Age- and gender-specific risks of myocarditis and pericarditis after Covid-19 messenger RNA vaccines – Nature Communications

Characteristics of the study population

Between May 12, 2021 and October 31, 2021, within a population of 32 million people aged 12 to 50 years, 21.2 million first (19.3 million seconds) doses of the BNT162b2 vaccine and 2.86 million first (2.58 million seconds) doses of the mRNA -1273 vaccine were received (Table S1† In the same period, 1,612 cases of myocarditis (of which 87 [5.4%] also had pericarditis as an associated diagnosis) and 1,613 cases of pericarditis (37 [2.3%] with myocarditis as an associated diagnosis) were registered in France. We matched those cases to 16,120 and 16,130 control subjects, respectively. The characteristics of the cases and their corresponding controls are shown in Table 1† For both myocarditis and pericarditis, the main differences between cases and controls were a greater proportion in cases with a history of myocarditis or pericarditis, a history of SARS-CoV-2 infection, and receipt of an mRNA Covid-19 vaccine. The mean age and percentage of women were lower in patients with myocarditis than in patients with pericarditis.

Table 1 Characteristics of case studies and controls.

Risk of myocarditis and pericarditis associated with vaccination

For both vaccines, the risk of myocarditis was increased in the seven days after vaccination (Table 2† in the rest of the text we will refer to multivariable odds ratios). For the BNT162b2 vaccine, the odds ratios were 1.8 (95% confidence interval [CI]: 1.3–2.5) for the first dose and 8.1 (95% CI, 6.7–9.9) for the second. The association was stronger for the mRNA-1273 vaccine with odds ratios of 3.0 (95% CI, 1.4–6.2) for the first dose and 30 (95% CI, 21–43) for the second. . The risk of pericarditis was increased in the seven days after the second dose of both vaccines, with odds ratios of 2.9 (95% CI, 2.3-3.8) for the BNT162b2 vaccine and 5.5 (95 % CI, 3.3-9.0) for the mRNA. -1273 vaccine. Vaccination in the preceding 8 to 21 days with either the BNT162b2 or mRNA-1273 vaccine was not associated with a risk of myocarditis or pericarditis. Independent of vaccination status, a history of myocarditis was strongly associated with a risk of developing myocarditis during the study period, with an odds ratio of 160 (95% CI, 83-330). The same was true for pericarditis, with an odds ratio of 250 (95% CI, 120-540). No interaction was found between a history of myocarditis or pericarditis and exposure to the vaccine. Infection with SARS-CoV-2 in the previous month was also associated with a risk of myocarditis (odds ratio, 9.0 [95% CI, 6.4–13]) or pericarditis (odds ratio, 4.0 [95% CI, 2.7–5.9]†

Table 2 Relationship between myocarditis and pericarditis and exposure to mRNA vaccines within 1 to 7 days and 8 to 21 days.

Subgroup estimates by gender and age classes

The risk of myocarditis was significantly increased in the first week after vaccination in both males and females (Fig. 1 and table S2† Odds ratios associated with the second dose of mRNA-1273 vaccine were consistently highest, with values ​​up to 44 (95% CI, 22-88) and 41 (95% CI, 12-140), in males and females, respectively. ages 18 to 24, but remains high in older age groups. Odds ratios for the second dose of BNT162b2 vaccine tended to decrease with age, from 18 (95% CI, 9-35) and 7.1 (95% CI, 1.5-33), respectively. in men and women aged 12 to 17 years, to 3.0 (95% CI, 1.5-5.9) and 1.9 (95% CI, 0.39-9.3), respectively in men and women aged 40 to 51 years.

fig. 1: Association between myocarditis and exposure to mRNA vaccines within 7 days, by gender and age group.
Figure 1

The adjusted odds ratio (aOR) of the multivariable model is presented in a logarithmic base 10 scale according to age groups (X-axis), by gender (columns), and vaccine dose ranking (rows). Colors indicate the type of vaccine. The middle value is an OR point estimate and error bars represent 95% confidence intervals. The number of cases (N) by age group (12–17, 18–24, 25–29, 30–39, 40–50, and 12–50 years) are as follows, respectively: N= 137, 480, 210, 273, 181 and 1281 for men, and N= 29, 106, 40, 88, 68 and 331 for women. aOR could not be calculated in categories where no vaccine exposure cases have been recorded, for example, for men and women aged 12 to 17 years who received the mRNA-1273 vaccine.

An increased risk of pericarditis was also found in the first week after the second dose of one of the mRNA vaccines in both males and females (Fig. 2 and table S3† Odds ratios for the second dose of BNT162b2 vaccine showed a downward trend between age groups with values ​​up to 6.8 (95% CI, 2.3-20) and 10 (95% CI, 2.5-41), respectively. in men and women aged 12 to 17 years. The second dose of mRNA-1273 vaccine was associated with pericarditis in males and females only between the ages of 30 and 39 (odds ratio 20 [95% CI, 3.5–110]) and age 40 to 50 years (odds ratio 13 [95% CI, 3.5–49]†

fig. 2: Association between pericarditis and exposure to mRNA vaccines within 7 days, by gender and age group.
Figure 2

The adjusted odds ratio (aOR) of the multivariable model is presented in a logarithmic base 10 scale according to age groups (X-axis), by gender (columns), and vaccine dose ranking (rows). Colors indicate the type of vaccine. The middle value is an OR point estimate and error bars represent 95% confidence intervals. The number of cases (N) by age group (12–17, 18–24, 25–29, 30–39, 40–50, and 12–50 years) are as follows, respectively: N= 65, 194, 106, 282, 342 and 989 for men, and N= 36, 118, 91, 183, 196 and 624 for women. aOR could not be calculated in categories where no vaccine exposure cases have been recorded, for example, for men and women aged 12 to 17 years who received the mRNA-1273 vaccine.

Associations between vaccination in the previous seven days and risk of myocarditis or pericarditis were of the same magnitude when the analysis was limited to the period prior to the warning against myocarditis and pericarditis as adverse reactions sent to prescribers on July 19, 2021 (Fig. S1 and table S4† The results were unchanged in models excluding patients with a history of SARS-CoV-2 infection within the last month, patients with a history of myocarditis or pericarditis within five years, patients diagnosed with both myocarditis and pericarditis, or patients with hospitalization within one month prior to the index date.

Excess events

We estimated the number of additional cases attributable to vaccines by gender and age group (Fig. 3† The number of additional cases of myocarditis per 100,000 doses administered to adolescent males 12 to 17 years of age was 1.9 (95% CI, 1.4-2.6) for the second dose of BNT162b2 vaccine and for young adults of 18 to 24 years of age who achieved 4.7 (95% CI, 3.8-5.8) for the second dose of the BNT162b2 vaccine and 17 (95% CI, 13-23) for the second dose of the mRNA 1273 vaccine (Fig. 3† This translates into one case of vaccine-associated myocarditis per 52,300 (95% CI, 38,200-74,100) second doses of the BNT162b2 vaccine under 12-17 years of age and 21,100 (95% CI, 17,400-26,000) second doses of the BNT162b2 vaccine and 5900 (95% CI, 4400-8000) second doses of the mRNA-1273 vaccine at 18-24 years of age (Table S5† Estimates of excess cases were lower for older age groups and in general for women. However, the rate of excess myocarditis attributable to the second dose of mRNA-1273 vaccine was consistently higher. In women aged 18 to 24 years, the estimated rate of myocarditis in excess per 100,000 doses reached 0.63 (95% CI, 0.34-1.1) for the second dose of BNT162b2 vaccine (equivalent to 1 case per 159,000 [95% CI, 90,800–294,400] doses) and 5.3 (95% CI, 3.0–9.1) for the second dose of mRNA-1273 vaccine (corresponding to 1 case per 18,700 [95% CI, 11,000–33,400] doses). The number of excess cases of pericarditis is shown in Fig. 3† For myocarditis, estimates for the second dose of mRNA-1273 vaccine were consistently higher.

fig. 3: Excess cases of myocarditis and pericarditis attributable to mRNA vaccines by gender and age group, per 100,000 doses.
figure 3

Excess cases are based on the risk in the 7 days after vaccination. Colors indicate the type of vaccine and the shape of the point estimate indicates the rank of the vaccine dose. Middle values ​​are point estimates of redundant cases and error bars represent 95% confidence intervals. Number of cases (N) by age group (12–17, 18–24, 25–29, 30–39, 40–50, and 12–50 years) are as follows, respectively: for cases of myocarditis, N= 137, 480, 210, 273, 181 and 1281 in males, and N= 29, 106, 40, 88, 68 and 331 in females; for cases of pericarditis, N= 65, 194, 106, 282, 342 and 989 in males, and N= 36, 118, 91, 183, 196 and 624 in females. Excess cases were calculated only in categories with a significant positive association between vaccine exposure and outcome (adjusted odds ratio >1).

Characteristics of cases of myocarditis and pericarditis occurring after vaccination

Among the exposed cases, the delay between vaccine administration and hospitalization was (Fig. S2) was shorter after the second dose than after the first dose, both for myocarditis (median of 4 days versus 10 days after the BNT162b2 vaccine and 3.5 days versus 9 days after the mRNA-1273 vaccine) and for pericarditis ( median of 6 days versus 10 days after the BNT162b2 vaccine and of 3 days versus 11 days after the mRNA-1273 vaccine).

Table 3 shows the characteristics of cases acquired within 7 days of vaccination (supposed post-vaccination cases) compared to cases acquired within a greater delay or without vaccination. The post-vaccination cases were significantly younger (primarily aged 18 to 24 years), were more likely to involve males for myocarditis but not pericarditis, and without a history of myocarditis or pericarditis, or SARS-CoV-2 infection, respectively. Length of hospital stay was not significantly different in post-vaccination cases of myocarditis (median 4 days) and pericarditis (median 2 days) than in unexposed cases. The frequency of intensive care admission, mechanical ventilation, or death was lower for post-vaccination cases than for unexposed cases. At a follow-up of 30 days after discharge, 4 (0.24%) deaths in myocarditis cases (none among exposed to vaccine) and 5 (0.31%) deaths in pericarditis cases (including one patient receiving a vaccine received 8 to 21 days prior to diagnosis) were reported. Of these, 3 and 2 died during their hospital stay for myocarditis and pericarditis, respectively.

Table 3 Description of hospitalized patients by exposure to mRNA vaccines.

Drug treatments within 30 days of hospital discharge are shown in Fig. S3 and S4† Regardless of vaccination status, the therapeutic classes most frequently used during the follow-up of myocarditis cases were beta-blockers (63% of patients), analgesics (52%) and agents that act on the renin-angiotensin system (46%). The corresponding treatments of pericarditis cases were analgesics (83%), colchicine (69%) and beta-blockers (14%) (Fig. S4

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