Diagnosis and Treatment of Myocarditis in Children in the Current Era
2014; Lippincott Williams & Wilkins; Volume: 129; Issue: 1 Linguagem: Inglês
10.1161/circulationaha.113.001372
ISSN1524-4539
AutoresCharles E. Canter, Kathleen E. Simpson,
Tópico(s)Cardiac Structural Anomalies and Repair
ResumoHomeCirculationVol. 129, No. 1Diagnosis and Treatment of Myocarditis in Children in the Current Era Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBDiagnosis and Treatment of Myocarditis in Children in the Current Era Charles E. Canter, MD and Kathleen E. Simpson, MD Charles E. CanterCharles E. Canter From the Division of Pediatric Cardiology, Department of Pediatrics, Washington University, St. Louis, MO. and Kathleen E. SimpsonKathleen E. Simpson From the Division of Pediatric Cardiology, Department of Pediatrics, Washington University, St. Louis, MO. Originally published7 Jan 2014https://doi.org/10.1161/CIRCULATIONAHA.113.001372Circulation. 2014;129:115–128is corrected byCorrectionIntroductionMyocarditis has been defined by the World Health Organization/International Society and Federation of Cardiology as an inflammatory disease of the heart muscle diagnosed by established histological, immunologic, and immunohistological criteria.1 Insights into its clinical manifestation and treatment in both adults2–7 and children8–12 have been the subject of a number of recent reviews. It is caused primarily by numerous infectious agents, but it may also accompany autoimmune disease, hypersensitivity reactions, and toxins (Table 1). In North America and developed countries, it primarily has a viral origin. In Central and South America, Trypanosoma cruzi (Chagas disease) is a common cause. Diphtheria often causes myocarditis in countries without widespread immunization.13 Although enteroviruses have classically been identified as the prime viral agent, new techniques to extract viral genome from myocardium with polymerase chain reaction techniques have in both children and adults revealed previously unrecognized viruses such as adenovirus, parvovirus B19, human herpesvirus 6, hepatitis C, Epstein-Barr virus, and cytomegalovirus.2,3,14–19 Interestingly, the pattern of identified viral pathogens in myocarditis has evolved over the last 20 years from enteroviruses and adenoviruses to primarily parvovirus and herpesvirus 6. Endomyocardial fibroelastosis, a once frequent cause of infantile dilated cardiomyopathy that is now rarely seen, was linked to the mumps virus via viral polymerase chain reaction analysis of archived pathological sample, suggesting that its reduced prevalence might be attributed to immunization.20Table 1. Various Causes of Myocarditis3,5CausesExamplesInfectiousViral: adenoviruses, echoviruses, enteroviruses (eg, coxsackieviruses), herpesviruses (human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6), hepatitis C virus, human immunodeficiency virus, influenza A virus, parvovirus B19Bacterial: chlamydia, Corynebacterium diphtheria, legionella, Mycobacterium tuberculosis, mycoplasma, staphylococcus, streptococcus A, Streptococcus pneumoniaeFungal: actinomyces, aspergillus, candida, cryptococcusHelminthic: Echinococcus granulosus, Trichinella spiralisProtozoal: Toxoplasma gondii, Trypanosoma cruziRickettsial: Coxiella burnetti, Rickettsia typhiSpirochetal: Borrelia burgdorferi, leptospira, Treponema pallidumAutoimmune diseasesCeliac disease, Churg-Strauss syndrome, Crohn disease, dermatomyositis, giant cell myocarditis, hypereosinophilic syndrome, Kawasaki disease, lupus erythematodes, lymphofollicular myocarditis, rheumatoid arthritis, sarcoidosis, scleroderma, ulcerative colitisHypersensitivity reactionsPenicillin, ampicillin, cephalosporins, tetracyclines, sulfonamids, antiphlogistics, benzodiazepines, clozapine, loop and thiazide diuretics, methyldopa, smallpox vaccine, tetanus toxoid, tricyclic antidepressantsToxic reactions to drugsAmphetamines, anthracyclines, catecholamines, cocaine, cyclophosphamide, 5-fluorouracil, phenytoin, trastuzumabToxicEthanolOthersArsenic, copper, iron, radiotherapy, thyrotoxicosisIn a somewhat confusing fashion, the American Heart Association's contemporary definitions of cardiomyopathies classify myocarditis as an inflammatory cardiomyopathy but also lists the same infectious causes of dilated cardiomyopathy as those found with myocarditis.21 This conundrum typifies myocarditis. Its myriad presentations range from minimal symptoms to severe heart failure and sudden death. It is commonly associated with typical abnormalities observed in ECGs, cardiac imaging, and cardiac biomarkers, but it may exist in the absence of those abnormalities. It is a disease defined by observable myocardial pathology but may be present despite normal-appearing cardiac biopsies. Immunosuppression and immunomodulation have been used to treat myocarditis in children for >20 years, but their use remains controversial. These variations and controversies make the diagnosis and treatment of myocarditis in children a fascinating challenge and are the subject of this report.DiagnosisHistory and Physical ExaminationTachypnea and an abnormal respiratory examination were the most frequently described presenting symptoms in emergency department patients ultimately diagnosed with myocarditis.22 Isolated gastrointestinal symptoms of anorexia, abdominal pain, and vomiting may also occur.23,24 Chest pain, syncope, and palpitations may also be presenting complaints. Fever may or may not be present. The majority of patients present with a resting tachycardia, but other cardiac-specific signs such as pallor, hypotension, edema, and hepatomegaly occur in only a minority of cases. Often, multiple visits to medical personnel occur over time before a diagnosis is made.25ElectrocardiographyECGs are virtually always abnormal in children with myocarditis, but a normal ECG does not rule out the possibility of the disease.23 ECG abnormalities, however, are widely variable, and there is not one specific abnormality that occurs with enough frequency to be a specific marker. Low-voltage QRS complexes can exist. ST-T wave abnormalities to ST-segment elevation mimicking acute myocardial infarction may occur.26,27 Atrial and ventricular delays and prolongation of QT intervals may also occur. Premature contractions and a wide variety of tachyarrhythmias and bradyarrhythmias occur in myocarditis, including complete atrioventricular block.28,29BiomarkersNonspecific markers of inflammation (white blood cell count, C-reactive protein, and erythrocyte sedimentation rate) are often elevated in myocarditis, but normal studies do not exclude a myocardial inflammatory process.5 Since the development of blood levels of cardiac troponin T and I as a marker of cardiomyocyte damage or death, elevations of these cardiac proteins in the blood are observed in a substantial minority, but not a majority, of adults and children with myocarditis.30–32 Their absence does not rule out the presence of the disease. Some of the highest values of high-sensitivity troponin are observed in myocarditis patients.33 One pediatric study22 found elevation of serum aspartate aminotransferase commonly present in their myocarditis patients. B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide can be elevated in myocarditis,7 and elevated levels may aid in distinguishing a cardiac from a noncardiac reason for respiratory symptoms in children.34 Cardiac protein autoantibodies are often found in the serum of adult myocarditis patients, but their role as a pathogenic agent remains uncertain.35 In a small pediatric pilot study,36 antibodies to cardiac myosin were found in myocarditis patients at the time of diagnosis and persisted in previously diagnosed patients both with and without myocardial recovery.Assessment of Viral InfectionAlthough determining acute and convalescent viral serologies is the traditional way to diagnose viral infections, it is likely of limited, if any, use in the determining viral origin in myocarditis.5 Many of the viruses associated with myocarditis are highly prevalent in the population, and the development of myocarditis may occur well after the acute viral phase of the disease has resolved. Although viral polymerase chain reaction testing on endomyocardial biopsy samples is a clinically available test, polymerase chain reaction assessment of virus from the respiratory tract and other sites has also been recommended in children.37 A potentially cardiotoxic virus was indentified from urine, stool, or upper respiratory secretion in 22.3% of pediatric dilated cardiomyopathies at presentation in the Australian registry.38 Evaluation of new-onset pediatric myocarditis patients in a small pilot study39 of blood polymerase chain reaction samples at the time of presentation found the presence of enterovirus, adenovirus, parvovirus B19, or human herpesvirus 6 in 43% of the patients compared with only 4% of a pediatric control group receiving a same-day surgery elective procedure.EchocardiographyEchocardiography remains the most common tool to assess left ventricular structure and function in pediatrics. Although the most common echocardiographic finding associated with myocarditis is a dilated cardiomyopathy phenotype of left ventricular dilatation and reduced ejection fraction, hypertrophic and restrictive phenotypes have been described in histologically proven myocarditis.40 Segmental wall motion abnormalities mimicking an ischemic cardiomyopathy can be observed.41 Pericardial effusions suggestive of myopericarditis may also be observed and help to make a diagnosis. Fulminant myocarditis, a distinct symptom complex from acute myocarditis with a good prognosis, has a characteristic echocardiographic phenotype in adults42 and children43 of reduced left ventricular ejection, normal left ventricular cavity size, and increased septal thickening. It predicts a better chance for ultimate normalization of cardiac function.Cardiac Magnetic Resonance ImagingCurrently, cardiac MRI (cMRI) may be the most helpful imaging tool for the diagnosis of myocarditis. In addition to its ability to accurately assess left ventricular ejection, chamber size, and wall thickness, cMRI can localize tissue injury, including edema, hyperemia, and fibrosis.44 Assessment of myocardial edema is performed with T2-weighted imaging.45 Hyperemia may be assessed with the use of T1 sequences obtained within minutes after gadolinium injection (early enhancement), which are highly reproducible but not the most specific for the diagnosis of myocarditis.44,46 Late gadolinium enhancement in the subepicardial or transmural areas suggests the presence of myocardial fibrosis associated with myocarditis compared with the subendocardial pattern associated with ischemia.47 Enhancement is often regional as opposed to global. A recent consensus conference44 determined that cMRI can be used optimally in the diagnosis of myocarditis if a combination of these 3 criteria is used (Lake Louise criteria; Table 2). If 2 or more of these criteria are positive, cMRI findings correlated with clinical histology with a diagnostic accuracy of 78%. cMRI may be more helpful in the diagnosis of acute myocarditis if performed within 14 days of the onset of symptoms.48 Identification of associated pericardial effusions may enhance diagnostic certainty.49 Recent refinements in T150 and T251 mapping techniques may improve cMRI assessment of myocardial findings in myocarditis.Table 2. Lake Louise Cardiac MRI Diagnostic Criteria for Suspected Myocarditis43Cardiac MRI finding are consistent with myocardial inflammation if at least 2 of the following criteria are present Regional or global myocardial signal intensity increase in T2-weighted images Increased global myocardial early enhancement ratio between myocardium and skeletal muscle in gadolinium-enhanced T1-weighted images There is at least 1 focal lesion with nonischemic regional distribution in inversion-recovery prepared gadolinium-enhanced T1-weighted images (delayed enhancement)Cardiac MRI study is consistent with myocyte injury or scar caused by myocardial inflammation if the third criterion is presentA repeat cardiac MRI study between 1 and 2 wk after the initial cardiac MRI study is recommended if None of the criteria are present but onset of symptoms isvery recent and there is strong clinical evidence for myocardial inflammation One of the criteria is presentThe presence of left ventricular dysfunction or pericardial effusion provides additional supportive evidence for myocarditisMRI indicates magnetic resonance imaging.Endomyocardial BiopsyPathological confirmation of myocardial inflammation continues to be required for a definitive diagnosis of myocarditis.1 More than 25 years ago, a pathological definition of myocarditis was developed (the Dallas criteria), requiring inflammatory cellular infiltrate with and without associated myocyte necrosis.52 It has become apparent that the Dallas criteria are limited by a high interobserver variability in biopsy interpretation, the need for multiple samples, and the inability to detect noncellular inflammatory processes.7,53 The patchy nature of myocarditis also contributes to sampling error. The Dallas criteria may also be limited in the detection of myocarditis from viruses such parvovirus B19 and human herpesvirus 6, in which the primary pathology resides in endothelial injury.4 Over the past decade, immunohistochemistry techniques have improved the detection of inflammation in endomyocardial biopsies. Monoclonal antibodies to CD3 allow the detection and localization of T cells and macrophages, respectively. HLA antigen can used to detect HLA class II expression in antigen-presenting immune cells. The World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies has defined inflammation in an endomyocardial biopsy by immunohistochemical detection of focal and diffuse mononuclear infiltrates (T cells and macrophages) with >14 cells/mm2, in addition to enhanced expression of HLA class II molecules.1 A recent study54 developed an assay of transcriptomic biomarkers from a single biopsy sample to diagnose myocarditis with a high degree of accuracy. These techniques, if confirmed, could substantially change diagnostic algorithms for the detection of myocarditis.A combined AHA/American College of Cardiology/European Society of Cardiology statement55 on the indications for endomyocardial biopsy does not support its routine clinical use for the diagnosis of myocarditis. Biopsy is recommended only in patients with new-onset heart failure (<2 weeks) with hemodynamic compromise with and without left ventricular dilatation; new-onset heart failure of 2 weeks' to 3 months' duration with a dilated left ventricle, ventricular arrhythmia, and high-grade atrioventricular block (Mobitz type II or third-degree atrioventricular block); or symptoms unresponsive to treatment in 1 to 2 weeks. The last 2 scenarios occur in giant cell myocarditis, a rare disorder that occurs primarily in adults but has been reported in children.56 Giant cell myocarditis has a grim prognosis but if identified can respond to treatment with immunosuppression.57Sagar et al6 have proposed a 3-tier classification for the clinical diagnosis of myocarditis (Table 3). Definite myocarditis would require histological or immunohistological evidence of myocarditis. Possible subclinical acute myocarditis describes a clinical situation of possible myocardial injury without cardiovascular symptoms but with at least 1 of the following: increased levels of cardiac injury biomarkers, ECG findings of cardiac injury, or abnormal cardiac function on echocardiogram or cMRI. Many cases of myocarditis are thought to be asymptomatic. Possible subclinical myocarditis would describe situations such as that observed in the influenza A epidemic (H3N2) in Japan from 1998 to 1999, in which myosin light chain was elevated in 11.4% of patients,58 or when 0.5% of patients had increased troponin I levels without cardiac symptoms after smallpox vaccination.59 Probable acute myocarditis would be diagnosed with the same conditions as possible subacute myocarditis plus the presence of cardiovascular symptoms.Table 3. Diagnostic Classification for Patients With Myocarditis6CriteriaPathological ConfirmationECG or ImagingPossible subclinical acute myocarditisAbsentNeeded In the clinical context of possible myocardial injury without cardiovascular symptoms but with at least 1 of the following Biomarkers of cardiac injury raised ECG findings suggestive of cardiac injury Abnormal cardiac function on echocardiogram or cardiac MRIProbable acute myocarditisAbsentNeeded In the clinical context of possible myocardial injury with cardiovascular symptoms and at least 1 of the following: Biomarkers of cardiac injury raised ECG findings suggestive of cardiac injury Abnormal cardiac function on echocardiogram or cardiac MRIDefinite myocarditisNeededNot needed Histological or immunohistologicalMRI indicates magnetic resonance imaging.Cardiovascular Syndromes Observed With Pediatric MyocarditisSudden DeathSudden death in the pediatric population is commonly associated with myocarditis. Sudden death occurred in 57% of autopsied patients with a diagnosis of myocarditis at a single pediatric center60 over 10 years at a median age of 10 months (range, 10 days–16 years). Studies of sudden infant death syndrome have linked infection with viruses such as enterovirus, adenovirus, parvovirus B19, and Epstein-Barr virus and myocarditis to sudden infant death syndrome victims.61,62 Myocarditis accounted for ≈9% of sudden deaths in young athletes in the United States in whom a confirmed cardiovascular event was documented.63ArrhythmiasSymptoms such as palpitations and syncope occur in pediatric myocarditis patients even in the absence of heart failure or demonstrable reduction of left ventricular function. Myocarditis should always be considered in a child with acquired complete heart block. Lyme carditis64 and Chagas disease65 have been associated with complete heart block. Although the majority of children may recover atrioventricular conduction,29 most patients need implantation of a permanent pacemaker because recovery may take weeks to months. Pediatric ventricular arrhythmias in structurally normal hearts66 and ventricular tachyarrhythmias in athletes have been associated with myocarditis.67Chest Pain/Myocardial InfarctionMore than 20 years ago, it was recognized in adults68 and children69 that myocarditis may mimic myocardial infarction with severe symptomatic chest pain, characteristic ECG findings, and elevation of serum creatinine kinase in the presence of normal coronary angiograms. Coronary spasm has been observed with this presentation in adults.70 Parvovirus B19 has been found in the myocardium of such patients, as well as adenovirus and Epstein-Barr virus.71 In a study of 4436 patients presenting to a pediatric emergency department with chest pain, 24 had a confirmed cardiac origin, of whom 4 were diagnosed with myocarditis.72 A recent study27 of pediatric patients presenting with myocarditis and a chest pain/myocardial infarction pattern found that all had elevations of cardiac troponin I (peak range, 6.54–64.59 ng/mL) in the presence of normal values of erythrocyte sedimentation rate and C-reactive protein. Echocardiograms demonstrated a mild reduction in left ventricular function in 57% of the patients, and 5 of 6 patients demonstrated cMRI findings consistent with myocarditis. The prognosis was good with resolution of cardiac abnormalities within a few weeks, similar to the adult experience.Acute Heart Failure With a Dilated Cardiomyopathy PhenotypeThe classic presentation of myocarditis is the development of symptoms of heart failure with a dilated cardiomyopathy phenotype a few weeks after a history compatible with viral illness, including fever, myalgias, and respiratory or gastrointestinal symptoms. Myocarditis accounts for 30% to 35% of children with dilated cardiomyopathy phenotypes in the Australian73 and North American74 pediatric cardiomyopathy registries and for 22% of new-onset left ventricular dysfunction in the United Kingdom.75Fulminant myocarditis76 is a distinct subset of acute myocarditis characterized by heart failure with severe hemodynamic compromise requiring inotropic or mechanical circulatory support and at least 2 of the following criteria: fever, distinct onset of heart failure symptoms within a 1- to 2-day period, and a history consistent with viral illness within the 2 weeks before hospitalization. Despite the severe presentation, outcomes are substantially better than in adults with acute myocarditis. Acute myocarditis presenting with severe heart failure, arrhythmias, and lack of responsiveness to supportive care after 1 to 2 weeks leads to concern for giant cell myocarditis, which can be diagnosed by biopsy and has a grim prognosis, although is responsive to immunosuppression.55Myocarditis in children is associated with a high rate of congestive heart failure, hospitalization, intensive care unit stay, and use of inotropic support at the time of diagnosis compared with children with idiopathic dilated cardiomyopathy.43 A recent study of hospitalized patients in the United States77 found that nearly half of the patients required inotropic support, 37.5% required mechanical ventilation, and 7.4% required extracorporeal membrane oxygenator (ECMO) support. Fulminant myocarditis has been described in children with mortalities varying from 48.4% in Japan24 to 9% in France.78Acute myocarditis in children has been associated with a good prognosis with a good chance for ultimate recovery of left ventricular dysfunction.12,74,77,79,80 Within the North American Pediatric Cardiomyopathy Registry (PCMR;43Figure 1), 372 myocarditis patients diagnosed by biopsy (n=119) or clinical criteria (n=253) were compared with 1123 patients diagnosed with idiopathic dilated cardiomyopathy. Outcomes were similar in the biopsy and clinically diagnosed myocarditis patients and substantially better than in children diagnosed with idiopathic dilated cardiomyopathy. These results are similar to an estimated 58% spontaneous recovery in acute adult myocarditis gleaned from an adult meta-analysis.81Download figureDownload PowerPointFigure 1. Competing outcomes analysis of crude incidence rates of echocardiographic normalization, cardiac transplantation, and death in patients diagnosed with myocarditis within the Pediatric Cardiomyopathy Registry.43A, Myocarditis diagnosed by endomyocardial biopsy. B, Myocarditis diagnosed clinically.TreatmentActivity LimitationsAnimal models of myocarditis have shown an association with sustained aerobic exercise and increased mortality.82 Given these findings and the known association of myocarditis with sudden death in young athletes,63 current guidelines from the 2005 Bethesda Conference for activity with acute myocarditis include exclusion from competitive athletics and other vigorous exercise for at least 6 months with a return to training and competition possible if left ventricular function is normal and there are no clinically relevant arrhythmias.83Medical TherapyHuman studies on the use of conventional heart failure and arrhythmia therapy in myocarditis are lacking, but a number of animal studies have shown benefits to treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers,84–86 aldosterone antagonists,87 calcium channel blockers,88 and carvedilol.89 Metoprolol has been associated with increased mortality in acute murine coxsackievirus B3 myocarditis.90 In adults, a recent study91 showed that lack of β-blocker therapy was associated with a poor outcome. In adults, in recent-onset dilated cardiomyopathy in the Intervention in Myocarditis and Acute Cardiomyopathy II (IMAC-2) study,92 routine use of angiotensin-converting enzyme inhibitors and β-blockers led to a transplantation-free survival of 88% and a survival free of heart failure hospitalization of 78%.Digoxin is not recommended in the treatment of acute myocarditis5 because animal studies have shown increased myocardial injury in virus-infected mice.93 In a similar fashion, nonsteroidal anti-inflammatory drugs are also not recommended because of evidence of increased inflammation and mortality in murine models of myocarditis.94,95Current recommendations in adult2–6 and pediatric9,10,12 myocarditis emphasize that supportive medical therapy should be the primary therapy for acute myocarditis. Treatment of heart failure and left ventricular dysfunction should proceed according to established guidelines of the AHA, American College of Cardiology, European Society of Cardiology, and Heart Failure Society of America.96–98 These guidelines suggest angiotensin-converting enzyme inhibition for asymptomatic left ventricular dysfunction (American College of Cardiology/AHA stage B heart failure), a combination of angiotensin-converting enzyme inhibition and β-blockade with selective use of aldosterone antagonists in symptomatic heart failure, and the use of inotropic agents with mechanical ventilatory or circulatory support for patients with cardiogenic shock or patients who deteriorate despite medical treatment. Because of the potential to treat giant cell or eosinophilic myocarditis with immunosuppression,3–6,57 endomyocardial biopsy is recommended in this situation.55Complete heart block is treated with pacemaker therapy, and therapy may be considered in second-degree block in entities such as giant cell myocarditis in which progressive block may occur.57 Ventricular arrhythmias are treated by conventional guidelines.99 Implantable defibrillators are implanted for symptomatic ventricular arrhythmias or previous cardiac arrest from ventricular fibrillation, but routine prophylactic implantation is often delayed in the hope that left ventricular function will improve with medical therapy.5Immunomodulation, Immunosuppression, and Antiviral TherapyAnimal studies have suggested that myocarditis has a 3-phased course.3,4,7,100 Phase 1 involves initial direct myocardial injury from the actively replicating virus or the innate immunological response from infection of cardiac myocytes, fibroblast, or endothelial cells. Phase 2 is marked by activation of antigen-specific immunity involving T cells, B cells, and antibody production. Various chemokines are present that may contain the inflammatory response but extend tissue injury. Development of autoantibodies and persistent T-cell activation can be induced by antigens intrinsic to the myocardium that cross-react with viral peptides (molecular mimicry). Ultimate outcomes may vary, as illustrated in Figure 2. Negative immune modulation may occur rapidly after elimination of the infectious pathogens, leading to a cessation of the inflammatory response with complete recovery or little long-term myocardial damage. However, phase 3 may occur in which acute myocarditis leads to a chronic dilated cardiomyopathy. This may result from severe myocardial injury caused by the acute event; an ongoing inflammatory, autoimmune process that may occur without the persistent presence of virus in the myocardium (inflammatory dilated cardiomyopathy); or ongoing direct injury from virus with or without a persistent myocardial inflammatory response (viral heart disease).101Download figureDownload PowerPointFigure 2. Proposed mechanism of how infection of cardiac endothelial cells or cardiac myocytes by virus leads to direct cellular damage. A subsequent innate and adaptive immune response develops that can evolve into resolution and healing or dilated cardiomyopathy resulting from severe initial injury, persistent inflammation, or persistent viral infection. Adapted from Schultheiss et al4 with permission of the publisher. Copyright © 2011, Oxford.These findings have suggested a role for both immunosuppressive and antiviral therapies in the treatment of myocarditis. Human studies have found biopsy evidence of cardiac inflammation in adults with idiopathic dilated cardiomyopathy102,103 and immunohistochemical evidence of myocardial inflammation in up to 40% of adults with a chronic dilated cardiomyopathy unresponsive to supportive care.104 Viral genomes have been found in children6 and adults105 with idiopathic dilated cardiomyopathy, and 1 study found that viral persistence over time was associated with progressive cardiac dysfunction.106 However, another study91 found only persistent immunohistological signs of inflammation, not persistent positive histology or viral presence, to be predictive of poor outcomes. Other studies107,108 have questioned whether the presence of virus in patients with chronic dilated cardiomyopathy has a functional or prognostic relevance and argue against a role for antiviral therapy.109Antiviral therapy might have its greatest efficacy in the very early stages of myocarditis. Most patients with acute myocarditis are diagnosed weeks after viral infection, making it questionable whether the therapy could be given early enough to be beneficial. A small case study110 demonstrated viral clearance, improvement in left ventricular size and function, and symptomatic improvement with the use of subcutaneous interferon-β in enteroviral and adenoviral myocarditis. A subsequent randomized, placebo-controlled phase II trial has been performed in adult virus + inflammatory dilated cardiomyopathy and by report4,5,108,109,111 showed some clinical benefit but a diminished response in terms of viral clearance with parvovirus B19 and human herpesvirus 6 infections. This trial, however, has not been yet been published in full form.On the basis of its known antiviral, anti-inflammatory, and immunomodulating effects112 and a single-center study in pediatric myocarditis,113 the use of intravenous immunoglobulin (IVIG) in recent-onset dilated cardiomyopathy was teste
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