Multisystem Inflammatory Syndrome in Children (MIS-C), a Post-viral Myocarditis and Systemic Vasculitis—A Critical Review of Its Pathogenesis and Treatment

Abstract

MIS-C is a newly defined post-viral myocarditis and inflammatory vasculopathy of children following COVID-19 infection. This review summarizes the literature on diagnosis, parameters of disease severity, and current treatment regimens. The clinical perspective was analyzed in light of potential immunopathogenesis and compared to other post-infectious and inflammatory illnesses of children affecting the heart. In this paradigm, the evidence supports the importance of endothelial injury and activation of the IL-1 pathway as a common determinant among MIS-C, Kawasaki disease, and Acute Rheumatic fever.

The Trilogy of SARS-CoV-2 in Pediatrics (Part 2): Multisystem Inflammatory Syndrome in Children

“…Additionally, many present with elevated troponin and brain natriuretic peptide (BNP) related to cardiac involvement. 18 To date, no relationship between the degree of BNP elevation and MIS-C disease severity has been established.…”

“…17 Interleukin-1-mediated inflammation manifests broadly throughout the body, affecting the ears, lungs, liver, kidneys, brain, eyes, pancreas, lymph nodes, skin, joints, and bone marrow.17 In addition, IL-1 stimulates downstream expression of multiple cytokines and activation of T cells, thereby priming the adaptive immune response.18 Excessive or uninhibited IL-1β production is a primary contributor for immune response dysregulation related to COVID-19-associated and MIS-C-associated morbidity and mortality. 17,19 Genetic predisposition and/or SARS-CoV-2 superantigen-like characteristics are highly suspected to contribute to the overall pathogenesis of MIS-C. 18 Particular genetic traits are thought to potentiate nucleotide-binding oligomerization domain and leucine-rich repeat containing proteins 3 (NLRP3) activation and immune dysregulation; however, such specifics will not be discussed in this review.18 Superantigens (i.e., Streptococcus and Staphylococcus species) are known to be potent inducers of IL-1β, T cells, and B cells, and complement pathways, resulting in hyperinflammation. SARS-CoV-2 possesses intrinsic superantigen-like properties and shares motifs similar to that of staphylococcal endotoxins.…”

“…A cytokine cascade is induced, destabilizing balance and leading to Specific risk factors in adults and children, such as atherosclerosis or Ehlers-Danlos syndrome, may place an individual at a higher risk of CAAs secondary to SARS-CoV-2 myocarditis. 18 Children have a higher likelihood of aneurysm development secondary to ongoing growth. Individuals with disease states known to impact the integrity of the internal elastic lamina of the arteries may also be at a higher risk of CAAs.18…”

“…Standardized follow-up recommendations for patients with MIS-C are still evolving. 18 Cardiology reassessments and follow-up should be geared toward the type and severity of MIS-C. 18 If adapting from the KD treatment guidelines, an ECHO should be obtained at baseline and repeated as clinically necessary up to 6 to 8 weeks after. If the baseline ECHO is abnormal, repeat ECHOs should be more frequent, especially during the first week.…”

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“…Discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2), an endothelial secreted protein associated with vascular injury [ 39 ], were also more elevated in KD than MIS-C. Matrix metalloproteinase 1 and 10, proteins involved in arterial disease, were also differentially expressed [ 40 ]. MIS-C and KD likely have overlapping immune profiles, as both have endothelial damage and IL-1β upregulation and significant downstream IL-6 elevation [ 41 ].…”