Post-COVID Versus Non-COVID Myocarditis: Comparison of Morphological Activity, Toll-like Receptor Distribution and Responses to Immunosuppressive Therapy.

Background: A prior direct clinical and morphological comparison between non-coronavirus disease (COVID) myocarditis diagnosed before the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) pandemic and post-COVID myocarditis has not been performed.

Purpose: To compare morphological activity, Toll-like receptor distribution, and response to immunosuppressive therapy in patients with non-COVID and post-COVID myocarditis.

Methods: In total, 77 patients (52 male and 25 female, 48.7 ± 11.7 years old) with biopsy-proven myocarditis, New York Heart Association (NYHA) class 2 or higher heart failure diagnoses, and an ejection fraction (EF) <45% were included. The exclusion criteria comprised a history of myocardial infarction, verified cardiomyopathies, systemic autoimmune diseases, and viral DNA in the myocardium, except parvovirus B19. A right ventricular endomyocardial biopsy was performed using hematoxylin and eosin and Van Gieson staining assays, alongside the polymerase chain reaction (PCR) for viruses (herpes viruses, parvovirus B19, adeno-, enteroviruses, and SARS-CoV-2). Moreover, immunohistochemical assays were conducted for CD3, CD45, CD68, CD20, nucleocapsid/spike proteins of SARS-CoV-2, and the subcellular distribution of Toll-like receptors (TLRs) type 4 and 9 (in 38 patients). The steroids (methylprednisolone 24-40 mg per day), azathioprine, and mycophenolate mofetil were prescribed. This study was observational and non-interventional. The mean follow-up was 15.0 [6.0; 35.5] months.

Results: Myocarditis was diagnosed in 45 patients before the SARS-CoV-2 pandemic (giant cell in one case and lymphocytic in the others). Another 32 patients had post-COVID myocarditis that was positive for RNA or/and proteins of SARS-CoV-2 (giant cell in one case, eosinophilic in three cases, and lymphocytic in the others). There were no differences in age, NYHA classification, C-reactive protein (CRP) and anti-heart antibodies levels, echocardiographic parameters (mean EF: 30.2 ± 7.8 vs. 28.7 ± 6.7%), parvovirus B19 positivity (22 vs. 34%), methylprednisolone dosages (24-40 mg/day), and death/transplantation rate (11.1 vs. 9.4%). Differences between non-COVID and post-COVID myocarditis focused on higher CD3, CD 45*, and toll-like receptors (TLR)-4 (4+ vs. 6+) and TLR-9 (0 vs. 2+) levels, alongside subcellular distribution and a better response to therapy ((10% or more increase in EF in 53 vs. 86%* of patients, mean EF (43.9 ± 12.3 vs. 49.8 ± 7.6%*) by the end of follow-up); *p < 0.05).

Conclusion: Post-COVID myocarditis is characterized by different morphological types, higher morphological activity, the tendency to increase TLR expression, and an improved response to immunosuppressive therapy compared to non-COVID myocarditis.