951

Viral Myocarditis Darryl M. See and Jeremiah G. TIlles

From the Division of Infectious Diseases, Department of Medicine, University of California, Irvine, California

Viral agents are believed to cause most of the clinically detected myocarditis in the United States. The wide spectrum of the clinical disease ranges from asymptomatic, transient inflammation to a fulminant course with an array of manifestations that may include heart failure, arrhythmias, and/or sudden death. Considerable evidence suggests that the disease progresses, on occasion, to dilated cardiomyopathy, a disorder that remains the most common indication for cardiac transplantation [1-6]. Treatment is now largely supportive because of a variety of factors, including a poor understanding of the pathogenesis of the disease, delayed or nonspecific diagnosis, and a lack of effective antiviral agents. However, much investigational work is now being done in both animals and humans to solve these problems and to develop effective therapy.

Etiology and Epidemiology The most frequent etiologic organisms of viral myocarditis are members of the genus Enterovirus. Among these, the coxsackieviruses B have been associated with over 50 % of all cases. Other viruses in the genus, such as coxsackieviruses A, echoviruses, and polioviruses, have also been implicated. Many other viruses have occasionally been associated with myocarditis. In the United States, these other agents include adenoviruses, cytomegaloviruses, and influenza A and B, rubeola, rubella, mumps, hepatitis A and B, varicella-zoster, rabies, and lymphocytic choriomeningitis viruses [7]. The in-

Received 12 July 1990; revised 7 November 1990. Reprints and correspondence: Dr. Jeremiah G. Tilles, Department of Infectious Diseases, University of California Irvine Medical Center, Orange, California 92668. Reviews of Infectious Diseases 1991;13:951-6 © 1991 by The University of Chicago. All rights reserved. 0162-0886/9 1Il30S-0044$02.00

cidence of myocarditis in patients with AIDS is higher than that in healthy persons [8-10]. Although the role of the human immunodeficiency virus itself in myocarditis is not yet clear, recent evidence has implicated the myocyte as a target cell for this virus [11]. A clinical syndrome suggestive of viral myopericarditis was first widely recognized in the mid-1800s, although a viral etiology was not determined at that time [12]. Later in the century, the first link between viral infection and heart disease was established during an outbreak of mumps in Europe, when a high proportion of affected individuals were noted to have cardiac symptoms [13]. This relationship was strengthened during the influenza epidemic of 1918, when pathologists found a high incidence of cardiac pathology in patients who had died from influenza [14]. The first evidence of an association between an enterovirus and myocarditis occurred in the 1930s, when cardiac inflammation was noted post-mortem in patients afflicted with poliomyelitis [15]. During the 1950s and 1960s, enteroviruses were first isolated from the hearts of patients, especially neonates, affected with clinical myocarditis [16-20]. During an epidemic of coxsackievirus B5 in Europe in 1965, a firm epidemiologic link was established between coxsackievirus B5 and acute myocarditis. In a study in Finland, 16 of 18 hospitalized patients with acute myocarditis or myopericarditis had evidence of recent infection with coxsackievirus B5, i.e., isolation of the virus from the stool and/or serologic demonstration of acute infection [21]. Since then, serologic studies have demonstrated an association of other coxsackieviruses B, echoviruses, and coxsackieviruses A with acute myocarditis [22-27]. The overall incidence of viral myocarditis is unknown; the number of reported clinical cases varies from year to year and presumably reflects the prevalence and virulence of the etiologic agents. For the enteroviruses, two patterns of incidence, endemic and epidemic, have been reported [28]. Some, like coxsackievirus A9, coxsackievirus B2, and coxsackievi-

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Although most cases of viral myocarditis are subclinical, some patients develop overt symptomatic disease. These patients may present with findings that range from benign myopericarditis to frank heart failure. Furthermore, a growing body of evidence links viral myocarditis with idiopathic dilated cardiomyopathy, sudden death, and chronic arrythmias. The pathogenesis of the disease is currently incompletely understood in humans but is being investigated in animal models. A multifactorial process involving direct viral damage, autoimmunity, and possibly vascular damage is emerging. Breakthroughs in rapid diagnosis, such as the use of DNA probes, are occurring and may soon provide the opportunity for early intervention. Although there is currently no widely accepted standard of treatment, promising new therapeutic modalities are under investigation. These include the use of general immunosuppressive agents, T cell monoclonal antibody, interferon, specific immunization, and synthetic antiviral agents.

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Pathogenesis The pathogenesis of human viral myocarditis is incompletely understood. In neonates the mechanism seems to be direct damage to cells by the virus. Such a mechanism is supported by the clinical presentation, in which the onset of clinical myocardial disease occurs with the signs of systemic viral illness [33-35]. In adults, as in neonates, concomitant systemic illness and myocardial disease can occur, although the onset of clinical myocarditis usually follows the systemic disease. The evidence suggests that T cell-mediated autoimmune destruction of myocardial cells is the principal cause of myocardial damage. Investigators have demonstrated defective T suppressor cell function and altered systemic and myocardial cellular immunity in patients with myocarditis [36-39]. The data, although supportive, do not prove an autoimmune mechanism. The pathogenesis of viral myocarditis has been better established in mice. There seem to be three mechanisms by which the cardiotropic viruses cause disease; these depend on the causative organism. The first mechanism, exemplified in the coxsackievirus A9 and coxsackievirus Bl models, involves direct viral destruction of myocardial cells [32, 40, 41]. Susceptibility to infection varies according to the age and strain of the mouse, but in no case is there evidence of autoimmune disease. In fact, immune suppression is often required to induce myocarditis. The second mechanism, characterized in the coxsackievirus B2 and coxsackievirus B3 models, clearly involves a biphasic disease process [42-45]. Initially, the virus achieves high titers in the myocardial tissue but generates little cytopathic damage before live virus can no longer be retrieved from the myocardium. Later, a T cell-mediated inflammatory process supervenes. Requirement of an intact T cell system for the induction of myocarditis due to coxsackievirus B3 has been repeatedly demonstrated [46-49]. In these experiments, mice either treated with antithymocyte serum [50]

or thymectomized and then irradiated before inoculation of virus did not develop the myocarditis that occurred in immunecompetent controls. Reconstitution of the immune system with normal T cells exacerbated the myocardial damage. Evidence of an autoimmune process in these models is abundant [51-53]. Experiments have shown that virus-specific alterations in infected myocardial tissue are capable of stimulating the production of cytotoxic T lymphocytes (CTLs), which lyse myocardial cells of the host in a virus-specific manner [45]. Other CTLs kill myocardial cells whose cellular metabolism has been altered by viruses in a nonspecific manner. Still another population of CTLs apparently attacks the receptors of coxsackievirus B3 on myocytes ofthe host. It is postulated that the presence of coxsackievirus B3 up-regulates the production of the receptors, thereby leading to enhanced autoimmunity [54]. The biochemical mediators ofCTL-associated myocardial damage are now under investigation. Perforin is the first of these to have been identified [55]. Other investigators have shown cross-reactivity between antibody to certain coxsackieviruses and murine cardiac myosin and actin [29]. Furthermore, immunochemical studies have demonstrated autoimmune activity against cardiac myosin and that cardiac myosin immunization has successfully induced myocarditis [31, 56]. A third possible mechanism, not as well studied as the first two, involves damage to the coronary vasculature, with luminal narrowing, intraluminal thrombus formation, and obstruction. This condition has been demonstrated in mice infected with coxsackievirus B3 in one study and with encephalomyocarditis virus in another [57, 58]. Presumably, obstruction to flow could result in ischemic damage to the myocardium. In humans a growing body of evidence links viral myocarditis with the subsequent development of dilated cardiomyopathy [59-61]. Some investigators have shown that patients with dilated cardiomyopathy have serologic evidence of exposure to coxsackieviruses at a greater frequency than do healthy subjects [62]. Other researchers have shown that patients who recover from clinically suspected acute myocarditis later develop dilated cardiomyopathy more often than do controls [63]. Furthermore, active inflammation may be seen in biopsy specimens from patients with unexplained dilated cardiomyopathy [64]. The frequency of histologic evidence of myocarditis in these patients varies widely from study to study [2]; this discrepancy is likely due to sampling error added to the fact that, until recently, no widely accepted histologic criteria existed to establish the diagnosis of active myocarditis. Attempts to standardize these criteria are now being implemented. More recently, complementary DNA (eDNA) probes have been utilized to determine the presence of replicating enteroviral RNA in the myocardia of patients with unexplained dilated cardiomyopathy. In one study [47], eight of 27 patients with this condition but none of 31 patients with myocardial disease of demonstrable nonviral etiology, such as ischemia

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rus B3, are primarily endemic, with little yearly variation in incidence. Larger outbreaks of infections due to these viruses do occur on occasion, however, and actual epidemics have been reported. There may be a low, constant rate of symptomatic cardiac disease associated with these viruses and then an increased incidence of myocarditis during times of increased prevalence of the virus. Other infections due to viruses, such as coxsackievirus B5, occur largely in epidemics. During an epidemic due to a coxsackievirus, up to 5 % of the population have been noted to develop symptomatic cardiac disease. The incidence of disease depends on the virulence of the strain and other factors [29]. Youngchildren and men are more commonly and severely affected with cardiac disease than are older children and women. Among the population as a whole, susceptibility to disease may reflect individual genetic predisposition, as is the case with laboratory animals [30-32].

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or metabolic derangements, had evidence of enteroviral heart disease. In another study [65], results of cDNA probes for nine of 17 patients with unexplained cardiomyopathy who had histologic evidence of inflammation were positive, while none of four patients with dilated cardiomyopathy who did not have evidence of inflammation had positive results. The exquisite sensitivity of these probes has been clearly established, but their specificity has not yet been verified.

Diagnosis

a high titer of virus-specific serum IgM. The demonstration of acute infection with a cardiotropic virus, however, does not by itself establish a definitive diagnosis of virus-induced myocarditis. Histologic differentiation between inflammation caused by viral infection and by other causes of myocarditis on biopsy specimens is not possible. Furthermore, electron microscopy is limited in its utility because of the smallness of enteroviruses. Recently, the ability oflabelcd, cloned cDNA probes of coxsackievirus B3 or coxsackievirus B4 to hybridize with replicating enteroviral RNA in infected cells has been used in diagnosis [66, 67]. Due to significant genome homology between the different enteroviruses, this technique appears to have potential as a broad-spectrum diagnostic reagent for enteroviruses. It also has two other useful attributes. First, the procedure is fairly rapid. When a high concentration of viral genome is present in the myocardial cells, positive radiographic signals can be detected within 48 hours after application of the probe to infected cells. Second, the procedure is highly sensitive, allowing diagnosis when only a low concentration of the virus is present in myocardial cells, as may be the case in a virus-induced autoimmune process. Standardization is now being applied to this technique to enhance specificity.

Treatment Treatment of clinical disease in humans is now largely supportive. Only bed rest has been uniformly accepted as being of benefit. This treatment modality is supported by evidence gathered from animal experiments that shows more-extensive myocardial disease in animals forced to exercise [68, 69]. Clinical trials are currently being conducted to assess the efficacy of immunosuppression in treating dilated cardiomyopathy, a suspected sequela of viral myocarditis. Preliminary, uncontrolled experiments with immunosuppressive agents have yielded inconclusive and often conflicting data [2, 70]. Fortunately, experimental strategies for murine myocarditis are being developed. If successful, they may provide a foundation for further clinical studies in humans. One of the experimental treatment strategies for murine myocarditis utilizes the naturally occurring antiviral agent interferon. Three studies have demonstrated the efficacy of interferon in diminishing or eliminating myocarditis in infected animals if interferon in given within 24 hours of inoculation of virus [71-73], but the medication had no effect if it was administered more than 24 hours after the mice were infected. Obviously, for there to be any practical application of this treatment for human use, interferon would have to be beneficial as late as the time symptoms occur. A second treatment strategy utilizes synthetic antiviral agents. Ribavirin is a broad-spectrum antiviral agent that acts by inhibiting RNA polymerase [74, 75]. It has been shown to be efficacious in treating murine enteroviral myocarditis

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The presumptive clinical diagnosis of acute disease is based on symptoms and signs of myocarditis or myopericarditis that are coupled with evidence of antecedent or intercurrent viral infection. Infants will often present with a fulminant syndrome characterized by fever, cyanosis, respiratory distress, tachycardia, cardiac failure, electrocardiographically evident changes, and, often, involvement of other organs. Older children usually develop less-severe disease. Symptomatic adult patients may present with variable complaints, including fatigue, dyspnea on exertion, palpitations, and precordial pain consistent with pericarditis. Systemic symptoms of viral infection have usually subsided by the time myocarditis develops but have usually occurred within 2 weeks of presentation. Common physical findings include fever, sinus tachycardia, pleural or pericardial rubs, arrhythmias, and, in severe cases, signs of heart failure. Abnormal results of laboratory tests include variable serum elevations of one or more cardiac enzymes. These levels may range from normal to several times the baseline level. They tend to rise and fall over a period of days, in contrast to the sharper peaks seen in cases of myocardial infarction. Often there is moderate leukocytosis. The chest roentgenogram may show cardiomegaly. The electrocardiogram usually reveals abnormalities including diffuse, nonspecific S-T segment elevation or depression, T wave inversions, arrythmias, or classical evidence of pericarditis. Echocardiography may reveal impaired myocardial function and pericardial effusion. Magnetic resonance imaging often shows evidence of diffuse myocardial inflammation. An incontrovertible diagnosis of viral myocarditis can currently be established either by isolation of virus from the myocardium or by localization of the type-specific virus in myocardial tissue by immunofluorescence or peroxidaselabeled antibody. These procedures require biopsy or autopsy specimens. In clinical situations the diagnosis frequently proves to be unreliable or delayed. The use of labeled antibody is impracticable because it requires specific antibody for each of the serologically distinct enteroviral types that might be implicated in the disease. A diagnosis of viral infection can be made by isolation of virus from samples of stool, pharyngeal secretions, or blood; by demonstration of a fourfold rise in virus-specific neutralizing antibodies from paired acute- and convalescent-phase sera; or by demonstration of

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Conclusion Although viral myocarditis in most humans is likely to be subclinical or transient, in some individuals it can be severe and even fatal. The variation in outcome is related both to viral factors such as dose and virulence of the strain and to host factors such as genetic predisposition, sex, age, and state of health. Especially significant is the probable link of this disease to dilated cardiomyopathy, a condition that may lead to cardiac transplantation. Recent advances in viral myocarditis include rapid, precise diagnosis using in situ hybridization with DNA probes and an accepted standard for histologic evaluationof myocarditis. New light is being shed on the pathogenesis of the disease through use of murine models. The multifactorial process emerging involves direct viral cellular necrosis, T cell-mediated autoimmunity, and possibly ischemia from vascular damage as well. At the same time, effective antiviral treatment in mice is being developed. Thus, although treatment is still largely supportive, promising new modalities are on the horizon. A multicenter study using immunosuppressive agents in humans is under way. Potential treatments such as interferon, synthetic antiviral agents, T cell monoclonal antibody, and specific immunization are being evaluated in mice and may lead to analogous clinical studies in humans.

References

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if it is administered early in the disease process. Unlike interferon, however, ribavirin is beneficial in experiments when it is not administered until 4 days after viral inoculation, a time when viral titers in the heart are at peak levels in mice. Unfortunately, ribavirin was effectiveonly in doses that would be toxic to humans. A new class of synthetic antiviral drugs, with disoxaril as the prototype, prevents viral uncoating and has been shown to be effective against many enteroviruses both in vitro and in vivo [76-80]. However, evaluation of these drugs for murine or human viral myocarditis has not yet been undertaken. A third potential treatment is immunosuppression. As noted above, multiple studies have established the role of. T cell-mediated autoimmunity in the pathogenesis of munne myocarditis caused by coxsackievirus B3. It follows that treatment regimens designed to suppress T cell function would be of benefit. Tothis end, multiple immunosuppressive agents, including cyclosporine, cyclophosphamide, and steroids, have been tried [30, 48,81]. Uniformly, these efforts have demonstrated either no effect or a deleterious effect on the disease process. However, complete elimination of the Tcell population, as in thymectomized, irradiated mice, has been shown to diminish the myocarditis process significantly. It has been postulated that these drugs either have not been used in sufficient doses or do not affect the responsible T cell subpopulation. A recent study has demonstrated that T c~ll mon~­ clonal antibody dramatically reduces both the histologic evidence of myocarditis and the mortality of infected mice [82]. This intervention was successful even if begun late in the disease process, when mice already had evidence of severe myocardial inflammation. This type of intervention may prove to be very useful in humans for the type of viral myocarditis that involves an autoimmune mechanism. A fourth experimental modality involves the use of virusspecific immunization to prevent the devel~p~ent of ~yo~ar­ ditis in animals [83]. Both active and passive immumzations have been successful in preventing the development of myocarditis following challenge with a cardiotropic virus. However, despite its potential specific efficacy, the clinical utility of immunization will probably be limited because of the large number of antigenically distinct viruses that have been implicated in myocarditis. Immunization may be of significant benefit, however, for high-risk persons in the event of a large epidemic caused by a known virus or of a hospital or laboratory outbreak involving a single type of virus. Multivalent vaccines for active use may provide an opportunity for more widespread intervention. Peeled hyperimmune sera for passive use may also prove to be of benefit in this regard, although the application of such sera could be limited by a potential to exacerbate the autoimmune process that occurs in myocardia infected with certain viruses.

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