Abstract
Background
Pediatric myocarditis is an inflammatory condition of the heart muscle typically caused by viral infections, drugs, toxins, bacteria, or autoimmune disease.
Aim of review
The purpose of this article is to review pediatric myocarditis, including epidemiology, pathophysiology, clinical features, diagnosis, treatment, and prognosis.
Key scientific concepts of review
The incidence of myocarditis in children is 0.2 to 2 cases per 100,000 children aged <18 years. Myocarditis is most often caused by a virus such as coxsackievirus, adenovirus, parvovirus B19, human herpesvirus 6, or SARS-CoV-2 entering cardiomyocytes via virus-specific receptors. Pediatric myocarditis may be acute or chronic. A key feature of acute myocarditis is a viral prodrome that may occur one to four weeks before the onset of symptoms associated with cardiac pathology. The criterion standard for diagnosis is histology from an endomyocardial biopsy. Cardiac magnetic resonance imaging changes suggestive of myocarditis may be considered confirmatory, but access to this study is not readily available. Echocardiography is typically the first imaging study used in the diagnosis of pediatric myocarditis, given its ubiquity. Chest radiographic findings in pediatric myocarditis may include cardiomegaly, pulmonary venous congestion, and pleural effusion. Electrocardiography in patients who have pediatric myocarditis may show nonspecific ST-segment changes, T wave inversion, atrioventricular block, ST-segment elevation, and low-voltage QRS complexes in aVR, aVL, and aVF leads. Treatment includes anti-inflammatory medications and hemodynamic support. Patients who are hemodynamically unstable may require heart failure treatment in an intensive care unit. In rapidly deteriorating patients, early mechanical circulatory support may be important, including extracorporeal membrane oxygenation, a ventricular assist device, an implantable cardioverter-defibrillator, or heart transplant. Noval therapies, including use of mesenchymal stem cells, are also under investigation. Myocarditis may resolve, and ventricular function may improve with supportive therapy, but some patients may develop complications associated with major morbidity and mortality. Regular cardiology follow-up may be advised after diagnosis to monitor changes to the myocardium.
Highlights
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Pediatric myocarditis is commonly caused by viral infection.
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The criterion standard for diagnosis is histology from an endomyocardial biopsy, but cardiac MRI may be seen as confirmatory.
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Treatment may include anti-inflammatory medications and hemodynamic support.
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Hemodynamically unstable patients may require heart failure treatment.
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Some patients develop complications that may cause major morbidity and mortality.
1
Introduction
Pediatric myocarditis is an inflammatory condition of the heart muscle typically caused by viral infections, drugs, toxins, bacteria, or autoimmune disease [ ]. Common symptoms may include chest pain, shortness of breath, and palpitations, and patients may experience flu-like symptoms before onset of myocarditis symptoms [ ]. Some patients may be asymptomatic. Most patients do not have long-lasting serious health effects, but some patients may have prolonged decreased cardiac strength, heart rhythm abnormalities, and acute heart failure [ ].
Dilated cardiomyopathy is another complication leading to chronic inflammation and myocyte injury that may persist beyond the viral illness [ ]. Dilated cardiomyopathy and cardiogenic shock that is not responsive to medical management may necessitate treatment with ventricular assist devices or heart transplant. Fulminant myocarditis is the most severe form of myocarditis and includes sudden and severe myocardial inflammation, myocyte necrosis, edema, and cardiogenic shock [ ]. Fulminant myocarditis may cause death in 68.8 % of affected children within 7 days of hospital admission [ ]. Early diagnosis is important in pediatric myocarditis associated with severe symptoms to prevent mortality.
Pediatric myocarditis is a disease that may be difficult to diagnose and treat. Before the introduction of endomyocardial biopsy and advanced imaging techniques, causes of myocarditis were identified primarily through autopsy [ ]. The incidence of pediatric myocarditis may be underestimated because of the occurrence of asymptomatic or mildly symptomatic cases. Myocarditis may be associated with sudden infant death syndrome, underscoring the need for improved screening and diagnostic methods [ ].
Endomyocardial biopsy has traditionally been considered the criterion standard for diagnosing acute myocarditis. However, due to it being an invasive procedure with associated risks, cardiac magnetic resonance imaging may be a safer and equally effective alternative [ ]. Early and accurate detection is important and may markedly improve health outcomes and survival. Further research is being performed to refine diagnosis and treatment.
There is controversy about optimal treatment of pediatric myocarditis, in part because of the diversity of presentation and progression. Current therapies often target viral replication and immune suppression, but individualized treatment plans are needed because of variability in disease progression. Prognosis may vary based on several factors, such as severity of symptoms, age of onset, and timing of diagnosis. Although pediatric patients may recover, long-term complications may include dilated cardiomyopathy, heart failure, and death [ ].
The purpose of this article is to review pediatric myocarditis, including epidemiology, pathophysiology, clinical features, diagnosis, treatment, and prognosis. The goal is to provide clinicians and researchers with up-to-date information about evaluation and treatment to aid improvement in patient outcomes and to guide future research.
2
Epidemiology
Limited information is available about the epidemiology of myocarditis in childhood. The incidence of myocarditis in children is 0.2 to 2 cases per 100,000 children aged <18 years [ ]. However, the incidence may be underestimated because affected children may be asymptomatic or have mild symptoms and may not be evaluated or treated. Myocarditis is found in about 2 % of infant autopsy cases, with >50 % of all myocarditis reported from autopsy being in infants younger than 1 year old [ ]. Furthermore, 16 % to 20 % of children who have sudden infant death syndrome may have myocarditis shown on autopsy as the possible cause of death [ ]. Sudden cardiac death may be more common in infants than in older children and adolescents. Myocarditis has also been observed at autopsy in 12 % of teenagers after sudden cardiac death [ ].
Ethnic differences have been documented in children diagnosed with myocarditis. In children hospitalized with myocarditis, the odds of death are 1.25 and 1.29 in African American and Hispanic children compared to White children, in part associated with possible differences in hospital care or response to therapy [ ]. In African American children, the odds of cardiac arrest is 1.23, and the odds of extracorporeal membrane oxygenation use is 1.46 compared to White children [ ]. These differences may be associated with ethnicity or social determinants of health, such as limited access to health care and treatment options provided.
Hospital admissions due to myocarditis are uncommon in children. In a Finnish study of pediatric myocarditis cases in patients 15 years or younger, myocarditis comprised 0.02 % of all hospital admissions, with the median age of patients being 14 years [ ]. There is no difference in the incidence of diagnosis of myocarditis between boys versus girls aged 0 to 6 years [ ]. However, in children aged 6 to 15 years, boys may have a significantly higher risk of developing myocarditis than girls [ ]. In Finland, the incidence of myocarditis increased more rapidly in boys than girls after 3 years of age, with the incidence rate in boys aged 15 years being approximately 18 per 100,000 person-years compared to approximately 4 per 100,000 person-years in girls. Pediatric myocarditis is most frequently caused by viral infection, especially parvovirus and human herpesvirus 6, but other causes of myocarditis include bacterial or fungal infection, toxins, drugs, and autoimmune diseases [ , ]. Enteroviruses such as coxsackievirus infection also may be a common cause of myocarditis [ ]. The prevalence of viral myocarditis may vary based on the viral circulation in the population, and the incidence may coincide with outbreaks. In an outbreak of coxsackievirus infection in Europe in 1965, 5 % to 12 % of patients had cardiac manifestations after infection [ ].
Myocarditis in children may also be caused by Borrelia burgdorferi , which is the causative agent of Lyme disease, and Trypanosoma cruzi, which causes Chagas disease and is a common infection in Central and South America [ ]. Furthermore, drugs, such as phenytoin, anthracyclines, and sulfonamides, may be cardiotoxic or cause hypersensitivity reactions that may damage the heart [ ].
Children presenting to the emergency department with myocarditis typically have previous symptoms of an upper respiratory or gastrointestinal infection [ ]. Primary factors associated with poor outcomes include young age, female sex, symptoms and signs of heart failure on admission, and myocarditis confirmed with polymerase chain reaction for cardiotropic viruses from pericardial fluid, blood, pharyngeal swab, or stool. [ ]. Death from myocarditis may occur in 15.4 % of patients requiring intensive care and 66.7 % of patients who require treatment with a ventricular assist device [ ].
3
Pathophysiology
Myocarditis is most often caused by a virus such as coxsackievirus, adenovirus, parvovirus B19, human herpesvirus 6, or SARS-CoV-2 entering cardiomyocytes via virus-specific receptors [ ]. This invasion may cause cardiomyocyte necrosis and degradation of the extracellular matrix, which may cause the release of endogenous molecules known as damage-associated molecular patterns and the pathogen also produces pathogen-associated molecular patterns. These molecules activate pattern-recognition receptors on innate immune response cells such as neutrophils, monocytes, and macrophages, resulting in amplification of inflammatory response to infection [ ].
Toll-like receptor 4 is the pattern recognition receptor most commonly implicated in the inflammatory response of myocarditis via production of proinflammatory cytokines such as interleukin 1β, tumor necrosis factor-α, interferon γ, and interleukin 18. Toll-like receptor 3 is another pattern-recognition receptor associated with the production of type I interferons, which may cause less severe but higher incidence of myocarditis [ ].
Nucleotide-binding oligomerization domain 2 is another pattern-recognition receptor located in the cytoplasm of cardiomyocytes that may recognize single-stranded RNA from viruses and may contribute to inflammation, fibrosis, and left ventricular remodeling. Nucleotide-binding oligomerization domain 2 may activate the NLRP3 inflammasome, an intracellular multiprotein complex, which may cause cell death and production of interleukin 1β and interleukin 18 [ ].
The cytokines and chemokines released by cardiomyocytes into the extracellular matrix may induce chemotaxis of neutrophils, monocytes, and macrophages. Mice that are depleted in neutrophils, monocytes, and macrophages may have less severe myocarditis despite higher viral load. Monocytes are the predominant cell type activated in acute myocarditis, and when infected with coxsackievirus B, they produce tumor necrosis factor-α and become cytotoxic to cardiomyocytes. Monocytes also produce interleukin 10, which has anti-inflammatory properties [ ].
Several days after the acute phase of myocarditis, CD4+ T cells and interleukin 17 may facilitate cardiac remodeling and activation of fibroblasts, resulting in cardiac scarring and complications such as dilated cardiomyopathy [ ].
Immune checkpoint inhibitors, which are anticancer drugs that can potentially be used in the treatment of 50 % of all cancer patients, may also cause myocarditis. Immune checkpoint inhibitors most commonly target cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 on T cells, which function in distinguishing between self and nonself antigens. Immune checkpoint inhibitors may prevent the identification of cardiomyocytes as self and may trigger an autoimmune response against the heart. Further study is needed to characterize the association between immune checkpoint inhibitors and myocarditis and how this information can be used to develop new therapies for myocarditis [ ].
4
Clinical presentation
Pediatric myocarditis may be acute or chronic. A key feature of acute myocarditis is a viral prodrome that may occur one to four weeks before the onset of symptoms associated with cardiac pathology [ ]. The timing of myocarditis may vary with disease severity. In a review of pediatric myocarditis at German medical centers, the average onset of symptoms before hospital admission was 16.1 days [ ].
Previous studies have ranked the frequency of various symptoms associated with myocarditis in children. The American Heart Association reported that the most common presenting symptoms included fatigue (70 % of patients), shortness of breath (65 %), nausea/vomiting or abdominal pain (48 %), rhinorrhea (44 %), cough (44 %), chest pain (42 %), and palpitations (16 %) [ ]. Physical examination findings in pediatric myocarditis may vary and include abnormal findings on heart auscultation, respiratory compromise, and systemic signs associated with secondary heart failure.
Most patients with pediatric myocarditis present with an abnormality on the respiratory physical examination. The most common physical examination findings of pediatric myocarditis in the emergency department may include tachypnea, dyspnea, or other indicators of respiratory distress [ , ]. A sign of respiratory distress may be present in 68 % of emergency department patients who are diagnosed with pediatric myocarditis, such as grunting, chest indrawing, or tracheal tugging [ ]. Other common physical findings on respiratory examination in pediatric patients with myocarditis may include abnormal lung auscultation, and signs of respiratory tract infection [ ].
Other clinical signs of myocarditis in children include tachycardia, a murmur or gallop on auscultation, edema, hepatomegaly, and decreased peripheral pulses [ ]. Fever, hypotension, and pallor also may be present, depending on the time course and disease severity [ ].
5
Diagnostic evaluation
The criterion standard for diagnosis of pediatric myocarditis is endomyocardial biopsy. A positive endomyocardial biopsy is considered proof, and positive cardiac magnetic resonance imaging is considered confirmation [ ]. The diagnosis may be supported by results of other imaging studies, electrocardiography, and laboratory studies. New diagnostic tools also may aid in the diagnosis and prediction of prognosis in pediatric patients who have myocarditis.
5.1
Endomyocardial biopsy
Although invasive and not universally available, endomyocardial biopsy, for many years, has been the criterion standard for diagnosing pediatric myocarditis. Complications of endomyocardial biopsy may occur in 12 % to 15 % of patients undergoing the procedure [ ]. While a positive finding on endomyocardial biopsy may confirm the diagnosis of myocarditis, a negative result may not definitively exclude the presence of the disease since infiltration within the myocardial tissue may be patchy [ ].
The most common finding on histologic analysis is lymphocytic infiltration of the myocardium. [ ]. The lymphocytic infiltrate may be further characterized with immunohistochemistry (see Fig. 1 ) [ ]. A review of data from the Registry for Children and Adolescents with Suspected Myocarditis, also known as the MYKKE registry, classified myocarditis into three forms based on histologic findings: (1) acute myocarditis, with at least 14 leukocytes per mm 2 and the presence of myocyte damage; (2) healing or chronic myocarditis, with >14 leukocytes per mm 2 and identifiable fibrosis but without damage to cardiomyocytes; and (3) healed myocarditis, with multifocal fibrosis but without evidence of inflammation [ ].
