Phenotypic Heterogeneity of Fulminant COVID-19--Related Myocarditis in Adults

J Am Coll Cardiol. 2022 Jul 26;80(4):299-312. doi: 10.1016/j.jacc.2022.04.056.


Background: Adults who have been infected with SARS-CoV-2 can develop a multisystem inflammatory syndrome (MIS-A), including fulminant myocarditis. Yet, several patients fail to meet MIS-A criteria, suggesting the existence of distinct phenotypes in fulminant COVID-19-related myocarditis.

Objectives: This study sought to compare the characteristics and clinical outcome between patients with fulminant COVID-19-related myocarditis fulfilling MIS-A criteria (MIS-A+) or not (MIS-A-).

Methods: A monocentric retrospective analysis of consecutive fulminant COVID-19-related myocarditis in a 26-bed intensive care unit (ICU).

Results: Between March 2020 and June 2021, 38 patients required ICU admission (male 66%; mean age 32 ± 15 years) for suspected fulminant COVID-19-related myocarditis. In-ICU treatment for organ failure included dobutamine 79%, norepinephrine 60%, mechanical ventilation 50%, venoarterial extracorporeal membrane oxygenation 42%, and renal replacement therapy 29%. In-hospital mortality was 13%. Twenty-five patients (66%) met the MIS-A criteria. MIS-A- patients compared with MIS-A+ patients were characterized by a shorter delay between COVID-19 symptoms onset and myocarditis, a lower left ventricular ejection fraction, and a higher rate of in-ICU organ failure, and were more likely to require mechanical circulatory support with venoarterial extracorporeal membrane oxygenation (92% vs 16%; P < 0.0001). In-hospital mortality was higher in MIS-A- patients (31% vs 4%). MIS-A+ had higher circulating levels of interleukin (IL)-22, IL-17, and tumor necrosis factor-α (TNF-α), whereas MIS-A- had higher interferon-α2 (IFN-α2) and IL-8 levels. RNA polymerase III autoantibodies were present in 7 of 13 MIS-A- patients (54%) but in none of the MIS-A+ patients.

Conclusion: MIS-A+ and MIS-A- fulminant COVID-19-related myocarditis patients have 2 distinct phenotypes with different clinical presentations, prognosis, and immunological profiles. Differentiating these 2 phenotypes is relevant for patients' management and further understanding of their pathophysiology.

Keywords: COVID-19; RNA polymerase III autoantibodies; SARS-CoV-2; VA-ECMO; cytokines; fulminant myocarditis; multisystem inflammatory syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autoantibodies
  • COVID-19* / complications
  • Female
  • Humans
  • Male
  • Middle Aged
  • Myocarditis* / diagnosis
  • Myocarditis* / etiology
  • Myocarditis* / therapy
  • Phenotype
  • Retrospective Studies
  • SARS-CoV-2
  • Stroke Volume
  • Systemic Inflammatory Response Syndrome
  • Ventricular Function, Left
  • Young Adult


  • Autoantibodies
  • anti-RNA-polymerase III autoantibody

Supplementary concepts

  • adult multisystem inflammatory disease, COVID-19 related