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Acute myocarditis following a third dose of COVID-19 mRNA vaccination in adults.

Author information

Affiliations

  • 1. Department of Cardiology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, USA.
      Authors
    • Simone A 1
    • Herald J 1
    • Nayak R 1
    • Shen YA 1
    • Lee MS 1
    (5 authors)
  • 2. Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA.
      Authors
    • Chen A 2
    (1 author)

International Journal of Cardiology, 21 Jul 2022, 365:41-43
https://doi.org/10.1016/j.ijcard.2022.07.031 PMID: 35870635 PMCID: PMC9299985

This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
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Abstract 

Introduction

Myocarditis has been reported following the second dose of COVID-19 mRNA vaccination. Whether administration of additional doses of COVID-19 vaccines further increases the risk of myocarditis is unknown.

Methods

We included individuals who received one to three doses of BNT162b2 or mRNA-1273 mRNA vaccine between 12/14/2020 and 2/18/2022. Myocarditis within 21 days of vaccine administration was identified using electronic medical records. Incidence rate ratios were calculated by comparing the observed incidence with the expected incidence from the same population during a 365-day baseline period.

Results

Of 3,076,660 KPSC members who received at least one dose of COVID-19 mRNA vaccines, 2,916,739 (94.5%) received at least two doses, and 1,146,254 (47.0%) received three doses. The incidence rate ratio for myocarditis was 0.86 (95% CI 0.31-1.93) for the first dose, 4.22 (95% CI 2.63-6.53) for the second dose, and 2.61 (1.13-5.29) for the third dose. Most myocarditis cases following the second and third dose occurred within seven days of vaccination.

Conclusion

Myocarditis was a rare event observed after the second or third dose of vaccination. Most cases presented within seven days of vaccination. The incidence of myocarditis following the third dose was not significantly higher than that observed after the second dose.

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Logo of pheelsevierLink to Publisher's site
Int J Cardiol. 2022 Oct 15; 365: 41–43.
Published online 2022 Jul 21. https://doi.org/10.1016/j.ijcard.2022.07.031
PMCID: PMC9299985
PMID: 35870635

Acute myocarditis following a third dose of COVID-19 mRNA vaccination in adults

Anthony Simone,a John Herald,a Aiyu Chen,b Rohith Nayak,a Yuh-Jer Albert Shen,a and Ming-Sum Leea,[low asterisk]
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Associated Data

Supplementary Materials

Abstract

Introduction

Myocarditis has been reported following the second dose of COVID-19 mRNA vaccination. Whether administration of additional doses of COVID-19 vaccines further increases the risk of myocarditis is unknown.

Methods

We included individuals who received one to three doses of BNT162b2 or mRNA-1273 mRNA vaccine between 12/14/2020 and 2/18/2022. Myocarditis within 21 days of vaccine administration was identified using electronic medical records. Incidence rate ratios were calculated by comparing the observed incidence with the expected incidence from the same population during a 365-day baseline period.

Results

Of 3,076,660 KPSC members who received at least one dose of COVID-19 mRNA vaccines, 2,916,739 (94.5%) received at least two doses, and 1,146,254 (47.0%) received three doses. The incidence rate ratio for myocarditis was 0.86 (95% CI 0.31–1.93) for the first dose, 4.22 (95% CI 2.63–6.53) for the second dose, and 2.61 (1.13–5.29) for the third dose. Most myocarditis cases following the second and third dose occurred within seven days of vaccination.

Conclusion

Myocarditis was a rare event observed after the second or third dose of vaccination. Most cases presented within seven days of vaccination. The incidence of myocarditis following the third dose was not significantly higher than that observed after the second dose.

Keywords: Vaccination, Myocarditis, COVID-19, Booster, Third-dose, Adverse event, Hospitalization

1. Introduction

The COVID-19 mRNA vaccines are effective in reducing COVID-19-related severe disease and death [1]. Waning vaccine effectiveness has prompted the recommendation to administer additional (booster) doses. Third-dose vaccination is associated with improved protection [2]. Recent studies suggest some individuals benefit from receiving a fourth dose [3]. With additional doses of COVID-19 mRNA vaccines being recommended, it is essential to monitor its safety. Myocarditis has been reported following COVID-19 mRNA vaccination [[4], [5], [6], [7]]. Studies showed the rates of myocarditis to be highest after the second dose. Whether administration of a third vaccination dose further increases the risk of myocarditis is not known.

This study aimed to evaluate whether a third dose of COVID-19 mRNA vaccine was associated with an increased risk of myocarditis.

2. Methods

We included Kaiser Permanente Southern California (KPSC) members aged ≥18 years who received one to three doses of the BNT162b2 (Pfizer) or mRNA-1273 (Moderna) mRNA vaccine between 12/14/2020 and 2/18/2022. KPSC is an integrated healthcare delivery system with more than 4 million members in the United States. Members enroll through the Kaiser Foundation Health Plan for comprehensive insurance including prescription coverage. Comprehensive medical information of KPSC members is prospectively captured electronically. This includes demographics, administrative, pharmacy, laboratory, and healthcare utilization data from both ambulatory and inpatient encounters. The present study was approved by the KPSC Institutional Review Board. A waiver of informed consent was obtained due to the study's observational nature.

We used International Classification of Diseases (ICD), 10th Revision codes to identify individuals hospitalized for myocarditis within 21 days of vaccine administration. All cases were independently reviewed and adjudicated by two cardiologists. The following criteria were used to confirm myocarditis: 1) symptoms consistent with myocarditis, 2) elevated troponin I level above the upper limit of normal, 3) electrocardiogram findings consistent with myocarditis, new wall motion abnormalities on cardiac imaging, or cardiac magnetic resonance imaging findings consistent with myocarditis, and 4) presentation not attributed to other causes.

The observed incidence of myocarditis following vaccination after each dose was compared with the expected incidence using data obtained from the same population during a 365-day baseline period, two years before the vaccination date. Incidence rate ratios (IRR) and 95% confidence intervals (CIs) were calculated. A 2-sided p-value of <0.05 was considered statistically significant. Statistical analyses were performed using STATA/MP 17 (Stata-Corp, College Station, TX).

2.1. Findings

Of 3,076,660 KPSC members who received at least one dose of COVID-19 mRNA vaccines, 2,916,739 (94.5%) received at least two doses, and 1,146,254 (47.0%) received three doses. Table 1 shows the baseline characteristics. Median age was 47 years (IQR 32, 62), 53.6% were women, 29.7% White, 7.1% Black, 38.8% Hispanic, and 13.3% were Asian. 1,673,672 (54.5%) received at least one dose of BNT162b2, and 1,490,941 (48.5%) received at least one dose of mRNA-1273.

Table 1

Baseline characteristics.

First dose (n = 3,076,660)Second dose (n = 2,916,739)Third dose (n = 1,446,254)
Age group, year
 18–391,171,382 (38.1)1,093,029 (37.5)372,622 (25.8)
 40–641,270,414 (41.3)1,205,345 (41.3)626,221 (43.3)
 65–80523,502 (17.0)510,168 (17.5)372,504 (25.7)
 >80111,362 (3.6)108,197 (3.7)74,907 (5.2)
Gender
 Male1,426,331 (46.4)1,343,771 (46.1)641,073 (44.3)
 Female1,649,909 (53.6)1,572,593 (53.9)805,050 (55.7)
 Other420 (0.01)375 (0.01)131 (0.01)
Race / Ethnicity
 White912,348 (29.7)869,085 (29.8)491,720 (34.0)
 Black218,051 (7.1)205,877 (7.1)101,882 (7.0)
 Hispanic1,194,059 (38.8)1,132,149 (38.8)496,420 (34.3)
 Asian409,385 (13.3)393,616 (13.5)239,961 (16.6)
 Other342,817 (11.1)316,012 (10.8)116,271 (8.0)
Medical comorbidities
 Hypertension515,015 (16.7)497,828 (17.1)333,763 (23.1)
 Diabetes257,715 (8.4)248,946 (8.5)166,900 (11.5)
 Obesity296,401 (9.6)282,867 (9.7)159,558 (11.0)
 Heart failure54,571 (1.8)52,363 (1.8)34,091 (2.4)
 Renal failure137,146 (4.5)133,079 (4.6)94,009 (6.5)
 Liver disease75,429 (2.5)72,004 (2.5)44,219 (3.1)
 Pulmonary disease215,606 (7.0)206,790 (7.1)126,793 (8.8)
 Hypothyroidism143,614 (4.7)138,642 (4.8)91,232 (6.3)

Within 21 days after vaccination, there were 6 cases of myocarditis following the first dose, 26 cases following the second dose, and 9 cases following the third dose (Table 2 ). The incidence rate ratio for myocarditis was 0.86 (95% CI 0.31–1.93) for the first dose, 4.22 (95% CI 2.63–6.53) for the second dose, and 2.61 (1.13–5.29) for the third dose (Fig. S1). Most myocarditis cases following the second and third dose occurred within seven days of vaccination. The increased incidence was observed primarily among patients younger than 40 years (Supplementary Table S1).

Table 2

Incidence rate ratios of myocarditis in vaccinated individuals compared to control groups.

Myocarditis cases, no.Follow-up time, person-daysIncidence rate ratio (95% CI)P value
First dose (n = 3,076,660)
 Day 1–7a221,536,6200.86 (0.10–3.18)0.92
 Day 8–14b221,536,6200.86 (0.10–3.18)0.92
 Day 15–21c221,536,6200.86 (0.10–3.18)0.92
 Day 1–21d664,609,8600.86 (0.31–1.93)0.76
 Baseline comparison intervale1211,122,980,900reference
Second dose (n = 2,916,739)
 Day 1–7a2120,417,17310.23 (6.09–16.4)<0.0001
 Day 8–14b320,417,1731.46 (0.30–4.39)0.5
 Day 15–21c220,417,1730.97 (0.11–3.61)0.95
 Day 1–21d2661,251,5194.22 (2.63–6.53)<0.0001
 Baseline comparison intervale1071,064,609,735reference
Third dose (n = 1,446,254)
 Day 1–7a710,123,7786.08 (2.34–13.3)0.0003
 Day 8–14b210,123,7781.74 (0.21–6.56)0.44
 Day 15–21c010,123,77800.32
 Day 1–21d930,371,3342.61 (1.13–5.29)0.01
 Baseline comparison intervale60527,882,710reference
aRisk interval: day 1 to day 7 after vaccination.
bRisk interval: day 8 to day 14 after vaccination.
cRisk interval: day 15 to day 21 after vaccination.
dRisk interval: day 1 to day 21 after vaccination.
eRisk interval: 2 years prior to vaccination date until 1 year prior to vaccination date (i.e., a 365-day risk interval).

Of the nine cases of myocarditis following the third dose, eight were men, and five were between 18 and 40 years of age. Median follow-up was 224 days (IQR 167, 336). During the follow-up period, one patient died from events unrelated to myocarditis (cancer). All other patients recovered with resolution of symptoms.

3. Discussion

In this population-based cohort study of 3,076,660 individuals who received one, two, or three doses of COVID-19 mRNA vaccines, myocarditis was a rare event observed after the second or third dose of vaccination. Most cases presented within seven days of vaccination. The incidence of myocarditis following the third dose did not appear to be significantly higher than that observed after the second dose.

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. Several study limitations should be acknowledged. First, only myocarditis cases that required hospitalization were included, and patients who did not seek care could not be captured. Second, myocarditis was managed at the discretion of the treating clinicians; there was a lack of uniform testing, and myocardial biopsy was not performed. Third, the follow-up period was short, and potential long-term risks of vaccination could have been missed. Fourth, despite drawing from more than 3 million vaccinated individuals, the number of myocarditis cases was still small, limiting the precision of the point estimates. Fifth, myocarditis cases were identified using ICD codes, so cases not diagnosed as myocarditis by the primary clinician would have been missed. Finally, no causal relationship between COVID-19 mRNA vaccination and post-vaccination myocarditis can be established, given the observational nature of this study.

Funding

None.

CRediT authorship contribution statement

Anthony Simone: Conceptualization, Data curation, Writing – original draft. John Herald: Conceptualization, Data curation, Writing – review & editing. Aiyu Chen: Data curation, Investigation, Methodology, Formal analysis, Validation. Rohith Nayak: Conceptualization, Investigation, Writing – review & editing. Yuh-Jer Albert Shen: Conceptualization, Data curation, Writing – review & editing. Ming-Sum Lee: Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Writing – original draft.

Declaration of Competing Interest

None.

Acknowledgement

None.

Footnotes

Appendix ASupplementary data to this article can be found online at https://doi.org/10.1016/j.ijcard.2022.07.031.

Appendix A. Supplementary data

Supplementary material

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