Two reports in the current issue of JAMA Cardiology describe cases of acute myocarditis that occurred among persons who received the BNT162b2-mRNA (Pfizer-BioNTech) or mRNA-1273 (Moderna) messenger RNA (mRNA)–based COVID-19 vaccines authorized for use in the US.1,2 During the clinical evaluations of these patients, alternative etiologies for myocarditis were not detected.
The first report describes 4 cases of myocarditis with symptom onset 1 to 5 days after receipt of a second dose of mRNA-based COVID-19 vaccine (2 receiving the BNT162b2-mRNA vaccine and 2 receiving the mRNA-1273 vaccine) who were evaluated in a single tertiary care medical center (Duke University Medical Center) that attempted to define its catchment population.1 Three cases occurred in men aged 23 to 36 years and the fourth in a 70-year-old woman; details about the medical history of the fourth patient were not provided, but she received coronary angiography during her evaluation and no atherosclerosis was found. All presented with severe acute chest pain, had abnormal electrocardiogram results, and had evidence of myocardial injury demonstrated by elevated troponin levels. Cardiac magnetic resonance imaging was performed in these 4 patients on days 3 through 5 after vaccine receipt, and the findings were consistent with acute myocarditis as defined by recent expert consensus guidelines.3
The second, larger case report comes from the US Military Health System and describes 23 individuals with acute myocarditis who presented within 4 days after mRNA-based COVID-19 vaccination.2 All patients were male, 22 of 23 were on active duty, and the median (range) age was 25 (20-51) years; 20 cases occurred after receipt of a second dose of an mRNA-based COVID-19 vaccine. Clinical presentations and laboratory findings were similar to those described in the smaller case series1; 8 of 23 patients in this series received cardiac magnetic resonance imaging, and all 8 demonstrated findings again consistent with acute myocarditis.2
A separate case report published by Marshall et al4 provides additional context in a younger population. They report 7 US male adolescents aged 14 to 19 years who presented with myocarditis or myopericarditis within 4 days after receipt of a second dose of the BNT162b2-mRNA COVID-19 vaccine.4 These adolescents were found to have elevated troponin levels, abnormal electrocardiogram results, and findings on cardiac magnetic resonance imaging consistent with acute myocarditis.
Although the extent of the search for alternative etiologies for acute myocarditis varied for each patient in these 3 reports,1,2,4 no evidence of common causes of acute myocardial injury in healthy persons was found, and findings of tests for enterovirus and adenovirus infection were negative. The striking clinical similarities in the presentations of these patients, their recent vaccination with an mRNA-based COVID-19 vaccine, and the lack of any alternative etiologies for acute myocarditis suggest an association with immunization. Myocarditis or pericarditis were not detected in the clinical trials for these vaccines; however, it is possible that any association is too rare for recognition in a clinical trial enrolling less than several hundred thousand participants. The patients described in these US-based case series had resolution of symptoms or are recovering after receipt of brief supportive care and continue to be monitored during recovery from the acute illness.
What do we know about this possible association between myocarditis and immunization with mRNA-based COVID-19 vaccines, and what remains unclear? Acute onset of chest pain 3 to 5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism.5 Myocarditis following receipt of other vaccines is rare and is recognized as causally linked only with smallpox immunization.6 For example, myopericarditis has been reported in healthy adults after receipt of replication-competent live vaccinia virus vaccines.7 These highly reactogenic smallpox vaccines differ dramatically by composition and by immunologic responses compared with the mRNA-based lipid nanoparticle vaccines currently in use for prevention of COVID-19. We do not know the specific mechanisms by which immunologic responses to mRNA-based COVID-19 vaccines could lead to myocarditis. Further investigation is critical and should be informed by the fact that most cases occurred following the second dose of a 2-dose series, some in patients with a history of prior COVID-19 infection. We know that infection with SARS-CoV-2 can result in acute cardiac compromise in substantial proportions of hospitalized patients and that it might lead to cardiac magnetic imaging findings suggestive of myocarditis in competitive college athletes with evidence of COVID-19, although the mechanisms that could lead to either direct SARS-CoV-2 viral injury or immunopathologic injury of myocardial tissues are unclear and under active investigation.8
None of the US case series reports are population based,1,2,4 and therefore, estimating rates of myocarditis following COVID-19 vaccination is problematic. However, based on data available to date, we can say that myocarditis occurring after COVID-19 immunization is rare. Kim et al1 estimated that more than 560 000 persons in the 6 counties surrounding their tertiary care institution had received 2 doses of an mRNA-based COVID-19 vaccine by April 30, 2021; they detected 4 myocarditis cases by that date.1 The Military Health System administered more than 2.8 million doses of mRNA-based vaccines through April 30, 2021, and detected 23 myocarditis cases.2 Based on the military’s extensive experience with vaccinia-associated myocarditis,9 it is possible that the military system may be more likely to detect mild myocarditis cases than most civilian medical centers. Among the 436 000 male active-duty military who have received 2 mRNA vaccine doses, Montgomery et al2 estimated that 0 to 8 cases of myocarditis might be expected based on US data on the background incidence rate of myocarditis, whereas they detected 19 myocarditis cases in that group.2 The most comprehensive data about the risk of myocarditis following immunization with mRNA vaccines comes from Israel. The Israeli Ministry of Health recently posted data describing 121 myocarditis cases occurring within 30 days of a second dose of mRNA vaccine among 5 049 424 persons, suggesting a crude incidence rate of approximately 24 cases per million following a second dose in this subset of their vaccinated population.10
While more definitive data on the incidence of myocarditis following immunization with mRNA COVID-19 vaccines and associated risk will eventually be provided by large population-based vaccine adverse event monitoring systems, including the US Centers for Disease Control and Prevention Vaccine Safety Datalink,11 several interim conclusions can be offered. Cardiac injury after SARS-CoV-2 infection occurs and may result in severe outcomes.8 Based on currently available data, myocarditis following immunization with current mRNA-based vaccines is rare. All possible myocarditis cases should be reported to the US Vaccine Adverse Events Reporting System to help better define the characteristics of this syndrome and its relationship to receipt of mRNA-based COVID-19 vaccines authorized for use in the US. At present, the benefits of immunization in preventing severe morbidity favors continued COVID-19 vaccination, particularly considering the increasing COVID-19 hospitalization rates among adolescents reported during spring 2021.12 Many questions remain. What modifications to the vaccine schedule, if any, should be considered among persons with a history of possible or confirmed myocarditis after a first dose of COVID-19 vaccine? How should postvaccine myocarditis be managed, particularly given the apparently benign outcomes described thus far and the success of supportive or conservative management alone? How often should follow-up assessments, including repeated cardiac imaging, be performed in these patients, and how might follow-up assessments affect recommendations to avoid vigorous physical activity following the diagnosis of myocarditis? Do all likely cases of acute myocarditis that appear to be uncomplicated require cardiac magnetic resonance imaging for more definitive diagnosis? While the data needed to answer such questions are being collected, there is an opportunity for researchers with expertise in myocarditis to develop a comprehensive, national assessment of the natural history, pathogenesis, and treatment of acute myocarditis associated with receipt of mRNA-based COVID-19 vaccines.
Finally, the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices held a public meeting from June 23 to 25, 2021. On June 23, the committee heard presentations about the epidemiology of myocarditis and pericarditis, an update on COVID-19 vaccine safety, including myocarditis following receipt of mRNA-based COVID-19 vaccines, and a benefit-risk assessment of COVID-19 mRNA vaccination programs in adolescents and young adults. Advisory Committee on Immunization Practices discussions and recommendations are summarized on the Centers for Disease Control and Prevention website.13
Corresponding Author: David K. Shay, MD, MPH, CDC COVID-19 Response Team, US Centers for Disease Control and Prevention, 1600 Clifton Rd NE, MS A-20, Atlanta, GA 30329 (email@example.com).
Published Online: June 29, 2021. doi:10.1001/jamacardio.2021.2821
Conflict of Interest Disclosures: None reported.
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention (CDC). Mention of a product or company name is for identification purposes only and does not constitute endorsement by the CDC.
Additional Contributions: We thank C. Buddy Creech, MD (Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University, School of Medicine, Nashville, Tennessee), and Matthew E. Oster, MD (National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia). Neither were compensated for their reviews.
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