Clinical manifestations and diagnosis of myocarditis in children

INTRODUCTION — Myocarditis is an inflammatory disease of the myocardium with many different etiologies, most of which are infectious (table 1). Affected patients can present with a broad clinical spectrum of signs and symptoms ranging from subclinical disease to cardiogenic shock, arrhythmias, and sudden death (table 2).

The incidence, clinical manifestations, and diagnosis of myocarditis in children are reviewed here. The treatment and prognosis of myocarditis are discussed separately. (See "Treatment and prognosis of myocarditis in children".)

Myocarditis related to coronavirus disease 2019 (COVID-19) infection and vaccination is discussed elsewhere. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis" and "COVID-19: Vaccines", section on 'Myocarditis'.)

ETIOLOGY — The causes of myocarditis are diverse and include infectious, toxic, and autoimmune etiologies (table 1). Infectious, particularly viral, etiologies are most common in children. The most common causes of viral myocarditis are enterovirus (coxsackie group B), adenovirus, parvovirus B19, Epstein-Barr virus, cytomegalovirus, and human herpes 6 [1]. Cases may be sporadic or epidemic and have seasonal and geographical variation [2,3]. Rarely, pediatric myocarditis may be associated with autoimmune disorders and drug hypersensitivity. The etiology and pathogenesis of myocarditis are presented in greater detail separately. (See "Myocarditis: Causes and pathogenesis".)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause a clinical picture that mimics acute viral myocarditis; however, it is thought to occur as a secondary effect of the virus rather than direct myocarditis. In children, this clinical picture is most commonly seen in the context of multisystem inflammatory syndrome in children (MIS-C; also called pediatric inflammatory multisystem syndrome [PIMS]), which is discussed separately. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

Myocarditis and pericarditis have also been described as rare complications following receipt of the mRNA SARS-CoV-2 vaccines, particularly in male adolescents and young adults. (See "COVID-19: Vaccines", section on 'Myocarditis'.)

In a single-center retrospective study describing the clinical findings in pediatric patients hospitalized for classic viral myocarditis (n = 43), MIS-C (n = 149), or SARS-CoV-2 vaccine-associated myocarditis (n = 43), most patients with MIS-C and vaccine-associated myocarditis had mild to no ventricular dysfunction at presentation, whereas those with classic myocarditis tended to have more significant left ventricular dysfunction [4]. Patients with MIS-C and vaccine-associated myocarditis had rapid recovery with nearly all patients having normal cardiac function at discharge, whereas approximately one-quarter of those with classic myocarditis had ongoing cardiac dysfunction at the time of discharge.

INCIDENCE — Myocarditis is rare in children, with an estimated annual incidence of 1 to 2 per 100,000 children [5-9]. In a retrospective study from a single tertiary pediatric center, the estimated prevalence of myocarditis among children presenting to their emergency department was 0.5 cases per 10,000 visits [10]. In another report, myocarditis represented 0.3 percent of 14,322 patients seen over a 23-year period at Texas Children's Hospital [11]. Most studies report a bimodal age distribution with peaks in infancy and adolescence [12,13].

However, these data likely underestimate the true incidence of pediatric myocarditis since some affected children may have subclinical disease. In addition, the diagnosis can be difficult to establish given the nonspecific symptoms and lack of a sufficiently sensitive and specific diagnostic test for myocarditis. (See 'Diagnosis' below.)

In autopsy studies, evidence of myocarditis is noted in approximately 10 to 20 percent of infants and children who died suddenly and unexpectedly [14-19]. (See "Sudden unexpected infant death including SIDS: Initial management", section on 'Differential diagnosis' and "Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) in children", section on 'Etiology'.)

CLINICAL MANIFESTATIONS

Presentation — The clinical presentation of myocarditis is variable. Affected patients can present with a broad clinical spectrum of signs and symptoms ranging from subclinical disease to cardiogenic shock, arrhythmias, and sudden death (table 2) [1].

●Viral prodrome – Because the most common etiology of pediatric myocarditis is viral, patients often have a history of a recent respiratory or, less commonly, gastrointestinal illness within the previous two weeks. Patients typically have a prodrome of fever, myalgia, and malaise several days prior to the onset of symptoms of heart dysfunction.

●Nonspecific symptoms – Nonspecific signs and symptoms such as respiratory distress or gastrointestinal symptoms (anorexia, abdominal pain, and vomiting) may be the most prominent features at presentation. These nonspecific symptoms are often more suggestive of other diagnoses (eg, respiratory tract infection, gastroenteritis, appendicitis), leading to an incorrect initial diagnosis in many children [1,10,20,21]. (See 'Differential diagnosis' below.)

●Heart failure symptoms – Infants and children usually have signs and symptoms of heart failure at presentation. This may include dyspnea at rest, exercise intolerance, syncope, tachypnea, persistent tachycardia, and hepatomegaly [1,22-25]. (See "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

●Arrhythmias – Supraventricular and ventricular arrhythmias and complete heart block may be present [2,24,26,27]. In a case series of pediatric patients hospitalized at two tertiary centers, arrhythmias occurred in 45 percent either at presentation or during hospitalization [28]. Arrhythmias may contribute to cases that present as unexpected death, presumably due to ventricular arrhythmia [14,15].

●Fulminant myocarditis – A subset of patients have fulminant myocarditis and present with an acute onset of severe hemodynamic compromise [2,29,30]. These critically ill children present with signs of decreased cardiac output, including hypotension, weak pulses, poor perfusion, acidosis, and hepatomegaly, which may progress to cardiovascular collapse. Malignant arrhythmias are also commonly seen. In some cases, the clinical course progresses so rapidly that it is challenging to make the diagnosis and provide appropriate therapy before progression to severe cardiogenic shock and death [29]. In a study investigating predictors of mortality in pediatric patients with myocarditis, 50 percent of those patients who died had cardiac arrest within three hours of hospital admission [31]. Because it is difficult to distinguish fulminant myocarditis from other types of shock initially, such patients are usually treated broadly (including empiric treatment for septic shock). (See "Shock in children in resource-abundant settings: Initial management".)

In a report of 171 pediatric patients with myocarditis seen at a single institution, the following signs and symptoms were noted [13]:

●Chest pain (45 percent)

●Respiratory distress (28 percent)

●Gastrointestinal symptoms (27 percent)

●Hepatomegaly (27 percent)

●Gallop rhythm (20 percent)

●Poor perfusion/diminished extremity pulses (16 percent)

●Viral prodrome (41 percent)

Physical examination — In symptomatic patients, the physical examination often reveals direct evidence of cardiac dysfunction [1], although these findings are not specific to myocarditis:

●Respiratory findings include tachypnea, retractions, and rales (see "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Physical examination')

●Third heart sound (S3) and, occasionally, fourth heart sound (S4) gallops may be present and are important signs of impaired ventricular function, particularly when biventricular acute myocardial involvement results in systemic and pulmonary congestion (see "Auscultation of heart sounds")

●If the right or left ventricular dilation is severe, auscultation may reveal murmurs of functional mitral or tricuspid insufficiency (see "Auscultation of cardiac murmurs in adults")

●In acute fulminant myocarditis, signs of low cardiac output and shock may be present, including hypotension, poor pulses and perfusion, edema, hepatomegaly, and altered mental status (see "Pathophysiology and classification of shock in children", section on 'Stages of shock')

●A pericardial friction rub and effusion may become evident in some patients with myopericarditis (see "Myopericarditis", section on 'Clinical presentation')

INITIAL EVALUATION — Initial testing generally is focused on determining the presence and severity of cardiac dysfunction and includes [1,32]:

●Electrocardiography (ECG)

●Cardiac biomarkers (troponin)

●Brain natriuretic peptide (BNP) or N-terminal-proBNP (NT-proBNP)

●Chest radiography

●Echocardiography

Electrocardiogram — The ECG in myocarditis is usually abnormal, although changes are neither specific nor sensitive [33]. Changes include ST-segment and T wave abnormalities (eg, inverted T waves), abnormal axis, ventricular or atrial enlargement, and decreased voltage (waveform 1) [22-24,34]. The rhythm is most commonly sinus tachycardia; however, ventricular premature beats, atrial premature beats, supraventricular tachycardia, and ventricular tachycardia may be seen [35,36]. Complete heart block occurs less often [2,24,26,27].

Cardiac biomarkers (troponin) — Elevated levels of cardiac biomarkers (eg, cardiac troponin I and troponin T) reflect myocardial injury. Elevated troponin is seen in most, but not all, patients with myocarditis [37]. However, this is a nonspecific finding and should be interpreted in conjunction with other clinical and echocardiographic findings [1]. Although elevated levels of troponin I and troponin T are seen in the majority of patients with myocarditis, the degree of elevation does not consistently correlate with disease severity. In one multicenter review of pediatric patients presenting with myocarditis, patients with mild ventricular dysfunction had significantly higher levels of troponin I than those with moderate or severe ventricular dysfunction [13]. In another single-center retrospective review of 94 pediatric patients with myocarditis, troponin I levels were higher in non-survivors. Non-survivors in this study also had other indicators of poor prognosis (eg, hypotension, severely depressed left ventricular systolic function). Thus, an elevated troponin should be viewed as corroborating evidence for a diagnosis of myocarditis and should be considered within the context of other clinical indicators of disease severity and prognosis [31]. (See "Troponin testing: Clinical use" and "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Laboratory tests'.)

An elevated troponin level can help distinguish acute myocarditis from chronic dilated cardiomyopathy [38,39]. This was illustrated in a study in children with acute heart failure that showed troponin T levels were higher in patients with myocarditis compared with those with dilated cardiomyopathy, reflecting ongoing myocellular damage in the former [40]. However, there was overlap between the two groups of patients, so a target level could not be ascertained to differentiate between the two conditions. In addition, a small percentage of pediatric patients with myocarditis may have normal troponin levels. As a result, elevation of cardiac biomarkers is a nonspecific finding of myocarditis in children.

Natriuretic peptides — BNP and NT-proBNP concentrations may be elevated in myocarditis and may help distinguish between respiratory symptoms related to heart failure and those related to primary pulmonary pathology [41-43]. In a small series of 19 patients with parvovirus B19 myocarditis, BNP levels were elevated in all 12 patients who were tested, ranging from 348 to >8000 pg/mL [42]. (See "Natriuretic peptide measurement in heart failure".)

Chest radiograph — Chest radiography may be abnormal in approximately one-half of the cases of myocarditis [10,44]. Findings are nonspecific and include cardiomegaly, pulmonary vascular congestion, and, less commonly, pleural effusions (image 1 and image 2).

Echocardiogram — The echocardiogram typically shows impaired left ventricular function [45]. The systolic dysfunction is generally global, but regional or segmental abnormalities may also be seen. Changes in left ventricular geometry (eg, development of left ventricular dilation with a more spheroid shape), wall motion abnormalities, and mitral regurgitation may also be seen. Pericardial effusion is a common finding but is nonspecific [10].

The use of speckle-tracking echocardiography may allow earlier diagnosis of inflammation. One report found that this technique identified reduction in global and segmental strain patterns in patients with preserved ventricular function that correlated with findings of myocarditis confirmed by cardiac magnetic resonance (CMR) [46].

The echocardiogram also rules out noninflammatory cardiac diseases such as anomalous left coronary artery from the pulmonary artery (ALCAPA), which may have a similar presentation [25]. (See "Congenital and pediatric coronary artery abnormalities" and "Congenital and pediatric coronary artery abnormalities", section on 'Variations of coronary artery origin from the pulmonary artery'.)

Other studies — Additional laboratory tests that are often performed in children who present with signs and symptoms of cardiovascular dysfunction include the following:

●Markers of inflammation – The erythrocyte sedimentation rate and C-reactive protein are frequently elevated in myocarditis, but these are nonspecific findings and not useful in establishing a diagnosis

●A complete blood count may show evidence of infection, but this is a nonspecific finding

●Blood gases may demonstrate a metabolic acidosis in children with acute fulminant myocarditis resulting in inadequate systemic perfusion

DIAGNOSIS

Overview — Cardiac magnetic resonance (CMR) is increasingly used to diagnose myocarditis in children [12,32]. Endomyocardial biopsy (EMB) is considered the gold standard to confirm a clinical diagnosis of myocarditis; however, EMB has a fairly low sensitivity and it requires invasive cardiac catheterization, which carries risks, particularly in small children and those who are critically ill [47]. (See 'Endomyocardial biopsy' below and 'Cardiac magnetic resonance' below.)

In settings where CMR and EMB are not available, or when the risks of cardiac catheterization or general anesthesia for CMR are thought to be too high, the diagnosis can be made based on clinical findings. (See 'Clinical diagnosis' below.)

In a study of 514 pediatric patients hospitalized for myocarditis in the United States between 2006 and 2011, most patients did not undergo EMB or CMR [12]. EMB was performed in just 26 percent of patients, and CMR was performed in 15 percent. Over the five-year study period, the use of EMB decreased from 25 to 14 percent, whereas the use of CMR increased from 5 to 28 percent.

Our approach — At the authors' institution, the decision to perform CMR and/or EMB is individually assessed for each patient based on the risk and benefit of the procedure.

●We perform CMR in the majority of patients with new-onset heart failure in the absence of structural heart disease unless the risk of the test is perceived to be higher than the benefit of diagnostic confirmation. Although CMR is considered a noninvasive test, infants, small children, and those who are severely affected still require intubation and mechanical ventilation to facilitate required breath-holding sequences and reduce motion to improve imaging quality. These risks must be considered in patients who have significant ventricular dysfunction with minimal hemodynamic reserve.

●At the authors' institution, EMB is performed selectively given the high rate of adverse events and the risks associated with intubation and mechanical ventilation for the procedure. We generally reserve EMB for patients who require catheterization for another reason (eg, for creation of an atrial septal defect for left atrial decompression) and/or those already supported with extracorporeal membrane oxygenation (ECMO). If EMB is performed, it is done as early in the disease course as is possible and multiple samples are obtained to optimize diagnostic accuracy and reduce sampling errors. Hemodynamic data can also be obtained during cardiac catheterization, which may help guide heart failure therapy.

Because of the risks associated with these procedures, management includes anticipation and preparation for cardiac arrest and the availability of ECMO.

Endomyocardial biopsy — EMB is considered the gold standard for the diagnosis of myocarditis. The histopathologic diagnosis of myocarditis has historically been made by standard light microscopy according to the Dallas criteria; however, this approach is limited by poor sensitivity. Additional testing (ie, immunohistochemistry and viral genome analysis) has enhanced the diagnostic potential of EMB [1,33,48]. EMB is suggested in selected children with fulminant or acute, unexplained heart failure [49]. (See "Endomyocardial biopsy", section on 'Unexplained cardiomyopathy in children'.)

In a retrospective study of 41 children who underwent EMB at five centers in Italy between 2009 and 2011, EMB (including histologic examination and molecular testing) yielded an etiologic diagnosis in 63 percent but led to treatment changes in just 29 percent [47]. The rate of EMB-related complications was 16 percent in this series. (See 'Complications' below.)

Light microscopy (Dallas criteria) — The Dallas criteria were developed by a panel of cardiac pathologists in 1986 to establish standard histopathologic criteria using light microscopy for myocarditis. These criteria are used by most investigators to define the disease as follows [50]:

●Active myocarditis is defined as "an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischemic damage associated with coronary heart disease." The infiltrates usually are mononuclear but may be neutrophilic or, occasionally, eosinophilic (picture 1A-B).

●Borderline myocarditis is the term used if lymphocytic infiltration is present without myocyte destruction.

The sensitivity of EMB using light microscopy is poor because myocarditis is confirmed by biopsy using the Dallas criteria in less than 20 to 50 percent of pediatric patients with clinically suspected disease [51-53]. In one study of 76 biopsies in 63 children with suspected myocarditis, only eight had inflammatory cell infiltrates and myocyte necrosis consistent with the diagnosis [51]. These patients all had duration of symptoms less than six weeks. All four patients who presented with cardiogenic shock had positive biopsies.

Because the sensitivity is affected by the focal and transient nature of the inflammatory infiltrates, sampling errors occur due to the following:

●Focal inflammatory pattern – The pattern of cardiac involvement is often patchy. As a result, sampling errors occur when uninvolved areas are biopsied. Increasing the number of biopsy specimens obtained increases the sensitivity of the test [54] but also increases the risk of complications.

●Timing of the biopsy – A positive result is more likely if the biopsy is performed soon after the onset of symptoms when the degree of inflammation is greatest [51].

In addition, although the Dallas criteria are widely used, their interpretation remains somewhat subjective and does not include chronic changes. As an example, findings of chronic changes such as fibrosis may help differentiate myocarditis from cardiomyopathy.

Other tests — Additional tests to standard light microscopy that improve the sensitivity and specificity of EMB include [1,33]:

●Molecular techniques – The use of molecular techniques such as in situ hybridization and polymerase chain reaction amplification of viral DNA is probably the most helpful approach. In one study, viral genomes were detected in 239 of 624 specimens (38 percent) of adults and children with suspected myocarditis [55]. Adenovirus and enterovirus were the most common viral genomes detected. In a multicenter retrospective case series, addition of molecular techniques increased the diagnostic yield of EMB from 41 to 64 percent, though EMB drove treatment changes in only one-third of cases [47].

●Immunocytochemistry techniques – Immunocytochemistry techniques can detect inflammation in the EMB by using monoclonal and polyclonal antibodies against white blood cell subsets, including anti-CD3, T lymphocytes, anti-CD68, macrophages, and anti-human leukocyte antigen (HLA)-DR.

●Viral culture – Viral culture of biopsy specimens can potentially identify the etiology of myocarditis. However, cultures are rarely positive, especially if obtained later in the disease course.

Complications — Reported rates of complications of EMB in children range from 1 to 16 percent in series in which the procedure was performed for suspected myocarditis or surveillance for heart transplant rejection [47,56-58]. The complication rate in infants is as high as 30 to 40 percent [47,59,60]. In one study, perforation of the right ventricle was the most frequent serious complication and was most likely to occur in patients being evaluated for myocarditis, requiring inotropic support, or weighing <10 kg [56]. Other complications included arrhythmias, pneumothorax, and flail tricuspid leaflet.

Cardiac magnetic resonance — CMR can document the location and extent of inflammation in patients with myocarditis. Findings associated with myocarditis consist of detecting areas of inflammatory hyperemia and edema, myocyte necrosis, and scarring.

CMR findings that are consistent with myocarditis include (image 3):

●Increases in T2 signal intensity consistent with edema

●Increased early myocardial contrast enhancement relative to skeletal muscle consistent with hyperemia in gadolinium-enhanced T1-weighted images

●Presence of late gadolinium enhancement in T1-weighted images consistent with necrosis or scar

These criteria are based largely on data from adults. Studies in adults have reported diagnostic accuracy approaching 80 percent when two of the three findings are present. (See "Clinical manifestations and diagnosis of myocarditis in adults", section on 'Cardiovascular magnetic resonance'.)

Comparable data are not available in pediatric patients with myocarditis. In a multicenter retrospective study of 143 children and adolescents with a diagnosis of myocarditis who underwent CMR, the most common findings included late gadolinium enhancement abnormalities (81 percent of patients) and T2 signal intensity consistent with edema (74 percent) [61]. The CMR was interpreted as positive for myocarditis in 82 percent of patients, negative in 13 percent, and equivocal in 5 percent. These findings suggest that CMR is a useful tool for diagnosing myocarditis in children; however, since only a small subset of patients (22 percent) underwent EMB, it is difficult to draw a firm conclusion. In another report, 23 consecutive patients with a clinical diagnosis of acute myocarditis were retrospectively analyzed and compared with 39 controls using native T1, T2, and extracellular volume fraction with good sensitivity and specificity [62].

Clinical diagnosis — In settings where EMB and CMR are unavailable, or when the risks of cardiac catheterization or general anesthesia for CMR are thought to be too high, the diagnosis of myocarditis can be made based on a combination of clinical findings. Affected patients may have all or only some of these findings [1,33]:

●Present in most patients to variable degrees:

•Signs and symptoms of acute cardiac dysfunction (eg, dyspnea, exercise intolerance, syncope, exertional chest pain, tachypnea, unexplained tachycardia, hepatomegaly, gallop rhythm)

•Elevated troponin

•Echocardiographic evidence of ventricular dysfunction without an underlying structural cardiac defect

●Present in some but not all patients:

•Prodromal illness (respiratory or gastrointestinal) within two weeks of presentation

•Electrocardiographic (ECG) changes suggestive of acute myocardial injury or arrhythmia

ETIOLOGIC EVALUATION — Further diagnostic evaluation is performed to determine the underlying etiology of myocarditis. This includes:

●Viral testing – Viral infection should be suspected in patients with acute onset of symptoms, especially in those with a prodrome of fever, myalgias, and malaise. Swabs from rectal and nasal mucosa should be tested with rapid diagnostic testing and viral culture. In the absence of positive viral cultures, acute and convalescent antibody titers can be helpful in the diagnosis of a specific viral infection. If an endomyocardial biopsy (EMB) is performed, samples should be sent for genomic viral analysis and bacterial and viral culture. (See 'Endomyocardial biopsy' above.)

●A thorough history and physical examination may suggest less frequent infectious etiologies such as Lyme carditis [63] or acute rheumatic fever, and diagnostic testing should be adjusted appropriately. (See "Lyme carditis" and "Acute rheumatic fever: Clinical manifestations and diagnosis", section on 'Carditis'.)

●For patients who have signs and symptoms of associated systemic disease, additional testing for autoimmune or inflammatory conditions may be appropriate (eg, systemic lupus erythematosus, coronavirus disease 19 [COVID-19]-related multisystem inflammatory syndrome in children [MIS-C]). (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Cardiac' and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis", section on 'Evaluation'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis includes other conditions that present with findings of acute heart failure or respiratory distress.

Acute heart failure — The following conditions may present acutely with heart failure symptoms. They are differentiated from myocarditis by echocardiography, cardiac magnetic resonance (CMR), or endomyocardial biopsy (EMB). (See "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Etiology and pathophysiology'.)

●Structural heart disease (eg, such as anomalous left coronary artery from the pulmonary artery [ALCAPA] or valvar heart disease) is differentiated from myocarditis by echocardiography. (See "Congenital and pediatric coronary artery abnormalities" and "Valvar aortic stenosis in children".)

●Cardiomyopathy due to other causes (eg, hypertrophic, restrictive, or arrhythmogenic right ventricular cardiomyopathy). (See "Hypertrophic cardiomyopathy in children: Clinical manifestations and diagnosis" and "Restrictive cardiomyopathies" and "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis".)

Differentiation between idiopathic dilated cardiomyopathy and acute myocarditis may be difficult. Generally, history of acute onset of symptoms (within <2 weeks), recent viral illness, and lack of significant left ventricular dilation favor a diagnosis of acute myocarditis. CMR and EMB may be useful to confirm a diagnosis of myocarditis; however, if these tests are negative, it does not exclude a diagnosis of myocarditis. In some cases, the diagnosis is made after a patient recovers normal ventricular function, which is more likely in the setting of acute myocarditis.

●Severe sepsis, especially septic shock, may be difficult to differentiate from fulminant myocarditis initially. As a result, patients with a fulminant presentation should receive empiric antibiotic therapy and cardiovascular supportive therapy while undergoing further diagnostic testing, such as echocardiography and CMR, which will differentiate between the two conditions. (See "Sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis" and "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)".)

●Kawasaki disease (KD) – Patients with KD may present with myocardial involvement. Mild ventricular dysfunction is commonly seen on echocardiography during the acute phase of KD, though severe ventricular dysfunction is rare. KD can be distinguished from acute viral myocarditis by the presence of persistent high fevers and other characteristic findings (table 3). (See "Kawasaki disease: Clinical features and diagnosis".)

●Coronavirus disease 2019 (COVID-19)-related multisystem inflammatory syndrome in children (MIS-C) – The presentation of MIS-C overlaps with that of KD, and many affected children present with cardiac involvement, including elevated cardiac biomarkers and depressed ventricular function, which can be severe. MIS-C can be distinguished from acute viral myocarditis by the presence of persistent high fevers, other findings of multisystem involvement, and evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or exposure (table 4). (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

●Primary arrhythmias – Patients with primary arrhythmias who have a high burden of ectopy or prolonged duration of arrhythmia can present with depressed ventricular function. However, patients with myocarditis also often have ectopy and arrhythmias. In some cases, it may be difficult to know which is the primary problem (ie, whether the arrhythmia led to the ventricular dysfunction or if the ventricular dysfunction and myocardial inflammation led to the arrhythmia). The clinical history might provide a clue (eg, a recent viral prodrome suggests myocarditis). Follow-up assessment of ventricular function can also help. Progressive ventricular dysfunction despite well-managed arrhythmia leads toward a diagnosis of a primary myocardial process. Ultimately, CMR and/or EMB are necessary to confirm the diagnosis of myocarditis. (See "Arrhythmia-induced cardiomyopathy".)

Respiratory distress — Some patients with myocarditis may present initially with respiratory distress. A high index of suspicion is needed to distinguish myocarditis from other far more common pediatric respiratory illnesses such as bronchiolitis, asthma, and pneumonia. Particular findings that should raise suspicion for myocarditis in this setting include a gallop rhythm, tachycardia out of proportion to other symptoms, hepatomegaly, altered systemic perfusion, and/or ectopy or other abnormalities on cardiac monitoring or electrocardiogram (ECG). Additional evaluation including chest radiograph and laboratory tests (eg, troponin, brain natriuretic peptide [BNP]) can help distinguish myocarditis from primary respiratory conditions. Serial assessment of the vital signs and physical examination in response to treatment can also be informative. For example, if the patient responds to intravenous fluid resuscitation with clinical deterioration (eg, increased tachycardia, dyspnea, rales) rather than improvement, ventricular dysfunction and possible myocarditis should be considered. Ultimately, echocardiography is necessary to confirm a cardiac etiology. The approach to evaluating children with respiratory distress is discussed in greater detail separately. (See "Acute respiratory distress in children: Emergency evaluation and initial stabilization", section on 'Evaluation'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately:

●(See "Society guideline links: Myocarditis".)

●(See "Society guideline links: Heart failure in children".)

●(See "Society guideline links: Acute rheumatic fever and rheumatic heart disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

●Basics topics (see "Patient education: Myocarditis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Myocarditis is an inflammatory disease of the myocardium with many different etiologies, most of which are infectious (table 1). Myocarditis is rare in children, with an estimated annual incidence of 1 to 2 per 100,000 children. Most studies report a bimodal age distribution with peaks in infancy and adolescence. (See 'Etiology' above and 'Incidence' above.)

●Clinical presentation – The clinical presentation of myocarditis is variable. Affected patients can present with a broad clinical spectrum of signs and symptoms ranging from subclinical disease to cardiogenic shock, arrhythmias, and sudden death (table 2). Patients typically have a prodrome of fever, myalgia, and malaise several days prior to the onset of symptoms of heart dysfunction. Infants and children usually have signs and symptoms of heart failure at presentation. This may include dyspnea at rest, exercise intolerance, syncope, tachypnea, persistent tachycardia, and hepatomegaly. Supraventricular and ventricular arrhythmias are common. (See 'Clinical manifestations' above.)

●Initial evaluation – Initial testing in children with suspected myocarditis is focused on determining the presence and severity of cardiac dysfunction and includes (see 'Initial evaluation' above):

•Electrocardiography (ECG) (waveform 1) (see 'Electrocardiogram' above)

•Cardiac biomarkers (troponin) (see 'Cardiac biomarkers (troponin)' above)

•Brain natriuretic peptide (BNP) or N-terminal-proBNP (NT-proBNP) (see 'Natriuretic peptides' above)

•Chest radiography (image 1 and image 2) (see 'Chest radiograph' above)

•Echocardiography (see 'Echocardiogram' above)

●Diagnosis – Cardiac magnetic resonance (CMR) is increasingly used to diagnose myocarditis in children. Endomyocardial biopsy (EMB) is considered the gold standard to confirm the diagnosis; however, EMB is associated with considerable risk and has a fairly low sensitivity. In settings where CMR and EMB are not available, or when the risks of cardiac catheterization or general anesthesia for CMR are thought to be too high, the diagnosis is made clinically (see 'Diagnosis' above):

•CMR – The diagnosis of myocarditis can be made with CMR using consensus criteria based on studies in adults (image 3). CMR has the advantage of being less invasive than EMB, though young children require general anesthesia and mechanical ventilation to successfully perform the study. (See 'Cardiac magnetic resonance' above.)

•EMB – At the authors' institution, EMB is reserved for patients who require catheterization for another reason and/or those already supported with extracorporeal membrane oxygenation (ECMO). If EMB is performed, it should be done as early in the disease course as is possible and multiple samples should be obtained to optimize diagnostic accuracy and reduce sampling errors. The diagnosis of myocarditis is made based on standard light microscopy (Dallas criteria), immunohistochemistry, viral polymerase chain reaction, and viral culture. (See 'Endomyocardial biopsy' above.)

•Clinical diagnosis – The diagnosis of myocarditis can be made clinically based on a combination of clinical findings, though affected patients may not have all of these findings (see 'Clinical diagnosis' above):

-Signs and symptoms of acute cardiac dysfunction (eg, dyspnea, exercise intolerance, syncope, exertional chest pain, tachypnea, unexplained tachycardia, hepatomegaly, gallop rhythm)

-Elevated troponin

-Echocardiographic evidence of ventricular dysfunction without an underlying structural cardiac defect

-Prodromal illness (respiratory or gastrointestinal) within two weeks of presentation

-ECG changes suggestive of acute myocardial injury or arrhythmia

●Etiologic evaluation – Additional diagnostic evaluation is performed to determine the underlying etiology of myocarditis. For most patients with suspected viral myocarditis, this consists of routine viral testing. For patients who have signs and symptoms of associated systemic disease, additional testing for autoimmune or inflammatory conditions may be appropriate (eg, systemic lupus erythematosus, coronavirus disease 19 [COVID-19]-related multisystem inflammatory syndrome in children [MIS-C]). (See 'Etiologic evaluation' above.)

●Differential diagnosis – The differential diagnosis of myocarditis includes other diseases that present acutely with heart failure symptoms (eg, anomalous left coronary artery from the pulmonary artery [ALCAPA], noninfectious cardiomyopathies, severe sepsis, Kawasaki disease [KD], MIS-C, primary arrhythmias) or respiratory distress (eg, bronchiolitis, asthma, pneumonia). These conditions usually can be distinguished from myocarditis by history, examination, laboratory tests, and echocardiography. (See 'Differential diagnosis' above.)