Cardiology in the Young (2011), 21, 241251

r Cambridge University Press, 2011

doi:10.1017/S1047951110001964

Review Article The evolving approach to paediatric myocarditis: a review of the current literature
Lindsay J. May,1 David J. Patton,1,2 Deborah S. Fruitman1,2
1

Department of Pediatrics; 2Division of Cardiology, University of Calgary, Alberta Childrens Hospital, Calgary, Alberta, Canada Abstract Paediatric myocarditis remains challenging from the perspectives of diagnosis and management. Multiple aetiologies exist and the majority of cases appear to be related to viral illnesses. Enteroviruses are believed to be the most common cause, although cases related to adenovirus may be more frequent than suspected. The clinical presentation is extremely varied, ranging from asymptomatic to sudden unexpected death. A high index of suspicion is crucial. There is emerging evidence to support investigations such as serum N-terminal B-type natriuretic peptide levels, as well as cardiac magnetic resonance imaging as adjuncts to the clinical diagnosis. In the future, these may reduce the necessity for invasive methods, such as endomyocardial biopsy, which remain the gold standard. Management generally includes supportive care, consisting of cardiac failure medical management, with the potential for mechanical support and cardiac transplantation. Treatments aimed at immunosuppression remain controversial. The paediatric literature is extremely limited with no conclusive evidence to support or refute these strategies. This article summarises the current literature regarding aetiology, clinical presentation, diagnosis, and management of myocarditis in paediatric patients.
Keywords: Cardiomyopathy; myocardium; ventricular dysfunction Received: 27 September 2010Accepted: 8 December 2010; First published online: 28 January 2011

especially in the paediatric age group. It has potential for significant morbidity including diminished cardiac function and cardiac failure, occasionally necessitating aggressive circulatory support. Dilated cardiomyopathy is a significant sequela of myocarditis and is a common indication for cardiac transplantation. Myocarditis is also identified as the cause of sudden unexpected death in young patients. Nevertheless, this condition remains somewhat enigmatic from the perspective of diagnosis and there exists considerable variation in management practices. This article aims to summarise the current research and emphasise pertinent aspects of myocarditis for the general paediatrician.
Correspondence to: D.S. Fruitman, MD, FRCP(C), Department of Pediatrics, Division of Cardiology, Alberta Childrens Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta T3B 6A8, Canada. Tel: 403 955 7858; Fax: 403 955 7621; E-mail: deborah.fruitman@albertahealthservices.ca

YOCARDITIS IS A VERY HETEROGENEOUS DISEASE,

Definition In 1995, the World Health Organization created the following definition:1 Inflammatory cardiomyopathy is defined by myocarditis in association with cardiac dysfunction. Myocarditis is an inflammatory disease of the myocardium and is diagnosed by established histological/immunological, and immunohistological criteria. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy are recognized. Notably, this inflammation occurs in the absence of ischaemia. Epidemiology
The true incidence and prevalence remain unknown because of the highly variable clinical presentation.2 On the basis of screening electrocardiograms in Japan, the approximate incidence of myocarditis is estimated to be about 7 per 60,000 (0.012%) asymptomatic children.3

242

Cardiology in the Young

June 2011

Over half of all cases of myocarditis occur in patients below the age of 40 years.4 A recent retrospective review reported the prevalence of myocarditis to be 0.5 cases per 10,000 emergency department visits.5 Children in this study were diagnosed using history, clinical exam, and various supportive investigations. An approximate incidence may lie between 0.15% and 0.6% in the overall population based on postmortem histology.6,7 As myocarditis is also associated with sudden cardiac death in young patients, this may further confound estimates of incidence and prevalence.2,8,9

or cardiac compromise in cases of H1N1 infection. Further population data are required to clarify the clinical course of H1N1-associated myocarditis.

Aetiology The multiple aetiologies of myocarditis are summarised in Table 1. Infectious exposures, especially viruses, account for the vast majority of paediatric myocarditis in Canada and the United States, whereas globally the most common cause is Trypanosoma cruzi (Chagas disease).10 The majority of paediatric cases are believed to be due to adenoviruses and enteroviruses, such as coxsackieviruses A and B, parvovirus, echovirus, and poliovirus.1117 The relative frequency of cases related to these viruses is variable and there is much discussion as to which is more common. In the past, enteroviruses, especially the coxsackie viruses, were considered the most common aetiology. A recent study suggested that adenovirus may be a more significant pathogen than previously recognised.18 Among patients given a clinical diagnosis of myocarditis, those with positive adenovirus polymerase chain reaction were less likely to have a corresponding histologic diagnosis of acute myocarditis compared with the enterovirus group (40% versus 79%).18 This suggests that adenovirus is associated with a lesser degree of inflammation in the myocardium. This may suggest a higher prevalence of adenovirus than suspected. A subsequent study reviewed aetiologies for biopsy-confirmed myocardial inflammation and found parvovirus B 19 to be the most common, followed by enterovirus, human herpes virus 6, and then adenovirus.19 Following the H1N1 Influenza A pandemic, there were case reports of associated myocarditis. Of the 80 confirmed viral infections reported by one group, there were four cases of associated myocarditis, three of which presented with fulminant myocarditis:20 one patient had a fatal outcome due to acute atrioventricular block and two required extracorporeal membrane oxygenation support due to severely reduced left ventricular systolic function. Extracorporeal membrane oxygenation is implemented in many paediatric tertiary centres for either respiratory failure

Pathology and pathophysiology There are several proposed mechanisms of myocardial injury in viral myocarditis.4 These include the excessive immune-mediated destruction of the myocardium by infiltrating immune cells targeting the infected cardiomyocytes; autoimmune-mediated destruction of cardiac cells by circulating autoantibodies; and direct virus-induced cardiac myocyte injury. It is proposed that three phases of viral myocarditis exist, beginning with a period of viral replication, followed by acute injury to the myocytes, and subsequent evolution of dilated cardiomyopathy, associated with profound alteration in the extracellular matrix of heart muscle.4 Up to 27% of dilated cardiomyopathy cases in children may be attributable to viral myocarditis.21 Clinical presentation The diagnosis of paediatric myocarditis is especially challenging because of the variable clinical presentation, ranging from asymptomatic patients with only subtle findings on an electrocardiogram to fulminant cardiac failure and sudden death. Diagnosis remains largely based on clinical judgement, supported by ancillary tests; therefore, a high index of suspicion is necessary. Clinical features are often those of congestive cardiac failure and myocarditis is identified as the most common cause of new onset cardiac failure in previously well children.22 Even patients with mild symptoms are at risk of deterioration, and therefore early diagnosis is important in establishing appropriate monitoring and supportive care. Common symptoms and signs are listed in Table 2. There are several paediatric studies that have examined the most common signs and symptoms of patients with myocarditis. Shortness of breath, respiratory distress, or an abnormal respiratory exam were commonly observed.5,23 In two studies, 84% of patients required more than one visit to a physician within 14 days before the diagnosis of myocarditis or dilated cardiomyopathy was made.23 Children were often given an initial diagnosis of asthma or pneumonia.5 Resting tachycardia is also an important subtle feature, and although this is not always a consistent finding, it may be the only finding of mild disease.5,23 Isolated vomiting is observed and this may be due to gut ischaemia secondary-to-low cardiac output. Hepatomegaly is a

Vol. 21, No. 3

Table 1. Aetiologies of myocarditis. Viral Adenovirus Coxsackie viruses Cytomegalovirus Dengue Echovirus Encephalo-myocarditis Epstein-Barr Hepatitis Human Herpes Virus-6 Human Immunodeficiency Virus Influenza A including H1N1 Influenza B Herpes Simplex Virus-1 Mumps Parvovirus B-19 Rabies Rhabdovirus Respiratory syncitial virus Rubella Vaccinia (smallpox vaccine) Varicella Zoster Variola Yellow fever Bacterial Borrelia sp. Brucella sp. Clostridia sp. Corynebacterium diptheriae Coxiella burnetti chaffeensis Haemophilus influenzae Klebsiella sp. Legionella pneumophilia Leptospira sp. Mycoplasma pneumoniae Neisseria meningitides Rickettsia sp. Salmonella sp. Streptobacillus monilliformis Streptococcus pneumoniae Tryponema pallidum Vibrio cholerae Other infectious Ascaris sp. Aspergillus sp. Blastomyces sp. Candida sp. Coccidioides Cryptococcus sp. Cysticercosis Echinococcus granulosus Entamoeba sp. Heterophyes Histoplasma sp. Nocardia Rickettsia sp. Schistosoma sp. Taenia solium Toxocara canis Toxoplasma gondii Trichinella spiralis Trypanosoma cruzi Wucheria bancrofti Visceral larva migrans Immune Alloantigen (cardiac transplant recipient) Chagas disease Giant cell myocarditis Kawasaki disease Autoimmune Polymyositis Rheumatoid arthritis Rheumatic fever Sarcoidosis Scleroderma Systemic Lupus Erythematosus Ulcerative colitis Wegeners granulomatosis Toxins Amitriptyline Amphoteracin B Anthracyclines Arsenic, cannabis Carbon monoxide Cephalosporins Colchicine Copper, clozapine Cyclophosphamide Electric shock Ethanol Furosemide Hymenoptera Hyperpyrrexia Iron, isoniazid Lead, lidocaine Loxoscelism Methyldopa Neomercazole Nonsteriodal anti-inflammatories Penicillin, Phenytoin Snake or scorpion venom Sulfonamides Tetracycline, Thiazides Trastuzumab

May et al: The evolving approach to paediatric myocarditis

243

244
Table 2. Signs and symptoms of myocarditis. Signs Respiratory distress Wheeze, crackles Tachypnea Hypoxia, cyanosis Apnea Hypotension Hypoperfusion Resting tachycardia Bradycardia Irregular rhythm Murmur Extra heart sounds Hepatomegaly Peripheral oedema Reduced urine output Symptoms Shortness of breath Cough Rhinorrhea

Cardiology in the Young

June 2011

biopsy reveals ongoing inflammation, myocardial damage, and active scar tissue. Chronic persistent myocarditis is described in the setting of normal left ventricular function and palpitations or atypical chest pain, with persistent inflammation on biopsy.

Chest pain Palpitations Orthostatic symptoms Exercise intolerance

Abdominal pain Nausea Vomiting Anorexia Poor feeding, feed intolerance Dizziness Syncope Seizure

Lethargy, altered level of consciousness Diaphoresis Fever

common feature on physical exam and may present as non-specific abdominal pain.5,23 In contrast to adults with myocarditis, chest pain is seldom reported in younger children though it may be a more common feature in adolescents. A case series of several teenage patients diagnosed with myocarditis described symptoms of severe chest pain, in combination with elevated cardiac troponin-I, ST-segment, and T-wave changes.24 Unfortunately, sudden cardiac death may be the presenting feature of myocarditis, and in these cases the diagnosis is often made histologically. It is suggested that some cases may be the result of inflammatory infiltrates that act as arrhythmogenic foci, leading to fatal arrhythmia.25 Despite the existence of echocardiographic and endomyocardial biopsy criteria26 for myocarditis and resulting cardiomyopathy, expert opinion currently suggests that the diagnosis of probable myocarditis is based on clinical judgement.27,28 A broad clinicopathological classification system can be used in which there are four categories of myocarditis in the setting of viral illness.4 Fulminant myocarditis is associated with symptoms of significant left ventricular dysfunction and unexpected cardiac failure within 23 weeks of the onset of viral infection. Subacute myocarditis can be described as moderate left ventricular dysfunction and has less distinct clinical features of the disease. Chronic active myocarditis is associated with moderate left ventricular dysfunction, indistinct symptoms, and endomyocardial

Investigations Despite many diagnostic modalities, suspicion of myocarditis is mainly based on clinical criteria. Diagnostic work-up should include baseline investigations listed in Table 3. Abnormal troponin levels may support a diagnosis of myocarditis, but there are limited data in the current paediatric literature.23,29 An elevated creatine kinase level may also be observed in myocarditis, although it is a non-specific marker. It has been suggested that, in comparison with creatine kinase, cardiac troponin-T may provide better sensitivity for detecting micronecrosis in myocarditis because of a proportionally higher and longer-lasting elevation of serum levels.30 In the Myocarditis Treatment Trial, elevations of cardiac troponin I occurred more frequently than did elevations of creatine kinase muscle and brain subunits in patients with biopsy-proven myocarditis.31 There was one paediatric study that illustrated a cut-off point for a cardiac troponin T level of 0.052 nanograms per millilitre for diagnosing acute myocarditis with a sensitivity of 71% and specificity of 86%, although there was no correlation between cardiac troponin T level and ejection fraction.32 Use of the N-terminal segment of the B-type natriuretic peptide prohormone levels may be helpful in the setting of myocarditis, especially with respect to recovery. In one study, elevated N-terminal B-type natriuretic peptide levels correlated well with clinical status and echocardiographic findings in patients with dilated cardiomyopathy or myocarditis.33 N-terminal B-type natriuretic peptide levels had 78% sensitivity and 100% specificity for the diagnosis of persistent left ventricular dysfunction. Patients who recovered had N-terminal B-type natriuretic peptide levels that were within normal limits.34 Chest X-ray findings often include cardiomegaly, and may demonstrate pulmonary oedema, infiltrates, or pleural effusions.5,23 An abnormal electrocardiogram is very common, found in over 93% of patients.5,23 The most common abnormalities include sinus tachycardia, criteria for ventricular hypertrophy, ST segment, and T-wave abnormalities. Less commonly, arrhythmia, bundle branch block, prolonged corrected QT interval, and atrioventricular block are observed.23 Abnormal QRS axis and low voltage QRS may be present. The combination of an electrocardiogram with chest X-ray in the setting of possible myocarditis has very good sensitivity for the diagnosis.5

Vol. 21, No. 3

May et al: The evolving approach to paediatric myocarditis

245

Table 3. Initial investigations in suspected myocarditis. Investigation CBC with differential, electrolytes, troponin levels, ESR, CRP, urea, creatinine, electrolytes, liver enzymes, CK-MB, NT-proBNP Blood and urine cultures, nasopharyngeal, or endotracheal aspirates for viral PCR or viral culture, stool studies as relevant Chest X-ray Potential findings Elevated WBC, ESR, CRP Elevated troponin-C, troponin-I, troponin-T Evidence of end organ dysfunction May not yield positive results and if positive, may not necessary reveal the causative agent of myocarditis Cardiomegaly Pulmonary oedema Infiltrate Pleural effusions Sinus tachycardia Ventricular hypertrophy ST segment and T-wave abnormalities Arrhythmia Bundle branch block Prolonged QTc AV block Abnormal QRS axis Low voltage QRS Increased ventricular end-systolic or diastolic dimensions Regional wall motion abnormalities Thickened ventricular wall or septum Reduced fractional shortening or ejection fraction Atrioventricular valve regurgitation Thrombus

12-lead electrocardiogram

Echocardiogram

AV 5 atrioventricular; CBC 5 complete blood count; CK-MB 5 creatine kinase muscle, brain; CRP 5 C-reactive protein; ESR 5 erythrocyte sedimentation rate; NT-proBNP 5 N-terminal B-type natriuretic peptide prohormone; PCR 5 polymerase chain reaction; QTc 5 corrected QT interval; WBC 5 white blood count

Echocardiographic findings may include increased ventricular end-systolic or diastolic dimensions, reduced shortening or ejection fractions, atrioventricular valve regurgitation, and regional wall motion abnormalities.35 Echocardiography is also important to rule out coronary abnormalities as a cause of depressed myocardial function. Abnormal right ventricular function on echo may be associated with increased likelihood of adverse outcomes including cardiac transplantation or death.36 Other methods of non-invasive imaging are being investigated in the setting of myocarditis. Nuclear medicine techniques have not been used widely in paediatrics, in part due to concerns of excessive radiation exposure for children.37 Cardiovascular magnetic resonance imaging is a widely accepted tool to assess myocarditis. This technique provides not only detailed functional and morphological assessment of the heart, but also reliable visualisation of tissue markers of myocarditis including oedema, inflammation, and fibrosis.3841 Previously, oedema could not be well imaged; however, cardiac magnetic resonance is now able to visualise myocardial oedema without using radiation or contrast agents.44 Currently, cardiac magnetic resonance may be considered the single best

non-invasive imaging study for this indication, and standardised protocols for cardiac magnetic resonance imaging of myocarditis are available.42,43 In acute myocarditis, cardiac magnetic resonance assessment of myocardial oedema is performed using T2-weighted short TI inversion recovery imaging in which regions of myocardial oedema appear bright, whereas fat and blood signals are suppressed (Fig 1).45 The sensitivity and specificity of this technique were 78% and 91%, respectively.37 In general, the presence of myocardial oedema may reflect the acuity of myocardial injury and can become evident within the first 23 weeks from the insult.46 Gadolinium contrast-enhanced cardiac magnetic resonance may be used to assess myocardial hyperaemia.40 An increased ratio of myocardial signal intensity post-contrast compared to pre-contrast and normalised to skeletal muscle signal is indicative of myocardial hyperaemia and capillary leakage. The sensitivity and specificity of T1-weighted images in patients with suspected chronic myocarditis were 62% and 86%, respectively, using immunohistological methods as the gold standard.39 Similar to myocardial oedema, early enhancement normalises approximately 4 weeks after clinical presentation and therefore may be used as a marker of the acuity of

246

Cardiology in the Young

June 2011

Figure 1. Cardiovascular magnetic resonance imaging of acute myocarditis in a teenage male patient. (a) T2-weighted short TI inversion recovery image of the left ventricle in short axis demonstrating bright signal intensity in the regions of myocardial oedema. (b) Late enhancement (T1-weighted gradient echo sequence with myocardial nulling) of fibrotic areas of the myocardium (bright signal) in a four-chamber orientation 10 minutes after intravenous gadolinium administration.

myocardial injury.47 In a small proportion of patients, early enhancement may persist, and is correlated to reduced cardiac function. It is not currently known whether persistently elevated early enhancement truly reflects ongoing viral infection. The cardiac magnetic resonance technique of gadolinium late enhancement allows visualisation of myocardial necrosis and fibrosis associated with myocarditis. Gadolinium accumulates in regions of fibrosis, leading to increased signal intensity in late enhancement images (Fig 1). In the setting of myocarditis, the pattern of myocardial fibrosis varies considerably but typically involves patchy focal fibrosis of the sub-epicardium or mid-myocardial wall, rarely extending to the sub-endocardium.41 The presence of myocardial fibrosis detected by cardiac magnetic resonance late enhancement is more

common in males and younger patients, and the pattern of myocardial injury sustained in young patients tends to be more regional and more severe, with a higher incidence of irreversible myocardial scarring.48 This pattern of myocardial injury may explain why younger patients are at risk for adverse cardiac outcomes. The presence of gadolinium late enhancement 4 weeks after acute presentation is also correlated with reduced left ventricular ejection fraction and clinical symptomatology at 30-month follow-up.47 To standardise cardiac magnetic resonance imaging to diagnose myocarditis, the International Consensus Group on Cardiovascular Magnetic Resonance created new criteria, known as the Lake Louise Criteria.43 These recommendations describe indications for cardiac magnetic resonance in patients with suspected myocarditis, cardiac magnetic resonance protocol standards, terminology for reporting cardiac magnetic resonance findings, and diagnostic cardiac magnetic resonance criteria for myocarditis. These guidelines report that the greatest balance of diagnostic sensitivity and specificity for acute myocarditis is achieved with the presence of any two or more of the following three criteria: myocardial oedema (T2 short TI inversion recovery), hyperaemia/capillary leak (early enhancement), or myocardial fibrosis (late gadolinium enhancement). The gold standard for diagnosis of myocarditis remains endomyocardial biopsy; however, this approach has significant limitations.26 According to the Dallas Criteria, endomyocardial specimens are considered diagnostic of active myocarditis, if routine light microscopy reveals infiltrating lymphocytes and myocytolysis.26 Borderline or ongoing myocarditis is defined as lymphocytic infiltration in the absence of myocytolysis. Biopsy is considered negative, if both lymphocytic infiltration and myocytolysis are absent. A potential reason to proceed with biopsy is that the presence of immune complexes and complement deposits supports an immune-mediated process; therefore, the management may differ from that of the case of viral infection. For example, immune suppression is not indicated in cardiomyopathy but may be worthwhile in viral myocarditis. Biopsy may be useful in the setting of eosinophilic infiltrates, which could suggest a hypersensitivity response to an exogenous agent. In this case, once the histology is confirmed, the offending agent can be removed and the clinical picture may improve. A significant limitation of cardiac biopsy is that myocarditis affects the myocardium in a patchy fashion, and therefore negative biopsy may not exclude disease. There remains controversy as to whether or not to proceed with biopsy, especially since biopsy can be associated with arrhythmia and

Vol. 21, No. 3

May et al: The evolving approach to paediatric myocarditis

247

perforation of cardiac tissue. Paediatric literature also suggests that the highest rate of complication occurs in patients being evaluated for myocarditis, as well as those requiring inotropic support.49 Despite the overall complication rate being relatively low (16%), with mortality between 0.0% and 0.4%, risk-benefit analysis occurs on a case-by-case basis.43,4952

Treatment
Despite improved understanding of the pathogenesis of myocarditis, treatment strategies remain controversial and the general approach is supportive. Stabilisation of children who present with haemodynamic compromise and early involvement of paediatric cardiology specialists are crucial. Treatment of congestive cardiac failure may include diuretics, afterload reduction, inotropic support, anticoagulation, arrhythmia management, and ventilatory support. Aggressive administration of intravenous fluids initially may exacerbate cardiac failure. Transfusions of packed red blood cells may be required to optimise oxygen carrying capacity. The use of inotropes such as dopamine, dobutamine, and milrinone may be necessary. Afterload reduction, if it can be tolerated, with phophodiesterase inhibitors such as milrinone can be extremely useful. It is also suggested that the early introduction of angiotensin-converting enzyme inhibitors, as well as beta-blockers, once the acute decompensatory phase has begun to resolve, may be beneficial. These medications may help prevent the remodelling that evolves to dilated cardiomyopathy as well as relieving vasospasm to some degree.25,53 In paediatric patients, carvedilol was suggested in this regard but has not been studied extensively.54 Anticoagulation may be recommended if the ejection fraction is severely decreased or in the setting of atrial arrhythmias.55 Some patients may require ventilatory support as a means of reducing cardiac demand. Ventilation and oxygenation may be best managed with continuous positive airway pressure or other non-invasive methods, for several reasons. Increased intrathoracic pressure via nasal or mask continuous positive airway pressure may help to reduce left ventricular afterload by reducing transmural myocardial wall tension, without causing the hypotension associated with pharmacologic afterload reduction. Intubation medications can cause hypotension and acute cardiovascular collapse; therefore, continuous positive airway pressure may also circumvent this and is an excellent adjunctive therapy for decompensated cardiac failure.5658 Those with more severe cases of myocarditis may require circulatory support in the form of

extracorporeal membrane oxygenation or ventricular assist devices. Extracorporeal membrane oxygenation may also be used to support patients through to recovery from acute myocarditis, or it may serve as a bridge to transplant in dilated cardiomyopathy.59 Patients over 15 kilograms may respond best to pulsatile ventricular assist devices.60 There have been case reports of prolonged support using a ventricular assist device as a bridge to recovery or transplant.61

Immune suppression An area of significant controversy involves the use of immune suppression and immune modulators in the context of myocarditis. There are large-scale adult studies with respect to immune suppression, and overall the data have shown some limited, short-term response to these therapies. In two large adult prospective studies, immunosuppression including prednisone with or without azathioprine or cyclosporine was used.62,63 With prednisone alone, there was modest improvement in left ventricular function in patients with evidence of inflammation on biopsy; however, this improvement was not sustained.62 The Myocarditis Treatment Trial found no significant improvement in function and no difference in survival when compared with controls.63 Despite the existence also of a handful of uncontrolled studies that showed benefit with various immunosuppressive regimes, some meta-analyses of adult studies did not show a significant beneficial effect of immunosuppression.6469 It is always difficult to extrapolate the findings of adult studies to the paediatric population. Paediatric studies are limited and there are no randomised controlled trials. Many used prednisolone and did find some benefit, though not always statistically significant, by adding a second agent. In one trial, patients were stratified into either standard treatment, or given one of three immunosuppressive therapies, prednisolone, prednisolone and azathioprine, or prednisolone and cyclosporin A.70 The groups receiving immunosuppressive treatment with a second agent, in addition to the prednisolone, showed improved haemodynamic parameters, as well as histological improvement in inflammation.70 Some small case series suggested some clinical benefit to immunosuppressive treatment, again using corticosteroids with an additional agent; however, most were small, uncontrolled studies.7175 A meta-analysis of paediatric studies between 1984 and 2003 systematically reviewed the impact of immunosuppressive therapy in children with myocarditis and overall found no consistent

248

Cardiology in the Young

June 2011

benefit.76 This included nine paediatric studies, all of which were small and very heterogeneous in design. Many of the studies were retrospective and uncontrolled, introducing significant bias. Intravenous immunoglobulin was also examined as a potential immunomodulating therapy to potentially decrease inflammation. Despite some studies observing a trend towards improved cardiac status following treatment, there are no randomised controlled trials using intravenous immune globulin in children with myocarditis. Robinson et al77 conducted a comprehensive multi-database search including patients of all ages with myocarditis treated with intravenous immune globulin. They concluded that if there is evidence that ongoing, active infection may be causing persistent cardiac dysfunction, intravenous immune globulin may be helpful. Even if postinfectious inflammation is the most likely aetiology, intravenous immune globulin may still be beneficial by preventing formation of cytokines.78 There is one multi-centre adult randomised controlled trial using intravenous immune globulin.79 They found no significant difference in rates of survival, cardiac transplantation, use of ventricular assist devices, improvement in ventricular function, or functional capacity at 1 year of follow-up. A Cochrane review of intravenous immune globulin in dilated cardiomyopathy or myocarditis showed no benefit in adults; however, some case reports and case series suggested that adults treated with intravenous immune globulin did exhibit improved cardiac function.66,7779,8086 Some case reports and series in children have shown improved ventricular function and clinical improvement after high-dose intravenous immune globulin, however with small numbers.8791 Overall, it was felt that the validity of many of these studies was compromised due to lack of control groups. There was one case report of coxsackie virus A19 myocarditis in which intravenous immune globulin was not effective and another case series found no additional benefit by adding intravenous immune globulin to steroid treatment.92,93 Studies using immunosuppressive or immunomodulating treatments, therefore, were difficult to translate into an effective, routine therapy for children or adults with myocarditis. Many patients with myocarditis have spontaneous improvement. It is difficult to know if the observed improvement after treatment with immunosuppression or intravenous immune globulin is attributable to treatment versus the natural course of disease. Potentially, some aetiologic types of myocarditis respond differently and certain histologic characteristics may make specific patients better responders than others.73,75,94 Further studies are needed to determine the possible utility of immunosuppressive or immunomodulating therapy.

Outcomes and prognosis

As described, it is difficult to estimate the true incidence and prevalence of myocarditis because of the broad spectrum of symptoms. It is said that the prognosis for children with viral myocarditis tends to be more positive than the outcomes with dilated cardiomyopathy.71,87,95 Survival rates for paediatric patients with myocarditis can be as high as 93%.9597 However, a large, multi-centre study including all age groups showed that there was a significant mortality in neonates and infants (3345% survival, 2332% improvement) with better outcomes in children between 1 and 18 years of age (7880% survival, 4667% improvement).18 A study of 28 children with a diagnosis of myocarditis also observed that only 17 survived to hospital discharge with variable degrees of improved heart function, whereas the remaining 11 patients developed intractable cardiac failure leading to cardiac transplant listing (seven cases) or death (four cases).98 Predictors of a poor outcome were found to be ejection fraction less than 30%, shortening fraction less than 15%, left ventricular dilatation, and moderate-to-severe mitral valve regurgitation.98 The authors of several case series involving children requiring mechanical support for myocarditis have reported survival rates of 6783%.95,97,99101 An updated review of the extracorporeal membrane oxygenation registry revealed a survival rate of 61% for children supported through acute myocarditis.102 This is comparable to, and perhaps better than, survival rates of children supported with extracorporeal membrane oxygenation after repair or palliation of congenital cardiac disease, in which survival rates range between 37% and 42%.101,103105 Hetzer reported that of 21 children supported with the Berlin Heart Excor device for myocarditis or cardiomyopathy, 90% survived to hospital discharge.106 Collective experience with ventricular assist devices in this setting, however, is quite limited. The prognosis in biopsy-proven myocarditis may depend on the severity of symptoms, histologic classification, and biomarkers. Acute fulminant myocarditis is associated with better overall survival.107109 Giant cell myocarditis, although rare, is associated with especially poor outcomes and a reported median duration of survival, if untreated, of 5.5 months.110 It also carries an 89% rate of death or transplant. Myocarditis may account for nearly half of all children with dilated cardiomyopathy.111,112 The outcomes for patients with acute viral myocarditis are much better than cases with established dilated cardiomyopathy.71,87,95 For this reason, a high index of suspicion for the disease, and early effective supportive care are crucial. Myocarditis remains a relatively common indication for transplant listing.

Vol. 21, No. 3

May et al: The evolving approach to paediatric myocarditis

249

Overall, 18% of patients with acute myocarditis eventually go on to transplant.25 Owing to the potential for recovery, even with severe disease at presentation, patients are not typically listed for cardiac transplant unless recovery is considered extremely unlikely despite reasonable management and a period of observation.

Conclusions
Acute myocarditis comprises a wide clinical spectrum including the asymptomatic patient with subclinical myocardial dysfunction to severe cardiac failure or sudden cardiac death. In paediatrics, the symptoms and signs can mimic many other common diseases and a high index of clinical suspicion is imperative. Treatment of myocarditis remains supportive and should be initiated even before solidifying the diagnosis. Biopsy remains the gold standard for diagnosis; however, it has significant limitations. Cardiac magnetic resonance imaging has become a widely accepted non-invasive imaging modality for myocarditis and standardised protocols are now available for myocarditis. There exist controversial data and no consensus with respect to immunosuppressive or immunomodulating therapy for myocarditis. Similarly, there is no foundation of evidence to indicate a routine treatment strategy other than standard cardiac failure management for these patients. Most patients with myocarditis have spontaneous improvement in their cardiac function and symptoms; however, there remains significant morbidity and mortality associated with this condition. Additional studies are a necessity to clarify the most appropriate management options in paediatrics to improve outcomes.

Acknowledgement
Sources of funding: None. Conflicts of Interest: None.

References
1. Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation 1996; 93: 841842. 2. Feldman AM, McNamara D. Myocarditis. N Engl J Med 2000; 343: 13881398. 3. Press S, Lipkind RS. Acute myocarditis in infants. Initial presentation. Clin Pediatr (Phila) 1990; 29: 7376. 4. Esfandiarei M, McManus BM. Molecular biology and pathogenesis of viral myocarditis. Annu Rev Pathol 2008; 3: 127155. 5. Freedman SB, Haladyn JK, Floh A, et al. Pediatric myocarditis: emergency department clinical findings and diagnostic evaluation. Pediatrics 2007; 120: 12781285.

6. Okada R, Kawai S, Kasyuya H. Nonspecific myocarditis: a statistical and clinicopathological study of autopsy cases. Jpn Circ J 1989; 53: 4048. 7. Waller BF, Catellier MJ, Clark MA, et al. Cardiac pathology in 2007 consecutive forensic autopsies. Clin Cardiol 1992; 15: 760765. 8. Daubeney PE, Nugent AW, Chondros P, et al. Clinical features and outcomes of childhood dilated cardiomyopathy: results from a national population-based study. Circulation 2006; 114: 26712678. 9. Eckart RE, Scoville SL, Campbell CL, et al. Sudden death in young adults: a 25-year review of autopsies in military recruits. Ann Intern Med 2004; 141: 829834. 10. Whitton JL, Feuer R. Myocarditis, microbes and autoimmunity. Autoimmunity 2004; 37: 375386. 11. Bowles NE, Towbin JA. Molecular aspects of myocarditis. Curr Opin Cardiol 1998; 13: 179184. 12. Chany C, Lepine P, Lelong M, et al. Severe and fatal pneumonia in infants and young children associated with adenovirus infections. Am J Hyg 1958; 67: 367378. 13. Hirschman SZ, Hammer GS. Coxsackie virus myopericarditis. A microbiological and clinical review. Am J Cardiol 1974; 34: 224232. 14. Martin AB, Webber S, Fricker FJ, et al. Acute myocarditis. Rapid diagnosis by PCR in children. Circulation 1994; 90: 330339. 15. Drew JH. Echo 11 virus outbreak in a nursery associated with myocarditis. Aust Paediatr J 1973; 9: 9095. 16. Rosenberg HS, McNamara DG. Acute Myocarditis in Infancy and Childhood. Prog Cardiovasc Dis 1964; 7: 179197. 17. Woodruff JF. Viral myocarditis. A review. Am J Pathol 1980; 101: 425484. 18. Bowles NE, Ni J, Kearney DL, et al. Detection of viruses in myocardial tissues by polymerase chain reaction. Evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol 2003; 42: 466472. 19. Kuhl U, Pauschinger M, Seeberg B, et al. Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 2005; 112: 19651970. 20. Bratincsak A, El-Said HG, Bradley JS, et al. Fulminant myocarditis associated with pandemic H1N1 influenza A virus in children. J Am Coll Cardiol 2010; 55: 928929. 21. Leonard EG. Viral myocarditis. Pediatr Infect Dis J 2004; 23: 665666. 22. Calabrese F, Rigo E, Milanesi O, et al. Molecular diagnosis of myocarditis and dilated cardiomyopathy in children: clinicopathologic features and prognostic implications. Diagn Mol Pathol 2002; 11: 212221. 23. Durani Y, Egan M, Baffa J, et al. Pediatric myocarditis: presenting clinical characteristics. Am J Emerg Med 2009; 27: 942947. 24. Kern J, Modi R, Atalay MK, et al. Clinical myocarditis masquerading as acute coronary syndrome. J Pediatr 2009; 154: 612615. 25. Ellis CR, Di Salvo T. Myocarditis: basic and clinical aspects. Cardiol Rev 2007; 15: 170177. 26. Aretz HT. Myocarditis: the Dallas criteria. Hum Pathol 1987; 18: 619624. 27. Grenier MA, Osganian SK, Cox GF, et al. Design and implementation of the North American Pediatric Cardiomyopathy Registry. Am Heart J 2000; 139: S86S95. 28. Batra AS, Lewis AB. Acute myocarditis. Curr Opin Pediatr 2001; 13: 234239. 29. Lippi G, Salvagno GL, Guidi GC. Cardiac troponins in pediatric myocarditis. Pediatrics 2008; 121: 864865. 30. Franz WM, Remppis A, Kandolf R, et al. Serum troponin T: diagnostic marker for acute myocarditis. Clin Chem 1996; 42: 340341.

250

Cardiology in the Young

June 2011

31. Smith SC, Ladenson JH, Mason JW, et al. Elevations of cardiac troponin I associated with myocarditis. Experimental and clinical correlates. Circulation 1997; 95: 163168. 32. Soongswang J, Durongpisitkul K, Nana A, et al. Cardiac troponin T: a marker in the diagnosis of acute myocarditis in children. Pediatr Cardiol 2005; 26: 4549. 33. Nasser N, Perles Z, Rein AJ, et al. NT-proBNP as a marker for persistent cardiac disease in children with history of dilated cardiomyopathy and myocarditis. Pediatr Cardiol 2006; 27: 8790. 34. Nir A, Bar-Oz B, Perles Z, et al. N-terminal pro-B-type natriuretic peptide: reference plasma levels from birth to adolescence. Elevated levels at birth and in infants and children with heart diseases. Acta Paediatr 2004; 93: 603607. 35. Checchia PA, Kulik TJ. Acute viral myocarditis: diagnosis. Pediatr Critical Care Med 2006; 7: S8S11. 36. Mendes LA, Dec GW, Picard MH, et al. Right ventricular dysfunction: an independent predictor of adverse outcome in patients with myocarditis. Am Heart J 1994; 128: 301307. 37. Jeserich M, Konstantinides S, Pavlik G, et al. Non-invasive imaging in the diagnosis of acute viral myocarditis. Clin Res Cardiol 2009; 98: 753763. 38. Abdel-Aty H, Boye P, Zagrosek A, et al. Diagnostic performance of cardiovascular magnetic resonance in patients with suspected acute myocarditis: comparison of different approaches. J Am Coll Cardiol 2005; 45: 18151822. 39. Gutberlet M, Spors B, Thoma T, et al. Suspected chronic myocarditis at cardiac MR: diagnostic accuracy and association with immunohistologically detected inflammation and viral persistence. Radiology 2008; 246: 401409. 40. Friedrich MG, Strohm O, Schulz-Menger J, et al. Contrast media-enhanced magnetic resonance imaging visualizes myocardial changes in the course of viral myocarditis. Circulation 1998; 97: 18021809. 41. Mahrholdt H, Goedecke C, Wagner A, et al. Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation 2004; 109: 12501258. 42. Skouri HN, Dec GW, Friedrich MG, et al. Noninvasive imaging in myocarditis. J Am Coll Cardiol 2006; 48: 20852093. 43. Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: a JACC White Paper. J Am Coll Cardiol 2009; 53: 14751487. 44. Friedrich MG. Myocardial edema a new clinical entity? Nat Rev Cardiol 2010; 7: 292296. 45. Abdel-Aty H, Simonetti O, Friedrich MG. T2-weighted cardiovascular magnetic resonance imaging. J Magn Reson Imaging 2007; 26: 452459. 46. Cocker M, Friedrich MG. Cardiovascular magnetic resonance of myocarditis. Curr Cardiol Rep 2010; 12: 8289. 47. Wagner A, Schulz-Menger J, Dietz R, et al. Long-term follow-up of patients paragraph sign with acute myocarditis by magnetic paragraph sign resonance imaging. MAGMA 2003; 16: 1720. 48. Cocker MS, Abdel-Aty H, Strohm O, et al. Age and gender effects on the extent of myocardial involvement in acute myocarditis: a cardiovascular magnetic resonance study. Heart 2009; 95: 19251930. 49. Pophal SG, Sigfusson G, Booth KL, et al. Complications of endomyocardial biopsy in children. J Am Coll Cardiol 1999; 34: 21052110. 50. Deckers JW, Hare JM, Baughman KL. Complications of transvenous right ventricular endomyocardial biopsy in adult patients with cardiomyopathy: a seven-year survey of 546 consecutive diagnostic procedures in a tertiary referral center. J Am Coll Cardiol 1992; 19: 4347. 51. Felker GM, Hu W, Hare JM, et al. The spectrum of dilated cardiomyopathy. The Johns Hopkins experience with 1,278 patients. Medicine (Baltimore) 1999; 78: 270283.

52. Holzmann M, Nicko A, Kuhl U, et al. Complication rate of right ventricular endomyocardial biopsy via the femoral approach: a retrospective and prospective study analyzing 3048 diagnostic procedures over an 11-year period. Circulation 2008; 118: 17221728. 53. Tominaga M, Matsumori A, Okada I, et al. Beta-blocker treatment of dilated cardiomyopathy. Beneficial effect of carvedilol in mice. Circulation 1991; 83: 20212028. 54. Bruns LA, Chrisant MK, Lamour JM, et al. Carvedilol as therapy in pediatric heart failure: an initial multicenter experience. J Pediatr 2001; 138: 505511. 55. Gunthard J, Stocker F, Bolz D, et al. Dilated cardiomyopathy and thrombo-embolism. Eur J Pediatr 1997; 156: 36. 56. Bradley TD, Holloway RM, McLaughlin PR, et al. Cardiac output response to continuous positive airway pressure in congestive heart failure. Am Rev Respir Dis 1992; 145: 377382. 57. Naughton MT, Rahman MA, Hara K, et al. Effect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Circulation 1995; 91: 17251731. 58. Bohn D, Benson L. Diagnosis and management of pediatric myocarditis. Paediatr Drugs 2002; 4: 171181. 59. Sezai A, Hata M, Niino T, et al. Mechanical circulatory support for fulminant myocarditis. Surg Today 2008; 38: 773777. 60. Potapov EV, Stiller B, Hetzer R. Ventricular assist devices in children: current achievements and future perspectives. Pediatr Transplant 2007; 11: 241255. 61. Jones CB, Cassidy JV, Kirk R, et al. Successful bridge to recovery with 120 days of mechanical support in an infant with myocarditis. J Heart Lung Transplant 2009; 28: 202205. 62. Parrillo JE, Cunnion RE, Epstein SE, et al. A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med 1989; 321: 10611068. 63. Mason JW, OConnell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. The myocarditis treatment trial investigators. N Engl J Med 1995; 333: 269275. 64. Jones SR, Herskowitz A, Hutchins GM, et al. Effects of immunosuppressive therapy in biopsy-proved myocarditis and borderline myocarditis on left ventricular function. Am J Cardiol 1991; 68: 370376. 65. Vignola PA, Aonuma K, Swaye PS, et al. Lymphocytic myocarditis presenting as unexplained ventricular arrhythmias: diagnosis with endomyocardial biopsy and response to immunosuppression. J Am Coll Cardiol 1984; 4: 812819. 66. McNamara DM, Rosenblum WD, Janosko KM, et al. Intravenous immune globulin in the therapy of myocarditis and acute cardiomyopathy. Circulation 1997; 95: 24762478. 67. OConnell JB, Mason JW. Immunosuppressive therapy in experimental and clinical myocarditis. Pathol Immunopathol Res 1988; 7: 292304. 68. Maisch B, Herzum M, Hufnagel G, et al. Immunosuppressive treatment for myocarditis and dilated cardiomyopathy. Eur Heart J 1995; 16 Suppl O: 153161. 69. Garg A, Shiau J, Guyatt G. The ineffectiveness of immunosuppressive therapy in lymphocytic myocarditis: an overview. Ann Intern Med 1998; 129: 317322. 70. Camargo PR, Snitcowsky R, da Luz PL, et al. Favorable effects of immunosuppressive therapy in children with dilated cardiomyopathy and active myocarditis. Pediatr Cardiol 1995; 16: 6168. 71. Chan KY, Iwahara M, Benson LN, et al. Immunosuppressive therapy in the management of acute myocarditis in children: a clinical trial. J Am Coll Cardiol 1991; 17: 458460. 72. Ciszewski A, Bilinska ZT, Lubiszewska B, et al. Dilated cardiomyopathy in children: clinical course and prognosis. Pediatr Cardiol 1994; 15: 121126.

Vol. 21, No. 3

May et al: The evolving approach to paediatric myocarditis

251

73. Balaji S, Wiles HB, Sens MA, et al. Immunosuppressive treatment for myocarditis and borderline myocarditis in children with ventricular ectopic rhythm. Br Heart J 1994; 72: 354359. 74. Ino T, Okubo M, Akimoto K, et al. Corticosteroid therapy for ventricular tachycardia in children with silent lymphocytic myocarditis. J Pediatr 1995; 126: 304308. 75. Kleinert S, Weintraub RG, Wilkinson JL, et al. Myocarditis in children with dilated cardiomyopathy: incidence and outcome after dual therapy immunosuppression. J Heart Lung Transplant 1997; 16: 12481254. 76. Hia CP, Yip WC, Tai BC, et al. Immunosuppressive therapy in acute myocarditis: an 18 year systematic review. Arch Dis Child 2004; 89: 580584. 77. Robinson JL, Hartling L, Crumley E, et al. A systematic review of intravenous gamma globulin for therapy of acute myocarditis. BMC Cardiovasc Disord 2005; 5: 12. 78. Kishimoto C, Shioji K, Kinoshita M, et al. Treatment of acute inflammatory cardiomyopathy with intravenous immunoglobulin ameliorates left ventricular function associated with suppression of inflammatory cytokines and decreased oxidative stress. Int J Cardiol 2003; 91: 173178. 79. McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 2001; 103: 22542259. 80. Goland S, Czer LS, Siegel RJ, et al. Intravenous immunoglobulin treatment for acute fulminant inflammatory cardiomyopathy: series of six patients and review of literature. Can J Cardiol 2008; 24: 571574. 81. Takeda Y, Yasuda S, Miyazaki S, et al. High-dose immunoglobulin G therapy for fulminant myocarditis. Jpn Circ J 1998; 62: 871872. 82. Shioji K, Matsuura Y, Iwase T, et al. Successful immunoglobulin treatment for fulminant myocarditis and serial analysis of serum thioredoxin: a case report. Circ J 2002; 66: 977980. 83. Tedeschi A, Airaghi L, Giannini S, et al. High-dose intravenous immunoglobulin in the treatment of acute myocarditis. A case report and review of the literature. J Intern Med 2002; 251: 169173. 84. Stouffer GA, Sheahan RG, Lenihan DJ, et al. The current status of immune modulating therapy for myocarditis: a case of acute parvovirus myocarditis treated with intravenous immunoglobulin. Am J Med Sci 2003; 326: 369374. 85. Karaaslan S, Oran B, Caliskan U, et al. Hemolysis after administration of high-dose immunoglobulin in a patient with myocarditis. Turk J Haematol 2003; 20: 237240. 86. Abe S, Okura Y, Hoyano M, et al. Plasma concentrations of cytokines and neurohumoral factors in a case of fulminant myocarditis successfully treated with intravenous immunoglobulin and percutaneous cardiopulmonary support. Circ J 2004; 68: 12231226. 87. Drucker NA, Colan SD, Lewis AB, et al. Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation 1994; 89: 252257. 88. Nigro G, Bastianon V, Colloridi V, et al. Human parvovirus B19 infection in infancy associated with acute and chronic lymphocytic myocarditis and high cytokine levels: report of 3 cases and review. Clin Infect Dis 2000; 31: 6569. 89. Tsai YG, Ou TY, Wang CC, et al. Intravenous gammaglobulin therapy in myocarditis complicated with complete heart block: report of one case. Acta Paediatr Taiwan 2001; 42: 311313. 90. Khan MA, Das B, Lohe A, et al. Neonatal myocarditis presenting as an apparent life threatening event. Clin Pediatr (Phila) 2003; 42: 649652.

91. Kim HS, Sohn S, Park JY, et al. Fulminant myocarditis successfully treated with high-dose immunoglobulin. Int J Cardiol 2004; 96: 485486. 92. Wang CY, Li Lu F, Wu MH, et al. Fatal coxsackievirus A16 infection. Pediatr Infect Dis J 2004; 23: 275276. 93. English RF, Janosky JE, Ettedgui JA, et al. Outcomes for children with acute myocarditis. Cardiol Young 2004; 14: 488493. 94. Parrillo JE. Inflammatory cardiomyopathy (myocarditis): which patients should be treated with anti-inflammatory therapy? Circulation 2001; 104: 46. 95. Lee KJ, McCrindle BW, Bohn DJ, et al. Clinical outcomes of acute myocarditis in childhood. Heart 1999; 82: 226233. 96. Gagliardi MG, Bevilacqua M, Bassano C, et al. Long term follow up of children with myocarditis treated by immunosuppression and of children with dilated cardiomyopathy. Heart 2004; 90: 11671171. 97. Duncan BW, Bohn DJ, Atz AM, et al. Mechanical circulatory support for the treatment of children with acute fulminant myocarditis. J Thorac Cardiovasc Surg 2001; 122: 440448. 98. Kuhn B, Shapiro ED, Walls TA, et al. Predictors of outcome of myocarditis. Pediatr Cardiol 2004; 25: 379384. 99. Lin CH, Chang JS, Li PC. The rescue of acute fulminant myocarditis by extracorporeal membrane oxygenation in pediatric patients. Acta Paediatr Taiwan 2005; 46: 201205. 100. Wu ET, Huang SC, Chen YS, et al. Children with fulminant myocarditis rescued with extracorporeal membrane oxygenation. Heart 2006; 92: 13251326. 101. ECMO Registry of the Extracorporeal Life Support Organization (ELSO), Ann Arbor, Michigan, January 2008. https://www.elso. med.umich.edu 102. Rajagopal SK, Almond CS, Laussen PC, et al. Extracorporeal membrane oxygenation for the support of infants, children, and young adults with acute myocarditis: a review of the extracorporeal life support organization registry. Crit Care Med 2010; 38: 382387. 103. Kolovos NS, Bratton SL, Moler FW, et al. Outcome of pediatric patients treated with extracorporeal life support after cardiac surgery. Ann Thorac Surg 2003; 76: 14351441. 104. Chaturvedi RR, Macrae D, Brown KL, et al. Cardiac ECMO for biventricular hearts after paediatric open heart surgery. Heart 2004; 90: 545551. 105. Morris MC, Ittenbach RF, Godinez RI, et al. Risk factors for mortality in 137 pediatric cardiac intensive care unit patients managed with extracorporeal membrane oxygenation. Crit Care Med 2004; 32: 10611069. 106. Hetzer R, Stiller B. Technology insight: use of ventricular assist devices in children. Nat Clin Pract Cardiovasc Med 2006; 3: 377386. 107. Amabile N, Fraisse A, Bouvenot J, et al. Outcome of acute fulminant myocarditis in children. Heart 2006; 92: 12691273. 108. McCarthy RE 3rd, Boehmer JP, Hruban RH, et al. Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med 2000; 342: 690695. 109. Chau EM, Chow WH, Chiu CS, et al. Treatment and outcome of biopsy-proven fulminant myocarditis in adults. Int J Cardiol 2006; 110: 405406. 110. Cooper LT Jr, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med 1997; 336: 18601866. 111. Liu PP, Mason JW. Advances in the understanding of myocarditis. Circulation 2001; 104: 10761082. 112. Towbin JA, Lowe AM, Colan SD, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 2006; 296: 18671876.