Myopericarditis is a severe adverse event to coronavirus disease 2019 (COVID-19) vaccines.1  The highest risk has been reported in males aged 12 to 29 years.24  According to the US Vaccine Adverse Event Reporting System, the risk in children aged 5 to 11 years is low with 11 reported cases following 8.7 million doses of Pfizer-BioNTech vaccine.5  However, these numbers may be underestimated because of underreporting.6 

On November 25, 2021, Denmark became the first country in Europe in which the Pfizer-BioNTech COVID-19 vaccine was recommended for children aged 5 to 11 years. Based on a prospective nationwide study, we aimed to estimate the risk of myopericarditis in children aged 5 to 11 years after COVID-19 vaccination, compared with immunized adolescents and background incidence.

This prospective population-based cohort study included patients aged 5 to 11 years fulfilling the case definition for myocarditis and/or pericarditis following Pfizer-BioNTech vaccination from November 25, 2021, to March 1, 2022, according to Brighton Collaboration case definitions.7  Cases were identified through a pediatric nationwide COVID-19 research collaboration including all 18 Danish Pediatric Departments providing 24 hours emergency service for Danish inhabitants ≤17 years of age. All 18 departments had a principal investigator responsible for prospective real-time data collection of COVID-19-associated disease from March 12, 2020.4,8,9 

We estimated the risk of myopericarditis following vaccination using the number of individuals aged 5 to 11 years who received at least 1 vaccine, obtained from the Danish COVID-19 surveillance system, from November 25 to February 1, 2022, to take into account the approximately 4-week interval from first vaccination to the development of myopericarditis. We compared this risk with our previously reported estimated risk in immunized adolescents4  and the background incidence of myocarditis and pericarditis based on ICD-10 codes identified through the National Patient Registry from 2014 to 2018.

The study was registered at www.clinicaltrials.gov (NCT05186571) and approved by the Ethics Committee (H-20028631) and the Data Protection Agency (P-2019-29). Informed parental consent was provided.

A total of 208 088 of 433 484 (48.0%) eligible children aged 5 to 11 years were vaccinated, among whom 1 previously healthy male aged 11 years with myocarditis was included (probable case; level of certainty 2). He was hospitalized 1 day with chest pain, shortness of breath, and elevated troponin T of 35 ng/L (normal <14 ng/L) 14 days after the first Pfizer-BioNTech vaccine, with no other identifiable causes, including negative severe acute respiratory syndrome coronavirus 2 disease (SARS-CoV-2) polymerase chain reaction-tests before and during hospitalization. The patient had no known recent COVID-19 contacts.

Thus, the risk of myopericarditis was 4.8 (95% confidence interval [CI], 0.1–26.8) per 1 000 000 vaccinated individuals aged 5 to 11 years, significantly lower than the risk in individuals aged 12 to 17 years of 57.4 (95% CI, 32.1–94.7) per 1 000 000. The relative risk of myopericarditis following COVID-19 vaccination to the background incidence of myopericarditis for individuals aged 5 to 11 years was 4.6 (95% CI, 0.1–156.1), not statistically different than the relative risk for individuals aged 11 to 17 years of 3.3 (95% CI, 1.4–8.1) (Table 1).

TABLE 1

Myopericarditis Following COVID-19 Vaccination and the Background Incidence

Myopericarditis Following Vaccination and in the Pre-COVID Era
 Per 1 000 000 (95% CI) 
Age, y 5–11 12–17 
Risk following COVID vaccine 4.8 (0.1–26.8)a 57.4 (32.1–94.7) 
Background incidence (2014–2018)b 1.0 (0.0–10.6)b 17.4 (7–36) 
Risk ratio (incidence following vaccination versus background incidence) 4.6 (0.1–156.1)c 3.3 (1.4–8.1) 
Myopericarditis Following Vaccination and in the Pre-COVID Era
 Per 1 000 000 (95% CI) 
Age, y 5–11 12–17 
Risk following COVID vaccine 4.8 (0.1–26.8)a 57.4 (32.1–94.7) 
Background incidence (2014–2018)b 1.0 (0.0–10.6)b 17.4 (7–36) 
Risk ratio (incidence following vaccination versus background incidence) 4.6 (0.1–156.1)c 3.3 (1.4–8.1) 
a

The risk of myopericarditis following COVID vaccination was significantly lower in individuals aged 5 to 11 years (1 case among 208 088 vaccinees) compared with individuals aged 12 to 17 years (15 cases among 261 334 vaccinees);3 P = .005 (Pearson’s χ2 test).

b

The background risk of myopericarditis was significantly lower for individuals aged 5 to 11 years than for 12 to 17 years; P < .001 (Pearson’s χ2 test). The incidences were calculated for the 3-mo and 4-mo inclusion periods for individuals aged 5 to 11 years and 12 to 17 years, respectively, with the absolute numbers of 9 cases among 433 484 individuals aged 5 to 11 years and 107 cases among 409 661 individuals aged 12 to 17 years during a 5-year period.

c

The risk ratio for individuals aged 5 to 11 years was not statistically different compared with the risk ratio for individuals aged 12 to 17 years (ratio of relative risk = 1.4; 95%, CI 0.3–61.0).

In this prospective Danish cohort study, we found a low risk of myopericarditis following COVID-19 vaccination in children aged 5 to 11 years, as also reported by the Vaccine Adverse Event Reporting System.5  The phenotype of the single case in this study was mild. We found the risk of myopericarditis relative to the background risk to be similar between children and adolescents. Accordingly, the lower risk of myopericarditis following Pfizer-BioNTech vaccination in children aged 5 to 11 years, compared with immunized adolescents, may reflect an overall lower susceptibility of developing myopericarditis in this age group.

When estimating the risk of myopericarditis after vaccination during the COVID-19 pandemic, it is important to consider a possible risk of SARS-CoV-2-associated myopericarditis, a condition described in adults. The vaccine-associated case in this study did not have any recent COVID-19 contacts and had negative nasopharyngeal tests. In addition, SARS-CoV-2-associated myopericarditis seems to be an extremely rare condition in children since (1) no such cases, independent of multisystem inflammatory system in children, has to our knowledge been reported in individuals aged 5 to 11 years and (2) a population-based nationwide study identified no cases of isolated SARS-CoV-2-associated myocarditis in children and adolescents during the first 1.5 years of the pandemic in Denmark.10 

A study limitation is the occurrence of only 1 case and the small population size. Thus, the incidence of myopericarditis following COVID-19 vaccination in children aged 5 to 11 years could not be precisely estimated. The risk of myopericarditis could be underestimated as the denominator, ie the number vaccinees, was children who had received at least 1 dose 4 weeks before the end of the study period, whereas most reported cases of myocarditis have presented within 1 week after the second vaccine.11  We chose this denominator, combined with 4-week follow-up, as some develop myopericarditis after only 1 dose,4  including our case, and since most included vaccinees (81%) had received 2 doses 1 week before the end of the study period. The study strengths are the nationwide prospective research set-up and the estimation of the background risk of myopericarditis in the same population.

In conclusion, we found the risk of myopericarditis following Pfizer-BioNTech vaccination to be approximately 5 in 1 000 000 vaccinees aged 5 to 11 years, significantly lower compared with immunized adolescents.

Drs Stensballe and Hartling, Mr Nygaard, Mr Holm, and Ms Espenhain conceptualized this nationwide study, collected cases for the study, verified and analysed data for the study, drafted the initial manuscript, and reviewed and revised the manuscript; Ms Hee conceptualized this nationwide study, analysed data for the study, contributed to the data interpretation, and critically reviewed the manuscript for important intellectual content; Dr Matthesen conceptualized this nationwide study, collected data for the study, contributed to the data interpretation, and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

This trial is registered at www.clinicaltrials.gov (identifier NCT05186571).

FUNDING: The study was funded by a COVID-19 grant from the National Ministry of Higher Education and Science (grant no. 0237-00004B) and Innovation Fund Denmark (0176-00020B).

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest to disclose.

     
  • COVID-19

    coronavirus disease 2019

  •  
  • SARS-CoV-2

    severe acute respiratory syndrome coronavirus 2 disease

1
Patone
M
,
Mei
XW
,
Handunnetthi
L
, et al
.
Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection
.
Nat Med
.
2022
;
28
(
2
):
410
422
2
Witberg
G
,
Barda
N
,
Hoss
S
, et al
.
Myocarditis after Covid-19 vaccination in a large health care organization
.
N Engl J Med
.
2021
;
385
(
23
):
2132
2139
3
Gargano
JW
,
Wallace
M
,
Hadler
SC
, et al
.
Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: update from the Advisory Committee on Immunization Practices - United States, June 2021
.
MMWR Morb Mortal Wkly Rep
.
2021
;
70
(
27
):
977
982
4
Nygaard
U
,
Holm
M
,
Bohnstedt
C
, et al
.
Population-based incidence of myopericarditis after COVID-19 vaccination in Danish adolescents
.
Pediatr Infect Dis J
.
2022
;
41
(
1
):
e25
e28
5
Hause
AM
,
Baggs
J
,
Marquez
P
, et al
.
COVID-19 vaccine safety in children aged 5–11 years - United States, November 3–December 19, 2021
.
MMWR Morb Mortal Wkly Rep
2021
;
70
(
5152
):
1755
1760
6
Blumenthal
KG
,
Robinson
LB
,
Camargo
CA
Jr
, et al
.
Acute allergic reactions to mRNA COVID-19 vaccines
.
JAMA
.
2021
;
325
(
15
):
1562
1565
7
Sexson Tejtel
SK
,
Munoz
FM
,
Al-Ammouri
I
, et al
.
Myocarditis and pericarditis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data
.
Vaccine
.
2022
;
40
(
10
):
1499
1511
8
Nygaard
U
,
Holm
M
,
Hartling
UB
, et al
.
Incidence and clinical phenotype of multisystem inflammatory syndrome in children after infection with the SARS-CoV-2 delta variant by vaccination status: a Danish nationwide prospective cohort study
.
Lancet Child Adolesc Health
.
2022
;
6
(
7
):
459
465
9
Hartling
UB
,
Holm
M
,
Glenthoej
JP
, et al
.
The need for hospitalization due to SARS-CoV-2 in children: a population-based estimate
.
Pediatr Infect Dis J
.
2021
;
40
(
6
):
e250
e251
10
Kildegaard
H
,
Lund
LC
,
Højlund
M
, %
Stensballe
LG
,
Pottegård
A
.
Risk of adverse events after covid-19 in Danish children and adolescents and effectiveness of BNT162b2 in adolescents: cohort study
.
BMJ
.
2022
;
377
:
e068898
11
Jain
SS
,
Steele
JM
,
Fonseca
B
, et al
.
COVID-19 vaccination-associated myocarditis in adolescents
.
Pediatrics
.
2021
;
148
(
5
):
e2021053427