**1. Introduction**

38 Myocarditis

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unexplained ventricular arrhythmias: diagnosis with endomyocardial biopsy and

Myocarditis is the term used to describe acute or chronic inflammation of the myocardium. For two decades, there has been increasing confrontations concerning the diagnosis, management and clinical outcome of the myocarditis. The cause of myocarditis frequently remains unknown. However, infections, systemic diseases, toxins and drugs have been reported being associated with inflammation of the myocardium (Kearney et al., 2001 & Mahrholdt H et al, 2006). The majority of cases are supposed to be due to infectious agents and it was recognized that any infectious agents could initiate myocarditis (Brodison & Swann, 2001). In North America and Europe, viral infection is the most common causes of myocarditis (Magnani & Dec, 2006). The true overall incidence of myocarditis remain obscure due to inconsistency of its definition and clinical manifestation in the paediatric population. Post-mortem study from Sweden reported incidence of myocarditis to be 1.06 % in 12.747 consecutive autopsies (Gravanis & Sternby, 1991). Since the clinical presentation of myocarditis is so variable, high index of suspicion is essential. Patients are asymptomatic and diagnosis is incidental in the majority of cases. The spectrum of disease ranges from nonspecific findings (chest pain, fever, myalgia, atrial or ventricular tachycardia) to acute heart failure and sudden death. Myocarditis as a cause of sudden death has been reported in up to 12% of young adults (Doolan et al., 2004). However, population based study from Finland (Kyto et al, 2007) documented that the incidence of fatal myocarditis (1.59 per 100000) was highest in infants under one year of age and incidence was lowest in young adults (5-24 years, 0.12-0.17/100000). Recently, Weber et al have also suggested that myocarditis is an infrequent, corresponding to approximately 2% of paediatric deaths (Weber et al., 2008).

Previous researches (Felker et al, 1999 & Lipshultz et al, 2003) strongly suggested that acute myocarditis may proceed to dilated cardiomyopathy. Diagnostic evaluation of a series of 1.278 patients (mean age: 50 years, range 15-87 years) with cardiomyopathy revealed that 9.8% of cases was diagnosed with myocarditis (Felker et al, 1999). In a paediatric study assessing the incidence of cardiomyopathy, viral myocarditis was found to be responsible for 27% of cases with dilated cardiomyopathy (Lipshultz et al, 2003). Moreover, in a prospective cohort study (Towbin et al, 2006), it has been shown that most common known cause of dilated cardiomyopathy is myocarditis (46%). Several mechanisms were postulated for progression of myocarditis to dilated cardiomyopathy, including direct viral injury,

Myocarditis in Childhood: An Update on Etiology, Diagnosis and Management 41

have been investigated with the improvements in understanding pathogenesis of the myocarditis (Drucker et al, 1994 & Camargo et al 2009). It is the aim of this review to give a brief and complete discussion of pathogenesis, diagnosis and management of myocarditis.

The vast majority of myocarditis in the developed countries result from viral infections (Table 1). The causes other than infections are autoimmune-systemic diseases, toxins and hypersensitivity to drugs (Brodison & Swann, 2001). Enteroviruses (particularly Coxsackie) and adenovirus were recognized as the major cause of viral myocarditis (Baboonian& Treasure, 1997; Pauschinger et al, 1999). During the last decade, parvovirus B19 (PVB19) and human herpesvirus 6 (HHV6) have been described as new pathogens (Kuhl et al, 2003). Moreover, investigators from Germany found that PVB19 and HHV6 are the most common causes of biopsy-confirmed viral myocarditis (Kuhl et al, 2005 & Mahrholdt et al, 2006). An investigation analysing the potential role of PVB19 in the clinical setting of acute myocarditis revealed that PVB19 was the most common agent. Kuhl et al had also noticed that Dallas criteria was frequently negative in patients with positive PVB19 PCR and macrophages were augmented in virus positive cases (Kuhl et al, 2003). These findings support the postulation of Bowles et al that different viruses have various pathogenic mechanisms such as lymphocyte-dependent vs. macrophage-dependent (Bowles et al, 2005). Nevertheless, PVB19 DNA has also been revealed in the myocardium of healthy donors (Donosa et al, 2005), in hearts of adults with dilated cardiomyopathy (Lotze et al, 2004), and in hearts of the patients with lupus and amyloidosis (Kuethe et al, 2007), despite the number of subjects studies was small. From these results, the question arises whether PVB19 certainly cause the underlying heart disease or whether it is just spectator attending in the heart as a result of former infection which is usual in young adults or children. A study by Kuethe et al was conducted to investigate this question. They suggested that PVB19 displays lifelong persistence, identification of PVB19 DNA was not correlated with clinical symptoms and serological analysis should be standardized procedure for future studies considering

Polymerase chain reaction (PCR) analyses of myocardium in children and adult patients have showed the existence of adenoviral genome in cases with myocarditis and dilated cardiomyopathy with a larger frequency than enterovirus (Pauschinger et al, 1999 & Bowles et al, 2003). Geographical variation in viral etiology is also remarkable that hepatitis C virus has been more commonly documented in Japanese patients and parvovirus B19 is more frequently detected by PCR in German population (Magnani & Dec, 2006). Matsumori et al found that hepatitis C virus infection is often found in cases with dilated cardiomyopathy and that hepatitis C virus have an crucial role in the pathogenesis of cardiomyopathy (Matsumori et al, 1995). It was also suggested that antiviral therapeutics against hepatitis C virus could be indicated in these cases. Other viruses linked with myocarditis include Epstein-Barr virus, cytomegalovirus, herpes simplex virus, influenza A-B and HIV (Magnani & Dec, 2006). Multiple infections with different viruses have also been detected in cases (approximately one quarter of all cases) with systolic left ventricular dysfunction (Kuhl et al, 2005). Influenza A and B may also involve a combined myocarditis risk, particularly in patients with pre-existing cardiovascular diseases (Friman et al, 1995). From the study (Bowles et al, 2003) conducted in 624 patients with myocarditis (116 neonates, 191 infants), it was concluded that most common amplified viral genomes in myocardial tissues

**2. Etiology** 

prevalence of PVB19 (Kuethe et al, 2009).

autoimmune response of body through the effects of lymphocytes, natural killer cells, cytokines and apoptotic cell death (Kawai, 1999).

Diagnosis of acute myocarditis can be difficult owing to the lack of accepted and standardized criteria in addition to the nonspecific pattern of clinical presentation. The other issue hampered agreement on the most proper diagnostic criteria and documentation of cases, is broad diversity of aetiologies associated with myocarditis (Dec et al, 1985). At present, diagnosis has been made by use of pathological classification, commonly referred to as Dallas criteria (Aretz et al, 1987). The identification of inflammatory infiltrate with or without myocardial cell necrosis on conventionally stained myocardial tissue biopsy specimens is essential for histological diagnosis. On the basis of these criteria, myocarditis is described as active or borderline myocarditis in accordance with the presence or absence, respectively, of myocardial necrosis. The inflammatory infiltrate should be further identified as lymphocytic, eosinophilic or granulomatous (Figure 1). Sampling error, low sensitivity and specificity, discrepancy in expert interpretation remain limitations to the use of endomyocardial biopsy for diagnosis of acute myocarditis (Hauck et al, 1989 & Shanes et al, 1987). Inflammation in acute myocarditis may be focal, therefore it is challenging to biopsy the inflamed area of myocardium (Robinson et al, 2005). Additionally, it is invasive and potentially dangerous procedure, particularly in the paediatric patient (Checchia & Kulik, 2006). According to the some researchers (Parillo, 2001), this histopathological criteria could not be considered the gold standard for diagnosing acute myocarditis. Molecular pathological analyses, such as polymerase chain reaction (PCR) and in-situ hybridization allows rapid detection and documentation of the viral genetic material in the myocardium (Angelini et al, 2002 & Bock et al, 2010). In 2008, it was reported that immunohistological signs of myocarditis has been associated with poor outcome in myocarditis (Kindermann et al, 2008).

Fig. 1. The pathological diagnosis of viral myocarditis necessitates the manifestation of a inflammatory infiltrate associated with myocyte necrosis. The infiltrate consists of predominantly mononuclear cells (Stained by hematoxylin and eosin, magnification X 400; Text and image courtesy of Ragip Ortac, Gulden Diniz, Malik Ergin)

Therapy of myocarditis in children with inotropes and afterload reduction is usually sufficient. Although the long-term sequels are rare, dilated cardiomyopathy and sudden cardiac death may develop in clinical course. Extracorporeal membrane oxygenation and mechanical ventilations are other options for severe cases (Vashist & Singh, 2009). Newer therapeutic strategies such as intravenous immunoglobulin and immunosuppressive agents have been investigated with the improvements in understanding pathogenesis of the myocarditis (Drucker et al, 1994 & Camargo et al 2009). It is the aim of this review to give a brief and complete discussion of pathogenesis, diagnosis and management of myocarditis.
