What is multisystem inflammatory syndrome (MIS) in children (MIS-C) and how is it diagnosed?

Updated: Apr 02, 2021
  • Author: James J Dunn, PhD, D(ABMM), MT(ASCP); more...
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COVID-19 in children often has a relatively mild presentation. However, starting in April 2020, reports from the United Kingdom and other countries described a Kawasaki-like disease in children and adolescents linked to SARS-CoV-2 infection. [71] The condition has been recognized as multisystem inflammatory syndrome (MIS) in children (MIS-C). MIS is considered a rare, yet serious, complication of SARS-CoV-2 infection. The exact pathophysiology and incidence of MIS remain to be determined.

The CDC and the World Health Organization (WHO) have each provided criteria for an MIS-C case definition. The definitions require patients to be less than age 21 years (CDC criteria) or less than age 19 years (WHO criteria) and to have evidence of recent or current SARS-CoV-2 infection or exposure (CDC only), the presence of documented fever, elevated markers of inflammation, at least two signs of multisystem involvement, and lack of an alternative diagnosis (eg, bacterial sepsis, toxic shock syndrome). The CDC also includes the presence of severe illness requiring hospitalization in the case definition. As more published data emerge, diagnostic criteria may be altered.

It is believed that immune dysregulation underlying MIS-C is related to past rather than acute infection with SARS-CoV-2. Serology testing for the presence of anti–SARS-CoV-2 antibodies plays an essential role in MIS-C diagnosis, since the majority of pediatric patients have a negative SARS-CoV-2 PCR result at the time of presentation with the syndrome. [71]

Laboratory tests recommended for the initial diagnosis and monitoring of disease progression include complete blood count (CBC), kidney and liver function markers, cardiac function biomarkers, and coagulation parameters. Cell counts with CBC differential, with special attention paid to platelet, lymphocyte, and neutrophil counts, allow for control of lymphopenia, neutrophilia, mild anemia, and thrombocytopenia in patients with moderate or severe symptoms. Serum electrolytes and renal function have been reported as abnormal even in patients with mild symptoms.

Although not fully understood, myocardial injury is one of the main clinical manifestations of MIS-C. [72] Therefore, close monitoring of the levels of markers of myocardial function such as troponin and brain natriuretic peptides (BNPs) are an essential part of the MIS-C workup. Inflammatory markers whose levels have been shown to correlate with disease severity include C-reactive protein (CRP), which has been reported as critically elevated in the majority of patients; erythrocyte sedimentation rate (ESR); and interleukin 6 (IL-6). Coagulopathy resulting in high fibrinogen, D-dimer, partial thromboplastin time (PTT), prothrombin time (PT), and factor VIII levels has been observed in MIS-C patients experiencing moderate to severe symptoms. Ferritin is also elevated in MIS-C, being higher in 55-76% of patients.

With the rapid spread of SARS-CoV-2, reports have emerged of MIS in adult patients (MIS-A) as well. [73]  Since there have been only a limited number of reported cases, however, the epidemiology, comorbidities, and incidence of MIS-A remain largely unknown. Similar to MIS-C, clinical presentation includes cardiovascular, gastrointestinal, and dermatologic symptoms in patients with confirmed SARS-CoV-2 infection.

Serology testing for the presence of anti–SARS-CoV-2 antibodies is crucial in the diagnosis of MIS-A. Published reports have shown that up to 30% of patients had a negative NAAT but were positive for the presence of SARS-CoV-2 antibodies. [73] The working case definition of MIS-A includes severe illness requiring hospitalization in patients aged 21 years or older, along with current or previous infection with SARS-CoV-2. Patients are evaluated for the presence of severe dysfunction of extra-pulmonary organs, including cardiac abnormalities, toxic shock, acute liver injury, and coagulopathy in the absence of severe respiratory illness. The laboratory-confirmed presence of severe inflammation is important for the diagnosis of MIS-A. The same markers are evaluated in MIS-A as in MIS-C, with CRP, ferritin, D-dimer, and IL-6 being greatly elevated. [74]

Additional, carefully conducted research is needed to understand the pathophysiology and long-term effects of MIS in children and adults. Currently, the differential diagnosis of MIS-C and MIS-A is broad, and clinicians and health departments should consider multidisciplinary care for patients who meet the criteria for these conditions.

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