In this chapter, I will discuss inflammatory diseases of the heart, excluding rheumatic fever (see Chapter 54A, Chapter 54B ), Kawasaki disease (see Chapter 52 ), and infectious endocarditis (see Chapter 55 ). Although the heart may be the primary target organ, inflammatory disease of non-rheumatic origin is often more generalised in nature. Usually such diseases affect various structures of the heart in combination. Only rarely will they be limited to the endocardium, the myocardium, or the pericardium. To clarify the discussion, however, I will distinguish between myocarditis and pericarditis.
MYOCARDITIS
Myocarditis is defined as an inflammatory response within the myocardium. Its aetiology and pathogenesis are very variable. In many patients, the precise mechanisms involved still remain unclear. The clinical consequences of myocarditis are largely determined by the degree and extent of myocardial injury. The disease may first present with pump failure, or with abnormalities of rhythm and conduction. In the acute stage, sudden death may occur, often before the diagnosis is made.
The heart is often dilated, with histological studies revealing myocardial necrosis, with accompanying inflammatory reactions ( Fig. 53-1 ). The degree and extent of myocardial necrosis may vary considerably, as may the type of inflammation. Usually, neither one of these histological findings is diagnostic as far as aetiology and pathogenesis are concerned. In more advanced stages of the disease, part of the damaged myocardium may be replaced by scar tissue. Eventually, the histology of the affected heart may be dominated by interstitial fibrosis. In such instances, the condition is often described as chronic myocarditis. Various schemes for the histological grading of myocarditis have been described, most notably the Dallas criterions. 1 Recently, it has been established that the use of these criterions is unreliable when assessing endomyocardial biopsies to diagnose myocarditis. 2 The myocardial changes are not uniform, and the findings depend on the site of sampling. Furthermore, there are significant differences in interpretation of the histology between histopathologists. It is now established that virus may be present in the myocardium without the Dallas criterions for myocarditis being fulfilled. 3 Most importantly, the Dallas classification does not predict prognosis, nor response to immunosuppressive therapy.
Myocarditis may be associated with a variety of aetiological factors including infections, ischaemia, and generalised inflammatory conditions. In children, two main classes of non-rheumatic myocarditis can be recognised: the infectious and generalised autoimmune variants.
Infectious Myocarditis
Infectious myocarditis can occur as a complication of almost any infectious disease. Viral infections are by far the most important in the industrialised Western world, but in other parts of the world, protozoal infections may rank highest. Many acute bacterial infections can result in myocarditis. It can occur as a complication of tuberculosis, Lyme disease, and haemolytic uraemic syndrome. 1,4–6 Infectious myocarditis is a frequent complication of opportunistic infections in patients with immune deficiencies, either primary or secondary, such as those that occur in patients treated with immunosuppressive drugs. Obviously, therefore, the type and incidence of infectious myocarditis will vary considerably from one part of the world to another. Moreover, its true prevalence in any given population is, as yet, unknown. This is because the disease may take a subclinical course in many patients, and, hence will go undetected. In others, the presence of an infectious myocarditis may be completely masked by the more overt signs and symptoms of other affected organs. Depending on the histological criterions used, evidence of myocarditis has been found in up to one-twentieth of postmortems. 7 It has been demonstrated to be present in approximately one in ten sudden deaths in young adults, and a similar proportion of patients with dilated cardiomyopathy. 8
Viral Myocarditis
The majority of the cases of myocarditis seen in the West are of viral origin. Almost any viral disease can be complicated by myocarditis. Hence, the clinician should always be alert to this possibility. Viral myocarditis can present with ventricular dysfunction of rapid onset, or with progressive ventricular dysfunction and dilation. Viruses are known to be present in the myocardium of many patients with dilated cardiomyopathy even when the histological criterions for myocarditis are not evident. Enteroviruses, particularly those of Coxsackie group B, have been considered important causes, but molecular studies using the polymerase chain reaction have shown that adenoviruses are more commonly found in the myocardium in patients with clinical myocarditis. 9 Cytomegalovirus, echovirus, hepatitis C, respiratory syncytial virus, and the viruses producing influenza, mumps, and rubella have also been implicated. 10,11 Human immunodeficiency virus also commonly infects the heart. 12 In children, it can cause myocarditis and pericarditis, often presenting with the picture of a dilated cardiomyopathy. 13,14
The viral infection may be acquired transplacentally or postnatally. The infection may present in neonates and infants, with myocarditis as the leading abnormality. Infections in older children often cause pericarditis as the dominant feature. The mechanisms involved in producing the myocardial injury are complex. Invasion of the myocardial cells by viruses, or elaboration of toxins, may play an important role. Alternatively, cellular immune mechanisms and circulating autoantibodies may be of great importance. A combination, which may vary considerably between individual patients, of viral infection and subsequent abnormal immune response, causing either ineffective viral clearance or autoimmune myocyte damage, seems to underlie the clinical manifestation of the disease. Persistence of the virus, or continuing immune reactions after the viral infection has cleared, may produce chronic myocardial damage and present as chronic dilated cardiomyopathy.
Clinical Features
The clinical onset of myocarditis usually occurs after a latent period following the onset of a systemic viral infection. The signs and symptoms of myocarditis are highly variable, but are principally the result of cardiac failure or disturbances of rhythm. It is understandable, therefore, that there is no single characteristic clinical profile for myocarditis. Indeed, a whole spectrum of abnormalities may exist. At the one end, a child may develop an infectious myocarditis that remains completely unnoticed. At the other end, a child may become acutely ill with signs of both left- and right-sided cardiac failure and low cardiac output, often further complicated by disturbances of rhythm and sudden death.
All signs and symptoms, even the most subtle ones, which indicate failing pump function or abnormalities in rhythm and conduction, should alert the physician to a cardiac complication. This is particularly so when noticed in the setting of a viral disease. In this respect, the important features that may give a clue to the diagnosis are cardiac enlargement, cardiac failure, tachycardia, gallop rhythm, tachypnoea, dyspnoea, fatigue, and the appearance of an apical murmur indicating mitral insufficiency. There may be chest pain from accompanying pericarditis. Non-specific symptoms, such as fever, diarrhoea, problems with feeding, pallor, mild jaundice, and lethargy, often mark the clinical onset of the principal disease. Occasionally, the clinical picture may be dominated by severe respiratory distress secondary to left ventricular failure, so much so that initially a respiratory infection is mistakenly diagnosed. The clinical picture of cardiac failure in a previously well child with often a minor, preceding viral infection is typical.
Laboratory Findings
The sedimentation rate is usually elevated but may be normal. The level of C-reactive protein may also be elevated, and this may be of prognostic significance. 15 The white cell count is variable, as are the levels of the cardiac enzymes, all depending on the severity of the disease and the nature of the infection. Levels of troponin are frequently, but not invariably, elevated.
All available diagnostic procedures should be used, including close collaboration with the bacteriological laboratory, in an attempt to identify an infectious agent. Despite all studies, however, the diagnosis of a viral origin is often based on circumstantial evidence, along with the exclusion of other possible aetiologies, rather than positive identification of an aetiological agent.
Investigations
Radiology
The size of the heart may be normal, particularly in the early period of the disease. More frequently, the heart will be enlarged, with normal lung fields. Occasionally, pulmonary venous congestion will be evident.
Electrocardiography
Electrocardiographic abnormalities are common in myocarditis, but are non-specific ( Fig. 53-2 ). There is often a sinus tachycardia, with lowering of the QRS complexes in the standard leads and/or precordial leads, flattening or inversion of the T waves, and changes in the ST segment. Arrhythmias are often present and may lead to unexpected death. Occasionally, disturbances of conduction are seen, with varying degrees of heart block. Complete atrioventricular block is rare. The QRS complexes may be broadened, with left or right bundle branch block configuration. The electrocardiographic changes may disappear during the course of the disease, or they may show a progressive evolution to overt abnormalities. The abnormalities may persist after the patient has recovered clinically, most likely because of myocardial fibrosis.
Echocardiography
Echocardiography may demonstrate important, albeit non-specific, features. There is usually dilation of the heart chambers, usually predominantly the left ventricle. When the onset is rapid, producing so-called fulminant myocarditis, there may be ventricular dysfunction without dilation. Ventricular dysfunction is usually much more evident in the left ventricle than in the right, and may be either global or segmental. The left atrium may also be enlarged, especially in the presence of mitral insufficiency ( Fig. 53-3 ). The motion of the ventricular septum, and of the ventricular walls, may be reduced and abnormal, while the ejection fraction may be decreased. Echocardiographic tissue characterisation, tissue Doppler imaging, and measurements of myocardial velocity have been shown to differentiate myocarditis from other causes of ventricular dysfunction, albeit that further work will be needed to determine their value in a clinical setting.
The echocardiogram is of great importance in demonstrating or excluding a pericardial effusion and intracardiac thrombosis, and for excluding structural causes of ventricular dysfunction. Identical echocardiographic findings are found in chronic myocarditis and dilated cardiomyopathy.
Other Imaging Techniques
Radionuclide scans have been used for the detection of myocarditis, using either gallium-67 scans or indium-111–labelled monoclonal antimyosin antibody. 16 In practise, the most valuable role of radionuclide imaging is the serial measurement of left ventricular function, where it provides a more reproducible measurement of function than does echocardiography.
Early studies with contrast-enhanced magnetic resonance imaging have shown considerable promise in detecting myocarditis. Focal myocardial enhancement correlates with myocardial injury and histological changes. This has been used to guide biopsy of affected regions, improving the accuracy of histological diagnosis. 17
Endomyocardial Biopsy
The place of routine endomyocardial biopsy in suspected myocarditis is still unclear. The histological changes of myocarditis are patchy, and so there can never be total confidence that a negative biopsy excludes myocarditis. There is little evidence that biopsy is of value in determining prognosis, or in helping further management. 18 The risk of the biopsy procedure is highest in the acutely unwell young child with severe ventricular dysfunction. 19 After many years of pursuing a policy of routine biopsy in suspected cases, in our own centre we have been unable to demonstrate any benefit, and have abandoned the practise. It is increasingly being used to enable identification of the viral aetiology by analysis of the polymerase chain reaction. 9 Biopsy may be justified in selected cases with unusual or rapidly progressive presentation, or where histology is used to guide therapy. 8
Treatment
If an infectious agent has been identified as the cause of the myocarditis, and a specific treatment is available, then that should be started. In most cases, the causative agent is not identified. Treatment will then be non-specific, aiming at lowering the cardiac pre- and afterload, and at preventing and controlling complications such as cardiac failure and disturbances of rhythm.
Bedrest is advised for at least 14 days in the acute stage in order to reduce the workload of the heart. A good response is characterised by a sleeping pulse rate of less than 100 beats per minute in children, and of less than 120 beats per minute in infants. Restlessness and hypoxic stress should be avoided. If necessary, oxygen is administered.
Diuretics and inotropic agents may well need to be given intravenously in the initial stages of treatment. In a minority of patients, ventilation and circulatory support may be needed. The place of extracorporeal membrane oxygenation is not well established. As the ventricular function can recover, it should be considered in critically ill patients. Cardiac failure should be treated with diuretics, inhibitors of angiotensin-converting enzyme, and β -blockade.
Patients should be closely monitored for the occurrence of arrhythmias. When present, these disturbances should be treated if they have a deleterious haemodynamic effect. Many antiarrhythmic drugs will further depress myocardial contractility and should be used with care.
Thrombosis can occur in those with very dilated atrial and ventricular chambers. In such patients, transoesophageal echocardiography is needed to exclude intracardiac thrombosis with confidence. Anticoagulation should always be considered in these circumstances. If evidence of intracardiac thrombosis is seen echocardiographically, anti-coagulation should be continued until the left ventricular function has improved.
The value of prescribing drugs that suppress the inflammatory reaction is unclear. 20 Immunosuppression is used more commonly in children than in adults with myocarditis. There is no scientific justification for this diversity of approach. It was advocated in the expectation that immunosuppressive therapy would resolve the cellular infiltrate in the myocardium and, hence, reduce mortality and morbidity. The use of corticosteroids is advocated for patients with biopsy-proven disease who fail to respond to conventional therapy. 21 Steroids have been reported to help in the treatment of heart block or ventricular tachycardia brought on by myocarditis. 22 Despite this anecdotal evidence, a trial has shown no benefit from the routine use of prednisolone combined with either cyclosporin A or azothioprine. 23 Immunosuppression has been shown to be of value in a rare histological variant of myocarditis—giant cell myocarditis. 24 Immunoglobulin given intravenously in high doses may be beneficial in improving the recovery of ventricular function. 25 It is widely used in children, but clinical trials have not yet shown that it improves the recovery of left ventricular function or the long-term outcome. 26
Children may die during the acute phase of the illness. In those whose left ventricular function is poor, failing to improve and remaining dependent on diuretics or inotropic agents given in high doses intravenously to control cardiac failure, or in those who develop intractable life-threatening arrhythmias, the option of cardiac transplantation should be considered. Transplantation may also be necessary for those who recover from the acute phase of myocarditis but continue to have poor left ventricular function over the longer term.
Prognosis
Many children make a full recovery from myocarditis. Older children, and those with a lower ejection fraction at presentation, have a worse prognosis. 27 The clinical signs and symptoms usually subside within a few weeks or months. It may take a little longer for the size of the heart and the electrocardiogram parameters to normalise. In some patients, this may take a year or more. Occasionally, the heart may remain enlarged, or episodes of cardiac failure may recur after an initial favourable response. The prognosis in these patients is usually poor. One recent large study showed that two-thirds of children presenting with cardiac myocardial failure were alive without cardiac transplantation at 1 year. Including the patients that had transplantation, more than four-fifths were surviving at 1 year, albeit that most were still on medication 1 year after presentation. 28 A further study showed an overall incidence of dilated cardiomyopathy in children under 18 years of 0.57 cases per 100,000. Of these almost half were diagnosed as myocarditis, three-tenths had died or required transplantation at 1 year, and only just over half were alive at 5 years. 29
Differential Diagnosis
Myocarditis needs to be distinguished from other anomalies that present with signs and symptoms of acute cardiac failure early in life. A variety of metabolic diseases may present with dilated cardiomyopathy in infancy, and these should be excluded (see Chapter 49 , Chapter 57 ). When the left coronary artery arises anomalously from the pulmonary trunk, the characteristic features are the electrocardiographic signs of an anterolateral myocardial infarction. The diagnosis can be confirmed echocardiographically, or by angiocardiography. Enlargement of the heart and cardiac failure may also be caused by longstanding and severe anaemia of various causes. Dilation of the heart may occur also as a secondary phenomenon in patients with systemic arterio-venous fistulas. Occasionally, a child may present with all the signs and symptoms of dilated cardiomyopathy without a history of an acute disease. Acute cardiac failure accompanied by mitral insufficiency is often the leading symptom. From a clinical viewpoint, there is no difference from chronic myocarditis.
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