SARS-CoV-2 is a viral infection that enters a host protein by binding its spike protein to the human ACE2 receptor. It was originally predicted that COVID-19 would not affect children, whether that be due to lower levels of ACE2 receptors or a more robust humoral immune response. Cases of MIS-C have been reported in the United Kingdom, Italy, Spain, France, Switzerland, and the United States ^[1][14]. Although it is still unknown if the same clinical etiologies that lead to respiratory failure and shock with SARS-CoV-2 also lead to the shock associated with MIS-C, many have concluded that the most likely cause of MIS-C is a post-infectious, immunologically mediated hyperinflammatory response to COVID-19 ^[2][3][4,13]. SARS-CoV-2 has not been proven to be the definitive cause of MIS-C; however, the sudden appearance during the global pandemic and positive serum anti-SARS-CoV-2 antibodies in most patients is highly likely to have a high impact indicating that the two diseases are connected ^[1][14].

While the pathogenesis of MIS-C is still unknown, it is strongly suspected to be due to vasculitis and an autoimmune etiology ^[4][15]. In the Quantitative SARS-CoV-2 Serology study of MIS-C, Rostad et al. reported that children with MIS-C had significantly higher levels of SARS-CoV-2 receptor binding domain immunoglobulin G (IgG) antibody titers than those with COVID-19, KD, and hospital controls. They also found that titer levels were correlated with prolonged hospital and ICU lengths of stay ^[5][16]. Both KD and MIS-C tend to show increased levels of TNF-α. However, KD is most associated with elevations in IL-1, IL-2, and IL-6.

In contrast, the hypercytokinemia found in MIS-C patients is believed to have a very specific hyperinflammatory process that is not associated with the cytokines IL-1R, IL-2, IL-4, IL-12p70, or IL-13 ^[6][17]. Diorio et al. found that, unlike patients with severe COVID-19, patients with MIS-C were noted to have burr cells, elevated IL-10 and TNF-α, rare schistocytes, toxic granulation on peripheral blood smears, and leukocytopenia, and many had an increased number of immature myeloid cells ^[6][17]. Consiglio et al. found that IL-17A mediates hyperinflammation in KD but not in MIS-C. They also concluded that MIS-C has a much more diffuse endothelial involvement and immunopathology due to the higher levels of biomarkers associated with arthritis and coronary artery disease than KD ^[4][15]. Kabeerdoss et al. proposed the following immunological mechanism of MIS-C: “after infection with SARS-CoV-2. Those genetically susceptible may produce viral-specific antibodies that may be cross-reactive with host antigens bind to Fcγ receptors in neutrophils and macrophages. This may lead to the secretion of pro-inflammatory cytokines leading to the clinical manifestation of MIS-C” ^[2][4]. In conclusion, while the pathogenesis of MIS-C is still unknown, laboratory findings in patients with MIS-C suggest a high probability of an autoimmune etiology.

MIS-A has been described in the literature as very similar to Kawasaki disease seen in children and shares many of the same clinical features as MIS-C. Cases have been described of adults having a Kawasaki-like illness in the context of a COVID-19 infection ^[4][15] (p. 19) ^[7][18]. These cases have been termed MIS-A, as they share similar symptomatology to MIS-C. This similar symptomatology suggests a similar pathophysiology of an autoimmune process in MIS-A.

There is still a lot of unknown information regarding the epidemiology of MIS-C. Interestingly, it has been shown that patients who present with MIS-C were otherwise previously healthy children ^[3][8][13,19]. While initial studies found that less than 5% of children affected by SARS-CoV-2 experienced severe effects of the disease, the risk of the severe hyperinflammatory disease MIS-C is not to be ignored. According to the CDC, as of October 2020, there have been over 1000 confirmed MIS-C cases and 20 deaths related to MIS-C ^[9][20]. Gender is not a risk factor. However, race does seem to play a possible role in epidemiology. In a review of over 371 articles by Ahmed et al., including 662 children with MIS-C, children of African American, Afro-Caribbean, or African race/ethnicity represented 34.7% of the population ^[10][5]. MIS-C also tends to affect older children and adolescents ^[1][14]. It has also been postulated that there may be a genetic component in MIS-C development ^[2][4]. In terms of MIS-A, it is unclear who will develop this syndrome and who will not at this time.

The main goal of treatment is to stabilize the patient and prevent long-term cardiac sequelae ^[11][21]. Vital signs, hydration, electrolytes, and metabolic status need to be continuously monitored ^[12][22]. Empiric therapy with broad-spectrum antibiotics has also been a first-step approach to treating MIS-C ^[9][20]. Hypotensive shock is a risk factor for MIS-C. It should be treated with epinephrine as a first-line treatment, IV fluids, other vasopressors, and possibly dobutamine due to the drug’s selective inotropic effects ^[12][22]. Data show that vasopressors are needed in about 66% of cases of MIS-C due to marked hypotension, and inotropic therapy is used in about 67% of patients with the disease ^[7][9][18,20].

Due to the similar presentation and diagnostic criteria of KD, most MIS-C cases are treated using the standard protocol for KD. This protocol includes treatment with acetylsalicylic acid (ASA), intravenous immunoglobin (IVIG), and corticosteroids. A multidisciplinary team consisting of pediatric rheumatologists, adult rheumatologists, pediatric cardiologists, pediatric infectious disease specialists, and pediatric critical care physicians, collectively termed “The Task Force”, has studied the treatment plans of MIS-C to date and devised a recommended treatment protocol for patients with MIS-C ^[11][21]. The Task Force states that low-dose ASA is recommended in all MIS-C patients without active bleeding ^[11][21]. By binding and inhibiting the inducible isoform, COX-2, the inflammatory mediators that lead to rheumatologic symptoms are decreased ^[13][23]. The antiplatelet properties of ASA also make it beneficial for use in MIS-C due to the increased risk of coagulopathies. ASA toxicity has not been reported in treating patients with MIS-C ^[9][20]. The Task Force states that IVIG should be given to all MIS-C patients who require hospitalization at a 2 gm/kg dose based on body weight. IVIG is a combined blood product from thousands of donors that contains extremely high levels of immunoglobins (Igs) ^[14][24]. IVIG has many anti-inflammatory effects and proposed mechanisms. It is believed that IVIG interacts with FcγRs present on monocytes and macrophages, limiting antibody-dependent cytotoxicity and inhibiting B-cell activation. Other proposed mechanisms involve the neutralization of circulating autoantibodies and induction of a block in B-cell proliferation. IVIG also interferes with the activated complement system components and forms the membrane attack complex ^[14][24]. There are numerous beneficial effects of IVIG for managing hyperinflammation. The administration of this treatment to patients with MIS-C has been shown to lead to a rapid resolution of fever and a reduction in the inflammatory-mediated response ^[9][20]. The Task Force also states that glucocorticoids should also be given as adjunctive therapy in ill-appearing patients with elevated BNP levels, unexplained tachycardia, or who present with shock and/or organ-threatening disease ^[11][21]. Corticosteroids have long been used for treating rheumatologic disorders due to their ability to downregulate the transcription factor NF-kB, leading to fewer pro-inflammatory cells such as TNF-α. Methylprednisolone and prednisolone have been used extensively and successfully in patients with MIS-C ^[7][9][18,20].

Treatment for MIS-C is still evolving. Although there is no standardized universal guideline for the administration of treatment, the regimens recommended above have been shown to have great success in treating children affected by the disease. Treatment for MIS-A in the available case studies has been mainly vasopressors, with one case study using tocilizumab ^[4][15] (p. 19).