Myocarditis and Pericarditis Following mRNA COVID-19 Vaccination: 2024 Status and Management Update

In 2021, the Canadian Journal of Cardiology published a "Practical Clinical Practice Update" to address emerging concerns about myocarditis and pericarditis following mRNA COVID-19 vaccines.1 Since publication, researchers have underscored the importance of standardizing diagnostic criteria and evaluation of incident cases.In this brief review, we summarize new evidence about the epidemiology and outcomes of patients with mRNA COVID-19 post-vaccine myocarditis and pericarditis. We also provide consensus guidance for evaluation, management, and follow-up. Finally, we identify persistent knowledge gaps that inform the National Active Surveillance Study of Myocarditis and/or Pericarditis following mRNA COVID-19 Vaccination (MYCOVACC) and areas for future research. In 2021, the Canadian Journal of Cardiology published a "Practical Clinical Practice Update" to address emerging concerns about myocarditis and pericarditis following mRNA COVID-19 vaccines.1 Since publication, researchers have underscored the importance of standardizing diagnostic criteria and evaluation of incident cases. In this brief review, we summarize new evidence about the epidemiology and outcomes of patients with mRNA COVID-19 post-vaccine myocarditis and pericarditis. We also provide consensus guidance for evaluation, management, and follow-up. Finally, we identify persistent knowledge gaps that inform the National Active Surveillance Study of Myocarditis and/or Pericarditis following mRNA COVID-19 Vaccination (MYCOVACC) and areas for future research. The Brighton Collaboration case definitions are used to evaluate myocarditis and pericarditis following COVID-19 vaccination in Canada.1Luk A. Clarke B. Dahdah N. et al.Myocarditis and pericarditis after mRNA COVID-19 vaccination: practical considerations for care providers.Can J Cardiol. 2021; 37: 1629-1634Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar,2Public Health Agency of Canada. Canadian COVID-19 vaccination safety report. Ottawa: Public Health Agency of Canada; January 19, 2024. https://health-infobase.canada.ca/covid-19/vaccine-safety/ .Google ScholarThese include graduated levels of certainty (1 definite, 2 probable, 3 possible). Events occurring within 6 weeks of vaccination are considered more likely to be vaccine-associated. When myocarditis and pericarditis overlap, symptoms are evaluated against both case definitions and a level of certainty reported for each diagnosis. The incidence of post-vaccine myocarditis and/or pericarditis is low. As of January 2024, over 105 million COVID-19 vaccine doses have been administered in Canada, with 1,231 cases of myocarditis or pericarditis meeting Brighton Collaboration level of certainty 1 to 3 reported to the Public Health Agency of Canada (PHAC) and Health Canada through the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS)2Public Health Agency of Canada. Canadian COVID-19 vaccination safety report. Ottawa: Public Health Agency of Canada; January 19, 2024. https://health-infobase.canada.ca/covid-19/vaccine-safety/ .Google Scholar. This yields an overall incidence rate of 1.2 per 100,000 vaccine doses, noting this includes all doses and vaccines, which is consistent with estimates worldwide. The incidence of myocarditis following mRNA COVID-19 vaccination varies significantly by age and sex. In a Canadian living evidence synthesis3Gaudet LA, Pillay J, Saba S, et al. Incidence, natural history, specific populations and hypothesized mechanisms of myocarditis and pericarditis following mRNA COVID-19 vaccination: living evidence synthesis update #4. SPOR Evidence Alliance, COVID-END Network; March 29, 2023. https://sporevidencealliance.ca/wp-content/uploads/2023/03/les9.5_vaccine-related-myocarditis_report_2023-03-29_final.pdf.Google Scholar updated in March 2023 the incidence following a second dose of either mRNA vaccine was less than 2.0 per 100,000 doses in males and females under 12 years of age, increasing in males 12 to 17 and 18 to 29 years of age to between 1.3 to 39.0 cases and 2.9 to 15.7 cases per 100,000 doses, respectively. Myocarditis is less frequent in females across all age groups following a second dose acknowledging greater imprecision in these estimates. The incidence of pericarditis following mRNA COVID-19 vaccination and booster doses is uncertain across age and sex. A recent meta-analysis summarized the presenting symptoms and clinical course of post-vaccine myocarditis in 106 studies including patients over 12 years of age.4Ilonze O.J. Guglin M.E. Myocarditis following COVID-19 vaccination in adolescents and adults: A cumulative experience of 2021.Heart Failure Reviews. 2022; 27: 2033-2043Crossref PubMed Scopus (18) Google Scholar Among 238 patients, the mean age was 27.4+16.0 years, and the majority were male (n=208, 87.1%). Mean duration from vaccination to symptom onset was 4.8+5.5 days, typically after the second dose. The most common presenting symptom was chest pain (93%). Although most cases were mild, 5 patients died: ages 22 to 70 years, 2 females, 2 after first and 3 after second vaccination. All 5 patients presented with cardiogenic shock with left ventricular ejection fraction <30% requiring intensive care. The meta-analysis confirmed the favorable short-term prognosis of post-vaccine myocarditis, while highlighting rare instances of cardiogenic shock requiring rapid escalation of care including mechanical circulatory support. Suspected cases should be referred to specialist care (e.g., cardiology or internal medicine) for investigation and management. Evaluation includes use of standardized criteria to diagnose myocarditis/pericarditis, excluding alternative diagnoses (e.g., COVID-19 polymerase chain reaction test, chest x-ray, D-Dimer for pulmonary embolism), and myocarditis/pericarditis specific testing (Figure 1). Myocarditis/pericarditis investigations include cardiac enzymes (troponin with or without creatinine kinase/CK-MB), inflammatory markers (C-reactive protein and erythrocyte sedimentation rate), electrocardiogram (ECG), echocardiography and cardiac magnetic resonance (CMR) imaging where available. When access to CMR imaging is limited, especially in the emergency department, the minimal initial investigations should include the remainder of the abovementioned investigations. Patients with cardiac risk factors or over 45 years of age should undergo coronary evaluation with coronary computed tomography (CCT) or coronary angiogram. CMR imaging provides diagnostic and potentially prognostic information and should be pursued in all patients with suspected post-vaccine myocarditis/pericarditis, even in the absence of other testing abnormalities. Patients diagnosed clinically with pericarditis alone may have myocardial involvement on CMR imaging. Further, inflammatory markers and cardiac enzymes rapidly normalize and may be normal in delayed presentations. Since access to CMR imaging and endomyocardial biopsy are limited based on geography, patients in remote settings with moderate or higher risk profile (Table 1) should be transferred to a tertiary centre with CMR imaging capabilities when feasible. When CMR imaging is readily available, the threshold for testing should be very low irrespective of risk profile.Table 1Investigations and immediate management of post-vaccine myocarditis or pericarditis, according to risk profile.Risk ProfileLow Risk (Uncomplicated)Moderate Risk (Complicated)High Risk (Complicated)SymptomsChest pain, dyspnea, palpitations, diaphoresis, syncope, or edema.Same as low risk + acute HF, recurrent diseaseSame as moderate risk + cardiogenic shock, cardiac arrest, sudden death.Assessment for Alternative EtiologyCOVID-19 PCR, chest x-ray, D-Dimer, and relevant individualized testingSame as low risk + autoimmune testing + infectious testing (i.e., Lyme in endemic areas)Same as moderate risk + in-depth investigationCardiac Enzymes (Troponin and CK)Normal, mildly elevated, or downtrendingNormal, elevated, or uptrendingElevated or uptrendingInflammatory Markers (CRP and ESR)Normal, mildly elevated, or downtrendingNormal, elevated, or uptrendingElevated or uptrendingECG or HolterNormal or non-specific changesNormal, ectopy or non-specific changesVentricular arrhythmia or high-grade heart blockEchocardiographyLVEF ≥ 50%, small or no pericardial effusionLVEF 30-49%, moderate pericardial effusion without tamponadeLVEF <30%, any pericardial effusion with tamponadeCMRNo LGE or edema; normal parametric mapping (CMR recommended)Normal, or minimally abnormal LGE, edema, or parametric mapping sequences (CMR recommended)Generally abnormal with LGE, edema, or abnormal parametric mapping (CMR recommended when stable)CoronaryEvaluationYes, if risk factors for CAD, infarct-like presentation, or age >45Endomyocardial BiopsyNoMay considerYesTreatmentSettingInpatient or outpatient; ED discharge with follow-up in 2-4 weeks may be considered in adult patients with resolved or improving markers of inflammationInpatientInpatientFollow-upSpecialistSpecialistSpecialistAEFI ReportingYesYesYesAEFI, Adverse Event Following Immunization; CAD, coronary artery disease; CK, creatinine kinase; CMR, cardiac magnetic resonance imaging; CRP, C-reactive protein; ECG, electrocardiogram; ECG, electrocardiogram; ED, Emergency Department; ESR, erythrocyte sedimentation rate; HF, heart failure; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; PCR, polymerase chain reaction test. Open table in a new tab AEFI, Adverse Event Following Immunization; CAD, coronary artery disease; CK, creatinine kinase; CMR, cardiac magnetic resonance imaging; CRP, C-reactive protein; ECG, electrocardiogram; ECG, electrocardiogram; ED, Emergency Department; ESR, erythrocyte sedimentation rate; HF, heart failure; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; PCR, polymerase chain reaction test. Endomyocardial biopsy is generally reserved for patients who are too unstable for CMR imaging, suffer recurrent disease, or have complicated presentations in the setting of diagnostic uncertainty. 1Luk A. Clarke B. Dahdah N. et al.Myocarditis and pericarditis after mRNA COVID-19 vaccination: practical considerations for care providers.Can J Cardiol. 2021; 37: 1629-1634Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar,5Ammirati E. Moslehi J.J. Diagnosis and treatment of acute myocarditis: a review.JAMA. 2023; 329: 1098-1113Crossref PubMed Scopus (30) Google Scholar A low threshold to transfer patients with clinical deterioration to a CMR imaging and endomyocardial biopsy capable centre is recommended. Table 1 summarizes our proposed risk stratification based on presentation and investigations, along with recommended treatment setting and follow-up. For example, uncomplicated adult patients with mild disease, tolerable symptoms and resolved/improving inflammation with relatively normal investigations may be managed in the outpatient setting with timely CMR imaging and clinical follow-up within 2 to 4 weeks. Complicated presentations include recurrent disease, left ventricular dysfunction, cardiogenic shock, high-grade heart block, ventricular arrhythmia, or heart failure. These moderate and high-risk profiles require admission, inpatient investigation, and close observation. All patients, irrespective of risk, require specialist follow-up. The management of post-vaccine myocarditis and/or pericarditis should follow established guidelines for each condition. There are no randomized controlled trials of any treatment specifically in this population. Patients with chest pain should be treated with nonsteroidal anti-inflammatory drugs and/or colchicine provided there are no contraindications. Complications such as left ventricular systolic dysfunction and arrhythmia should be treated with guideline-directed heart failure therapy. As with myocarditis of many etiologies, the role of immunosuppression in severe presentations is uncertain. Selective use of corticosteroids for a short duration may be considered, balancing the risk and potential benefits of immunosuppression. Rarely, escalation of immunosuppressive therapies may be considered in fulminant disease along with mechanical circulatory support at experienced centres. However, it must be emphasized that severe presentation is rare. Return to play recommendations for myocarditis (competitive athletes and non-athletes) and pericarditis (competitive athletes) are similar. Typically, patients should restrict exercise for 3 to 6 months and then be re-evaluated. However, earlier return to play may be considered on a case-by-case basis in those with uncomplicated pericarditis in non-athletes that is quick to resolve. Based on clinician judgement and CMR imaging availability, it is reasonable to repeat CMR imaging 3 to 6 months following symptom onset to assess for ongoing inflammation in patients with persistent symptoms, ongoing abnormal cardiac testing (ECG, troponin, or echocardiography), or active inflammation on prior CMR imaging. Important knowledge gaps remain regarding risk factors, natural history, and optimal management strategies. One pressing area requiring further study concerns the risk of recurrent myocarditis and pericarditis with subsequent vaccination. Public health recommendations suggest avoiding further mRNA vaccination in cases of definite post-vaccine myocarditis until further data is available. The central question is how to consider the small risk of post-vaccine myocarditis in the context of public health measures to prevent severe disease secondary to COVID-19 infection. Given the relative rarity of these events, the true risk of myocarditis following vaccination cannot be ascertained from clinical trial data. Rather, continued population-level surveillance and timely reporting of post-vaccine myocarditis/pericarditis are needed to support public health guidance on the use of COVID-19 vaccines. In addition, improved understanding of the risk factors and pathologic mechanisms resulting in myocarditis/pericarditis secondary to mRNA COVID-19 vaccinations may help predict future risk and facilitate vaccine development that mitigates this risk. It is unknown whether pre-existing cardiovascular and non-cardiovascular conditions predispose to these complications or portend worse outcomes. The follow-up and management of patients who develop post-vaccine myocarditis/pericarditis also requires further evaluation to determine if etiology-specific interventions are needed. Given the disease severity tends to be less than typical viral myocarditis, the implications for clinical surveillance and risk for subsequent major adverse cardiovascular events may differ. Further, there is a paucity of data to guide management and return to play recommendations in post-vaccine myocarditis/pericarditis, so recommendations are extrapolated from other etiologies of myocarditis/pericarditis. Similarly, CMR imaging is often used in myocarditis to evaluate the presence and burden of fibrosis as measured by late gadolinium enhancement. Conventionally, the degree of fibrosis and persistence of edema is used to assess immediate and future risk of major cardiovascular events in patients. The presence, persistence, and implications of such CMR imaging findings in patients with post-vaccine- myocarditis requires ongoing study. Finally, long-term outcomes require evaluation. This includes the presence of chronic cardiac changes detected by imaging (such as echocardiography and CMR imaging), objective measures of functional capacity (such as exercise capacity as measured by cardiopulmonary exercise testing), and patient-reported outcome measures (such as health-related quality of life, the occurrence of cardiac symptoms, and worries, attitudes, and perceptions of COVID-19 and subsequent vaccinations). To address existing knowledge gaps in the Canadian context, the Canadian Cardiovascular Society received funding from PHAC to conduct MYCOVACC. This pan-Canadian study aims to describe the overall health and functional outcomes, as well as cardiac-specific outcomes, for those with myocarditis/pericarditis following mRNA COVID-19 vaccination. Insights from MYCOVACC will represent valuable progress towards understanding the natural history of this phenomenon and the long-term health implications for Canadians. This paper is intended to guide clinical practice; it is not an original research report. Applicable ethics guidelines were respected. The authors confirm that patient consent is not applicable to this review; patient data were not used. Production of this document has been made possible through a financial contribution from the Public Health Agency of Canada. The views expressed herein do not necessarily represent the views of the Public Health Agency of Canada.