Review of Cardiac Involvement in Multisystem Inflammatory Syndrome in Children

In late 2019, a novel coronavirus was isolated in Wuhan, China, as the cause of a cluster of severe cases of pneumonia and acute respiratory distress syndrome.¹ The virus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease was called coronavirus disease 2019 (COVID-19). The virus rapidly spread worldwide, leading the World Health Organization (WHO) to declare a pandemic on March 11, 2020. As of this writing, COVID-19 has infected >58 million people and resulted in >1 million deaths.² Initial reports indicated that children were largely spared from the most severe symptoms of COVID-19 and were often asymptomatic.³ In late April 2020, reports emerged from the United Kingdom of children presenting with fever and hyperinflammation temporally associated with COVID-19 and with clinical features similar to incomplete Kawasaki disease (KD), toxic shock syndrome, macrophage activating syndrome, or bacterial sepsis.⁴ This new syndrome has been named multisystem inflammatory syndrome in children (MIS-C) by the US Centers for Disease Control and Prevention. This syndrome was also referred to as pediatric multisystem inflammatory syndrome and pediatric inflammatory multisystem syndrome.^5–7 In this article, we use the term MIS-C. Knowledge and experience in caring for patients with MIS-C is rapidly evolving. The objective of this review is to describe the current published data on MIS-C effects on the cardiovascular system and provide clinical considerations for cardiac evaluation and follow-up based on the available data.⁸

Literature Review

Because of the emergent and evolving nature of COVID-19 and MIS-C, we reviewed the published literature in MEDLINE through PubMed and assessed early reports using a search for COVID-19, MIS-C, pediatric multisystem inflammatory syndrome, pediatric inflammatory multisystem syndrome, and SARS-CoV-2 in medRxiv and bioRxiv from January 1, 2020, until June 22, 2020. We had personal communications with multiple organizations worldwide and contacted leaders in the fields of pediatric rheumatology, immunology, and cardiology caring for children with MIS-C. In addition, the websites of the health organizations including the WHO and the Centers for Disease Control and Prevention were reviewed to provide up-to-date numbers and available recommendations.

COVID-19 in Children

Susceptibility to infection and the rate of clinical symptoms in infected individuals are both highly dependent on age.⁹ Individuals younger than 18 years are considerably less susceptible to becoming infected on exposure to SARS-CoV-2, with ≈40% developing infection compared with >80% in those ≥18 years of age. Among children and adolescents who develop viral infection, clinical manifestations of COVID-19 are present in only ≈20% to 30% compared with >60% of those >60 years of age. Similarly, severity of symptoms and mortality rate are higher in older patients, particularly the elderly.^10–12 Of the initial reported cases from Wuhan, 2% were in individuals younger than 20 years and <1% in individuals younger than 10 years.^13,14 The hospitalization rate among children who tested positive was low (<2%).^15–17 Early in the pandemic, a large nationwide case series from China included 2143 pediatric patients with COVID-19.¹⁸ Severe disease with hypoxia was reported in 5% of the pediatric cases, largely in children with underlying comorbidities, and only 13 (0.6%) patients had critical disease with acute respiratory distress syndrome or multiorgan failure.¹⁸ Similarly, initial reports evaluating COVID-19 in children in the United States described primarily respiratory symptoms and indicated that severe infection was rare and more likely in children with comorbidities.⁸ Beginning in late April 2020, MIS-C was recognized as a new clinical entity in children, temporally associated with COVID-19 activity in the community. Since the original reports from the United Kingdom and Italy, there has been a rapidly accumulating number of reports of similarly affected children in other parts of the world, including the United States.^5,19

Epidemiology and Pathophysiology

MIS-C is a rare complication of SARS-CoV-2 infection in children. The incidence is unknown because of the rapidly evolving nature of MIS-C during the pandemic. MIS-C takes place in clusters, occurring ≈4 weeks after the peak incidence of COVID-19 in heavily affected regions, initially in Western Europe and subsequently throughout North America.^5,20,21

The initial report from England included 8 patients.⁴ Subsequent larger series were reported from France/Switzerland (35 cases), England (58 cases), multiple series from New York (33 cases, 17 cases), and across the United States (168 cases).^5,20,21 The majority of the cases (79% to 95%) occurred in previously healthy children, with the most common preexisting comorbidities being asthma and obesity.^5,21 Minority populations have been overrepresented in MIS-C case series published to date, with children of African or East Indian descent representing 69% of cases in the largest UK case series and Hispanic or Black children accounting for 48% of cases in the New York case series.^6,20,22 The cause for the overrepresentation of minority populations in MIS-C case series is unknown but may be related to increased exposure to COVID-19.

The majority of cases have positive immunoglobulin G serology (75% to 90%) and negative polymerase chain reaction (PCR) assays for the virus (53% to 80%).^6,23 The combination of the timing of MIS-C cases and the positive serology with negative PCR in most patients suggests that MIS-C represents a postinfectious, immune-mediated complication rather than an acute infection.^6,23

The pathophysiology of MIS-C is thought to be attributable to a hyperimmune response to the virus in a genetically susceptible child. Presenting symptoms can overlap with KD, toxic shock syndrome, macrophage activating syndrome, bacterial sepsis, and cytokine release syndrome.^5,7,20,21 The cytokine release syndrome “cytokine storm” is characterized by persistent fever with markedly elevated inflammatory markers and elevated proinflammatory cytokines such as interleukin-6. The data on cardiovascular involvement with COVID-19 and MIS-C are growing.^5,24 In adults, acute myocardial injury affects up to 20% of patients with COVID-19.²⁵ COVID-19 may result in cardiac injury through multiple hypothesized mechanisms, including cardiomyocyte injury attributable to an acute and dysregulated inflammatory response related to cytokine storm, microvascular dysfunction, viral invasion of cardiomyocytes resulting in cellular damage, and ischemic injury.¹¹ In MIS-C, the etiology of cardiovascular involvement is likely multifactorial, as summarized in Figure 1. In addition, SARS-CoV-2 infection is associated with endothelial injury and activation of the coagulation cascade, resulting in high D-dimer, which has also been commonly described in MIS-C.²⁶ D-dimer is a degradation product of cross-linked fibrin indicating augmented thrombin generation and fibrin dissolution. In adults with COVID-19, very elevated levels of D-dimer correlate with disease severity and may increase the risk for venous and arterial thrombosis although similar associations are not described in MIS-C.²⁷ Endothelial injury as well as platelet activation and coagulation abnormalities theoretically increase the risk for both arterial and venous thrombosis in MIS-C, although reported clinical cases have been rare.^26,28

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Clinical Manifestations

Case definitions have been recently published by the WHO, the Royal College of Paediatrics and Child Health, and the Centers for Disease Control and Prevention.^6,29–31 All definitions included fever, criteria for multisystem organ involvement, evidence of significant inflammation, and evidence of SARS-CoV-2 infection or exposure with no alternative plausible diagnosis (Table 1).²⁹ The WHO case definition requires a minimum duration of fever of 3 days and provides more cardiac-specific features including myocardial dysfunction, pericarditis, valvulitis, and coronary artery aneurysms.³⁰

The clinical presentation of MIS-C includes persistent fever with a median duration of 4 days at time of diagnosis in published cases.^29,30 Case series have reported that at least 50% of patients present in shock that is vasodilatory, cardiogenic, or a combination. These percentages can be affected by selection bias, as many studies included only patients with cardiac dysfunction or who needed to be admitted to the intensive care unit.⁵ Gastrointestinal symptoms including vomiting, diarrhea, and abdominal pain are common and are reported in 60% to 97% of patients. Rash (most commonly polymorphic rash in 50% to 60% and rarely erythema multiforme, petechiae, or gangrene), neurologic symptoms (headache, lethargy, or confusion in 30% to 58%), and respiratory symptoms (32% to 65%) are also common based on case series published to date.^29,32 Most respiratory symptoms are mild and the severe acute respiratory distress syndrome commonly seen in adults is not typically seen in children with MIS-C.³³ Signs typical of KD including bilateral conjunctival injection (32% to 45%), mucous membrane involvement (19% to 29%), and swollen hands and feet (8% to 16%) are less common but can occur.²⁹

Laboratory testing typically shows neutrophilia and lymphopenia, elevated inflammatory markers including C-reactive protein, fibrinogen, and ferritin, and elevated D-dimer.^5,34 BNP (B-type natriuretic peptide) levels may be markedly elevated and can be associated with modest elevations in troponin. All patients with suspected MIS-C should have viral PCR on nasopharyngeal swab and serologic testing.³⁵ Because false-negative PCR tests are possible and seroconversion to positive antibody status can occur over time, repeat PCR testing and serology are indicated if the index of suspicion is high.

Cardiac Findings in MIS-C

The cardiac manifestations of MIS-C are summarized in Table 2 and include ventricular dysfunction, coronary artery dilation or aneurysms, arrhythmia and conduction abnormalities, and more rarely pericarditis and valvulitis.^5,30

Acute myocardial dysfunction is the most common cardiac finding in patients with MIS-C.³⁶ In the initial case series from the United Kingdom and Italy, 6 of 8 and 5 of 10 patients were reported to have left ventricular (LV) systolic dysfunction. Subsequent larger case series have reported depressed LV ejection fraction in ≈50% to 60%, with patients presenting in shock having the highest risk of LV dysfunction.^5,21,36,37 Elevated troponin (64% to 95%) and BNP (73% to 95%) are also common and associated with presentation in shock and LV dysfunction. A recent study reported a series of 35 patients from 14 intensive care units in France and Switzerland with acute heart failure attributable to MIS-C. A total of 31 of 35 (88%) tested positive for SARS-CoV-2 infection by PCR of nasopharyngeal swab or serology and the others had a history of COVID-19 exposure. LV ejection fraction was depressed in all patients as it was one of the inclusion criteria and severely depressed (ejection fraction <30%) in one-third. In this high acuity cohort, 80% required inotropic support and 28% were managed with extracorporeal membrane oxygenation (ECMO). Mean NT-proBNP (N-terminal pro–B-type natriuretic peptide) was substantially elevated (5743 pg/mL) and all patients had an elevated troponin level. After treatment, LV function normalized in 71% of patients, with most patients experiencing rapid improvement in LV systolic function (median of 2 days from diagnosis to LV recovery). Despite being a high acuity cohort, there were no deaths in this study. Grimaud et al³⁸ reported on 20 patients admitted with cardiogenic/vasoplegic shock and a median LV ejection fraction of 35% (interquartile range, 25% to 55%). Nineteen of 20 patients required inotropes/vasopressors but no ECMO support was needed. All patients had a full recovery of LV function before discharge from the pediatric intensive care unit. In the largest case series to date (n=286), a study by Valverde et al³⁵ published in this issue of Circulation reported elevation in NT-proBNP and troponin in 93% of patients and depressed LV ejection fraction in 52%. This study showed an association between degree of elevation of the cardiac and inflammatory markers and the need for critical care.

Coronary artery dilation and aneurysms have been described in MIS-C.^21,39,40 The incidence of coronary artery abnormalities varies significantly among reports. Most of the larger series have reported coronary changes in 8% to 24% of patients.³⁵ Although the majority of patients demonstrated small aneurysms (z score 2.5 to 5), there have been rare cases of large/giant aneurysms (z score ≥10) and aneurysms that developed later during the convalescent period.^19,21 The pathologic mechanism of coronary artery dilation/aneurysm in MIS-C has not been elucidated. Coronary dilation in MIS-C may be related to fever and circulating inflammatory mediators or may be attributable to inflammation and disruption of the arterial wall as is seen in KD. The percentage of patients with LV dysfunction and coronary artery involvement in the case series published to date is shown in Figure 2.

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In addition to the potential for coronary artery aneurysms, other similarities between KD and MIS-C include prolonged fever, presenting clinical signs, and multisystem inflammation.⁴¹ However, there are several important differences. KD most often affects children younger than 8 years and is more common in Asians. This is different from MIS-C, where the average age is 9 to 11 years and it is more common in Black and Hispanic patients.^5,41 The clinical symptoms of MIS-C are more varied and feature more prominent gastrointestinal and neurologic symptoms. Laboratory features also distinguish MIS-C from KD, with patients with MIS-C having lower absolute lymphocyte and platelet counts, higher ferritin and D-dimer levels, and higher likelihood of elevated troponin or BNP. Ventricular dysfunction and presentation in shock are more common in MIS-C, with >50% of MIS-C cases presenting in shock compared with 5% to 10% in KD.⁴²

Cardiac electric abnormalities and arrhythmias, including heart block, have been reported in MIS-C.^4,43,44 In adults with severe COVID-19, both atrial and ventricular tachycardia have been reported.⁴³ Because MIS-C is a new entity, the incidence of arrhythmia remains to be determined. Atrioventricular conduction delay, most commonly first-degree heart block and more rarely high-grade heart block, has been reported and appears to occur more commonly in patients with depressed LV systolic function. Persistent ventricular arrhythmias requiring ECMO support have also been reported. ECGs may also show ST segment changes, QT prolongation, and T-wave abnormalities in patients with MIS-C.³⁶

Given the increased risk for severe COVID-19 in adults with underlying cardiac involvement, there is concern that patients with congenital heart disease may likewise be at increased risk for severe infection.¹¹ However, in the initial case series, CHD has not emerged as a clear risk factor for MIS-C.⁴⁵ Patients with cardiac transplant are at risk for prolonged excretion of the virus but their risk for MIS-C is unknown.

Treatment

Because MIS-C is a newly described entity, the following suggestions for management and surveillance strategies are speculative based on the review of the current literature. There are no controlled trials or comparative effectiveness studies evaluating treatment for MIS-C to date. Treatment protocols are derived from experience with KD, septic shock, and myocardial injury treatment. Because of multiorgan involvement in MIS-C, a multidisciplinary team approach is vital for diagnosis and treatment. Supportive care with fluid resuscitation, inotropes, mechanical ventilation, and, in the most severe cases, ECMO support are essential for some patients in the acute phase. Current treatment protocols for MIS-C are based on expert consensus because of the absence of evidence-based data and are largely directed at blunting the inflammatory response with immunomodulators that are commonly used in KD, other vasculitides, and cytokine storm. Intravenous immunoglobulin has been used most commonly in the published case series (in ≈70% to 100%). In patients presenting in shock and those with refractory manifestations, treatment with corticosteroids is reasonable. Immunomodulatory agents, including interleukin-1, interleukin-6, and tumor necrosis factor-α blockers, have been reported and may be considered in severe or refractory cases.⁵ The role of antiviral treatment with remdesivir is uncertain and should be limited to severe disease with active viral infection.⁴⁶ Patients with MIS-C may be at increased risk for thrombotic complications, especially in the setting of severe ventricular dysfunction or coronary artery aneurysms. Antiplatelet therapy should be considered in patients who meet the criteria for KD, have coronary artery changes, or have other risk factors for thrombosis. Therapeutic anticoagulation should be strongly considered in all patients with severe ventricular dysfunction or large/giant coronary artery aneurysm. For the remainder of patients with MIS-C, antithrombotic therapies should be tailored to individual assessment of risk; some groups have used the degree of elevation in D-dimer to determine need for anticoagulation.²⁶ Antiplatelet agents and anticoagulants may interact with other therapies, so inclusion of a clinical pharmacist in management decisions can be critically important in some cases.^26,47

Prognosis

The prognosis in MIS-C is not yet known as it is a new entity and our understanding is evolving. Mortality has been reported in 5 of the ≈230 suspected cases through mid-May 2020.^7,21 A recent case series reported 33 cases and 1 mortality in a patient after withdrawal of care secondary to stroke while on ECMO.²² Ventricular dysfunction improves in the majority of cases within the first week after treatment, but has persisted or worsened in a small number of patients. Arrhythmias have also tended to resolve. The natural history of coronary artery involvement is uncertain. No data are available on the longer-term effect of MIS-C on coronary architecture. In KD, coronary artery aneurysms typically develop in the first 8 to 14 days of the disease, although in few cases aneurysms can develop in the third week of illness, and can continue to enlarge over the ensuing weeks.⁴¹ Systematic longer-term follow-up as well as standardized approaches to coronary artery imaging and interpretation are needed to provide clarity on the evolution of coronary abnormalities in MIS-C. Table 3 summarizes the published studies on the cardiac manifestations of MIS-C.

Follow-Up

A standardized approach to cardiac testing and follow-up is needed to optimize outcomes and advance knowledge on the medium- and long-term cardiac outcomes in MIS-C. Table 4 shows a summary of suggested cardiac testing and follow-up. Of concern, emergence of new coronary artery aneurysms has been reported in the convalescent phase of illness, and therefore serial follow-up echocardiograms are needed even in patients with no cardiac abnormalities in the acute phase of illness.²¹ In patients with initially normal function and normal coronary artery dimensions, a repeat echocardiogram in 1 to 2 weeks to assess coronary artery dimensions is recommended.^35,41 For patients with coronary artery dilation/aneurysm on initial echocardiogram (z score >2.5), we suggest repeating the echocardiogram every 2 to 3 days until the coronary size is stable and then tailoring frequency of follow-up according to the severity of coronary artery aneurysm as described in the American Heart Association KD guidelines.⁴¹ For patients with systolic dysfunction and normal coronary arteries on initial echocardiogram, we suggest repeating echocardiograms as clinically indicated, at a minimum in 1 to 2 weeks, and continuing to image the coronary arteries with future echocardiograms. A follow-up echocardiogram in 4 to 6 weeks is suggested in all patients with MIS-C as coronary artery involvement may develop in the convalescent phase. Cardiac CT scan can provide accurate evaluation of the coronary artery anatomy and may be considered in patients with difficult acoustic windows. Cardiac magnetic imaging may be useful during the initial hospitalization or ≈3 months after acute illness to evaluate ventricular function and myocardial characteristics including edema, diffuse fibrosis, and scar by myocardial late gadolinium enhancement. Patients’ clinical stability and need for anesthesia, unless already intubated and sedated, must also be considered, especially during hospital admission during the acute illness. Because arrhythmia and heart block can occur, we recommend electrocardiograms at diagnosis and at a minimum of every 48 hours while inpatient. Patients with conduction abnormalities should be monitored on telemetry and treated appropriately. Finally, cardiac evaluation, including an echocardiogram and ECG at 1 year, is reasonable in patients with MIS-C, particularly those who had cardiac abnormalities during the acute or subacute period. New information is emerging rapidly on MIS-C and it is important to continue to follow the guidelines from the WHO, the Centers for Disease Control and Prevention, state health departments, and local hospital practices. MIS-C is a reportable disease in many states, which will facilitate tracking cases to better understand the prevalence and the prognosis of MIS-C.

Summary

SARS-CoV-2 infection–related MIS-C is a rare but serious hyperimmune response in children and adolescents that occurs ≈4 weeks after acute viral infection. LV dysfunction is the most common cardiac manifestation of MIS-C, followed by coronary artery aneurysm and electric conduction abnormalities. Hemodynamic support and immunomodulatory therapies are the primary treatments. Most children recover from MIS-C, but medium- and long-term sequelae are unknown. Standardized approaches to cardiac monitoring and follow-up are vital for optimizing patient care and advancing understanding of outcomes in MIS-C. We present a suggested protocol for cardiac testing and follow-up based on the available literature and the previous KD clinical guidelines. Because of multiorgan involvement in MIS-C, a multidisciplinary team approach is vital for diagnosis and treatment.

Footnotes