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Two COVID-19--Related Myocarditis Phenotypes Emerge: What Is the Impact?

  • Authors: News Author: Megan Brooks; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 9/2/2022
  • Valid for credit through: 9/2/2023, 11:59 PM EST
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This activity is intended for primary care providers, cardiologists, intensive care specialists, infectious disease specialists, nurses, pharmacists, physician assistants, and other members of the healthcare team who care for patients with complications of COVID-19.

The goal of this activity is for learners to be better able to distinguish phenotypes of fulminant myocarditis among patients with COVID-19.

Upon completion of this activity, participants will:

  • Assess characteristics of patients with acute myocarditis due to COVID-19
  • Distinguish phenotypes of fulminant myocarditis related to COVID-19
  • Outline implications for the healthcare team


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News Author

  • Megan Brooks

    Freelance writer, Medscape


    Megan Brooks has no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine


    Charles P. Vega, MD, has the following relevant financial relationships:
    Consultant or advisor for: GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

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  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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  • Yaisanet Oyola, MD

    Associate Director, Accreditation and Compliance, Medscape, LLC


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Two COVID-19--Related Myocarditis Phenotypes Emerge: What Is the Impact?

Authors: News Author: Megan Brooks; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 9/2/2022

Valid for credit through: 9/2/2023, 11:59 PM EST


Note: The information on the coronavirus outbreak is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available. It is the policy of Medscape Education to avoid the mention of brand names or specific manufacturers in accredited educational activities. However, manufacturer names related to the approved COVID-19 vaccines are provided in this activity in an effort to promote clarity. The use of manufacturer names should not be viewed as an endorsement by Medscape of any specific product or manufacturer.

Clinical Context

Fulminant myocarditis is one of the most serious complications of COVID-19, and the authors of the current study reinforced that there are some typical characteristics among patients with acute myocarditis due to COVID-19. These characteristics were reinforced in their study of 38 patients with acute myocarditis due to COVID-19. About two-thirds (66%) of patients were men, and the median age of patients was young (27.5 years). Generally, patients were healthy before acquiring COVID-19, but none had been vaccinated.

The median delay between the onset of COVID-19 symptoms and the first symptoms of myocarditis was 5 days. Nearly all (95%) of the cohort experienced fever, and 47% had chest pain; 42% of patients had dyspnea. Serology for antibodies against SARS-CoV-2 was positive in 68% of patients.

There appear to be 2 phenotypes of acute myocarditis related to COVID-19, principally defined by the presence or absence of multisystem inflammatory syndrome (MIS-A). The current study by Barhoum and colleagues focuses on differences between patients with acute myocarditis related to COVID-19 with and without MIS-A.

Study Synopsis and Perspective

Researchers from France have identified 2 distinct phenotypes of fulminant COVID-19--related myocarditis in adults, with different clinical presentations, immunologic profiles, and outcomes.

Differentiation between the two bioclinical entities is important to understand for patient management and further pathophysiologic studies, they said.

The first phenotype occurs early (within a few days) in acute SARS-CoV-2 infection, with active viral replication (polymerase chain reaction [PCR]-positive) in adults who meet criteria for multisystem inflammatory syndrome (MIS-A--positive).

In this early phenotype, there is "limited systemic inflammation without skin and mucosal involvement, but myocardial dysfunction is fulminant and frequently associated with large pericardial effusions. These cases more often require extracorporeal membrane oxygenation [ECMO]," Guy Gorochov, MD, PhD, Sorbonne University, Paris, told | Medscape Cardiology.

The second is a delayed, postinfectious, immune-driven phenotype that occurs in adults who fail to meet the criteria for MIS-A (MIS-A--negative).

This phenotype occurs weeks after SARS-CoV-2 infection, usually beyond detectable active viral replication (PCR-negative) in the context of specific immune response and severe systemic inflammation with skin and mucosal involvement. Myocardial dysfunction is more progressive and rarely associated with large pericardial effusions, Gorochov explained.

The study was published in the July 26 issue of the Journal of the American College of Cardiology.[1]

Evolving Understanding

The findings are based on a retrospective analysis of 38 patients without a history of COVID-19 vaccination who were admitted to the intensive care unit (ICU) from March 2020 to June 2021 for suspected fulminant COVID-19 myocarditis.

Patients were confirmed to have SARS-CoV-2 infection by PCR and/or by serologic testing. As noted in other studies, the patients were predominantly young men (66%; median age, 27.5 years). Twenty-five (66%) patients were MIS-A--positive, and 13 (34%) were MIS-A--negative.

In general, the patients who tested negative for MIS-A were sicker and had worse outcomes.

Specifically, compared with the patients who tested positive for MIS-A, patients who tested negative for MIS-A had a shorter time between the onset of COVID-19 symptoms and the development of myocarditis, a shorter time to ICU admission, and more severe presentations assessed using lower left ventricular ejection fraction (LVEF) and sequential organ failure assessment (SOFA) scores.

Patients who tested negative for MIS-A also had higher lactate levels, were more likely to need venoarterial extracorporeal membrane oxygenation (VA-ECMO) (92% vs 16%), had higher ICU mortality (31% vs 4%), and a had lower probability of survival at 3 months (68% vs 96%) compared with their peers who were MIS-A-positive.

Immunologic Differences

The immunologic profiles of these two distinct clinical phenotypes also differed.

In MIS-A--negative early-type COVID-19 myocarditis, RNA polymerase III autoantibodies are frequently positive, and serum levels of antiviral interferon-alfa and granulocyte-attracting interleukin-(IL)-8 are elevated.

In contrast, in MIS-A--positive delayed-type COVID-19 myocarditis, RNA polymerase III autoantibodies are negative, and serum levels of IL-17 and IL-22 are highly elevated.

"We suggest that IL-17 and IL-22 are novel criteria that should help to assess in adults the recently recognized MIS-A," Gorochov told | Medscape Cardiology.

"It should be tested whether IL-17 and IL-22 are also elevated in children with MIS-C," he added.

The researchers also observed "extremely" high serum IL-10 levels in both patient groups. This has been previously associated with severe myocardial injury and an increase in the risk for death in patients with severe COVID-19.

The researchers said the phenotypic clustering of patients with fulminant COVID-19--related myocarditis "seems relevant" for their management.

MIS-A--negative cases, owing to the high risk for evolution toward refractory cardiogenic shock, should be "urgently" referred to a center with VA-ECMO and closely monitored to prevent a "too-late" cannulation, especially under cardiopulmonary resuscitation, known to be associated with poor outcomes, they advised.

They noted that the 5 patients who died in their series had late VA-ECMO implantation while undergoing multiple organ failures or resuscitation.

Conversely, they said, the risk for evolution to refractory cardiogenic shock is lower in MIS-A--positive cases; however, identifying MIS-A--positive cases is "all the more important given that numerous data support the efficacy of corticosteroids and/or intravenous immunoglobulins in MIS-C," Gorochov and colleagues wrote.

In a linked editorial[2], Ajith Nair, MD, Baylor College of Medicine, and Anita Deswal, MD, MPH, The University of Texas MD Anderson Cancer Center, both in Houston, Texas, noted that fulminant myocarditis is rare and can result from either of two mechanisms: viral tropism or an immune-mediated mechanism.

"It remains to be seen whether using antiviral therapy vs immunomodulatory therapy on the basis of clinical and cytokine profiles will yield benefits," they wrote.

"Fulminant myocarditis invariably requires hemodynamic support and carries a high mortality risk if it is recognized late; however, the long-term prognosis in patients who survive the critical period is favorable, with recovery of myocardial function," they added.

"This study highlights the ever-shifting understanding of the pathophysiology and therapeutic approaches to fulminant myocarditis," Nair and Deswal concluded.

This research was supported in part by the Foundation of France, French National Research Agency, Sorbonne University, and Clinical Research Hospital. The researchers have filed a patent application based on these results. Nair and Deswal have no relevant disclosures.

Study Highlights

  • Researchers performed a retrospective case analysis from one tertiary ICU in France. They focused on patients admitted with a proven infection with SARS-CoV-2 between March 2020 and June 2021 who also had fulminant acute myocarditis.
  • Data collected included demographic and medical information, and the key variable in the study was the presence of MIS-A.
  • Researchers compared levels of inflammatory cytokines based on the presence of MIS-A, and they also evaluated levels of anti-interferon alfa and RNA polymerase III autoantibodies.
  • 38 patients comprised the study cohort. Median LVEF at admission was 20% (interquartile range [IQR], 20%-45%), and the median high-sensitivity T-troponin level was 1300 [IQR, 486, 4750] ng/mL. 79% of patients presented in cardiogenic shock.
  • 10 patients underwent coronary angiography, which was normal in all cases.
  • The median length of stay in the ICU was 6 days. Half of patients received mechanical ventilation, and 29% had renal replacement.
  • 74% of patients received glucocorticoids and immunoglobulins.
  • The in-hospital mortality rate was 13%. At a median of 235 [IQR, 155-359] days after admission, 32 patients were alive, and all save 1 had a normal LVEF.
  • 66% of patients met criteria for MIS-A. Patients without MIS-A had a shorter duration of COVID-19 before myocarditis (median delay of 3 vs 8 days), and they were more quickly admitted to the ICU.
  • 15% of patients without MIS-A had positive serology for SARS-CoV-2 compared with 96% of patients with MIS-A.
  • Rates of VA-ECOM were 92% and 16% in the MIS-A--negative and MIS-A--positive groups, respectively. The respective ICU mortality rates were 31% and 4%.
  • The presence of MIS-A was associated with higher levels of IL-22, IL-17, and tumor necrosis factor-α. Conversely, the absence of MIS-A was marked by higher levels of interferon alfa-2 and IL-8.

Clinical Implications

  • Patients with acute myocarditis due to COVID-19 tend to be male, younger, and generally healthy before infection. In the current study by Barhoum and colleagues, no patients with acute myocarditis were vaccinated against COVID-19, and the median delay between COVID-19 general symptom onset and myocarditis symptoms specifically was 5 days.
  • The absence of MIS-A was associated with a faster onset of fulminant myocarditis in the current study, with negative serology for SARS-CoV-2. The absence of MIS-A was associated with higher rates of VA-ECMO and ICU mortality.
  • Implications for the healthcare team: Members of the team should be prepared to provide critical-level care for patients with AM related to COVID-19 who do not meet criteria for MIS-A, as these patients were found to be sicker with worse outcomes.


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