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Multisystem inflammatory syndrome in children (or MIS-C) is a serious complication of Covid-19 infection, usually showing up about a month after infection.

CDC worked with several hospitals around the U.S. to discern whether vaccination in adolescents would lessen the likelihood of this outcome. A vaccine hadn’t yet been approved, as it now is, for kids between 5 and 11).

The bottom line is that vaccination with BNT162b2 (colloquially known as Pfizer-BioNTech) proved over 90% effective in preventing MIS-C.

Listen in as we discuss the work with CDC’s Laura Zambrano. The interview runs about 15 minutes.

The article in MMWR (free)

TRANSCRIPT

Joe Elia:

Multisystem Inflammatory Syndrome in Children or MIS-C is a troubling complication of COVID-19 infection. Does vaccination lower the risk?

You’re listening to Clinical Conversations from the NEJM Group. I’m Joe Elia, and I’m here with a principal co-author of a paper in MMWR published last week.

Dr. Laura Zambrano, the senior epidemiologist in the [Multisystem Inflammatory Syndrome] unit, which is a part of CDC’s COVID-19 Emergency Response Task Force, is here with us. Welcome, Dr. Zambrano.

Dr. Laura Zambrano:

Well, thank you. And thank you so much for having me.

Joe Elia:

You’ve been busy there at the CDC, I’ll bet. What prompted this research into MIS-C and how did you go about doing it?

Dr. Laura Zambrano:

MIS-C, as you mentioned, stands for Multisystem Inflammatory Syndrome in Children. And we understand it to be a post-acute hyperinflammatory syndrome that generally occurs between two and six weeks after a child tests positive for SARS-CoV-2. And it is a severe syndrome. It is characterized by fever, systemic inflammation and affects multiple organs throughout the body with a combination of severe cardiac, respiratory, gastrointestinal, mucocutaneous, hematologic, neurologic, or renal complications.

MIS-C was first described among patients in the United Kingdom and then in New York City in the spring of 2020. And since then, it has been reported worldwide. And higher MIS-C incidence really closely follows peaks of reported SARS-CoV-2 circulation, and it’s really a function of the number of infections reported among children. As of last week, we have received over 6,400 reports of children with MIS-C meeting our CDC case definition. And given the occurrence and recent surge of COVID we are anticipating, unfortunately, that a wave of MIS-C will soon follow, so we have our eyes on that.

So, all that to say we understand that severe outcomes related to COVID-19 can, and absolutely do occur in children, and MIS-C is one of them. And this is an outcome we are clearly hoping to avoid in children. We already have many studies that broadly show high vaccine efficacy and effectiveness against SARS-CoV-2 infection and severe COVID disease, but real-world effectiveness against MIS-C is a little bit trickier to assess. For one, MIS-C generally occurs after infection and can follow infections in children that are generally milder or even asymptomatic. And we felt we needed to quantify the degree of protection inferred by a vaccination against MIS-C in addition to some of these other analyses that have examined severe COID-related outcomes.

Joe Elia:

You describe the work as a test-negative case-control design, so could you oversimplify that for me?

Dr. Laura Zambrano:

Sure, of course. In any case-control study we’re looking to enroll patients who have a specific syndrome or outcome. And then we’re interested in exploring on a broad basis what exposures may have led to that outcome. And here, of course, the exposure is vaccination, really the protection. You know the exposure here is not being vaccinated, right, and development of MIS-C. So, what a test-negative case-control analysis involves, generally this is a standard study design used for other vaccine effectiveness studies: we take patients with a specific outcome, in this case MIS-C, and we match them to hospitalized controls.

In this case, these were hospitalized controls who fit into two categories: they either had a respiratory or COVID-like illness and actually tested negative for COVID-19 in the hospital generally by RT-PCR or possibly antigen, generally RT-PCR; or they could be syndrome-negative completely. And so, these could be children who are hospitalized for any other number of reasons, you know, they could be hospitalized, for example, as a trauma victim, but of course without any COVID-related symptoms. And so, we essentially pooled those together ultimately in our analysis, but one thing to note is that the vast majority, of course, of our syndrome-negative patients also tested negative for SARS-CoV-2 upon hospital admission.

Joe Elia:

Okay. And the way that you collected these cases, Dr. Zambrano — you had people across the country contributing these records. Can you talk a little bit about that?

Dr. Laura Zambrano:

Oh, yeah. So, this actually goes into this longstanding relationship that the CDC has had with Boston Children’s Hospital. And Boston Children’s Hospital has led a hospital network, and this is led by Dr. Adrienne Randolph who is really our principal investigator there, and the purpose of the original network was really to examine the effects of severe influenza in children. But early on in the pandemic we leveraged this network to create the Overcoming COVID-19 Network to better understand the clinical course of children hospitalized with severe COVID-19 and MIS-C.

We’ve used this platform to collect detailed clinical information on children hospitalized at over 70 hospitals across the United States. And one of these activities includes examining vaccine effectiveness against both hospitalization and critical COVID-19 illness in children and adolescents, and of course assessing vaccine effectiveness against MIS-C. In this particular study, we had 24 of these network hospitals that participated.

Joe Elia:

I see. Now, in terms of numbers of patients. You had, roughly speaking, and I’m going to talk in rough numbers here, you had roughly 100 patients with MIS-C.

Dr. Laura Zambrano:

One hundred and two, yeah.

Joe Elia:

These were all adolescents between the ages of 12 and 18.

Dr. Laura Zambrano:

Yes.

Joe Elia:

And then you had another, roughly, 200 hospitalized adolescents who were matched by various criteria. All right. So, what did you find?

Dr. Laura Zambrano:

Sure, I think really we had three overarching key findings.

Number one, the key finding here, I think, overall is that COVID-19 vaccination is highly effective in preventing MIS-C in adolescents. And how effective? We estimate 91 percent effective.

Number two, among the MIS-C patients we enrolled, 95 percent of them — 95 percent — were unvaccinated.

And number three (and while I still think it might be a little too early to tell for sure just because of the sample sizes that we were working with) overall, unvaccinated MIS-C patients appear to have more severe disease. This is really illustrated by the fact that nearly 40 percent of them required life support: they required some combination of invasive mechanical ventilation, vasoactive infusions to treat shock, and ECMO. But in contrast, none of the vaccinated patients included in the study required these treatments.

Those, I think, are the three overarching findings.

Joe Elia:

So, if I were to choose just one finding I would say ”Wow, only five percent of the MIS-C patients were fully vaccinated!”

Dr. Laura Zambrano:

Yes. Yes.

And you know one thing, I think, that is remarkable is we’ve seen that statistic highlighted time and time again regardless of almost whatever severe outcome we are looking at related to COVID-19. That, really, the overwhelming majority of patients exhibiting severe outcomes are unvaccinated.

Joe Elia:

So, the vaccination even among those children who came down with the syndrome, in that small group, their syndromes were less severe, that none of them required life support, or ECMO. And so, it seems, and as you calculated, the vaccine was roughly 90 – 91 percent effective in preventing MIS-C in those adolescents.

Dr. Laura Zambrano:

Yeah. And of course of note too, you know, one thing that we did notice is that ICU admissions also, I mean of course the sample size is small, but still, ICU admissions appear to be lower as well among the MIS-C patients. And so, we’ve seen consistently in our surveillance cohorts, for example, that the proportion (and this is looking at vaccination before or data from before vaccinations were available) that adolescents. requiring ICU admission has consistently ranged between 61 and 66 percent.

And again in this analysis we see among the unvaccinated patients about 63 percent of MIS-C patients required ICU admission, but among the five vaccinated patients only one — or really 20 percent — required ICU-level care. So, it’s still very early data. I don’t, you know, want to overinterpret it, but I do think it’s a promising sign.

Joe Elia:

And speaking of small samples, because you only had, I think, 81 or 84 or something like that cases, does this surveillance, does this research continue? Is it ongoing?

Dr. Laura Zambrano:

Sure. So, we have 102 cases, but absolutely the enrollment is continuing. And we really wanted to get this data out as soon as we felt like we had a sufficient sample size to get a reasonably precise estimate of vaccine effectiveness. But we absolutely are continuing to enroll patients. And you know specifically, I think, our next steps really are to look at the next-youngest age group, those 5 to 11 years old, who of course vaccination was just recommended for them starting back in November. And we didn’t have sufficient time, of course, to include them in this round of the analysis, but you know we are enrolling more of the 12- to 18-year-olds and we are enrolling the 5- to 11- year-olds right now.

Joe Elia:

And all the children who were vaccinated had received the Pfizer-BNT vaccine because that was the one that was available and had been approved by the FDA.

Dr. Laura Zambrano:

Yes, absolutely. And you know we set an exclusion criterion ahead of time that you know if a child had received another vaccine for some odd reason, even if they weren’t approved to do so, we would exclude them, but we actually did not see that. These children that were within this analysis all received the Pfizer vaccine.

Joe Elia:

Okay. Is there a question you wish I had asked you that I did not?

Dr. Laura Zambrano:

That’s a great question. You know one thing that I do want to emphasize, and of course this doesn’t have to go into the podcast this is just more me floating this by you, but this 5 to 11 age group is actually really important to us. And so, I would actually love to expand upon that a little bit more, mainly because the 5 to 11 year olds really appear to be the age group that’s disproportionately affected by MIS-C. And so, I’d love to just kind of talk about that age group a little bit more and the implications in this analysis for younger kids.

Joe Elia:

Sure, go ahead. And you’ve given a good introduction to the question, so I won’t ask it formally. Go right ahead.

Dr. Laura Zambrano:

The fact that the study here was focused on adolescents was really a function of timing. So, of course, the Pfizer-BioNTech vaccine was recommended for teens in mid-May, so we had this really nice window of time from July to December to study vaccine effectiveness in this group. But one thing that’s of real concern to us is that MIS-C is actually more common in younger kids. So, for example, the next age group eligible for vaccination, these 5- to 11-year-olds, are disproportionately more affected by MIS-C compared to other age groups.

So, as of last week, you know, when we posted this to our CDC website — to the CDC COVID Data Tracker, we have actually an MIS-C module there and I could direct your listeners to that webpage — but as of last week these 5- to 11-year-olds comprised 46 percent of all cases reported to the CDC. The Pfizer-BioNTech vaccine was only recommended for this age group back in November, you know, well that’s really the reason we weren’t really able to include them in this analysis, but we are currently investigating vaccine effectiveness in this group.

And one thing I want to emphasize is even though we don’t have a vaccine effectiveness estimate for the 5- to 11-year-olds yet, I don’t think there’s any reason to believe that vaccinations wouldn’t also protect these kids from developing MIS-C. So, we really want to use these findings from this study to encourage all parents to get their kids vaccinated to protect against the worst outcomes of this virus.

Joe Elia:

Okay. Well, I want to thank you for your time today, Dr. Zambrano.

Dr. Laura Zambrano:

Thank you so much for having me. And, Joe, one question that I would love to…or I do have a couple of statements I would love to make and you could sort of paste this or append this earlier in the podcast or where you see fit. But the one, I think, plea that I have for the public or for pediatric care providers in particular is truly, I mean, aside from being a public health professional and a scientist, I’m also the mom of a 4-year-old little boy and he is the light of my life. And so, this issue is extremely personal for me, and from that perspective I really view it as our responsibility to protect our kids and then really empower parents and pediatric providers with the information that will help them protect theirs.

Joe Elia:

Okay. I should emphasize that Dr. Zambrano’s views are her own and not necessarily those of the Centers for Disease Control and Prevention. That was our 280th Clinical Conversation. We come to you from the NEJM Group and the writers and editors of NEJM Journal Watch. Kristin Kelley is our executive producer, and I’m Joe Elia. Thank you for listening.