Fulminant myocarditis before and after the COVID-19 pandemic: a comparative analysis of clinical phenotypes, histological findings, and outcomes in a contemporary cohort

Background The etiopathogenetic role of SARS-CoV-2 in fulminant myocarditis (FM) remains undefined. Furthermore, the concordance between nasopharyngeal SARS-CoV-2 detection and molecular analysis of endomyocardial biopsy (EMB) has not been systematically investigated. Purpose (1) To compare clinical features, diagnostic findings, and outcomes of FM cases before and after the COVID-19 pandemic; (2) to assess concordance between SARS-CoV-2 detection by serological or molecular testing on nasopharyngeal swabs and viral polymerase chain reaction (PCR) on EMB specimens. Methods We retrospectively analyzed consecutive FM patients hospitalized at a tertiary referral center between 2001 and November 2025. The cohort was stratified into two groups based on the COVID-19 pandemic onset (pre-COVID period: diagnosed before March 2020; post-COVID period: after March 2020). The primary composite outcome included death, heart transplantation (HTx), or myocarditis relapse. Survival-free outcome was estimated using Kaplan-Meier curves. Results Forty-nine FM patients were included (median age 39 years [31–47]; 57% male); 20 (41%) were diagnosed in the post-COVID period. Clinical presentation and diagnostic characteristics were comparable between cohorts. Arrhythmic presentation prevailed (53%), with ventricular fibrillation and ventricular tachycardia occurring in 34% and 20% of patients, respectively. Median left ventricular ejection fraction (LVEF) was 40% [29–47]. Elevated troponin (90%) and C-reactive protein (77%) were common. EMB (performed in 84%) revealed lymphocytic myocarditis (n=32), followed by giant-cell (n=5) and eosinophilic (n=1) forms, without inter-period differences. Viral genomes were detected in 27% of EMBs (mainly Parvovirus B19); SARS-CoV-2 was not identified in any EMB specimen. PCR for SARS-CoV-2 was negative even in two patients with concurrent SARS-CoV-2 infection during index hospitalization. No post-vaccination myocarditis occurred among 13 vaccinated patients. Overall, 27% of patients (n=13) received immunosuppressive therapy, all with EMB-proven virus-negative myocarditis. Over a median follow-up of 34 months, 11 deaths were recorded, including 6 during index hospitalization; 2 patients underwent Htx, and 9 experienced disease relapse. Survival analysis showed no significant differences in time to primary composite outcome between pre- and post-pandemic cohorts over the first 2 years following diagnosis (log-rank p=0.15). Multivariable analysis confirmed that baseline LVEF (OR 0.94 for each 1% increase; 95% CI 0.88–0.99; p=0.04), but not diagnosis within the pandemic period, was the main driver of adverse outcomes. Conclusions FM patients showed similar clinical presentation, histopathology, and outcomes before and after the COVID-19 pandemic. The absence of SARS-CoV-2 detection on EMB despite positive nasopharyngeal testing argues against a direct causative role of SARS-CoV-2 in FM within this cohort.