key: cord-0817170-lrlptnnm authors: Woo, Wongi; Kim, Ah Y.; Yon, Dong K.; Lee, Seung W.; Hwang, Jimin; Jacob, Louis; Koyanagi, Ai; Kim, Min S.; Moon, Duk H.; Jung, Jo W.; Choi, Jae Y.; Jung, Se Y.; Eun, Lucy Y.; Lee, Sungsoo; Shin, Jae Il; Smith, Lee title: Clinical characteristics and prognostic factors of myocarditis associated with the mRNA COVID‐19 vaccine date: 2021-12-14 journal: J Med Virol DOI: 10.1002/jmv.27501 sha: b37ef429972059c4d023222e4ab020d0b1de1358 doc_id: 817170 cord_uid: lrlptnnm To analyze the clinical presentation and outcomes of myocarditis after administration of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) messenger RNA (mRNA) vaccine. Nine case series and 15 case reports (74 patients) of myocarditis after administration of the BNT162b2 or mRNA‐1273 vaccine were reviewed from PubMed, Scopus, Embase, and Web of Science. We analyzed clinical manifestations, diagnostic findings, and outcomes. In addition, we performed a pooled analysis and investigated risk factors leading to admission to the intensive care unit and recovery with conservative care. Most patients were male (94.6%), and the median age (range) was 17.6 (14–70) years. Patients who received the BNT162b2 (n = 58, 78.4%) vaccine presented fewer systemic symptoms and left ventricular dysfunction than mRNA‐1273 recipients. Although patients under 20 years experienced more fever and myalgia, they had better ejection fraction and less prominent myocardial inflammation in magnetic resonance imaging than older patients. The clinical course of all patients was favorable without mortality, and one‐third of patients resolved with conservative care alone. Risk factor analyses revealed that patients with gastrointestinal symptoms required intensive care (odds ratio: 20.3, 95% confidence interval 1.90–217, p = 0.013). The risk of fatality in myocarditis subjected to mRNA vaccination seems to be low. However, patients with gastrointestinal symptoms received more intensive care, and a significant proportion of patients recovered with conservative management. myocarditis subjected to mRNA vaccination seems to be low. However, patients with gastrointestinal symptoms received more intensive care, and a significant proportion of patients recovered with conservative management. infection by neutralizing antibodies. [2] [3] [4] They have been proven safe in large-scale trials in which adverse cardiovascular effects related to the vaccine were studied, wherein an incidence of <0.05% was reported, and myocarditis was not reported. 3 Additionally, there were 54 deaths reported, suggesting that it is a very important issue that needs to be addressed and should not be overlooked. 7, 8 Thus far, case reports and case series of myocarditis related to mRNA vaccine are accumulating; however, owing to insufficient sample size, it is difficult to draw consistent, significant conclusions regarding their clinical presentation and treatment. Moreover, no study has analyzed the differential outcomes of COVID-19 vaccineassociated myocarditis, such as recovery with conservative care and intensive care unit (ICU) admission, along with associated risk factors. Given this background, the present systematic review aimed to study previously published case reports and case series associated with COVID-19 mRNA vaccine-related myocarditis, and investigate the risk factors related to clinical outcomes. Although our findings are limited in their generalizability, our study can provide clinicians a comprehensive understanding of this rare, adverse event, and also support people who require more information before getting vaccinated. This systematic review was performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P, Table S1). 9 As reports are being updated every day, a rapid review was conducted to summarize all published cases of myocarditis related to mRNA vaccines. The inclusion criteria of studies were as follows: (1) | 1567 case series to analyze at individual patient level with sufficient raw data. We excluded cases if they had received any other type of COVID-19 vaccine or were diagnosed as having pericarditis alone. We further excluded review articles, letters to the editors, abstracts, articles that did not contain sufficient information on the patient characteristics or outcomes, and duplicate cases. We initially carried out a search on PubMed/Medline, EPub, Scopus, Embase, and Web of Science databases, that include all articles available on patients with COVID-19 mRNA vaccine-associated myocarditis published up to August 25, 2021. Our initial search yielded 63 articles. After reviewing individual abstracts and full texts of the articles, we identified 20 studies (12 case reports and 8 case series) that met the inclusion criteria for this systematic review. [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] In addition, we carried out an additional search in the same databases on September 10, 2021, and added one case series and three case reports. [30] [31] [32] [33] The search terms used are described in detail in Table S2 . The detailed selection process is depicted in Figure S1 , and the characteristics of individual case studies are shown in Tables S3-S4. Three reviewers (J.I. Shin, W. Woo, and A.Y. Kim) independently examined the studies, and any disagreement among the reviewers was resolved by consensus. For each eligible case report and case series, we extracted data on the demographic, clinical, and laboratory findings at presentation, types of treatment, clinical course, and outcome. We identified 24 studies on myocarditis related to immunization with BNT162b2 or mRNA-1273 COVID-19 vaccines, and collected data on demographic and clinical characteristics, including information on treatments, outcomes, age, sex, onset of symptoms, pre-existing conditions, laboratory results, immunologic assays, results of electrocardiography (ECG) and echocardiogram, as well as radiological findings of cardiac magnetic resonance (CMR) imaging, and finally, the length of hospitalization, length of ICU stay, and mortality. Spearman's correlation analysis was carried out to determine the relationships between continuous variables, and phi correlation coefficients were calculated to measure the strength of association between categorical variables. We included patients' demographics, clinical presentation, and diagnostic findings, then logistic regression analyses were used to identify independent risk factors for ICU admission, recovery with conservative care, and left ventricular dysfunction. Variables with a p-value of <0.10 in the univariate analysis were entered into a multivariate analysis and a two-tailed p-value of <0.05 was considered significant. Only significant variables in multivariate analyses were listed in the multivariate analyses. anti-inflammatory medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, steroids, or intravenous immunoglobulin. In addition, 16.2% of them were treated with heart failure medications, including beta-blockers, angiotensin-converting-enzyme (ACE) inhibitors/ angiotensin-receptor-blocker (ARB)s, diuretics, or inotropics (Table S6) . About 5% of patients (n = 4) experienced complications, including one major (multiorgan failure) and three minor cases (nonsustained ventricular tachycardia). Twelve patients (16.2%) required ICU care, and about half (43.2%) of the patients were discharged within 4 days. When we divided patients into two groups based on their age, that is, at or over 20 and under 20 years ( Notably, our study compared clinical characteristics, diagnostic findings, and outcomes based on the type of mRNA vaccines and the patients' age. This review provides clinicians with a comprehensive understanding of this rare adverse event. It is generally accepted that the acute onset of vaccineassociated myocarditis is attributable to allergic/hypersensitivity reactions as observed in other vaccines. 37 reaction. This laboratory result could support our finding that chills and LV dysfunction were more prevalent in mRNA-1273 recipients. 45 However, due to the limited number of mRNA-1273 myocarditis cases and the nonavailability of laboratory data on the levels of antibodies, it is currently challenging to make definitive conclusions regarding an association between myocarditis and antibody levels. Also, contrary to clinical symptoms and echocardiography findings, more patients who received mRNA-1273 were discharged within four days compared to those who received BNT162b2. Further studies are necessary to draw conclusions and understand the difference between the two vaccines regarding myocarditis as an adverse event. In addition, young patients were more likely to experience systemic symptoms such as fever and myalgia. Richards et al. evaluated humoral antibody levels after the primary immunization, and the younger age group showed significantly higher antibody response than older individuals. 45 A possible explanation could be a more potent immune response in younger patients, which can also explain the higher rate of side effects to the vaccines in this age group. 46 However, this age group (<20 years) reported fewer cases of LV dysfunction, and the number of patients with prominent myocardial inflammation findings in the CMR was lower than that observed in older patients in our review. Due to insufficient reports on adolescents who received mRNA vaccines, further analyses for young individuals are necessary. In agreement with previous reports on these patients' relatively 70 Recently published data from the health care organization in Israel estimated the incidence of myocarditis due to COVID-19 infection as 11.0 cases per 100 000 persons (95% CI, 5.6-15.8), and the incidence of myocarditis following the BNT1621b vaccine was 2.7 cases per 100 000 persons (95% CI, 1.0-4.6). 71 The systematic reviews of 42 myocarditis cases related to COVID-19 infection revealed a high mortality rate and severe complications, 35, 36 compared to the present review's findings. Although the incidence of myocarditis in the vaccinated population is higher than in unvaccinated individuals, the risk of myocarditis due to COVID-19 and its fatal outcome is much lower among vaccinated people. Moreover, infection with SARS-CoV-2 has more adverse events beyond myocarditis, and thus, it is necessary to encourage the public to get vaccinated. The present systematic review has several limitations. First, it is difficult to generalize the study findings due to rapidly evolving medical knowledge about SARS-CoV-2 and its mRNA vaccines. This rare adverse event could be attributable to genetic predispositions of a specific population, as we mentioned the possible mechanism forehead. Furthermore, as we reviewed case reports, information about myocarditis related to mRNA vaccines has been updated continuously, and the eligibility of mRNA vaccination has also evolved. Cautious interpretation of our data is necessary based on this ever-changing medical environment. 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However, both equally contributed to conceptualization, data curation, analysis, and writing the manuscript.This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.