Chapter 38. Myocarditis and Pericarditis

Myocarditis is a term used to describe an inflammatory infiltrative process within the muscular walls of the heart leading to degeneration and necrosis of cardiac myocytes. It is now understood that a spectrum of disease with overlapping clinical and histological characteristics exists, beginning with myocarditis and progressing to dilated cardiomyopathy. The clinical presentation ranges from the asymptomatic patient with mild ventricular dysfunction, ECG changes, and a self-resolving process to the patient with fulminant heart failure leading to dilated cardiomyopathy. Pericarditis, inflammation of the pericardium, may occur in isolation or with myocarditis and often presents in a similar fashion.

The most common causes of myocarditis and pericarditis are infectious diseases, specifically viral etiologies, though specific diagnosis is achieved in less than half of cases.1 Therefore, myocarditis is most often deemed idiopathic. While the majority of cases are sporadic, there are reports of epidemics. Other causes of myocardial or pericardial inflammation include immune-mediated conditions, toxins, and medication side effects. This chapter focuses on the infectious etiologies of myocarditis and pericarditis, diagnosis, and disease management.

Pathogenesis

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.

Clinical Presentation

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.

Signs and Symptoms

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.

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.

Differential Diagnosis

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.

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.

Diagnosis

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.

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).

Electrocardiographic Findings

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).

Echocardiographic Findings

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).

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

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

Treatment

Immunotherapies

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

Cardiovascular Support

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.

Outcome

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

Pericardial disease describes pathology related to the pericardial membranes and potential fluid space surrounding the heart. Pericarditis may be associated with congenital causes, inflammatory conditions, infection, and other chronic disease processes. An approach to the patient with suspected pericarditis is shown in Figure 38–5.

Pathogenesis

Acute pericarditis comprises an inflammatory infiltration of the pericardial membranes, often with excessive pericardial fluid accumulation. The pericardial sac normally contains approximately 15–35 mL of serous fluid in the average adult, and exists because of a space between the inner visceral pericardium (epicardium) and outer parietal pericardium. Inflammatory fluid causing pericarditis can be either effusive (constrictive hemodynamics persist after the pericardial effusion is removed) or noneffusive, and can cause tamponade physiology in extreme cases.

Clinical Presentation

Chest pain is present in many cases of acute pericarditis, but may be absent when disease has been more indolent. The quality of the pain tends to be sharp and precordial in nature, often worse upon inspiration or with coughing. Pain is usually most severe in the recumbent position, can radiate to the left shoulder or arm, and may be partially relieved by leaning forward or upon sitting upright. Fever is a common symptom, particularly with infectious etiologies. Cardiac auscultation often reveals a pericardial friction rub. Patients may present with evidence of sepsis, particularly in bacterial pericarditis.

Constrictive pericarditis, which can occur with chronic fibrosis of the pericardium, may present with signs and symptoms of heart failure (including dyspnea, orthopnea, and hepatomegaly) caused by restricted ventricular filling and an increase in diastolic pressures among all four cardiac chambers.

Pericardial Effusion and Tamponade

Acute pericarditis is often associated with the accumulation of excess pericardial fluid, which may be transudative or exudative in nature. These pericardial effusions, depending on their overall size and rate of accumulation, have a varying effect on cardiac function. In cases where fluid accumulates slowly and the pericardium is compliant enough to avoid elevation in intrapericardial pressure, cardiac function is preserved. However, cardiac tamponade or cardiac failure can occur in small or large effusions when they accumulate rapidly, causing increased intrapericardial pressure and limited venous return to the heart. This ultimately causes decreased diastolic filling and resultant compromised cardiac output. The classic finding in tamponade physiology is pulsus paradoxus, defined as a decrease in systolic blood pressure greater than or equal to 10mmHg with inspiration. This can be detected by Korotkoff sounds with manual blood pressure measurement or by a change in the pulse-oximetry waveform during inspiration.39 ECG in tamponade demonstrates diffusely low QRS voltages.

Differential Diagnosis

Etiologies of pericarditis are listed in Table 38–7 and include infectious as well as noninfectious causes. Both viral and bacterial infections can cause acute pericarditis with significant pericardial effusions. Noninfectious causes include autoimmune conditions, connective tissue disease, malignancy, postpericardiotomy syndrome, and trauma.

Diagnosis

Chest Radiograph Findings

On chest radiograph, the cardiac silhouette may be enlarged in cases where a sizeable effusion is present. Associated pleural fluid may be visible as well, commonly on the left side of the diaphragm. Potential etiologies may be suggested by additional findings, such as pneumonia or evidence of malignancy.

Electrocardiographic Findings

ECG findings early in disease, may demonstrate J-point and S–T elevation in the inferior and anterior leads, as well as PR segments that are deflected in a direction opposite to the P wave in each lead. With progression of disease, J-points may return to baseline with T wave flattening and eventual inversion.

Echocardiographic Findings

Echocardiography is considered the primary imaging modality for the evaluation of pericardial effusion. However, loculated effusions are often difficult to detect using echocardiography and can be better visualized using CT or MRI (Figure 38–6). Another advantage to echocardiography is its ability to assess ventricular function and Doppler evidence for tamponade physiology.

Laboratory Evaluation

The value of blood tests is limited in screening for acute pericarditis. Cardiac troponin may be elevated, but may be more representative of adjacent myocardial inflammation. Other systemic markers of inflammation may be elevated, such as peripheral white blood cell count and erythrocyte sedimentation rate. Testing for specific diseases known to cause pericardial disease are indicated when suggested by history and examination features. Fluid analysis, when obtained during pericardiocentesis, may be diagnostic in cases because of bacterial or malignant etiologies. In general, pericardial biopsy is not considered helpful in diagnosis.

Treatment

Nonsteroidal anti-inflammatory medications, such as ibuprofen, are the first-line treatment for pericarditis. In cases that do not respond adequately to this intervention, corticosteroids may be given. Pericardiocentesis is reserved for cases in which tamponade physiology is present or when particularly large fluid volumes are present. This procedure is generally performed using percutaneous needle aspiration in the subxiphoid region, ideally with the guidance of ultrasound or fluoroscopy. Acutely while awaiting drainage, intravascular volume expansion may aid in cardiac filling. Inotropes and vasoconstrictors are generally ineffective in tamponade physiology. Recurrent effusions that do not respond to medical management often require surgical pericardotomy.