Patients

Between December 20, 2020, and May 24, 2021, a total of 2,558,421 Clalit Health Services members received at least one dose of the BNT162b2 mRNA Covid-19 vaccine; of these patients, 2,401,605 (94%) received two doses. Initially, 159 potential cases of myocarditis were identified according to ICD-9 codes during the 42 days after receipt of the first vaccine dose. After adjudication, 54 of these cases were deemed to have met the study criteria for a diagnosis of myocarditis. Of these cases, 41 were classified as mild in severity, 12 as intermediate, and 1 as fulminant.

Of the 105 cases that did not meet the study criteria for a diagnosis of myocarditis, 78 were recodings of previous diagnoses of myocarditis without a new event, 16 did not have sufficient available data to meet the diagnostic criteria, and 7 preceded the first vaccine dose; in 4 cases, a diagnosis of a condition other than myocarditis was determined to be more likely (Fig. S1). Community health records were available for all the patients who had been identified as potentially having had myocarditis. Discharge summaries from the index hospitalization were available for 55 of 81 potential cases (68%) that were not recoding events and for 38 of 54 cases (70%) that met the study criteria.

Table 1. Table 1. Characteristics of the Study Population and Myocarditis Cases at Baseline.

The characteristics of the patients with myocarditis are provided in Table 1. The median age of the patients was 27 years (interquartile range [IQR], 21 to 35), and 94% were boys and men. Two patients had contracted Covid-19 before they received the vaccine (125 days and 186 days earlier, respectively). Most patients (83%) had no coexisting medical conditions; 13% were receiving treatment for chronic diseases. One patient had mild left ventricular dysfunction before vaccination.

Figure 1. Figure 1. Kaplan–Meier Estimates of Myocarditis at 42 Days.

Shown is the cumulative incidence of myocarditis during a 42-day period after the receipt of the first dose of the BNT162b2 messenger RNA coronavirus disease 2019 (Covid-19) vaccine. A diagnosis of myocarditis was made in 54 patients in an overall population of 2,558,421 vaccinated persons enrolled in the largest health care organization in Israel. The vertical line at 21 days shows the median day of administration of the second vaccine dose. The shaded area shows the 95% confidence interval.

Among the patients with myocarditis, 37 (69%) received the diagnosis after the second vaccine dose, with a median interval of 21 days (IQR, 21 to 22) between doses. A cumulative incidence curve of myocarditis after vaccination is shown in Figure 1. The distribution of the days since vaccination until the occurrence of myocarditis is shown in Figure S2. Both figures show events occurring throughout the postvaccination period and indicate an increase in incidence after the second dose.

Incidence of Myocarditis Table 2. Table 2. Incidence of Myocarditis 42 Days after Receipt of the First Vaccine Dose, Stratified According to Age, Sex, and Disease Severity.

The overall estimated incidence of myocarditis within 42 days after the receipt of the first dose per 100,000 vaccinated persons was 2.13 cases (95% confidence interval [CI], 1.56 to 2.70), which included an incidence of 4.12 (95% CI, 2.99 to 5.26) among male patients and 0.23 (95% CI, 0 to 0.49) among female patients (Table 2). Among all the patients between the ages of 16 and 29 years, the incidence per 100,000 persons was 5.49 (95% CI, 3.59 to 7.39); among those who were 30 years of age or older, the incidence was 1.13 (95% CI, 0.66 to 1.60). The highest incidence (10.69 cases per 100,000 persons; 95% CI, 6.93 to 14.46) was observed among male patients between the ages of 16 and 29 years. In the overall population, the incidence per 100,000 persons according to disease severity was 1.62 (95% CI, 1.12 to 2.11) for mild myocarditis, 0.47 (95% CI, 0.21 to 0.74) for intermediate myocarditis, and 0.04 (95% CI, 0 to 0.12) for fulminant myocarditis. Within each disease-severity stratum, the incidence was higher in male patients than in female patients and higher in those between the ages of 16 and 29 than in those who were 30 years of age or older.

Clinical and Laboratory Findings Table 3. Table 3. Presentation, Clinical Course, and Follow-up of 54 Patients with Myocarditis after Vaccination.

The clinical and laboratory features of myocarditis are shown in Table 3 and Table S3. The presenting symptom was chest pain in 82% of cases. Vital signs on admission were generally normal; 1 patient presented with hemodynamic instability, and none required inotropic or vasopressor support or mechanical circulatory support on presentation. Electrocardiography (ECG) at presentation showed ST-segment elevation in 20 of 38 patients (53%) for whom ECG data were available on admission; the results on ECG were normal in 8 of 38 patients (21%), whereas minor abnormalities (including T-wave changes, atrial fibrillation, and nonsustained ventricular tachycardia) were detected in the rest of the patients. The median peak troponin T level was 680 ng per liter (IQR, 275 to 2075) in 41 patients with available data, and the median creatine kinase level was 487 U per liter (IQR, 230 to 1193) in 28 patients with available data.

During hospitalization, cardiogenic shock leading to extracorporeal membrane oxygenation developed in 1 patient. None of the other patients required inotropic or vasopressor support or mechanical ventilation. However, 5% had nonsustained ventricular tachycardia, and 3% had atrial fibrillation. A myocardial biopsy sample obtained from 1 patient showed perivascular infiltration of lymphocytes and eosinophils. The median length of hospital stay was 3 days (IQR, 2 to 4). Overall, 65% of the patients were discharged from the hospital without any ongoing medical treatment.

A patient with preexisting cardiac disease died the day after discharge from an unspecified cause. One patient who had a history of pericarditis and had been admitted to the hospital with myocarditis had three more admissions for recurrent pericarditis, with no further myocardial involvement after the initial episode. Additional clinical descriptions are provided in Table S4.

Echocardiography and Other Cardiac Imaging

Echocardiographic findings were available for 48 of 54 patients (89%) (Table S5). Among these patients, left ventricular function was normal on admission in 71% of the patients. Of the 14 patients (29%) who had any degree of left ventricular dysfunction, 17% had mild dysfunction, 4% mild-to-moderate dysfunction, 4% moderate dysfunction, 2% moderate-to-severe dysfunction, and 2% severe dysfunction. Among the 14 patients with some degree of left ventricular dysfunction at presentation, follow-up echocardiography during the index admission showed normal function in 4 patients and similar dysfunction in the other 10. The mean left ventricular function at discharge was 57.5±6.1%, which was similar to the mean value at presentation. At a median follow-up of 25 days (IQR, 14 to 37) after discharge, echocardiographic follow-up was available for 5 of the 10 patients in whom the last left ventricular assessment before discharge had shown some degree of dysfunction. Of these patients, all had normal left ventricular function; follow-up results on echocardiography were not available for the other 5 patients.

Cardiac magnetic resonance imaging was performed in 15 patients (28%): in 5 patients during the initial admission and in 10 patients at a median of 44 days (IQR, 21 to 70) after discharge. In all cases, left ventricular function was normal, with a mean ejection fraction of 61±6%. Data from quantitative assessment of late gadolinium enhancement were available in 11 patients, with a median value of 5% (IQR, 1 to 15) (Table S6).