Pediatric Nonviral Myocarditis

Myocarditis is an inflammatory disease of the heart muscles, with most cases having a viral etiology.[1, 2, 3, 4] However, many nonviral causes are also recognized[2, 3, 4, 5] and, indeed, a number of common infectious illnesses of childhood may be associated with myocarditis in pediatric patients.[6] In addition, myocarditis can be a manifestation of hypersensitivity or it can be secondary to a drug reaction. The severity of myocarditis varies from relatively asymptomatic disease to fulminant, severe disease with a rapid, progressive, downhill course. (See Etiology, Presentation, and Workup.)[7, 8]

Epidemiologically, myocarditis appears to be sporadic. The most common cause is thought to be coxsackievirus B, but the condition can also arise from bacterial, parasitic, fungal, toxic, and drug-related causes. (See Treatment and Medication.)

When clinically significant myocarditis (regardless of cause) occurs, myocardial function is reduced in the presence of, and as a result of, extensive interstitial inflammation and/or injury. Systolic function of the left ventricle with concomitant dilatation of the heart and cardiac enlargement occurs. The overall result is an attendant reduction in cardiac output.

In addition, progressive congestive heart failure (CHF) with increased left ventricular end-diastolic volume and pressure results in an increase in left atrial pressure, which is transmitted into the pulmonary venous system. This may also result in pulmonary edema secondary to increased pulmonary arterial hydrostatic forces.

Finally, during the healing stages of myocarditis, fibroblasts may replace existing myocytes with resultant scar formation. Chronic CHF may develop. An autopsy sample that shows scarring in the ventricles is seen below.

Pediatric nonviral myocarditis. This image is reveals myocarditis with scarring at autopsy. It is a short-axis gross photograph from an 8-year-old child who had clinical myocarditis, showing scarring of both ventricles, more prominent in the left. The fibrosis depicts a random distribution with epicardial, myocardial, and pericardial involvement.

Causes of myocarditis, including nonviral causes, include the following[4, 9] :

• Viral

• Rickettsial: Rickettsia rickettsii, R tsutsugamushi

• Bacterial organisms/infections: Klebsiella species, Leptospira species, Salmonella species, Brucella species, Legionella pneumophila, meningococci, clostridia, streptococci (scarlet fever), staphylococci, pneumococci, tuberculosis, syphilis, tetanus

• Protozoa and protozoal infections: Trypanosoma cruzi (Chagas disease), toxoplasmosis, amebiasis

• Other parasites and parasitic infections: Toxocara canis, schistosomiasis, heterophyiasis, cysticercosis, echinococci, visceral larva migrans

• Fungal infections: Actinomycosis, coccidioidomycosis, histoplasmosis, candidiasis

• Toxic etiology: Scorpion envenomations, diphtheria

• Drugs: Cyclophosphamide, phenylbutazone, acetazolamide, amphotericin B, indomethacin, tetracycline, isoniazid, methyldopa, phenytoin, penicillin, sulfonamides

• Hypersensitivity/autoimmune: Rheumatoid arthritis, rheumatic fever, ulcerative colitis, systemic lupus erythematosus (SLE), Kawasaki syndrome, dermatomyositis

• Other: Sarcoidosis, scleroderma, idiopathic, giant cell, peripartum myocarditis

Although rare, some of the more common causes of nonviral myocarditis are discussed below in greater detail.

Chagas disease

Chagas disease is caused by a protozoal infestation with T cruzi. It is very uncommon in North America but can affect as much as half the population in endemic areas, such as South America.[10]  Acute infection can cause protracted heart failure and death. Endomyocardial biopsy and microscopic examination typically demonstrate organisms, neutrophils, lymphocytes, macrophages, and eosinophils.

Giant cell myocarditis

In giant cell myocarditis, giant cells are present in the myocardium with or without granulomas. This type of myocarditis may be evidenced with tuberculosis, syphilis, rheumatoid arthritis, or rheumatic heart disease, or with fungal or parasitic infections. The characteristic cell is probably histiocytic in origin and is usually found in nonviral myocarditis. Similar cells have been noted in patients with myocarditis associated with drugs such as phenylbutazone. This type of myocarditis may not be specific[11]  but, rather, may represent a final common pathologic pathway.

Systemic lupus erythematosus

Patients with SLE may have myocardial fibrinoid lesions in the connective tissue, with an accompanying cellular reaction. This reaction may also affect the cardiac valves, most notably the mitral and aortic valves.[12] Although the predominant cardiac manifestation of SLE is pericarditis, myocardial involvement with congestive heart failure (CHF) can occur. The treatment of choice is corticosteroids.

Kawasaki disease

Kawasaki disease may include myocardial involvement, which usually occurs in the acute phase; it can occur independent of any coronary artery involvement and usually resolves completely. In some cases, however, the diffuse myocarditis may be severe, and it may lead to heart failure and death. Although the pathophysiologic mechanisms that occur in Kawasaki disease are not known, a generalized autoimmune disorder is suspected.

Dermatomyositis

Dermatomyositis, a multisystem (probably autoimmune) disease, is characterized by diffuse, nonsuppurative inflammation of skeletal muscle and skin. However, cardiac involvement, including a loss of striations, fragmentation, and vascularization of muscle fibers, has been reported. The interstitium may also show a variable amount of edema. Tachycardia and conduction abnormalities are described, but heart failure is uncommon. Long-term therapy with prednisone is beneficial in most cases. Children have a good long-term prognosis, as most recover, and medication may be discontinued in 1-2 years.

Myocarditis is most frequently affects younger adults aged 20 to 40 years.[3] However, when it occurs in children, this patient population appears to have a more severe presentation than that of adults, with a higher percentage requiring temporary mechanical circulatory support. In addition, the elderly may be underdiagnosed.

In general, men are affected more frequently than women,[3, 4] and certain forms of myocarditis (eg, cardiac sarcoidosis) affect black populations more than white populations in the United States.[3] Most forms of myocarditis have no known ethnic predisposition.

Although no widely available test exists that is applicable at a population level for the incidence and prevalence of myocarditis, global estimates of the burden of myocarditis have been extrapolated from population-based studies of heart muscle disease (heart disease not related to blocked arteries or abnormal heart valves), such that 2010 global data indicate about 400,000 people died of heart muscle disease (cardiomyopathy that includes myocarditis) (240,000 men, 160,000 women).[3] Expert consensus opinion suggests that up to 40% of dilated cardiomyopathy results from myocarditis,[3]  and about 10% of initially unexplained cases of cardiomyopathy are caused by myocarditits[2]

The prognosis for myocarditis varies and depends on age, etiology, and severity at the time of presentation.[1, 2, 3, 4] The mortality rate in newborn infants is high (75%) in some reports. Older infants and children have a better prognosis, with mortality rates ranging from 10% to 25% in clinically recognizable cases. Some studies have suggested complete recovery in as many as 50% of the cases.

Perhaps as many as 25%-35% of patients who present with clinical myocarditis may be left with a significant chronic dilated cardiomyopathy and may require cardiac transplantation.

The cause of myocarditis may affect prognosis. For example, patients with conduction abnormalities or arrhythmias secondary to diphtheric myocarditis tend to have a poor prognosis.[13]

In a retrospective analysis of clinical and magnetic resonance imaging (MRI) prognostic factors from 58 pediatric myocarditis cases (nonviral and viral) over a 5-year period, Sachdeva et al found that risk factors for poor outcomes included an ejection fraction below 30% on presentation, peak brain natriuretic peptide levels above 10,000 ng/L, and late enhancements on cardiac MRI.[14]

In another retrospective analysis (2008-2012) of 75 patients aged up to 19 years admitted with a diagnosis of myocarditis and normal left ventricular systolic function at seven tertiary pediatric hospitals, factors associated with poor outcomes included significantly higher baseline levels of B-type natriuretic peptide (BNP), troponin I (TnI), and creatine kinase.[15]

The clinical presentation of nonviral myocarditis varies considerably; factors that influence the clinical presentation include etiologic agent, age, sex, and immunocompetence.[1, 2, 3, 4] Many patients with myocarditis are asymptomatic, whereas others may present with a fulminant, rapidly progressive, fatal illness.

Clinical manifestations of myocarditis, regardless of etiology, tend to be more severe in newborns than in older infants and children. Symptoms in newborns are nonspecific and include the following:

• Lethargy

• Poor feeding

• Cyanosis

• Respiratory distress

• Tachypnea

• Tachycardia

• Vomiting

In older infants and children, the symptoms often encountered include the following:

• Low-grade fever

• Irritability

• Mild respiratory symptoms

• Abdominal pain

The physical examination may include verification of the symptoms listed under History. The nonspecific signs and symptoms noted in infants with myocarditis may be evidenced on physical examination but may also be documented in the patient's history. Fever, irritability, respiratory signs, and abdominal pain may be noted on physical examination of children and adults with myocarditis. If the disease has progressed, physical examination usually reveals the following:

• Decreased cardiac output

• Pallor and cool skin in distal extremities

• Rapid respirations

• Possible thready pulse

• Tachycardia usually present (gallop rhythm may be heard)

• Progressive heart failure

A mitral regurgitant murmur—a blowing, holosystolic murmur heard best at the apex of the heart—may be present. The lung examination may show scattered rhonchi and rales. Full cardiovascular collapse is possible.

Echocardiography

Echocardiography is critical in making the diagnosis of myocarditis. Typically, the presence of diminished ventricular function with dilatation of one or several chambers of the heart becomes obvious. Echocardiography aids in ruling out pericardial effusion or structural congenital heart disease as the etiology of the symptoms.[16]

Cardiac magnetic resonance imaging (CMRI)

CMRI is noninvasive and can aid not only in the diagnosis of myocarditis but also for monitoring of disease progression.[3, 4, 9]  This imaging modality can also clarify the presence of inflammation or fibrosis, function, and pericardial effusion, but it is not a substitute for endomyocardial biopsy for determining the etiology of myocarditis.[17]

Electrocardiography

Sinus tachycardia out of proportion to the degree of fever may be noticeable in patients with myocarditis. Arrhythmias and ST-T wave changes in as many as 80% of patients, may be associated with myocarditis. These changes may be sensitive indicators of myocardial ischemia, or they may be nonspecific findings.

Histologic findings

The major purposes of a tissue biopsy are to establish a diagnosis of myocarditis and to classify the stage of disease as acute, healed, or chronic. The specific histologic findings differ based on the particular etiologic agent associated with myocarditis.

The role of endomyocardial biopsy in the diagnosis of myocarditis remains controversial. Biopsy may present somewhat of a risk in the acutely ill and unstable patient, and a histologic diagnosis may not be easy.

The Heart Failure Society of America recommends consideration of endomyocardial biopsy in patients with an acute deterioration of cardiac function of unknown etiology who are unresponsive to medical therapy,[1]  and the European Society of Cardiology indicates performing endomyocardial biopsy in those with clinically suspected myocarditis after ischemia has been ruled out with coronary angiography[9]

Typical sampling usually includes small areas of the right ventricle (septal area). Because myocarditis may be focal and may primarily involve the left ventricle, results of the sampling techniques used may not fully represent the true incidence of myocarditis. That is, a negative biopsy result does not rule out myocarditis.

A major problem with endomyocardial biopsy is the possibility of overinterpretation or misinterpretation of the biopsy specimen. In addition, some clinicians argue that the results of endomyocardial biopsy may not change the treatment of myocarditis. This may be true, at least until a clearer role emerges for immunosuppression therapy in patients with this disease. Little work in pediatric patients has been done in this area.

The high-contrast and high-resolution fluorescent imaging of confocal laser scanning microscopy and super-resolution microscopy may potentially increase the diagnostic yield of endomyocardial biopsy.[18] These modalities appear to provide improved quantitative digital analysis and may thereby improve precision and accuracy in the evaluation of critical pathologic features.[18]

Performing a biopsy to establish a subset of pediatric patients with active myocarditis may be useful in order to study different therapies in a controlled, prospective manner.

Medical therapy for congestive heart failure (CHF) is fairly standard.[1] The general principles of therapy for CHF are applicable to patients with myocarditis. These principles include the manipulation of preload, afterload, and contractility. Therefore, fluid restriction and diuretics, inotropic support to optimize contractility with continuous intravenous (IV) inotropic agents, and IV vasodilator agents, are all important potential interventions for CHF caused by myocarditis of a nonviral origin.

Additional general maneuvers to reduce the workload of the heart, thereby improving symptoms of CHF, include the following:

• Inotropes via continuous drip

• Afterload reducing agents

• Diuretics

• Digitalis

• Beta-blockers

• Mechanical ventilation

• Arrhythmia therapy

• Anticoagulation

• Metabolic demand reduction

• Bed rest

Treatment of the specific causes of the myocarditis (ie, bacterial sepsis, rickettsial disease) is necessary. However, it is still not entirely clear if the use of immunosuppressive therapy for myocarditis is indicated.[1, 2]

Some rationale for immunosuppressive therapy for myocarditis has been put forth, because the pathophysiology of myocarditis appears to involve the immune system's reaction against the myocardium. Adult studies have failed to clearly determine the role of immunosuppressive therapy. Some preliminary data suggest that certain combinations of immunosuppressive agents may be beneficial in patients with acute myocarditis.[19]

Guidelines recommendations

The Heart Failure Society of America does not recommend routine use of immunosuppressive therapies for patients with myocarditis.[1]  The European Society of Cardiology guidelines have the following recommendations regarding immunosuppressive therapies for myocarditis[9] :

• Only initiate immunosuppression after active infection has been ruled out on endomyocardial biopsy by polymerase chain reaction.
• Consider immunosuppression in proven autoimmune (eg, infection-negative) forms of myocarditis, without immunosuppression contraindications (eg, giant cell myocarditis, cardiac sarcoidosis, myocarditis associated with known extracardiac autoimmune disease).
• Steroid therapy is indicated in cardiac sarcoidosis in the presence of ventricular dysfunction and/or arrhythmia and in some forms of infection-negative eosinophilic or toxic myocarditis with heart failure and/or arrhythmia.
• On an individual patient basis, immunosuppression may be considered in infection-negative lymphocytic myocarditis refractory to standard therapy in patients with no contraindications to immunosuppression.
• Follow-up endomyocardial biopsy may be required to guide the intensity and the length of immunosuppression.

Surgical therapy

Surgical care for patient with myocarditis is primarily recommended if medical treatment fails and if the patient is symptomatic.

Some children with fulminant myocarditis develop progressive and fatal course and these patients should be supported by extracorporeal membrane oxygenation (ECMO) or ventricular assist devices (VAD) acutely.[7] Because complete recovery is possible in a high percentage of these patients, active consideration for mechanical circulatory support (ECMO or VAD) should be given to treat these children.

Surgical treatment may include cardiac transplantation for patients that develop a chronic, symptomatic dilated cardiomyopathy.

Pediatric ventricular assist devices (VADs) have been used as bridges to children with end-stage heart failure, including those resulting from myocarditis.[20]

Another surgical procedure that may be used is left ventricular volume reduction (Battista operation).

Inpatient care

Need for, and length of, inpatient care varies with severity of the illness. Prolonged supportive therapy may be required until the patient can resume spontaneous ventilation and be adequately maintained on oral anticongestive therapy.

Patient follow-up

Patients require close outpatient follow-up care with clinical assessment, electrocardiography, and echocardiography,[9] especially if significant residual CHF is present. Some patients may continue to have symptoms of moderate to severe CHF that may require eventual cardiac transplantation. However, some patients do completely recover and have normal cardiac function and may only need occasional follow-up evaluation.

Advise patients with chronic, moderate to severe heart failure that a "no-added-salt" diet is probably beneficial. Otherwise, ensure adequate calories and nutrition for growth.

During the acute phase of myocarditis, most clinicians agree that bed rest should be recommended (eg, ≥6 months[17] ) until the inflammation has resolved based on cardiac magnetic resonance imaging findings or endomyocardial biopsy results, as well as once cardiac function has normalized.[17]

Several animal studies have suggested that exercise during the acute viremia can potentiate the disease. However, after recovery and during the healing and/or chronic phases of myocarditis, activity as tolerated is believed to be acceptable.

Medical therapy for heart failure includes the use of inotropic agents, afterload reducing agents, diuretics, beta blockers, and anticoagulants. Antiarrhythmic agents may also be required if secondary rhythm disturbances erupt. Drugs used in the treatment of patients with myocarditis include the following:

• Dopamine

• Epinephrine

• Milrinone

• Digoxin

• Furosemide

• Nitroprusside

• Captopril

• Warfarin

• Enoxaparin

• Aspirin

Class Summary

These agents are used to increase cardiac contractility. Positive inotropic agents increase the force of contraction of the myocardium and are used to treat acute and chronic CHF. Some may also increase or decrease the heart rate (ie, positive or negative chronotropic agents), provide vasodilatation, or improve myocardial relaxation. These additional properties influence the choice of drug for specific circumstances.

Dopamine

Dopamine stimulates adrenergic and dopaminergic receptors. Its hemodynamic effect is dependent on the dose. Lower doses predominantly stimulate dopaminergic receptors that, in turn, produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation are produced by higher doses. After initiating therapy, increase the dose by 1-4 mcg/kg/min every 10-30 minutes until the optimal response is obtained. More than 50% of patients are satisfactorily maintained on doses of less than 20 mcg/kg/min.

Epinephrine (Adrenalin)

Epinephrine has alpha-agonist effects that include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Beta-agonist effects include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.

Milrinone

Digoxin (Lanoxin)

Digoxin is a cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system. It directly acts on cardiac muscle, increasing myocardial systolic contractions. Digoxin's indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

Class Summary

These agents promote excretion of water and electrolytes by the kidneys. They are used to treat heart failure or hepatic, renal, or pulmonary disease when sodium and water retention have resulted in edema or ascites. These agents cause preload reduction through diuresis.

Furosemide (Lasix)

Furosemide is the mainstay of diuresis (reducing preload) in acute CHF. It increases the excretion of water by interfering with the chloride-binding cotransport system, resulting in the inhibition of sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule.

Class Summary

These agents reduce systemic vascular resistance and increase systemic blood flow resulting from CHF. They cause vasodilation, resulting in afterload reduction.

Nitroprusside (Nitropress)

Nitroprusside is a potent vasodilating agent and increases inotropic activity of the heart. At higher dosages, it may exacerbate myocardial ischemia by increasing the heart rate.

Captopril

Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. Useful in chronic CHF and in transition to oral agents from IV agents. The dosage range is wide and can be titrated to effect.

Class Summary

These agents are used to prevent recurrent or ongoing thromboembolic occlusion. They are recommended in patients with severe left ventricular dysfunction and/or in patients with documented left heart thrombus.

Warfarin (Coumadin)

Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Tailor the dose to maintain an international normalized ratio (INR) in the range of 2-2.5.

Enoxaparin (Lovenox)

Enoxaparin is a low ̶ molecular-weight derivative of heparin. It is used to prevent deep venous thrombosis (DVT), which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. Enoxaparin enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, it preferentially increases the inhibition of factor Xa.

Class Summary

Probable mechanisms that underlie the therapeutic benefits of aspirin include inhibition of platelet aggregation.

Aspirin (Bayer Aspirin, Ecotrin, Aspirtab, Aspercin, Bufferin )

Aspirin inhibits prostaglandin synthesis, which prevents the formation of platelet-aggregating thromboxane A2. In the absence of thrombus in the heart, and with moderate left ventricular dysfunction, aspirin may be indicated at an antiplatelet dosage.