Myocarditis in infants and children: A review for the paediatrician

Abstract

Clinical myocarditis is uncommon in infants and children. The most common pathogen is Coxsackievirus B. The offending agent triggers an immune response, which results in myocardial edema with subsequent impairment of systolic and diastolic function. Newborns and infants are more severely affected because the immature myocardium has limited ways of adapting to an acute insult. Children typically present with sinus tachycardia and gallop on auscultation, cardiomegaly on chest x-ray and small voltages on electrocardiogram. The echocardiogram shows reduced ventricular function. Viral studies can isolate the pathogen. Myocardial biopsy is useful diagnostically, but carries a significant risk for the sick infant. The first line of treatment includes measures such as rest, oxygen and diuretics. Inotropic agents are useful in moderate to severe heart failure. The role of immunosuppressive therapy is not yet clearly established in the paediatric age group. Prognosis is guarded in newborns but more favourable in older children.

Myocarditis is defined as inflammation of the myocardium. Clinically, the manifestation of myocarditis is relatively uncommon in infants and children. It represented only 0.3% of 14,322 patients seen over a 23-year period at Texas Children’s Hospital, Houston, Texas (1). Subclinical myocarditis is much more prevalent. On the other hand, classic histological features of myocarditis have been documented in infants and children who were victims of sudden unexpected death (2).

EPIDEMIOLOGY AND ETIOLOGY

The majority of cases of myocarditis are secondary to a viral infection. The most common agent in children is Coxsackievirus B, in particular serotypes 1 to 6 (3,4). Coxsackievirus B is usually responsible for sporadic cases, although outbreaks have been reported (5). Other enteroviruses (6), influenza (7), rubella (8) and adenoviruses (9), and a host of other agents, have also been implicated in cases of myocarditis (Table 1).

TABLE 1:

Some causes of myocarditis

Viral

Coxsackievirus B

Coxsackievirus A

Adenoviruses

Echoviruses

Hepatitis viruses

Herpes simplex virus

Epstein-Barr virus

Cytomegalovirus

Polio viruses

Varicella virus

Influenza viruses

Bacterial

Diphtheria

Salmonella

Leptospira

Streptococcus

Mycoplasma bacteria

Legionella

Rickettsial

Rickettsia ricketsii

Protozoal

Trypanosoma cruzi

Parasitic

Toxocara canis

Schistosomiasis

Cystercosis

Visceral larva migrans

Fungal

Histoplasmosis

Candida

Drugs

Amphotericin B

Tetracycline

Sulfonamides

Phenylbutazone

Cyclophosphamide

Autoimmune

Systemic lupus erythematosus

Rheumatic fever

Ulcerative colitis

Rheumatoid arthritis

Other

Sarcoidosis

Idiopathic

PATHOLOGY

At gross examination, the myocardium appears pale and flabby. The ventricular cavities are dilated, with wall thinning and an increase in myocardial mass. A mural thrombus is occasionally present.

Microscopic inspection demonstrates a predominantly mononuclear inflammatory cell infiltrate. Interstitial edema and, in more severe cases, myocyte necrosis are present.

Experiments in murine models have shown that myocarditis is an immune process that is triggered by a locally produced neoantigen (10,11). Cell-mediated cytotoxicity carried out by cytotoxic T cells and natural killer cells is the primary pathological process, with humoral defences contributing to the insult (12,13). The immune response is modulated by locally produced cytokines that play an important role in the development of chronic myocarditis (14).

PATHOPHYSIOLOGY

The primary pathophysiological processes are the development of myocardial necrosis and interstitial edema, with consequent impairment in the contractile performance of the heart muscle. Chamber dilation and thinning of the ventricular wall increases wall tension, augments myocardial oxygen demand and stimulates hypertrophy. Preload reserve is minimal in the immature myocardium, and the maintenance of an adequate cardiac output in the face of failing contractility is dependent on chronotropic upregulation. Comorbid fever and anemia can place further stress on the heart. When compensatory mechanisms are depleted, the heart fails, resulting in a low output state. A decrease in cardiac compliance, along with incomplete emptying of the left ventricle, raises left ventricular diastolic and pulmonary venous pressures, and predisposes patients to pulmonary edema.

In the majority of cases, the myocardial insult is limited, and the heart recovers normal function within months. When myocardial damage is more extensive, scar tissue replaces necrotic myocardium during healing, and the recovery of function is incomplete.

CLINICAL PRESENTATION

Dyspnea with feeding, vomiting and pallor are common presenting complaints in infants. Older children present with a marked decrease in stamina and shortness of breath in the context of a viral infection. Complaints of palpitation suggest coexistent arrhythmia. Chest pain is nonspecific and indicates a possible associated pleural or pericardial inflammation.

On physical examination, the child is tachypneic, tachycardic and febrile. Hypotension suggests severely depressed cardiac function. Pallor and peripheral vasoconstriction due to sympathetic activation are usually noted. Peripheral capillary refill is delayed. In children, the earliest sign of fluid retention secondary to congestive heart failure is eyelid puffiness. More severe failure presents with hepatomegaly and generalized edema. A pericardial rub and distant heart sounds suggest the presence of an associated pericardial effusion. A soft first heart sound is common but nonspecific and often difficult to appreciate in the tachycardic infant. A gallop rhythm produced by a third heart sound is frequent and best heard at the apex. A high pitch regurgitant murmur detected at the apex indicates coexistent mitral insufficiency.

DIFFERENTIAL DIAGNOSIS

Sepsis, severe dehydration or anemia should be considered as diagnostic possibilities in the ill neonate or infant. Primary endocardial fibroelastosis and metabolic dilated cardiomyopathy are myocardial disorders that can present in a similar fashion. Congenital structural lesions, such as critical coarctation of the aorta or anomalous origin of the left coronary artery from the pulmonary artery, must be ruled out.

DIAGNOSIS

The chest x-ray classically displays cardiomegaly and pulmonary venous congestion. An associated pericardial effusion can accentuate the degree of cardiomegaly.

The 12-lead electrocardiogram typically shows sinus tachycardia and low voltage QRS complexes (less than 5 mm total amplitude in all limb leads), with lowamplitude or slightly inverted T waves, and a small or absent Q wave in leads V5 and V6. PR and QT interval prolongation are common but nonspecific.

The presence of arrhythmia in the context of a febrile illness should point the clinician to the possibility of myocarditis. Paroxysmal atrial tachycardia (15), ventricular ectopy (16–18) and various degrees of heart block (19) have all been described in association with myocarditis.

The echocardiogram is essential in the diagnosis and follow-up of myocarditis. Structural heart disease and pericarditis can be readily ruled out. Myocardial function is assessed at the time of diagnosis, and serves as a baseline for future monitoring of disease progression and response to therapeutic interventions.

Isolation of the offending virus from stool, throat washings or blood is possible early in the disease (20). Otherwise, serological diagnosis relies on a fourfold increase in virus-specific antibody titres between acute and convalescent blood samples.

The role of myocardial biopsy in establishing the diagnosis of myocarditis is controversial. Endomyocardial biopsy can establish the diagnosis and degree of involvement (21). Polymerase chain reaction performed on myocardial tissue has been recently shown to be both sensitive and specific to the diagnosis of enteroviral and adenoviral myocarditis (9). The utility of biopsy must be weighed against the risk of perforation and death, particularly in the ill infant (22). In addition, patchy right ventricular disease or isolated left ventricular involvement can escape detection when random biopsy samples are limited to the right ventricular septum.

TREATMENT

Treatment of the infant and child affected by myocarditis is tailored to the severity of disease. The child is hospitalized, and telemetry is implemented when coexistent arrhythmia is present. Ancillary therapeutic measures include supplemental oxygen, diuretics and bed rest. Anemia is corrected whenever present. Fluid and salt intake are controlled. For more severe disease, an inotropic agent, such as dopamine or dobutamine, is added, especially if cardiac function is depressed on echocardiogram. Administration of these drugs requires admission to the intensive care unit and intravascular blood pressure monitoring. Nitroprusside, an intravenous afterload-reducing agent, can be considered in the absence of hypotension. Digitalis should be used with extreme care during the acute phase of the disease because its enhanced activity on the inflammed myocardium can precipitate serious dysrhythmia (23). If myocarditis results in dilated cardiomyopathy and chronic heart failure, digoxin and an angiotensin-converting enzyme inhibitor are therapeutically useful (24).

The administration of immunosuppressive agents in the acute treatment of myocarditis in children is controversial. The small cohort sizes in most paediatric studies, and the lack of large double-blind controlled trials prohibit any clear-cut recommendations. Steroids, azathioprine and gamma globulins have been used with variable success reported. In the Myocarditis Treatment Trial, mostly adult patients treated with azathioprine and prednisone or with cyclosporine and prednisone did not fare any better than patients treated with conventional treatment alone (25). In a smaller paediatric study, patients treated with immunosuppressive agents did better than patients treated with conservative measures alone (26). There have been some recent encouraging results with the use of gamma globulin (27,28).

PROGNOSIS

Myocarditis has an ominous prognosis in newborns, with 75% mortality when Coxsackievirus B is the suspected pathogen (29). Older children fare better; mortality is less than 25%, while another 25% of children will suffer from chronic symptoms of heart failure. Recovery is complete in about one-half of diagnosed cases (30).