Cases of Myocarditis
Among 9,289,765 Israeli residents who were included during the surveillance period, 5,442,696 received a first vaccine dose and 5,125,635 received two doses (Table 1 and Fig. S2). A total of 304 cases of myocarditis (as defined by the ICD-9 codes for myocarditis) were reported to the Ministry of Health (Table 2). These cases were diagnosed in 196 persons who had received two doses of the vaccine: 151 persons within 21 days after the first dose and 30 days after the second dose and 45 persons in the period after 21 days and 30 days, respectively. (Persons 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 review of the case histories, we ruled out 21 cases because of reasonable alternative diagnoses. Thus, the diagnosis of myocarditis was affirmed for 283 cases. These cases included 142 among vaccinated persons within 21 days after the first dose and 30 days after the second dose, 40 among vaccinated persons not in proximity to vaccination, and 101 among unvaccinated persons. Among the unvaccinated persons, 29 cases of myocarditis were diagnosed in those with confirmed Covid-19 and 72 in those without a confirmed diagnosis.
Of the 142 persons in whom myocarditis developed within 21 days after the first dose of vaccine or within 30 days after the second dose, 136 received a diagnosis of definite or probable myocarditis, 1 received a diagnosis of possible myocarditis, 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 persons showed foci of endointerstitial edema and neutrophils, along with mononuclear-cell infiltrates (monocytes or macrophages and lymphocytes) with no giant cells. No other patients underwent endomyocardial biopsy. The clinical features of myocarditis after vaccination are provided in Table S3.
In the 136 cases of definite or probable myocarditis, the clinical presentation in 129 was generally mild, with resolution of myocarditis in most cases, as judged by clinical symptoms and inflammatory markers and troponin elevation, electrocardiographic and echocardiographic normalization, and a relatively short length of hospital stay. However, one person with fulminant myocarditis died. The ejection fraction was normal or mildly reduced in most persons and severely reduced in 4 persons. Magnetic resonance imaging that was performed in 48 persons showed findings that were consistent with myocarditis on the basis of at least one positive T2-based sequence and one positive T1-based sequence (including T2-weighted images, T1 and T2 parametric mapping, and late gadolinium enhancement). Follow-up data regarding the status of cases after hospital discharge and consistent measures of cardiac function were not available.
Shown is the timing of the diagnosis of myocarditis among recipients of the first dose of vaccine (Panel A) and the second dose (Panel B), according to sex, and the distribution of cases among recipients according to both age and sex after the first dose (Panel C) and after the second dose (Panel D). Cases of myocarditis were reported within 21 days after the first dose and within 30 days after the second dose.
The peak number of cases with proximity to vaccination occurred in February and March 2021; the associations with vaccination status, age, and sex are provided in Table 1 and Figure 1. Of 136 persons with definite or probable myocarditis, 19 presented after the first dose of vaccine and 117 after the second dose. In the 21 days after the first dose, 19 persons with myocarditis were hospitalized, and hospital admission dates were approximately equally distributed over time. A total of 95 of 117 persons (81%) who presented after the second dose were hospitalized within 7 days after vaccination. Among 95 persons for whom data regarding age and sex were available, 86 (91%) were male and 72 (76%) were under the age of 30 years.
Comparison of Risks According to First or Second Dose
A comparison of risks over equal time periods of 21 days after the first and second doses according to age and sex is provided in Table 3. Cases were clustered during the first few days after the second dose of vaccine, according to visual inspection of the data (Figure 1B and 1D). The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19); the overall risk difference was 3.19 (95% CI, 2.37 to 4.02) among male recipients and 0.39 (95% CI, 0.10 to 0.68) among female recipients. The highest difference was observed among male recipients between the ages of 16 and 19 years: 13.73 per 100,000 persons (95% CI, 8.11 to 19.46); in this age group, the percent attributable risk to the second dose was 91%. The difference in the risk among female recipients between the first and second doses in the same age group was 1.00 per 100,000 persons (95% CI, −0.63 to 2.72). Repeating these analyses with a shorter follow-up of 7 days owing to the presence of a cluster that was noted after the second vaccine dose disclosed similar differences in male recipients between the ages of 16 and 19 years (risk difference, 13.62 per 100,000 persons; 95% CI, 8.31 to 19.03). These findings pointed to the first week after the second vaccine dose as the main risk window.
Observed versus Expected Incidence
Table 4 shows the standardized incidence ratios for myocarditis according to vaccine dose, age group, and sex, as projected from the incidence during the prepandemic period from 2017 through 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 driven mostly by the diagnosis of myocarditis in younger male recipients. Among boys and men, the standardized incidence ratio was 13.60 (95% CI, 9.30 to 19.20) for those 16 to 19 years of age, 8.53 (95% CI, 5.57 to 12.50) for those 20 to 24 years, 6.96 (95% CI, 4.25 to 10.75) for those 25 to 29 years, and 2.90 (95% CI, 1.98 to 4.09) for those 30 years of age or older. These substantially increased findings were not observed after the first dose. A sensitivity analysis showed that for male recipients between the ages of 16 and 24 years who had received a second vaccine dose, the observed standardized incidence ratios would have required overreporting of myocarditis by a factor of 4 to 5 on the assumption that the true incidence would not have differed from the expected incidence (Table S4).
Rate Ratio between Vaccinated and Unvaccinated Persons
Within 30 days after receipt of the second vaccine dose in the general population, the rate ratio for the comparison of the incidence of myocarditis between vaccinated and unvaccinated persons was 2.35 (95% CI, 1.10 to 5.02) according to the Brighton Collaboration classification of definite and probable cases and after adjustment for age and sex. This result was driven mainly by the findings for males in younger age groups, with a rate ratio of 8.96 (95% CI, 4.50 to 17.83) for those between the ages of 16 and 19 years, 6.13 (95% CI, 3.16 to 11.88) for those 20 to 24 years, and 3.58 (95% CI, 1.82 to 7.01) for those 25 to 29 years (Table 5). When follow-up was restricted to 7 days after the second vaccine dose, the analysis results for male recipients between the ages of 16 and 19 years were even stronger than the findings within 30 days (rate ratio, 31.90; 95% CI, 15.88 to 64.08). Concordance of our findings with the Bradford Hill causality criteria is shown in Table S5.