Current understanding of disease pathogenesis in myocarditis has come in large part from murine models. Three overlapping stages of disease have been described: (1) direct myocardial invasion by a cardiotropic triggering agent (usually thought to be viral); (2) immunologic activation; and (3) ongoing inflammation, circulation of antiheart antibodies and abnormal ventricular remodeling.2
In acute viral myocarditis, data suggest that cardiotropic viral RNA (ribonucleic acid) enters the myocytes through endocytosis and produces viral protein that activates an immune cascade in the host. Inflammatory cellular infiltration with macrophages and natural killer cells enhances expression of inflammatory cytokines, specifically interleukin IL-1, IL-2, tumor necrosis factor (TNF), and interferon-γ,3,4 resulting in further inflammatory cell recruitment. Cytokines activate inducible nitric oxide synthase in cardiac myocytes.5 Nitric oxide has been shown to play an important role both in inhibiting viral replication and in producing intense myocardial inflammation.6,7 In addition, circulating autoantibodies directed against cardiac contractile, structural, and mitochondrial proteins have been detected in cardiac biopsy specimens in both humans and mice with myocarditis.8 Removal of autoantibodies by immunoabsorption techniques seems to improve cardiac function and decrease inflammation.9–11
It is therefore deduced that a normal host immune response facilitates clearance of infectious agents. However, with immunologic imbalance, infectious agents may persist in the myocardium leading to ongoing immune-mediated myocyte destruction and myocardial injury. Detection of viral RNA in autopsy specimens of patients with dilated cardiomyopathy has supported the theory that persistence of viruses in the myocardium is capable of inducing ongoing myocardial injury resulting in acute or chronic dilated cardiomyopathy.
History and Physical Examination
With differences in age and overall immune status, pediatric myocarditis may have variable clinical presentations. Many cases of myocarditis are suspected to be subclinical without apparent illness. The ability of most pediatric patients to compensate for decreased cardiac function can cause cardiovascular symptoms to be minimal in myocarditis until acute collapse or sudden death occurs.
Infants often present with poor feeding, vomiting, fever, irritability, and cardiorespiratory symptoms. Pallor and cyanosis may be evident on physical examination with mottled skin when depressed cardiac output causes poor perfusion. Respirations may be rapid and labored. Cardiovascular examination findings relate to congestive heart failure and include tachycardia, a prominent third heart sound (“gallop”) with muffled heart sounds on auscultation. A systolic murmur at the cardiac apex may be appreciated when mitral regurgitation is present. Lung auscultation may reveal diffuse rales. The liver is often enlarged. Infants with injury related to intrauterine myocarditis may present with more chronic signs and symptoms.
Older children and adolescents may complain of palpitations and chest pain in addition to lethargy and abdominal pain. Low-grade fever is common and a history of recent viral illness is often reported, usually 1–2 weeks prior to presentation. As disease progresses and cardiac output is affected, diaphoresis, exercise intolerance, and respiratory symptoms become more prominent. Syncope or even sudden death may result from either myocardial dysfunction or cardiac arrhythmias. Examination findings suggest congestive heart failure, and in contrast to infants may include jugular venous distention and rales on pulmonary examination. Resting tachycardia is a prominent feature of myocarditis. Because myocarditis can occur in the setting of more systemic illness, additional examination findings related to other organ system dysfunction may be present.
A complete medication history should be obtained, as well as an account of other exposures that can cause toxin-mediated myocarditis. Preexisting rheumatologic or autoimmune disease accompanied by a history and examination suggestive of cardiac disturbance should raise concern for myocardial inflammation.
Tachycardia almost always accompanies fever in the pediatric patient, and, therefore, extra diligence is required for recognizing tachycardia out of proportion to the degree of fever. Persistent tachycardia is often the only initial suggestion of myocarditis. If tachycardia does not improve appropriately after competing causative factors (such as fever, pain, and dehydration) are addressed, further cardiac evaluation is warranted. Signs and symptoms of myocarditis are listed in Table 38–1 and may include fever, tachycardia, pallor, cyanosis, respiratory distress if pulmonary edema ensues, a gallop, and hepatosplenomegaly caused by venous congestion. Evidence of an upper respiratory illness is common in viral myocarditis.
Table 38–1. Signs and Symptoms Associated with Myocarditis ||Download (.pdf)
Table 38–1. Signs and Symptoms Associated with Myocarditis
- Poor feeding
- Periodic pallor
- Mild cyanosis
Children and Adolescents
- Low-grade fever
- Poor appetite
- Abdominal pain
- Exercise intolerance
- Respiratory distress
- Resting tachycardia
- Jugular venous distention
- Pulmonary rales
- Sudden death
In noninfectious cases of myocarditis, signs, and symptoms related to the underlying cause should be elicited. With autoimmune and rheumatologic illnesses, a rash or joint findings may also be evident. More chronic symptoms may be present in these diseases.
Table 38–2 summarizes the differential diagnosis of myocarditis. Although infectious causes of myocarditis are most common (Tables 38–3 and 38–4), noninfectious etiologies (Table 38–5) should be considered when evaluating a patient with signs and symptoms of myocarditis. The most common viral pathogens include enteroviruses, particularly coxsackievirus B, as well as adenovirus serotypes 2 and 5, and influenza. Other infectious etiologies include Rickettsiae, other bacteria, parasites, fungi, protozoa, and yeast.
Table 38–2. Differential Diagnosis of Myocarditis ||Download (.pdf)
Table 38–2. Differential Diagnosis of Myocarditis
- Anatomic heart disease
- Idiopathic dilated cardiomyopathy
- Barth's syndrome
- Endocardial fibroelastosis
- Anomalous left coronary artery from the pulmonary artery
- Cerebral arterial venous malformation
- Idiopathic dilated cardiomyopathy
- X-linked dilated cardiomyopathy
- Autosomal-dominant dilated cardiomyopathy
- Anomalous left coronary artery from the pulmonary artery
- Endocardial fibroelastosis
- Chronic tachyarrhythmia
Table 38–3. Viral Causes of Myocarditis ||Download (.pdf)
Table 38–3. Viral Causes of Myocarditis
- Cocksackievirus A, B
- Influenza A/B
- Epstein–Barr virus
- Herpes simplex
- Hepatitis B, C
Table 38–4. Nonviral Infectious Causes of Myocarditis ||Download (.pdf)
Table 38–4. Nonviral Infectious Causes of Myocarditis
- Treponema pallidum
- Trypanosoma cruzi
- Toxocara canis
- Visceral larva migrans
Fungi and Yeasts
Table 38–5. Noninfectious Causes of Myocarditis ||Download (.pdf)
Table 38–5. Noninfectious Causes of Myocarditis
- Ecstacy (3,4-methylenedioxy-N-methylamphetamine)
- Interleukins-2, 4
- Amphotericin B
- Tricyclic antidepressants
- Kawasaki disease
- Inflammatory bowel disease
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Diabetes mellitus
- Rheumatic fever
- Wegener's granulomatosis
- Takayasu's arteritis
Drugs may cause myocarditis, in particular, some antimicrobials and antifungals. Underlying autoimmune diseases, such as juvenile rheumatoid arthritis and ulcerative colitis as well as collagen vascular diseases, are known to be associated with myocarditis.
The diagnosis of myocarditis can be difficult to confirm, but should be suspected when a patient presents with unexplained congestive heart failure or ventricular tachycardia (Figure 38–1). Table 38–6 summarizes the laboratory and radiologic evaluation of the patient with suspected myocarditis.
Algorithm for evaluation of suspected myocarditis in the pediatric patient.
Table 38–6. Evaluation of Patient with Suspected Myocarditis ||Download (.pdf)
Table 38–6. Evaluation of Patient with Suspected Myocarditis
- Cardiac MRI
- Cardiac catheterization (for biopsy and hemodynamic evaluation)
- CT scan of head and abdomen (for transplant evaluation)
- Electrolytes, BUN, CR, Uric acid
- Liver function tests, total serum albumin
- Thyroid function tests
- CBC with differential
- Coagulation profile
- Troponin C
- Toxicology screen
- For newborns and infants:
- Metabolic evaluation: Lactate, ammonia, pyruvate, carnitine level (total and free), acylcarnitine, serum organic acids and amino acids, chromosomal analysis
- Prior to blood product transfusion or IVIG:
- Serologies for enterovirus, adenovirus, coxsackie A and B, echovirus, influenza, HIV, CMV, RSV, EBV, hepatitis, and Lyme.
- Transplant serologies
- Urine organic acids
- Nasopharyngeal aspirate or endotracheal tube aspirate
- Rapid viral panel
Chest Radiograph Findings
Chest radiograph may be normal early in disease progression. Cardiomegaly and prominent pulmonary vasculature markings consistent with pulmonary edema and congestive heart failure occur in more advanced disease (Figure 38–2).
The chest radiograph reveals an enlarged cardiac silhouette with prominent pulmonary vascular markings on both anterior–posterior and lateral views. (With permission from Geggel R, ed. Multimedia Library of Congenital Heart Disease. Boston, MA: Children's Hospital. http://www.childrenshospital.org/mml/cvp.)
ECG findings in acute myocarditis are generally nonspecific and may include sinus tachycardia. Low voltages in the QRS complexes (generally less than 5 mm total amplitude in all limb leads) may be seen, although prominent left-sided forces may be seen when a patient presents with left ventricular dilation. Low-voltage or inverted T waves may also be present. Evidence of myocardial ischemia with widened Q waves (>35 ms) and S–T changes may be seen. Arrhythmias may occur and include supraventricular tachycardia, ventricular tachycardia, as well as A-V block and atrial fibrillation (Figure 38–3).
The electrocardiogram tracing shows left ventricular forces at the upper limits of normal (S wave in V2 30 mm, 95% for age) and nonspecific T-wave flattening in the inferior and lateral leads). T-wave abnormalities are common in patients with myocarditis. (With permission from Geggel R, ed. Multimedia Library of Congenital Heart Disease. Boston, MA: Children's Hospital.http://www.childrenshospital.org/mml/cvp.)
A dilated left ventricle with depressed function may be seen, evident by global hypokinesis as well as increased left ventricular end-diastolic and end-systolic dimensions and decreased shortening and ejection fractions. Pericardial effusion is not uncommon in association with myocarditis. Coronary artery abnormalities (e.g., anomalous left coronary artery from the pulmonary artery) or other structural variants should be excluded as alternate causes of dilated cardiomyopathy when performing echocardiography (Figure 38–4).
Shown is a still frame from an apical four chamber echocardiographic view of a child with myocarditis. The left ventricle is markedly dilated and poorly functioning. (With permission from Geggel R, ed. Multimedia Library of Congenital Heart Disease. Boston, MA: Children's Hospital.http://www.childrenshospital.org/mml/cvp.)
Serum Markers for Myocardial Injury
Myocardial muscle creatinine kinase isoenzyme (CK-MB) and cardiac troponin T are both serum markers that may be elevated in acute myocarditis. However, data to support their utility in diagnosis and following clinical course among patients with myocarditis is limited.12,13 CK-MB and cardiac troponin T levels tend to be higher among patients with acute viral myocarditis compared with dilated cardiomyopathy patients with congestive heart failure. There is recently reported data to support the use of cardiac troponin T levels of 0.052 ng/mL or greater as a reliable noninvasive indicator of acute myocarditis in children.14,15
Magnetic Resonance Imaging
Advanced noninvasive imaging methods are now used to assess the extent of inflammation in patients with acute myocarditis, including contrast-enhanced cardiovascular magnetic resonance imaging.16,17 Adult studies of advanced cardiovascular magnetic resonance technology have further demonstrated its use as a tool for noninvasive diagnosis with the ability to detect small, often patchy areas of myocardial injury and inflammation.18
Endomyocardial biopsy should be strongly considered in consultation with a pediatric cardiologist after competing etiologies of dilated cardiomyopathy have been excluded and refractory symptoms of heart failure persist despite standard medical management. Significant and life-threatening arrhythmias, symptoms suggestive of a systemic immune-mediated process, such as rash, fever, or eosinophilia, or other evidence of collagen vascular disease, give further reason to perform a biopsy for tissue analysis.
Biopsy of endomyocardial tissue has historically been the gold standard method for diagnosing acute myocarditis. However, its ability to demonstrate myocardial inflammation by histology is limited by the patchy nature of inflammatory infiltrate present in this disease. The “Dallas criteria” were developed in 1986 for diagnostic standardization in adult patients and require “a process characterized by an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of ischemic damage” to definitively diagnose myocarditis.19 The Dallas criteria have historically been applied to pediatric patients. Because of the patchy nature of myocardial injury, at least five tissue samples for histologic analysis should be obtained from the right ventricular free wall during cardiac catheterization. However, among patients who died of postmortem-confirmed myocarditis, Dallas criteria were met in only about 50% of cases.20,21 Other studies report similarly limited results using biopsy for diagnosis.22–24 Furthermore, a virus has been identified in tissue samples that did not meet Dallas criteria for myocarditis.25 Finally, the presence of Dallas criteria myocarditis has not been shown to identify patients who will respond to immune modulation therapy and does not predict prognosis.26
Recognizing that the incidence of myocarditis has been underrepresented using traditional biopsy diagnosis, broader clinical–pathological criteria that incorporate newer diagnostic techniques are used for more accurate identification of patients with myocarditis. In patients in whom biopsy is indicated, MRI may be used to target areas of myocardial inflammation, which are most likely to yield tissue samples representative of disease.
In an effort to identify viral presence in myocarditis patients for diagnosis, treatment, and prognosis, biopsy specimens are now routinely tested using polymerase chain reaction (PCR) and ribonucleic acid hybridization for rapid and specific viral detection.
Detection of Viruses in Myocardial Tissue
Viruses are considered the most common cause of myocarditis, but confirmation relies on identification of a viral pathogen in the myocardial tissue. In the past, this has depended on successful viral isolation using peripheral culture methods and or serial serology. Endomyocardial biopsy samples of myocardium were routinely culture-negative in cases of suspected acute viral myocarditis. With the advent of PCR, viral detection is becoming more common from cardiac tissue and body fluids. Using PCR in 38 myocardial tissue samples from patients with suspected myocarditis and 17 control samples, Martin et al. detected virus in 68% of myocarditis patients and none from the controls.25 A study by Bowles et al.27 sampled myocardial tissue from 624 patients with myocarditis and 149 patients with dilated cardiomyopathy, and used PCR analysis for viral diagnosis. Viral genome was detected from 38% of myocarditis patients (142 with adenovirus, 85 with enterovirus, 18 with cytomegalovirus), as well as a few cases with influenza, herpes simplex virus, Epstein–Barr virus, parvovirus, respiratory syncytial virus, and influenza A. Importantly, viral material was also detected among 20% of the dilated cardiomyopathy patients (18 with adenovirus and 12 with enterovirus), supporting persistent viral infection as an etiologic factor in the development of dilated cardiomyopathy. Pauschinger et al. found 24 of 94 patients with idiopathic dilated cardiomyopathy had adenoviral or enteroviral positive PCR testing from cardiac tissue samples.28
Variable success has been reported using immunotherapies in the early treatment of acute myocarditis, including the use of immune globulin, prednisone, methylprednisolone, azathioprine, and OKT3.29–32 The goal in using these agents has been to reduce the inflammatory response that is thought to lead to myocardial injury. However, there is a debate whether suppressing the body's initial systemic immune response to a viral illness, as in acute viral myocarditis, leads to delayed or insufficient viral clearance. Unfortunately, clear evidence of efficacy and improved clinical outcome in pediatric patients with acute myocarditis, who receive immunosuppressive therapies, remains controversial.33–35 However, significant benefit has been reported in adults with acute myocarditis who have evidence of cardiac autoantibodies on biopsy compared to a lack of benefit among patients without autoantibodies.36
For patients with severely compromised ventricular function and in whom symptoms of decreased oxygen delivery are present, support with inotropic agents, phosphodiesterase inhibitors, and diuretics is necessary. Cardiogenic shock with circulatory collapse may require mechanical support of the circulation with extracorporeal membrane oxygenation or ventricular assist device. Extracorporeal membrane oxygenation and ventricular assist device therapies are often used as a “bridge” to cardiac transplantation.
The overall survival rate without cardiac transplant among pediatric patients with biopsy-proven myocarditis has been estimated at 75–80%, with no significant difference using immunosuppressive therapies.31,37 Interestingly, adult data show an improved long-term survival rate at 5 years after biopsy-proven myocarditis among patients with fulminant myocarditis when compared to those with acute (nonfulminant) myocarditis.38