Viral Genome Search in Myocardium of Patients with Fulminant Myocarditis

Fulminant myocarditis (FM) is a form of acute myocardial inflammation leading to acute-onset clinical presentation requiring inotropic and, in severe cases, mechanical circulatory support.1 As highlighted by recent registries, FM is associated with high rates of death and heart transplant.2, 3 Endomyocardial biopsy (EMB) is the gold standard for the diagnosis of acute myocarditis and allows histologic characterization.1, 4 The role of viruses in myocarditis aetiology has been historically recognized, with parvovirus (PV) B19, adenoviruses, human herpes virus type 6 (HHV6) and enteroviruses being the most common agents identified in myocardium.4-6 A growing body of literature indicates that viruses, particularly PVB19, may be found in a large proportion of patients who do not have myocarditis, and additional studies are needed to determine their causal role.7 It has been stated that the presence of specific viruses in the heart may contraindicate the use of immunosuppression, particularly in lymphocytic forms, where its role is mostly controversial.1 On the other hand, immunosuppressive therapy, even though not standardized, is the cornerstone of treatment for eosinophilic and giant-cell myocarditis, cardiac sarcoidosis, and, regardless of the underlying histology, for myocarditis related to systemic autoimmune diseases and immune checkpoint inhibitor therapy.4 Although the latest scientific statement of the European Society of Cardiology recommends that immunosuppression should be started only after ruling out active infection on EMB by polymerase chain reaction (PCR),4 the need to search for viral genome by PCR in the setting of FM patients is debatable and its real clinical value remains unclear. In addition, the relative frequency with which viral genome PCR on EMB is being performed in FM has not been reported previously. We thus aimed to characterize the extent of use of PCR-based viral genome search in a large cohort of histologically proven FM patients, mostly focusing on lymphocytic FM. Data were derived from a retrospective, international, multicentre cohort study. A detailed description of the organization of the international registry on acute myocarditis has been published elsewhere.2 In brief, data were collected from patients seen at 16 tertiary hospitals 13 (81.3%) with heart transplant programmes across the United States (n = 3), Europe (n = 9), and Japan (n = 4) with histologically proven acute myocarditis (onset of symptoms <30 days), all presenting with left ventricular systolic dysfunction (data collection period from January 2001 to March 2018). Data on nested PCR performed in myocardial tissue for the detection of cardiotropic viruses, including enteroviruses, PVB19, adenoviruses, cytomegalovirus, Epstein–Barr virus, and HHV6, were collected. The study population included 220 patients (FM 165, non-FM 55), of whom 141 were from Europe (64%), 35 from the United States (16%), and 44 from Japan (20%). Among patients with FM, lymphocytic myocarditis was diagnosed in 120, giant-cell myocarditis in 24, eosinophilic myocarditis in 19, and cardiac sarcoidosis in 2. Myocardium PCR-based viral search was performed in 33 FM patients (20%). The use of PCR-based viral genome detection was higher in Europe (34%), compared to United States (17%) and Japan (3%). Viral search was performed in 6/45 non-lymphocytic FM patients (13%), yielding positive results in one patient (17%) with Epstein–Barr virus and eosinophilic FM. Among patients with lymphocytic FM, 27 (22%) had a PCR-based viral genome search performed, yielding positive results in five patients (18%), with PVB19 identified in all positive cases. Three cases had low viral titres of myocardial PVB19 genome equivalents per microgram of isolated nucleic acids, one case had high titre and in one case titre was not reported; two cases were treated with intravenous immunoglobulin. When comparing lymphocytic FM patients with and without a myocardium PCR-based viral search performed (Table 1), there were no statistically significant differences in demographics, early management, including prevalence of use of immunosuppressive therapy, and 1-year outcome. Viral genome search was performed in 22% of lymphocytic FM patients, with PVB19 being the only detected virus in all five positive cases. This is consistent with previous findings from cohorts of myocarditis patients, although not specifically addressing FM, where PVB19 was the most frequently identified virus.5 Of note, recent evidence suggests that immunosuppression does not seem to aggravate PVB19 replication in myocardium of patients with inflammatory cardiomyopathy and PVB19 persistence.8 Available literature on the role of myocarditis management based on viral genome identification has been mostly derived from small studies in patients affected by chronic myocarditis or inflammatory dilated cardiomyopathy and the results obtained have been inconsistent. Our survey is limited by its retrospective nature, a relatively small sample size, the lack of systematic viral genome search in the whole cohort, and the presence of heterogeneity in the techniques used for viral search analysis, based on local standards. Notwithstanding this, it provides unique information about the frequency of use of PCR-based viral genome identification in myocardium of FM patients. Whether a routine viral genome search in myocardial tissue, a time-consuming procedure, improves patient management guiding immunosuppression therapy in patients with FM remains to be proven. In acute myocarditis, especially in FM, where early immunosuppression may be crucial, initiation of immunosuppressive treatment (e.g. pulse steroid therapy) before obtaining PCR results might represent a reasonable approach. Decisions on cessation or implementation of a tailored immunosuppression may be procrastinated after final histopathological characterization and eventual virus detection. Large prospective studies are warranted to address the role of viral genome identification in acute and fulminant myocarditis. Conflict of interest: none declared.