Hello, I'm Adrienne Randolph, and thank you for inviting me to give an update on acute COVID-19 and multisystem inflammatory syndrome in children. I am going to put up my slides here, and I will be giving an update, and I have no major disclosures. I will be talking really about a critical care perspective, since this is a PED-CCM review course, and although a lot of some MIS-C and a lot of COVID-19 is on the ward or outpatient, I'm going to talk quite a bit about MIS-C, the initial emergence and diagnostic criteria, how to distinguish MIS-C from acute COVID. We'll talk a bit about current management recommendations and practice, neurologic involvement, and then vaccine effectiveness, and then lessons learned for the next pandemic. So in early 2020, COVID-19 complications were milder in children until MIS-C emerged. First in Bergamo, Italy, there was an outbreak of 19, then 10 cases of a severe Kawasaki-like disease with higher shock and macrophage activation syndrome-like features. Then in London, UK, these were in places where COVID was peaking at the time, and it emerged weeks later, and both of these were published in Lancet in May, and then as COVID moved over to New York State, it emerged there. There was a total of only about 38 cases reported initially, but public health alerts were sent to clinicians in the UK and in New York State to look out for this. There was a lot of Kawasaki disease features in these patients, and they were wondering, is this Kawasaki disease, just these are the criteria for those people needing to remember. And then May 2020, there was an official worldwide alert. In Europe, the European Center for Disease Control called it PIMS-TS, or Pediatric Inflammatory Multisystem Syndrome, temporally associated with SARS-CoV-2. And then in the US, the CDC and the World Health Organization both called it MIS-C, or Multisystem Inflammatory Syndrome in children. There were some differences in the definitions between the CDC and the World Health Organization. One was age. The CDC went up to age 20, whereas the WHO went up to age 19. The WHO definition required fever for at least three days, where just one day of fever, even tactile fever, counted for the CDC definition. There was a lot of other different types of inflammation that were allowed for the CDC definition. However, both where the WHO was more restrictive, and the WHO was more restrictive in what kind of organ system involvement. It had to be cardiovascular, or rash, or coagulopathy, or GI, where the CDC allowed respiratory renal neurologic. And the CDC restricted the hospitalized patients. This is important because respiratory is where the biggest overlap with acute COVID. And acute COVID can lead to multisystem involvement in very severe, critically ill cases. So both definitions, however, had to have evidence of SARS-CoV-2 infection. Some of it could be historic with just exposure to an individual who was positive, especially before antibodies became available widely. And then no alternative microbial cause of infection, or other cause of infection. So MIS-C really differed from acute COVID. In the first wave, there was a JAMA-Peds article that described critically ill cases across the U.S. and Canada, really showing a lot of comorbid conditions. Critical illness was uncommon, they were intubated for hypoxic failure when they did become critically ill, and had upper respiratory symptoms, whereas MIS-C was mostly previously healthy children, a lot of GI symptoms, fever, shock, Kawasaki signs, they were really mostly in the ICU for shock. And it emerged about three to four weeks after the peak of COVID in an area. This is in the Massachusetts area. So we got funded, the POLICI Network, which is the Pediatric Acute Lung Injury and Substance Investigators, which has over 80 U.S. sites and Canadian sites, and a lot of international affiliations, to try to understand what was going on with COVID in children, including MIS-C. Initially in year one, we were funded to enroll 2,000 patients in a registry and 400 patients in an immunobiology study. And then in year two, we got another 2,000 patients, another 400 patients. And in year two, we also did a study of risk factors and outcomes of MIS-C, as well as looking at COVID-19 vaccine effectiveness. Both of these were public health investigations for five to 18 years, and then less than six months looking at maternal vaccination for acute COVID. The one thing that was really important here is that we had this pandemic surveillance protocol that we had been using for a long time and waiting for a pandemic to come. We, of course, thought this was going to be an influenza pandemic, because most of our prior studies had been on influenza. And we maintained this since 2013. And it allowed us to implement this registry really quickly, because we already had case report forms, a REDCap data set, IRB approvals, and a network. We had to modify them for COVID and MIS-C. And for the immunobiology study, we already were doing a flu vaccine effectiveness study, and so we added it to it. We already had a single IRB, and we expanded it. So we were able to initiate these studies super rapidly. And one thing that's really important to understand is the difference in a pandemic between public health surveillance and research. So public health surveillance, you don't need to get consent, informed consent, written informed consent. You're doing it because it's a public health authority has deemed it a public health surveillance activity. It's very limited in scope to answering whatever is needed to answer the question at hand. In this case, the question was, how is COVID affecting children? What are the understanding the severe complications related to SARS-CoV-2? We were able to very rapidly submit a paper to the New England Journal on Multisystem Inflammatory Syndrome. I'm going to go over what those findings were and how they may have changed over time. It was published in late June. And we reported 186 MIS-C cases across 26 U.S. states. It had come peaking mainly in the area where COVID started to go across the United States in the early pandemic. And we, as others had shown, that there was a lag in the MIS-C cases emerging by about three to four weeks from the positive COVID-19 test peaking in those same regions that we were doing surveillance at. At the same time, a New York State investigation used very similar methods and republished 99 cases in the same issue of New England Journal. And so across the two, there was 300 cases. And our findings were very, very similar. All the cases met five criteria. They were hospitalized under 21, fever for at least a day, laboratory evidence of inflammation, at least two organs involved, evidence of SARS-CoV-2. And there was a predominance of Hispanic, Latino, and Black children in our cohort, as was found in other areas of the world where they were starting to report this. It was overrepresented in minority populations. There was a predominance of males, which was consistent across all countries. These have remained consistent across the pandemic in year two as well. And there was a peak age group of middle childhood, about 5 to 12, and that's remained the same. There was also a very common impact on the cardiovascular system. Overall, this first series that we reported was maybe a little bit more than now. It's gone down a bit, but at least 40% now have impaired ejection fraction, or another 40 to 50% would be on vasopressor or vasoactive infusion support. Arrhythmias are common, both rady and tachyarrhythmias, and about 8 to 10% consistently have aneurysms, coronary artery aneurysms, which is a Z-score in the left anterior descending or right coronary of at least 2.5. A dilation would be 2.0 to less than 2.5. But we were just focused on aneurysms. It's important when reading reports to know whether they're actually talking about dilations or aneurysms and what their cutoff is. Other organ systems, you know, it's a multi-system problem, so other organ systems were also involved. GI was the most common in EGI involvement, mostly abdominal pain, nausea, vomiting, diarrhea. Hematologic was the next most common, along with mucocutaneous. And then respiratory was actually pretty common, but infiltrates on chest X-rays seemed to be higher in the older patients. That's important to note because that's where it appears that there may be an overlap with severe acute COVID-19 and importance to distinguish between the two versus a post-infectious syndrome. And musculoskeletal complaints as well were common, but neurologic and renal were relatively uncommon. Now, one thing that's important to understand is whether or not this is how much overlap is there really with Kawasaki disease. And we found this early in the pandemic and it's been fairly consistent that Kawasaki disease meeting all criteria, four to five KD features, what is fairly common, but in about 20 percent, or meeting partial criteria for Kawasaki disease where you have two to three features, but also labs. And then you still get the patient still gets the diagnosis. So about 40 percent met criteria. That's been fairly consistent. And it's also been a bit younger patients meeting all the KD criteria. And although the CDC criteria, which we were using to diagnose these patients with MIS-C only required the fever for one day, most of these patients had been febrile for three days or more of the ones that we enrolled. There was a lot of oral mucosal changes and rashes. But, you know, the aneurysms, which is what the big concern about Kawasaki's disease is, is about aneurysms, which is why people treat them with these anti-inflammatories. It was in all categories of patients and some of them with the atypical or incomplete KD, maybe a little bit more. And people were treating it like KD. Most of these patients got intravenous immune globulin. That's important. There was a shortage at the time internationally. And these are bigger patients. They were getting two grams per kilo. They often got a second dose. Half of these patients got steroids and then other anti-inflammatories. Now, IVIG is more like 90 percent. Systemic steroids is now, and I'll show you some data later on, even more common. And in some places, it's the first line treatment. About half of these patients, due to the risk of thrombosis, got systemic anticoagulation. Most of these patients were admitted to the ICU and more commonly for vasoactive support. But most survived, fortunately. And when we did this report, a lot of the patients were still hospitalized. But across reports, mortality in MIS-C has been less than two percent internationally. For most countries. And length of hospitalization has been relatively brief, with about a week for most on average, with some going on to ECMO, having complications and taking longer to recover. Now, although there's an overlap with Kawasaki disease, you know, Kawasaki disease is very different in many ways. The age category is usually less than five years, where this is six to 12 is the peak age. And almost none of these patients are under a year of age, it's uncommon. They're less ill, most are admitted to the ward for Kawasaki disease and Kawasaki shock is very uncommon. Where shock in MIS-C is very common. As I mentioned, almost 40 to 50 percent had shock. MIS-C appears to have much higher degree of cytokine storm. Higher D-dimers, ferritin, troponin, BNP. So cardiac markers and coagulation markers, inflammatory markers, lower platelets, more thrombocytopenia instead of thrombophilia. Lower absolute lymphocyte count. And but, you know, patients with Kawasaki disease who have two or more organs involved would meet criteria for MIS-C, according to the CDC definition, there is a footnote there. If they meet, you know, some of these patients with MIS-C may meet KD criteria. There seems to be commonly a move now that if they meet KD criteria, they're getting just the KD diagnosis. But it is part of the MIS-C diagnosis currently. And, you know, over 2021, this has been consistent, as I've been mentioning, the same age group predominance in that middle childhood. The same, you know, disproportionate representation in Black, non-Hispanic and Hispanic patients. Few cases were reported in Asia, even though KD is really the peaks in the Asian community of any population. And it's very common in China and other parts of Asia. Cardiovascular involvement continues to be about 40 percent with vasopressors, ICU admission, most of the patients. And coronary artery aneurysms across studies are frequent, but most are transient and gone quickly. This was a paper we did comparing acute COVID to MIS-C, 539 with MIS-C to 577 with acute COVID. And what we found is comparing the two groups, there was age difference. The youngest ones, especially under a year and the teenagers, were more likely to be severe acute COVID. The middle childhood MIS-C, compared to white, non-Hispanic children and adolescents, Black, non-Hispanic appeared to be at higher risk. And predominantly it was previously healthy children where acute COVID, most of those patients, 70 percent had underlying conditions, a lot of them respiratory neurologic, whereas only 30 percent had underlying conditions with MIS-C. And a lot of it was asthma in the underlying conditions. The cardiovascular system was more commonly involved where it was respiratory without cardiovascular system. And the MIS-C was much more inflamed, a higher neutrophil to lymphocyte ratio. So they had neutrophil, lymphocytopenia, and it was more extreme than in acute COVID. So we reviewed over 1,200 echocardiogram reports from this surveillance registry with two pediatric cardiologists. And as I mentioned, about 40 percent of these have impaired left ventricular ejection fraction. But most of this resolved really quickly, 75 percent within three to eight days. Now, all of these patients were mostly treated with anti-inflammatories. As I mentioned, IVIG plus minus steroids, which are treatments for Kawasaki disease. And only nine percent had coronary artery aneurysms and almost all resolved by hospital discharge. So these we thought were more potentially, we hypothesized, dilations than a true vasculitis. Maybe due to the severe inflammation, those were more transient dilations. Where in Kawasaki disease, this is a long lasting condition with vasculitis. Now, there's follow up studies through the Pediatric Heart Network and others internationally trying to look at this over time to make sure this is true. But, you know, the reason we're treating these patients in part is because with the IVIG and steroids is in part because we're concerned about those aneurysms and the effect long term on the heart. That's the main reason. So we took all of the data that we had. And this citation I have with the page numbers is for the overcoming COVID-19 study, but the BAT study was published in the same edition. It has different page numbers though. And we compared IVIG plus glucocorticoids where you say, okay, treatment on day zero, that's the first day a patient got treatment after hospitalization. We compared IVIG plus glucocorticoids to IVIG alone. And we found that our outcome was resolution of cardiovascular dysfunction by day two or more of treatment. And we found that it resolved quicker and they were less likely to use adjunctive therapies. Where BAT study, which was international, compared IVIG plus glucocorticoids or glucocorticoids alone. Now, our cohort had 518 patients, all U.S. It was March through October, 2020. So it wasn't the Delta predominant period. This was all earlier in the pandemic. You know, standard age, previously healthy, low mortality, predominance of male, 5% of underrepresented minorities. And there, but our patient population was very sick. Over half had five or more organ systems involved. Most were in the ICU. Almost half needed vasopressors and 40% had a low left ventricular ejection fraction. About 40% again, incomplete or complete Kawasaki criteria. BATS was an international cohort and a very important study, including countries with very limited resources. They were overall, however, less likely to be critically ill with about 12% on vasopressors and 1.5% on mechanical ventilation. And the WHO definition was used for BATS and they don't require the patients to be hospitalized, but most of their patients were hospitalized. So treatment did change over time. Most patients received IVIG, some getting a second infusion of IVIG. Now remember, IVIG takes about 12 hours to infuse. You can't just push it in. And more patients over time started receiving IVIG plus glucocorticoids. And usually that was a rescue treatment added when patients failed to improve. Some patients received these biologics, Anakinra, Infliximab, and then Tadorset and Tocilizumab. Usually they were used as a rescue therapy many days later, not as a first line therapy. But sometimes glucocorticoids were used as a first line. We had to exclude those because it wasn't commonly used. And often it appeared that those patients could be acute COVID-19 patients because they're PCR positive with a lot of respiratory disease. Now, why didn't we do a randomized trial in either of these investigations? Well, it was very hard to design and conduct a randomized trial quickly with this relatively rare presentation, where it was moving around following the peak of COVID-19 in a community where it would come and go. And sicker patients usually got more treatments initially and over time, and were treated more aggressively. So what we did do is a propensity matching where we controlled for the disease severity. We assessed the treatments over time. We basically used these two types of propensity score matching, controlled for a lot of different factors that could potentially influence the outcome. And in the end, we only came down to 103 patients whose initial treatment on day zero was IVIG alone versus 103 patients with initial treatment on day zero, IVIG plus steroids. And so then we were able to match for a disease severity. We couldn't look at these other things alone because we didn't have the numbers to do so. And our primary outcome was cardiovascular dysfunction. That's different than the BATS outcome where it was a death or mechanical ventilation or vasopressor use. But ours was really focused on the heart because that's why you give these treatments. And we basically found that on day two or more after initial treatment, it was more likely if you gave upfront to the sicker patients IVIG plus glucocorticoids, you would have more rapid improvement versus IVIG alone. This was similar to a study from France that also showed more rapid improvement that was published in JAMA prior to our study, it was smaller. And we also found much less use of later rescue therapy. The most common later treatment used in those initially treated with IVIG was steroids. So most of these patients later would get steroids added onto it, 70% would then later get steroids usually. So sparing them upfront did save in some cases, but not many. So interpreting these disparate findings, the US cohort, it was very different because ours was all really referral centers. These were larger PICUs, they were referral centers for communities. And in some places, the only major ICU in the state with similar availability of ICU care and treatments where that was international, it was harder in some of these places to obtain IVIG. We had in part, maybe because we were a critical care referral network, the most sick patients in ours and used a cardiovascular outcome where they had less critically ill patients and included just a composite outcome. But both of these studies are really, really important because for many of these countries, IVIG is not an option. And steroids is an option to be used alone. And what we found is that in the most sick patients, giving both upfront will hasten cardiovascular recovery. But most of these patients did recover over time if just given IVIG alone. And the word is still not out on whether it prevented long-term heart effects by treating aggressively upfront, but because people are still doing those follow-up studies. Now, how common is MIS-C? In 2020, we did a estimated incident study. And we, across the US, and we basically had to find areas where we knew the risk of getting SARS-CoV-2 in certain age groups. And we knew the frequency of MIS-C and then do this calculation. And we found about three per 10,000 SARS-CoV-2 infected persons. We're redoing this now in the era of vaccination and a lot of people already being previously infected to see if this has gone down. And we're redoing this in 2021. And in areas where vaccination has occurred, there is a letter to the editor in JAMA showing that the incidence of MIS-C went down in France after vaccination in that country. MIS-C is less common in infants. And the presentation in them is often Kawasaki-like, and it's less severe. And the risk in the first year of life is extremely uncommon, as I said, but severe COVID is common in infants, which is surprising. We published this in Pediatric Infectious Disease Journal. The two peak age groups with the more severe cases or in hospitalizations in our cohort was these infants. And then the teenagers were the most common in numbers. So in these age groups, they really didn't include in these trials. We had a viewpoint early on in the pandemic. There was 275 trials and only 30 were open to children less than 18. Most were 16. Only a couple went to age 12. Then we didn't have dosing data. Although severe disease was infrequent in children at these referral centers, there was many hundreds of cases. And we published this in Pediatric Journal of Pediatric Infectious Disease Society in January that we basically were copying in the ICUs in the US exactly what was recommended at the time for adults. So early in the pandemic, even infants got hydroxychloroquine when they had COVID-19 admitted to the ICU or step-down unit. Later on in the pandemic, remdesivir was prescribed. There really was no data, but by the towards overall in this report, it was in the year 2022. The frequency of using these treatments was about 67% got remdesivir in the ICU. It was targeted at more severely ill patients. And the use of therapies really copied what was in adults. Now, why couldn't we include, would it have made sense to include these patients in the adult trials? Well, the patients here, the teenagers, you know, the mortality and even the invasive mechanical ventilation was much less than what was reported in the elderly for sure. And the overall duration of hospitalization was relatively brief because the green here mean, the gray here means they're discharged. So, you know, picking off the sickest patients would however have made sense to enroll across intensive care units because some of these patients were on the ward in our registry. However, in the under one year of age, it doesn't necessarily make sense to necessarily include them in the, you know, older trials. Very few were intubated and they probably need their own studies of how best to treat them. Another big concern here is that the neurologic involvement that we were seeing in patients with acute COVID or MIS-C, this was, we reported this in GEM and neurology and there was a lot of images which are copyrighted that I can't show in this slide show, but it basically shows that, you know, most of this, it was common to have neurologic involvement, but most of it was transient. Like they came in, they had altered mental status, they were very agitated, delirious, they had seizures, inability to walk or crawl, that they had lost a milestone. However, 43 of these patients, 12% actually had severe life-threatening neurologic disorders. We had these neurologists and neurocritical care experts adjudicate all these cases with the ICU attendings. And we found a lot of different range of complications, encephalitis, encephalopathy, cerebral venous sinus thrombosis, stroke, both ischemic and hemorrhagic, acute fulminant cerebral edema with four deaths, Guillain-Barre, and, you know, these patients with the severe complications had a lot of sequelae with many of over a quarter dying and 40% surviving with new neurologic severe sequelae. But fortunately, overall neurologic involvement was, although common, it was mostly transient, but these severe cases did occur. So what is important here is that, you know, severe cases of COVID-19 do occur in infants, children, and adolescents, and how do we prevent them? And, you know, how do we do studies when we couldn't really do a randomized trial in this population, because it would take many hundreds of thousands of patients to get enough with severe complications. So we, you know, if it's a rare or infrequent event, a case control design makes the most sense. And so there are these test negative case control designs that have been used for influenza and other vaccine effectiveness studies for many, many years. And in babies, we can also look at maternal vaccination and passive transfer of antibodies at birth. And so we published early, our first publication was this MMWR where we looked at the teenagers because they were eligible for vaccine first. And so we were able to look at the effectiveness of vaccination and found, and this was mostly, a lot of this was Delta because it was June through September, 2021, 464 patients, 97% were unvaccinated despite the fact that it was available vaccine uptake in the adolescent population was low. And none of, although some of these were vaccinated, none of the vaccinated ones were admitted to the ICU. And this was updated recently, we published February 24th. We then had 445 cases of severe acute COVID-19, 775 controls, and we confirmed this finding for the Delta variant effectiveness against life-threatening illness was 98%. And we also confirmed that it was, yeah, so that was for the teenagers. And then we also in MMWR early on looked at MIS-C in the teenagers, the 12 to 18 year olds. And we found 91%, this was also during Delta, mostly Delta because Omicron didn't come in really until December, and 95% were unvaccinated. And none of the vaccinated MIS-C patients required vasopressors or other life support. We also published in MMWR that when we looked at, we got the, we looked at all the infants who were hospitalized and we got the mother's vaccine history and found about 60% reduction in risk of COVID-19 in the VE study, looking at the pregnant women. Now we've expanded this now and it's ongoing and we have enrolled over 500 infants now. So we recently published March 30th in New England Journal an update on including Omicron. And we also included the five to 11 year olds. Now they were really only eligible for vaccine in November. And then by the earliest they could get two vaccines and be considered fully vaccinated would be December. And we found durability of protection in the 12 to 18 year olds that even 23 to 44 weeks after the second dose, it's still protected against Delta. But during Omicron, the overall protection went down against hospitalization, but it was still 80% against critical illness. It didn't prevent infection, but it did prevent critical illness. Even these patients who were mostly vaccinated much earlier on. And for five to 11 year olds, who really was all pretty much Omicron and vaccinated more recently with 34 days since their full vaccination, it was about 68% effective with of course a confidence limit but for influenza, you would be very happy with 68% vaccine effectiveness estimates for influenza vaccine. So I just wanted to make a point about what we need to learn as well for the next pandemic, which will come and it probably will be influenza given that we haven't had influenza for many years now, much influenza during the pandemic and our immunity to it has waned from natural infection and vaccination rates are very low. And we also don't know how to match to whatever strains are going to come out since it hasn't been circulating as much internationally. So we really need to be prepared to collect data because it can be very useful in informing us what is going on with children. These large patient registries can be highly informative. What are the phenotypes and outcomes, understanding these rare complications, miss seeing neurologic involvement, how do these differ across states, being able to compare to other countries and regions, understanding what populations are being most affected and what treatments are being used, even though we may not be able to quickly throw together a randomized trial unless we have, and also our numbers may not be sufficient. We can do these registries, we can use propensity matching, but we should be ready to do a randomized trial if it is influenza, which really does heavily affect children. The adults in the adult populations, they were able to rapidly put together these randomized trials, and we really need to do that as well and be prepared. Case control designs are very essential for understanding vaccine effectiveness and will be needed in the future as well. We also do an immunobiology study. We've enrolled over 800 patients, but these answers come slower. It's tedious, it takes time, and many of the early findings have not been replicated. But it's very important to be able to collect samples so that we understand the disease and understand it for the next pandemic. So I just wanted to thank all of my collaborators at the Center for Disease Control and Prevention, my core team, including my manager of all my projects and my other collaborators, as well as all the site clinicians in the Polisi Network and all of the coordinators and my collaborators at the FDA. Thank you very much for your attention, and I look forward to taking your questions at a later time. Thank you.

MIS-C

acute COVID-19

Dr. Adrienne Randolph

vaccine effectiveness

intravenous immune globulin

neurologic involvement

cardiovascular dysfunction

pandemic preparedness