Myocarditis and pericarditis are temporally associated with BNT162b2 COVID-19 vaccine in adolescents: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-4715038/v1

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Myocarditis and pericarditis are temporally associated with BNT162b2 COVID-19 vaccine in adolescents: a systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-4715038/v1

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The incidence of myocarditis and pericarditis has been documented in adolescents after COVID-19 vaccinations. This study aims to assess the risk of myopericarditis in adolescents following COVID-19 vaccination, using a meta-analysis of the published cases. We performed a comprehensive literature search of the following databases on July 5, 2023: MEDLINE, EMBASE, PubMed, and the Cochrane Library. We performed a meta-analysis using a random-effects model to estimate the incidence of myopericarditis per million of administered COVID-19 vaccine doses or COVID-19 infections. A total of 33 studies were included in the meta-analysis. Twenty-nine studies reported the incidence of myopericarditis after COVID-19 vaccination, whereas four studies reported the incidence following COVID-19 infection. The incidence of myopericarditis per million COVID-19 infections (1583.9 cases, 95% CI 751.8–2713.8) was approximately 42 times higher than that for COVID-19 vaccine administrations (37.6 cases, 95% CI 24.2–53.8). The risk of myopericarditis after COVID-19 vaccination was particularly high among the 16–19 age group (39.5 cases, 95% CI 25.8–56.0), males (43.1 cases, 95% CI 21.6–71.9), and those who received the second dose (47.7 cases, 95% CI: 22.2–82.2). Regionally, the highest incidence rate of myopericarditis following COVID-19 vaccination was observed in Europe (49.0 cases, 95% CI: 16.4–98.4), followed by the Western Pacific (39.7 cases, 95% CI: 18.1–69.5) and the Americas (27.7 cases, 95% CI: 14.0-45.7), although no statistically significant differences were noted (p = 0.51). Adolescents faced a potential risk of myopericarditis after COVID-19 vaccination, but this risk is less harmful than that of myopericarditis following COVID-19 infection.

COVID-19 vaccines

myocarditis

pericarditis

adolescent

global health

The occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 triggered a global health crisis.¹⁾ While most SARS-CoV-2 infections result in mild symptoms and positive prognoses, a subset leads to severe outcomes, such as acute respiratory distress syndrome, multi-organ failure, and fatalities.²⁾ The evolution of the virus generates mutations, some enhancing the transmissibility of coronavirus disease 2019 (COVID-19), prompting global vaccination efforts as the most efficacious strategy for prevention.³⁾ However, clinical evidence on the safety and efficacy of approved COVID-19 vaccines remains limited. Notably, instances of myocarditis and pericarditis have been documented among adolescents and young adults in various countries.⁴⁾⁵⁾ Myocarditis, characterized by inflammation of the cardiac muscle, and acute pericarditis, manifesting as severe chest pain behind the sternum, are believed to have resulted from autoinflammatory processes linked to the immune response triggered by viral infections.⁶⁾

We assessed the risk of myocarditis and pericarditis among adolescents, following COVID-19 vaccination, through a meta-analysis of published cases. We consolidated insights from previously published case reports and series, emphasizing the risk differences among different geographic locations. This study aims to present a comprehensive overview of the situation.

Search strategy and screening

The systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (Registration Number: CRD 42023452284).

We performed a comprehensive literature search using the following databases on July 5, 2023: MEDLINE, EMBASE, PubMed, and Cochrane Library. We used the EMBASE “Advanced Search” interface through EBSCOhost to approach MEDLINE, EMBASE, and PubMed databases. We described the detailed search strategies for each search interface in Supplementary Table 1.

We included randomized clinical trials (RCT) and observational studies (cohort, case-control, cross-sectional, and self-controlled case series), reporting on children aged 0–19 years, who experienced myopericarditis following COVID-19 vaccination or COVID-19 infection. We excluded case reports, review articles, editorials, comments, and observational studies that did not report the number of myopericarditis cases, COVID-19 vaccines administered, and COVID-19 infected patients. When the data sources were duplicated and the study periods overlapped by 6 months or more, we included studies with larger sample sizes. Additionally, we excluded studies with a smaller sample size (n < 5000) to accurately measure the incidence of myopericarditis following COVID-19 vaccine or COVID-19 infection.

Data extraction and quality assessment

We extracted information on the country, data source, study period, study design, age, sex, vaccine type and dose, COVID-19 infected patients, myocarditis cases, pericarditis cases, and myopericarditis cases. We combined the occurrences of myocarditis, pericarditis, and myopericarditis and collectively referred to them as 'myopericarditis.’ When the number of myopericarditis cases was represented as a range, we utilized the maximum value from that range. In studies presenting multiple timeframes, data were extracted based on the longest time window. Quality assessment was performed by two reviewers, using the tool developed by Hoy et al., to assess the risk of bias in prevalence studies.⁷⁾ This tool assesses internal and external validity using 10 items. Studies scoring 0–3, 4–6, and 7–9 indicate low, moderate, and high risks of bias, respectively.

Statistical analysis

We performed a meta-analysis by employing a random-effects model to calculate the incidence of myopericarditis per million administered COVID-19 infections or vaccine doses. We performed a subgroup analysis to identify differences in the incidence of myopericarditis following COVID-19 vaccination, based on age, sex, number of vaccine doses, vaccine type, and WHO region. Heterogeneity across the studies was determined using I² statistics. An I² value exceeding 50% indicated a high degree of heterogeneity, whereas a value below 50% indicated a lower degree of heterogeneity. Publication bias was evaluated using funnel plots, Begg's Test, and Egger's test. All statistical analyses and generation of the forest plot were performed using STATA 18.0 (STATA Corp, College Station, TX).

Ethical statement

The present study protocol was reviewed and approved by the Institutional Review Boards at Korea University Anam Hospital (IRB No. 2023AN0326).

A comprehensive literature search identified 1429 studies (Figure 1). Two additional studies were included manually during the review. After removing the duplicates, 928 studies were reviewed. After reviewing titles and abstracts, 780 studies were excluded. We assessed 148 full-text articles and excluded 115. Finally, 33 studies underwent a qualitative assessment and were included in the meta-analysis.^8-40)

Twenty-nine studies reported the incidence of myopericarditis after COVID-19 vaccination,^8-36) whereas four studies reported the incidence following COVID-19 infection.^37-40) The risk of bias assessment for each study indicated that 30 studies were at low risk, three were at moderate risk, and there were no high-risk studies (Supplementary Table 2).

The incidence of myopericarditis per million COVID-19 infections (1583.9 cases, 95% CI 751.8–2713.8) was approximately 42 times higher compared to the incidence per million COVID-19 vaccine administrations (37.6 cases, 95% CI 24.2–53.8) (Figure 2). In the United States, the incidence of myopericarditis following COVID-19 infection (1674.9 cases, 95% CI 604.9-3272.0) was approximately 48 times higher than that following COVID-19 vaccination (35.0 cases, 95% CI 12.2-68.7) (Supplementary Figure 1).

In the subgroup analysis, the incidence of myopericarditis per million COVID-19 vaccine administrations was highest in the age group of 16-19 years (39.5 cases, 95% CI 25.8-56.0), followed by 12-15 years (37.6 cases, 95% CI 8.8-85.2), and 5-11 years (1.9 cases, 95% CI 0.0-8.0) (Figure 3). Male children experienced a 5-fold higher incidence of myopericarditis following COVID-19 vaccination (43.1 cases, 95% CI 21.6-71.9), compared to female children (7.7 cases, 95% CI 4.1-12.2) (Figure 4).

The incidence of myopericarditis was 4-fold higher following the second dose (47.7 cases, 95% CI 22.2-82.2), as compared to the first dose (10.8 cases, 95% CI 5.1-18.3), of the COVID-19 vaccine (Figure 5). There was no significant difference in the incidence of myopericarditis when comparing only the Pfizer vaccine (41.6 cases, 95% CI 26.4-60.0) with the combination of Pfizer and other vaccines (27.4 cases, 95% CI 5.6-64.0, p=0.45) (Figure 6).

In the analysis by WHO region, the European region showed the highest incidence of myopericarditis per million COVID-19 vaccine administrations (49.0 cases, 95% CI 16.4-98.4), followed by the Western Pacific region (39.7 cases, 95% CI 18.1-69.5), and the Region of the Americas (27.7 cases, 95% CI 14.0-45.7), though the difference was not statistically significant (p=0.51) (Figure 7). These studies showed the high heterogeneity, with I² statistics exceeding 95%. There was no evidence of publication bias for COVID-19 infection (Begg’s test p=0.73, Egger’s test p=0.95) or vaccine (Begg’s test p=0.99, Egger’s test p=0.18) studies (Supplementary Figure 2).

In this meta-analysis encompassing 33 studies, the incidence rates of myopericarditis following COVID-19 infection were 1583.9 cases per million individuals (95% CI: 751.8–2713.8). This rate was approximately 42 times higher than that following COVID-19 vaccination (37.6 cases per million individuals, 95% CI: 24.2–53.8). The incidence rate of myopericarditis after COVID-19 vaccination varied by age, with the highest rate observed in the 16-19 age group (39.5 cases, 95% CI: 25.8-56.0). Additionally, the incidence rate among boys (43.1 cases, 95% CI: 21.6-71.9) was five times higher than that among girls (7.7 cases, 95% CI: 4.1-12.2) after COVID-19 vaccination. The incidence rate of myopericarditis after the second dose of vaccination (47.7 cases, 95% CI: 22.2-82.2) was four times higher than after the first dose (10.8 cases, 95% CI: 5.1-18.3). Regionally, the highest incidence rate of myopericarditis per million individuals following COVID-19 vaccination was observed in the European region (49.0 cases, 95% CI: 16.4-98.4), followed by the Western Pacific region (39.7 cases, 95% CI: 18.1-69.5) and the Americas region (27.7 cases, 95% CI: 14.0-45.7), although no statistically significant differences were noted (p=0.51).

Among the existing meta-analyses, Voleti et al. conducted a study comparing myocarditis after COVID-19 infection and vaccination across all age groups.⁴¹⁾ Their meta-analysis revealed that the relative risk (RR) for myocarditis was more than seven times higher in the infection than in the vaccination group [RR: 15 (95% CI: 11.09–19.81, infection group] and RR: 2 (95% CI: 1.44-2.65, vaccine group)]. The risk of myocarditis after vaccination is higher in men than in women. Another meta-analysis reported that the BNT162b2 and mRNA-1273 vaccines increase the risk of myocarditis and pericarditis, while other vaccines were not associated with a significantly elevated risk.⁴²⁾ Specifically, mRNA vaccines were reported to be associated with an increased risk of myocarditis and pericarditis.⁴³⁾⁴⁴⁾ The mechanism of myocarditis post-vaccination may be associated with the active component of the vaccine, the mRNA sequence, or the immune response that follows vaccination.⁸⁾⁴²⁾ This meta-analysis⁴²⁾ showed that the risk of myocarditis and pericarditis is higher with the second dose and at a younger age. No significant differences were observed between men and women. Regionally, the incidence of myocarditis and pericarditis was higher in Western countries and East Asia, with the suggested explanation being that these regions predominantly administer mRNA vaccines. In a meta-analysis focused on adolescents receiving COVID-19 BNT162b2 vaccination, the pooled incidence of myocarditis/pericarditis was reported as 4.5 (95% CI: 3.14–6.11) per 100,000 vaccinations across all doses.⁴⁵⁾ In this meta-analysis, the second dose and male gender were identified as risk factors. Overall, the results of the vaccine were favorable.

This recent meta-analysis investigated myocarditis/pericarditis following COVID-19 vaccination in adolescents, encompassing all vaccine types. Although there is a risk of myocarditis/pericarditis after vaccination in adolescents, it remains significantly lower than that after the infection, emphasizing the ongoing favorable effectiveness of vaccines. When stratified by age within the adolescent group, the risk was highest among those aged 16–19 years, decreasing for younger age groups. In particular, this study investigated the regional incidence rates of myocarditis/pericarditis after COVID-19 vaccination, revealing the highest rates in Europe, followed by the Western Pacific region and the Americas. This discrepancy may be attributed to racial differences or, as suggested in previous publications, variations in the preferred vaccines in each region. Further research is needed to explore these regional differences.

This study has several limitations. First, there may have been variations in the diagnostic criteria for myocarditis/pericarditis across different studies. Second, although we divided the region into three areas, regional variations still exist within each area. Third, although our study included various types of vaccines, the predominance of the Pfizer vaccine in our dataset may have limited the generalizability of our findings to other vaccines.

This meta-analysis, examining myocarditis/pericarditis after COVID-19 vaccination among adolescents, observed that the risk was particularly high in the 16-19 age group, males, and with the second dose. Geographically, the incidence rates were highest in Europe, followed by the Western Pacific and the Americas. Adolescents faced a potential risk of myopericarditis after COVID-19 vaccination, but this risk is less harmful than that of myopericarditis following COVID-19 infection.

Funding: This study was supported by grants from Korea Disease Control and Prevention Agency (Grant no. 2023-05-001).

Conflict of interest: All authors have no potential conflicts of interest.

Data sharing statement: Data sharing is not applicable because consent of subjected was not obtained for data sharing.

Authors contribution statement: The authors confirm contribution to the paper as follows: study conception and design: S Park; data collection: SH Shin, MJ Hwang, HS Choi, S Na; analysis and interpretation of results: HM Kang, JH Kim, S Park, JS Lee, YJ Choe, Y Yoon; draft manuscript preparation: Y Choi, JS Lee. All authors reviewed the results and approved the final version of the manuscript.

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Table 1. Characteristics of studies included in the meta-analysis

Study	Country	Database	Study period	Study design	Type of Vaccine	Definition of myopericarditis	Age(y)	Number of vaccine doses	Number of myopericarditis	Risk bias
COVID-19 Vaccine
Wood et al. 2022⁹⁾	Australia	Aus Vaxsafety surveillance	From July 1, 2022 to May 1, 2022	Cohort study	Pfizer-BioNTech	Not definition (self-reported)	5-15	384540	0	Moderate
Lee et al. 2022¹⁰⁾	USA	VARES	From May 10, 2021 to September 30, 2021	Cohort study	Pfizer-BioNTech	Not definition	12-15	9252431	211	Low
Lai et al. 2022¹¹⁾	Hongkong	Department of health of the Hong Kong gov.	From January 1, 2018 to September 30, 2021	Cohort study	Pfizer-BioNTech	ICD-9 and ICPC	12-18	257805	38	Low
Kim et al. 2022¹²⁾	Korea	Covid-19 vaccination management system	From March 5, 2021 to July 2, 2022	Cohort study	Pfizer-BioNTech	Not definition (self-reported)	5-17	4995280	103	Moderate
Le Vu et al. 2022¹³⁾	France	National Health Data System (SNDS)	From May 12, 2021 to October 31, 2021	Matched case-control study	Pfizer-BioNTech and Mrna-1273	ICD-10	12-17	6745593	62	Low
Krug et al. 2022¹⁴⁾	USA	VARES	From January 1, 2021 to June 18, 2021	Cohort study	Pfizer-BioNTech	CDC definition	16-17	5029481	124	Low
Cho et al. 2023¹⁵⁾	Korea	KDCA	From February 26, 2021 to December 31, 2021	Cohort study	Pfizer-BioNTech	BC	12-17	2076259	78	Low
Chua et al. 2022¹⁶⁾	Hongkong	Department of health of the Hong Kong gov.	From June 14, 2021 to September 4, 2021	Cohort study	Pfizer-BioNTech	BC	12-17	305284	33	Low
Goddard et al. 2022¹⁷⁾	USA	vaccine safety surveillance data (VSD)	From December 14, 2020 to August 20, 2022	Cohort study	Pfizer-BioNTech	ICD-10 and CDC definition	5-17	2106739	58	Low
Mevorach et al. 2021⁸⁾	Israel	Ministry of health database	From December 1, 2020 to May 30, 2021	Cohort study	Pfizer-BioNTech	ICD-9 and BC	16-19	842799	35	Low
Cheng et al. 2022¹⁸⁾	Australia	SAFEVIC	From February 22, 2021 to February 22, 2022	Cohort study	Pfizer-BioNTech and Mrna-1273	BC	12-17	871689	75	Low
Li et al. 2022¹⁹⁾	Hongkong	Hong Kong territory wide electronic health record	From March 10, 2021 to October 18, 2021	Cohort study	Pfizer-BioNTech	ICD-9	12-17	387078	43	Low
Shiyovich et al. 2022²⁰⁾	Israel	Clalit health services	From June 2, 2021 to November 20, 2021	Cardiac magnetic resonance imaging study	Pfizer-BioNTech	ICD-9	12-15	182605	23	Low
Buchan et al. 2023²¹⁾	Canada	Passive vaccine safety surveillance	From December 14, 2020 to November 21, 2021	Cohort study	Pfizer-BioNTech	BC	12-17	1650638	77	Low
Rahman et al. 2023²²⁾	Malaysia	Nationwide vaccine registry and Ministry of health Malaysia	From February 1, 2021 to February 8, 2022	Cohort study	Pfizer-BioNTech, CoronaVac and ChAdOx1 nCoV-19	ICD-10	12-17	5040475	30	Low
Naveed et al. 2022²³⁾	Canada	BC COVID-19 cohort	From December 15, 2020 to March 10, 2022	Cohort study	Pfizer-BioNTech	ICD-10	12-17	644705	19	Low
Matson et al. 2023²⁴⁾	USA	Mayo clinic health system	From January 5, 2021 to August 5, 2022	Cohort study	Pfizer-BioNTech	CDC definition	5-17	56436	8	Low
Yap et al. 2022²⁵⁾	Singapore	Health sciences authority	From December 1, 2020 to July 25, 2021	Cohort study	Pfizer-BioNTech and Mrna-1273	CDC definition	12-19	524051	13	Low
Nygaard et al. 2022 -1²⁶⁾	Denmark	Multicenter (all 18 Danish pediatric departments)	From May 15, 2021 to September 15, 2021	Cohort study	Pfizer-BioNTech	Not definition	12-17	261334	15	Low
Alami et al. 2022²⁷⁾	USA	VARES	From December 14, 2020 to July 9, 2021	Cohort study	Pfizer-BioNTech	CDC definition	12-17	14939919	307	Low
Su et al. 2023²⁸⁾	China	Taiwan Vaccine Adverse Event Reporting System	From March 22, 2021 to February 9, 2022	Cohort study	Pfizer-BioNTech	BC	12-17	2114917	107	Low
Nygaard et al. 2022 -2²⁹⁾	Denmark	Danish COVID-19 surveillance system	From November 25, 2021 to March 1, 2022	Cohort study	Pfizer-BioNTech	BC	5-17	469422	16	Low
Kobayashi et al. 2023³⁰⁾	Japan	JCAEVDSPAFSMHW	From February 17, 2021 to November 14, 2021	Cohort study	Pfizer-BioNTech and Mrna-1273	ICD-10	10-19	12575991	81	Low
Salvo et al. 2023³¹⁾	France	French spontaneous reporting database	To September 30, 2021	Cohort study	Pfizer-BioNTech and Mrna-1273	Not definition	12-17	5820744	38	Low
Thonginnetra et al. 2022³²⁾	Thailand	Single center	From September 20, 2021 to November 11, 2021	Cohort study	Sinopharm BIBP	Not definition	10-17	50104	1	Moderate
Choe et al. 2022³³⁾	Korea	Ministry of education and immunization registry	From July 19, 2021 to Ongoing	Cohort study	Pfizer-BioNTech	Not definition	16-18	886338	27	Low
Nordström et al. 2023³⁴⁾	Sweden	Public health agency of Sweden	From January 1, 2022 to June 5, 2022	Cohort study	Pfizer-BioNTech and Mrna-1273	ICD-10	11-19	645355	107	Low
Hause et al. 2022³⁵⁾	USA	VARES	From October 31, 2021 to February 27, 2022	Cohort study	Pfizer-BioNTech	CDC definition	5-11	16502416	20	Low
Hu et al. 2023³⁶⁾	USA	CVS health, Health core, Optum	From December 11, 2020 to June 25, 2022	Cohort study	Pfizer-BioNTech	BC	5-17	4487656	183	Low
COVID-19 infection					COVID-19 testing tool			Number of COVID-19 infection	Number of myopericarditis
Katsuta et al. 2023³⁷⁾	Japan	Japan Pediatric Society (JPS)	From February 202 to April 2022	Cohort study	PCR and loop-mediated isothermal amplification test	Not definition	<16	5411	7	Low
Encinosa et al. 2023³⁸⁾	USA	AHRQ and HUCP	From February 1 to October 20, 2022	Cross-sectional study	ICD-10	ICD-10-CM	5-18	23686	78	Low
Boehmer et al. 2021³⁹⁾	USA	PHD-SR	From January 2019 to May 2021	Cohort study	ICD-10	ICD-10-CM	<16	64898	86	Low
Kompaniyets et al. 2022⁴⁰⁾	USA	Health Verity medical claims database	From March 1, 2020 to January 31, 2022	Cohort study	ICD-10	ICD-10-CM	0-17	781419	692	Low

ICPC, International Classification of Primary Care; AHRQ, Agency for Healthcare Research and Quality; HUCP, Healthcare Cost and Utilization Project; PHD-SR, Premier Healthcare Database Special COVID-19 Release; PCR, Polymerase chain reaction; BC, Brighton Collaboration; CDC, Center for Disease Control and Prevention; JCAEVDSPAFSMHW, Joint Committee on Adverse Events of Vaccines and Drug Safety of Pharmaceutical Affairs and Food Safety of the Ministry of Health, Laboure, and Welfare in Japan; VARES , Vaccine adverse event reporting system; KDCA, Korea Disease Control and Prevention Agency; SAFEVIC, Surveillance of Adverse Events Following Vaccination in the Community

No competing interests reported.

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Myocarditis and pericarditis are temporally associated with BNT162b2 COVID-19 vaccine in adolescents: a systematic review and meta-analysis

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