March 25, 2022
Like Zoom birthdays and designer masks, multi-system inflammatory syndrome in children (MIS-C) is a unique product of the COVID-19 pandemic. Appearing about 4 weeks after COVID-19 infection has cleared, it likely represents a disordered immune response that can cause appendicitis-like GI symptoms, Kawasaki-like skin findings, and most alarmingly, cardiac dysfunction and pump failure. Recognizing MIS-C’s presentation and having a diagnostic approach in mind will be increasingly important for pediatricians as we enter Omicron’s afterglow. Today’s episode will aim to cover that territory through a case-based presentation in addition to other typical disease processes on the differential.
Dr. Angela Kade Goepferd: This is Talking Pediatrics, a clinical podcast by Children’s Minnesota, home to the Kid Experts, where the complex is our every day. Each week, we bring you intriguing stories and relevant pediatric healthcare information as we partner with you in the care of your patients. Our guests, data, ideas, and practical tips will surprise, challenge, and perhaps change how you care for kids.
Welcome to Talking Pediatrics. I’m your host, Dr. Angela Kade Goepferd. The COVID-19 pandemic has changed the landscape of pediatrics in so many ways. For the kids that we take care of, they now can’t remember a life before masks. They have learned to do schoolwork and socializing over Zoom, and they now know the meaning of the word quarantine having experienced it multiple times over the last two years. It’s also changed the way that we practice pediatrics. And perhaps one of the most profound ways is the introduction of MIS-C, a new syndrome associated with COVID-19 infection. On this episode of Crack The Case with Bryan Fate, Dr. Fate will dive into an MIS-C case and teach us more about diagnostic approach as we enter a new era of post-COVID care.
Dr. Bryan Fate: Welcome to Crack The Case where we dive into real cases seen in our Minneapolis continuity clinic to highlight medical decision making, approaches to general pediatrics topics, and life in primary care. We’ll also incorporate music written by myself and friends at the end of every episode to highlight teaching points and hopefully engage the emotive side of your brain. Greetings from a spring lake Minneapolis. I’m Dr. Bryan fate, a primary care pediatrician at Children’s Minneapolis. And with me today, another one of our outstanding University of Minnesota pediatric residents, Dr. Katelyn Baier. So to start off, we do a little Crack The Case icebreaker. On your last shift of residency after three years of very little sleep, grueling hours, unrivaled, intellectual and emotional intensity, what song is playing as you walk out the doors?
Dr. Katelyn Baier: Well, thank you so much for having the today. This is a really tough question. I think the song I would choose is less of a celebratory song, but more of a song that has kind of been a support for me during med school and residency. I have always loved Billy Joel and the song Vienna has always been one of my favorite songs of his and has been a song I’ve gotten to kind of when I just needed a little bit of a pick me up. So I think that would be the song I would listen to.
Dr. Bryan Fate: Billy Joel is a excellent choice. We can talk more about that after the episode, Dr. Baier. Let’s start the case.
Dr. Bryan Fate: Like Zoom birthdays and designer masks, multisystem inflammatory syndrome in children, or MIS-C is a unique product of the COVID-19 pandemic. Appearing about four weeks after COVID-19 infection has occurred, it represents a disordered immune response that can cause a variety of symptoms, lots of GI, distress, Kawasaki-like skin findings, and most alarmingly cardiac dysfunction and pump failure. Recognizing MIS-C’s presentation and having a diagnostic approach in mind will be increasingly important for pediatricians as we enter Omicron’s afterglow. Today’s episode will aim to cover that territory in addition to other typical disease processes on the differential.
Dr. Katelyn Baier: Patient is a five-year-old male who presented to clinic with a history of three days of fever, diarrhea, and vomiting. His parents report he was having non-bloody diarrhea up to 10 to 12 times a day. He was also having non-bloody, non-bilious emesis two to three times per day over the last three days. He had decreased PO intake and somewhat decreased urine output from what parents had noticed. His parents also said that his fever had gotten as high as 104 degrees. He had been complaining of fatigue, a headache, and parents had also noticed that his cheeks seemed more flushed than usual.
Prior to the current infection, the patient was in his usual state of health, and he didn’t have any cough or cold symptoms. He had been seen in a viral screening clinic just two days prior, at which time he had a negative COVID test. The provider at that time had also gotten a CBC, ferritin, and a reticulocyte count actually just due to concern for acute on chronic fatigue that parents had noticed over the last few months. Those labs at the time were completely normal. So the CBC, ferritin, and reticulocyte count were all normal. So those are the symptoms that he presented to our clinic with.
Other things of note about this patient, he was a previously healthy kiddo. His past medical history was completely unremarkable. He was growing well, developing appropriately. He was not taking any medications. He did not have any known drug allergies or seasonal allergies that parents knew about. Family history was remarkable for latent TB in his mom.
Dr. Bryan Fate: To just jump into a bit of a framework for MIS-C. I think there’s two main components that we’re thinking about. And the first is proximity to a recent COVID-19 infection. And we have a couple tools for that such as serology and PCR. So obtaining a detailed COVID history and exposure story is key. Part two is the inflammatory piece. There is a very wide spectrum of how MIS-C can present. Number one is fever. You can’t have it without fever, which is essential to this diagnosis. We’ll talk about the range of different other symptoms that can occur. But just pointing out that this is a distinctive process from the acute COVID infection, this is a body wide multi-system inflammatory response in which our body is likely confused and does not actually indicate damage from the virus and the initial infection itself.
So with the inflammatory piece, we need fever and the other symptoms can be broad, but as we talked about, need to hit on at least two systems to help navigate this, which can be a challenging diagnosis given how widely variable it can present. We do have an excellent pathway and guide at Children’s here that’s available to all pediatricians. Dr. Hester has actually done a couple podcasts before on this topic. So I encourage people reaching out and seeing what those guidelines are, because this is something that can be worked out in an outpatient setting.
In terms of symptoms, so number one is GI complaints. So a lot of kids have abdominal pain, diarrhea, vomiting. At times, it can present almost like appendicitis and they’ll get ultrasounds to rule out an acute abdomen. So that’s actually the most common. Number two in terms of more classic presentations are these Kawasaki-like mucocutaneous findings, including rash, strawberry tongue, lymphadenopathy, peeling hands and feet, the whole Kawasaki that we know and have been trying to explain for some time. Initially we thought this was actually just another manifestation of Kawasaki disease, but as we’ve studied it more, we know that this is a distinctive process in its own right. And then the rest of the laundry list of symptoms is broad and can include headaches, sore throat, and frequently cardiac involvement, which we’ll discuss.
So returning to your patient, Dr. Baier, we have the fever, we have the GI symptoms. We’re not quite as sure about a COVID history. So we should definitely dig more into that. And then we do have these headaches. So we do have at least two systems involved with headaches and GI, and more uncommon manifestations of MIS-C can include almost like a meningitis or encephalitis picture where you have confusion, headache, poor energy, potentially a true altered mental status. And then I think we really need to look at cardiac, physical exam, and vital signs too, because the heart is very frequently involved in MIS-C. So getting a blood pressure and a heart rate in particular systolic function can be decreased, which can lead to tachycardia in almost a sepsis-like shock picture. So getting full vital signs is going to be really key. So framing this patient in that context of MIS-C, what other things were you thinking at the time, Dr. Baier?
Dr. Katelyn Baier: Patient’s vital signs are as follows. So his blood pressure was 117/57. His heart rate was 132. His temp was 40 degrees Celsius. Respiratory rate was 20 and he was satting 98% on room air. So the things I was thinking about were high on my list of differentials. While this patient didn’t have a known history of acute COVID infection or a family history of known acute COVID infection, I think in the setting of our global pandemic, I think we have to be thinking about MIS-C whenever a patient comes in with these sorts of symptoms.
He did have three days of pretty high fever. So we always do think about Kawasaki. He didn’t have any skin findings. Parents hadn’t noted a rash and didn’t have any swelling of his tongue or red tongue that parents had noticed either. Still important to have that on your list that when you’re thinking of a differential. With the frequent diarrhea and GI symptoms, of course viral gastroenteritis can be part of that picture as well. You can definitely think about appendicitis. That would fit with the symptoms that our patient was having. Those were kind of the big things that I was thinking right off of the bat for him.
Dr. Bryan Fate: So it’s important to point out that there’s a lot of overlap between other very common diagnoses we see in gen peds like gastroenteritis. Hand, foot, and mouth would technically involve two symptoms with the rash and GI components. Strep though this patient does have diarrhea, which is a little less common with strep, but still possible. And then also on our differential is the more uncommon bucket of widespread inflammatory diseases. And our labs will help guide this differential a little bit more too, but things like toxic shock syndrome where we have that staph exotoxin circulating and can present in a shock-like state. So hypotensive, tachycardic, can have that sunburn like rash, things like HLH and other widespread cytokine inflammatory disorders. So overlap with other widespread inflammatory disorders like HLH, MAS.
And the history and physical can help guide this process per usual, as well as the lab work if that’s the route we decide to go. And I think how the patient looks and particularly their proximity to COVID again is going to be a very important piece in discerning whether it’s MIS-C and whether there’s that essentially gap between that acute infection. So you mentioned no skin findings, Dr. Baier. Anything else you want to point out on exam or vitals?
Dr. Katelyn Baier: Yes. For physical exam findings, let me jump into those more in depth. So the patient overall was well-appearing. He didn’t appear to be in significant distress. However, he did appear pretty dehydrated. He had delayed cap refill as I noted on the vital. He was tachycardic and he did have dry mucus membranes. As far as our skin exam, he didn’t have any rash noted or any lower extremity swelling or anything like that. His abdominal exam was actually relatively unremarkable, which I think is surprising. He didn’t have any tenderness to palpation whatsoever. And I think it’s an important distinguishing factor when we’re thinking about our differential. Really the most prominent thing on our exam was the dehydration. But everything else on his physical exam was normal.
Dr. Bryan Fate: Yeah. So reviewing, he does have tachycardia which can occur out of proximity to fever with kids presenting with MIS-C given that pump failure status. So that’s a little bit more concerning to me though. We do know he looks fluid depleted, so it could be compensatory response of that. So we have to address his fluid status. And then I think neuro status is also important with the headache. Just making sure that he doesn’t have any neck stiffness, altered mental status that your cranial nerve exam is normal in terms of things like meningitis, encephalitis. And then you did an excellent job of describing as abdominals exam, which does not appear to be concerning for an acute abdomen that would require further imaging right now.
So to summarize, we have a five year old previously healthy kiddo with three days of fever, vomiting, diarrhea that most acutely is tachycardic and behind on our fluid status per our exam. He’s also had headache, flushed cheeks, fatigue. So in terms of what we need to do now, I think his cardiac exam and his status with fluids is most pressing. And in terms of framework for MIS-C, he does have fever, which we said is got to have fever. And then we checked off two system boxes with his GI symptoms and headaches. We do need to delve more into his COVID exposure history from this framework. And in terms of the differential, like we said, this can be challenging because there’s a lot of overlap between things like viral gastroenteritis, the flu, EBV, adenovirus. Bacterial colitis could be considered if he had bloody stool. So this can be a very challenging diagnosis given how variably it can present. So it sounds like the biggest issue right now to address is fluid status in addition to pursuing more diagnostic steps. What did you decide to do next, Dr. Baier?
Dr. Katelyn Baier: So we did get some labs and I can report kind of what the results were here, but we did a pretty thorough lab workup for this kiddo. And we followed initially the tier one MIS-C labs. So we of course got a CBC, which was remarkable for some thrombocytopenia. His platelet count was 144 and then lymphopenia as well. We got a BMP, which was just remarkable for some hyponatremia. His sodium was 134, otherwise within normal limits. We also got a Quant Gold, which doesn’t of course fit into our typical MIS-C labs. But mom did have latent TB. That diagnosis doesn’t necessarily fit very well with what our patient is experiencing. We felt it was important to kind of check that off the list and make sure we were being thorough with that.
We did get a COVID antibody because this patient’s history of COVID was not slam dunk. We didn’t have a story where family had had a COVID infection a couple weeks ago. So we were curious to see because of course that is a huge factor in our diagnosing MIS-C, and his COVID antibodies were reactive. So it did look like he had had a prior COVID infection. And then our Quant Gold did come back negative, which was reassuring.
Dr. Bryan Fate: So assessing those first tier labs, the COVID PCR and serology were done, and the serology was positive, documenting a timeline of COVID infection. So some evidence of previous COVID infection, and then the CBC demonstrated thrombocytopenia. So platelets were low. Elevated CRP and ESR, which again is indicative of this widespread inflammatory response. Things are burning hot in many different places. So there are some somewhat unique findings, more typical for MIS-C that we can help tease apart from other competing diagnoses. Other things to talk about include lymphopenia, so lymphocyte count less than a thousand. Thrombocytopenia was already discussed. Hyponatremia. So low sodium, less than 135, which this case exhibited neutrophilia. So ANC more than 7,700 and then an albumin less than 3. So we do have this fever, two systems, this serology indicative of some link to COVID, and a few of these different lab factors.
In terms of our next steps, there are second tier labs if our index of suspicion is high enough. That can be done in the ED or inpatient. From an outpatient perspective, I think the first tier labs are something that can be done out in the community and are points that we’re mostly familiar with out there for general pediatricians, including again, one that evidence of previous COVID exposure with the PCR and the serology, and then additionally, CBC, a complete metabolic panel, ESR and CRP. And there are, once again, guidelines for interpreting those to see if we need to get to tier two. But it does sound like we have a lot of this lab work that is looking like an MIS-C picture with that proximity to COVID. And in terms of lab work, I do want to point out that it can help us distinguish from Kawasaki. Again, these two processes were thought to be potentially the same thing at the beginning of MIS-C times when we’ve since learned a lot, but we now believe through a lot of immunologic studies that these are two distinctive processes and have distinctive profiles.
So for Kawasaki, in terms of lab work, the platelets tend to be high. So you have thrombocytosis. And in MIS-C you have thrombocytopenia, so that can help distinguish. There’s also a different age profile. So for Kawasaki, we tend to think of these angry, inflamed, very unhappy toddlers. And with MIS-C we’ve actually seen more grade school age kids. So age can be a distinguisher as can ethnicity. So we know Kawasaki is more predominant Asian backgrounds. And then MIS-C is more in the black, Latinx in terms of association with ethnicity. And then GI involvement too. Once again, MIS-C lots of GI symptoms. Kawasaki, not quite as much.
And then next steps for this patient would be, they’re probably admitted now, but thinking about an echo, chest X-ray. And the echo is especially important given again this pump systolic dysfunction that can occur with MIS-C and one other distinguishing factor is that there can be coronary involvement with MIS-C, but it’s less common than Kawasaki. So more likely to have this pump failure presentation. So what happened next, Dr. Baier?
Dr. Katelyn Baier: So, as I have mentioned before, we did recommend that the patient go to the emergency room straight from clinic just with the concern for dehydration and an inability to keep down any oral intake. And he did require admission from the ED. And in the emergency room, they did also get an EKG as well as the blood culture and the urine culture, and some of the additional lab workup that you mentioned. And interestingly enough, the EKG was concerning for PR prolongation, and the emergency room physician felt pretty confident calling this MIS-C given in the labs, the clinical picture, the positive COVID antibodies, and now heart involvement as well.
I think the rest of the clinical course and how it evolves is incredibly interesting as well. They did get an echo on admission, which was actually totally normal. They did start the patient on MIS-C treatment, which for this kiddo included aspirin, methylprednisone, and IVIG. However, they found through kind of lab follow up that his CRP and his BNP continued to rise even after treatment. And so on day of hospitalization four, his BNP was remarkably elevated. And so they got a repeat echo, which at that time was concerning for a slightly dilated left main coronary artery, which required re-treatment. And with IVIG that’s kind of how the course evolved, which is I think really interesting that it’s in a stepwise process and wasn’t a linear kind of course like we can see with MIS-C I think if we go back and think about this patient’s history.
On his first or second day of illness, he was seen in viral clinic where he just kind of coincidentally had some of our MIS-C screening labs, including the CBC, ferritin, and reticulocyte count, which were all normal at the time. It wasn’t until we saw him in clinic on day of illness three that those labs were remarkable. And I think just extending that into his hospitalization, his echo on day of illness four was totally normal on remarkable, and it wasn’t until day of illness seven or eight that the echo did find the findings of dilated main coronary artery.
Dr. Bryan Fate: So it’s a journey. We are not always certain where it goes, what systems are involved though, that we’re learning more and more, and we refined our treatment approach over time. And I think that wide differential is also a challenging thing for clinicians everywhere. The good news is that most of these kids do really well. They’re going to follow up with cardiology very closely after discharge, but we’ve been finding that they have normal cardiac function six months out, and we’re still collecting data, but they have demonstrated full cardiac recovery because we know how malleable kids are.
We’re also looking a little bit more into whether different variants of MIS-C have a higher propensity to cause this widespread inflammatory response. So this is again something that clinicians need to have their eyes peeled for and have a good illness script for as we enter that four to six week post spike of the most recent Omicron wave. And then the last thing is that based on our last grand rounds with our infectious disease team, it turns out vaccines are being shown to be protective against this. So, if vaccinated, lower chance of having MIS-C. I mean, there’s still work being published on this. Once again, a good reason to have those long discussions with family about the benefits of vaccination. So Dr. Baier, if you had just a few take home points for our listeners, what would those be?
Dr. Katelyn Baier: Well, I think the first one would be that the initial MIS-C workup can be done in an outpatient setting because we’ve talked about a couple times that this patient did have some of the traditional tier one MIS-C labs drawn in viral clinic and then repeated in our clinic. And you brought up the wonderful Children’s Minnesota clinical guideline for MIS-C, but just to point providers to that because it’s a really, really good resource, especially if you aren’t quite sure that your patients are requiring hospitalization at that time, you can kind of get the ball rolling in clinic. And this guideline can be a good blueprint for that.
Next one, I think would be if you have high clinical suspicion for MIS-C, but your patient’s labs normal or don’t necessarily point towards that diagnosis, don’t completely remove MIS-C from your differential. As I mentioned a couple of times, this patient did have normal lab evaluation on day two of illness even after the GI upset, headache, et cetera, had already started.
The last one which kind of ties into the second one is that MIS-C is an evolving process in our clinical evaluation and treatment has to reflect that. And as I mentioned, our patient had a normal echo on day of admission and it wasn’t until day of illness eight that the echo was concerning for a dilated coronary artery even after treatment. So just continuing to assess the patient for what you’re seeing in front of you will be really important.
Dr. Bryan Fate: Wonderful. Thank you so much, Dr. Baier, for being here. You’re an incredibly talented physician, and I know you’ve thought about intensive care in the future, but I would beg you to consider primary care as well. And now, as promised, an original musical number to help solidify our key concepts and hopefully tug at your heartstrings.
Dr. Angela Kade Goepferd: Thank you for joining us for Talking Pediatrics. Come back each week for a new episode with our caregivers and experts in pediatric health. Our executive producer and showrunner is Ilze Vogel. Episodes are engineered, produced, and edited by Jake Beaver. Lexi Dingman is our marketing representative. For more information and additional episodes, visit us at childrensmn.org/talkingpediatrics, and to rate and review our show, please go to childrensmn.org/survey.