key: cord-0866738-uxc5ejql
authors: Beroukhim, Rebecca S.; Friedman, Kevin
title: Children at risk: multisystem inflammatory syndrome and COVID-19
date: 2020-06-16
journal: JACC Case Rep
DOI: 10.1016/j.jaccas.2020.06.016
sha: 8b7bc2fe4008344560f3c1f60516b0a6949c0eee
doc_id: 866738
cord_uid: uxc5ejql

[Figure: see text]

in 2019 in China and rapidly spread across the world. Early data from China demonstrated that approximately 6% of children diagnosed with COVID-19 had severe or critical illness, and a subset of patients had myocardial injury or heart failure (1) . As the pandemic spread world-wide, 

The prevalence of COVID-19 infection is low in children (<2% of cases, although children represent 22% of the population) (6) . Furthermore, the rate of hospitalization among children who test positive (<2%) is low compared to older age groups, reflecting milder disease severity (6) (7) (8) . Adult studies have shown that patients with comorbidities, including hypertension, diabetes and coronary artery disease, are more susceptible to severe illness (9) . The same is likely true for children; a high percentage (23-28%) of children with MIS-C in Europe and the United States had comorbidities including asthma, obesity, cardiovascular disease, and immunosuppression (5, 6) . Although mortality in children with COVID-19 admitted to critical care units remains relatively low at <5%, racial and ethnic disparities in rates of infection and mortality have already been recognized (10) . Furthermore, indirect effects of the pandemic worldwide carry the potential for a devastating impact on maternal and child health, particularly in low-income and middle-income countries (11) . Additional cardiac findings have included coronary artery aneurysms in up to 20% of patients, and conduction abnormalities including high-grade AV block (Figure) .

The clinical syndrome of MIS-C overlaps with many features of Kawasaki disease (KD), an acute vasculitis of children that preferentially affects medium-sized arteries, in particular coronary arteries (12) . KD is thought to arise from an immune response to an infectious antigen in a genetically susceptible patient with progression to a hyperinflammatory state; however, since its first description in 1967, a unifying etiology and pathogenesis has not been established (13) . Early reports from Italy of COVID-19 infection in children suggest that MIS-C results from a similar, late-onset, dysregulated inflammatory response to the SARS-CoV-2 antigen, with many patients testing positive for IgG antibody and negative viral titers (2) . However, the Italian cases of a KD-like illness (now recognized as MIS-C) had several important differences from typical KD cases: they were older (7.5 ± 3.5 vs. 3.0 ± 2.5 yo), more likely to present in shock (50% vs. 0%), more likely to have cardiac involvement (abnormal echocardiogram in 60% vs 10%), and more likely to have elevation in troponin or BNP (80% had elevations in troponin, BNP or both). A similar report from 14 centers in France and Switzerland described 35 pediatric patients (median age 10 yo) admitted to intensive care units with MIS-C who developed acute left ventricular failure with markedly and universally elevated troponin and NT-proBNP (5).

Fever and gastrointestinal symptoms at presentation were common, and coronary artery dilation was present in 17% of cases. Additional data is needed to identify the degree of overlap/divergence between the two diseases, and to what extent standard treatment for KD is effective for patients with MIS-C.

To date, testing and treatment algorithms have been developed locally at individual hospitals without peer-reviewed guidelines. Generally, evaluation of patients with evidence of MIS-C requires a multi-disciplinary approach involving the intensive care unit, infectious disease specialist, cardiology, and rheumatology. Laboratory testing includes evaluation for inflammatory markers, as well as cardiac laboratory testing (for example, troponin, CK-MB, BNP), electrocardiogram, ECG, and echocardiogram. Current treatment protocols for MIS-C are largely directed at dampening the inflammatory response/cytokine storm with immunomodulators and, in cases of active viral infection, potentially use of antivirals (Table) . A CDC-funded nationwide study, called Overcoming COVID-19, is aimed at understanding the full range of severity of COVID-19 in children, predisposing factors for severe disease, and response to treatment with real-time data from over 35 U.S. children's hospitals. Modifications to treatment algorithms will likely arise from data obtained through this study, as well as ongoing clinical trials.

Children with COVID-19 are at risk for a MIS-C with cardiovascular manifestations. As we gain more knowledge about this disease, we will likely see an evolution in diagnostic criteria, as well as treatment guidelines. Although the vast majority of children appear to recover within a few days of infection, the long term sequelae remain unknown. 

Epidemiology of COVID-19 Among Children in China

An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study

Hyperinflammatory shock in children during COVID-19 pandemic

Cardiac dysfunction and thrombocytopeniaassociated multiple organ failure inflammation phenotype in a severe paediatric case of COVID-19

Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic

Coronavirus Disease 2019 in Children -United States

COVID-19 epidemic: Disease characteristics in children

SARS-CoV-2 infection in children -Understanding the immune responses and controlling the pandemic

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Hospitalization and Mortality among Black Patients and White Patients with Covid-19

Early estimates of the indirect effects of the COVID-19 pandemic on maternal and child mortality in low-income and middle-income countries: a modelling study

Coronary Artery Aneurysms in Kawasaki Disease: Risk Factors for Progressive Disease and Adverse Cardiac Events in the US Population

A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan