key: cord-1050776-gr8zq6s9 authors: Ahmed, S. K.; Mohamed, M. G.; Essa, R. A.; Ahmed Rashad, E. A.; Ibrahim, P. K.; Khdir, A. A.; Wsu, Z. H. title: Global Reports of Myocarditis Following COVID-19 Vaccination: A Systematic Review and Meta-Analysis date: 2022-03-31 journal: nan DOI: 10.1101/2022.03.27.22273007 sha: 85c311606bc3e04f99fedbf2f8976fb03b69a4ca doc_id: 1050776 cord_uid: gr8zq6s9 In December 2020, the FDA granted emergency approval to Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) COVID-19 vaccines. There have been recent media reports of myocarditis after receiving COVID-19 vaccines, particularly the messenger RNA (mRNA) vaccines, causing public concern. This review summarizes information from published case series and case reports, with a strong emphasis on reporting patient and disease characteristics, investigation, and clinical outcome, to provide a comprehensive picture of the condition. Forty studies, including 147 cases, participated in this systematic review. The median age was 28.9 years; 93.9% were male and 6.1% were female. 72.1% of patients received the Pfizer-BioNTech (BNT162b2) vaccine, 24.5% of patients received the Moderna COVID-19 Vaccine (mRNA-1273), and the rest of the 3.3% received other types of vaccines. Furthermore, most myocarditis cases (87.1%) occurred after the second vaccine dose, after a median time interval of 3.3 days. The most frequently reported symptoms were chest pain, myalgia/body aches and fever. Troponin levels were consistently elevated in 98.6%. The admission ECG was abnormal in 88.5% of cases, and the left LVEF was lower than 50% in 26.5% of cases. The vast majority of patients (93.2%) resolved symptoms and recovered, and only 3 patients died. These findings may help public health policy to consider myocarditis in the context of the benefits of COVID-19 vaccination as well as to 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. A comprehensive search of major electronic databases (PubMed and Google Scholar) was conducted on February 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 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 data papers were excluded in 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. The Rayyan website was used by two independent authors (SKA and RAE) to screen abstracts and full-text articles based on inclusion and exclusion criteria [5] . The third author (RAE) resolved any discrepancies between the two independent authors. Microsoft Excel spreadsheets were used to collect 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. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 31, 2022. ; https://doi.org/10.1101/2022.03.27.22273007 doi: medRxiv preprint Overall, forty studies, including 147 cases each, from the United States, Italy, Israel, Germany, Poland, France, Korea, Brazil, Japan, Mexico, and Iran participated in this systematic review. The median age was 28.9 years; 93.9% were male and 6.1% were female. 72.1% of patients received the Pfizer-BioNTech (BNT162b2) vaccine, 24 .5% of patients received the Moderna COVID-19 Vaccine (mRNA-1273), and the rest of the 3.3% received other types of vaccines (Johnson & Johnson, AstraZeneca, Sinovac). The vast majority of cases are from the United States. All patients were diagnosed with myocarditis or myopericarditis following COVID-19 vaccination, regardless of the type of vaccine and dose. Furthermore, most myocarditis cases (87.1%, n = 128) occurred after the second vaccine dose, after a median time interval of 3.3 days. The most frequently reported symptoms were chest pain (100% n = 147), fever (46.9% n = 69), myalgia/body aches (54.4% n = 80), and also variable reports of viral prodromes such as chills, headaches, and malaise. Troponin levels were consistently elevated in 98.6% (n = 145) of the cases where they were reported, consistent with myocardial injury. The admission electrocardiogram (ECG) was abnormal in 88.5% (n = 130) of cases, and the left ventricular ejection fraction (LVEF) was lower than 50% in 26.5% (n = 39) of cases. The median length of hospital stay was 5.2 days in 127 patients but unknown in 20 patients. The vast majority of patients (93.2%) (n = 137) resolved symptoms and recovered, and only 3 patients died ( Table 2 ). The current systematic review summarized evidence from the original case reports and case series that explored the development of myocarditis after COVID-19 vaccination. Throughout the selected studies, most of the participants were male, from the USA, and their mean age 28.94 was years old. The mechanism of vaccineinduced myocarditis is not known 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 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) [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 of the 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. The findings extend these observations, which include the median onset of symptoms after vaccine administration was 3.32 days. The most common symptoms are chest pain, followed by myalgia/ body aches and fever. These findings matched with Pillay et al (2021) [15] , who reported in a systematic review observation that the majority of myocarditis cases had a short symptoms onset of 2 to 4 days after a second dose, and the . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In patients with severe myocarditis, the diagnosis is often established by heart biopsy. In patients with mild myocarditis, the diagnosis is based on compatible clinical findings and confirmed by elevated levels of blood markers or an electrocardiogram (ECG) indicative of cardiac injury, with the presence of new abnormalities on echocardiography or cardiac MRI [17] . Cardiac-specific investigations revealed that troponin levels were elevated in almost all of the cases, consistent with myocardial injury, which is associated with autoimmune processes matched with vaccine protein and the case immune system. Vaccination in October 2020-October 2021, mentions that all reported cases have an elevated troponin level in keeping with myocardial injury. In our study, less than one third of cases had left ventricle ejection friction (LVEF) was less than 50%. Compared to patients with COVID-19 illness, patients with vaccine associated myocarditis had a higher LVEF. This finding is consistent with the findings of Fronza et al. (2022) [18] , who investigated myocardial injury patterns at MRI in COVID-19 Vaccine and discovered that more than half of the cases had more than 50% LVEF. Also, Shiyovich et al. (2022) [19] , who analyzed myocarditis following the third (Booster) dose of COVID-19 vaccination found that the mean left ventricular ejection fraction was 61 ± 7% (range 53-71%) and regional wall motion abnormalities were present in one of the patients only. Global T1 values were increased in one (25%) of the patients, while focal values were increased in 3 (75%) of the patients. Global T2 values were increased in one (25%) of the patients, while focal values were increased in all of the patients (100%). Global ECV was increased in 3 (75%) of the patients, while focal ECV was increased in all the patients (100%). LGE was present in all the patients. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Management of myocarditis remains largely supportive and is based on the restoration of hemodynamic stability and the administration of guideline-directed heart failure and arrhythmia treatment. Patients with preserved ventricular function and non-severe features were often treated with colchicine or non-steroidal antiinflammatory drugs. According to our findings, all cases were treated with NSAIDs, beta blockers, calcium channel blockers, and/or diuretics. The median length of hospital stay was 5.2 days in 127 patients, and the vast majority of patients resolved symptoms and recovered, and only 3 patients died. 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]. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) In conclusion, these findings may help public health policy to consider myocarditis in the context of the benefits of COVID-19 vaccination as well as to 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-1273 vaccine. There is no conflict to be declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit 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 the order of authors listed in the manuscript has been approved by all of us. 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. Kristjansson, AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both, Bmj. 358 (2017). [5] M. Ouzzani, H. Hammady, Z. Fedorowicz, A. Elmagarmid, Rayyan-a web and mobile app for systematic reviews, Syst Rev. 5 (2016) 1-10. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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