**6. Treatment**

In spite of the significant progress in understanding the mechanisms of myocarditis pathogenesis in last two decades, advances in treatment strategies are still limited and the supportive care is the principal therapy. Most patients with acute myocarditis presenting with dilated cardiomyopathy respond favorably to standard anticongestive therapy including afterload reduction, diuretics, angiotensin converting enzyme inhibitors and the introduction of β blockers such as carvedilol or metoprolol succinate once the acute phase is controlled. Various experimental studies with β adrenoreceptor inhibitors or agonists showed different effects in acute myocarditis. Treatment with propranolol in mice infected with encephalomyocarditis virus (EMCV) reduced the severity of myocarditis and mortality (Wang et al., 2005). On the other hand, carvedilol, non-selective β blocker, improved the survival and decreased the virus replication of mice infected with EMCV through the enhancement of IL-12 and IFN-γ production, whereas metoprolol had no effect on this murine model (Nishio et al., 2003). Despite the lack of extensive studies in pediatric patients, administration of carvedilol has been found to be associated with improvement of left ventricle function and clinical symptoms and normalization of antioxidant enzyme activity (Bajcetic et al., 2008). Similar to effects of β blockers, ACE inhibitors and angiotensin receptor blockers have been documented to lessen viral myocardial injury in murine models (Yamamoto et al., 2003). It is also proposed that early introduction of beta-blockers and ACE inhibitors might prevent the remodelling that advances to dilated cardiomyopathy (Ellis&DiSalvo, 2007). Phosphodiesterase inhibitors such as milrinone, if well tolerated, can

Myocarditis in Childhood: An Update on Etiology, Diagnosis and Management 55

acute myocarditis (Chan et al., 1991, Camargo et al., 1995). However, studies in children are inadequate and yet, no randomized controlled trials are present. In a study (Camargo et al., 1995) conducted among 68 children with severe dilated cardiomyopathy, patients were classified into either conventional treatment or given one of three immune suppressive agents, prednisolone, prednisolone plus azathioprine and prednisolone with cyclosporine. Children taking immunosuppression treatment with a second agent, demonstrated enhanced hemodynamic parameters, as well as histological improvement in inflammation. A meta analysis (Hia et al., 2004) assessing the impact of immunosuppression on the outcome of acute myocarditis in children was published in 2004. Better outcome was observed among children who received immunosuppressive therapy. On the other hand, the findings were not statistically significant. Randomized large controlled studies are needed to conclude that immunosuppressive therapy is beneficial for outcome of children with acute myocarditis. On the contrary, one trial published in 1997, demonstrated that survival was improved with the treatment of cyclosporine and corticosteroids in patients with giant cell myocarditis (Cooper et al., 1997). A different approach has also been investigated, in which Wojnicz et al. used HLA expression on endomyocardial specimens to classify inflammatory cohort (Wojnicz et al., 2001). Of 202 patients with dilated cardiomyopathy, 84 patients with increased HLA expression were randomized to receive either placebo or immunosuppression for 3 months. After 2 years, significant improvement in ejection fraction and end diastolic diameter were noted only among the

It was suggested that intravenous immunoglobulin (IVIG) may be an useful therapy for acute myocarditis due to its both antiviral and immunomodulating effects. Previously, it has been shown that IVIG may be used in several autoimmune disorders, including idiopathic thrombocytopenic purpura, systemic vasculitis and Kawasaki disease (Rosen et al., 1993, Wolf et al., 1996). Up to date, there are no randomized controlled studies evaluating the use of IVIG to treat the children with acute myocarditis. A systemic review conducted by Robinson et al., evaluated the use of intravenous immunoglobulin therapy in acute myocarditis in both adults and children (Robinson et al., 2005). They determined that intravenous immunoglobulin might be useful in the presence of ongoing or active infection which may be causing obstinate cardiac failure. In a study conducted in children with presumed viral myocarditis, high dose IVIG treatment was found to be associated with improved recovery of left ventricular function and with a tendency of better survival (Drucker et al., 1994). In adults, the results of a randomized clinical trail suggested that for patients with recent onset dilated cardiomyopathy, IVIG did not enhance an improvement in ejection fraction (McNamara et al., 2001). However, in this cohort, ejection fraction was increased considerably during follow-up and short term prognosis remained favourable. Despite the presence of several case reports indicating that adults treated with intravenous immunoglobulin reveal better cardiac function, Cochrane review of IVIG administration in myocarditis and dilated cardiomyopathy demonstrated no benefit in adults (McNamara et al., 1997, Tedeschi et al., 2002). On the other hand, little is known about the exact mechanisms responsible for potential benefits of IVIG in the therapy of patients with acute myocarditis. Several studies both in the clinical setting and experimental models propose that immunoglobulin may reduce inflammatory cytokines that have direct negative

inotropic effects and decrease the oxidative stress (Kishimoto et al., 2003).

Numerous cases with myocarditis recover spontaneously. It is hard to know if the noted improvement is a consequence of therapy with IVIG or immunosuppression versus natural

immunosuppressive group.

be really helpful. A recent multi-institutional analysis revealed that milrinone was used most often for vasoactive support in children (Klugman et al., 2009). Anticoagulants should be considered if ejection fraction is severely decreased or in the setting of atrial arrhythmia (Gunthard et al., 2009). Digoxin should be used in low dose and with caution in patients with viral myocarditis since high dose digoxin was proven to increase mortality in animals with EMVC induced myocarditis as well as elevate intracardiac production of cytokines (Matsumori et al., 1999). Ventilation and oxygenation could be best achieved with continuous positive airway pressure (CPAP) or other non-invasive methods. CPAP, unloads inspiratory muscles and leads to decreased left ventricular afterload without compromising cardiac index via increasing intrathoracic pressure. Medications used for intubation can cause hypotension and acute cardiovascular collapse, thus CPAP also avoids this and is an outstanding adjunctive therapy for cardiac failure and myocarditis (Bradley et al., 1992, Naughton et al., 1995).

Extracorporeal membrane oxygenation support and ventricular assist device might be particularly useful for patients with fulminant myocarditis. Extracorporeal membrane oxygenation may also be considered in those who are in the recovery phase from acute myocarditis (Sezai et al., 2007). For patients with cardiogenic shock because of the acute myocarditis who worsen despite ideal medical therapy, extracorporeal membrane oxygenation and ventricular assist device may help as a bridge to transplant (Moloney et al., 2005). The full mobilization, survival rates up to 90% for fulminant myocarditis and decreased anticoagulation make these pulsatile ventricular assist device systems as the alternative choice of therapy for children (Patopov et al., 2007). Cardiac transplantation is reserved only for patients who are intractable with medical management and mechanical circulatory support. Almost half of the annual cardiac transplantation cases are performed for idiopathic dilated cardiomyopathy, at least 10% of which represent as myocarditis (Ellis&DiSalvo, 2007).

#### **6.1 Immune therapy**

It is well known that the long term morbidity and mortality following viral myocarditis seem to be dependent on cellular and humoral immunity abnormalities. Therefore, many investigations have been conducted to search the use of immunosuppressants and immunemodulator agents for treatment of acute myocarditis and dilated cardiomyopathy. However, debate still persists on whether immune therapy for acute myocarditis is useful or not. Initial adult studies investigating the effect of prednisone with or without azathioprine and cyclosporine demonstrated a slight improvement in left ventricular function. But, this improvement was temporary (Mason et al., 1995, Parillo et al., 1989). In a study conducted by Parillo et al., patients were grouped as reactive or nonreactive on the basis of histopathology, immunoglobulin deposition on EMB, an increased erythrocyte sedimentation rate or a positive gallium scan. At three months, reactive patients who were treated with prednisone (60 mg daily) had a statistically significant increase in ejection fraction compared with controls. After six months, improvement seen earlier was no longer present. In 1995, the Myocarditis Treatment Trial failed to show neither an improvement in left ventricle ejection fraction at 28 weeks nor an improvement in survival up to 4.3 years (Mason et al., 1995). Although a few uncontrolled studies showed benefit with several immune suppressive agents, meta analysis of adult studies did not confirm a significant favourable effect of immunosuppression (Garg et al., 1998, Maisch et al., 1998). There were also investigations to evaluate the results of immune suppressive regime in children with

be really helpful. A recent multi-institutional analysis revealed that milrinone was used most often for vasoactive support in children (Klugman et al., 2009). Anticoagulants should be considered if ejection fraction is severely decreased or in the setting of atrial arrhythmia (Gunthard et al., 2009). Digoxin should be used in low dose and with caution in patients with viral myocarditis since high dose digoxin was proven to increase mortality in animals with EMVC induced myocarditis as well as elevate intracardiac production of cytokines (Matsumori et al., 1999). Ventilation and oxygenation could be best achieved with continuous positive airway pressure (CPAP) or other non-invasive methods. CPAP, unloads inspiratory muscles and leads to decreased left ventricular afterload without compromising cardiac index via increasing intrathoracic pressure. Medications used for intubation can cause hypotension and acute cardiovascular collapse, thus CPAP also avoids this and is an outstanding adjunctive therapy for cardiac failure and myocarditis (Bradley et al., 1992,

Extracorporeal membrane oxygenation support and ventricular assist device might be particularly useful for patients with fulminant myocarditis. Extracorporeal membrane oxygenation may also be considered in those who are in the recovery phase from acute myocarditis (Sezai et al., 2007). For patients with cardiogenic shock because of the acute myocarditis who worsen despite ideal medical therapy, extracorporeal membrane oxygenation and ventricular assist device may help as a bridge to transplant (Moloney et al., 2005). The full mobilization, survival rates up to 90% for fulminant myocarditis and decreased anticoagulation make these pulsatile ventricular assist device systems as the alternative choice of therapy for children (Patopov et al., 2007). Cardiac transplantation is reserved only for patients who are intractable with medical management and mechanical circulatory support. Almost half of the annual cardiac transplantation cases are performed for idiopathic dilated cardiomyopathy, at least 10% of which represent as myocarditis

It is well known that the long term morbidity and mortality following viral myocarditis seem to be dependent on cellular and humoral immunity abnormalities. Therefore, many investigations have been conducted to search the use of immunosuppressants and immunemodulator agents for treatment of acute myocarditis and dilated cardiomyopathy. However, debate still persists on whether immune therapy for acute myocarditis is useful or not. Initial adult studies investigating the effect of prednisone with or without azathioprine and cyclosporine demonstrated a slight improvement in left ventricular function. But, this improvement was temporary (Mason et al., 1995, Parillo et al., 1989). In a study conducted by Parillo et al., patients were grouped as reactive or nonreactive on the basis of histopathology, immunoglobulin deposition on EMB, an increased erythrocyte sedimentation rate or a positive gallium scan. At three months, reactive patients who were treated with prednisone (60 mg daily) had a statistically significant increase in ejection fraction compared with controls. After six months, improvement seen earlier was no longer present. In 1995, the Myocarditis Treatment Trial failed to show neither an improvement in left ventricle ejection fraction at 28 weeks nor an improvement in survival up to 4.3 years (Mason et al., 1995). Although a few uncontrolled studies showed benefit with several immune suppressive agents, meta analysis of adult studies did not confirm a significant favourable effect of immunosuppression (Garg et al., 1998, Maisch et al., 1998). There were also investigations to evaluate the results of immune suppressive regime in children with

Naughton et al., 1995).

(Ellis&DiSalvo, 2007).

**6.1 Immune therapy** 

acute myocarditis (Chan et al., 1991, Camargo et al., 1995). However, studies in children are inadequate and yet, no randomized controlled trials are present. In a study (Camargo et al., 1995) conducted among 68 children with severe dilated cardiomyopathy, patients were classified into either conventional treatment or given one of three immune suppressive agents, prednisolone, prednisolone plus azathioprine and prednisolone with cyclosporine. Children taking immunosuppression treatment with a second agent, demonstrated enhanced hemodynamic parameters, as well as histological improvement in inflammation. A meta analysis (Hia et al., 2004) assessing the impact of immunosuppression on the outcome of acute myocarditis in children was published in 2004. Better outcome was observed among children who received immunosuppressive therapy. On the other hand, the findings were not statistically significant. Randomized large controlled studies are needed to conclude that immunosuppressive therapy is beneficial for outcome of children with acute myocarditis. On the contrary, one trial published in 1997, demonstrated that survival was improved with the treatment of cyclosporine and corticosteroids in patients with giant cell myocarditis (Cooper et al., 1997). A different approach has also been investigated, in which Wojnicz et al. used HLA expression on endomyocardial specimens to classify inflammatory cohort (Wojnicz et al., 2001). Of 202 patients with dilated cardiomyopathy, 84 patients with increased HLA expression were randomized to receive either placebo or immunosuppression for 3 months. After 2 years, significant improvement in ejection fraction and end diastolic diameter were noted only among the immunosuppressive group.

It was suggested that intravenous immunoglobulin (IVIG) may be an useful therapy for acute myocarditis due to its both antiviral and immunomodulating effects. Previously, it has been shown that IVIG may be used in several autoimmune disorders, including idiopathic thrombocytopenic purpura, systemic vasculitis and Kawasaki disease (Rosen et al., 1993, Wolf et al., 1996). Up to date, there are no randomized controlled studies evaluating the use of IVIG to treat the children with acute myocarditis. A systemic review conducted by Robinson et al., evaluated the use of intravenous immunoglobulin therapy in acute myocarditis in both adults and children (Robinson et al., 2005). They determined that intravenous immunoglobulin might be useful in the presence of ongoing or active infection which may be causing obstinate cardiac failure. In a study conducted in children with presumed viral myocarditis, high dose IVIG treatment was found to be associated with improved recovery of left ventricular function and with a tendency of better survival (Drucker et al., 1994). In adults, the results of a randomized clinical trail suggested that for patients with recent onset dilated cardiomyopathy, IVIG did not enhance an improvement in ejection fraction (McNamara et al., 2001). However, in this cohort, ejection fraction was increased considerably during follow-up and short term prognosis remained favourable. Despite the presence of several case reports indicating that adults treated with intravenous immunoglobulin reveal better cardiac function, Cochrane review of IVIG administration in myocarditis and dilated cardiomyopathy demonstrated no benefit in adults (McNamara et al., 1997, Tedeschi et al., 2002). On the other hand, little is known about the exact mechanisms responsible for potential benefits of IVIG in the therapy of patients with acute myocarditis. Several studies both in the clinical setting and experimental models propose that immunoglobulin may reduce inflammatory cytokines that have direct negative inotropic effects and decrease the oxidative stress (Kishimoto et al., 2003).

Numerous cases with myocarditis recover spontaneously. It is hard to know if the noted improvement is a consequence of therapy with IVIG or immunosuppression versus natural

Myocarditis in Childhood: An Update on Etiology, Diagnosis and Management 57

Prognosis of myocarditis is as changed as its clinical presentations. Although the fewer data are available on the natural history of myocarditis in children, it is proposed that the outcomes in pediatric patients presenting with acute heart failure secondary to acute myocarditis tends to be more positive than the prognosis with dilated cardiomyopathy (Drucker et al., 1994, Lee et al., 1999). In a retrospective analysis of 36 children with histologically proven lymphocytic myocarditis (Lee et al., 1999), excellent outcomes have been demonstrated in children with myocarditis, especially those surviving 72 hours after presentation. Gagliardi and colleagues, classified 114 children into three groups as acute myocarditis, borderline myocarditis and non-inflammatory cardiomyopathy according to histological analysis (Gagliardi et al., 2004). Best survival rate (97%) was found in acute myocarditis group. They suggested that this high long term survival rate of this cohort may be due to effect of short term immunosuppressive therapy. On the other hand, in a multicenter study including children and adults, difference in outcomes between age groups was noted (Bowles et al., 2003). Survival rate for neonates and infants (33 and 45%, respectively) were significantly lower than the other groups. Survival rate was noted to be greatest in adolescent age group. A retrospective study involving 28 children with acute myocarditis, analysed the predictors of outcome. It was observed that ejection fraction < 30%, shortening fraction < 15%, left ventricle dilatation and moderate to severe mitral regurgitation at admission were associated with poor outcome (Kuhn et al., 2004). However, it was understood from the findings of adult trials that syncope, right ventricle dysfunction, elevated pulmonary artery pressure and advanced New York Heart Association functional class were predictors of increased probability of death or requirement for transplantation (Mendes et al, 1994, McCarthy et al., 2000, Magnani&Dec, 2006, Kindermann et al., 2008). Histological classification and severity of symptoms may also give a clue about prognosis. Giant cell myocarditis has a chance of 89% of death or transplantation. Surprisingly, acute

fulminant myocarditis may have a better prognosis (Ellis & DiSalvo, 2007).

unlikely despite judicious management.

necessity for additional investigations.

**8. Conclusion** 

In general, transplantation is needed in 1-8% of patients with acute myocarditis (Ellis & DiSalvo, 2007). In spite of severe disease at presentation, there is a probability of improvement. Patients should not be listed promptly unless recovery is believed extremely

Myocarditis in children is challenging given a variety of clinical manifestations that may share common pediatric illnesses such as respiratory infections and gastrointestinal disorders. A high index suspicion is so vital in the diagnosis. With the introduction of new additional diagnostic modalities including cardiac magnetic resonance imaging and biomarkers, cases will be identified easily in the future that would have been formerly missed. Myocarditis causes dilated cardiomyopathy in a significant portion of children. Prognosis for cases with acute viral myocarditis is much better than cases with established cases of dilated cardiomyopathy. Therefore, prompt diagnosis and early effective supportive care are crucial. Even if, much improvement has been achieved in pathogenesis, diagnosis and treatment of myocarditis, many questions remain to be answered and indicate the

**7. Outcome** 

course of the disease. Therefore, studies assessing immunomodulation and immune suppressive agents were problematic to decode into an applicable, routine treatment for children and adults with acute myocarditis. One should also consider that initiating agents for acute myocarditis and following clinical course may change from time to time and by geographic site. Although such a controversy remains to be settled, IVIG may be used only in selected pediatric patients with acute myocarditis.

#### **6.2 Antiviral treatment & vaccines**

While viral infection is the most frequent cause of myocarditis, it might be possible to think that vaccines and antiviral agents might be helpful in the treatment of myocarditis. It is obvious that studies using polymerase chain reaction identified viral genomes in patients with acute myocarditis (Bowles et al., 2003). Bu, there are a few studies which demonstrated that requirement for transplantation and mortality was not dependent on the presence of viral genome (Kindermann et al., 2008, Kuhl et al., 2005). So, many investigators suggested that the presence of viral antigens or nucleotides in the myocardium alone is not satisfactory to prove that the virus is the cause of myocarditis (Matsumori et al., 2007). Since the diagnosis of viral myocarditis is frequently challenging and the diagnostic approaches have not been established or standardised, the number of clinical trials for virus proven myocarditis is limited. For that reason, in order to investigate therapeutic and preventative methods for myocarditis, various animal models have been developed. Several promising new agents including peroxisome proliferator activated gamma receptor activator, rapamycine, pycogenol, SUNC8079 and mycophenol mofetil have been studied in murine models of myocarditis during the last decade (Komiyoshi et al., 2005, Ellis&DiSalvo, 2007, Matsumori, 2007). It has been demonstrated that these agents decrease the severity of myocarditis and improve cardiac function, blocks activation of NF-κ, blocks mRNA expression of key cytokines (IL-1, IL-6 and TNF) and stabilizes mast cell (Matsumori, 2007). Synergistic effect of IFN- α and ribavirin has been demonstrated against both EMCV and coxsackie virus infection (Okada et al., 1992, Matsumori, 2007). IFN- β has reported to be effective in studies including small number of patients with left ventricular dysfunction whose biopsy specimens were positive for adenovirus or enterovirus (Kuhl et al., 2003).

Although various strategies for the prevention of acute myocarditis have been studied in murine models, up to now, there have been no vaccination trial in humans. Vaccination against mumps, rubella, poliomyelitis, measles and influenza has made myocarditis consequent to these infections quite rare and increases the arguments on whether vaccination against other cardiotropic viruses might prevent myocarditis in the future. A classical example in this regard was supported by the study of EFE described previously (Ni et al., 1997). The mumps virus vaccine has entirely eliminated this form of dilated cardiomyopathy. It is unlikely that antiviral vaccines to battle this disease will be improved in the near future due to low incidence of the disease.

#### **6.3 Physical activity**

Recommendations concerning physical activity affirm that all patients with presumed or definite myocarditis discontinue competitive sports and undergo a prudent convalescence period around six months after the onset of clinical manifestations. Athletes may return to sports activity if LV function, dimensions and wall motions return to normal, markers of inflammation in blood have resolved, 12-lead ECG has normalized and clinically relevant arrhythmias are absent on Holter ECG or graded exercise testing (Maron et al., 2005).
