Abstract
Background
Cardiac problems may occur in children who have acute COVID-19 but are more prevalent with multisystem inflammatory syndrome in children (MIS-C).
Aim of review
The purpose of this article is to review the cardiac manifestations of COVID-19 in children and MIS-C, including evaluation and treatment.
Key scientific concepts of review
Myocarditis in children who have COVID-19 may occur from a combination of direct viral injury and immune-mediated cardiac tissue damage. Treatment of myocarditis in children includes supportive therapy, intravenous immunoglobulin, corticosteroids, and other immunomodulatory medications. Pericarditis may occur in 4.5 % of children with acute COVID-19 and 12 % to 25 % with MIS-C; treatment may vary with severity of pericarditis and may include pharmacotherapy with high-dose ibuprofen, colchicine, and anakinra, pericardiocentesis, and pericardiectomy. Ventricular dysfunction primarily involves the left ventricle and is observed in patients who have MIS-C but typically not acute COVID-19; treatment may include intravenous immunoglobulin and corticosteroids, but some patients may have deterioration and develop cardiogenic shock. Coronary artery abnormalities, including dilation and aneurysm, may occur in 0.9 % of patients who have severe acute COVID-19 and 13 % to 24 % of patients who have MIS-C; treatment may include prophylactic anticoagulation, especially in children aged >12 years. Arrhythmias occur in children who have severe cases of COVID-19 and 7 % to 60 % of children who have MIS-C and may include atrial tachycardia, atrial fibrillation, complete atrioventricular block, and ventricular tachycardia. Cardiovascular complications associated with COVID-19 may be difficult to diagnose in children. Longitudinal studies about the cardiovascular effects of COVID-19 in children may help identify patients who may have the highest risk of morbidity and mortality.
Graphical abstract
Highlights
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SARS-CoV-2 infection may cause cardiovascular hyperinflammation.
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Cardiac disease may occur in children with severe acute COVID-19.
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Cardiac disease is common with multisystem inflammatory syndrome in children.
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Cardiac complications of COVID-19 in children include myocarditis and pericarditis.
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Ventricular dysfunction, coronary artery aneurysms, and arrhythmias may occur.
1
Introduction
SARS-CoV-2, which is an enveloped, nonsegmented single-stranded RNA virus of the coronavirus family, causes COVID-19. As of May 11, 2023, approximately 15.6 million children tested positive for SARS-CoV-2 since the start of the pandemic in the United States, representing 17.9 % of total cumulative cases for all ages [ ].
SARS-CoV-2 infection may cause a wide range of disease severity, from asymptomatic disease to fatal infection [ ]. In children, SARS-CoV-2 infection may cause respiratory failure, acute kidney injury, shock, coagulopathy, and multiorgan failure. Risk factors for developing severe COVID-19 include children aged <2 years and those with premature birth, airway abnormalities, chronic lung disease, neurological disorders, and cardiovascular disease. In patients between age 2 and 17 years, severe disease is associated with feeding tube dependence, diabetes mellitus, and obesity [ ].
Cardiac complications of acute COVID-19 in children include myocarditis, pericarditis, ventricular dysfunction, coronary artery abnormalities, and arrhythmias. The pathophysiology includes viral binding of the SARS-CoV-2 virus spike protein to angiotensin-converting enzyme 2 receptors on the surface of host cells, which promotes viral uptake. In addition to cardiovascular injury associated with direct viral invasion of cardiomyocytes that express angiotensin-converting enzyme 2, other mechanisms of cardiac damage include hyperinflammation, endothelial overactivation, hypoxia-induced myocardial ischemia, and hypercoagulable state [ ].
Cardiac involvement is also observed in multisystem inflammatory syndrome in children (MIS-C), which is a severe, hyperinflammatory, multisystem complication of SARS-CoV-2 infection that may occur at 2 to 6 weeks after initial COVID-19 [ , , ]. MIS-C is defined as an illness in a person aged <21 years presenting with fever, systemic inflammation (C-reactive protein level ≥ 3.0 mg/dL), severe illness requiring hospitalization, multisystem disease (at least two of these criteria: shock, cardiac, mucocutaneous, gastrointestinal, hematologic involvement), no alternative diagnoses, and close contact with a case of COVID-19 and a positive test for SARS-CoV-2 virus within 60 days before hospitalization [ ]. The gastrointestinal system is most commonly involved in MIS-C, and the mucocutaneous system is the second most commonly involved [ , , ]. Most MIS-C patients present with abdominal pain, diarrhea, vomiting, and symptoms caused by inflammation of the ileum and colon and thickening of the bowel. Other symptoms include erythema of the palms of hands and soles of feet, periorbital erythema and swelling, strawberry tongue, and rash [ , ]. Hypotension may be more frequent in older than younger patients and hypovolemic or cardiogenic shock may occur [ ]. MIS-C is rare, with only 9722 cases and 79 associated deaths in the United States reported to the Centers for Disease Control and Prevention on or before September 5, 2024 [ ].
Cardiac manifestations may occur with acute COVID-19 (12 % of patients) but are more prevalent with MIS-C (63 %–84 %) [ , , , ]. Similarities in clinical presentation and complications have been observed between MIS-C and Kawasaki disease, and the treatment of MIS-C has been based on pediatric experience with Kawasaki disease.
The purpose of this article is to review the cardiac manifestations of COVID-19 in children and MIS-C, including the evaluation and treatment of myocarditis, pericarditis, ventricular dysfunction, coronary artery abnormalities, and arrhythmias.
2
Myocarditis
Myocarditis associated with SARS-CoV-2 infection in children may be observed with acute COVID-19 and 76 % of cases of MIS-C [ ]. From March 2020 to January 2021, the risk of myocarditis in children aged <16 years and diagnosed with COVID-19 was 0.133 %, and the risk of myocarditis was 37 times greater in children with than without COVID-19 [ ]. Therefore, the study of COVID-19 myocarditis in children is important despite its rarity.
The myocardium is a specific target tissue for SARS-CoV-2 virus, which may cause myocarditis and other cardiovascular problems [ ]. The pathophysiology of COVID-19 myocarditis may be a combined effect of direct viral injury and immune-mediated damage of cardiac tissue [ ]. Immune dysregulation and cytokine storm associated with COVID-19 may also contribute to myocardial damage [ ]. SARS-CoV-2 RNA was identified in cardiac tissue of a fatal case of MIS-C, suggesting that myocardial inflammation may be attributed to viral damage of cardiac cells. Viral particles observed within neutrophils provide evidence for inflammation induced by the virus [ ]. In 5 children with COVID-19 myocarditis, autopsy findings also supported the hypothesis that direct injury induced by the virus may cause COVID-19 myocarditis, with SARS-CoV-2 virus identified in cardiac cells of all patients and endothelial cells of the heart and brain in two patients [ , ]. Furthermore, extracellular vesicles harboring viral mRNA may evade the immune system and travel through the lymphatics or bloodstream to the heart, where they may be taken up by antigen presenting cells and infect cardiac cells [ , ].
The clinical presentation is similar for general, COVID-19, and MIS-C myocarditis. Flu-like symptoms may occur before onset, and further symptoms include chest pain, shortness of breath, and palpitations [ ]. Children with COVID-19 myocarditis commonly present with fever, fatigue, chest pain, and shortness of breath [ ].
Diagnostic evaluation for suspected COVID-19 myocarditis includes analysis of cardiac enzyme levels, inflammatory markers, an electrocardiogram, and an echocardiogram [ ]. The absence of an elevated troponin level does not exclude the presence of COVID-19 myocarditis, which may occur without necrosis [ ]. The electrocardiogram in MIS-C may include atrioventricular block, repolarization abnormalities, sinus bradycardia, and tachyarrhythmias [ ]. If myocarditis is detected, an endomyocardial biopsy may confirm the diagnosis but is associated with risks such as arrhythmia and perforation of cardiac tissue. False results can occur due to sampling error, as myocardial involvement is often patchy [ ]. An echocardiogram is typically performed within 12 h after admission to the hospital and may show abnormal ventricular function associated with myocarditis, coronary artery abnormalities, and a pericardial effusion [ ]. Follow-up electrocardiograms and echocardiograms are obtained every 2 to 3 days during acute MIS-C and less frequently after hospital discharge [ , ]. Cardiac magnetic resonance imaging may show myocardial edema in 33 % of patients who have MIS-C, pericardial effusion in 24 %, and late gadolinium enhancement in 14 % but may be normal ( Fig. 1 ) [ , ]. Follow-up cardiac magnetic resonance imaging may be normal at 2 months after symptomatic illness [ ]. Patients who have transient hyperinflammation may have overall good cardiac outcome [ , ].
Treatment of COVID-19 myocarditis in children consists of supportive care, including mechanical circulatory support, supplemental oxygen, and fluid management [ ]. The treatment of myocarditis in patients who have MIS-C may include immunomodulatory treatment [ ]. Immunosuppressive medication may decrease mortality or the need for heart transplant, and immunoglobulin therapy may also be helpful [ ]. Combination therapy with intravenous immunoglobulin and corticosteroids has been recommended as first-line therapy for severe MIS-C and may promote rapid recovery [ ].
Biological response modifier drugs were approved by the United States Food and Drug Administration for the treatment of autoimmune diseases and may be used to treat refractory MIS-C, but these medications are avoided in patients who have other active infections, such as tuberculosis [ ]. In addition, interleukin 1–receptor antagonists have been used in Kawasaki disease to prevent the development of coronary artery aneurysms; therefore, the interleukin 1–receptor antagonist anakinra may be used in children who have MIS-C to decrease inflammation and risk of developing tissue damage [ ]. Anakinra may be considered for MIS-C patients who fail to improve or have contraindications to intravenous immunoglobulin and glucocorticoids [ ]. Interleukin 6–receptor antagonists have also been considered, but more research is needed to evaluate use in COVID-19 patients and the risks of developing coronary artery aneurysm [ , ]. Tumor necrosis factor-α blockers also may be a potential treatment for MIS-C, but it is unknown whether it may be used together with interleukin 1–receptor antagonists [ ].
3
Pericarditis
Viral infections are the most common cause of pericarditis in children. Children with severe cases of COVID-19 also may develop pericarditis. Pericarditis after SARS-CoV-2 infection may be caused by a systemic hyperimmune response without direct damage from viral invasion of pericardial tissue [ ]. The systemic immune response causes major inflammation and endothelial dysfunction, systemic cytokine circulation, and T-cell–mediated inflammation [ ]. Therefore, pericarditis is a common cardiac abnormality in patients who have MIS-C [ ]. Pericarditis may occur in 4.5 % of children with acute COVID-19 and 12 % to 25 % with MIS-C [ , , , ].
Case reports about pericarditis in children show that the primary symptom may be chest pain that may worsen with inspiration [ ]. Fever, cough, dyspnea, and orthopnea may be present. Diagnosis of acute pericarditis may be based on the presence of at least 2 of 4 characteristics (chest pain, pericardial rub, pericardial effusion, electrocardiogram changes) [ ]. Physical examination may be unremarkable or show distant, muffled heart sounds, a pericardial friction rub, or signs of COVID-19-related pneumonia.
Laboratory findings may include leukocytosis or leukopenia, elevated erythrocyte sedimentation rate and C-reactive protein level, and elevated D-dimer level and levels of cardiac markers such as troponin-I, troponin-T, creatine kinase MB fraction, or B-type natriuretic peptide. Chest radiography may show an enlarged cardiac silhouette and bilateral pleural effusions [ ]. Chest computed tomography scan may show findings of COVID-19 pulmonary complications such as bilateral pulmonary infiltrates, peripheral ground-glass opacities, and pleural effusion [ , ]. A 12‑lead electrocardiogram may show typical changes such as diffuse ST elevation and PR depression, as well as T-wave inversion in the anteroseptal or inferolateral leads and low QRS voltage. The echocardiogram typically shows a pericardial effusion ( Fig. 2 ) [ , , , ].
Treatment may vary with severity of pericarditis and may include pharmacotherapy with high-dose ibuprofen, colchicine, anakinra, pericardiocentesis, and pericardiectomy. In reported cases, prognosis was favorable; patients were discharged from the hospital after 4 to 15 days, and there were no deaths [ ].
4
Ventricular dysfunction
Ventricular dysfunction primarily involves the left ventricle and is observed in patients who have MIS-C but typically not acute COVID-19 [ , ]. In patients who have MIS-C, 29 % to 42 % of children may present with ventricular dysfunction and 5 % with congestive heart failure [ , , , , , ]. Ventricular dysfunction may be a component of myocarditis and associated with increased cardiac enzyme levels, but some patients may have dysfunction with normal biomarkers, possibly because of disease without direct cardiomyocyte injury [ ].
Elevated levels of N-terminal pro-B-type natriuretic peptide and troponin may be associated with cardiac inflammation and directly correlated with heart failure severity in patients with COVID-19 [ ]. Ventricular dysfunction, determined from the observation of decreased ejection fraction (EF) with echocardiography, is commonly present in patients who have MIS-C. In a study of 21 patients who had MIS-C with features of Kawasaki disease, 16 patients (76 %) had myocarditis with decreased ejection fraction (median EF, 42 %; range, 10 %–57 %) [ ]. Another study of 186 patients with MIS-C showed that ejection fraction was decreased (30 % to <55 %) in 33 % of patients and markedly decreased (<30 %) in 5 % of patients [ ]. In a comparative study, ejection fraction was decreased (<55 %) in 172 of 539 patients with MIS-C (32 %) but only 13 of 577 patients with severe acute COVID-19 (2 %) [ ].
Deterioration of ventricular dysfunction may cause cardiogenic shock. Children admitted with MIS-C may have signs of vasodilatory shock [ ]. Cardiac failure requiring treatment with vasopressors or vasoactive medication may occur in half of MIS-C patients [ , ], in contrast with only 5 % of children who have Kawasaki disease [ , ]. In addition, patients with cardiac failure from acute COVID-19 or MIS-C may require extracorporeal membrane oxygenation (ECMO) [ ]. Patients with MIS-C may require invasive mechanical ventilator support in 9 % to 20 % of patients, and extracorporeal membrane oxygenation in 1.5 % to 4 % of patients [ , , ].
Whether the pathophysiology of ventricular dysfunction observed is directly related to the infection itself or MIS-C, the treatment for ventricular dysfunction may include supportive care, intravenous immunoglobulin, and corticosteroids to target the exaggerated inflammatory response [ ]. Ventricular dysfunction may improve and become normal within several days or weeks after the diagnosis of MIS-C, suggesting that the dysfunction may be attributable to acute stress and an exaggerated systemic inflammatory response [ , ].
5
Coronary artery abnormalities
Coronary artery dilation and aneurysms typically are delayed after onset of COVID-19 and may be a manifestation of MIS-C and are rarely associated with acute COVID-19 ( Fig. 3 ). Coronary artery abnormalities may occur in 0.9 % of patients who have severe acute COVID-19 and 13 % to 24 % of patients who have MIS-C [ , , , , , ].
The pathophysiology of coronary artery dilation and aneurysms in COVID-19 and MIS-C is unknown but may be similar to the pathophysiology in Kawasaki disease [ ]. Weakening of coronary arteries may occur from acute necrotizing arteritis, characterized by vessel wall infiltration by neutrophils and aneurysm formation. Macrophages and T lymphocytes may infiltrate the damaged vessel wall and cause chronic vasculitis and stenosis [ ]. Coronary aneurysms in MIS-C may be smaller and return to normal diameter sooner than in Kawasaki disease, consistent with the hypothesis that coronary artery involvement in MIS-C may be associated with vasodilation secondary to the hyperinflammatory state [ , , , , ].
As with other conditions related to inflammation and endothelial dysfunction, hypercoagulability may occur in patients who have COVID-19 and MIS-C. In a study of patients who had MIS-C, 90 % of patients tested had high D-dimer levels (median, 2599 ng/mL) [ ]. Evaluation of children with MIS-C may include D-dimer level, tests for other cardiac and inflammatory markers, and echocardiograms. With MIS-C, echocardiography is recommended at diagnosis and during follow up to evaluate coronary dimensions ( Fig. 4 ). If there is concern for distal coronary artery aneurysms, a cardiac CT can be considered if they are not visualized on echocardiography [ , ].
