I usually like to post when there is a solid evidence base in order to answer the fundamental question of “why we do what we do.” But, when reports began circulating of a Kawasaki like illness in children during the COVID-19 pandemic, I knew that I had several questions that I wanted to at least begin to answer. the purpose of this post is to begin to answer some of the questions that I, and likely you, are having about what is being called Multisystem inflammatory syndrome in children (MIS-C) – the eponymous “Kawasaki like” illness that has been all over the news.
What is the best “case definition” available at this time?
It is broad, but the CDC recently released a health advisory and noted that the case definition for MIS-C includes patients less than 21 years of age presenting with…
Fever: A temperature >38C or subjective fever for at least 24 hours
Laboratory evidence of inflammation: This includes elevated CRP, ESR, fibrinogen, procalcitonin, d-dimer, LDH, IL-6, neutrophils and/or reduced lymphocytes, and low albumin
Greater than two organs involved: Cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, and/or neurologic.
– AND –
No alternative plausible diagnoses
– AND –
Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antibody test – OR – COVID-19 exposure within the four weeks prior to the onset of symptoms
Defining dysfunction of an organ system can be done by clinical and/or lab based criteria. Here are some examples of how one might define organ involvement.
- Cardiac: Shock, elevated troponin, fluid refractory tachycardia, need for vasopressors
- Renal: elevated creatinine, any other sign of acute renal failure
- Respiratory: Signs of difficulty breathing, Hypoxia, respiratory failure, apnea, respiratory acidosis on a blood gas, abnormal chest X-Ray or other imaging
- Hematologic: evidence of coagulopathy, abnormal bleeding, or concern for venous thrombosis
- Gastrointestinal: Severe abdominal pain, intractable vomiting, severe diarrhea
- Dermatologic: skin rashes of all manner
- Neurologic: Seizures, altered mental status, delirium, coma
OK, so that’s a lot to unpackage. But what this means as of May 2020, is that the definition is justifiably broad since we don’t actually have a well defined case definition like Kawasaki. So why then is the news saying “Kawasaki-like” illness?
How is traditional Kawasaki defined and how is this different?
Traditional Kawasaki disease is a medium vessel vasculitis that has a well-defined case definition and pathway to diagnosis. The main diagnostic features are:
≥5 days of fever PLUS ≥4 of the following
- Oral mucosal changes
- Bilateral conjunctivitis
- Edema or erythema of hands/feet (later peeling of fingers/toes)
- Cervical lymphadenopathy (lymph node ≥1.5cm)
Yes there is “incomplete” or “atypical” Kawasaki disease, which consists of fever for 5 days and 2 or 3 or the other symptoms. But even then, well defined lab criteria help make the diagnosis. Kawasaki is also more common in the younger age set – 3 to 5 years of age. No age prevalence estimate can reliably be made about MIS-C at this time.
So why then, has there been traction in noting that there’s a “Kawasaki like” illness out there? Anchoring helps us situate ourselves in unfamiliar situations. Many, but not all of these children have rashes and cardiac dysfunction – two of the things that happen in Kawasaki disease, which is a familiar disease to medical professionals. However, most parents I’ve talked to have no idea what Kawasaki disease is – but they are scared about this new “possibly related to COVID-19 disease.” More on that later.
Other diagnoses that MIS-C has been likened to include, but are not limited to include Toxic Shock Syndrome, Mast Cell Activation Syndrome, Macrophage Activation Syndrome, and Hemophagocytic Lymphohistiocytosis (HLH).
What do we know about the children who have been diagnosed with MIS-C?
Let’s take a look at the limited case series data that is out there.
The authors looked at all patients diagnosed with Kawasaki disease like illnesses over the past 5 years and divided them into before and after COVID-19. They had 19 patients in the pre COVID-19 group, and 10 in the post COVID-19 group, which comprised a vastly shorter epoch. Only 8 of the 10 had positive SARS-CoV-2 serology.
Salient features of the 10 post COVID-19 patients are most important to describe here, since I think a comparison, other than illustrating how frequent the MIS-C cases were and how they differed from traditional KD, is not necessarily going to be able to give us substantially beneficial data given that a precise case definition for MIS-C is still being developed. They saw seven boys and three girls. On average patients were admitted after six days of fever. The characteristics varied across the ten children, and the authors provided a table of their clinical and lab characteristics which I recommend that you take a look at. Six of the ten had abnormal echocardiograms, and the sodium, white blood cell, leukocyte count and platelet count were lower than KD. Ferritin was significantly higher in the post COVID-19 group. Overall the post COVID-19 group were sicker, with higher Kobayashi and Kawasaki Disease Shock Syndrome scores.
Treatments in the post COVID-19 patients included 2 g/kg IVIg, high dose aspirin, and methylprednisolone, starting at 2 mg/kg and then tapered over two weeks. Not all patients got steroids – just the sicker ones. No conclusions could be drawn regarding treatment protocols. Given the circumstances the physicians in Italy used data from a previous illness and tried the best they could to support very sick children with a similar but not identical illness to Kawasaki Disease.
Physicians in London noted a limited sample of eight children in mid April with a “hyperinflammatory” presentation with shock. Six of eight Eight were of Afro-Caribbean descent and five male. One patient died. All 8 patients tested positive for SARS-CoV-2 through antibody testing. The great contribution of this paper is its tabular representation of all eight patients, which I have inserted into this post. It gives you a sense of how sick they were.
There has been further data shared by the CDC in a recent emergency brief. The New York City Department of Health received reports of similar patients in early May. Between April 16 and May 4, 2020, 15 patients (Age 2 years to 15 years) were hospitalized with several in the PICU. As of May 12, 2020, the New York State Department of Health noted 102 patients with similar presentations. Many of whom tested positive for SARS-CoV-2 by RT-PCR or serologic assay. Additional reports are being made in Michigan, California, New Jersey and Illinois, as well as Spain.
What do I do if I think I have a child with MIS-C in my ED?
First, don’t panic. Seriously. It is also still possible that the child has roseola, scarlet fever, or one of the many other syndromes common in childhood. Nevertheless, this is a frightening new development. So based on what I’ve learned thus far I can offer the following advice:
Have a high index of suspicion, and if the child is ill appearing work them up! If your hospital has a protocol or process then follow it. If not, then I would consider getting the following labs:
- CBC with differential
- Blood culture
- Renal/electrolyte panel – get an albumin separately if not included
- Hepatic profile (making sure there’s AST, ALT in there of course)
- SARS-CoV-2 RT-PCR, serology, or antibody testing
Other labs that have been obtained include IL-6, IL-10, creatine kinase, and triglycerides. You should also get an EKG, and chest X-Ray. Any patient with shock or evidence of cardiac dysfunction should have an echo – ideally by Pediatric Cardiology ASAP. Other imaging should be targeted to symptoms and findings (think abdominal ultrasound or CT if severe belly pain etc,.). Overall this kind of seems like a “shotgun” approach – and it is. But remember, we are dealing with a new, as of yet incompletely defined entity. This data may be helpful with your index of suspicion, but it will also be helpful to further define the ongoing work being done to define the characteristics of MIS-C.
Treatment should focus on the ABCs initially. Provide oxygen and appropriate respiratory support. Follow aerosol procedure generating guidelines for your institution and PROTECT YOUR SELF AND YOUR COLLEAGUES first and foremost. Resuscitate with normal saline or lactated ringer’s – but pay attention to signs of cardiac dysfunction, especially before your labs return and you can get further workup. Consider 10ml/kg boluses with frequent reassessments. You can use an appropriate vasopressor for refractory shock – like epinephrine or norepinephrine – through a peripheral IV as long as you have a plan to get central access safely and in a timely fashion. A half hour of peripheral vasopressors is fine (seriously) if you check for infiltration frequently.
Treatment specifics have not yet been defined. Early data and recommendations center around the use of IVIg and high dose aspirin if the child meets Kawasaki Disease criteria, and IVIg if they meet criteria for toxic shock syndrome. This is also an illness that should be reported to your local infectious disease specialist and more broadly to the CDC or other governmental organization. Follow local policies when applicable.
How do you talk to an anxious parent of a child with fever and rash about MIS-C?
I recommend honesty and compassion – in general, and in this circumstance. If the child is well appearing and afebrile, and presents with a rash it is not going to fit within the current case definition of MIS-C. Be honest about the level of uncertainty and understand that a parent’s biggest fear is going to be that their child could die from this. Most of all, just be there for them.
Verdoni et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020. Advance online publication, doi: 10.1016/ S0140-6736(20)31129-6