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.