Children at Risk: Multisystem Inflammatory Syndrome and COVID-19.

Coronavirus disease-2019 (COVID-19) is a novel pandemic caused by severe acute respiratory syndrome coronavirus-2 that began 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 has spread worldwide, clinicians have developed an increased awareness of an unusual systemic inflammatory response linked to the virus, frequently with a delayed onset up to several weeks after acute infection. Multisystem inflammatory syndrome in children (MIS-C) involves injury to multiple organs, including but not limited to the heart. Patients may present with a combination of ventricular dysfunction, shock, and/or a Kawasaki-like disease. In this issue of JACC: Case Reports, Joshi et al. (2) describe 3 cases of children who had classic cardiovascular manifestations of MIS-C. All children presented with shock, elevated inflammatory markers, and evidence of cardiac injury, and all recovered ventricular function within 3 to 5 days of intensive care unit admission. The clinical courses of these patients are consistent with published reports of MIS-C around the world (3, 4, 5, 6).

Epidemiology of COVID-19 in Children

The prevalence of COVID-19 is low in children (<2% of cases, although children represent 22% of the population) (7). Furthermore, the rate of hospitalization among children who test positive (<2%) is low compared with older age groups, reflecting milder disease severity (7, 8, 9). Adult studies have shown that patients with comorbidities, including hypertension, diabetes, and coronary artery disease, are more susceptible to severe illness (10). The same is likely true for children; a high percentage (23% to 28%) of children with MIS-C in Europe and the United States had comorbidities, including asthma, obesity, cardiovascular disease, and immunosuppression (6,7). 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 (11). 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 (12).

Clinical Criteria for MIS-C

Case definitions published by the Centers for Disease Control and Prevention (13) and the World Health Organization (14) have recently been published. They both include criteria for multisystem organ involvement, evidence of inflammation, and evidence of novel coronavirus infection or exposure with no alternative plausible diagnosis. The World Health Organization preliminary case definition describes more cardiac-specific features, including features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities including echocardiographic findings or elevated troponin or N-terminal pro–brain natriuretic peptide (BNP). The cases presented by Joshi et al. (2) highlight several of the key features that have been described in the case series of MIS-C published to date, including clinical presentation (fever, prominent abdominal symptoms, hypotension, shock), laboratory findings (bandemia, lymphopenia, marked elevation of inflammatory markers and d-dimer), and cardiac findings (left ventricular systolic dysfunction that often improves quickly with resolution of inflammation and elevations in BNP and troponin). Additional cardiac findings have included coronary artery aneurysms in up to 20% of patients and conduction abnormalities, including high-grade atrioventricular block (Figure 1).

Figure 1

Conceptual Diagram of Potential Factors Leading to Cardiovascular Injury in Children With Multisystem Inflammatory Syndrome

BNP = brain natriuretic peptide; COVID-19 = coronavirus disease-2019.

Hyperinflammatory State and Resemblance to Kawasaki Disease

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 (15). 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 have not been established (16). Early reports from Italy of COVID-19 in children suggest that MIS-C results from a similar, late onset, dysregulated inflammatory response to the severe acute respiratory syndrome coronavirus-2 antigen, with many patients testing positive for immunoglobulin G antibody and negative viral titers (3). However, the Italian cases of a KD-like illness (now recognized as MIS-C) had several important differences from typical KD cases: the patients were older (7.5 ± 3.5 years vs. 3.0 ± 2.5 years), more likely to present in shock (50% vs. 0%), more likely to have cardiac involvement (abnormal echocardiographic findings in 60% vs. 10%), and more likely to have elevations 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 years) admitted to intensive care units with MIS-C who developed acute left ventricular failure with markedly and universally elevated troponin and N-terminal pro-BNP (6). Fever and gastrointestinal symptoms at presentation were common, and coronary artery dilation was present in 17% of cases. Additional data are needed to identify the degree of overlap or divergence between the 2 diseases and to what extent standard treatment for KD is effective for patients with MIS-C.

Evaluation and Treatment

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 multidisciplinary approach involving the intensive care unit, infectious disease specialists, cardiology, and rheumatology. Laboratory testing includes evaluation for inflammatory markers, as well as cardiac laboratory testing (e.g., troponin, creatine kinase-MB, BNP), electrocardiography, and echocardiography. Current treatment protocols for MIS-C are largely directed at dampening the inflammatory response or cytokine storm with immunomodulators and, in cases of active viral infection, potentially antiviral agents (Table 1). A Centers for Disease Control and Prevention–funded nationwide study, 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 more than 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.

Table 1

Potential Treatment Options for Children With MIS-C

Treatment	Indications	Dosing	Precautions	Side Effects
Immunomodulators
IVIG	• Recommend for patients with KD features and/or with coronary artery changes • Consider for myocarditis	• 2 g/kg for KD features • 1 g/kg for myocarditis	• Baseline laboratory assessment (CBC, BUN/Cr)	• Infusion reactions, anaphylaxis, transaminitis, aseptic meningitis, hemolysis (dose-dependent effect, highest risk in non-O blood type)
Corticosteroids	• Consider for high-risk patients with KD features (age <6 months, coronary artery z-score >2.5 on baseline echocardiography, IVIG resistance) • Consider for MIS-C with cytokine storm (rheumatology/ID consult) • Consider for ARDS	• 1–2 mg/kg divided bid (prednisone, prednisolone, methylprednisolone)		• Hypertension • Hyperglycemia
Anikinra (IL-1 inhibitor)	• Consider for MIS-C with cytokine storm (rheumatology/ID consult) • Consider for high-risk patients with KD in whom steroids are not an option	• 2–4 mg/kg/dose bid, can increase to tid if clinically needed • Maximum dose 100 mg	• Treatment with more than 1 biologic agent is not recommended • Avoid live viral vaccines
Canakinumab	• Consider for MIS-C with cytokine storm (rheumatology/ID consult) • Consider for high-risk patients with KD in whom steroids are not an option	• 5–8 mg/kg SQ • Maximum dose 300 mg	• Treatment with more than 1 biologic agent is not recommended • Avoid live viral vaccines
Tocilizumab (IL-6 inhibitor)	• Consider for MIS-C with cytokine storm (rheumatology/ID consult)	• <30 kg: 12 mg/kg IV • ≥30 kg: 8 mg/kg IV • Maximum dose 800 mg	• Treatment with more than 1 biologic agent is not recommended • Avoid live viral vaccines
Antivirals
Remdesivir	• Severe COVID-19 manifestations (rheumatology/ID consult)	• Day 1: 5 mg/kg dose IV × 1 over 30–60 min • Maximum dose 200 mg • Days 2–10: 2.5 mg/kg/dose IV daily over 30–60 min • Maximum dose 100 mg	• Daily laboratory assessment (Chem-7, LFTs, CBC, PT, UA)	• Hepatotoxicity • Avoid NSAIDs (nephrotoxicity) • Requires dose adjustment (or avoid) in patients with renal insufficiency
Chloroquine (or hydroxychloroquine)	• Consider for severe COVID-19 if remdesivir is not an option (rheumatology/ID consult)	• Loading dose: 6.5 mg/kg/dose PO bid × 2 doses • Maximum dose: 400 mg • Maintenance 3.25 mg/kg/dose PO bid × 8 doses • Maximum dose: 200 mg	• Monitor QTc interval • Avoid other QTc-prolonging medications	• Myelosuppression • Hemolytic anemia • Cardiomyopathy • Common side effects: hypoglycemia, GI symptoms
Other
Convalescent plasma	• Consider for severe COVID-19 disease and if no improvement with antiviral therapy

ARDS = acute respiratory distress syndrome; bid = twice daily; BUN = blood urea nitrogen; CBC = complete blood count; COVID-19 = coronavirus disease-2019; Cr = creatine; GI = gastrointestinal; ID = infectious disease; IL = interleukin; IV = intravenous; IVIG = intravenous immunoglobulin; KD = Kawasaki disease; LFT = liver function test; MIS-C = multisystem inflammatory syndrome in children; NSAID = nonsteroidal anti-inflammatory drug; PO = orally; PT = prothrombin time; QTc = corrected QT; SQ = subcutaneous; tid = thrice daily; UA = urine analysis.

Conclusions

Children with COVID-19 are at risk for 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.