key: cord-0294326-8d210q9w authors: Ahmed, Sirwan Khalid; Mohamed, Mona Gamal; Essa, Rawand Abdulrahman; Ahmed Rashad, Eman Abdelaziz; Ibrahim, Peshraw Khdir; Khdir, Awat Alla; Wsu, Zhiar Hussen title: Global reports of myocarditis following COVID-19 vaccination: A systematic review and meta-analysis date: 2022-05-27 journal: nan DOI: 10.1016/j.dsx.2022.102513 sha: d0607b4103c7dec00ca86f8ea8a28e611df7a268 doc_id: 294326 cord_uid: 8d210q9w Background and aims Recent media reports of myocarditis after receiving COVID-19 vaccines, particularly the messenger RNA (mRNA) vaccines, are causing public concern. This review summarizes information from published case series and case reports, emphasizing patient and disease characteristics, investigation, and clinical outcomes, to provide a comprehensive picture of the condition. Methods A systematic literature search of PubMed and Google scholar was conducted from inception to April 27, 2022. Individuals who develop myocarditis after receiving the COVID-19 vaccine, regardless of the type of vaccine and dose, were included in the study. Results Sixty-two studies, including 218 cases, participated in the current systematic review. The median age was 29.2 years; 92.2% were male and 7.8% were female. 72.4% of patients received the Pfizer-BioNTech (BNT162b2) vaccine, 23.8% of patients received the Moderna COVID-19 Vaccine (mRNA-1273), and the rest of the 3.8% received other types of COVID-19 vaccine. Furthermore, most myocarditis cases (82.1%) occurred after the second vaccine dose, after a median time interval of 3.5 days. The most frequently reported symptoms were chest pain, myalgia/body aches and fever. Troponin levels were consistently elevated in 98.6% of patients. The admission ECG was abnormal in 88.5% of cases, and the left LVEF was lower than 50% in 21.5% of cases. Most patients (92.6%) resolved symptoms and recovered, and only three patients died. Conclusion These findings may help public health policy to consider myocarditis in the context of the benefits of COVID-19 vaccination. International efforts to drive vaccinations are critical to restoring health and economic and social recovery as the SARS-CoV-2 coronavirus (COVID-19)-caused pandemic continues [1] . The COVID-19 vaccines developed by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) were granted emergency approval by the Food and Drug Administration (FDA) of the United States in December 2020. Reports of myocarditis after the COVID-19 vaccination, notably after the messenger RNA (mRNA) vaccines, have recently received widespread media attention, causing widespread concern among the general public [1] . Myocarditis is diagnosed in about ten to twenty people per 100,000 in the general population each year, and it is more common in men and younger age groups [2] . Myocarditis following mRNA COVID-19 vaccination was first reported in Israel in April 2021, and then several case reports and case series were reported around the world. Specifically, this report examines the current literature on myocarditis following COVID-19 vaccination, summarizing available information from previously published case reports and case series, with a strong attention on reporting patient and disease characteristics, as well as investigation and clinical outcome, in order to provide a comprehensive picture of the condition. The main objective is to clarify the potential occurrence of myocarditis associated with vaccination and elaborate on the demographic and clinical characteristics of COVID-19 vaccinated individuals who develop myocarditis and how many cases have been reported in the literature. The review is written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines for the systematic review of available literature [3] . The protocol of the review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with ID CRD42022308997. The AMSTAR-2 checklist was also used to evaluate this study, and it was found to be of high quality [4] . This review article does not require ethics approval. A comprehensive search of major electronic databases (PubMed and Google Scholar) was conducted on April 27 10, 2022, to locate all publications. The AND operator was used to connect two of the most important concepts in the search terminology ("COVID-19" AND "Myocarditis"). ("Myocarditis" and "COVID-19" OR "SARS-CoV-2" OR "Coronavirus Disease 2019" OR "severe acute respiratory syndrome coronavirus 2" OR "coronavirus infection" OR "2019-nCoV" AND "vaccine, vaccination, OR vaccine" were used in the search. To make sure the search was completed, we checked the references of all relevant papers. All case series and case reports on post-COVID-19 vaccine myocarditis in humans were included. Individuals who develop myocarditis after receiving the COVID-19 vaccine, regardless of the type of vaccine and dose. The references of the relevant articles will also be reviewed for additional articles that meet the inclusion criteria. Narrative and systematic reviews, original and unavailable J o u r n a l P r e -p r o o f data papers were excluded from this review. Moreover, articles other than English were excluded in this review. PRISMA 2020 was used to guide every step of the data extraction process from the original source. Two independent authors (SKA and RAE) used the Rayyan website to screen abstracts and full-text articles based on inclusion and exclusion criteria [5] . The discrepancies between the two independent authors were resolved by discussion. Microsoft Excel spreadsheets collected the necessary information from the extracted data. Author names, year of publication, age, gender, type of COVID-19 vaccine, dose, days to symptoms onset, symptoms, troponin level, LVEF 50% or LVEF > 50%, ECG, length of hospital stay/days, treatment, and outcomes were extracted from each study. To assess the quality of all included studies, we used the Joanna Briggs Institute's critical appraisal tool for case series and case reports [6] . Two different authors (SKA and RAE) evaluated each article, each of whom worked independently. Paper evaluation disputes were resolved through discussion. Articles with an average score of 50 percent or higher were included in the data extraction process. The AMSTAR 2 criteria were used to evaluate the results of our systematic review [4] . The AMSTAR 2 tool assigned a "moderate" rating to the overall quality of our systematic review. All the articles included in the current systematic review were analyzed, and the data were extracted and pooled. This included (authors' names, year of publication; gender; type of COVID-19 vaccine, J o u r n a l P r e -p r o o f dose, days to symptoms onset, troponin level, LVEF below or above 50%, ECG, length of hospital stay/days; treatment and outcomes). We gathered this data from the results of eligibility studies. COVID-19 vaccine recipients who developed myocarditis were included in the study. When we searched the major databases (PubMed and Google Scholar) on April 27, 2022, we discovered 2979 articles relevant to our search criteria. A citation manager tool (Mendeley) was then used to organize the references, and 397 articles were automatically removed because they contained duplicate content. Next, the titles, abstracts, and full texts of 2585 articles were checked for accuracy, and 2494 articles were rejected because they did not meet the criteria for inclusion. Besides that, 91 articles were submitted for retrieval, but twenty-seven were rejected because they did not meet our inclusion requirements. The current systematic review was limited to 62 articles in total (Fig 1) . The details of case reports and case series are shown in (Table 1) . Table 2 ). The current systematic review summarized evidence from the original case reports and case series that explored the development of myocarditis after the COVID-19 vaccination. Throughout the selected studies, most of the participants were male, from the USA, and their mean age 29.2 was years old. The vaccine-induced myocarditis mechanism is unknown but may be related to the active pathogenic component of the vaccine and specific human proteins, which could lead to immune cross-reactivity resulting in autoimmune disease, which is one cause of myocarditis [7] [8] [9] [10] . The occurrence of myocarditis in men may be related to sex hormone variations, as testosterone hormone suppresses anti-inflammatory immune cells while promoting more aggressive T helper cells [7, 11] . These findings were matched with Oster et al. (2022) [12] , who found the incidence rate of myocarditis among vaccinated male people was similar to that seen in typical cases of myocarditis and there was a strong male predominance for both conditions [13] . Fatima et al (2022) [7] found most patients who developed myocarditis were males. Moreover, Patone et al (2022) [14] mentioned that the incidence of myocarditis was among England males younger than 40 years old. Similarly, a systematic review study found that the Incidence of myocarditis following mRNA vaccines is low but probably highest in males aged 12-29 years old [15] . Another important finding in the current systematic review is that most participants received Pfizer-BioNTech (BNT 162b2) followed by the Moderna CVID-19 vaccine (mRNA-1273), and most of the cases who complained of myocarditis received two doses of the vaccine. This indicates that mRNA vaccines are associated with a higher risk of developing myocarditis than viral vector vaccines, including Janssen, Oxford, and Sinovac. Bozkurt et al (2021) [2] , have assumed that autoantibody generation could attack cardiac myocytes in response to the mRNA vaccine, increasing the risk. Oster et al. (2022) [12] concluded that the risk of myocarditis after the mRNA vaccine was increased after the second dose in adolescents and young males. This finding is matched with Patone (2022) [14] , who mentioned the risk of myocarditis increased within a week of receiving the This finding broadly supports the work of other studies in this area. Woo et al [22] reported that many patients who received anti-inflammatory agents such as NSAIDs, colchicine, steroids, and intravenous immunoglobulin recovered without further medical treatment, with a hospital stay lasting 3-6 days. In accordance with the present results, previous studies have demonstrated that almost all of the cases experienced a prompt recovery with no residual cardiac dysfunction. The median length of stay for all myocarditis cases was around 2-3 days, with a range of 2-10 days [23] . In conclusion, these findings may help public health policy consider myocarditis in the context of the benefits of COVID-19 vaccination and assess the cardiac condition before the choice of vaccine, which is offered to male adults. In addition, it must be carefully weighed against the very substantial benefit of vaccination. Moreover, further research is required to assess the long-term consequences and other risk factors following immunization, specifically the mRNA vaccines. There is no conflict to be declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We declare that this manuscript is original, has not been published before, and is not currently being considered for publication elsewhere. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We confirm that all have agreed with the order of authors listed in our manuscript. We understand that the Corresponding Author is the sole contact for the Editorial process. He is responsible for communicating with the other authors about progress, submissions of revisions, and final approval of proofs. All relevant data are within the manuscript and its supporting information files. 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