Incidence, risk factors, natural history, and hypothesised mechanisms of myocarditis and pericarditis following covid-19 vaccination: living evidence syntheses and review

  1. Jennifer Pillay
  2. Lindsay Gaudet
  3. Aireen Wingert
  4. Liza Bialy
  5. Andrew S Mackie
  6. D Ian Paterson
  7. Lisa Hartling

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Abstract

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.

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  1. Version published to 10.1136/bmj-2021-069445
  2. ScreenIT

    SciScore for 10.1101/2022.02.28.22271643: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variableWe rated down for risk of bias when only studies having high risk for case ascertainment contributed to an outcome (e.g., passive surveillance where we assume there is under-ascertainment), and for indirectness for comparisons across both sexes or if the age group reported did not match one of our groups of interest (e.g., 13-39 year olds) and the incident rates may vary substantially among ages.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Literature Search: We worked with an experienced medical information specialist to develop the search strategy, which was peer-reviewed (see Acknowledgements).18 Searches combined concepts for COVID-19, vaccines, and myocarditis/pericarditis/cardiovascular manifestations/adverse events/surveillance; each concept included various key word and Medical Subject Heading (MeSH) terms.
    MeSH
    suggested: (MeSH, RRID:SCR_004750)
    & Other Non-Indexed Citations and Daily <1946 to January 10, 2022> and Embase <1974 to 2022 January 10>.
    Embase
    suggested: (EMBASE, RRID:SCR_001650)
    In January, we searched L-OVE, CT.gov, Cochrane COVID Reg, WHO Covid reg, and Google Scholar for additional grey literature.
    Cochrane COVID
    suggested: None
    Google Scholar
    suggested: (Google Scholar, RRID:SCR_008878)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Several limitations exist in the mechanistic literature we identified: i) little direct empiric evidence was available to support or refute the proposed hypotheses; where direct empiric evidence was available, it often derived from case reports or small series, ii) when assessing laboratory findings in case reports/series/retrospective studies, it is not clear whether any differences seen (e.g., increases in NK cells, autoantibodies) reflect a causal pathological immune response or reactive adaptive responses to the myocardial inflammation, iii) the emergence of new studies refuting some of the proposed mechanisms; for example, articles stating no reports of eosinophilia, are out-dated due to reports finding evidence of this, iv) there has been a lack of invasive investigations (e.g., biopsy, tissue morphology, special studies to detect injury, immune activity, virus, etc.) given the typically mild course of the clinical conditions observed, and v) it is difficult to confirm a causal link; for example, an important proportion of cases observed or reported may not be vaccine-related and this will contribute to the heterogeneity of presentations, clinical characteristics, and resulting hypotheses. Choi et al.87 described a fatal case of myocarditis after mRNA vaccination and compared the case to another fatality reported by Verma et al.69 both of which had comprehensive clinicopathological analysis. The two cases were remarkably different, suggesting “that myocarditis after COV...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2022.02.28.22271643v1 on medRxiv
  4. ScreenIT

    SciScore for 10.1101/2021.11.19.21266605: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variableWe downrated for risk of bias when studies using passive surveillance (assuming some under ascertainment) and unverified cases contributed to a synthesis, and for indirectness for comparisons across all ages and both sexes, due to the large heterogeneity in incidence rates across ages (for males) and sexes.
    RandomizationFor randomized controlled trials (RCTs), we used the report of the largest population as the primary (included) publication and cited associated papers used for data extraction; sub-studies within RCTs, for example of different ages, were considered different studies.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Other Non-Indexed Citations and Daily <1946 to October 05, 2021> and Embase <1974 to 2021 October 05>.
    Embase
    suggested: (EMBASE, RRID:SCR_001650)
    We also searched the Cochrane Library and medRxiv (last 2 months).
    Cochrane Library
    suggested: (Cochrane Library, RRID:SCR_013000)
    We used the Cochrane Collaboration ROB 2.0 tool18 for RCTs, and the JBI (formally Joanna Briggs Institute) checklist for cohort studies19 for observational studies/surveillance data.
    Cochrane Collaboration ROB
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The key messages from the patient/parent perspective, co-developed with our patient partners, include: Strengths and limitations of the review: There are several strengths of this review. A comprehensive, peer-reviewed search strategy was used and inclusion of gray literature captured in several cases very recent data. A second reviewer screened the most relevant (based on machine learning) citations, and verified all data and risk of bias assessments. GRADE assessments were based on team consensus including clinical experts. Patient partners reviewed the evidence and developed interpretations from the patient perspective. The main limitation is that in the era of COVID-19 the literature base is evolving with incredible rapidity and new evidence will emerge; nevertheless, there was some moderate certainty evidence found in this review. Because many reports used overlapping populations and reported findings based on different methods of case ascertainment (e.g., risk interval, whether cases were verified) a quantitative synthesis was not undertaken and some of the descriptive summary statements may not fully account for this. We also avoided making any conclusions about any one possible estimate of average incidence and instead relied on ranges.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  5. Version published to 10.1101/2021.11.19.21266605v1 on medRxiv