MYocarditis and/or Pericarditis Following mRNA COVID-19 VACCination National Surveillance Study
Conditions: Myocarditis, Myocarditis Acute, Pericarditis, Pericarditis Acute
Sponsor: Cardiology Research UBC

MYCOVACC 
 
Canadian Cardiovascular Society 
Protocol version 3.0 
2023-0412 
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Canadian Cardiovascular Society 
 
Title: MYocarditis and/or pericarditis following mRNA COVID-19 
VACCination national surveillance study 
 
MYCOVACC 
 
Protocol 
 
 
 
 
 

MYCOVACC 
 
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Protocol version 3.0 
2023-0412 
Page 2 of 26  
Contents 
1. 
STUDY MANAGEMENT AND REGULATORY ............................................................................................... 4 
1.1 
Principal investigator contacts .............................................................................................................. 4 
1.2 
Co-investigators ..................................................................................................................................... 4 
1.3 
Steering Committee ............................................................................................................................... 4 
1.4 
Governance structure ............................................................................................................................ 4 
1.5 
Patient advisors ..................................................................................................................................... 5 
1.6 
Role of study funders and sponsors ...................................................................................................... 5 
1.6.1 
Public Health Agency Canada (PHAC) ................................................................................................ 5 
1.6.2 
Canadian Cardiovascular Society ....................................................................................................... 5 
1.6.3 
University of British Columbia coordinating centre .......................................................................... 5 
1.7 
Data ownership ..................................................................................................................................... 5 
1.8 
Confidentiality Statement ..................................................................................................................... 5 
2. 
INTRODUCTION AND BACKGROUND ......................................................................................................... 5 
2.1 
Vaccine associated myocarditis/pericarditis ......................................................................................... 5 
2.2 
MYCOVACC study overview ................................................................................................................... 6 
2.3 
Public health imperative ........................................................................................................................ 6 
2.4 
Case definition of vaccine associated myocarditis/pericarditis ............................................................ 6 
2.5 
COVID-19 myocarditis............................................................................................................................ 7 
2.6 
Multisystem Inflammatory Syndrome in Children and Adults (MIS-C/A) myocarditis ......................... 7 
2.7 
Novelty................................................................................................................................................... 7 
2.8 
Clinical management ............................................................................................................................. 8 
2.9 
Repeat vaccination ................................................................................................................................ 8 
2.10 
Prognosis ............................................................................................................................................... 8 
2.11 
Impact and public health surveillance ................................................................................................... 8 
3. 
STUDY OBJECTIVES AND OUTCOMES ........................................................................................................ 8 
3.1 
Primary objectives ................................................................................................................................. 8 
3.2 
Secondary objectives ............................................................................................................................. 9 
3.3 
Primary endpoints ................................................................................................................................. 9 
3.4 
Secondary endpoints ............................................................................................................................. 9 
4. 
STUDY DESIGN ........................................................................................................................................... 9 
4.1 
Study design .......................................................................................................................................... 9 
4.2 
Study setting ........................................................................................................................................ 10 
4.3 
Study population ................................................................................................................................. 10 
4.4 
Definitions ........................................................................................................................................... 10 
4.5 
Inclusion criteria .................................................................................................................................. 10 
4.5.1 
Inclusion criteria for vaccine associated myocarditis/pericarditis. ................................................. 10 
4.5.2 
Inclusion criteria for COVID-19 associated myocarditis/pericarditis .............................................. 11 
4.5.3 
Inclusion criteria for MIS-C/A myocarditis/pericarditis ................................................................... 11 
4.5.4 
Inclusion criteria alternative etiology myocarditis. ......................................................................... 11 
4.6 
Exclusion criteria .................................................................................................................................. 11 
4.7 
Case identification ............................................................................................................................... 11 
4.7.1 
Provincial and territorial adverse event following immunization (AEFI) reporting. ....................... 11 
4.7.2 
Collaborating networks. .................................................................................................................. 11 
4.7.3 
Electronic health records ................................................................................................................. 12 
4.8 
Cohort time period .............................................................................................................................. 12 
4.9 
Ethical considerations .......................................................................................................................... 12 
4.10 
Retrospective chart review .................................................................................................................. 12 
4.12 
Prospective follow-up invitation ......................................................................................................... 12 
4.13 
Consent process .................................................................................................................................. 13 
4.13.1 
Conventional written consent ......................................................................................................... 13 
4.13.2 
Virtual electronic consent ............................................................................................................... 13 
4.13.3 
Mental Capacity ............................................................................................................................... 13 
4.13.4 
Withdrawal criteria .......................................................................................................................... 14 

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4.13.5 
Confidentiality ................................................................................................................................. 14 
4.13.6 
Protocol amendments ..................................................................................................................... 14 
4.13.7 
Declaration of conflict of interest .................................................................................................... 14 
5. 
VISIT SCHEDULE AND PROCEDURES ........................................................................................................ 14 
5.1 
Schedule for new cases ....................................................................................................................... 15 
5.1.1 
Baseline visit .................................................................................................................................... 15 
5.1.2 
Follow-up visits ................................................................................................................................ 15 
5.2 
Schedule for remote (previous) cases ................................................................................................. 15 
6. 
DATA MANAGEMENT, STATISTICAL ANALYSIS, KNOWLEDGE TRANSLATION ......................................... 15 
6.1 
Data collection ..................................................................................................................................... 15 
6.2 
Sample size estimation ........................................................................................................................ 15 
6.3 
Statistical analysis ................................................................................................................................ 15 
6.4 
Gender-based Analysis Plus ................................................................................................................. 16 
6.5 
Knowledge translation plan ................................................................................................................. 16 
7. 
APPENDICES ............................................................................................................................................. 17 
7.1 
Appendix 1. Brighton Collaboration myocarditis case definition and levels of diagnostic certainty .. 17 
7.2 
Appendix 2. Brighton Collaboration myocarditis case definition flow chart ...................................... 18 
7.3 
Appendix 3. Brighton Collaboration pericarditis case definition and levels of diagnostic certainty .. 19 
7.4 
Appendix 4. Brighton Collaboration pericarditis case definition flow chart ....................................... 20 
7.5 
Appendix 5. Clinical symptoms associated with myocarditis and/or pericarditis. 19 .......................... 21 
7.6 
Appendix 6. Multisystem Inflammatory Syndrome in Children and Adults (MIS-C/A) criteria ........... 22 
7.7 
Appendix 7. Data collection variables ................................................................................................. 24 
7.8 
Appendix 8. Schedule of assessment .................................................................................................. 25 
7.9 
Appendix 9. Abbreviations .................................................................................................................. 25 
7.10 
Appendix 9. References ....................................................................................................................... 26 
 
 
 
 
 
 

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1. 
STUDY MANAGEMENT AND REGULATORY 
 
1.1 
Principal investigator contacts 
Dr. Carolyn Pullen (Co-PI), Chief Executive Officer, Canadian Cardiovascular Society. 
150 Elgin Street, Suite 1000, Ottawa, Ontario, K2P 1L4, Canada 
Phone: (877/613) 569-3407 Extension: 401 pullen@ccs.ca  
 
Dr. Nathaniel Hawkins (Co-PI), MD. Associate Professor of Medicine, UBC Division of Cardiology. 
2775 Laurel Street, 9th Floor Cardiology, Room 9123, Vancouver, British Columbia, V5Z 1M9, Canada 
Phone: 604 875 5487. Fax: 604 875 5504 nat.hawkins@ubc.ca 
 
1.2 
Co-investigators 
Dr. Tahir Kafil (University of Ottawa Heart Institute). 
Dr. Michael Khoury (University of Alberta). 
Dr. Peter Liu (University of Ottawa Heart Institute). 
Dr. Michael McDonald (University of Toronto). 
Dr. Monika Naus (University of British Columbia). 
Dr. Susanna Ogunnaike-Cooke (Public Health Agency of Canada). 
Dr. Alexander Singer (University of Manitoba). 
Dr. Karina Top (Dalhousie University). 
Dr. Sean Virani (University of British Columbia). 
Dr. Meredith Wright (Canadian Cardiovascular Society). 
 
1.3 
Steering Committee 
The MYCOVACC Steering Committee (SC) provides direction, guidance and decision-making about study 
activities. Specifically, the SC guides implementation, operations and funding; and ensures key deliverables 
are achieved. The SC will ensure the study being conducted in accordance with the principles of Good 
Clinical Practice (GCP) and the relevant regulations. The membership of the Committee will include a 
chairperson, vice-chairperson, CCS Chief Executive Officer, representatives of the CCS Council/Board 
Executive, representatives of major partners, CCS members with expertise related to MYCOVACC, 
representatives of Public Health Agency of Canada, Immunization Senior Scientist. The SC will have its own 
charter outlining the role and responsibilities of its members. The SC may invite other attendees from the 
study team to present or participate in discussions on particular topics. These attendees will be non-voting 
members.  
 
1.4 
Governance structure 
The study has 4 main governance structures. 
1. Steering Committee. 
2. Integrated Knowledge Translation Committee. Develops and implements the Integrated Knowledge 
Translation. 
3. Scientific and Data Management Committee. Ensures high-quality data and ethical data collection, 
storage, and use; reviews and approves all protocols, publications, and reports 
4. Investigator Committee. Provides a forum for collaborative engagement among site investigators; 
contributes to the design and direction of the project 
 
 
Steering 
Committee 
IKT Committee 
Scientific & Data 
Management 
Committee 
Investigator 
Committee 

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1.5 
Patient advisors 
Patients or their carers who have experienced vaccine associated myocarditis/pericarditis will be invited to 
participate as study patient advisors and members of MYCOVACC committees. Advisors will help to refine 
study methods, communications and knowledge translation plans and activities. 
 
1.6 
Role of study funders and sponsors 
 
1.6.1 Public Health Agency Canada (PHAC) 
Public Health Agency Canada are funding this study. The funder will delegate specific roles to the Principal 
Investigators and other third parties. These arrangements will be clearly documented in agreements. The 
funder will have input into the study design, conduct, analysis, interpretation, and reporting. Final decision 
regarding all aspects of the study resides with the principal investigators and steering committee. 
 
1.6.2 Canadian Cardiovascular Society 
The Canadian Cardiovascular Society (CCS) is co-sponsoring this study. The sponsor will have input into the 
study design, conduct, analysis, interpretation, and reporting. Final decision regarding all aspects of the 
study resides with the principal investigators and steering committee. 
 
CCS is the national professional home for Canada’s cardiologists, cardiac surgeons, and scientists. 
Along with a mandate in clinical practice standards setting and education, CCS members, numbering more 
than 2,300, have a 75-year history of cardiovascular care leadership and research excellence in national and 
international arenas.  
 
1.6.3 University of British Columbia coordinating centre 
The study will be coordinated from a single coordinating centre located in British Columbia, the Centre for 
Cardiovascular Innovation (https://cci-cic.org/) which is an approved UBC Faculty of Medicine Centre. 
 
1.7 
Data ownership 
UBC is the Data Controller of all the data generated from patients recruited to this study in Canada. The 
study data will be analysed and published by the clinical research team. The MYCOVACC data remains the 
proprietary of the PIs. 
 
1.8 
Confidentiality Statement  
This protocol contains confidential information that must not be disclosed to anyone other than the 
sponsor, Canadian Cardiovascular Society, the Investigator Team, PHAC, regulatory authorities, and 
members of the Research Ethics Committee. 
 
2. 
INTRODUCTION AND BACKGROUND 
2.1 
Vaccine associated myocarditis/pericarditis 
Myocarditis is inflammation of the myocardium (heart muscle). Pericarditis is inflammation of the 
pericardium (lining surrounding the heart muscle). There are many different causes for myocarditis and 
pericarditis including viral infections and COVID-19 infection. Myocarditis is defined by the presence of 1) 
cardiac symptoms, 2) an elevated cTn, and 3) abnormal electrocardiographic, echocardiographic, cardiac 
magnetic resonance imaging, and/or histopathologic findings. 
 
In rare instances myocarditis and pericarditis have occurred following mRNA COVID-19 vaccination. 
Canadian and international data indicate a higher rate of myocarditis and/or pericarditis following COVID-
19 mRNA vaccination than would normally be expected in the general population.1-7 Most reports suggest 
an incidence of up to 2 to 3 cases per 100,000 vaccinations. Male adolescents and male young adults are at 
the highest risk of myocarditis after mRNA vaccination for COVID-19,8,9 with recent review indicating the 
incidence of myocarditis for might be as high as 140 cases per million for this cohort.9 Although cases of 
myocarditis and/or pericarditis appear to be mild and self-limiting in the short-term follow-up, the long-
term health and functional implications of the acute myocardial injury are currently unknown.9,10 
 

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2.2 
MYCOVACC study overview 
MYCOVACC is a multi-centre pan-Canadian surveillance study commissioned by The Public Health Agency of 
Canada to examine the outcomes of a cohort of adult and pediatric patients with post-mRNA myocarditis 
and/or pericarditis. 
 
2.3 
Public health imperative 
The MYCOVACC surveillance study is commissioned by The Public Health Agency of Canada. Post-
vaccination myocarditis/pericarditis was first identified in spring 2021. While still relatively rare, it has 
garnered significant public and media attention and has affected vaccine confidence in COVID-19 mRNA 
vaccines, particularly due to its higher risk among young people. The longer-term effects of myocarditis 
and/or pericarditis following mRNA COVID-19 vaccination remain unknown. These knowledge gaps 
negatively impact vaccine confidence, particularly in children and adolescents. In addition, as we face a 
seventh (and likely additional) wave of COVID-19 and possible repeated annual or bi-annual vaccine 
boosters, the need to establish an approach to monitor clinical and mental health outcomes is increasingly 
evident. mRNA platforms may carry inherent risk for myocarditis and/or pericarditis, and as such, 
understanding of long-term outcomes will likely impact confidence and use of future types of mRNA 
vaccines that may be approved for use in Canada. 
 
The Public Health Agency of Canada has therefore identified that Canada needs a robust national 
surveillance study to answer emerging research and public health questions about this risk of mRNA COVID-
19 vaccination. This is supported by the July 16, 2021 report of the Chief Science Advisor of Canada, which 
identified “active, coordinated and longer-term post-vaccine surveillance, including prospective cohort 
studies that monitor cardiac and immune parameters” as a priority for action. 
 
Exploration conducted by the Centre for Immunization Surveillance of PHAC in summer and fall 2021 
determined that there were no ongoing Canadian studies, national in scope, that could be promptly 
leveraged to address this gap. A comprehensive nation-wide approach for Canadian data is critical as the 
few international studies on long-term outcomes may not be representative of all people affected by this 
adverse event, and may not be readily applicable to Canada given population differences, health care 
system differences, and in the varying COVID-19 vaccination approaches used during the pandemic. In 
particular, there are no other countries with vaccine roll-out parameters similar to those implemented in 
Canada – two mRNA platforms, vaccine interchangeability, varying inter-dose intervals, booster intervals, 
and more recently, the introduction of two protein subunit vaccines. 
 
The Public Health Agency of Canada therefore solicited a proposal from the Canadian Cardiovascular 
Society on the development of a national-in-scope surveillance study that would address the knowledge 
gap. The Canadian Cardiovascular Society is well placed for the project by virtue of their role as the national 
voice for cardiovascular clinicians and scientists, representing more than 2,300 cardiologists, cardiac 
surgeons and other heart health specialists and clinical investigators. To develop the proposal, the 
Canadian Cardiovascular Society formed a project team and approached Dr. Nathaniel Hawkins (Centre for 
Cardiovascular Innovation, University of British Columbia) to be the project’s scientific lead. 
 
2.4 
Case definition of vaccine associated myocarditis/pericarditis 
There are two major case definition criteria currently in use for post-vaccine myocarditis. These are from 
the CDC and the Brighton Collaboration. They are very similar, but the Brighton Collaboration criteria have 
been updated and more widely used (Appendices 1 to 5). Similarities include some symptom combinations, 
troponin positivity, histopathologic confirmation, cardiac magnetic resonance imaging features of 
myocarditis and echocardiographic abnormalities. For the purposes of our study, we will primarily use 
Brighton Criteria case definitions for myocarditis and pericarditis because they are more inclusive. 
However, the CDC criteria will also be analysed to allow for international comparison. 
 
This study will also include patients with COVID-19 myocarditis/pericarditis and MIS-C/A myocarditis. 
COVID-19 myocarditis/pericarditis will use the same case definitions as vaccine-myocarditis/pericarditis, 
but the precipitant is COVID-19 infection in the prior 42 days. MIS-C/A myocarditis uses the same case 
definition as Brighton criteria for vaccine myocarditis, but requires the criteria for MIS-C/A to be met (see 
Appendix 6). 
 

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2.5 
COVID-19 myocarditis 
Myocarditis has been recognized as an uncommon but serious complication of SARS-CoV-2 infection as well 
as COVID-19 mRNA vaccination. Prevalence rates widely varying depending upon the population studied. 
Several mechanisms may contribute including direct virus invasion, host inflammatory or immune 
responses, microvascular angiopathy, and maladaptive host immune response. Management of patients is 
primarily dictated by the clinical course and empirically based on treatment of other forms of myocarditis. 
Use of intravenous corticosteroids may be considered in those with hemodynamic compromise. 
Importantly, a very favorable benefit-to-risk ratio exists with the COVID-19 vaccine for all age and sex 
groups i.e. far more cases of COVID-19 associated myocarditis are avoided than vaccine associated 
myocarditis cases occur. 
 
2.6 
Multisystem Inflammatory Syndrome in Children and Adults (MIS-C/A) myocarditis 
MIS-C is a rare but serious complication associated with SARS-CoV-2. MIS-C occurs in children, adolescents, 
and young adults and is characterized by inflammation across multiple body systems. MIS-C symptoms 
generally appear 2–6 weeks after infection. Children with MIS-C often had no or few symptoms of COVID-
19. In addition to fever, children with MIS-C commonly present with abdominal pain, vomiting, diarrhea, 
rash, conjunctivitis, and hypotension. The pathogenesis is uncertain, possibly the SARS-CoV-2 spike protein 
acts as a superantigen to promote a cytokine storm. Patients with MIS-C will likely be hospitalized and may 
need treatment in intensive care including intravenous immunoglobulin, steroids, and immune modulators. 
 
2.7 
Novelty 
Canada is uniquely placed to examine the longer-term outcomes in people with myocarditis and/or 
pericarditis following mRNA COVID-19 vaccination. In contrast to other countries, Canada has used mRNA 
vaccinations almost exclusively for second and booster doses. As well, Canada is one of the few countries to 
have implemented an extended interval vaccination schedule. Canada is seen as the right size for a cost-
effective surveillance study. 
 
This project shares the objectives of the “Myocarditis Outcomes after mRNA COVID-19 Vaccination 
Investigation” currently being conducted by the United States Centre for Disease Control (US-CDC), 
however, our Canadian study will allow for more in-depth analysis and has a number of advantages when 
compared to the US-CDC study.  
1. 
The US-CDC study primarily employs a survey-based approach. This inherently is prone to survey bias 
and has already encountered a significant number of survey non-responders, particularly from the 
marginalized and ethnic/minority populations.  Our approach is more comprehensive utilizing multiple 
sources of patient ascertainment, and engages healthcare providers across Canada including adult and 
pediatric cardiologists, infectious disease and public health specialists. 
2. 
The CDC criteria for vaccine-myocarditis/pericarditis is distinct from international Brighton Criteria. 
MYCOVACC will use both CDC criteria and Brighton Criteria to allow for comparison with both US and 
International data sets. 
3. 
The vaccines given in Canada are a different mix (AstraZeneca, Pfizer, Moderna, Johnson & Johnson, 
Medicago, Novavax) from the FDA approved vaccines (Pfizer, Moderna, Janssen) used in the US.  Canada 
also allows mix and match vaccine combinations, hence our ability to assess the benefits and risks 
associated with these combinations. For example, Canada is the first country to identify that the 
combination of Pfizer primer and Moderna follow-up combination incurred a very significant increase in 
risk of myocarditis compared to other combinations. 
4. 
Canada has the unique experience of varying vaccine time intervals such as the initial extended 
interval roll-out of 6 to 12 weeks. This allows assessment for whether risk is lower with delayed dosing, in 
contrast to a mostly fixed dose interval in the US. 
5. 
Canada’s universal healthcare allows more patients (including marginalized and impoverished 
groups) to be identified with this condition, whereas care in the US is more limited to patients with health 
insurance. Our study will also endeavor to collect more data on marginalized groups and Indigenous 
communities. 
 

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2.8 
Clinical management 
The recent 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults 
highlighted the lack of evidence based management strategies for vaccine associated 
myocarditis/pericarditis.11 The guidelines indicate nonsteroidal anti-inflammatory drugs, colchicine, and 
corticosteroids may be considered in those with ongoing symptoms. For those with those with rapidly 
improving symptoms, a normal or improving cTn level, and normal left ventricular ejection fraction, anti-
inflammatory medications may not be needed.11 However, these recommendations are all extrapolated 
from treatment of myocarditis/pericarditis of alternative etiologies. Whether similar strategies are effective 
for vaccine associated myocarditis/pericarditis is unknown. 
 
2.9 
Repeat vaccination 
Limited data currently exist regarding the safety of COVID-19 vaccination for individuals with a history of 
myocarditis or pericarditis unrelated to COVID-19 mRNA vaccines. Centers for Disease Control and 
Prevention (CDC) guidelines currently recommend that such individuals be vaccinated against COVID-19 
after their myocarditis/pericarditis episode has completely resolved. In contrast, the guidelines recommend 
that no further doses of any COVID-19 vaccine be given to those who developed myocarditis/pericarditis 
following COVID-19 mRNA vaccination. The guidelines acknowledge that this decision should be informed, 
however, by an individual’s risk for severe COVID-19 illness. The Canadian National Advisory Committee on 
Immunization (NACI) currently advise against subsequent vaccination. Members of NACI have expressed a 
particular interest in the secondary endpoints of MYCOVACC assessing subsequent vaccination patterns 
and associated outcomes.12 
 
2.10 Prognosis 
Myocarditis and/or pericarditis are established adverse events following the administration of mRNA 
vaccines against COVID-19. However, the longer-term health and functional implications of the acute 
myocardial injury (especially when incurred at a young age) are currently unknown. In a recent 
prospectively enrolled cohort of 20 patients with acute myocarditis within 10 days of mRNA-based COVID-
19 vaccination, convalescent cardiac magnetic resonance-based imaging at ≥3 months identified residual 
fibrosis in 90% of patients during follow up.13 Fibrosis is a recognized risk marker of future cardiovascular 
outcomes in non-COVID community-acquired myocarditis and highlights the importance of future studies 
to evaluate long-term clinical outcomes in this patient population. 
 
2.11 Impact and public health surveillance 
Vaccines are a key component of efforts to control the COVID-19 pandemic. The Public Health Agency of 
Canada has identified documentation of longer-term outcomes as critically important to inform its 
decisions about risks and benefits of mRNA COVID-19 vaccination for boosters and new variants. 
 
Assessment of the longer-term impact of adverse events following COVID-19 immunization is crucial 
for ongoing safety monitoring of vaccines, and informs best practices for clinicians, recommendations from 
national health advisory bodies, and expands public knowledge about vaccine safety. Public acceptance and 
trust in COVID-19 vaccine safety is necessary to support the long-term sustainable success of the ongoing 
vaccination campaign. 
 
The MYCOVACC study will provide insights on the longer-term health and functional impacts of 
myocarditis and/or pericarditis following mRNA COVID-19 vaccination in addition to healthcare utilization 
and health outcomes. Data from this study will provide urgently needed data to support critical decision-
making around the choice of COVID-19 vaccines for communities and individuals, particularly for boosters 
and new variants. 
 
3. 
STUDY OBJECTIVES AND OUTCOMES 
 
3.1 
Primary objectives 
1. 
Evaluate the incidence, type, and severity of major adverse cardiovascular events (MACE) in patients 
with vaccine associated myocarditis/pericarditis, COVID-19 myocarditis/pericarditis, and MIS-C/A 
myocarditis. 

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2. 
Assess cardiac function recovery in patients with vaccine associated myocarditis/pericarditis, COVID-
19 myocarditis/pericarditis, and MIS-C/A myocarditis. 
3. 
Evaluate functional outcomes including quality of life, depression, anxiety, and physical activity in 
patients with vaccine associated myocarditis/pericarditis, COVID-19 myocarditis/pericarditis, and MIS-C/A 
myocarditis. 
 
3.2 
Secondary objectives 
• Describe the spectrum of presentation, severity, and predisposing factors of vaccine associated 
myocarditis/pericarditis, COVID-19 myocarditis/pericarditis, and MIS-C/A myocarditis. 
• Describe the investigations and management of vaccine associated myocarditis/pericarditis in standard 
clinical practice, including care settings, diagnostic workup, imaging, and treatment. 
• Compare the incidence, type, and severity of major adverse cardiovascular events in patients with vaccine 
associated myocarditis/pericarditis in patients treated/not treated with NSAIDs, colchicine and other 
contemporary treatments according to standard clinical practice. 
• Develop a risk prediction score for MACE in patients with vaccine associated myocarditis/pericarditis. 
• Evaluate subsequent vaccination patterns and risk of COVID-19 infection in patients with and without 
subsequent vaccination after vaccine associated myocarditis/pericarditis. 
 
3.3 
Primary endpoints 
The primary endpoints for the three primary objectives are: 
 
1. Composite MACE at 30 days post vaccination (preferred by cardiovascular community) and at 42 days 
post vaccination (preferred by vaccine monitoring investigators) including any of: 
• Death from any cause. 
• Ventricular arrhythmia (ventricular fibrillation or ventricular tachycardia). 
• Heart block (type II or type III block). 
• Heart failure (national guideline criteria). 
• Left ventricular systolic dysfunction (left ventricular ejection fraction [LVEF] <55%). 
• Cardiac tamponade. 
 
2. Recovery of cardiac function in patients with previously documented abnormal cardiac function 
(LVEF<55% during anytime at baseline), with LVEF increase by 5% from worst baseline measurement. 
 
3. Quality of life, depression, anxiety, and physical activity using validated instruments at baseline, 3 
months,, 12 months, and annually. 
3a. Quality of life: EQ-5D-5L questionnaire for adults or EQ-5D-Y questionnaire for children.14,15 
3b. Depression and anxiety data: PHQ-9 and GAD-7.16,17 
3c. Physical activity: International Activity Questionnaire.18 
 
3.4 
Secondary endpoints 
• Individual components of primary composite endpoint at 30 days and 42 days post vaccination. 
• Atrial arrhythmias. 
• All-cause and cardiovascular mortality. 
• All-cause and cardiovascular hospitalization. 
• Recurrence of myocarditis/pericarditis. 
• Constrictive pericarditis. 
 
4. 
STUDY DESIGN 
 
4.1 
Study design 
The surveillance study is a cohort study combining 1) passive surveillance by chart review, 2) active 
surveillance by prospective follow-up integrated with standard clinical care. 
 

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4.2 
Study setting 
The study is a multi-centre study conducted in secondary and tertiary care centres treating myocarditis and 
pericarditis in the inpatient or outpatient setting in all provinces and territories in Canada. 
 
4.3 
Study population 
The study population will include any patient with: 
1. 
Vaccine associated myocarditis/pericarditis. 
2. 
COVID-19 myocarditis/pericarditis. 
3. 
MIS-C/A myocarditis/pericarditis 
4. 
Alternative etiology myocarditis. 
Patients will be required to satisfy the inclusion and exclusion criteria. Eligibility waivers to the 
inclusion/exclusion criteria are not permitted. 
 
4.4 
Definitions 
Patients will be diagnosed based on the Brighton Collaboration case definitions of the term “myocarditis” 
and “pericarditis”. This utilizes five degrees of certainty, of which three will be included: definitive case 
(level 1), probable case (level 2), and possible case (level 3). The Level 1 definition is highly specific for the 
identification of a case of myocarditis and pericarditis. Levels 2 and 3 offer a stepwise increase of 
sensitivity, with acceptable specificity. In this way it is hoped that all possible cases of myocarditis and 
pericarditis can be captured. Two additional levels (Levels 4 and 5) are helpful for real-world analysis. Level 
4 cases are reported myocarditis or pericarditis with insufficient evidence to meet the case definition of 
vaccine-induced cardiac inflammation. These are anticipated from centres without easy access to cardiac 
investigations. Level 5 cases are defined as “Not a case of myocarditis or pericarditis”. These are anticipated 
to be cases of undifferentiated chest-pain without objective findings of myocarditis or pericarditis. 
 
4.5 
Inclusion criteria 
 
4.5.1 Inclusion criteria for vaccine associated myocarditis/pericarditis. 
1. 
COVID-19 vaccination within previous 42 days. 
AND 
 
2. 
At least one cardiac symptom of suspected myocarditis/pericarditis (Appendix 5). 
OR 
 
At least two non-specific symptoms (Appendix 5). 
OR 
 
In infants and young children, at least two non-specific pediatric symptoms (Appendix 5). 
OR 
 
No symptoms, but abnormal histopathology or a combination of abnormal cardiac biomarkers with 
abnormal cardiac imaging (echo or MRI). 
AND 
 
3. 
At least one of the following objective findings (Brighton Criteria case definitions, Appendices 1 to 5): 
a. 
Histopathologic examination of myocardial tissue (autopsy or endomyocardial biopsy) showed 
myocardial inflammation. 
b. 
Elevated myocardial biomarker (Troponin T, Troponin I, or CK-MB). 
c. 
Cardiac MRI abnormality. 
d. 
Echocardiographic abnormality. 
e. 
New or worsening arrhythmia on electrocardiogram, Holter monitor, or telemetry. 
f. 
Elevated inflammation biomarkers: ESR, CRP, hs-CRP, or D-Dimer. 
g. 
Physical examination pericardial friction rub or pulsus paradoxus. 
h. 
Pericardial fluid or inflammation by imaging (echo, MRI, or CT). 
i. 
Enlarged heart on chest radiograph. 
AND 
 

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4. 
No alternative cause of presentation. e.g. infectious or autoimmune myocarditis. 
 
4.5.2 Inclusion criteria for COVID-19 associated myocarditis/pericarditis 
1. 
COVID-19 infection within the previous 42 days. 
AND 
 
2. 
Myocarditis/pericarditis as per Brighton Criteria for vaccine associated myocarditis/pericarditis. 
AND 
 
3. 
No alternative cause of presentation. 
 
4.5.3 Inclusion criteria for MIS-C/A myocarditis/pericarditis 
 
1. 
Brighton case definition for MIS-C/A (Level 1 to 3b). 
AND 
 
2. 
Myocarditis/pericarditis as per Brighton Criteria for vaccine associated myocarditis/pericarditis. 
AND 
 
3. 
No alternative cause of presentation. 
 
4.5.4 Inclusion criteria alternative etiology myocarditis. 
1. 
Myocarditis/pericarditis as per Brighton Criteria for vaccine associated myocarditis/pericarditis. 
 
AND 
2. 
No alternative cause of presentation. 
 
4.6 
Exclusion criteria 
• For prospective invitation and follow-up, inability to provide informed consent. Consent will be sought 
from patients or their authorised substitute decision maker. 
• Patients not fulfilling Brighton Criteria levels 1-3 will be excluded if they are level 4 (insufficient evidence 
for myocarditis) or Level 5 (not myocarditis) or have an alternative diagnosis such as myocardial infarction. 
 
4.7 
Case identification 
4.7.1 Provincial and territorial adverse event following immunization (AEFI) reporting. 
The Public Health Agency of Canada will connect us with all provincial and territorial public health 
authorities to discuss collaboration. Public health partners will be invited to a priority-setting exercise 
(along with other key stakeholders) to refine the data collection protocol, outcomes and analyses, and 
identify priorities. Several public health units are already counting on this study to provide follow-up for 
these patients as the individual units do not have the capacity to do so. 
 
4.7.2 Collaborating networks. 
COVID-VIHPR. This is a CIHR funded study to elucidate the potential underlying mechanisms of the 
pathogenesis of mRNA vaccine myocarditis, and incorporates very detailed imaging, biospecimen and 
immunological analysis with controls also exposed to the vaccine.  This study is not intended to be a broad 
comprehensive registry.  However, the patients in COVID-VIHPR will contribute relevant data into the 
MYCOVACC surveillance study.  Funding from MYCOVACC will support the longer term follow up of these 
patients. 
 
POPCORN, IMPACT, and SIC. We have been coordinating closely with the pediatric teams led by Karina Top 
(POPCORN, IMPACT, and SIC). IMPACT is able to identify patients but they offer no follow-up of the patients 
identified. Thus, MYCOVACC is the only infrastructure able to follow the patients longitudinally. 
 

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4.7.3 Electronic health records 
Patients will be identified by chart review of health records at participating sites by research teams led by 
site investigators according to their local guidelines and standard operating procedures. The study will be 
promoted through multiple communication channels of the Canadian Cardiovascular Society, including 
websites, emails, newsletters, and social media channels. 
 
4.8 
Cohort time period 
The cohort entry start date is December 1, 2020. This date corresponds to the first authorization of mRNA 
vaccine in Canada by Health Canada (Pfizer BioNTech on December 9, 2020). The cohort entry end date will 
be determined by renewal of funding for the surveillance study by the Public Health Agency of Canada. 
 
4.9 
Ethical considerations 
The study will be carried out in accordance with the World Medical Association Declaration of Helsinki 
(1964) and its revisions. Favourable ethical opinion will be sought from Research Ethics Committee (REC) in 
all jurisdictions where the study will be conducted. Patients will only be allowed to enter the prospective 
study once they have provided written informed consent. The PI will be responsible for updating the REC of 
any new information related to the study. 
 
4.10 Retrospective chart review 
The retrospective study will identify previous cases of vaccine associated myocarditis/pericarditis, COVID-
19 associated myocarditis/pericarditis, MIS-C/A myocarditis/pericarditis, and alternative etiology 
myocarditis.  
 
Recruiting clinicians will refer patients presenting with myocarditis/pericarditis since December 1, 
2020 to research staff (i.e., the date Health Canada approved the first mRNA vaccine for COVID19). Initial 
chart review to determine eligibility for the study and subsequent chart review for initial presentation and 
follow-up time points will be completed. As vaccination for COVID-19 and COVID-19 infections are 
occurring continually, chart review of eligible patients will follow the same structure as patients identified 
from December 1, 2020. 
 
The same clinical information as the prospective study will be collected, including presentation, 
clinical bloodwork, and cardiac imaging. No data will be collected for the purposes of this study that has not 
already been collected as part of routine follow-ups. Only available data will be extracted. Follow-up data 
will be extracted from charts using standardized chart extraction forms at 3 months,12 months, and 
annually for up to 3 years following the date of diagnosis of vaccine associated myocarditis/pericarditis, 
COVID-19 myocarditis/pericarditis or MIS C/A myocarditis/pericarditis. 
 
4.11 Retrospective chart review waiver of consent 
Waiver of consent is requested for retrospective chart review. Retrospective chart reviews are usually 
confined to a specific timeframe. However, this study has been commissioned by the Public Health Agency 
of Canada as a surveillance study for a new and unique disease entity for which our understanding is 
continually evolving and which has significant implications for vaccine confidence and public health. We 
therefore request permission to perform retrospective chart review of routine clinical care on an ongoing 
basis for the duration of the study. 
 
4.12 Prospective follow-up invitation 
The invitation to participate in prospective follow-up will follow local standard operating procedures as 
approved by the Research Ethics Committee in each participating centre, specific to the jurisdiction and 
patient circumstances. Invitation procedures may include: 
1. 
For patients attending a care provider for standard clinical care, the care provider will provide 
information regarding the study and ask permission for the research team to contact the patient. 
2. 
For patients who have previously provided general consent to contact for research of any form, 
which has been documented in the health record, the research team will contact the patient. 
3. 
For patients not attending a care provider nor with previously documented consent to contact, an 
invitation letter to receive further information regarding the study will be sent by mail or email by the 
research coordinator with approval of the primary care provider. 

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4. 
The invitation letter will include a registration telephone number and be available in English and 
French languages. The invitation for contact will include an option for the potential participant to contact 
the participating site to opt out of the study. Otherwise, a research coordinator will follow-up by telephone 
to discuss the study within 2 weeks. 
 
4.13 Consent process 
The Principal Investigators will retain overall responsibility for the informed consent of participants at their 
site and will ensure that any person delegated responsibility to participate in the informed consent process 
is duly authorized, trained and competent to participate according to the ethically approved protocol, 
principles of Good Clinical Practice (GCP) and Declaration of Helsinki. 
 
The consenting process will be undertaken with one of two methods: Conventional ‘in person’ 
written consent and E-Consent. Assenting patients will be given the option of what form they would like to 
consent to the study. This is to ensure that patients unable or unwilling to complete an e-consenting 
process are not disadvantaged. 
 
A copy of the consent form will be given to the patient, care giver, or parents. Copies will be filed in 
the study record and in the patient’s primary healthcare record. e-consenting will also be used if deemed 
appropriate by study team. The original consent form or completed e-consent form will be filed in the study 
file and sites will be required to scan and upload the consent forms into a secure study database for each 
consented patient. 
 
Where a participant is required to re-consent or new information is required to be provided to a 
participant, the PI will ensure this is done in a timely manner. The right of a participant to refuse 
participation without giving reasons will be respected. The PI takes responsibility for ensuring that all 
vulnerable subjects are protected and participate voluntarily in an environment free from coercion or 
undue influence. 
 
4.13.1 Conventional written consent 
The process of conventional ‘in-person’ consent will involve: 
• A discussion between the potential participant and an individual knowledgeable about the study about 
the nature and objectives of the study, and possible risks associated with their participation. 
• The presentation of written material to read and digest (e.g., patient information sheet and consent 
document which must be approved by the REC and be in compliance with GCP, local regulatory 
requirements and legal requirements). 
• The opportunity for potential participants to ask questions. 
• Potential participant will then be able to sign the consent form or decline to give their consent. 
 
4.13.2 Virtual electronic consent 
• Following verbal consent and collection of electronic contact details, potential participants will be sent an 
electronic consent form (via REDcap) for their review.  
• They will then review audio-visual and written information about the study – which will include 
information on the objectives of the study and outline any possible risks associated with taking part. This 
information (e.g., patient information sheet, electronic multimedia resources consent document which 
must be approved by the REC and be in compliance with GCP, local regulatory requirements and legal 
requirements) 
• Potential participants will be given the opportunity to ask any questions about the study either directly or 
at a later time. 
• The e-consent form can then be signed and electronically returned to the study team or the participant 
can decline to give their consent. 
 
4.13.3 Mental Capacity 
A person is assumed to have the mental capacity to make a decision unless it is shown to be absent. Mental 
capacity is considered to be lacking if, in a specific circumstance, a person is unable to make a decision for 
him or herself because of impairment or a disturbance in the functioning of their mind or brain. Patients 
that are unable to provide informed consent will not be included in this study. Where a participant is able 
to consent but later becomes incapacitated, they will be withdrawn from the trial. 

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An assent form will be used for children up to but not limited to 13 years of age and for those 14 and older 
with limited mental capacity.  Local REB guidelines and SOPs will be followed at participating sites. 
 
4.13.4 Withdrawal criteria 
Participants may withdraw consent to the study at any time without giving reasons and without prejudicing 
any aspect of standard clinical care. When withdrawal is requested, the study team will clarify the level of 
withdrawal and offer a pre-determined tiered list of options to the patient: 
• Complete withdrawal with no further in person visits, no virtual visits, no active data collection, and no 
outcome follow-up using administrative data. 
• Withdrawal with no in person visits, no virtual visits, and no active data collection, but continued 
outcome follow-up using administrative data. 
• Withdrawal with no in person and no virtual visits, but continued active data collection and outcome 
follow-up using administrative data. 
• Withdrawal with no person visits, but continued virtual visits with active data collection and outcome 
follow-up using administrative data. 
 
4.13.5 Confidentiality 
The signed version of the consent form will be stored in a separate file from de-identified, coded research 
records. A unique study ID code will be assigned to the subject. Study data will be entered in an electronic 
CRF which will identify the participant only by a unique study ID code. Consults and results collected from 
diagnostic tests will be de-identified by removing the patient name, date of birth, hospital ID number and 
any other identifying PHI. These will be replaced with the patient’s unique study ID code. All hard copies of 
data will be stored in a locked filing cabinet, only accessible by the study investigator and his/her research 
team. Electronic data will be entered on a central database stored on a secure computer network that is 
password protected. The master file that links the subject to the unique study ID code will be stored 
electronically at each study site in a separate folder on a password protected computer on a secure 
institutional network. No personal identifiers will leave the study sites. 
 
4.13.6 Protocol amendments 
Any protocol amendments will be communicated to the REB/IRB, co-investigators, and PIs at other study 
sites. Amendments will require ethics approval from coordinating and local site before implementation. 
 
4.13.7 Declaration of conflict of interest 
All investigators declare no conflict of interest. 
 
5. 
VISIT SCHEDULE AND PROCEDURES 
Consenting patients will be followed up clinically by their regular physician (e.g. Cardiologist, Internist, 
other physician) in collaboration with their local site-PIs, in accordance with the 2022 ACC/AHA standard of 
care guidelines for the management of myocarditis. 
 
Patients will be followed at 3 months and 12 months after diagnosis and annually thereafter for up to 
3 years. To standardize follow-up timing the date of vaccination will be assigned as the baseline date. 
However, baseline visit data will be collected from initial presentation and medical contact which is usually 
the date of diagnosis. This distinction is made because there is a variation between cases in date of 
vaccination to date of diagnosis/initial presentation. 
 
 
The case report form variable list (Appendix 7) outlines the essential elements to be collected 
including demographic data, vaccination status, presenting symptoms, physical examination findings, 
diagnostic testing (routine laboratory work, electrocardiogram, MRI), treatments, and patient outcomes. 
Quality of life, depression, anxiety, and physical activity will be measured at baseline, 3 months,, 12 
months, and annually thereafter using validated instruments: quality of life EQ-5D-5L questionnaire for 
adults or EQ-5D-Y questionnaire for children;14,15 depression PHQ-9 and anxiety GAD-7;16,17 physical activity 
International Activity Questionnaire.18 These will be conducted at clinical visits or by telephone if no 
concurrent clinical visit is scheduled. 

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Baseline data will be collected for all etiologies of myocarditis, but thereafter follow-up visits will only 
be undertaken for patients with vaccine associated myocarditis/pericarditis, COVID-19 
myocarditis/pericarditis, and MIS-C/A myocarditis/pericarditis (i.e. not alternative etiology myocarditis). 
 
5.1 
Schedule for new cases 
5.1.1 Baseline visit 
Routine blood work, electrocardiogram, Holter monitor, echocardiogram, MRI. Appendix 8 outlines the 
schedule of assessments. 
 
5.1.2 Follow-up visits 
3-month,12-month and annual clinical visits with bloodwork to ensure normalization of CRP, troponin, CK. 
Consider repeat troponin even if previously normalized (to capture recurrence), and repeat 
electrocardiogram, Holter monitor, echocardiogram or MRI if the initial test was abnormal. 
 
5.2 
Schedule for remote (previous) cases 
Cases of previous myocarditis and pericarditis will be identified from chart review using the same criteria as 
new cases. For example, if a patient case is out of the immediate post-diagnosis window or their experience 
of myocarditis/pericarditis occurrence more than 12 months ago, we will extract relevant information for 
Brighton diagnostic criteria from chart review. We will review relevant investigations that have already 
been completed previously rather than repeat delayed testing. These patients will be approached to 
participate in the surveillance study as outlined previously. 
 
After consent, they will join the study schedule at the nearest scheduled study visit e.g. If diagnosis 
was 13 months ago, they will join the 12-month visit. Each visit will have a range e.g., 12-month visit range 
will be 12-15 months. This will allow for health outcomes to be retrieved retrospectively and also collected 
moving forward from the time of joining the study. 
 
6. 
DATA MANAGEMENT, STATISTICAL ANALYSIS, KNOWLEDGE TRANSLATION 
 
6.1 
Data collection 
A single electronic case report form will be used. Data will be collected and managed using REDCap 
(Research Electronic Data Capture) electronic data capture tools, including electronic case report form 
(eCRF) (https://www.project-redcap.org/). REDCap is a secure, web-based application designed to support 
data capture, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data 
manipulation and export procedures; 3) automated export procedures for seamless data downloads to 
common statistical packages; and 4) procedures for importing data from external sources. REDCap is the 
most widely used data solution in the world, compliant with all security and privacy measures in Canada. 
 
6.2 
Sample size estimation 
We aim to enroll as many patients as possible. For our sample size calculation, we will use international 
comparison cohorts including from Israel as well as Canadian PHAC adverse events following immunization 
(AEFI) reports. For example, PHAC has 1,061 cases of myocarditis/pericarditis that meet Brighton Criteria 
levels 1 to 3. Mevorach et al. (2021) in Israel had 283 cases in 5.1 million fully vaccinated subjects (Pfizer 
only). If we scale this to Canada with a population of approximately 38 million people, the estimate is 2,094 
cases in Canada (Mevorach et al., 2021). A second study from Israel reported 54 cases in 2.5 million 
vaccinated subjects (Pfizer only). If we also scale this to 38 million people in Canada, the estimate is 810 
cases (Witberg et al., 2021). This provides us with a range of 810 to 2,094 cases. If we use a lower limit of 
capturing 60% of the 810 cases, accounting for loss to follow-up, our lower limit will be 486 cases. Our 
sample size will be between the lower and upper limits, and our goal will be to identify all 1,061 cases 
reported to PHAC as a starting point, while adding cases from our collaborators. 
 
6.3 
Statistical analysis 
The study will have a comprehensive Statistical Analysis Plan authored by the study statistician and agreed 
by the Investigators before the final analysis. The Centre for Cardiovascular Innovation will manage and 
analyze study data. 

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6.4 
Gender-based Analysis Plus 
Analyses to date suggest that age and gender impact the risk of myocarditis and/or pericarditis following 
mRNA COVID-19 vaccination. Young men are more predisposed to myocarditis than other groups (e.g., 
Farahmand et al., 2020).  To learn more about how myocarditis and/or pericarditis may impact different 
groups of people following mRNA COVID-19 vaccination, we plan to collect data about the patients’ sex and 
age, as well as culture, race, ethnicity, occupation, ability, socioeconomics, and gender. We will strive to 
include patient representatives from diverse backgrounds in our stakeholder consultations and on our 
Steering Committee to understand their priorities and to refine our data collection, knowledge translation 
and dissemination strategies based on their experiences and needs. This will ensure sex, gender, and other 
intersecting identify factors, are integrated throughout the project lifecycle, and the Gender-based Analysis 
Plus framework is used to inform future vaccination programs. 
 
6.5 
Knowledge translation plan 
Effective knowledge translation (KT) is foundational to this project. The Canadian Cardiovascular Society 
will use evidence-based models to develop a KT plan and resources to raise awareness and drive uptake 
over the duration of the funding period and beyond. To optimize collaboration and uptake, strategic 
activities and KT tools will be individualized for target stakeholder and community groups. The Canadian 
Cardiovascular Society will: 
▪ Update KT tools (clinical considerations and non-traditional (social approach to Management) with latest 
evidence; individualize for audience needs: cardiologists and other healthcare professionals as appropriate. 
▪ Disseminate KT tools in print and electronically to the Canadian Cardiovascular Society membership, 
national, provincial and territorial associations (as well as national, provincial and regional First Nations, 
Indigenous and Metis health organizations). 
▪ Develop & launch companion patient tools regarding myocarditis/pericarditis following mRNA vaccine. 
▪ Develop and host a series of webinars to raise awareness of the surveillance study, provide overviews of 
KT tools with tips for use in practice and provide live forums for discussion plus Q&A. 
 
We will canvass decision-makers for communication preferences and tailor knowledge translation 
materials, such as webinars, social media strategies, policy briefs and infographics and presentations 
accordingly. Materials will be translated in English, French and possibly other languages. The Canadian 
Cardiovascular Society will engage with the Public Health Agency of Canada and provincial and territorial 
public health agencies over the course of the project. The connections established with provincial and 
national health partners will also support the availability of timely evidence from this project for decision-
makers across the country. 
 
A communications plan will support the above initiatives and include the best approach to informing 
all stakeholders with the right information, through the right channels at the right time. Channels of 
communication may include journal ads, the Canadian Cardiovascular Society membership news, Project e-
newsletters, social media, web content. Key project information will be housed on the Canadian 
Cardiovascular Society website over the funding period and beyond and will be reviewed and updated as 
new evidence becomes available. 
 
 
 
 
 
 
 
 
 
 
 

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7. 
APPENDICES 
7.1 
Appendix 1. Brighton Collaboration myocarditis case definition and levels of diagnostic certainty  
 
 

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7.2 
Appendix 2. Brighton Collaboration myocarditis case definition flow chart 
 

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7.3 
Appendix 3. Brighton Collaboration pericarditis case definition and levels of diagnostic certainty 
 
 

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7.4 
Appendix 4. Brighton Collaboration pericarditis case definition flow chart 
 
 
 

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7.5 
Appendix 5. Clinical symptoms associated with myocarditis and/or pericarditis.  
 
 
Myocarditis 
Pericarditis 
Cardiac symptoms 
 
 
Acute chest pain or pressure, positional changes 
X 
X 
Palpitations 
X 
X 
Dyspnea after exercise, at rest, or lying down 
X 
X 
Diaphoresis 
X 
X 
Sudden death 
X 
X 
Non-specific symptoms 
 
 
Fatigue, malaise 
X 
X 
Abdominal pain 
X 
 
Dizziness or syncope 
X 
 
Edema 
X 
X 
Cough 
X 
X 
Cyanosis 
 
X 
Weakness 
 
X 
Altered mental status 
 
X 
Shoulder and/or upper back pain 
 
X 
Gastrointestinal – nausea +/or vomiting +/or diarrhea 
 
X 
Low grade intermittent fever (≥38ᵒ Centigrade) 
 
X 
Infants and young children 
 
 
Irritability 
X 
X 
Vomiting 
X 
X 
Poor feeding 
X 
X 
Lethargy 
X 
X 
Tachypnea 
X 
X 
 
 
 
 

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7.6 
Appendix 6. Multisystem Inflammatory Syndrome in Children and Adults (MIS-C/A) criteria 
 
 
 
 

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7.7 
Appendix 7. Data collection variables 
 
 
 
Eligibility 
Study inclusion/exclusion criteria 
Brighton Collaboration case definition criteria 
Diagnosis 
Myocarditis etiology 
Brighton Collaboration case definition level 
Demographics 
Age, date of birth (Month/year), gender, ethnicity 
Occupation, education, urban/rural 
Province, city, postal code (3 digit) 
Vaccine 
Doses 1, 2, 3, 4, 5, additional doses 
Vaccine type and date 
Covid-19 
infection 
Infections 1, 2, 3, 4, 5, additional infections 
Date symptom onset 
Date diagnosis 
Diagnostic test (PCR, rapid antigen, self-report, other) 
Symptoms 
Treatment 
Medical history 
Cardiovascular risk factors and disease 
Autoimmune condition 
Non-cardiovascular disease 
Medications 
NSAID, colchicine, steroid, PPI, other 
Laboratory tests 
CBC, renal function 
Cardiac biomarkers, inflammatory markers 
Examination 
Vital signs and clinical signs if recorded 
Hospitalization 
Date admission and discharge 
Diagnosis 
Presentation 
Management 
Death 
Date 
Location 
Cause 
Echocardiography Left and right ventricular function 
Pericardial 
Cardiac MRI 
Left and right ventricular function 
Late gadolinium enhancement 
ECG and Holter 
Date 
ECG abnormalities 
Holter abnormalities 
Arrhythmia classification 
Outcomes 
Primary and secondary endpoints 
 
 
 
 
 
 
 

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7.8 
Appendix 8. Schedule of assessment 
 
Tests/Procedures 
Baseline 
3 months 
(+/- 1 
month) 
12 months 
(+/- 1 
month) 
24 months 
(+/- 1 
month) 
36 months 
(+/- 1 
month) 
Eligibility 
x 
 
 
 
 
Demographics 
x 
  
  
  
  
Diagnosis 
x 
 
 
 
 
Medical history 
x 
 
 
 
 
Hospitalization 
x 
 
 
 
 
COVID-19 infection 
x 
 
 
 
 
Vaccination status 
x 
  
  
  
  
Physical exam 
x 
  
  
  
  
Vital signs 
x 
x 
x 
 
 
Clinical symptoms 
x 
  
  
  
  
Medications 
x 
 
 
 
 
Bloodwork 
SOC 
x^ 
x^ 
  
  
ECG, Holter, Echo, MRI 
SOC 
x^ 
x^ 
x^ 
 x^ 
QOL, EQ-5D-5L 
 x 
x 
x 
x 
x 
EQ-5D-Y 
 x* 
x* 
x* 
x* 
x* 
PHQ-9 
 x 
x 
x 
x 
x 
GAD-7 
 x 
x 
x 
x 
x 
International Activity 
Questionnaire 
 x 
x 
x 
x 
x 
Events, concomitant 
medication 
 x 
x 
x 
x 
x 
Outcomes 
 
x 
x 
x 
x 
 
* questionnaire for children only 
^ repeat diagnostic tests if initial test was abnormal 
Previous cases will join the study schedule at the nearest scheduled study visit 
 
 
 
 
 
7.9 
Appendix 9. Abbreviations 
 
GCP – Good Clinical Practice 
KT – knowledge translation 
LVEF – Left Ventricular Ejection Fraction 
MIS-C/A – Multisystem Inflammatory Syndrome Children/Adults 
PI – Principal Investigator 
SC – Steering Committee 
 
 
 
 

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7.10 Appendix 9. References 
 
References 
 
1. 
Barda N, Dagan N, Ben-Shlomo Y, et al. Safety of the BNT162b2 mRNA Covid-19 Vaccine in a 
Nationwide Setting. N Engl J Med. 2021;385:1078-1090 
2. 
Diaz GA, Parsons GT, Gering SK, et al. Myocarditis and Pericarditis After Vaccination for COVID-19. 
Jama. 2021;326:1210-1212 
3. 
Husby A, Hansen JV, Fosbol E, et al. SARS-CoV-2 vaccination and myocarditis or myopericarditis: 
population based cohort study. Bmj. 2021;375:e068665 
4. 
Klein NP, Lewis N, Goddard K, et al. Surveillance for Adverse Events After COVID-19 mRNA 
Vaccination. Jama. 2021;326:1390-1399 
5. 
Luk A, Clarke B, Dahdah N, et al. Myocarditis and Pericarditis After COVID-19 mRNA Vaccination: 
Practical Considerations for Care Providers. Can J Cardiol. 2021;37:1629-1634 
6. 
Mevorach D, Anis E, Cedar N, et al. Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in 
Israel. N Engl J Med. 2021;385:2140-2149 
7. 
Witberg G, Barda N, Hoss S, et al. Myocarditis after Covid-19 Vaccination in a Large Health Care 
Organization. N Engl J Med. 2021;385:2132-2139 
8. 
Karlstad O, Hovi P, Husby A, et al. SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study 
of 23 Million Residents. JAMA Cardiol. 2022;7:600-612 
9. 
Pillay J, Gaudet L, Wingert A, et al. Incidence, risk factors, natural history, and hypothesised 
mechanisms of myocarditis and pericarditis following covid-19 vaccination: living evidence syntheses and 
review. Bmj. 2022;378:e069445 
10. 
Switzer C, Loeb M. Evaluating the relationship between myocarditis and mRNA vaccination. Expert 
Rev Vaccines. 2022;21:83-89 
11. 
Gluckman TJ, Bhave NM, Allen LA, et al. 2022 ACC Expert Consensus Decision Pathway on 
Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute 
Sequelae of SARS-CoV-2 Infection, and Return to Play: A Report of the American College of Cardiology 
Solution Set Oversight Committee. J Am Coll Cardiol. 2022;79:1717-1756 
12. 
NACI. National Advisory Committee on Immunization (NACI): Statements and publications. COVID-19 
vaccine: Canadian Immunization Guide. https://www.canada.ca/en/public-
health/services/immunization/national-advisory-committee-on-immunization-naci.html. 2022 
13. 
Alhussein MM, Rabbani M, Sarak B, et al. Natural History of Myocardial Injury Following COVID-19 
Vaccine Associated Myocarditis. Can J Cardiol. 2022 
14. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20:1727-1736 
15. 
Wille N, Badia X, Bonsel G, et al. Development of the EQ-5D-Y: a child-friendly version of the EQ-5D. 
Qual Life Res. 2010;19:875-886 
16. 
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen 
Intern Med. 2001;16:606-613 
17. 
Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety 
disorder: the GAD-7. Arch Intern Med. 2006;166:1092-1097 
18. 
Craig CL, Marshall AL, Sjostrom M, et al. International physical activity questionnaire: 12-country 
reliability and validity. Med Sci Sports Exerc. 2003;35:1381-1395