Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older | Cardiology | JAMA Internal Medicine | JAMA Network
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Table 1.  Incidence Rates and Rate Ratios of Myocarditis in Vaccinated Individuals Compared With Control Groups
Incidence Rates and Rate Ratios of Myocarditis in Vaccinated Individuals Compared With Control Groups
Table 2.  Case Description and Clinical Coursea
Case Description and Clinical Coursea
1.
Jeyanathan  M, Afkhami  S, Smaill  F, Miller  MS, Lichty  BD, Xing  Z.  Immunological considerations for COVID-19 vaccine strategies.   Nat Rev Immunol. 2020;20(10):615-632. doi:10.1038/s41577-020-00434-6PubMedGoogle ScholarCrossref
2.
Polack  FP, Thomas  SJ, Kitchin  N,  et al; C4591001 Clinical Trial Group.  Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.   N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577PubMedGoogle ScholarCrossref
3.
Baden  LR, El Sahly  HM, Essink  B,  et al; COVE Study Group.  Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.   N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389PubMedGoogle ScholarCrossref
4.
Kim  HW, Jenista  ER, Wendell  DC,  et al.  Patients with acute myocarditis following mRNA COVID-19 vaccination.   JAMA Cardiol. 2021. doi:10.1001/jamacardio.2021.2828PubMedGoogle Scholar
5.
Montgomery  J, Ryan  M, Engler  R,  et al.  Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military.   JAMA Cardiol. 2021. doi:10.1001/jamacardio.2021.2833PubMedGoogle Scholar
6.
Diaz  GA, Parsons  GT, Gering  SK, Meier  AR, Hutchinson  IV, Robicsek  A.  Myocarditis and pericarditis after vaccination for COVID-19.   JAMA. 2021. doi:10.1001/jama.2021.13443PubMedGoogle Scholar
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    6 Comments for this article
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    Incidence and incidence rate ratio for subgroup including myocarditis cases
    Benjamin Fishman |
    The article reports that there 13 cases of confirmed myocarditis after the second dose of COVID-19 mRNA vaccination, and all were in men with an age of 18-40 years. In this age group, can the authors provide the incidence of confirmed myocarditis after the second dose and the incidence rate ratio?  
    CONFLICT OF INTEREST: None reported
    Response from the Study Authors:
    Ming Sum Lee, MD PhD | KP LAMC
    In our Research Letter, we included the “raw numbers” so that readers could perform their own calculations (if they are interested). If we had only included men age 18-40, then the incidence risk ratio would be higher than what was reported. Nevertheless, similar to other post-hoc analyses focusing on a small subgroup, these types of analyses should be considered exploratory and hypothesis-generating. Overall, myocarditis incidence is very low (15 cases in 2,392,924 individuals), and that is one of the main takeaways. We reported the overall incidence among all vaccinated patients because that was the primary outcome specified in the study protocol. Additional information on cohort demographics was included to allow readers to perform additional estimates if interested.
    CONFLICT OF INTEREST: None Reported
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    Age-Specific Rates are What Matter
    Richard Kravitz, MD, MSPH | UC Davis Department of Internal Medicine
    Clinicians' primary concern is not the overall incidence of a serious vaccine adverse effect in the entire population, but rather the likelihood of such an outcome in the patient at hand. Using the percentages given in the article, approximately (0.46)(.357)= 16.4% of the vaccinated population were men under 40, but myocarditis occurred only in young men; therefore the estimated incidence of myocarditis following a second dose in this group is not 5.8 per million but rather 5.8 per 164,000 or 1 in 28,276. In an observational study that is exploratory by nature, burying this calculation because it was not "pre-specified" seems to privilege formalism over the needs of clinical decision makers. In addition it should be emphasized that not all cases reported by Simone et al. were "mild"; two had reduced ejection fractions with global hypokinesis and no mention of degree of recovery. These results, while certainly not settling the issue, should make clinicians ponder whether the attenuated adenovirus formulation of the Covid-19 vaccine might be preferable to the mRNA-based alternatives for young men. But regardless of conclusions, those who care about defeating vaccine hesitancy need to be straight with the facts, even when they are unpalatable, mired in uncertainty, or both.
    CONFLICT OF INTEREST: None Reported
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    Concern about transparency of safety signal
    Margaret Ryan, MD, MPH | UC San Diego
    Dr. Simone’s team should be commended for analysis of an important adverse event following immunization in a well-defined, diverse population.

    It is concerning, however, that all the cases of myocarditis occurred in young males, yet the investigators only show rates and risk ratios for the entire population – a population that is mostly (54%) female and mostly (64%) older than age 40.

    The safety signal for this adverse event following immunization has a clear demographic association in younger males. That signal is obscured when reporting results in a non-stratified way. Both the primary report,
    and the accompanying editorial briefly acknowledge the identification of cases in younger males, but do not quantify the safety signal or describe its full potential importance.

    It is appreciated that vaccine advocacy is critical in a pandemic. But, as vaccines become more available and/or mandated for younger patients, these patients and their families have a reasonable expectation of full transparency in adverse event following immunization reporting.
    CONFLICT OF INTEREST: None Reported
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    We Now Await Data for the Kaiser Vaccinated Cohort Ages 12-18
    Binh Ngo, M.D. | Keck USC School of Medicine
    On May 10, 2021 the FDA cleared use of the Pfizer COVID-19 mRNA vaccination for children 12-15. In California. the Pfizer Covid-19 vaccination is mandated for eligibility to participate in school for ages 12 and above. The Kaiser group has now furnished excellent data including ethnicities for the incidence of post vaccination myocarditis for ages 18 and above. In his Comment Dr. Kravitz points out that age specific calculations are critical.

    It is of particular interest to compare the age group of males 12-15 with the
    age group 16-18 to the age group over 18. A follow-up to the article by Simone et al (1) is very important.

    (1) Simone A, Herald J, Chen A, et al. Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older. JAMA Intern Med. Published online October 04, 2021

    CONFLICT OF INTEREST: None Reported
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    Concerns about the Methods
    Jessica Rose, PhD | Institute of Pure and Applied Knowledge

    Incidence rates of myocarditis should not be calculated by using ‘vaccine administration’ as the denominator since the data source for the outcome of interest was spontaneously reported. Assessment of all persons must be completed to approach the problem of establishing a denominator. To clarify,  it is wrong to calculate how many people succumbed to myocarditis (the incidence rate) using the unassessed, vaccinated population as a denominator. With spontaneous reporting, vaccine administration is not used as the denominator to give a misleading conclusion of "rare" adverse event since this would require assessment of the total population to determine an outcome
    as done in clinical trials.

    CONFLICT OF INTEREST: None Reported
    READ MORE
    Research Letter
    October 4, 2021

    Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older

    Author Affiliations
    • 1Department of Cardiology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California
    • 2Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
    • 3Department of Cardiology, Kaiser Permanente Orange County Medical Center, Irvine, California
    • 4Department of Family Medicine, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California
    JAMA Intern Med. Published online October 4, 2021. doi:10.1001/jamainternmed.2021.5511

    Vaccination is an essential component of the public health strategy to end the COVID-19 pandemic.1-3 Recently, there have been reports of acute myocarditis following COVID-19 mRNA vaccine administration.4-6 We evaluated acute myocarditis incidence and clinical outcomes among adults following mRNA vaccination in an integrated health care system in the US.

    Methods

    We included Kaiser Permanente Southern California (KPSC) members aged 18 years or older who received at least 1 dose of the BNT162b2 (Pfizer) or mRNA-1273 (Moderna) mRNA vaccine between December 14, 2020, and July 20, 2021. Potential cases of postvaccine myocarditis were identified based on reports from clinicians to the KPSC Regional Immunization Practice Committee and by identifying hospitalization within 10 days of vaccine administration with a discharge diagnosis of myocarditis. All cases were independently adjudicated by at least 2 cardiologists. We calculated incidence rates and 95% confidence intervals (CIs) of myocarditis using vaccine administration as the denominator and compared it with the incidence of myocarditis in unexposed individuals between December 14, 2020, and July 20, 2021; and with vaccinated individuals during a 10-day period 1 year prior to vaccination. Incidence rate ratios (IRRs) and 95% CIs were calculated using STATA statistical software (version 14, Stata Corp). We described the characteristics and outcomes of acute myocarditis cases. A 2-sided P < .05 was used to define statistical significance. This study was approved by the institutional review board of KPSC with a waiver of informed consent because of the observational nature of the study in the course of standard care.

    Results

    Of 2 392 924 KPSC members who received at least 1 dose of COVID-19 mRNA vaccines, 50.2% received mRNA-1273 and 50.0% BNT162b2. In this cohort, 54.0% were women, 31.2% White, 6.7% Black, 37.8% Hispanic, and 14.3% were Asian individuals. Median age was 49 years (IQR, 34-64 years), 35.7% were younger than 40 years, and 93.5% completed 2 doses of vaccines. In the unexposed group of 1 577 741 individuals, median (IQR) age was 39 (28-53) years, 53.7% were younger than 40 years, 49.1% women, 29.7% White, 8.8% Black, 39.2% Hispanic, and 6.6% were Asian individuals.

    There were 15 cases of confirmed myocarditis in the vaccinated group (2 after the first dose and 13 after the second), for an observed incidence of 0.8 cases per 1 million first doses and 5.8 cases per 1 million second doses over a 10-day observation window (Table 1). All were men, with a median (IQR) age of 25 (20-32) years. Among unexposed individuals, there were 75 cases of myocarditis during the study period, with 39 (52%) men and median (IQR) age of 52 (32-59) years. The IRR for myocarditis was 0.38 (95% CI, 0.05-1.40) for the first dose and 2.7 (95% CI, 1.4-4.8) for the second dose. Sensitivity analyses using vaccinated individuals as their own controls showed similar findings (Table 1).

    Of the patients with myocarditis postvaccination, none had prior cardiac disease (Table 2). Eight patients received BNT162b2 and 7 received mRNA-1273. All were hospitalized and tested negative for SARS-CoV-2 by polymerase chain reaction on admission. Fourteen (93%) reported chest pain between 1 to 5 days after vaccination. Symptoms resolved with conservative management in all cases; no patients required intensive care unit admission or readmission after discharge.

    Discussion

    In this population-based cohort study of 2 392 924 individuals who received at least 1 dose of COVID-19 mRNA vaccines, acute myocarditis was rare, at an incidence of 5.8 cases per 1 million individuals after the second dose (1 case per 172 414 fully vaccinated individuals). The signal of increased myocarditis in young men warrants further investigation.

    This vaccinated cohort is unique in its racial and ethnic diversity and in receiving care at community hospitals with treatment reflective of real-world practice. Limitations of this study include the observational design; short follow-up time; absence of myocardial biopsy for definitive diagnosis; lack of uniform testing of all cases; possible more extensive workup of chest pain in vaccinated individuals during the immediate postvaccination period; and possible underdiagnosis of subclinical cases. No relationship between COVID-19 mRNA vaccination and postvaccination myocarditis can been established given the observational nature of this study.

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    Article Information

    Accepted for Publication: August 6, 2021.

    Published Online: October 4, 2021. doi:10.1001/jamainternmed.2021.5511

    Corresponding Author: Ming-Sum Lee, MD, PhD, Department of Cardiology, Kaiser Permanente Los Angeles Medical Center, 1526 N Edgemont St, 2nd Floor, Los Angeles, CA 90027 (mingsum,lee@kp.org).

    Author Contributions: Drs Simone and Lee had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Simone and Herald contributed equally.

    Concept and design: Simone, Herald, Shen, Lee.

    Acquisition, analysis, or interpretation of data: Simone, Herald, Chen, Gulati, Lewin.

    Drafting of the manuscript: Simone, Herald, Chen, Gulati, Lee.

    Critical revision of the manuscript for important intellectual content: Simone, Herald, Shen, Lewin.

    Statistical analysis: Simone, Herald, Chen, Lee.

    Administrative, technical, or material support: Herald, Gulati, Lewin.

    Supervision: Shen, Lee.

    Conflict of Interest Disclosures: None reported.

    References
    1.
    Jeyanathan  M, Afkhami  S, Smaill  F, Miller  MS, Lichty  BD, Xing  Z.  Immunological considerations for COVID-19 vaccine strategies.   Nat Rev Immunol. 2020;20(10):615-632. doi:10.1038/s41577-020-00434-6PubMedGoogle ScholarCrossref
    2.
    Polack  FP, Thomas  SJ, Kitchin  N,  et al; C4591001 Clinical Trial Group.  Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.   N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577PubMedGoogle ScholarCrossref
    3.
    Baden  LR, El Sahly  HM, Essink  B,  et al; COVE Study Group.  Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.   N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389PubMedGoogle ScholarCrossref
    4.
    Kim  HW, Jenista  ER, Wendell  DC,  et al.  Patients with acute myocarditis following mRNA COVID-19 vaccination.   JAMA Cardiol. 2021. doi:10.1001/jamacardio.2021.2828PubMedGoogle Scholar
    5.
    Montgomery  J, Ryan  M, Engler  R,  et al.  Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military.   JAMA Cardiol. 2021. doi:10.1001/jamacardio.2021.2833PubMedGoogle Scholar
    6.
    Diaz  GA, Parsons  GT, Gering  SK, Meier  AR, Hutchinson  IV, Robicsek  A.  Myocarditis and pericarditis after vaccination for COVID-19.   JAMA. 2021. doi:10.1001/jama.2021.13443PubMedGoogle Scholar
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