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.
Subject(s)
COVID-19 , Myocarditis , Brugada SyndromeABSTRACT
Objectives: Myocarditis and pericarditis are adverse events of special interest after vaccination with mRNA vaccines. This rapid systematic review examined incidence rates of myocarditis and pericarditis after COVID-19 vaccination, and the presentation and clinical course of cases. Design: Rapid systematic review Data sources: Medline, Embase and the Cochrane Library were searched from October 2020 to October 6, 2021; reference lists and grey literature (to Oct 21, 2021). Review methods: Randomized controlled trials (RCTs) and large population-based/multisite observational studies and surveillance data reporting on myocarditis or pericarditis in people of any age after receiving any COVID-19 vaccine; systematic reviews of case series. 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, data extractions, and (for incidence) risk of bias assessments using Cochrane Risk of Bias 2.0 and Joanna Briggs Institute tools. Certainty of evidence ratings for incidence were based on team consensus using GRADE. Patient partners provided key messages from their interpretations of the findings. Results: 3457 titles/abstracts and 159 full texts were screened. For incidence rates we included 7 RCTs (n=3732 to 44,325) and 22 large observational studies/data sources using passive (n=10) and active (n=12) surveillance; for case presentation, we included 11 case series published as articles and three based on publicly available websites (n=12,636 cases). Mainly due to imprecision, the RCTs provided very low certainty evidence for incidence of myocarditis or pericarditis. From observational data, the incidence of myocarditis following mRNA vaccines is low but probably highest in males 12-17 years (55 [7-day risk] to 134 [30-day risk] cases per million; specific to Pfizer) and 18-29 years (40 [7-day risk] to 99 [21-30 day risk]) cases per million) (Moderate certainty evidence). Incidence is lower (<20 per million) or little-to-none in older ages and across all ages of females (Low certainty). Evidence for pericarditis was of very low certainty. Among adult males under 40 years, Moderna compared with Pfizer vaccine may be associated with a small increase (<20 per million) in risk for myocarditis or (one of) myocarditis or pericarditis following vaccination (Low certainty); the evidence for youth under 18 years was very uncertain. No study examined differences in incidence based on pre-existing condition(s) or risk factors apart from age and sex. The majority of myocarditis cases involved males (often >90%) in their 20s, with a short symptom onset of 2 to 4 days after a second dose (71-100%). The majority of cases presented with chest pain/pressure and troponin elevation; a minority (<30%) had left ventricular dysfunction. Most were hospitalized (≥84%), without stays in intensive care units, for a short duration (2-4 d) and treated with anti-inflammatory and/or other supportive therapies. Almost all reports of death are from unverified cases and of unclear cause. Most cases of pericarditis were unconfirmed; for this outcome there appears to be more variation in age, sex, onset timing and rate of hospitalization. Conclusions: Incidence of myocarditis following mRNA vaccines is low but probably highest in males 12-29 years old. Existing evidence does not strongly support preference of one mRNA vaccine, even in young males. Continued active surveillance of myocarditis incidence out to 30 days from dosing is recommended with respect to i) new populations (i.e., children <12y), ii) third and subsequent doses, and iii) affected individuals receiving subsequent mRNA vaccine doses. Future research is needed to examine other risk factors and long-term effects.