Viral infections are a common cause of myocarditis, an inflammation of the heart muscle (myocardium) that can result in hospitalization, heart failure, and sudden death ( 1 ). Emerging data suggest an association between COVID-19 and myocarditis ( 2 – 5 ). CDC assessed this association using a large, U.S. hospital-based administrative database of health care encounters from >900 hospitals. Myocarditis inpatient encounters were 42.3% higher in 2020 than in 2019. During March 2020–January 2021, the period that coincided with the COVID-19 pandemic, the risk for myocarditis was 0.146% among patients diagnosed with COVID-19 during an inpatient or hospital-based outpatient encounter and 0.009% among patients who were not diagnosed with COVID-19. After adjusting for patient and hospital characteristics, patients with COVID-19 during March 2020–January 2021 had, on average, 15.7 times the risk for myocarditis compared with those without COVID-19 (95% confidence interval [CI] = 14.1–17.2); by age, risk ratios ranged from approximately 7.0 for patients aged 16–39 years to >30.0 for patients aged 30.0 for patients aged <16 years and ≥75 years. FIGURE 2 Adjusted risk ratio (A) and adjusted risk difference (B) of myocarditis comparing patients with and without COVID-19,* overall and by sex and age group — Premier Healthcare Database Special COVID-19 Release, United States, March 2020–January 2021 * The panels show adjusted risk ratios (A) and adjusted risk differences (B) of myocarditis comparing patients with COVID-19 to patients without COVID-19 (reference), obtained from a single logit model with the following covariates: a three-way interaction between presence of COVID-19, sex, and age group, including lower-order interactions and main effects; race/ethnicity; payer type; hospital U.S. Census region; and hospital urbanicity. 95% confidence intervals indicated by error bars. The figure is a forest plot showing the adjusted risk ratio (A) and adjusted risk difference (B) of myocarditis comparing patients with and without COVID-19, overall and by sex and age group, using data from the Premier Healthcare Database Special COVID-19 Release, in the United States, during March 2020–January 2021. Discussion In this study, the occurrence of myocarditis inpatient encounters was 42% higher in 2020 than in 2019. The risk for myocarditis among patients with COVID-19 during March 2020–January 2021 was nearly 16 times as high as the risk among patients without COVID-19, with the association between COVID-19 and myocarditis being most pronounced among children and older adults. Further, in this cohort, approximately 40% of patients with myocarditis had a history of COVID-19. These findings suggest an association between COVID-19 and myocarditis, although causality cannot be inferred from observational data, and are consistent with those from previous studies ( 2 – 5 ). Before this report, the two largest known studies, in the United States and in Israel, also found that COVID-19 was strongly associated with myocarditis (U.S. study: odds ratio = 8.17, 95% CI = 3.58–18.62; Israel study: risk ratio = 18.28, 95% CI = 3.95–25.12) ( 3 , 4 ). In this study, the association between COVID-19 and myocarditis was lowest for persons aged 25–39 years and higher among younger (<16 years) and older (≥50 years) age groups, a pattern that has not been previously described in age-stratified analyses and that warrants further investigation. This finding might be partially explained by age-related differences in COVID-19 case ascertainment, because younger adults with less severe disease might be less likely than older adults to have a health care encounter with a COVID-19 diagnosis captured within PHD-SR. This age-related differential misclassification (underascertainment) of COVID-19 status might bias risk differences and risk ratios toward the null more for younger adults and could partially explain the observed age-related association. The risk difference for myocarditis between persons with and without COVID-19 was higher among males than among females, consistent with some earlier studies ( 2 , 5 ). The finding of a higher risk ratio among females than among males is novel. However, it likely reflects the low risk for myocarditis among female patients without COVID-19 ( 5 ). Although the exact mechanism of SARS-CoV-2 infection possibly leading to myocarditis is unknown, the pathophysiology is likely similar to that of other viruses ( 1 ). Among persons with COVID-19 and myocarditis, some myocarditis diagnoses might represent cases of multisystem inflammatory syndrome (MIS), particularly among children aged <16 years ( 9 ). Further study is warranted to understand how the clinical course of myocarditis among patients with COVID-19 might differ by presence or absence of MIS ( 10 ). Since the introduction of mRNA COVID-19 vaccines in the United States in December 2020, an elevated risk for myocarditis among mRNA COVID-19 vaccine recipients has been observed, particularly among males aged 12–29 years, with 39–47 expected cases of myocarditis, pericarditis, and myopericarditis per million second mRNA COVID-19 vaccine doses administered ( 6 ). A recent study from Israel reported that mRNA COVID-19 vaccination was associated with an elevated risk for myocarditis (risk ratio = 3.24; 95% CI = 1.55–12.44); in the same study, a separate analysis showed that SARS-CoV-2 infection was a strong risk factor for myocarditis (risk ratio = 18.28, 95% CI = 3.95–25.12) ( 4 ). On June 23, 2021, the Advisory Committee on Immunization Practices concluded that the benefits of COVID-19 vaccination clearly outweighed the risks for myocarditis after vaccination ( 6 ). The present study supports this recommendation by providing evidence of an elevated risk for myocarditis among persons of all ages with diagnosed COVID-19. The findings in this study are subject to at least six limitations. First, the risk estimates from this study reflect the risk for myocarditis among persons who received a diagnosis of COVID-19 during an outpatient or inpatient health care encounter and do not reflect the risk among all persons who had COVID-19. Second, misclassification of COVID-19 and myocarditis is possible because conditions were determined by ICD-10-CM codes, which were not confirmed by clinical data (e.g., laboratory tests or cardiac imaging) and could be improperly coded or coded with a related condition (e.g., pericarditis). Third, encounters for COVID-19, myocarditis, and COVID-19 vaccination occurring outside of hospital systems that contribute to PHD-SR are not included within this data set. Fourth, underlying medical conditions and alternative etiologies for myocarditis (e.g., autoimmune disease) were not ascertained or excluded. Fifth, the obtained measures of association could be biased because of the choice of the comparison group (all patients without COVID-19) and if physicians were more likely to suspect or diagnose myocarditis among patients with COVID-19. Finally, the findings represent a convenience sample of patients from hospitals reporting to PHD-SR and might not be generalizable to the U.S. population. Myocarditis is uncommon among patients with and without COVID-19; however, COVID-19 is a strong and significant risk factor for myocarditis, with risk varying by age group. The findings in this report underscore the importance of implementing evidence-based COVID-19 prevention strategies, including vaccination, to reduce the public health impact of COVID-19 and its associated complications. Summary What is already known about this topic? Viral infections are a common cause of myocarditis. Some studies have indicated an association between COVID-19 and myocarditis. What is added by this report? During March 2020–January 2021, patients with COVID-19 had nearly 16 times the risk for myocarditis compared with patients who did not have COVID-19, and risk varied by sex and age. What are the implications for public health practice? These findings underscore the importance of implementing evidence-based COVID-19 prevention strategies, including vaccination, to reduce the public health impact of COVID-19 and its associated complications.
