with SARS-CoV-2, the virus that causes COVID-19, what kind of symptoms are displayed?
Bianchi: Children tend to be affected mildly. Relatively few children end up in intensive care units. The most common symptoms are: fever, in about 60 percent of children; cough; and a mild respiratory illness. It’s a different clinical presentation. Children seem to be more prone to vomiting, diarrhea, severe abdominal pain, and other gastrointestinal problems.
Collins: Are children as infectious as adults?
Bianchi: We suspect that older kids probably are. A recently published meta-analysis, or systematic review of the medical literature, also found about 20 percent of infected kids are asymptomatic. There are probably a lot of kids out there who can potentially infect others.
Collins: Do you see a path forward here for schools in the fall?
Bianchi: I think the key word is flexibility. We must remain flexible in the months ahead. Children have struggled from being out of school, and it’s not just the educational loss. It’s the whole support system, which includes the opportunity to exercise. It includes the opportunity to have teachers and school staff looking objectively at the kids to see if they are psychologically well.
The closing of schools has also exacerbated disparities. Schools provide meals for many kids in need, and some have had a lot of food insecurity for the past several months. Not to mention kids in homeless situations often don’t have access to the internet and other learning tools. So, on the whole, being in school is better for children than not being there. That’s how most pediatricians see it. However, we don’t want to put children at risk for getting sick.
Collins: Can you say a little bit more about the consequences, particularly for young children, of being away from their usual areas of social interaction? That’s true this summer as well. Camps that normally would be a place where lots of kids would congregate have either been cancelled or are being conducted in a very different way.
Bianchi: Thus far, most of the published information that we have has really been on the infection and the clinical presentations. Ultimately, I think there will be a lot of information about the behavioral and developmental consequences of not being exposed to other children. I think that older children are also really suffering from not having a daily structure, for example, through sports.
For younger children, they need to learn how to socialize. There are advantages to being with your parents. But there are a lot of social skills that need to be learned without them. People talk about the one-eyed babysitter, YouTube. The American Academy of Pediatrics has issued recommendations for limiting screen time. That’s gone out the window. I’ve talked with a lot of my staff members who are struggling with this balance between educating or entertaining their children and having so-called quality time, and the responsibility to do their jobs.
Collins: What about children with disabilities? Are they in a particularly vulnerable place?
Bianchi: Absolutely. Sadly, we don’t hear a lot about children with disabilities as a vulnerable population. Neither do we hear a lot about the consequences of them not receiving needed services. So many children with disabilities rely on people coming into their homes, whether it’s to help with respiratory care or to provide physical or speech therapy. Many of these home visits are on hold during the pandemic, and that can cause serious problems. For example, you can’t suction a trachea remotely. Of course, you can do speech therapy remotely, but that’s not ideal for two reasons. First, face-to-face interactions are still better, and, secondly, disparities can factor into the equation. Not all kids with disabilities have access to the internet or all the right equipment for online learning.
Collins: Tell me a little bit more about a rare form of consequences from COVID-19, this condition called MIS-C, Multi-System Inflammatory Syndrome of Children. I don’t think anybody knew anything about that until just a couple of months ago.
Bianchi: Even though there were published reports of children infected with SARS-CoV-2 in China in January, we didn’t hear until April about this serious new inflammatory condition. Interestingly, none of the children infected with SARS-CoV-2 in China or Japan are reported to have developed MIS-C. It seemed to be something that was on the European side, predominantly the United Kingdom, Italy, and France. And then, starting in April and May, it was seen in New York and the northeastern United States.
The reason it’s of concern is that many of these children are gravely ill. I mentioned that most children have a mild illness, but the 0.5 percent who get the MIS-C are seriously ill. Almost all require admission to the ICU. The scary thing is they can turn on a dime. They present with more of a prolonged fever. They can have very severe abdominal pain. In some cases, children have been thought to have appendicitis, but they don’t. They have serious cardiac issues and go into shock.
The good news is the majority survive. Many require ventilators and blood-pressure support. But they do respond to treatment. They tend to get out of the hospital in about a week. However, in two studies of MIS-C recently published in New England Journal of Medicine, six children died out of 300 children. So that’s what we want to avoid.
Collins: In terms of the cause, there’s something puzzling about MIS-C. It doesn’t seem to be a direct result of the viral infection. It seems to come on somewhat later, almost like there’s some autoimmune response.
Bianchi: Yes, that’s right. MIS-C does tend to occur, on an average, three to four weeks later. The NIH hosted a conference a couple weeks ago where the top immunologists in the world were talking about MIS-C, and everybody has their piece of the elephant in terms of a hypothesis. We don’t really know right now, but it does seem to be associated with some sort of exuberant, post-infectious inflammatory response.
Is it due to the fact that the virus is still hiding somewhere in the body? Is the body reacting to the virus with excessive production of antibodies? We don’t know. That will be determined, hopefully, within weeks or months. Collins: And I know that your institute is taking a leading role in studying MIS-C.
Bianchi: Yes. Very shortly after the first cases of MIS-C were being described in the United States, you asked me and Gary Gibbons, director of NIH’s National Heart Lung and Blood Institute, to cochair a taskforce to develop a study designed to address MIS-C. Staff at both institutes have been working, in collaboration with NIH’s National Institute of Allergy and Infectious Diseases, to come up with the best possible way to approach this public health problem.
The study consists of a core group of kids who are in the hospital being treated for MIS-C. We’re obtaining biospecimens and are committed to a central platform and data-sharing. There’s an arm of the study that’s looking at long-term issues. These kids have transient coronary artery dilation. They have a myocarditis. They have markers of heart failure. What does that imply long-term for the function of their hearts?
We will also be working with several existing networks to identify markers suggesting that a certain child is at risk. Is it an underlying immune issue, or is it ethnic background? Is it this a European genomic variant? Exactly what should we be concerned about?
Collins: Let me touch on the genomics part of this for a minute, and that requires a brief description. The SARS-CoV-2 novel coronavirus is crowned in spiky proteins that attach to our cells before infecting them. These spike proteins are made of many amino acids, and their precise sequential order can sometimes shift in subtle ways.
Within that sequential order at amino acid 614, a shift has been discovered. The original Chinese isolate, called the D version, had aspartic acid there. It seems the virus that spread from Asia to the U.S. West Coast also has aspartic acid in that position. But the virus that traveled to Italy and then to the East Coast of the U.S. has a glycine there. It’s called the G version.
There’s been a lot of debate about whether this change really matters. More data are starting to appear suggesting that the G version may be more infectious than the D version, although I’ve seen no real evidence of any difference in severity between the two.
Of course, if the change turned out to be playing a role in MIS-C, you would expect not to have seen so many cases on the West Coast. Has anyone looked to see if kids with the D version of the virus ever get MIS-C?
Bianchi: It hasn’t been reported. You could say that maybe we don’t get all the information from China. But we do get it from Japan. In Japan, they’ve had the D version, and they haven’t had MIS-C.
Collins: Let’s talk about expectant mothers. What is the special impact of COVID-19 on them?
Bianchi: Recently, a lot of information has come out about pregnant women and the developing fetus. A recent report from the Centers for Disease Control and Prevention suggested that pregnant women are at a greatly increased risk of hospitalization. However, the report didn’t divide out hospitalizations that would be expected for delivering a baby from hospitalizations related to illness. But the report did show that pregnant women are at a higher risk of needing respiratory support and having serious illness, particularly if there is an underlying chronic condition, such as chronic lung disease, diabetes or hypertension.
Collins: Do we know the risk of the mother transmitting the coronavirus to the fetus?
Bianchi: What we know so far is the risk of transmission from mother to baby appears to be small. Now, that’s based on the fact that available studies seem to suggest that the ACE2 receptor that the virus uses to bind to our cells, is not expressed in third trimester placental tissue. That doesn’t mean it’s not expressed earlier in gestation. The placenta is so dynamic in terms of gene expression.
What we do know is there’s a lot of ACE2 expression in the blood vessels. An interesting recent study showed in the third trimester placenta, the blood vessels had taken a hit. There was actual blood vessel damage. There was evidence of decreased oxygenation in the placenta. We don’t know the long-term consequences for the baby, but the placentas did not look healthy.
Collins: I have a friend whose daughter recently was ready to deliver her baby. As part of preparing for labor, she had a COVID-19 test. To her surprise and dismay, she was positive, even though she had no symptoms. She went ahead with the delivery, but then the baby was separated from her for a time because of a concern about the mother transmitting the virus to her newborn. Is separation widely recommended?
Bianchi: I think most hospitals are softening on this. [NOTE: The American Academy of Pediatrics recently issued revised recommendations about labor and delivery, as well as about breastfeeding, during COVID-19]
In the beginning, hospitals took a hard line. For example, no support people were allowed into the delivery room. So, women were having more home deliveries, which are far more dangerous, or signing up to give birth at hospitals that allowed support people.
Now more hospitals are allowing a support person in the room during delivery. But, in general, they are recommending that the mother and the support person get tested. If they’re negative, everything’s fine. If the support person is positive, he or she’s not allowed to come in. If the mother is positive, the baby is separated, generally, for testing. In many hospitals, mothers are given the option of reuniting with the baby.
There’s also been a general discussion about mothers who test positive breastfeeding. The more conservative recommendation is to pump the milk and allow somebody else to bottle-feed the baby while the mother recovers from the infection. I should also mention a recent meta-analysis in the United Kingdom. It suggested that a cesarean section delivery is not needed because of SARS-CoV-2 positivity alone. It also found there’s no reason for SARS-CoV-2 positive women not to breast feed.
Collins: Well, Diana, thank you so much for sharing your knowledge. If there’s one thing you wanted parents to take away from this conversation, what would that be?
Bianchi: Well, I think it’s natural to be concerned during a pandemic. But I think parents should be generally reassuring to their children. We’ll get through this. However, I would also say that if a parent notices something unusual going on with a child—skin rashes, the so-called blue COVID toes, or a prolonged fever—don’t mess around. Get your child medical attention as soon as possible. Bad things can happen very quickly to children infected with this virus.
For the expectant parents, hopefully, their obstetricians are counseling them about the fact that they are at high risk. I think that women with chronic conditions really need to be proactive. If they’re not feeling well, they need to go to the emergency room. Again, things can happen quickly with this virus.
But the good news is the babies seem to do very well. There’s no evidence of birth defects so far, and very limited evidence, if at all, of vertical transmission. I think they can feel good about their babies. They need to pay attention to themselves.
Collins: Thank you, Diana, for ending on those wise words.
Caption: Charlotte Phillips during a visit to a Missouri Mennonite community. Credit: Richard Hillman
At 1 a.m., most people are fast asleep in their beds. But Charlotte Phillips sometimes finds herself up at that odd hour, waiting anxiously in a deserted Missouri parking lot far from her home. Phillips drives there to meet a contact for a very special delivery: a packet of cheek swabs and blood samples from a newborn Mennonite baby at risk of a life-threatening genetic condition called maple syrup urine disease (MSUD).
For more than two decades, Phillips, an NIH grantee at the University of Missouri, Columbia, has volunteered to ensure that the DNA in these swabs and samples is tested for MSUD within hours of a baby’s birth. If found to be positive for the condition, the baby can receive a needed special formula. Without it, the baby would suffer brain damage within days from its inability to break down amino acids in protein-rich foods, including breast milk and standard infant formula. Hurrying off at a moment’s notice isn’t always convenient, but Phillips, who is not Mennonite, feels a personal calling to do it. She wouldn’t want any babies to die.