Children of any age can acquire COVID-19 with an incidence of infection similar to adults. Fortunately, children often are asymptomatic or encounter mild symptoms that self-resolve within 1-2 weeks. SARS-CoV-2 infection strongly triggers the expression of type 1 interferon-stimulated genes, which predominate in the host's early control of viral replication. Indeed, children with COVID-19 have elevated interferon signature gene scores relative to adults with severe or critical COVID. Emerging evidence also suggests that pediatric airway immune cells are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults. Collectively, these molecular mechanisms are hypothesized to protect children from critical manifestations of acute COVID-19 infection.

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. Cases of multisystem inflammatory syndrome in adults (MIS-A) are also reported.

As of July 2, 2024, the US Centers for Disease Control and Prevention (CDC) has documented 9698 cases, including 79 deaths, where patients met the case definition (see Look For) for MIS-C. Of these cases, the median age of patients with MIS-C was 9 years, with one-half of children with MIS-C aged 5-13 years. Cases in infants and young adults have been reported. Of the reported cases with race and ethnicity information available (N = 9017), 57% occurred in children who are Hispanic / Latino (2368 patients) or Black, non-Hispanic (2729 patients); 98% of patients had a positive test result for SARS-CoV-2, and the remaining 2% of patients had contact with someone with COVID-19. Male patients accounted for 60% of case reports. Children with MIS-C are typically otherwise healthy. Obesity is the most commonly documented medical condition. The fatality rate of MIS-C is reported to be higher than previous reports of Kawasaki disease (KD).

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. The findings of a 2024 study suggest that some patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8.

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 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, 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 topics: post-COVID conditions, skin and oral mucosal manifestations of COVID-19