Virus serology in patients with suspected myocarditis: utility or futility?

Inflammatory heart diseases can be classified according to clinical, clinicopathological and immunohistological criteria. In North America and Europe myocarditis is most often caused by viral infections. The clinical presentation and course of myocarditis may be quite variable. The diagnosis of myocarditis is based on histopathological and immunohistochemical findings of endomyocardial biopsies (EMBs). The detection and quantification of the viral genome in the heart can be performed by using molecular pathological techniques such as PCR or in situ hybridization. The immunohistochemically detected inflammation has been reported to associate with poor outcome. Viral infections have also been estimated to trigger 35-50% of inflammatory dilated cardiomyopathy (DCMi) and early diagnosis and treatment of viral myocarditis aims to prevent it. However, the availability of EMB and molecular pathological analyses is limited and in clinical practice virus serology is still used for the diagnosis of myocarditis, although not recommended  in international guidelines. The authors determined prospectively the diagnostic value of virus serology as compared to EMB and viral genome detection and immunohistochemistry in patients with clinically suspected myocarditis.

The patient group comprised 124 patients (age 40 + 15 years) with clinically suspected myocarditis.
Patients were included if they had a febrile infection of the bronchial tree, the gut, or the urinary tract within the last 6 months and at least one of the following: impaired global or regional left ventricular systolic function, increased serum concentrations of myocardial necrosis markers, pericardial effusion of unclear reason, VT or NS-VT, or VF of unknown origin. Subjects with familial cardiomyopathy were excluded. Samples for virus serology were collected before EMBs and in 30 patients second samples were drawn 7-28 days after the initial sample. Acute viral infection with enterovirus, adenovirus, parvovirus B19, cytomegalovirus, human herpesvirus, and Epstein-Barr virus was diagnosed by demonstrating IgM or IgA in the initial samples or IgG seroconversion during the follow-up. Before EMB each individual underwent left heart catheterization with coronary angiography. Cardiac MRI and echocardiography were performed before EMB to choose the optimal biopsy site. Histopathological and immunohistochemical analyzed were carried out in paraffin –embedded tissue sections. Molecular detection of viral genomes in the tissue was performed using PCR-based techniques. A biopsy was considered positive for viral infection if the viral genome could be demonstrated by PCR and specificity was confirmed by DNA sequencing of viral amplification products.

The authors report viral genome in the myocardium of 58 patients (47%) while acute viral infection was diagnosed in 20 patients (16%) by serology. Moreover, only in 5 out of 124 individuals (4%) serology was compatible with the same virus which was found by EMB. Sensitivity and specificity of virus serology were 9 and 77%, the positive predictive value 25% and the negative predictive value 49%. The authors point out that determination of viral antibody titers with follow-up samples is time-consuming and expensive. Often there is a considerable delay between the onset of the infection and clinical myocarditis, which diminishes the possibilities of using serology. The time when various antibodies appear, is also variable. Most viruses involved in the pathogenesis of myocarditis are also prevalent in the population and these facts complicate the interpretation of serological results. On the other hand, the disadvantages of using EMB include lack of specificity, risk of complications and the possibility of sampling errors. The authors emphasize that EMB still may provide important prognostic information since immunohistochemical signs of inflammation relate to poor outcome. They conclude that serological examinations should no longer be used as standard tool when myocarditis is suspected whereas EMB would offer the possiblity for exact diagnosis.

Comments

With a wide range of symptoms from mild chest pain to severe arrhythmias or sudden cardiac death, myocarditis presents a clinical challenge. Myocarditis may also lead to inflammatory DCM and heart failure. Viral infections are important causes of myocarditis but in clinical practice the ethiology of myocarditis quite often remains unclear. Recently, the use of viral genomic analyses in endomyocardial biopsies has been assessed for diagnostic purposes. Although the methods are highly sensitive for detection of viral pathogenes in EMBs, the number of specialized centers with extensive experience is limited. The role of antiviral or immunosuppressive treatment will probably be clarified in the future. According to current guidelines endomyocardial biopsy should be performed usually at least in patients with new-onset heart failure < 2 weeks’ duration associated with a normal sized or dilated left ventricle in addition to hemodynamic compromise or in the setting of unexplained new-onset heart failure of 2 weeks’ to 3 months’ duration associated with a dilated left ventricle and new ventricular arrhythmias, Mobitz type II second- or third-degree atrioventricular (AV) heart block, or failure to respond to usual care within 1 to 2 weeks.