Objectives To synthesise evidence on incidence rates and risk factors for myocarditis and pericarditis after use of mRNA vaccination against covid-19, clinical presentation, short term and longer term outcomes of cases, and proposed mechanisms. Design Living evidence syntheses and review. Data sources Medline, Embase, and the Cochrane Library were searched from 6 October 2020 to 10 January 2022; reference lists and grey literature (to 13 January 2021). One reviewer completed screening and another verified 50% of exclusions, using a machine learning program to prioritise records. A second reviewer verified all exclusions at full text, extracted data, and (for incidence and risk factors) risk of bias assessments using modified Joanna Briggs Institute tools. Team consensus determined certainty of evidence ratings for incidence and risk factors using GRADE (Grading of Recommendations, Assessment, Development and Evaluation). Eligibility criteria for selecting studies Large (>10 000 participants) or population based or multisite observational studies and surveillance data (incidence and risk factors) reporting on confirmed myocarditis or pericarditis after covid-19 mRNA vaccination; case series (n≥5, presentation, short term clinical course and longer term outcomes); opinions, letters, reviews, and primary studies focused on describing or supporting hypothesised mechanisms. Results 46 studies were included (14 on incidence, seven on risk factors, 11 on characteristics and short term course, three on longer term outcomes, and 21 on mechanisms). Incidence of myocarditis after mRNA vaccines was highest in male adolescents and male young adults (age 12-17 years, range 50-139 cases per million (low certainty); 18-29 years, 28-147 per million (moderate certainty)). For girls and boys aged 5-11 years and women aged 18-29 years, incidence of myocarditis after vaccination with BNT162b2 (Pfizer/BioNTech) could be fewer than 20 cases per million (low certainty). Incidence after a third dose of an mRNA vaccine had very low certainty evidence. For individuals of 18-29 years, incidence of myocarditis is probably higher after vaccination with mRNA-1273 (Moderna) compared with Pfizer (moderate certainty). Among individuals aged 12-17, 18-29, or 18-39 years, incidence of myocarditis or pericarditis after dose two of an mRNA vaccine for covid-19 might be lower when administered ≥31 days compared with ≤30 days after dose one (low certainty). Data specific to men aged 18-29 years indicated that the dosing interval might need to increase to ≥56 days to substantially drop myocarditis or pericarditis incidence. For clinical course and short term outcomes, only one small case series (n=8) was found for 5-11 year olds. In adolescents and adults, most (>90%) myocarditis cases involved men of a median 20-30 years of age and with symptom onset two to four days after a second dose (71-100%). Most people were admitted to hospital (≥84%) for a short duration (two to four days). For pericarditis, data were limited but more variation than myocarditis has been reported in patient age, sex, onset timing, and rate of admission to hospital. Three case series with longer term (3 months; n=38) follow-up suggested persistent echocardiogram abnormalities, as well as ongoing symptoms or a need for drug treatments or restriction from activities in >50% of patients. Sixteen hypothesised mechanisms were described, with little direct supporting or refuting evidence. Conclusions These findings indicate that adolescent and young adult men are at the highest risk of myocarditis after mRNA vaccination. Use of a Pfizer vaccine over a Moderna vaccine and waiting for more than 30 days between doses might be preferred for this population. Incidence of myocarditis in children aged 5-11 years is very rare but certainty was low. Data for clinical risk factors were very limited. A clinical course of mRNA related myocarditis appeared to be benign, although longer term follow-up data were limited. Prospective studies with appropriate testing (eg, biopsy and tissue morphology) will enhance understanding of mechanism. All of the data extracted for this review are included in the manuscript and associated supplementary files.

中文翻译：

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covid-19 疫苗接种后心肌炎和心包炎的发病率、危险因素、自然史和假设机制：活证据综合和回顾

目的 综合使用 mRNA 疫苗预防 covid-19 后心肌炎和心包炎的发病率和危险因素、临床表现、病例的短期和长期结果以及提出的机制的证据。设计生活证据综合和审查。数据源 Medline、Embase 和 Cochrane Library 检索时间为 2020 年 10 月 6 日至 2022 年 1 月 10 日；参考清单和灰色文献（至 2021 年 1 月 13 日）。一位审阅者完成了筛选，另一位审阅者验证了 50% 的排除，使用机器学习程序对记录进行优先排序。第二位评审员使用修改后的 Joanna Briggs Institute 工具验证了全文中的所有排除、提取数据和（针对发生率和风险因素）偏倚评估风险。团队共识使用 GRADE（建议分级、评估、开发和评估）确定发生率和风险因素的证据评级的确定性。选择研究的资格标准 大型（>10 000 名参与者）或基于人群或多地点的观察性研究和监测数据（发病率和风险因素）报告 COVID-19 mRNA 疫苗接种后确诊的心肌炎或心包炎；病例系列（n≥5、表现、短期临床过程和长期结果）；意见、信件、评论和主要研究侧重于描述或支持假设的机制。结果 共纳入 46 项研究（14 项关于发病率，7 项关于风险因素，11 项关于特征和短期病程，3 项关于长期结果，21 项关于机制）。mRNA 疫苗后心肌炎的发病率在男性青少年和年轻男性中最高（12-17 岁，范围为每百万 50-139 例（低确定性）；18-29 岁，每百万 28-147 例（中等确定性））。对于 5-11 岁的女孩和男孩以及 18-29 岁的女性，接种 BNT162b2（辉瑞/BioNTech）后心肌炎的发病率可能低于每百万 20 例（低确定性）。第三剂 mRNA 疫苗后的发病率的确定性证据非常低。对于 18-29 岁的个体，接种 mRNA-1273 (Moderna) 后心肌炎的发病率可能高于辉瑞 (中等确定性)。在 12-17、18-29 或 18-39 岁的个体中，与第 1 剂后 ≤30 天相比，接种 covid-19 mRNA 疫苗 ≥31 天后，心肌炎或心包炎的发生率可能较低（低确定性）。针对 18-29 岁男性的数据表明，给药间隔可能需要增加到 ≥56 天，以显着降低心肌炎或心包炎的发病率。对于临床过程和短期结果，仅发现一个针对 5-11 岁儿童的小型病例系列 (n=8)。在青少年和成人中，大多数 (>90%) 心肌炎病例涉及中位年龄为 20-30 岁的男性，并且在第二次给药后 2-4 天出现症状 (71-100%)。大多数人住院时间很短（≥84%）（两到四天）。对于心包炎，数据有限，但在患者年龄、性别、发病时间、和入院率。三个长期（3 个月；n=38）随访的病例系列表明 >50% 的患者存在持续的超声心动图异常，以及持续的症状或需要药物治疗或限制活动。描述了 16 种假设机制，几乎没有直接支持或反驳的证据。结论 这些研究结果表明，青少年和年轻成年男性在接种 mRNA 后患心肌炎的风险最高。对于这一人群来说，使用辉瑞疫苗而不是 Moderna 疫苗并在两次剂量之间等待超过 30 天可能是首选。5-11 岁儿童心肌炎的发病率非常罕见，但确定性很低。临床危险因素的数据非常有限。mRNA 相关心肌炎的临床过程似乎是良性的，尽管长期随访数据有限。具有适当测试（例如活检和组织形态）的前瞻性研究将增强对机制的理解。为本次审查提取的所有数据都包含在手稿和相关的补充文件中。