Myocarditis and Pericarditis After Vaccination for COVID-19 | Cardiology | JAMA | JAMA Network
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Figure.  Monthly Number of Inpatient and Emergency Department Cases of Myocarditis and Pericarditis at 40 Hospitals in the Western US
Monthly Number of Inpatient and Emergency Department Cases of Myocarditis and Pericarditis at 40 Hospitals in the Western US

A statistical process control c-chart was used for panels A and B, with control limits at ±3 times the standard deviation of the overall count. Orange circles are counts outside the control limits. Solid lines are incidence over the entire time frame; dashed lines are the ±3 sigma (control limits) about the incidence over the entire time frame.

Table.  Characteristics of Post–COVID-19 Vaccination Myocarditis and Pericarditis Casesa
Characteristics of Post–COVID-19 Vaccination Myocarditis and Pericarditis Casesa
1.
Montgomery  J, Ryan  M, Engler  R,  et al.  Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military.   JAMA Cardiol. Published online June 29, 2021. doi:10.1001/jamacardio.2021.2833PubMedGoogle Scholar
2.
Kim  HW, Jenista  ER, Wendell  DC,  et al.  Patients with acute myocarditis following mRNA COVID-19 vaccination.   JAMA Cardiol. Published online June 29, 2021. doi:10.1001/jamacardio.2021.2828PubMedGoogle Scholar
3.
Bautista García  J, Peña Ortega  P, Bonilla Fernández  JA,  et al.  Acute myocarditis after administration of the BNT162b2 vaccine against COVID-19.   Rev Esp Cardiol (Engl Ed). Published online April 27, 2021. doi:10.1016/j.recesp.2021.03.009PubMedGoogle Scholar
4.
Rosner  CM, Genovese  L, Tehrani  BN,  et al.  Myocarditis temporally associated with COVID-19 vaccination.   Circulation. Published online June 16, 2021. doi:10.1161/CIRCULATIONAHA.121.055891PubMedGoogle Scholar
5.
Su  JR, McNeil  MM, Welsh  KJ,  et al.  Myopericarditis after vaccination, Vaccine Adverse Event Reporting System (VAERS), 1990-2018.   Vaccine. 2021;39(5):839-845. doi:10.1016/j.vaccine.2020.12.046PubMedGoogle ScholarCrossref
6.
Wallace  M, Oliver  S. COVID-19 mRNA vaccines in adolescents and young adults: benefit-risk discussion. Slide 28. Published June 23, 2021. Accessed July 7, 2021. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-06/05-COVID-Wallace-508.pdf
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    5 Comments for this article
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    Simultaneous COVID-19 Infection?
    William Byars, MD | Tribe Clinical Research
    Assuming all patients with myocarditis and pericarditis diagnosed during the period of this review were tested for COVID-19 infection as a possible cause, those who tested negative could arbitrarily fall into two categories: those whose heart problem was associated with a recent COVID-19 vaccination and those who (unknowingly for all involved) had a false negative PCR test for COVID-19. Could overlapping cases who fall into both of these two groups represent a confounding factor in this review?
    CONFLICT OF INTEREST: None Reported
    Can We Discriminate Patients At Risk?
    Cesare De Gregorio | University of Messina, Italy
    Myocarditis and pericarditis have been recognized as (rare) complications of both COVID-19 disease and vaccinations. This study is interesting because it demonstrates that vaccine-related inflammation occurs not only in the young adult and adolescent males but also in women and older people. After prothrombotic thrombocytopenia, these complications are another warning for the medical community, because everyone (people with hypertension the most) can be affected, irrespective of history of autoimmune disorders. Although hospitalizations for myocarditis appear brief, questions about pathophysiological mechanisms, therapeutic options, and prognosis are unanswered. Autoantibody against self-antigens, and lymphocyte T and natural killer cells may be responsible for the underlying cytokine storm, but are we able to discriminate which subjects are at risk of such complications? (co-written with Nickolas G. Kounis, MD, Univ. of Patras, Greece)
    CONFLICT OF INTEREST: None Reported
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    Post-Vaccine Myocarditis in Teen Boys?
    David Epstein, MD | Delaware Modern Pediatrics, P.A.
    Post-vaccine myocarditis, though rare, seems to be more common in teenage boys than in the general population.

    In the State of Delaware, informal (not official) reports suggest about half a dozen boys developed it (no girls); all recovered fully. If we consider the number of teenage boys vaccinated in Delaware, we speculate a rate possibly of 0.04% - still very, very low, but enough that a few pediatricians in Delaware are concerned about these raw data.

    Do we have more hard data about incidence of myocarditis in teen boys after vaccination in a larger population?
    We would love to see reliable reports to reassure us.
    CONFLICT OF INTEREST: None Reported
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    Comparison With Infection-Related Events
    Binh Ngo, M.D. | Keck USC School of Medicine
    The authors leveraged the database of electronic medical records to locate patients who had either emergency room encounters or hospitalizations with a proven diagnosis of myocarditis and pericarditis. The strength of their approach is in the very large number of records emanating from a forty hospital consortium. It would be helpful to know how many patients were included in their hospital-derived database. One weakness in their current presentation is a lack of comparison of the vaccine-generated myocarditis and pericarditis to the events occurring in COVID-19-diagnosed patients. They clearly can access this data since COVID-19 was one of their exclusion criteria. Clearly, their dataset of documented diagnoses of myocarditis and pericarditis contrasts with the much higher incidence reported in screening studies of COVID-19 patients wherein there was an active search for clinical and subclinical myocarditis using screening procedures and magnetic resonance imaging (1). Hopefully, these hospital consortium investigators will expand their analysis to compare other events in the vaccinated and unvaccinated populations and in COVID-19 patients.

    Reference

    1) Daniels CJ, Rajpal S, Greenshields JT, et al. Prevalence of Clinical and Subclinical Myocarditis in Competitive Athletes With Recent SARS-CoV-2 Infection: Results From the Big Ten COVID-19 Cardiac Registry. JAMA Cardiol. Published online May 27, 2021. doi:10.1001/jamacardio.2021.2065

    CONFLICT OF INTEREST: None Reported
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    A possible role for preexisting plasma anti-PEG antibodies in post mRNA-vaccine myocarditis?
    Sui Huang, MD, PhD | Institute for Systems Biology
    This study joins a series of recent reports establishing a characteristic pattern for post-COVID19 vaccine myocarditis: it affects predominantly young male adults around age 30, mostly after the second, but in a substantial fraction, also after the first dose - and is associated specifically with mRNA-type vaccines
    (In this report almost 98% of cases occurred in patients receiving an mRNA vaccine - and unlike in previous studies, 3% of cases had the J&J adenovirus vector-based vaccine.)

    This pattern (young age, mRNA vaccine, timing, occasionally after first shot) is consistent with the hypothesis that it is a reaction mediated
    by preexisting circulating anti-PEG antibodies, which has a high prevalence among the young adults. The lipid nanoparticle (LNP) used in the mRNA vaccines contains PEG-conjugated lipids for stability reasons. Once opsonized with the anti-PEG antibodies, the LNP could activate the complement system which plays a critical role in triggering myositis. For a more complete exposition of the hypothesis, see https://tinyurl.com/66uejbpc.

    A similar phenomenon had also been observed after vaccinia immunization against small pox - the vaccinia- attenuated virus resembles in size the lipid-nanoparticle.

    Testing for the anti-PEG antibodies in these myositis patients is inexpensive and readily done, and if it supports this hypothesis, this could be a biomarker for potential of adverse reactions to PEGylated COVID19 vaccines, and might influence choice of vaccines.

    Young adults under 30 not only have drastically higher prevalence of plasma anti-PEG antibodies than the elderly, but they also have higher titer.

    This is of relevance as we now move to vaccinating this younger generation.

    CONFLICT OF INTEREST: None Reported
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    Research Letter
    August 4, 2021

    Myocarditis and Pericarditis After Vaccination for COVID-19

    Author Affiliations
    • 1Section of Infectious Diseases, Providence Regional Medical Center Everett, Everett, Washington
    • 2Providence Research Network, Renton, Washington
    • 3Medical Intensive Care Unit, Providence Regional Medical Center Everett, Everett, Washington
    • 4Department of Infection Prevention and Control, Providence Regional Medical Center Everett, Everett, Washington
    • 5Office of Clinical Research, Providence Health and Services, Southern California Region, Los Angeles
    JAMA. 2021;326(12):1210-1212. doi:10.1001/jama.2021.13443

    Rare cases of cardiac inflammation following SARS-CoV-2 vaccination have been reported.1-4 We reviewed the clinical records of vaccine recipients to identify cases of postvaccination myocarditis or pericarditis.

    Methods

    Forty hospitals in Washington, Oregon, Montana, and Los Angeles County, California, that were part of the Providence health care system and used the same electronic medical record (EMR) were included. All patients with documented COVID-19 vaccinations administered inside the system or recorded in state registries at any time through May 25, 2021, were identified. Vaccinated patients who subsequently had emergency department or inpatient encounters with diagnoses of myocarditis, myopericarditis, or pericarditis were ascertained from EMRs (see eTables 1 and 2 in the Supplement for exclusions and definitions).

    The monthly rates of first-time hospital diagnoses (excluding patients with previous diagnoses in January 2018–January 2019) in January 2019 through January 2021 (prevaccine period) and February through May 2021 (vaccine period) were compared.

    The Wilson method was used to calculate 95% confidence intervals for single proportions. Change in incidence between periods and 95% confidence intervals for incidence were assessed using an exact rate ratio test assuming Poisson distribution, with a 2-sided P < .05 defining statistical significance. R version 2021 statistical software (R Foundation) was used. The Providence institutional review board approved the study with a waiver of informed consent.

    Results

    Among 2 000 287 individuals receiving at least 1 COVID-19 vaccination, 58.9% were women, the median age was 57 years (interquartile range [IQR], 40-70 years), 76.5% received more than 1 dose, 52.6% received the BNT162b2 vaccine (Pfizer/BioNTech), 44.1% received the mRNA-1273 vaccine (Moderna), and 3.1% received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson). Twenty individuals had vaccine-related myocarditis (1.0 [95% CI, 0.61-1.54] per 100 000) and 37 had pericarditis (1.8 [95% CI, 1.30-2.55] per 100 000).

    Myocarditis occurred a median of 3.5 days (IQR, 3.0-10.8 days) after vaccination (mRNA-1273 vaccine, 11 cases [55%]; BNT162b2 vaccine, 9 cases [45%]) (Table). Fifteen individuals (75%; 95% CI, 53%-89%) were male, and the median age was 36 years (IQR, 26-48 years). Four persons (20%; 95% CI, 8%-42%) developed symptoms after the first vaccination and 16 (80%; 95% CI, 58%-92%) developed symptoms after the second. Nineteen patients (95%; 95% CI, 76%-99%) were admitted to the hospital. All were discharged after a median of 2 days (IQR, 2-3 days). There were no readmissions or deaths. Two patients received a second vaccination after onset of myocarditis; neither had worsening of symptoms. At last available follow-up (median, 23.5 days [IQR, 4.8-41.3 days] after symptom onset), 13 patients (65%; 95% CI, 43%-82%) had symptom resolution and 7 (35%; 95% CI, 18%-57%) were improving.

    Pericarditis developed after the first immunization in 15 cases (40.5%; 95% CI, 26%-57%) and after the second immunization in 22 cases (59.5%; 95% CI, 44%-74%) (mRNA-1273 vaccine, 12 cases [32%]; BNT162b2 vaccine, 23 cases [62%]; Ad26.COV2.S vaccine, 2 cases [5%]). Median onset was 20 days (IQR, 6.0-41.0 days) after the most recent vaccination. Twenty-seven individuals (73%; 95% CI, 57%-85%) were male, and the median age was 59 years (IQR, 46-69 years). Thirteen (35%; 95% CI, 22%-51%) were admitted to the hospital, none to intensive care. Median stay was 1 day (IQR, 1-2 days). Seven patients with pericarditis received a second vaccination. No patient died. At last available follow-up (median, 28 days; IQR, 7-53 days), 7 patients (19%; 95% CI, 9%-34%) had resolved symptoms and 23 (62%; 95% CI, 46%-76%) were improving.

    The mean monthly number of cases of myocarditis or myopericarditis during the prevaccine period was 16.9 (95% CI, 15.3-18.6) vs 27.3 (95% CI, 22.4-32.9) during the vaccine period (P < .001) (Figure). The mean numbers of pericarditis cases during the same periods were 49.1 (95% CI, 46.4-51.9) and 78.8 (95% CI, 70.3-87.9), respectively (P < .001).

    Discussion

    Two distinct self-limited syndromes, myocarditis and pericarditis, were observed after COVID-19 vaccination. Myocarditis developed rapidly in younger patients, mostly after the second vaccination. Pericarditis affected older patients later, after either the first or second dose.

    Some vaccines are associated with myocarditis,5 including mRNA vaccines,1-4 and the Centers for Disease Control and Prevention recently reported a possible association between COVID-19 mRNA vaccines and myocarditis, primarily in younger male individuals within a few days after the second vaccination, at an incidence of about 4.8 cases per 1 million.6 This study shows a similar pattern, although at higher incidence, suggesting vaccine adverse event underreporting. Additionally, pericarditis may be more common than myocarditis among older patients.

    Study limitations include cases missed in outside care settings and missed diagnoses of myocarditis or pericarditis (which would underestimate the incidence), as well as inaccurate EMR vaccination information. Temporal association does not prove causation, although the short span between vaccination and myocarditis onset and the elevated incidence of myocarditis and pericarditis in the study hospitals lend support to a possible relationship.

    Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Associate Editor.
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    Article Information

    Corresponding Author: George A. Diaz, MD, Providence Regional Medical Center Everett, 1700 13th St, Ste B3-018, Everett, WA 98201 (george.diaz@providence.org).

    Accepted for Publication: July 26, 2021.

    Published Online: August 4, 2021. doi:10.1001/jama.2021.13443

    Author Contributions: Dr Robicsek 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.

    Concept and design: Diaz, Robicsek.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Diaz, Parsons, Meier, Hutchinson, Robicsek.

    Critical revision of the manuscript for important intellectual content: Diaz, Gering, Hutchinson, Robicsek.

    Statistical analysis: Diaz, Meier, Robicsek.

    Administrative, technical, or material support: Parsons, Gering, Robicsek.

    Supervision: Robicsek.

    Conflict of Interest Disclosures: Dr Diaz reported receipt of clinical trial research support from Gilead Sciences, Regeneron, Roche, Boehringer Ingelheim, and Edesa Biotech and scientific advisory board membership for Safeology. No other disclosures were reported.

    Additional Contributions: We acknowledge the patients included in this study and the caregiver teams across the Providence organization.

    References
    1.
    Montgomery  J, Ryan  M, Engler  R,  et al.  Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military.   JAMA Cardiol. Published online June 29, 2021. doi:10.1001/jamacardio.2021.2833PubMedGoogle Scholar
    2.
    Kim  HW, Jenista  ER, Wendell  DC,  et al.  Patients with acute myocarditis following mRNA COVID-19 vaccination.   JAMA Cardiol. Published online June 29, 2021. doi:10.1001/jamacardio.2021.2828PubMedGoogle Scholar
    3.
    Bautista García  J, Peña Ortega  P, Bonilla Fernández  JA,  et al.  Acute myocarditis after administration of the BNT162b2 vaccine against COVID-19.   Rev Esp Cardiol (Engl Ed). Published online April 27, 2021. doi:10.1016/j.recesp.2021.03.009PubMedGoogle Scholar
    4.
    Rosner  CM, Genovese  L, Tehrani  BN,  et al.  Myocarditis temporally associated with COVID-19 vaccination.   Circulation. Published online June 16, 2021. doi:10.1161/CIRCULATIONAHA.121.055891PubMedGoogle Scholar
    5.
    Su  JR, McNeil  MM, Welsh  KJ,  et al.  Myopericarditis after vaccination, Vaccine Adverse Event Reporting System (VAERS), 1990-2018.   Vaccine. 2021;39(5):839-845. doi:10.1016/j.vaccine.2020.12.046PubMedGoogle ScholarCrossref
    6.
    Wallace  M, Oliver  S. COVID-19 mRNA vaccines in adolescents and young adults: benefit-risk discussion. Slide 28. Published June 23, 2021. Accessed July 7, 2021. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-06/05-COVID-Wallace-508.pdf
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