Potentially life-threatening emergency
Multisystem inflammatory syndrome in children in Child
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Synopsis
Multiple variants of the virus have circulated globally, including in the United States (the Alpha variant [B.1.1.7], the Beta variant [B.1.351], the Gamma variant [P.1], the Delta variant [B.1.617.2], B.1.621, the Delta plus variant [AY lineages], the Lambda variant [C.37], and the Omicron variant [B.1.1.529]). These variants – and in particular Delta and Omicron – seem to spread more easily and quickly.
The Delta variant was associated with an increase in hospitalization rates of children, although the proportion of children with severe disease requiring intensive care remained unchanged. As of December 20, 2021, the Omicron variant had been detected in most states and territories and has since become the dominant variant in the United States. Preliminary data suggest that the Omicron variant spreads more easily than the Delta variant and may cause more mild disease; however, severe disease can occur.
Each surge of COVID-19 cases within communities has been associated with a serious and potentially life-threatening syndrome in children termed multisystem inflammatory syndrome in children (MIS-C). This syndrome was first reported in April 2020 in the United Kingdom and has now been reported worldwide. MIS-C occurs 2-6 weeks after COVID-19 infection. Most patients are asymptomatic or only mildly symptomatic during acute infection.
The incidence of MIS-C is estimated to be 5 per 1 000 000 person months. True incidence of MIS-C is unknown. A study based in New York City cited an incidence rate of 11.4 cases per 100 000 individuals under the age of 20. The median age of onset is 8 years, but cases in infants and young adults have been reported. Race and ethnicity greatly impact MIS-C incidence. Black persons and Hispanic or Latino persons are 9 times more likely to have MIS-C, and Asian or Pacific Islander persons are 3 times more likely. Children with MIS-C are typically otherwise healthy. Obesity is the most commonly documented medical condition, seen in 30% of MIS-C cases. The fatality rate of MIS-C is reported at 1%-2%, approximately 10-fold higher than previous reports of Kawasaki disease (KD). Cases of multisystem inflammatory syndrome in adults (MIS-A) are also reported.
While the molecular mechanisms underlying MIS-C remain an area of ongoing investigation, the condition is known to be a dysregulated postinfectious immune response to previous SARS-CoV-2 infection. The hyperinflammatory response in MIS-C is associated with massive expansion of T cells expressing the Vβ21.3 T-cell receptor β-chain variable region (TRBV11-2). This is consistent with a superantigen phenomenon. At least one previous paper suggested that the SARS-CoV-2 spike protein could behave as a superantigen structure in MIS-C. However, the kinetics of T-cell expansion in MIS-C are delayed following SARS-CoV-2 infection, and the virus is commonly undetectable at the time of acute inflammation. More recent evidence has documented a polyclonal T-cell expansion that is not directed against SARS-CoV-2 antigenic peptides, raising speculation that immune complexes composed of autoantibodies to SARS-CoV-2 and endogenous antigens could behave as superantigen structures in MIS-C. This massive TRBV11-2 T-cell activation is transient, with normalization of the repertoire within days to weeks following acute inflammation. Elevated serum levels of soluble spike protein, inflammatory biomarkers including interferon (IFN)-γ, and autoantibodies directed against self-antigens have all been reported in MIS-C.
For the Centers for Disease Control and Prevention (CDC) case definition, see Look For.
Presentation
The typical presentation of MIS-C is fevers for 3-5 days, gastrointestinal symptoms (abdominal pain, vomiting, diarrhea), KD-like mucocutaneous features, and shock. Gastrointestinal symptoms are documented in 60%-90% of patients and can be so intense that they may mimic appendicitis. Other features include sore throat, myalgia, swollen hands / feet, and lymphadenopathy. Unlike acute COVID-19 infection, severe pulmonary disease is not common in MIS-C, and cough is not common.
Mucocutaneous features overlap with those seen in KD and can serve as an important clue in the initial evaluation of a child with MIS-C. The most common features include a nonpurulent conjunctivitis, hyperemia and cracking of the lips, strawberry tongue, and palmoplantar erythema. MIS-C exanthems may be urticarial, morbilliform, or scarlatiniform. Potentially unique features seen in MIS-C include upper eyelid erythema that may mimic a heliotrope rash and periorbital edema. In contrast to classic KD, desquamation in the groin is uncommon or absent. Periungual desquamation is seen in MIS-C. The presence of mucocutaneous features is not a predictor of disease severity, and there is no specific histopathology.
A critical feature of MIS-C is the risk for cardiac dysfunction and the need for hemodynamic support. Myocardial dysfunction indicated by either echocardiography, or elevated troponin, or brain natriuretic peptide (BNP) is seen in over 50% of reported cases. Children who present with shock have several distinguishing features including older age, being Black, not fulfilling criteria for typical or atypical KD, neurologic symptoms, respiratory symptoms, and higher inflammatory markers (specifically ferritin, C-reactive protein [CRP], D-dimer).
MIS-C children presenting with shock have more severe disease with higher rates of intensive care unit (ICU) admission, longer length of stay, and increased mortality. This MIS-C subgroup is also more likely to suffer from neurocognitive symptoms, including headache, confusion, irritability, and lethargy. Severe neurologic symptoms include hyporeflexia, generalized weakness, meningeal signs, and encephalopathy.
Younger children are more likely to present with features seen in typical or atypical KD, and older children are more likely to present with shock, myocarditis, and greater disease severity.
Long-term outcomes
The long-term outcomes of children diagnosed with MIS-C remain an area of active investigation. In a 6-month follow-up study of 50 MIS-C cases, children were found to make a quick turnaround with normalized cardiac function weeks after discharge, normal coronary arteries, and a lack of secondary infections. However, a subset of patients did have persistent diastolic cardiac dysfunction of unclear significance. A 3- to 4-month follow-up study of 60 children diagnosed with MIS-C also demonstrated quick functional recovery from myocardial injury.
Related topic: postacute COVID-19 syndrome (long COVID-19)
Codes
ICD10CM:M35.81 – Multisystem inflammatory syndrome
SNOMEDCT:
895448002 – Multisystem inflammatory syndrome in children
Look For
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Diagnostic Pearls
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Differential Diagnosis & Pitfalls
- Toxic shock syndrome – staphylococcal or streptoccocal
- Kawasaki disease
- Bacterial sepsis
- Macrophage activation syndrome
- Adenoviral infection
- Enteroviral infection
- Systemic lupus erythematosus
- Systemic juvenile idiopathic arthritis
- Reactive infectious mucocutaneous eruption (RIME) developing secondary to SARS-CoV-2 infection or other infectious agents
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References
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Last Reviewed:03/21/2021
Last Updated:02/16/2022
Last Updated:02/16/2022
Potentially life-threatening emergency
Multisystem inflammatory syndrome in children in Child