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  3. SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based accomplice study

Research

SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based accomplice study

BMJ 2021; 375 doi: https://doi.org/ten.1136/bmj-2021-068665 (Published 16 December 2021) Cite this equally: BMJ 2021;375:e068665

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Myocarditis later vaccination against covid-19

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  1. Anders Husby , physician1 2,
  2. Jørgen Vinsløv Hansen , statisticiantwo,
  3. Emil Fosbøl , consultant3,
  4. Emilia Myrup Thiesson , statistician2,
  5. Morten Madsen , statistician4,
  6. Reimar Due west Thomsen , acquaintance professor4,
  7. Henrik T Sørensen , professor4,
  8. Morten Andersen , professor5,
  9. Jan Wohlfahrt , chief statisticiantwo,
  10. Gunnar Gislason , professorhalf dozen seven 8,
  11. Christian Torp-Pedersen , professor9 x eleven,
  12. Lars Køber , professor3,
  13. Anders Hviid , professorii 5
  1. 1Department of Epidemiology and Biostatistics, Royal Higher London, London, UK
  2. twoSection of Epidemiology Research, Statens Serum Plant, Copenhagen, Denmark
  3. 3Department of Cardiology, Rigshospitalet, Copenhagen University Infirmary, Copenhagen, Kingdom of denmark
  4. ivDepartment of Clinical Epidemiology, Aarhus University Infirmary and Aarhus Academy, Aarhus, Denmark
  5. vPharmacovigilance Research Centre, Department of Drug Design and Pharmacology, Academy of Copenhagen, Copenhagen, Denmark
  6. 6Danish Center Foundation, Copenhagen, Denmark
  7. sevenSection of Cardiology, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
  8. 8Department of Clinical Medicine, Academy of Copenhagen, Copenhagen, Denmark
  9. nineSection of Cardiology, Nordsjaellands Hospital, Hillerød, Kingdom of denmark
  10. tenDepartment of Cardiology, Aalborg Academy Infirmary, Aalborg, Kingdom of denmark
  11. 11Department of Public Wellness, University of Copenhagen, Copenhagen, Denmark
  1. Correspondence to: A Husby andh{at}ssi.dk (or @a_husby on Twitter)
  • Accustomed 30 November 2021

Abstract

Objective To investigate the clan between SARS-CoV-2 vaccination and myocarditis or myopericarditis.

Design Population based accomplice report.

Setting Denmark.

Participants four 931 775 individuals anile 12 years or older, followed from i Oct 2020 to v Oct 2021.

Chief outcome measures The primary outcome, myocarditis or myopericarditis, was divers as a combination of a hospital diagnosis of myocarditis or pericarditis, increased troponin levels, and a infirmary stay lasting more than than 24 hours. Follow-upwards time before vaccination was compared with follow-up time 0-28 days from the solar day of vaccination for both starting time and second doses, using Cox proportional hazards regression with age as an underlying timescale to estimate hazard ratios adjusted for sex, comorbidities, and other potential confounders.

Results During follow-upwardly, 269 participants developed myocarditis or myopericarditis, of whom 108 (40%) were 12-39 years old and 196 (73%) were male person. Of 3 482 295 individuals vaccinated with BNT162b2 (Pfizer-BioNTech), 48 developed myocarditis or myopericarditis within 28 days from the vaccination date compared with unvaccinated individuals (adjusted adventure ratio 1.34 (95% confidence interval 0.xc to two.00); absolute charge per unit 1.four per 100 000 vaccinated individuals inside 28 days of vaccination (95% confidence interval 1.0 to 1.8)). Adjusted hazard ratios among female person participants only and male participants but were three.73 (1.82 to seven.65) and 0.82 (0.50 to 1.34), respectively, with corresponding accented rates of ane.3 (0.eight to 1.9) and 1.v (ane.0 to 2.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively. The adapted hazard ratio among 12-39 yr olds was ane.48 (0.74 to 2.98) and the absolute rate was 1.6 (i.0 to ii.6) per 100 000 vaccinated individuals inside 28 days of vaccination. Among 498 814 individuals vaccinated with mRNA-1273 (Moderna), 21 adult myocarditis or myopericarditis within 28 days from vaccination date (adjusted hazard ratio 3.92 (two.30 to six.68); absolute rate iv.2 per 100 000 vaccinated individuals within 28 days of vaccination (2.6 to half dozen.4)). Adjusted hazard ratios among women only and men only were 6.33 (two.11 to eighteen.96) and three.22 (one.75 to 5.93), respectively, with corresponding absolute rates of 2.0 (0.seven to 4.8) and 6.3 (iii.6 to 10.2) per 100 000 vaccinated individuals inside 28 days of vaccination, respectively. The adapted hazard ratio amidst 12-39 yr olds was 5.24 (2.47 to 11.12) and the absolute rate was five.7 (three.3 to ix.3) per 100 000 vaccinated individuals within 28 days of vaccination.

Conclusions Vaccination with mRNA-1273 was associated with a significantly increased chance of myocarditis or myopericarditis in the Danish population, primarily driven by an increased risk among individuals aged 12-39 years, while BNT162b2 vaccination was only associated with a significantly increased chance amid women. However, the accented rate of myocarditis or myopericarditis subsequently SARS-CoV-2 mRNA vaccination was low, even in younger age groups. The benefits of SARS-CoV-ii mRNA vaccination should be taken into account when interpreting these findings. Larger multinational studies are needed to further investigate the risks of myocarditis or myopericarditis after vaccination inside smaller subgroups.

Introduction

Pharmacovigilance reports, health system surveillance studies, and example series suggest an association between SARS-CoV-2 vaccination and myocarditis and myopericarditis.123456789 This association is thought to occur particularly after the 2d booster dose of mRNA vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). In their well-nigh severe forms, myocarditis and myopericarditis can event in chronic middle failure or decease, and are of import safety concerns. The biological mechanism is not articulate, but the same agin events take been attributed to use of the smallpox vaccine in adults.10 Both the Usa Centers for Affliction Control and Prevention and the European Medicines Agency have ongoing investigations into the clan using surveillance information,1112 merely to our knowledge, no publicly available controlled cohort studies have examined the association within a complete population.

Denmark has nationwide, population based registers containing data on vaccinations, hospital admissions, and results of laboratory assays of blood samples. By taking advantage of these registers, we explored the association between vaccination with SARS-CoV-two vaccines and a predefined endpoint consisting of a infirmary diagnosis of myocarditis or pericarditis, a blood measurement showing increased troponin levels, and a infirmary stay lasting more 24 hours.

Methods

Materials

Using individual level information on vaccinations from the Danish Vaccination Annals, hospital based diagnoses from the Danish National Patient Register, and the unique personal identifier issued by the Danish Civil Registration System,13 we created a full population cohort with information on vaccination status of all individuals in Denmark.fourteen The unique identifier ensures completeness concerning linkage to registered medical incidents considering it is used for registration of all contacts within the Danish healthcare system. We accessed the Annals of Laboratory Results for Research to obtain biochemical measurements of claret samples analysed at Danish hospitals. This register allowed characterisation of myocarditis or myopericarditis beyond a infirmary diagnosis, based on blood sample measurements of troponin levels.15 Additionally, we accessed information on SARS-CoV-two polymerase chain reaction (PCR) examination results from the Danish Microbiology Database.16 SARS-CoV-2 PCR tests were widely bachelor during the study period, regardless of symptom status and without the demand for referral past a medical professional. Furthermore, patients were regularly tested for SARS-CoV-2 on emergency hospital admission.

Study cohort

All Danish residents were followed from one October 2020 or from their 12th birthday (whichever occurred afterwards), until emigration, death, an event, or v October 2021. To avoid misclassification, individuals were included only if they were registered as residents of Denmark between 1 January 2017 and 1 Oct 2020. We excluded individuals who received a hospital based diagnosis of myocarditis or pericarditis between 1 January 2017 and 30 September 2020. Furthermore, individuals who received two different types of vaccines were censored on receipt of their second dose. Finally, we censored individuals with a positive SARS-CoV-ii test outcome, to avoid associating outcomes of SARS-CoV-2 infection with outcomes of SARS-CoV-2 vaccination.

Vaccination

Vaccinated individuals in the cohort received a vaccine against SARS-CoV-2 in Kingdom of denmark (approved by the European Medicines Agency) and were followed up from the date of vaccination with the first dose (with BNT162b2, mRNA-1273, ChAdOx1 nCoV-19 (AstraZeneca), or Ad26.COV2.Southward (Johnson and Johnson)). Only estimates for individuals vaccinated with BNT162b2 or mRNA-1273 are presented in the main analysis. Estimates for individuals vaccinated with ChAdOx1 nCoV-nineteen or Ad26.COV2.S are presented in the supplemental materials, considering these vaccines were withdrawn from the national mass vaccination programme and rarely used. The primary risk window of involvement was the 28 days later vaccination, which included day 0, the twenty-four hour period of vaccination. If study participants received a second dose, they re-entered a 28 day gamble window.

Study covariates

Written report covariates were age, sex, vaccine priority group, and clinical comorbidities (that is, asthma, chronic pulmonary illness (including chronic obstructive pulmonary illness), ischaemic eye disease, heart failure, atrial fibrillation or palpitate, diabetes mellitus, inflammatory bowel disease, malignancy, and renal failure), as defined by hospital registered ICD-10 codes (international classification of diseases, 10th revision; see table S1 for definitions of covariates). Comorbidities were categorised as binary variables (present or not nowadays) and ascertained at baseline (1 October 2020).

Outcomes

We defined the principal study outcome of myocarditis or myopericarditis as a hospital diagnosis code of myocarditis or pericarditis (ICD-x codes listed in table S1) and co-occurrence of increased troponin levels (that is, a troponin T or a troponin I measurement higher up the analysis specific upper normal limit), in addition to a hospital stay lasting more than than 24 hours. The benchmark of increased troponin levels in the result definition was chosen to focus on events characterised by biochemically verifiable myocardial damage. Troponin measurements occurring inside 48 hours before or later diagnosis was considered as co-occurring. The event date for co-occurring diagnosis and troponin measurement was defined as the latest date of diagnosis or measurement (run into flowchart in fig S1 for classification of outcomes). Myocarditis and pericarditis diagnosis codes were combined into one outcome owing to the big overlap in pathology, clinical findings, and symptoms of these two disease entities. As an additional secondary outcome, we estimated the association betwixt SARS-CoV-2 vaccination and the combined endpoint of cardiac arrest or death. This upshot was included to investigate any clan between SARS-CoV-ii vaccination and the most severe manifestations of myocarditis or myopericarditis. Finally, among participants with myocarditis or myopericarditis, we assessed Kaplan-Meier estimates of hospital admission lasting more than 72 hours; readmission within 28 days of discharge; heart failure within 28 days of issue; and death within 28 days of issue, past vaccination status, sex, and age group.

Statistical analysis

Report accomplice, covariates, principal outcomes, and statistical analysis blueprint were prespecified in our statistical analysis protocol and revisions suggested past editors and reviewers are described in our revised statistical assay protocol (supplementary fabric). Nosotros followed the accomplice from i October 2020 to 5 October 2021. Our main analysis compared follow-upward time within a 28 day risk window afterward vaccination with unvaccinated follow-upwardly time using Cox proportional hazards to estimate hazard ratios by vaccination condition, with age as the underlying timescale (see fig S2 for illustration of follow-upward time). Hazard ratios were adjusted for sex activity, vaccination priority group, season (1 Oct 2020 to 31 Dec 2020, one January 2021 to 31 March 2021, 1 Apr 2021 to thirty June 2021, and one July 2021 to 5 October 2021), and comorbidities. Vaccine priority group was assessed on 22 February 2021 and treated as a time invariant variable, except that individuals were coded as belonging to a separate group before ane Jan 2021. The proportional hazards assumption was evaluated by testing for interaction between the time windows of main involvement (within 28 days of BNT162b2 and mRNA-1273 vaccination) and the underlying timescale (age) treated as a linear variable. We found no indication that the proportional hazards assumption was violated. To evaluate written report menstruation effects, we varied the first of follow-up in sensitivity analyses. The significance level was set up at P<0.05.

Within our accomplice we also created a nested cocky-controlled instance series written report, consisting of only people with a diagnosis of myocarditis or myopericarditis during follow-up. The self-controlled example series design compares periods of follow-upwards fourth dimension according to vaccination status inside individuals, who also deed as their ain controls. As a outcome, time invariant characteristics (eg, sex, ethnic origin, or socioeconomic status) are implicitly taken into account. In addition, the self-controlled case series analysis is adapted for season, as divers in the cohort analysis. The report also had a 28 24-hour interval hazard window later on vaccination with BNT162b2 or mRNA-1273 and used the same study period and exclusion or censoring criteria (except that experiencing an effect did not conscience follow-up for an individual). The unvaccinated period was considered the reference period. Nosotros designated a 14 day pre-risk menstruum earlier vaccination with both the starting time and second dose; follow-up during this period was non included in the unvaccinated menses or in the 28 day gamble period if they overlapped. The reason for this is that individuals are unlikely to exist vaccinated shortly after diagnosis, leading to an upwardly biased risk period result and underestimation of gamble in the pre-gamble catamenia. The assumption of the self-controlled case series arroyo was that the probability of vaccination does not depend on having had a written report outcome. We evaluated this assumption by visual inspection of plots showing the temporal timing of myocarditis or myopericarditis events in relation to vaccination (fig S3). Nosotros as well applied Firth'southward method for bias reduction to evaluate the issue of thin events.

Additionally, we calculated the absolute number of people with myocarditis or myopericarditis within 28 days of vaccination per 100 000 vaccinated individuals (individuals vaccinated at least one time) and presented the cumulative incidences later offset and 2nd vaccine dose. To weigh the benefits of SARS-CoV-2 vaccination against SARS-CoV-2 infection, we also investigated the coordinating risk of myocarditis or myopericarditis after infection with SARS-CoV-2. We used the same cohort but instead measured a first positive PCR test for SARS-CoV-2 and censored individuals who received a SARS-CoV-2 vaccination. In this assay, we besides used a 28 day risk flow after infection as the principal fourth dimension period of interest.

Patient and public involvement

Due to the urgency of the study question, no patients were formally involved in the blueprint, analysis, or estimation of the study.

Results

Our population cohort included iv 931 775 individuals, who were followed until v October 2021, yielding iv 717 464 person years (1.0 years on average). Amid cohort members, 4 155 361 were vaccinated with a SARS-CoV-2 vaccine during follow-up, with 3 482 295 (83.8%) individuals vaccinated with BNT162b2 (Pfizer-BioNTech) and 498 814 (12.0%) individuals vaccinated with mRNA-1273 (Moderna), while the remaining vaccinated individuals were vaccinated with ChAdOx1 nCoV-19 or Ad26.COV2.S (Johnson and Johnson). Of the vaccinated cohort, 3 417 744 individuals vaccinated with BNT162b2 (98.i%) and 483 270 individuals vaccinated with mRNA-1273 (96.ix%) had received both vaccine doses. The median fourth dimension between administration of the start and 2nd dose was 35 days (interquartile range 24-36 days) for BNT162b2 and 31 days (28-35) for mRNA-1273. Additional characteristics of the population accomplice are presented in table 1.

Table 1

Hazard time characteristics of Danish nationwide population cohort, based on follow-up from ane October 2020.* Data are number (%) of person years

SARS-CoV-two mRNA vaccination and myocarditis or myopericarditis in accomplice analysis

During follow-upwardly, 269 individuals had myocarditis or myopericarditis, of whom 108 (40%) were 12-39 years old and 196 (73%) were male person. Amidst individuals vaccinated with BNT162b2 and mRNA-1273, 48 and 21 individuals had myocarditis or myopericarditis within 28 days of vaccination, respectively (fig one). Overall, individuals vaccinated with BNT162b2 had a non-significantly increased charge per unit of myocarditis or myopericarditis in the 28 days after vaccination compared with unvaccinated follow-up (adapted hazard ratio one.34, 95% confidence interval 0.90 to 2.00), after adjustment for age, sex, vaccine priority group, season, and clinical comorbidities. Amongst individuals anile 12-39 years, we also plant a non-significantly increased rate in the 28 days subsequently vaccination compared with unvaccinated follow-up (ane.48, 0.74 to 2.98). Individuals vaccinated with mRNA-1273 had a significantly increased rate of myocarditis or myopericarditis compared with unvaccinated follow-upward (3.92, 2.30 to vi.68). Among individuals aged 12-39 years, nosotros too establish a significantly increased rate of myocarditis or myopericarditis compared with unvaccinated follow-upwards (5.24, 2.47 to 11.12). Additionally, nosotros institute that both BNT162b2 and mRNA-1273 were associated with a markedly reduced take chances ratio of cardiac arrest or death (0.51 (0.49 to 0.53) and 0.41 (0.37 to 0.46), respectively) compared with unvaccinated follow-up. The tests for proportional hazards for the adjusted analyses yielded P=0.47 for BNT162b2 and P=0.14 for mRNA-1273.

Fig 1

Fig i

Hazard ratios of primary and secondary report outcomes within 28 days after vaccination in the cohort study, by vaccine type, with follow-up until 5 Oct 2021. Hazard ratios are adjusted for age and sex; adapted gamble ratios are adjusted for historic period, sex activity, vaccine priority grouping, flavor, and clinical comorbidities

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SARS-CoV-2 mRNA vaccination and myocarditis or myopericarditis in self-controlled case series assay

The self-controlled case serial corroborated our main assay, showing a significantly increased risk of myocarditis or myopericarditis by vaccination with mRNA-1273, while vaccination with BNT162b2 was associated with a not-significantly increased adventure of myocarditis or myopericarditis (fig two).

Fig 2

Fig 2

Rate ratios of myocarditis or myopericarditis within 28 days later on vaccination in the self-controlled case series, by vaccine type. Analyses use a xiv day pre-risk period for each dose and are adjusted for flavour. Rate ratios are given without and with Firth's correction

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Absolute rates of myocarditis or myopericarditis later on vaccination

The overall accented charge per unit of myocarditis or myopericarditis within 28 days of any SARS-CoV-two mRNA vaccination was 1.7 (95% conviction interval 1.3 to 2.2) per 100 000 vaccinated individuals. The rates for BNT162b2 or mRNA-1273 vaccinations separately were 1.4 (one.0 to 1.8) and 4.ii (2.six to half dozen.4) per 100 000 individuals within 28 days of vaccination, respectively. Amongst women, the corresponding rates for BNT162b2 or mRNA-1273 vaccinations were 1.3 (0.8 to 1.ix) and 2.0 (0.7 to four.eight), respectively. Amongst men, the corresponding rates for BNT162b2 or mRNA-1273 vaccinations were ane.5 (1.0 to 2.2) and 6.3 (3.6 to 10.ii) per 100 000 individuals within 28 days of vaccination, respectively. Among individuals aged 12-39 years, the respective rates of myocarditis or myopericarditis for BNT162b2 or mRNA-1273 vaccinations were 1.6 (1.0 to 2.6) and v.seven (3.iii to 9.three) per 100 000 individuals inside 28 days of vaccination, respectively. Among individuals aged 12-17 years, the rate was one.0 (0.ii to three.0) per 100 000 individuals within 28 days of BNT162b2 vaccination; myocarditis or myopericarditis was not recorded in this historic period group amongst individuals vaccinated with mRNA-1273, merely only 831 individuals in the cohort had been vaccinated with mRNA-1273 in this age group during follow-upwards. To further illustrate the proportion of myocarditis or myopericarditis events by time since vaccination, effigy iii presents the cumulative incidence of events by vaccine type and dose number.

Sensitivity analyses

In sensitivity analyses, BNT162b2 vaccination was not associated with an increased risk ratio of myocarditis or myopericarditis for any of our predefined age groups (12-39, 40-59, and ≥threescore years) within the start 28 days after vaccination compared with unvaccinated follow-up (table S2). Stratifying past sex, nosotros found that both BNT162b2 and mRNA-1273 vaccinations were significantly associated with myocarditis or myopericarditis events amid female participants (adjusted hazard ratio iii.73 (95% confidence interval 1.82 to 7.65) and 6.33 (two.11 to 18.96), respectively). Past contrast, but vaccination with mRNA-1273 was significantly associated with myocarditis or myopericarditis amidst male person participants (3.22 (i.75 to 5.93) for mRNA-1273 v 0.82 (0.50 to 1.34) for BNT162b2; table S3). Investigating effects by vaccine dose number, we did not find a significant association overall between BNT162b2 vaccination and myocarditis or myopericarditis, for either the kickoff or the 2nd dose (table S4). For mRNA-1273, only vaccination with a second dose was significantly associated with myocarditis or myopericarditis (table S4).

Nosotros too investigated potential long term effects of SARS-CoV-2 vaccination, unlike periods of follow-up, and association by vaccine technology. Using both a cohort design and a cocky-controlled case serial design, we found a significantly decreased rate of myocarditis or myopericarditis occurring 29 days or more after vaccination with BNT162b2 vaccination, but non with mRNA-1273 vaccination (table S5). Changing the written report menstruation, we found no difference in the association betwixt SARS-CoV-two vaccination and the occurrence of myocarditis or myopericarditis compared with our main analysis (table S6). Combining data by vaccine engineering science, we plant a significantly increased chance ratio of myocarditis or myopericarditis occurring after vaccination with any SARS-CoV-ii mRNA vaccine, just our cohort had too few individuals to reliably assess the clan afterwards vaccination with any SARS-CoV-2 viral vector vaccine (table S7).

In post hoc analyses, we estimated the adjusted run a risk ratio of myocarditis or myopericarditis amid young men (aged 12-39 years) after their 2nd dose of a SARS-CoV-2 vaccine (i.54 (95% confidence interval 0.62 to 3.81) for BNT162b2 and 9.80 (4.xx to 22.84) for mRNA-1273). The respective rates per 100 000 vaccinated individuals within 28 days of vaccination were 1.eight (0.8 to 3.4) for BNT162b2 and 9.iv (5.0 to 16.0) for mRNA-1273.

Clinical outcomes amongst vaccinated individuals with myocarditis or myopericarditis

Vaccination condition did non announced to exist associated with the clinical outcome of participants who had myocarditis or myopericarditis, although our precision is limited because our cohort had simply a few individuals with severe outcomes. Amongst 155 unvaccinated individuals who had myocarditis or myopericarditis, it was estimated that 47.7% (95% confidence interval 39.vii% to 55.three%) were nonetheless in hospital 72 hours after admission, four.5% (ii.2% to nine.two%) were diagnosed with middle failure, and 1.ix% (0.6% to 5.ix%) died inside 28 days of the myocarditis or myopericarditis outcome (table S8). Respective rates for the 48 individuals who had myocarditis or myopericarditis within 28 days of BNT162b2 vaccination were 58.3% (43.2% to 70.8%), 2.1% (0.3% to thirteen.nine%), and ii.1% (0.3% to thirteen.9%), respectively. For the 21 individuals who had myocarditis or myopericarditis within 28 days of mRNA-1273 vaccination, 40.0% (19.3% to 60.0%) were in hospital 72 hours later admission, while none was diagnosed with middle failure or died within 28 days of outcome.

Additional analyses of other vaccine types, different statistical adjustment, different censoring, different time windows, and troponin levels are presented in tables S9-S16 and effigy S4. We found no events of myocarditis or myopericarditis in the 28 days later SARS-CoV-2 mRNA vaccination amidst individuals who had a diagnosis of either myocarditis or pericarditis betwixt 1 January 2017 and 30 September 2020 (table S12). In addition, we found BNT162b2 to exist significantly associated with myocarditis or myopericarditis issue when using a narrowed fourteen day time window (adjusted hazard ratio i.89 (95% confidence interval 1.23 to two.90); table S14).

Myocarditis or myopericarditis afterward SARS-CoV-two infection

In comparative analyses of outcomes inside 28 days of a positive SARS-CoV-2 test (tables S17-S19 and fig S5), SARS-CoV-two infection was associated with an adjusted hazard ratio of 2.09 (95% confidence interval 0.52 to 8.47) for myocarditis or myopericarditis, but our statistical precision was limited. Withal, SARS-CoV-ii infection was associated with a fourteen-fold increased take chances of cardiac arrest or expiry in the 28 days afterwards a positive SARS-CoV-2 examination compared with uninfected follow-up.

Give-and-take

Principal findings

Using healthcare data covering the entire Danish population, we did observe a strong association between vaccination with mRNA-1273 and myocarditis or myopericarditis, divers every bit the combined outcome of a infirmary diagnosis of myocarditis or pericarditis, increased troponin levels, and a hospital stay lasting more than 24 hours. Vaccination with BNT162b2 was only associated with an overall increased charge per unit of myocarditis or myopericarditis among female person participants. In general, the rate of myocarditis or myopericarditis was near threefold to fourfold college for mRNA-1273 vaccination than that for BNT162b2 vaccination. Nevertheless, the accented number of events were low. Even in the youngest age group (12-39 years), the accented rates of myocarditis or myopericarditis were ane.half dozen (95% confidence interval 1.0 to two.6) and 5.7 (three.3 to 9.3) per 100 000 individuals inside 28 days of BNT162b2 vaccination and mRNA-1273 vaccination, respectively. Clinical outcomes among vaccinated people with myocarditis or myopericarditis were predominantly mild. We observed no readmissions, diagnoses of heart failure, or deaths amongst people with myocarditis or myopericarditis occurring inside 28 days of mRNA-1273 vaccination.

Comparing with other countries

Previous reports accept likewise suggested an increased risk of myocarditis in State of israel and the United States afterward vaccination with SARS-CoV-2 mRNA vaccines, indicating similar adverse effects in various populations.13489 We did non discover similarly clear overall findings for the full general Danish population with regards to vaccination with BNT162b2. When stratifying past vaccine dose number, we also did non observe the 2d vaccine dose of BNT162b2 to be associated with a markedly higher rate of myocarditis or myopericarditis. In contrast to previous reports, we found that BNT162b2 was associated with an increased hazard ratio of myocarditis or myopericarditis amidst female participants, but not in male person participants. This finding went against our previous behavior nigh the potential association. Our sensitivity analysis with a narrowed fourth dimension window of 14 days suggested an overall i.89-fold increased take a chance of myocarditis or myopericarditis after BNT162b2 vaccination, although the magnitude of take a chance was well-nigh threefold larger for mRNA-1273 than for BNT162b2.

Ane potential reason for the discrepancies between our findings for Denmark compared with those for Israel and the US could be that the vaccinated population in Denmark was older. Even so, our age stratified analysis did non suggest a stiff increased risk among younger individuals in Denmark vaccinated with BNT162b2. Furthermore, in our post hoc analysis of male participants aged 12-39 years vaccinated after a second dose of BNT162b2, we did not find a significantly increased rate of myocarditis or myopericarditis and an accented rate of only 1.8 (95% confidence interval 0.eight to 3.iv) per 100 000 vaccinated individuals inside 28 days of vaccination. Another explanation could be that the median time interval betwixt first and second doses was longer in Kingdom of denmark (median interval of v weeks for BNT162b2) than in Israel and the US (3 calendar week schedule).17 The longer interval between vaccinations in Kingdom of denmark could dampen an immediate vaccine immune response. Finally, fewer Danish residents have tested positive for SARS-CoV-two than residents in the other two countries,xviii which might have led to fewer immune reactions, including myocarditis or pericarditis, attributable to pre-existing amnesty against SARS-CoV-ii (as described previously).19

Strengths and limitations

Compared with previous reports, our study had the advantage of using prospectively collected data on vaccination and hospital admissions for a complete population, about eliminating recall and choice bias. In improver, employ of two unlike written report designs (the accomplice study and self-controlled example serial) allowed us to examine effects of unlike methodological approaches. Overall, nosotros did not find a discrepancy between our results in the two study analyses. This suggested no strong misreckoning effects from indigenous origin or socioeconomic status, which were not adapted for in the cohort analysis, but were automatically controlled for in the cocky-controlled case series analysis. Furthermore, use of registry data ensured a systematic evaluation of exposures, covariates, and outcomes. However, we were not able to obtain valid data concerning electrocardiography or cardiac imaging. In addition, infirmary diagnoses of myocarditis and pericarditis in the Danish National Patient Registry exercise not provide consummate certainty that these diseases actually occurred.twenty All the same, the newly amended Register of Laboratory Results for Research (which covers all biochemical assays of patient blood samples analysed at hospitals in Kingdom of denmark from October 2020 onwards) allowed us to confirm suspected myocarditis or myopericarditis by confirming concurrent increased troponin levels as a specific marker of myocardial harm.

A potential bias in our observational study is that the decision to become vaccinated is an active personal selection, which could confound the association between SARS-CoV-2 mRNA vaccination and myocarditis or myopericarditis. Even so, myocarditis or myopericarditis is a rare event. Most people with the weather condition have no known predisposing factors other than sexual activity and age, for which our analyses are adjusted. We thus have little reason to believe that vaccinated individuals have an inherently higher hazard of the event. However, one could contend that individuals who cull vaccination are more health conscious, leading to healthcare seeking bias, which would overestimate the risk of myocarditis or myopericarditis afterwards vaccination if people with mild disease are more likely to exist ascertained among vaccinated individuals. Furthermore, increased public sensation of potential side effects of vaccines (eg, chance of myopericarditis) could as well introduce detection bias in the vaccinated population and detection of myopericarditis that otherwise would not accept been diagnosed. Notwithstanding, such bias is probably minimal in our study, considering biochemically verified increases in troponin levels and 24 hour hospital access were criteria for the outcome.

Potential confounding by SARS-CoV-two exposure could occur if recent exposure to the virus (eg, from infected friends or family members) leads an individual to be vaccinated during a potential incubation period for the infection. Hypothetically, this bias as well could introduce a spurious association between SARS-CoV-two mRNA vaccination and myocarditis or myopericarditis, because SARS-CoV-2 infection too appears to be a crusade of this outcome. However, an infected individual who tested positive for SARS-CoV-ii, up to or at hospital access, would have been censored in our study design. The exclusion of these individuals is probable given the loftier rates of SARS-CoV-2 testing (of both individuals with or without symptoms) during follow-upwards and routine testing for SARS-CoV-ii on infirmary admission in Denmark. Furthermore, for contempo SARS-CoV-2 exposure to be a confounding cistron, the vaccination decision would take to be linked strongly to contempo SARS-CoV-2 exposure, but this association is not indicated past the loftier and stable vaccine uptake in Kingdom of denmark. SARS-CoV-2 incidence would also have to be high, given the relative rarity of myocarditis or myopericarditis later this viral infection, but this was not the case during virtually of the study period. Taken together, these circumstances suggest that confounding past contempo SARS-CoV-2 exposure is not an important factor in this study.

Some other possible limitation of our written report was potential surveillance bias, whereby an increased risk of myocarditis or pericarditis arises from closer scrutiny for signs of the diseases among recently vaccinated individuals. Withal, the dissimilar findings for BNT162b2 compared with mRNA-1273 propose that surveillance bias is not prominent. Finally, the fact that SARS-CoV-2 vaccines are rarely given to people with an acute or last affliction is a likely caption for the depression 28 day risk of cardiac arrest or death in our report.

We found a decreased charge per unit of myocarditis of myopericarditis 29 days afterwards vaccination with BNT162b2 compared with unvaccinated follow-upwardly. This finding could suggest that we underestimated the effect within 28 days of vaccination if the follow-up of unvaccinated people (who are mainly those being vaccinated later in the study period) has a higher baseline rate than the follow-upwards of vaccinated people. All the same, this pattern was not consistent with regards to mRNA-1273, suggesting that the result could be a spurious finding and not a systematic bias.

Policy implications

Uncertainty regarding the incidence and severity of myocarditis and pericarditis later on SARS-CoV-2 vaccination was a contributing factor for the Joint Committee on Vaccination and Immunisation to defer recommending full vaccination of children and immature people aged 12-17 years with SARS-CoV-2 mRNA vaccines in the U.k..21 Our population based findings do non back up a threefold or college overall increased hazard of myocarditis or myopericarditis for the youngest age group (12-39 years) when vaccinated with BNT162b2. Among this age group, the absolute rate of myocarditis or myopericarditis was simply ane.6 (95% conviction interval 1.0 to 2.6) per 100 000 individuals anile 12-39 years within 28 days of BNT162b2 vaccination. The charge per unit in the youngest historic period group (12-17 years) was only 1.0 (0.two to three.0) per 100 000 individuals anile 12-17 years inside 28 days of BNT162b2 vaccination. Past comparison, the estimated occurrence of multisystem inflammatory syndrome in individuals anile 12-17 years is 27 per 100 000 individuals with serologically determined SARS-CoV-two infection.22

Given the worldwide spread of the highly contagious SARS-CoV-2 delta and omicron variants, hereafter infection is the undesirable alternative to vaccination against SARS-CoV-2. Taken together with the potential long term sequelae of even mild SARS-CoV-2 infection,23 and with the risk of multisystem inflammatory syndrome among adolescents (which is associated with severe morbidity),24 our finding of a depression accented risk of myocarditis or myopericarditis with BNT162b2 or mRNA-1273 vaccination supports the overall benefits of such vaccination on an individual, societal, and global level.

Conclusions

We institute that mRNA-1273 vaccination was associated with an increased rate of myocarditis or myopericarditis compared with unvaccinated individuals overall, while BNT162b2 vaccination was associated with an increased charge per unit of myocarditis or myopericarditis amongst female individuals. However, the absolute rate of myocarditis or myopericarditis cases afterwards SARS-CoV-ii mRNA vaccination was low overall, amid female participants, and among younger historic period groups. In addition, the clinical outcomes afterward myocarditis or myopericarditis events were predominantly mild, providing show to support the overall condom of SARS-CoV-2 mRNA vaccines. Nevertheless, larger multinational studies and meta-analyses are needed to specify risks within smaller subgroups and the risk of myocarditis or myopericarditis after SARS-CoV-two infection versus vaccination.

What is already known on this topic

  • Contempo pharmacovigilance reports and studies within healthcare systems have suggested an increased take a chance of myocarditis or myopericarditis after vaccination with SARS-CoV-2 mRNA vaccines

  • No accomplice written report has investigated the association using information from a complete population

What this study adds

  • Vaccination with mRNA-1273 (Moderna) was associated with a significantly increased charge per unit of myocarditis or myopericarditis, especially amid individuals aged 12-39 years (adjusted hazard ratio 5.24 (95% confidence interval two.47 to 11.12); absolute charge per unit v.7 (three.3 to 9.3) per 100 000 individuals aged 12-39 years inside 28 days of vaccination)

  • Vaccination with BNT162b2 (Pfizer-BioNTech) was associated with a significantly increased rate of myocarditis or myopericarditis among women simply; in the 12-39 year age group, the absolute rate was 1.6 (95% confidence interval 1.0 to ii.half dozen) per 100 000 individuals anile 12-39 years inside 28 days of vaccination

  • Clinical outcomes of myocarditis or myopericarditis were predominantly mild and generally similar between vaccinated and unvaccinated individuals, although precision in describing clinical outcomes was limited owing to few myocarditis or myopericarditis events

Ethics statements

Ethical approval

The study was conducted using authoritative register information. Co-ordinate to Danish law, ethical blessing is not required for such inquiry.

Data availability statement

The datasets analysed in the report are stored in the Danish national covid-19 surveillance arrangement database at Statens Serum Institute. The data will be fabricated available for research on reasonable request and with permission from the Danish Data Protection Agency and Danish Wellness and Medicines Authority.

Footnotes

  • Contributors: All the authors designed the written report. AHu, JVH, EMT, and AHv processed the data. AHu and AHv directed the analyses, which were carried out by JVH and EMT. All authors participated in the discussion and interpretation of the results. AHu and AHv wrote the initial draft. All authors critically revised the manuscript for intellectual content, canonical the final version, and meet the ICMJE criteria for authorship. AHu and AHv are guarantors of the study. The corresponding author attests that all listed authors encounter authorship criteria and that no others meeting the criteria accept been omitted.

  • Funding: AHu is supported by a grant from the Lundbeck Foundation (grant R322-2019-2800). This funder had no role in considering the study design or in the collection, assay, interpretation of data, writing of the report, or determination to submit the article for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at world wide web.icmje.org/disclosure-of-interest/ and declare: back up from the Lundbeck Foundation for the submitted piece of work; MA declares that he has previously participated in research projects funded by Pfizer, Janssen, AstraZeneca, H Lundbeck and Mertz, and Novartis with grants received by Karolinska Institutet (no personal fees); MA has personally received fees for education from Atrium, the Danish Association of the Pharmaceutical Manufacture; the Pharmacovigilance Research Eye is supported past a grant from the Novo Nordisk Foundation (NNF15SA0018404) to the University of Copenhagen.

  • The lead writer (AHu) affirms that the manuscript is an honest, accurate, and transparent business relationship of the study beingness reported; that no of import aspects of the report have been omitted; and that any discrepancies from the written report equally originally planned (and, if relevant, registered) have been explained.

  • Broadcasting to participants and related patient and public communities: The results of the study will be disseminated through social media postings, press releases, and interviews explaining the result to news media and general public.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

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Source: https://www.bmj.com/content/375/bmj-2021-068665

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