Table 1: The CDC Case Definition for MIS-C
• Patients less than 21 years old presenting with fever ≥38°C and ≥24 hours
AND
• Evidence of multisystem (≥2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurologic)
AND
• Laboratory evidence of inflammation (including, but not limited to ≥1 of the following: elevated CRP, ESR, fibrinogen, procalcitonin, D-dimer, ferritin, LDH, or IL-6; elevated neutrophils; reduced lymphocytes; or low albumin
AND
• Positive for current or recent SARS-CoV-2 infection by PCR, serology, or antigen test, or exposure within 4 weeks prior to the onset of symptoms
AND
• No other plausible explanations
Adapted from https://www.cdc.gov/mis/index.html
3 – Laboratory evidence of inflammation
The current CDC case definition requires one or more objective finding of inflammation. Unfortunately, because inflammatory markers are non-specific, no single lab test is consistently elevated in all MIS-C patients. CRP is significantly elevated in the vast majority of confirmed MIS-C patients, but less so for other markers, such as ESR, ferritin and D-dimer.9
Additionally, because the significance of inflammatory markers including D-dimer and lactate dehydrogenase (LDH) in the context of MIS-C is not completely understood, the interpretation of these tests can sometimes be challenging.
Multiple observational studies have suggested that specific lab parameters may be useful for predicting MIS-C and distinguishing it from other inflammatory conditions. A recent meta-analysis suggests that when compared with non-severe COVID-19 patients, MIS-C patients have lower lymphocyte counts, LDH and platelets, and higher neutrophil counts, CRP and D-dimers. Further, elevated CRP and ferritin are associated with a higher odds of MIS-C.5
Objective lab findings have also been suggested to have clinical utility in discriminating disease severity related to MIS-C. For example, a recent study that sought to identify factors linked to severe outcomes in MIS-C found that lab findings, such as elevated D-dimer, troponin, BNP, CRP, ferritin, and interleukin-6 (IL-6) and decreased platelets and absolute lymphocytes, were associated with severe disease.5 Taken together, this information may provide clinicians with objective data to support a diagnosis of MIS-C and make evidence-based decisions to gauge disease severity and guide therapeutic decision making.
The uncertainties about what MIS-C is & the pathophysiology that initiates & perpetuates the uncontrolled inflammation have provided a diagnostic & therapeutic challenge to practicing pediatric rheumatologists.
Our patient’s inflammatory markers, such as CRP and ferritin, fulfilled the case definition of MIS-C, but his normal absolute lymphocyte and neutrophil counts were not consistent with the MIS-C literature and suggested an alternative diagnosis. Notably, although ferritin levels were elevated in roughly two-thirds of patients, they were not elevated to the extent as our patient’s.9
4 – Positive for current or recent SARS-CoV-2 infection by PCR, serology or antigen test, or exposure within four weeks prior to the onset of symptoms
The diagnosis of MIS-C depends on the attribution of inflammatory symptoms to a prior infection with SARS-CoV-2. Definitive symptoms of a prior SARS-CoV-2 infection are not reported in all patients, and it is suggested that MIS-C patients with the Kawasaki-like disease phenotype are more likely to not report a prior SARS-CoV-2 infection.
Additionally, a significant number of patients diagnosed with MIS-C do not have confirmatory PCR or serologies for SARS-CoV-2. For example, a recent meta-analysis showed that a significant proportion of patients did not exhibit objective evidence of previous SARS-CoV-2 infection, noting that about half of MIS-C patients were positive for SARS-CoV-2 by PCR test and roughly half of patients had positive COVID-19 serologies; another study estimated that COVID-19 serologies were negative in a quarter of patients labeled as MIS-C.17,18
The antibody response of children to COVID-19 is not well understood, but a recent study demonstrated that children produce SARS-CoV-2 antibodies of reduced breadth compared to adults, and they produce antibodies against S protein, but not N protein.19 Thus, it is proposed that children are able to clear COVID-19 infections more efficiently than adults due to a more robust innate immune response that makes a stronger antibody response unnecessary.
Based on these data, even though our patient’s SARS-CoV-2 IgG and PCR tests were both negative, the possibility of prior COVID-19 infection could not be formally excluded because negative serologies may be found in a quarter of MIS-C patients.
5 – No other plausible explanations
