Posted on by Dr. Francis Collins
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.
 Humoral signatures of protective and pathological SARS-CoV-2 infection in children. Bartsch YC, Wang C, Zohar T, Fischinger S, Atyeo C, Burke JS, Kang J, Edlow AG, Fasano A, Baden LR, Nilles EJ, Woolley AE, Karlson EW, Hopke AR, Irimia D, Fischer ES, Ryan ET, Charles RC, Julg BD, Lauffenburger DA, Yonker LM, Alter G. Nat Med. 2021 Feb 12.
COVID-19 Research (NIH)
“NIH effort seeks to understand MIS-C, range of SARS-CoV-2 effects on children,” NIH news release, March 2, 2021.
Lael Yonker (Massachusetts General Hospital, Boston)
Alter Lab (Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Cambridge)
NIH Support: National Institute of Allergy and Infectious Diseases; National Cancer Institute
Posted on by Dr. Francis Collins
For the 1 to 3 million Americans with type 1 diabetes, the immune system destroys insulin-producing beta cells of the pancreas that control the amount of glucose in the bloodstream. As a result, these individuals must monitor their blood glucose often and take replacement doses of insulin to keep it under control. Such constant attention, combined with a strict diet to control sugar intake, is challenging—especially for children.
For some people with type 1 diabetes, there is another option. They can be treated—maybe even cured—with a pancreatic islet cell transplant from an organ donor. These transplanted islet cells, which harbor the needed beta cells, can increase insulin production. But there’s a big catch: there aren’t nearly enough organs to go around, and people who receive a transplant must take lifelong medications to keep their immune system from rejecting the donated organ.
Now, NIH-funded scientists, led by Ronald Evans of the Salk Institute, La Jolla, CA, have devised a possible workaround: human islet-like organoids (HILOs) . These tiny replicas of pancreatic tissue are created in the laboratory, and you can see them above secreting insulin (green) in a lab dish. Remarkably, some of these HILOs have been outfitted with a Harry Potter-esque invisibility cloak to enable them to evade immune attack when transplanted into mice.
Over several years, Doug Melton’s lab at Harvard University, Cambridge, MA, has worked steadily to coax induced pluripotent stem (iPS) cells, which are made from adult skin or blood cells, to form miniature islet-like cells in a lab dish . My own lab at NIH has also been seeing steady progress in this effort, working with collaborators at the New York Stem Cell Foundation.
Although several years ago researchers could get beta cells to make insulin, they wouldn’t secrete the hormone efficiently when transplanted into a living mouse. About four years ago, the Evans lab found a possible solution by uncovering a genetic switch called ERR-gamma that when flipped, powered up the engineered beta cells to respond continuously to glucose and release insulin .
In the latest study, Evans and his team developed a method to program HILOs in the lab to resemble actual islets. They did it by growing the insulin-producing cells alongside each other in a gelatinous, three-dimensional chamber. There, the cells combined to form organoid structures resembling the shape and contour of the islet cells seen in an actual 3D human pancreas. After they are switched on with a special recipe of growth factors and hormones, these activated HILOs secrete insulin when exposed to glucose. When transplanted into a living mouse, this process appears to operate just like human beta cells work inside a human pancreas.
Another major advance was the invisibility cloak. The Salk team borrowed the idea from cancer immunotherapy and a type of drug called a checkpoint inhibitor. These drugs harness the body’s own immune T cells to attack cancer. They start with the recognition that T cells display a protein on their surface called PD-1. When T cells interact with other cells in the body, PD-1 binds to a protein on the surface of those cells called PD-L1. This protein tells the T cells not to attack. Checkpoint inhibitors work by blocking the interaction of PD-1 and PD-L1, freeing up immune cells to fight cancer.
Reversing this logic for the pancreas, the Salk team engineered HILOs to express PD-L1 on their surface as a sign to the immune system not to attack. The researchers then transplanted these HILOs into diabetic mice that received no immunosuppressive drugs, as would normally be the case to prevent rejection of these human cells. Not only did the transplanted HILOs produce insulin in response to glucose spikes, they spurred no immune response.
So far, HILOs transplants have been used to treat diabetes for more than 50 days in diabetic mice. More research will be needed to see whether the organoids can function for even longer periods of time.
Still, this is exciting news, and provides an excellent example of how advances in one area of science can provide new possibilities for others. In this case, these insights provide fresh hope for a day when children and adults with type 1 diabetes can live long, healthy lives without the need for frequent insulin injections.
 Immune-evasive human islet-like organoids ameliorate diabetes. [published online ahead of print, 2020 Aug 19]. Yoshihara E, O’Connor C, Gasser E, Wei Z, Oh TG, Tseng TW, Wang D, Cayabyab F, Dai Y, Yu RT, Liddle C, Atkins AR, Downes M, Evans RM. Nature. 2020 Aug 19. [Epub ahead of publication]
 Generation of Functional Human Pancreatic β Cells In Vitro. Pagliuca FW, Millman JR, Gürtler M, Segel M, Van Dervort A, Ryu JH, Peterson QP, Greiner D, Melton DA. Cell. 2014 Oct 9;159(2):428-39.
 ERRγ is required for the metabolic maturation of therapeutically functional glucose-responsive β cells. Yoshihara E, Wei Z, Lin CS, Fang S, Ahmadian M, Kida Y, Tseng T, Dai Y, Yu RT, Liddle C, Atkins AR, Downes M, Evans RM. Cell Metab. 2016 Apr 12; 23(4):622-634.
Type 1 Diabetes (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Pancreatic Islet Transplantation (National Institute of Diabetes and Digestive and Kidney Diseases)
“The Nobel Prize in Physiology or Medicine 2012” for Induced Pluripotent Stem Cells, The Nobel Prize news release, October 8, 2012.
Evans Lab (Salk Institute, La Jolla, CA)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute
Posted on by Dr. Francis Collins
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.
 Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection. Carter MJ, Fish M, Jennings A, Doores KJ, Wellman P, Seow J, Acors S, Graham C, Timms E, Kenny J, Neil S, Malim MH, Tibby SM, Shankar-Hari M. Nat Med. 2020 Aug 18.
 Children and COVID-19: State-Level Data Report. American Academy of Pediatrics. August 24, 2020.
 Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. Swann OV, Holden KA, Turtle L, Harrison EW, Docherty AB, Semple MG, et al. Br Med J. 2020 Aug 17.
 NIH-funded project seeks to identify children at risk for MIS-C. NIH. August 7, 2020.
Coronavirus (COVID-19) (NIH)
Kawasaki Disease (Genetic and Rare Disease Information Center/National Center for Advancing Translational Sciences/NIH)
Shane Tibby (Evelina London Children’s Hospital, London)
Manu Shankar-Hari (King’s College, London)
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
Posted on by Dr. Francis Collins
If somebody had told you last year that that our country, along with the whole world, would soon be facing a major health challenge like the coronavirus disease 2019 (COVID-19) pandemic, you’d have thought it almost unimaginable. Yet here we are.
To help flatten the pandemic’s deadly curve, a great many of us have been asked to remain at home. I have been faithfully adhering to that recommendation—I haven’t been to my office or lab at NIH in almost three weeks, though I can’t remember a time where I have worked harder. While helping to protect ourselves and others, this physical distancing can affect our mental well-being.
Recently, I had an opportunity to discuss these aspects of COVID-19 with Dr. Joshua Gordon, Director of NIH’s National Institute of Mental Health. Our conversation took place via videoconferencing, with him linking in from his home in the New York area and me from my home in Maryland. Here’s a condensed transcript of our chat:
Collins: So, Josh, tell me how you’re doing there. How’s everybody coping?
Gordon: Right now, my family and I are doing fine. My daughter and I are ensconced here at home, both working from home. She’s finishing up high school online and my wife works for New York City. She’s an essential employee, so she’s still going into work but, fortunately, she’s able to make sure that her workspace is very sparse and she’s able to commute by herself.
Collins: I’m glad you’re okay. Exactly how do you name this kind of stress that everybody’s feeling right now? Is it fear? Is it anxiety about being put in such an area of uncertainty? Is it just grief, the sense that something really profound has happened here and we are losing things in terms of our ability to move around freely? Certainly, we also grieve deeply about the suffering and the death that we see.
Gordon: For different people, it’s different combinations. I know that I feel anxiety for myself and my family in terms of our health. But it’s not just anxiety about contracting the coronavirus, it’s also fear and anxiety about what’s happening to society, what’s happening to our economy, what’s happening to our friends and relatives.
And then there is tremendous grief. We’ve acknowledged that we’ve all lost something already. Right? We’ve lost our normal day-to-day interactions. We’ve lost our ability to physically connect with people and it makes it more challenging to socially connect with people. And we’ve lost that sense of certainty and self-power.
Collins: Talking to my wife Diane about this, I think the grief part of it was something we were both feeling, but hadn’t quite named. Somehow being able to talk about it, experience it, and not try to run away from it turned out to be helpful.
Gordon: Yes, it’s important to talk about it. For most people, it’s a matter of being able to talk about your feelings, get it out into the open, and hear from others that are going through the same thing. They’re your friends that you’re Zooming with, they’re your parents or grandparents that you’re talking to on the phone.
Collins: I hope everybody will feel a little more free to be honest about what they are going through. Maybe sometimes we try to just be tough and keep it all to ourselves and don’t want others around us to be influenced, if we’re talking about our own emotions. But we need to share those things. Besides that, what other things, can be helpful to people who are trying to cope with the current circumstances?
Gordon: One important thing is to focus on the facts. There’s a lot of rumor, there’s a lot of hyperbole out there, and there’s a lot of, frankly, uncertainty. But to the extent that you can, learn and share the facts about the virus. If you know what’s happening, it reduces the uncertainty.
At the same time, one can get so taken up with reading the daily news, listening to the various news conferences that are going on, checking the websites, etc., that it becomes all-consuming. So, it’s really important to set aside periods of each day where you turn off social media, you turn off the TV, turn off the news, and do something that you enjoy. It could be art, it could be exercise, it could be picking up the phone and talking to someone about something other than COVID.
The other thing that’s really important is to take care of your body in addition to your mind. Taking care of your body can help your mind do better. So, yoga, exercise, resting, naps, regular meals, all these things can be helpful. Alcohol is often used as an escape mechanism when you’re feeling stressed. That can be a little tricky or dangerous, so try to avoid drinking excessively.
Connecting with others is really important in this day of physical distancing. I like to call it physical distancing, rather than social distancing, because I think we can be socially intimate and physically distant. So, connect with others, reach out to people, use digital tools, use telephones, use email and text, write a letter.
Collins: A letter?
Gordon: Yes, why not? I haven’t gotten mail for three days. Just saying. So, write a letter, connect with people that you can unwind with, that you can get joy from.
Collins: My wife Diane just stepped in and I want to have her to come over for a minute and say something about this, because I think part of the grief we were feeling was this disconnection from face-to-face interactions with people. Diane’s a very sociable person and this is particularly hard when you’re so isolated in one place. But she came up with something yesterday that seemed to be a help.
Diane Baker: Yes. I’ve got to say, the shelter in place order here in Maryland just surprised me. It took me down a couple of notches and I can’t say it was warranted, I was like I can’t take this. Even though it’s what we’ve been doing, it just emotionally really got to me. And so a friend came up with this idea. She went for a walk in her neighborhood, I went for a walk in my neighborhood, we pulled our phones out and we had a conversation. Even though it was cold rainy day, we didn’t mind it because we were talking to each other. So, we’re going to try and do that on a regular basis.
Gordon: You’re right, your social connectedness really helps. Like I can reach out to my parents in North Carolina, I can reach out to my brother in Philadelphia. We’ve had almost nightly Zoom get-togethers and I actually feel like I’m seeing my relatives more these last couple of weeks than I have in months.
Collins: That’s interesting. We’ve done that too. Every Sunday now we have a Zoom meeting with my daughters and my grandkids.
Diane Baker: The other thing I think it’s done is forced us to be more intentional about our communication. I think that’s something we take for granted. For instance, I have this book club I’ve been a part of for a long time, but we always talk books and politics and topical issues. Now, I’m starting to reach out to them on email and say, “Hey, I’m having a real tough time,” and we’re supporting each other in a way that we haven’t before. It’s been very nice. I’ll let you guys go on..
Gordon: Nice to see you, Diane.
Collins: I think we all feel this urge to do something, to try to contribute in some way. In many ways, we feel a little paralyzed by the fact that we’re stuck indoors and all of the things you might like to do might be risky for yourself or other people. What can we do as far as actions to help other people?
Gordon: Those of you who are working directly on COVID can take a lot of pride in the fact that you’re contributing to that mission. But everyone is contributing to that mission by staying home. I would add a more practical bent to all this, which is that it is important to set goals and priorities for yourself. Finally, there are volunteer opportunities that can be done remotely. There are donations that are being accepted. So, I encourage you, if you feel so moved and have the means to do so, contribute in that way.
Collins: Parents are worried about their kids in terms of how this is affecting them. So, what kind of advice can you give to parents about how to interact with children in this very unusual situation?
Gordon: Kids are, I’m sure, feeling anxious. First, recognize what they’re going through. Talk to them about it, find out what’s concerning them.
Kids always surprise you. They’re not necessarily anxious or worried about the things that you’re anxious or worried about. They might be worried about getting COVID, but they might also just be worried that they’re going to miss their best friend’s birthday next week. So, if you find out what’s bothering them, then you can help them. You can have them Zoom a happy birthday song or connect in some other way.
Reassuring them can help. But, more importantly, it’s just answering their questions as honestly as you can. When you don’t know, admit that you don’t, but say that you’ll be there for them.
Collins: Everybody is facing a certain amount of stress, anxiety, and grief at this time, but it hits some people even harder. What would be the signs that this is getting into a circumstance that might require some additional help?
Gordon: Let’s talk about how we recognize when this might be a thing that we can’t deal with and that is sending us over the edge. I went out grocery shopping last Friday. I managed to find a mask to wear and gloves, but I actually couldn’t take it. I was so anxious. I bought a few things and I had to leave. I felt in me something I’ve really never felt before. My heart started racing, I started breathing fast. I was getting a panic attack. That was something pushing me over the edge in ways that I hadn’t been challenged before.
If that happens to you, recognize it and seek help. So, what are the signs? We’re all feeling anxious, but if you feel so anxious you can’t get your work done, you actually can’t do the thing that you set out to do, reach out for help either from a friend or from a professional. Other signs would be you’re starting to withdraw from people, having trouble sleeping, change in appetite, change in physical energy levels, or starting to become irritable or angry.
For those with pre-existing mental illnesses, it’s really important that they reach out to their providers and find ways of connecting. Every mental health provider that I know of right now is moving to telehealth sessions. Not everyone is used to teleconferences, not everyone knows how to use them. So, plan in advance with your provider how you’re going to contact with them so that you can get the help you need when you need it. Make sure that you have enough medication in-house and work out with your pharmacy how you can get it delivered rather than having to go pick it up, whether that’s from a mail order pharmacy or getting your local pharmacy to deliver to you.
Finally, there are hot lines. For those experiencing distress with the COVID epidemic, the Substance Abuse and Mental Health Service Administration has the Disaster Distress Helpline. That’s 800-985-5990 or text “TalkWithUs” to 66746. For those who are really struggling, and are thinking of hurting or killing themselves, there’s the National Suicide Prevention Lifeline at 800-273-8255 or you can text “HOME” to the Crisis Text Line at 741741.
Collins: Before we close, I’d like to talk about how, despite the stress, the anxiety, and the grief that we’re all feeling, we might somehow learn something pretty significant about ourselves during this pandemic. Can you say something about that?
Gordon: One thing we know is that resilience isn’t necessarily about something you already have. It’s something that you learn, that people who’ve been through challenging times and risen to the occasion, they learn from that. They become resilient. They learn how to get through challenging situations in the future.
For many of us, this is an opportunity to learn more about ourselves and how we can grow as people, as human beings, and as fathers and mothers and daughters and sons. This is an opportunity to prove that we can respond to an emergency like this in a way that is thoughtful, in a way that is caring, and in a way that contributes to improving the situation for all of us
Collins: It does call us, doesn’t it, to focus on things that in our daily rush of business as usual, we neglect to think about. What are we really here for? What’s the meaning of all of this? What is our responsibility to try to make the world a better place?
I’d predict that all of us who are living through this COVID-19 experience will look back on it as a time of special significance in terms of what we learned about ourselves and about the perspective of what really matters in this world. So, yes, it’s stressful, it’s full of grief and sorrow, but maybe it’s a way in which you can gain something to carry forward. Josh, thank you so much.
The Disaster Distress Helpline, 1-800-985-5990 (Substance Abuse and Mental Health Services Administration)
Coping with Coronavirus: Managing Stress, Fear, and Anxiety, Director’s Messages (National Institute of Mental Health/NIH)
Stress and Coping, Coronavirus (Centers for Disease Control and Prevention)
Coronavirus (COVID-19) (NIH)