Myocarditis after BNT162b2 mRNA vaccine against Covid-19 in Israel
Case of myocarditis
Of 9,289,765 Israeli residents who were included during the surveillance period, 5,442,696 received a first dose of vaccine and 5,125,635 received two doses (Table 1 and figure S2). A total of 304 cases of myocarditis (as defined by the ICD-9 codes for myocarditis) have been reported to the Department of Health (Table 2). These cases were diagnosed in 196 people who had received two doses of the vaccine: 151 people within 21 days of the first dose and 30 days after the second dose and 45 people in the period after 21 days and 30 days, respectively. (People in whom myocarditis developed 22 days or more after the first dose of vaccine or more than 30 days after the second dose were considered to have myocarditis that was not in temporal proximity to the vaccine.) After A detailed history review, we excluded 21 cases due to reasonable alternative diagnoses. Thus, the diagnosis of myocarditis was affirmed for 283 cases. These cases included 142 among those vaccinated within 21 days of the first dose and 30 days after the second dose, 40 among those vaccinated not close to vaccination, and 101 among those unvaccinated. Among unvaccinated people, 29 cases of myocarditis have been diagnosed in those with confirmed Covid-19 and 72 in those without a confirmed diagnosis.
Of the 142 people in whom myocarditis developed within 21 days of the first dose of vaccine or within 30 days of the second dose, 136 were diagnosed with definite or probable myocarditis, 1 was diagnosed with myocarditis possible and 5 had insufficient data. Classification of cases according to the definition of myocarditis used by the CDC 4-6 is provided in Table S1.
Endomyocardial biopsy samples that were obtained from 2 people showed foci of endointerstitial edema and neutrophils, as well as infiltrates of mononuclear cells (monocytes or macrophages and lymphocytes) without giant cells. No other patient had an endomyocardial biopsy. The clinical features of myocarditis after vaccination are shown in Table S3.
In the 136 cases of definite or probable myocarditis, the clinical presentation in 129 cases was generally mild, with resolution of myocarditis in most cases, judged by clinical symptoms and inflammatory markers and elevation of troponin , electrocardiographic and echocardiographic normalization, and a relatively short hospital stay. However, a person with fulminant myocarditis has died. The ejection fraction was normal or slightly reduced in most people and severely reduced in 4 people. Magnetic resonance imaging performed in 48 people showed results consistent with myocarditis based on at least one T2-based positive sequence and one T1-based positive sequence (including T2-weighted images, parametric mapping T1 and T2 and enhancement with gadolinium). Follow-up data regarding the status of cases after hospital discharge and consistent measures of heart function were not available.
Timing of diagnosis of myocarditis in recipients of the first dose of vaccine (Part A) and second dose (Part B), by sex, and the distribution of cases among recipients by age and sex after first dose (Panel C) and after the second dose (Panel D). Myocarditis has been reported within 21 days of the first dose and within 30 days of the second dose.
The maximum number of cases close to vaccination occurred in February and March 2021; associations with immunization status, age and sex are provided in Table 1 and Figure 1. Of 136 people with definite or probable myocarditis, 19 presented after the first dose of vaccine and 117 after the second dose. During the 21 days after the first dose, 19 people with myocarditis were hospitalized and the hospital admission dates were spread roughly evenly over time. A total of 95 of 117 people (81%) who presented after the second dose were hospitalized within 7 days of vaccination. Of 95 people for whom age and sex data were available, 86 (91%) were males and 72 (76%) were under 30 years of age.
Comparison of risks by first or second dose
A comparison of risks over equal 21-day time periods after the first and second dose by age and sex is provided in Table 3. Cases were clustered within the first few days after the second dose of vaccine, based on visual inspection of the data (Figure 1B and 1D). The overall risk difference between the first and second dose was 1.76 per 100,000 people (95% confidence interval [CI], 1.33 to 2.19); the overall risk difference was 3.19 (95% CI, 2.37 to 4.02) in men and 0.39 (95% CI, 0.10 to 0.68) in women. The greatest difference was observed among male beneficiaries aged 16 to 19: 13.73 per 100,000 people (95% CI, 8.11 to 19.46); in this age group, the percent risk attributable to the second dose was 91%. The risk difference in recipient women between the first and second dose in the same age group was 1.00 per 100,000 people (95% CI, -0.63 to 2.72). Repeating these analyzes with a shorter 7-day follow-up due to the presence of a cluster that was noted after the second dose of vaccine revealed similar differences in male recipients aged 16 to 19 (difference in risk, 13.62 per 100,000 people; 95% CI, 8.31 to 19.03). These results indicated that the first week after the second dose of vaccine was the main window of risk.
Observed impact versus expected impact
Table 4 shows the standardized incidence ratios of myocarditis according to vaccine dose, age group and sex, as projected from the incidence during the prepandemic period from 2017 to 2019. Myocarditis after the second dose of vaccine had a standardized incidence ratio of 5.34 (95% CI, 4.48 to 6.40), which was primarily due to the diagnosis of myocarditis in young male recipients. In boys and men, the standardized incidence ratio was 13.60 (95% CI, 9.30 to 19.20) for 16 to 19 year olds, 8.53 (95% CI, 5, 57 to 12.50) for 20 to 24 year olds, 6.96 (95% CI, 4.25 to 10.75) for 25 to 29 year old, and 2.90 (95% CI, 1.98 to 4.09) for 30 years or more. These significantly increased results were not seen after the first dose. Sensitivity analysis showed that for male recipients aged 16 to 24 who received a second dose of vaccine, the observed standardized incidence ratios would have required overreporting of myocarditis by a factor of 4 to 5 in assuming that the actual impact would not have differed from the expected impact (Table S4).
Rate ratio between vaccinated and unvaccinated people
Within 30 days of receiving the second dose of vaccine in the general population, the rate ratio for comparing the incidence of myocarditis between vaccinated and unvaccinated individuals was 2.35 (95% CI, 1.10 to 5.02) according to the Brighton Collaboration classification and probable cases and after adjusting for age and sex. This result is mainly explained by the results for men in the younger age groups, with a rate ratio of 8.96 (95% CI, 4.50 to 17.83) for people aged 16 at 19 years, 6.13 (95% CI, 3.16-11.88). ) for 20 to 24 year olds, and 3.58 (95% CI, 1.82 to 7.01) for 25 to 29 year olds (Table 5). When follow-up was limited to 7 days after the second dose of vaccine, assay results for male recipients aged 16 to 19 were even stronger than results within 30 days (rate report, 31, 90; 95% CI: 15.88 to 64.08). The concordance of our results with the Bradford Hill causal criteria is presented in Table S5.