Development of myocarditis and pericarditis after COVID‐19 vaccination in children and adolescents: A systematic review

Abstract Myocarditis and pericarditis have been reported after COVID‐19 vaccine administration in children and adolescents, raising the concern about their possible association with these vaccines. The objective was to explore the incidence, clinical presentation, and association of myocarditis and pericarditis with COVID‐19 vaccines in children and adolescents. We conducted a systematic literature search on three databases, that is, Cochrane, MEDLINE/PubMed, and EMBASE from inception till March 2022. A total of three case reports, four case series, and six observational studies were included in the review. For case reports and case series, the mean age of the patients was 17.4 years, with 96.9% being male. Chest pain (n = 31, 93.9%), fever (n = 18, 54.5%), myalgias (n = 15, 45.4%) and headache (n = 9, 27.2%) were the most common presentations. Out of 33 patients, 32 (96.9%) of patients received Pfizer‐BioNTech whereas only one (3.03%) received Moderna (mRNA 1273). Clinical investigations revealed ST elevation (n = 32, 97%), and elevated CRP (n = 9, 27.2%) and cardiac troponin (n = 29, 87.8%). The pooled incidence of myocarditis and pericarditis from observational studies was (0.00063%) and (0.000074%) %, respectively. Myocarditis and pericarditis in children and adolescents after the COVID‐19 vaccines were more prevalent among males and more commonly observed after the second dose of Pfizer. Though the overall incidence was low, however, the clinicians should consider myocarditis and pericarditis as probable diagnosis when encountering young patients, with a history of vaccine administration, presenting with suggestive findings.


| INTRODUCTION
COVID-19 was initially reported in December 2019 in Wuhan, China, and over 317 million global cases of COVID-19 have been reported ever since. 1 To deal with this public health emergency of international concern (PHEIC), numerous expedited vaccination trials were con- fever, fatigue, headache, muscle pain, and diarrhea to serious adverse effects such as myocarditis, pericarditis, thrombocytopenia, lymphadenopathy, bell's palsy, and cerebrovascular accident. 4 Among these adverse effects, several cases of myocarditis and pericarditis following COVID-19 vaccine administration have also been reported around the world. 5 As of April 21, many cases of myocarditis and pericarditis in children and adolescents have been reported after administration of mRNA COVID-19 vaccine, however, most of the cases were mild and self-resolving with rare instances of hospital admission. 6 Myocarditis and pericarditis refers to the inflammation of myocardium and pericardium of heart respectively and commonly occurs as a consequence of viral infection. [7][8][9] It is usually a self-limited condition that responds to conservative management without any long-term sequelae but complications such as cardiomyopathy and heart failure have been reported. 10 The incidence of myocarditis in children is usually very low; accounting for 0.7% as reported in a large retrospective study. 11 Whereas, the incidence of myocarditis in adults is 1.5 million cases worldwide per year. 12 Viral infection has been reported to be the most common cause of myocarditis in children. 13,14 In the past, myocarditis has been reported as a side effect of live attenuated vaccines such as smallpox and influenza vaccines in children and adolescents. 15 The reporting of COVID-19 vaccine-related myocarditis and pericarditis cases are being investigated by safety agencies including the Centre of Disease Control and Prevention (CDC) in the United States and Pharmacovigilance Risk Assessment Committee (PRAC) in Europe. 16 Several published age, gender, and vaccine typebased analyses have reported an increased risk among young males following mRNA vaccines such as Pfizer-BioNTech and Moderna. 17 So far, it is still unclear if these results really reflect an increase in incidence or simply better reporting and recollection bias. The aim of this systematic review is to explore the incidence, clinical presentation, management, and association of myocarditis and pericarditis with the COVID-19 vaccines in children and adolescents. To the best of our knowledge, this is the first systematic review on this topic with the aim of providing a comprehensive outline of available evidence regarding COVID-19 vaccine-associated myocarditis and pericarditis.

| METHODS
The review has been registered on The International Prospective Register of Systematic Reviews (PROSPERO CRD 42021282961).
The study was performed according to the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. 18  We considered only those studies which included the population of children and adolescents (from birth up to 19 years of age) who had received their first or second dose of COVID-19 vaccine and had developed either myocarditis or pericarditis. Review articles, editorials, and those original articles that reported other side effects of vaccination but did not discuss myocarditis and pericarditis specifically, and articles in languages other than English were excluded from this review.
Initially, the articles were screened on the basis of title and abstract, after which full articles were reviewed. Articles were searched and extracted by two reviewers (M. F. and H. A. C) and a third investigator (M. H. A. K) was contacted to resolve any discrepancies.
Continuous variables were presented as means ± standard deviations, and categorical variables were presented as absolute values and percentages. Microsoft Excel was used to extract data and do calculations. Mendeley was used to add the references. The retrieved results of the case reports and case series are summarized in the form of two tables (Tables 1 and 2). One table focuses on the demographics, medical history, and outcomes, whereas the second is based on relevant medical investigations and diagnostic findings. The summary of included original articles (observational studies) has been delineated in Table 3. Table 3       Pfizer-BioNTech may be due to the fact that it is currently the only vaccination that has obtained complete FDA approval for use in adolescents. 30 Chest pain, myalgias, and headache were the most common presentations. 31  Only large-scale studies with advanced imaging techniques can provide any possible causative association. 38 The increased prevalence among males can be related to the differences in hormone signaling hence indicating its involvement in the pathophysiology of COVID-19 vaccine-related myocarditis. 39 There is a decrease in cell-mediated immune response in females Though the published literature emphasizes a possible association of COVID-19 vaccine and myocarditis, the incidence is too small to provide a causal association. Based on available data, the short time span between vaccine administration and development of myocarditis and pericarditis, and the elevated incidence in younger males does suggest a temporal relationship, however, due to the poorly understood mechanism behind this and lack of experimental studies it is difficult to provide a cause-effect association. 3,44 Healthcare workers and physicians working with young patients can benefit from the data synthesized in this review and remain updated regarding this association along with its diagnostic modalities and management. Since the majority of the cases were reported after the administration of Pfizer, this raises the concern in the emergency of approval of this vaccine for adolescents and children. The authors would like to acknowledge a few limitations in the review. Firstly, since there has been no large-scale clinical trial conducted so far to assess myocarditis/pericarditis associated with COVID-19 vaccines, this review is based on case reports, case series, and observational studies only. Second, a major proportion of included participants was from original articles, and we did not have access to individual-level data which imposes another limitation to the devised substantiation. Additionally, we lack sufficient data to support the findings for the population under the age of 12 years.

| Observational studies
Moreover, due to mild presentation and good recovery, there is a probability that a number of cases might have gone unreported which imposes a limitation in associating the development of myocarditis and pericarditis with the COVID-19 vaccine. Lastly, a possible publication bias can also exist due to the rarity of this condition. Cheema: Writingreviewing and editing.

DATA AVAILABILITY STATEMENT
The data underlying this article are available from the authors on reasonable request.