Abstract and Introduction
Purpose of Review: Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection primarily affecting children. MIS-C shares features with Kawasaki disease (KD) and cytokine storm syndrome (CSS) frequently requiring intensive care support. Although intravenous immunoglobulin (IVIg) and glucocorticoids (GCs) are effective therapeutics for most, refractory MIS-C is treated with various biologic disease-modifying antirheumatic drugs (bDMARDs). Understanding the clinical features, inflammatory cytokines, and genetic associations provides rationale for bDMARD in treating severe MIS-C.
Recent Findings: Children with MIS-C have clinical KD features and often present in hypovolemic and cardiogenic shock requiring volume repletion (gastrointestinaI losses) and cardiac pressor support (epinephrine). Investigation of MIS-C serum reveals elevated pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-18, interferon gamma (IFNγ), tumor necrosis factor (TNF)], but to a lesser extent than other established CSS. Gene sequencing of MIS-C children identifies heterozygous mutations in CSS associated genes. Treatment of refractory (IVIg and GC) MIS-C with bDMARDs to IL-1, IL-6, and TNF is efficacious for survival as well as resolving cardiac and coronary artery inflammation.
Summary: MIS-C is a postinfectious complication of SARS-CoV-2 resembling KD and CSS, both genetically and by pro-inflammatory cytokines. MIS-C that is refractory to IVIg and GC is routinely responsive to bDMARDs targeting IL-1, IL-6, and TNF.
As pediatricians, we were initially grateful that children were largely spared severe manifestations of coronavirus disease 2019 (COVID-19) associated with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. However, to everyone's surprise an increase in what appeared to be cases of Kawasaki disease (KD) were being reported in children in Europe,[2,3] and soon after in the northeastern United States,[4,5] approximately a month after COVID-19 blossomed in the respective regions of the planet. Although different terminologies were used to describe this novel disease entity (e.g. pediatric multisystem inflammatory syndrome or PMIS; multisystem inflammatory syndrome in children or MIS-C), it appeared to be largely restricted to previously healthy children and a few young adults (MIS-A). Definitions for MIS-C were established early on, and the United States Centers for Disease Control and Prevention (CDC) definition was as follows: under 21 years of age, fever, laboratory evidence of inflammation, severity requiring hospitalization, with multisystem (>2) organ involvement (cardiac, kidney, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic) and no alternative plausible diagnoses and positive for current or recent SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR), serology, or antigen test; or COVID-19 exposure within 4 weeks of symptom onset.[3,7]
Clinically, MIS-C appeared to effect younger children differently than adolescents, but with overlapping features in both populations. Younger children, particularly those under 5 years of age, presented much like KD with fever, mucocutaneous involvement, and risk for coronary artery abnormalities.[4,5] Other cardiovascular features included carditis (with decreased ejection fractions) and pericarditis.[4,5] In addition, over 90% of children of all ages with MIS-C suffered gastrointestinal involvement with nausea, vomiting, and diarrhea.[4,5] The combination of cardiovascular dysfunction and gastrointestinal fluid losses, particularly in the teenage population, frequently resulted in a state of shock requiring intensive care with intravenous volume repletion and vasopressor support (e.g. epinephrine). Some children even required invasive mechanical ventilation and occasionally extracorporeal membrane oxygenation (ECMO). Some of these children also had features of a cytokine storm syndrome, and early mortality rates for MIS-C ranged from 1 to 2%,[4,5] in the range of severe COVID-19 for adults.
Because of the shared features with KD, and the risk of coronary artery dilation and aneurysms, therapy for KD was utilized for MIS-C early on. This included intravenous immunoglobulin (IVIg) to prevent coronary changes, low dose aspirin (ASA) for coronary artery clot reduction, and glucocorticoids (GCs) to dampen inflammation in more severe disease.[3,9] Despite the severity of illness at presentation, the vast majority of children responded rapidly to this approach. Some centers reported an average length of hospital stay of 5 days for children with MIS-C, notably shorter than the small subset of children (mostly those with prior underlying health conditions like diabetes, neurodevelopmental disorders, obesity, etc. – similar to adults) with active SARS-CoV-2 infection hospitalized for severe COVID-19 (14 days mean stay). For those children with MIS-C refractory to IVIg and GCs, other biological disease modifying antirheumatic drugs (bDMARDs) were found to be effective (Table 1). These bDMARDs included agents targeting pro-inflammatory cytokines including interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF).[3,9,11,12] This review will cover the pathophysiologic rationales for employing bDMARDs to treat MIS-C, as well as their benefit.
Curr Opin Rheumatol. 2022;34(5):274-279. © 2022 Lippincott Williams & Wilkins