key: cord-0928202-51tc0gga
authors: Perez, Yalile; Levy, Emily R; Joshi, Avni Y; Virk, Abinash; Rodriguez-Porcel, Martin; Johnson, Matthew; Roellinger, Daniel; Vanichkachorn, Greg; Charles Huskins, W; Swift, Melanie D
title: Myocarditis Following Coronavirus Disease 2019 mRNA Vaccine: A Case Series and Incidence Rate Determination
date: 2021-11-03
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab926
sha: 1e127f0d1d3a5c28ece56c2facf81e2d3d734e1a
doc_id: 928202
cord_uid: 51tc0gga

BACKGROUND: Myocarditis following coronavirus disease 2019 (COVID-19) mRNA vaccines (Pfizer-BioNTech and Moderna) has been increasingly reported. Incidence rates in the general population are lacking, with pericarditis rather than myocarditis diagnostic codes being used to estimate background rates. This comparison is critical for balancing the risk of vaccination with the risk of no vaccination. METHODS: A retrospective case series was performed using the Mayo Clinic COVID-19 Vaccine Registry. We measured the incidence rate ratio (IRR) for myocarditis temporally related to COVID-19 mRNA vaccination compared with myocarditis in a comparable population from 2016 through 2020. Clinical characteristics and outcomes of the affected patients were collected. A total of 21 individuals were identified, but ultimately 7 patients met the inclusion criteria for vaccine-associated myocarditis. RESULTS: The overall IRR of COVID-19–related myocarditis was 4.18 (95% confidence interval [CI], 1.63–8.98), which was entirely attributable to an increased IRR among adult males (IRR, 6.69; 95% CI, 2.35–15.52) compared with females (IRR 1.41; 95% CI, .03–8.45). All cases occurred within 2 weeks of a dose of the COVID-19 mRNA vaccine, with the majority occurring within 3 days (range, 1–13) following the second dose (6 of 7 patients, 86%). Overall, cases were mild, and all patients survived. CONCLUSIONS: Myocarditis is a rare adverse event associated with COVID-19 mRNA vaccines. It occurs in adult males with significantly higher incidence than in the background population. Recurrence of myocarditis after a subsequent mRNA vaccine dose is not known at this time.

The coronavirus disease-2019 (COVID-19) outbreak was declared a pandemic by the World Health Organization on 11 March 2020, and development of a safe, effective COVID-19 vaccine rapidly became a global priority. In the United States, the BNT162b2 mRNA (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccines were granted emergency use authorization by the US Food and Drug Administration in December 2020 following interim results of phase 3 clinical trials [1, 2] . These clinical trials and real-world data have demonstrated more than 95% effectiveness of the mRNA vaccines, preventing 164 900 cases of COVID-19, 25 000 hospitalizations, and 3628 deaths per million doses of mRNA vaccines given in the United States [1] . With more than 216 million people having received at least 1 dose of the COVID-19 mRNA vaccine to date in the United States, recognition and understanding of the potential adverse events of these novel vaccines are essential [3] .

Myocarditis has been reported in association with immunizations, most notably the live attenuated smallpox vaccine [4] . Recently, cases of myocarditis following receipt of the COVID-19 mRNA vaccine in adolescents and young adults have been published [5] [6] [7] [8] . The Centers for Disease Control and Prevention (CDC) has issued clinical guidance alerting providers to this potential association, noting that the reported cases have been predominantly in male adolescents and young adults [9] . Available incidence rates in the general population for comparison are lacking, with pericarditis rather than myocarditis diagnostic codes being used to estimate background rates in the population [10] .

Here, we present a series of 7 patients (aged 22 to 71 years) with myocarditis presenting shortly after receipt of a dose of the COVID-19 mRNA vaccine (Pfizer-BioNTech or Moderna) from a registry designed to capture outcomes for a defined population of vaccinated individuals. We also calculated the incidence rate of myocarditis following COVID-19 mRNA vaccination and compared this to the background incidence rate of myocarditis in a comparable population.

A retrospective case series study was performed using the Mayo Clinic COVID- 19 The Rochester Epidemiology Project (REP) is a collaboration of clinics, hospitals, and other medical facilities in Minnesota and Wisconsin linking medical records for research purposes. Since 1996, the REP has enrolled hundreds of thousands of individuals who agreed to share their medical records and provided a comparable population for this study [11] . We conducted a query of the REP database using the ICD-10 codes listed above for the years 2016 through 2020 to identify the incidence of myocarditis among the REP population aged ≥16 years.

The observation window for vaccinated individuals in the vaccine registry varied from 6 weeks to 5 months. Because all cases of post-immunization myocarditis in the vaccine registry population presented within 13 days of receiving a dose of a mRNA vaccine, we assigned each vaccination dose an observation time of 14 days when calculating person-years of observation. In total, there were 12 648 person-years of observation in the vaccine registry cohort. Most individuals (145 876; 83%) had more than 30 days of follow-up since their last vaccination date.

Clinical presentation, diagnostic test results, comorbidities, treatment, and outcomes were extracted retrospectively from the electronic medical record. The American Heart Association and European Society of Cardiology have published guidelines for the diagnosis and management of myocarditis [12] . Recently, the CDC provided guidance regarding the diagnosis and management of COVID-19 vaccine-related myocarditis [13, 14] . The Mayo Clinic Institutional Review Board approved the study.

Frequencies and percentages are reported for categorical variables. Data are presented as median (interquartile range [IQR]) for nonnormally distributed data and mean ± standard deviation for normally distributed data. Differences between groups were tested using the χ 2 test or a Fisher exact test for categorical variables as appropriate. Incidence rates and incidence rate ratios (IRRs) were calculated. Statistical analyses were performed using OpenEpi (version 3) [1, 15] .

A total of 21 individuals were identified as having a clinical diagnosis of myocarditis via the Mayo Clinic COVID-19 Vaccine Registry after receiving at least 1 dose of a COVID-19 mRNA vaccine on or before 13 May 2021; records were screened by 2 physicians (M. D. S. and A. Y. J.). However, only 7 individuals had new onset myocarditis following vaccination. The remaining 14 patients were excluded since they did not have evidence of COVID-19 vaccine-related myocarditis; however, the diagnosis was used during a post-immunization clinical encounter due to a prior history of myocarditis. No cases of myocarditis were found following a dose of the Johnson & Johnson/ Janssen vaccine. Table 1 summarizes the demographic characteristics of the cohort. The median age at the time of diagnosis was 44 years (range, 22-71), and most patients were male (6 of 7, 86%). All patients self-identified as non-Hispanic White. The most common comorbidities were hypertension (5 of 7, 72%), obesity (4 of 7, 57%), obstructive sleep apnea (4 of 7, 57%), tobacco use (3 of 7, 42%), and dyslipidemia (3 of 7, 42%). One patient (14%) had a history of myocarditis, and another patient (14%) had a history of pericarditis. One patient (14%) was previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Three patients (42%) received the Pfizer-BioNTech vaccine and 4 (57%) received the Moderna vaccine. All cases occurred within 2 weeks of a dose of the COVID-19 mRNA vaccine, with the majority occurring within 3 days (range, 1-13). All except 1 case occurred after the second dose of the vaccine.

The clinical characteristics of the patients with COVID-19 vaccine-related myocarditis are shown in the Supplementary Table. The most common presenting symptoms were Five of 7 patients (71%) had abnormalities noted in the electrocardiogram (ECG), with ST-segment changes being the predominant finding. ECG changes in combination with elevated troponin T levels triggered further evaluation for acute coronary syndrome in 3 patients (43%). In this subgroup, 1 patient underwent a dedicated computerized tomography coronary angiogram that revealed normal coronary arteries, and 2 patients underwent cardiac catheterization that showed angiographically normal coronary arteries.

An echocardiogram was performed in 5 patients (71%). Although it is not indicated to make the diagnosis of myocarditis, it is helpful for the assessment of ventricular function and to look for regional wall motion abnormalities, valve regurgitation, or pericardial effusion. Three patients (60%) were noted to have reduced left ventricular ejection fraction; right ventricular dysfunction, albeit mild, was seen in 3 patients. Cardiac magnetic resonance imaging (MRI) was obtained in 6 patients (86%). Myocardial delayed enhancement was universal. Pericardial involvement was seen in 3 (50%) patients.

Treatment consisted of a combination of steroids (2 of 7, 29%), nonsteroidal antiinflammatory drugs (NSAIDs; 2 of 7, 29%), and colchicine (5 of 7, 71%), which is known to modulate multiple antiinflammatory pathways [16] . None of the patients received intravenous immunoglobulin. Angiotensin-converting enzyme (ACE) inhibitors and beta blockers were also prescribed for patients with left ventricular dysfunction. Overall, cases were mild, and there were no deaths.

The overall incidence rate of myocarditis among individuals in the COVID-19 vaccine registry was 55.35 (95% confidence interval [CI], 22.25-114.00) per 100 000 person-years during the 2 weeks following a dose of a COVID-19 mRNA vaccine (Table  2 ). In the REP population over the prior 5 years, the overall incidence rate of myocarditis was 13.25 (95% CI, 10.60-16.36) per 100 000 person-years. In both populations, incidence rates were higher in males. The IRR for myocarditis following COVID-19 mRNA vaccination was increased for males at 6.69 (95% CI, 2.35-15.52), but it was not statistically significant for females at 1.41 (95% CI, .03-8.45). Abbreviations: IRR, incidence rate ratio; LoCI 95 , lower limit of the 95th confidence interval; UpCI 95 , upper limit of the 95th confidence interval.

Clinical studies have shown an association between SARS-CoV-2 infection and cardiovascular disease such as myocardial injury, acute coronary syndrome, and arrhythmias [17] [18] [19] .

Since the emergence of the SARS-CoV-2 virus, the genomic sequence and protein structure of the virus have been extensively studied [20, 21] . However, the exact mechanism by which SARS-CoV-2 leads to myocardial damage has not been elucidated. Some theories include direct damage to the cardiac myocytes, systemic inflammation, and interferon-mediated immune response, among others [22] . Another postulated mechanism is molecular mimicry, whereby a foreign antigen, in this case moieties or proteins in the SARS-CoV-2 virus, share sequence or structural similarities to cardiac proteins, leading to cross-reaction and inflammation [23] [24] [25] .

Myocarditis is a consequence of myocardial damage that can be diagnosed histologically or clinically using a combination of clinical findings and diagnostic criteria [12, 26] . Most often, it results from infection caused by viruses; enterovirus and adenovirus are classically associated with myocarditis [27] . However, there is considerable geographic and temporal variation in the prevalence of these viral infections. Thus, a specific viral etiology for myocarditis may not be identified during the evaluation, and other causes such as bacteria, fungi, drug-induced hypersensitivity reactions, or autoimmune disorders need to be considered [28] . There is also a preponderance of males affected, and children may have a more fulminant course [29] .

Myocarditis after vaccination was reported following the live attenuated smallpox vaccine [4] . Recently, myocarditis has been reported after mRNA COVID-19 vaccination [5] [6] [7] [8] . For instance, a case series noted similar clinical presentations of post-immunization myocardial and pericardial inflammation in adolescents after receipt of the Pfizer-BioNTech vaccine [6] . Most of the affected patients were male, as in our case series. An important distinction in our study is that individuals of all ages, particularly adults, appeared to be at risk for this rare complication. Additionally, we found that myocarditis occurred within several days of COVID-19 vaccination and more often after receipt of the second dose of the vaccine, either the Pfizer-BioNTech or Moderna vaccine. Myocarditis has also been associated with the post-infection hyperinflammatory syndrome, multisystem inflammatory syndrome in children and adults [30, 31] . Similar to the lack of clarity for the pathogenesis of myocarditis caused by SARS-CoV-2, the mechanism of myocarditis after COVID-19 mRNA vaccination has not been elucidated.

The incidence of myocarditis in the general population remains unknown. For instance, one study found a background rate of 17 cases per 100 000 person-years among Finnish military recruits, which is very similar to our findings in the adult male population [32] . For purposes of comparing vaccine adverse events to background rates, pericarditis is commonly reported with or without myocarditis [10] . The incidence rates we observed following COVID-19 mRNA vaccination are significantly higher than those previously reported following smallpox vaccination [32] [33] [34] [35] . Montgomery et al recently reported the incidence of post-immunization myocarditis in a cohort of US military members [36] . They identified 23 military recruits who presented with acute chest pain within 4 days after receipt of a COVID-19 mRNA vaccine. They found that the observed number of male military members with post-vaccination myocarditis was higher than the expected number using an estimated incidence of 1 to 10 cases per 100 000 person-years in the United States. Simone et al also evaluated the incidence rate of myocarditis following COVID-19 mRNA vaccination and found that the observed incidence was 5.8 cases per 1 million second doses over a 10-day observation period [37] . The IRR was 3.3 (95% CI, 1.0-13.7) for the second dose compared with our IRR of 4.18 (95% CI, 1.63-8.98). Overall, the findings of both studies are consistent with ours in that males are disproportionally affected, most cases occur after receipt of the second vaccine dose, and cases are generally mild.

To our knowledge, this is the first case series to estimate a post-immunization incidence rate of myocarditis in a defined population of COVID-19 mRNA vaccine recipients, along with a background rate in a comparable population. This comparison is relevant as it is critical to balance the risk of vaccination with the risk of no vaccination.

In summary, physicians should consider myocarditis if patients present with chest pain shortly following a COVID-19 mRNA vaccine. The initial evaluation should include an ECG and laboratory testing for inflammatory markers and cardiac enzymes. If these biomarkers are elevated, point-of-care ultrasound and/or cardiac MRI in addition to early cardiology consultation should be considered. In patients at risk for atherosclerotic disease or those with preexisting cardiovascular disease, further evaluation for acute coronary syndrome is warranted. In addition to supportive care and NSAIDs, colchicine may constitute a low-cost and effective treatment for myocarditis. In the absence of left ventricular dysfunction, beta-blockers and ACE inhibitors are unlikely to be beneficial. The clinical course of this condition tends to be mild; although some patients in our study were hospitalized, they responded well to medical therapy. All patients survived to hospital discharge. The long-term sequelae, if any, of postimmunization myocarditis in this population remains to be determined.

Our study is subject to some limitations. The vaccine registry that was used contains patients vaccinated in a single health system in the upper Midwest, which may limit generalizability. All reported cases were non-Hispanic Caucasian patients, which may reflect selection bias due to regional population demographics. Because cases were identified using diagnostic codes associated with clinical care, there is a potential bias for most severe cases who present for clinical care and, therefore, the rates may be underestimated. However, this limitation also applies to the comparison REP population, so the increased IRR would remain valid. Additionally, the vaccination dates were chosen to coincide with vaccine availability in individuals aged >16 years. Thus, this cohort does not include younger adolescents who may experience different incidence rates of postimmunization myocarditis.

Myocarditis is a rare adverse event associated with COVID-19 mRNA vaccines; in adult males, it occurs with significantly higher incidence than in the background population. Patients with preexisting cardiovascular disease or prior history of myocarditis may be at increased risk for COVID-19 vaccine-related myocarditis, but more data are needed. The condition is more often seen after the second dose of the COVID-19 mRNA vaccine. Post-immunization myocarditis is relatively straightforward to diagnose and treat, and the clinical course tends to be mild in most patients.

As COVID-19 vaccination continues and expands to younger populations, physicians should remain vigilant and report suspected vaccine adverse events to the CDC through the Vaccine Adverse Event Reporting System, which has detected safety signals for this and other vaccine-associated adverse events. Despite the increased frequency of this rare condition following COVID-19 vaccination, the benefits of COVID-19 vaccination far exceed the risk, and vaccination is strongly recommended by the authors. Vaccination is an effective means to prevent COVID-19 infection, transmission, and related complications.

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. 

C4591001 Clinical Trial Group. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine

Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine

A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination

Myocarditis following COVID-19 vaccination

Symptomatic acute myocarditis in seven adolescents following Pfizer-BioNTech COVID-19 vaccination

Myocarditis following COVID-19 mRNA vaccination

Myocarditis and pericarditis after vaccination for COVID-19

Clinical Considerations: Myocarditis after mRNA COVID-19 Vaccines

S. population-based background incidence rates of medical conditions for use in safety assessment of COVID-19 vaccines

Data resource profile: expansion of the Rochester epidemiology project medical records-linkage system (E-REP)

European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases

Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: update from the advisory committee on immunization practices-United States

Clinical Considerations: Myocarditis after mRNA COVID-19 Vaccines

OpenEpi: Open Source Epidemiologic Statistics for Public Health

Colchicine-Update on mechanisms of action and therapeutic uses

Impact of complicated myocardial injury on the clinical outcome of severe or critically ill COVID-19 patients

SARS-CoV-2, COVID-19, and inherited arrhythmia syndromes

The effect of cardiovascular disease and acute cardiac injury on fatal COVID-19: a meta-analysis

Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Myocardial injury and COVID-19: possible mechanisms

Molecular mimicry as a mechanism of autoimmune disease

Mimicry and antibody-mediated cell signaling in autoimmune myocarditis

Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases

Recognition and initial management of fulminant myocarditis

High prevalence of viral genomes and multiple viral infections in the myocardium of adults with "idiopathic" left ventricular dysfunction

Management of myocarditis-related cardiomyopathy in adults

Demographics, trends, and outcomes in pediatric acute myocarditis in the United States

Multisystem inflammatory syndrome in children (MIS-C), a post-viral myocarditis and systemic vasculitis-a critical review of its pathogenesis and treatment

Centers for Disease Control and Prevention

Incidence of three presentations of acute myocarditis in young men in military service. A 20-year experience

Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel

Myopericarditis following smallpox vaccination

Myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination among civilians in the United States

Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military

Acute myocarditis following COVID-19 mRNA vaccination in adults aged 18 years or older