Myocarditis and pericarditis are rare but important causes of pediatric chest pain. The diagnositic criteria, clinical course, causes, and treatment of myocarditis is reviewed. There is particular attention to the relationship of myocarditis with dilated cardiomyopathy. Supportive therapy remains the standard of care for pump dysfunction. The identification and treatment of pericarditis with associated large pericardial effusion can be lifesaving. This article reviews the important clinical features that might lead the clinician to diagnose either myocarditis or pericarditis and thus separate the few patients with either of these conditions from the legions of children with noncardiac chest pain.
Myocarditis and pericarditis must be considered in a select group of pediatric patients with chest pain. The typical characteristics of chest pain in myocarditis and pericarditis are described in Box 1 . Chest pain can be present or absent in both disease entities. The diagnosis of myocarditis and pericarditis can often be elusive, thus the clinician must maintain a high index of suspicion and understand these disease entities have variable clinical presentations. The presentation of myocarditis may range from mild chest pain and tachypnea to fulminant disease with severe cardiovascular instability, or even sudden death. When myocarditis presents as more subtle disease, the diagnosis may be missed if it is not considered in the initial differential diagnosis. Such patients are often diagnosed after the disease has progressed or even postmortem on autopsy after unexpected death. Myocarditis is an important diagnosis to consider, as it is one of the most common causes of new onset heart failure in previously healthy pediatric patients. Pericarditis can present in an acute or chronic manner and ranges clinically from positional chest pain to cardiac tamponade. Vague symptoms including cough, dyspnea, abdominal pain, vomiting, and fever may be associated with pericarditis depending on the cause. Many patients with pericarditis have a benign course; however, a subset may develop complications including recurrent or constrictive pericarditis.
Myocarditis
Pain is variable, ranging from severe to mild or even absent
Caused by ischemia and myocardial damage
Crushing substernal chest pain with radiation
Worse with exertion
Pericarditis
Sharp stabbing pain caused by rubbing of irritated pericardium
Pain relieved by sitting up and leaning forward
Worse in supine position
Worse with respirations
This article reviews the clinical aspects of myocarditis and pericarditis, and is intended to help the clinician evaluate and manage such cases, as a possible cause of chest pain in the pediatric population.
Myocarditis
Definition
Myocarditis is the inflammation of the myocardium, which is the muscular wall of the heart. Myocarditis may also extend to the pericardium and endocardium. It can be caused by a variety of mechanisms from viral infection to cardiotoxic drugs. The end result of all causes of myocarditis is some degree of cardiac dysfunction ranging from mild subclinical effects, arrhythmias, heart failure, cardiogenic shock, to sudden death. Based on the severity of illness, myocarditis can be classified into 3 clinical categories: acute, fulminant, and chronic. The milder subclinical cases of myocarditis may have spontaneous resolution and go unrecognized by clinicians. In fulminant disease the patients present in extremis with overt cardiogenic shock. The chronic cases may progress to dilated cardiomyopathy.
The gold standard of diagnosis is endomyocardial biopsy. Despite many advances, this procedure presents an inherent risk to the patient and is not often sensitive, so the initial diagnosis of acute myocarditis is dependent on clinical evidence and suspicion as well as a variety of noninvasive tests, which are discussed in this article.
Epidemiology
The precise incidence of myocarditis is not known. Many cases may be subclinical or even difficult to diagnose given the nonspecific clinical symptoms early in the disease process and the lack of sensitivity of endomyocardial biopsy, which ranges from 10% to 63%. In a recent retrospective study from a Canadian pediatric tertiary care center, the estimated prevalence of pediatric myocarditis was 0.5 cases per 10,000 emergency department visits. Myocarditis was diagnosed in 0.3% of patients seen in the cardiology service of a pediatric tertiary care center in the United States in a 23-year period. During this same period a higher incidence of 1.15% was found on autopsy.
Because many cases are unrecognized, epidemiologic data are often found from autopsy studies. The higher incidence of myocarditis found on autopsies is shown by studies of patients who died of suspected sudden infant death syndrome (SIDS). Evidence of myocarditis on autopsy was found in 16% to 20% of infants with suspected SIDS. Myocarditis is also an important cause of sudden death in adolescents and young adults. A review of sudden cardiac death in adolescents found myocarditis to be the cause in up to 17% of cases. Thus, although myocarditis is generally believed to be a rare disease, it is still an important cause of morbidity and mortality in pediatric patients.
It is widely accepted that myocarditis may progress to dilated cardiomyopathy. This occurs via direct myocyte injury from pathogens such as viruses and by the ongoing inflammatory response of the host. In an epidemiologic study of pediatric cardiomyopathies in the United States, the investigators found that 27% of cases of dilated cardiomyopathy were secondary to viral myocarditis.
Myocarditis is usually a sporadic disease caused by viruses. The most commonly reported epidemics of myocarditis have been caused by coxsackie viruses. During outbreaks of this virus in Europe in 1965, 5% to 12% of patients infected with coxsackie virus B had cardiac manifestations of their disease.
Causes
Although a wide range of causes are possible, most cases of myocarditis in the United States and Western Europe are caused by viral infections. Often the inciting agent causing myocarditis is not identified. Advances in molecular techniques have enabled the increased detection of viruses in endomyocardial biopsy samples.
Enteroviruses, particularly coxsackie viruses, have been the most commonly identified pathogens. Other common viruses include parvovirus B19, human herpesvirus 6 (HHV6), influenza, parainfluenza, and adenovirus ( Box 2 ) provides a list of many but not all the causes of myocarditis. Myocarditis is also prevalent in patients with human immunodeficiency virus (HIV); 1 study reported that HIV was present in 52% of patients and was a common cause of left ventricular systolic dysfunction in these patients. During the recent pandemic of novel H1N1 influenza A virus, there were also reports of fulminant myocarditis caused by this virus in children. It is suggested that this strain of influenza may be more prone to causing myocarditis.
Viral
Enteroviruses (coxsackie A and B, echovirus, polio)
Adenovirus
Influenza A and B
Cytomegalovirus
Respiratory syncytial virus
Herpes simplex virus
Human herpesvirus 6
Varicella virus
Human immunodeficiency virus
Mumps
Rubella
Hepatitis viruses
Epstein-Barr virus
Bacterial
Meningococcus
Streptococcus
Klebsiella
Diphtheria
Tuberculosis
Spirochetal
Borrelia burgdorferi
Leptospira
Rickettsial
Rickettsia ricketsii
Rickettsia tsutsugamushi
Protozoal
Trypanosoma cruzii
Toxoplasmosis
Parasitic
Ascaris
Echinococcus
Visceral larva migrans
Fungal
Actinomycosis
Coccidioidomycosis
Histoplasmosis
Candida
Toxic
Scorpion
Radiation
Bee sting
Drugs
Sulfonamides
Chemotherapeutic agents
Phenytoin
Isoniazid
Autoimmune
Rheumatic fever
Inflammatory bowel disease
Systemic lupus erythematosus
Other infectious agents such as bacteria, parasites, and fungi have been known to cause myocarditis less frequently. Borrelia burgdorferi is the causative agent in Lyme disease and is also known to cause manifestations of myocarditis, particularly atrioventricular conduction abnormalities. Trypanosoma cruzi infection is more common in areas of Central and South America. Drugs are also known to cause myocarditis via hypersensitivity reactions or direct cardiotoxic effects (eg, chemotherapeutic agents).
Pathogenesis
Research on murine models has largely contributed to what is known about the pathogenesis of myocarditis in humans. It is well established that primary injury occurs to the myocardium directly by the inciting agent, such as a virus entering the myocyte and replicating, leading to focal necrosis and inflammation of the myocardium ( Fig 1 ). Next, host inflammatory mediators such as macrophages, natural killer (NK) cells, interleukins, tumor necrosis factor (TNF)-α are produced and function to limit viral replication. Experimental mice models with less of an acute immune response have more severe myocarditis. T cells also mediate ongoing injury to the myocardium by further stimulating cytokine release; this marks the most severe phase of myocardial damage, which is usually 7 to 14 days after the initial injury by the pathogen. Cytokines can circulate and persist in the host for weeks, leading to the ongoing inflammatory response and contributing to ongoing myocyte injury and inflammation. Cytokines limit cardiotoxic effects of the pathogen and can have a negative inotropic effect on the heart. The degree of myocyte injury and inflammatory response determines the severity of symptoms and degree of cardiac dysfunction. Thus, there is a wide clinical range of presentations in patients with myocarditis.
In murine models a variety of host factors (nutrition, exercise, genetics, immune state) also contribute to the susceptibility of the host to the inciting agent. Specific receptors for coxsackie virus and adenovirus have been identified on human myocytes, which possibly accounts for the higher incidence of myocarditis in infections with these pathogens, which are the most common causative agents in myocarditis.
As mentioned earlier, myocarditis can also progress to dilated cardiomyopathy (DCM), as shown by murine models and epidemiologic studies. In DCM systolic function is compromised from dilated ventricles, leading to heart failure. In a study of 1426 children with DCM, the most common known cause of DCM was myocarditis in 16% of patients. It is hypothesized that persistent myocyte injury occurs as a result of incomplete clearance of the pathogen, and the persistence of infection leads to an ongoing host inflammatory response causing progression of myocarditis to DCM.
Clinical Presentation
Children with myocarditis present with a variable spectrum of clinical disease. Suspicion for the initial diagnosis of myocarditis is highly dependent on the history and physical examination. Many cases may present with mild nonspecific prodromal symptoms typical of a viral illness and the cardiac manifestations of their illness may be subtle. In cases of fulminant myocarditis, children present with overt cardiovascular collapse and shock. Acute myocarditis may also cause sudden unexpected death in children, with preceding symptoms that are minimal or seemingly benign. In 2 retrospective studies of patients less than 20 years old who died suddenly and unexpectedly, 35% to 53% actually had prodromal symptoms that were not believed to be related to cardiac disease. A study of pediatric patients with myocarditis also found that 83% were not diagnosed at the first presentation to a clinician and required 2 or more visits to a medical provider before suspicion of myocarditis.
By history, the patient may have complaints that are associated with other common pediatric illnesses such as respiratory tract infections and gastroenteritis. Prodromal symptoms that children often present with include vomiting, diarrhea, fever, shortness of breath, respiratory symptoms, poor feeding, myalgias, fatigue, chest pain, and syncope. In a retrospective review of the presenting clinical characteristics of pediatric patients with myocarditis, the most common presenting symptoms were shortness of breath (69%), vomiting (48%), poor feeding (40%), upper respiratory symptoms (39%), fever (36%), and lethargy (36%). In a second study of clinical presentations, all children who presented with chest pain were more than 10 years of age.
On physical examination clinicians should look for signs of cardiac dysfunction. Respiratory distress may be caused by heart failure causing pulmonary venous congestion. An S3 or S4 gallop may be present, which is caused by decreased ventricular function and dilatation. Murmurs associated with mitral valve and tricuspid valve insufficiency are also associated with ventricular dysfunction. The cardiac chambers dilate in response to dysfunction, with the secondary effect of mitral and tricuspid valve annular dilation, thus leading to incomplete coaptation of the valve leaflets. Tricuspid and mitral valve regurgitation further volume load the heart, creating a positive feedback loop that leads to ever-worsening atrioventricular valve regurgitation. Severe mitral regurgitation and left atrial dilation can cause intermittent compression on the left bronchus, leading to further respiratory compromise. Cardiovascular instability caused by heart failure from myocarditis may also manifest as hypotension, poor pulses, poor perfusion, and a compensatory tachycardia. Other signs of heart failure include hepatomegaly, poor urine output, and altered sensorium. It is commonly believed that patients with myocarditis frequently have tachycardia out of proportion to fever or hydration status; however, 1 study found 66% of children actually had a normal heart rate at initial presentation. The patients in this study most commonly presented with the following physical examination findings: tachypnea (60%), heptomegaly (50%), respiratory distress (47%), fever (36%), and abnormal lung examination (34%).
Chest pain can be present or absent in myocarditis. When present, especially in association with increased troponin levels, the pain can be similar to adult ischemia with anterior chest pressure pain radiating to the neck and arms. As with other causes of ischemic chest pain, the pain of myocarditis worsens with activity or exercise, but does not vary with respiration. Patients with pancarditis (myocarditis and pericarditis) more typically present with precordial chest pain, with pain more prominent in the supine position. Deep breathing or coughing can exacerbate pericardial pain, which is improved in the sitting position.
Diagnostic Evaluation
The diagnosis of myocarditis is initially based on the clinical picture, particularly heart failure or arrhythmia preceded by a prodrome of flulike symptoms and respiratory difficulty. There are several invasive and noninvasive tests that can further support the diagnosis.
The gold standard for diagnosis of myocarditis is endomyocardial biopsy (EB). The Dallas criteria is a standardized classification system used to make the diagnosis of active myocarditis based on the presence of inflammatory cellular infiltrates and myocyte necrosis on pathology specimens from EB. Diagnosis based on biopsy is known to have a variable and low sensitivity because the disease process is patchy and the because of the variability of analysis of biopsy specimens between observers. In pediatric patients, only 20% to 40% have confirmation on EB. EB can help isolate infectious pathogens using molecular techniques, such as amplification of viral genome via polymerase chain reaction (PCR) and in situ hybridization. However, there is more of a focus on noninvasive modalities to diagnose myocarditis because of inherent risks associated with EB, particularly risk of perforation or tricuspid valve injury, which may be higher in younger patients. The diagnosis of myocarditis is thus usually based on the clinical picture with support of noninvasive tests to reach the final diagnosis, rather than biopsy proven disease.
Electrocardiogram (EKG) is a simple noninvasive initial test performed in suspected cases of myocarditis. Retrospective pediatric studies have found abnormal EKGs in 93% to 100% of patients with myocarditis. Sinus tachycardia with low-voltage QRS complexes and inverted T waves are the most typical findings on EKG. Other abnormalities that may be present include ventricular hypertrophy, ST segment changes, premature ventricular or atrial beats, arrhythmias (supraventricular tachycardia, ventricular tachycardia), heart block, and infarct patterns ( Figs. 2 and 3 ).
