Myocarditis and Pericarditis following COVID-19 Vaccination: Evidence Syntheses on Incidence, Risk Factors, Natural History, and Hypothesized Mechanisms

Abstract Objectives Myocarditis and pericarditis are adverse events of special interest after vaccination for COVID-19. Evidence syntheses were conducted on incidence rates, risk factors for myocarditis and pericarditis after COVID-19 mRNA vaccination, clinical presentation and short- and longer-term outcomes of cases, and proposed mechanisms and their supporting evidence. Design Systematic reviews and evidence reviews. Data sources Medline, Embase and the Cochrane Library were searched from October 2020 to January 10, 2022; reference lists and grey literature (to January 13, 2021). Review methods Large (>10,000) or population-based/multisite observational studies and surveillance data (incidence and risk factors) reporting on confirmed myocarditis or pericarditis after COVID-19 vaccination; case series (n≥5, presentation, short-term clinical course and longer-term outcomes); opinions/letters/reviews/primary studies focused on describing or supporting hypothesized mechanisms. A single reviewer completed screening and another verified 50% of exclusions, using a machine-learning program to prioritize 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. Results 46 studies were included (14 on incidence, 7 on risk factors, 11 on characteristics and short-term course, 3 on longer term outcomes, and 21 on mechanisms). Incidence of myocarditis after mRNA vaccines is highest in male adolescents and young adults (12-17y: range 50-139 cases per million [low certainty] and 18-29y: range 28-147 per million [moderate certainty]). For 5-11 year-old males and females and females 18-29 years of age, incidence of myocarditis after vaccination with Pfizer may be fewer than 20 cases per million (low certainty). There was very low certainty evidence for incidence after a third dose of an mRNA vaccine. For 18-29 year-old males and females, incidence of myocarditis is probably higher after vaccination with Moderna compared to Pfizer (moderate certainty). Among 12-17, 18-29 and 18-39 year-olds, incidence of myocarditis/pericarditis after dose 2 of an mRNA vaccine may be lower when administered ≥31 days compared to ≤30 days after dose 1 (low certainty). Data specific to males aged 18-29 indicated that the dosing interval may need to increase to ≥56 days to substantially drop incidence. For clinical course and short-term outcomes only one small series (n=8) was found for 5-11 year olds. In cases of adolescents and adults, the majority (>90%) of myocarditis cases involved 20-30 year-old males with symptom onset 2 to 4 days after second dose (71-100%). Most cases were hospitalized (≥84%) for a short duration (2-4 d). For pericarditis, data is limited but more variation has been reported in patient age, sex, onset timing and rate of hospitalization. Case series with longer-term (3 mo; n=38) follow-up suggest persistent ECG abnormalities, as well as ongoing symptoms and/or a need for medications or restriction from activities in >50% of patients. 16 hypothesized mechanisms are described, with little direct supporting or refuting evidence. Conclusions Adolescent and young adult males are at the highest risk of myocarditis after mRNA vaccination. Pfizer over Moderna and waiting more than 30 days between doses may be preferred for this population. Incidence of myocarditis in children aged 5-11 may be very rare but certainty was low. Data on clinical risk factors was very limited. Clinical course of mRNA related myocarditis appears to be benign although longer term follow-up data is limited. Prospective studies with appropriate testing (e.g., biopsy, tissue morphology) will enhance understanding of mechanism(s). Funding and Registration no This project was funded in part by the Canadian Institutes of Health Research (CIHR) through the COVID-19 Evidence Network to support Decision-making (COVID-END) at McMaster University. Not registered. Summary box What is already known about this topic? Case reports and surveillance signals of myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the two-layered sac surrounding the heart) after COVID-19 vaccination appeared as early as April 2021. These have prompted ongoing surveillance and research of these complications to investigate their incidence, possible attribution to the vaccines, and clinical course. What this study adds This review critically appraises and synthesizes the available evidence to-date on the incidence of and risk factors for myocarditis and pericarditis after COVID-19 vaccination in multiple countries. It summarizes the presentation and clinical course of over 8000 reported cases and describes some initial reports of longer term outcomes. Further, many possible mechanisms are outlined and discussed. Though low, the incidence of myocarditis is probably the highest in young males aged 12-29 years and is probably higher with Moderna than Pfizer mRNA vaccines. Longer dosing intervals may be beneficial. Most cases are mild and self-limiting, though data in 5-11 year-olds is very limited. Continued active surveillance with longer term follow-up is warranted.

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