The impact of the global health crisis due to the virus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)—the causative pathogen of the coronavirus disease 2019 (COVID-19)—has begun to alter with the timely development, approval and administration of vaccines []. Although SARS-CoV-2 infection primarily targets the respiratory system [], it is now recognised that the infection and its clinical manifestations are systemic [], and also affecting the cardiovascular system of adults and children []. Cardiac complications of variable severity with acute and long-term sequelae are now known to include acute myocardial injury, arrhythmias, vasculitis and endothelial dysfunction, thrombosis, myocardial fibrosis, and myocarditis []. The cardiovascular and cellular pathophysiology of COVID-19, and the clinical management of previously healthy subjects and patients with existing cardiovascular or other disease conditions remain under intense investigation particularly as early in the pandemic, myocarditis was identified as a risk factor for increased mortality in COVID-19 patients [].

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China.

COVID-19-associated suspected myocarditis as the etiology for recurrent and protracted fever in an otherwise healthy adult.

Current and new drugs for COVID-19 treatment and its effects on the liver.

Viral infections are a common cause of acute myocarditis, which usually presents with the hallmark of inflammatory infiltrate and myocardial cell injury unrelated to ischaemia, and in the absence of overt vascular disease []. In healthy subjects, anti-viral vaccine-associated immune eosinophilic myocarditis is rare but has previously been reported in healthy adults for the smallpox vaccine and the seasonal influenza vaccine [].

American Heart Association Pediatric Heart Failure and Transplantation Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young and Stroke Council

American Heart Association Pediatric Heart Failure and Transplantation Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young and Stroke Council Diagnosis and management of myocarditis in children: a Scientific Statement from the American Heart Association.

Not surprisingly, highly publicised adverse events following immunisation with COVID-19 vaccine have been of great concern to the public and to health authorities world-wide, particularly when associated with the death of ‘previously healthy’ individuals. There has been considerable focus on the rare occurrence of Thrombosis with Thrombocytopenia Syndrome (TTS), Guillain-Barré Syndrome and Capillary Leak Syndrome reported after receipt of the adenoviral vector vaccine made by AstraZeneca (Covishield/Vaxzevria), even though a causal relationship with each respective vaccination incident has not been consistently established and these events are not exclusive to the AstraZeneca vaccine. However, in the past few months there has been a growing international list of reports of the rare incidence of myocarditis and/or pericarditis within one week after receiving the second dose of mRNA COVID-19 vaccines (Pfizer-BioNTech BNT162b2/Comirnaty and Moderna mRNA-1273), more often in males, mostly in adolescents and young adults [].

Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: Update from the advisory Committee on Immunization Practices - United States, June 2021.

Government of Israel, Ministry of Health, June 02, 2021 Surveillance of Myocarditis (Inflammation of the Heart Muscle) Cases Between December 2020 and May 2021 (Including).

In Australia, to 11 July 2021, the Department of Health Therapeutic Goods Administration (TGA) has received 50 reports of suspected myocarditis and/or pericarditis out of 288 total adverse event reports after 3.7 million doses of Pfizer mRNA COVID-19 vaccine []. These reported cases of temporally associated possible myocarditis/pericarditis and their clinical course are being evaluated and may be an overestimate of the incidence; however, if all these events are confirmed as likely vaccination complications, this represents an incidence of 13.5 per million doses administered. After long delays in vaccine administration in Australia, as vaccine availability and the mRNA vaccination rate finally begin to ramp up over the next few months, TGA monitoring and clinician vigilance will be very important, as is consideration of the experience in North America and Europe with large populations where vaccine administration is most advanced.

International Monitoring of Post-COVID-19 Vaccine Myocarditis

Below, we draw attention to brief summaries of post-COVID-19 vaccine myocarditis accounts from Israel, the UK, Europe, Canada, and the USA. At the time of writing this report, event monitoring, clinical confirmation, patient outcomes and exploring a causal relationship with the vaccines remain in progress between respective governing health agencies and COVID-19 vaccine manufacturers. However, adjustment of product safety information risk statements is already being recommended and communicated to health care professionals.

[33] Government of Israel, Ministry of Health, June 02, 2021

Surveillance of Myocarditis (Inflammation of the Heart Muscle) Cases Between December 2020 and May 2021 (Including). One of the earliest reports was from Israel where from April 2021, the Ministry of Health detailed, by early June, over 62 cases of myocarditis out of 5 million vaccinated exclusively with the Pfizer mRNA vaccine (an incidence of 12.4 per million patients). Notably, the cases were predominantly younger than 30 years of age, mainly male, and had received their second dose of vaccine within the preceding 3 days. Importantly, all were previously well and although 60 had recovered within less than a week, there were 2 deaths (one male aged 35 years and one female aged 22 years []. Against a background of current considerations over whether to vaccinate children (<12 years) against COVID-19, adverse events and dosing regimen are being closely studied.

[34] Medicines and Healthcare Products Regulatory Agency (MHRA)

Coronavirus vaccine- weekly summary of Yellow Card reporting [Internet]. In the UK to 7 July 2021, 19.7 million first doses and about 11.6 million second doses of the Pfizer/BioNTech vaccine plus about 1.1 million first doses of the COVID-19 Vaccine Moderna have been administered []. As part of their open ’Yellow Card’ reporting, the UK Medicines and Healthcare Products Regulatory Agency (Department of Health and Social Care) have listed the incidence of suspected myocarditis and pericarditis after receiving the Pfizer/BioNTech vaccine (81 myocarditis, 63 pericarditis), and Moderna (9 myocarditis, 9 pericarditis, 1 endocarditis), with an incidence of 5.0 per million doses. Of interest is that, after administration of the AstraZeneca COVID-19 vaccine (adenoviral vector; not an mRNA vaccine), there were also reports of myocarditis (69) and pericarditis (107), after 24.7 million first doses and 22.3 million second doses (an incidence of 3.7 per million doses).

[35] European Medicines Agency Pharmacovigilance Risk Assessment Committee Summary June 7-10, 2021. The European Medicines Agency, as of the end of May 2021, cited vaccination with approximately 160 million COVID-19 vaccine doses for Pfizer, 19 million doses for Moderna, 40 million for AstraZeneca and 2 million for Janssen []. EudraVigilance adverse event data for these dose exposures reported myocarditis following vaccination with Pfizer (122 cases), Moderna (16 cases), and AstraZeneca (38 cases). Post-vaccine pericarditis was also reported for Pfizer (126 cases), Moderna (18), AstraZeneca (47) and the Janssen COVID-19 viral vector vaccine (1). This represented a very low incidence of reported myocarditis/pericarditis of 2.0 per million doses for viral vector vaccines and 1.6 per million doses for mRNA vaccines.

[36] Public Health Agency of Canada. COVID-19 daily epidemiology update. Ottawa (ON): Government of Canada; 2021 May 12 [cited May 13, 2021]. https://health-infobase.canada.ca/covid-19/epidemiological-summary-covid-19-cases.html AND weekly updated events https://health-infobase.canada.ca/covid-19/vaccine-safety/ [cited July 20, 2021]. The Public Health Agency of Canada (PHAC), Health Canada, as of 9 July 2021, has administered over 41.5 million COVID-19 vaccine doses and listed 163 cases of ‘myocarditis/pericarditis’ (median age, 39 years; range, 15–86) []. The breakdown is: 111 cases after Pfizer-BioNTech, 40 after Moderna, 11 cases after AstraZeneca; and 1 case with vaccine unspecified. This represents an incidence of 3.9 per million doses. The timing of post-vaccination onset of symptoms ranged from 5 hours to 92 days. There were 52 females (median age, 49 years; range, 15–86) and 59 males (median age, 38 years; range, 15–82). Interestingly, 67 cases occurred after the first dose, 26 cases after the second vaccine dose; and, 18 cases, no dose number specified. Detailed reporting of the cases, their clinical management and outcomes with regard to an association or a causal link between myocarditis/pericarditis and mRNA vaccines are in progress with the growing receipt of data.

[37] Center for Disease Control. United States of America Department of Health and Human Services

COVID-19 Vaccine Safety Technical (VaST) Work Group Report, June 28, 2021. [38] Gargano J.W.

Wallace M.

Hadler S.C.

Langley G.

Su J.R.

Oster M.E.

et al. Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: Update from the advisory Committee on Immunization Practices - United States, June 2021. [37] Center for Disease Control. United States of America Department of Health and Human Services

COVID-19 Vaccine Safety Technical (VaST) Work Group Report, June 28, 2021. [38] Gargano J.W.

Wallace M.

Hadler S.C.

Langley G.

Su J.R.

Oster M.E.

et al. Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: Update from the advisory Committee on Immunization Practices - United States, June 2021. [38] Gargano J.W.

Wallace M.

Hadler S.C.

Langley G.

Su J.R.

Oster M.E.

et al. Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: Update from the advisory Committee on Immunization Practices - United States, June 2021. The US Centers for Disease Control and Prevention (CDC) by mid-June 2021 had reported 1,226 cases of myocarditis after mRNA vaccination (Pfizer or Moderna, 29 December 2020–11 June 2021) from 296 million doses [], an incidence of 4.1 per million doses. As the median age of these cases was 26 years (range, 12–94 years) and the median onset of first symptom was 3 days (range, 0–179), it is important to note that more than half the patients were less than 30 years old, more than two-thirds were male, and more than 75% had received the second dose of mRNA vaccine []. Consequently, CDC physicians and cardiologists evaluated 484 cases of patients aged under 30 years, with 323 individuals that strictly met definitions as per Dallas Criteria and Lake Louise Criteria for acute myocarditis, acute pericarditis or myopericarditis []. The median age for these individuals was 19 years (range, 12–29 years) with first symptom onset at a median of 2 days (range, 0–40 days), and 92% with onset within 7 days. Of note is that 96% of these individuals were promptly hospitalised. Most patients were managed through mild clinical courses that resolved, with subsequent hospital discharge; there were no deaths.

39 Kim H.W.

Jenista E.R.

Wendell D.C.

Azevedo C.F.

Campbell M.J.

Darty S.N.

et al. Patients with acute myocarditis following mRNA COVID-19 vaccination. 40 Park J.

Brekke D.R.

Bratincsak A. Self-limited myocarditis presenting with chest pain and ST segment elevation in adolescents after vaccination with the BNT162b2 mRNA vaccine. 41 Muthukumar A.

Narasimhan M.

Li Q.Z.

Mahimainathan L.

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Fuda F.

et al. In depth evaluation of a case of presumed myocarditis following the second dose of COVID-19 mRNA vaccine. 42 D'Angelo T.

Cattafi A.

Carerj M.L.

Booz C.

Ascenti G.

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et al. Myocarditis after SARS-CoV-2 vaccination: a vaccine-induced reaction?. 43 Montgomery J.

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et al. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US Military. [43] Montgomery J.

Ryan M.

Engler R.

Hoffman D.

McClenathan B.

Collins L.

et al. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US Military. The mounting number of case and cohort studies that we have identified to date provide considerable detailed insight into patient demographics, disease at presentation, diagnosis, clinical management, and outcome []. The report by Montgomery et al. [] is one of the larger retrospective series: 23 male individuals were treated for chest pain and confirmed with myocarditis after mRNA COVID-19 vaccination between January and April 2021 (Pfizer, n=7 cases; Moderna, n=16 cases). All were military staff members with a high level of fitness and health. During this time 2.8 million doses of mRNA COVID-19 vaccine were administered by the US Military Healthcare Service. All patients had markedly elevated cardiac troponin levels, with consistent indications for myocarditis and no evidence of infection, existing autoimmune conditions, or ischaemic disease; however only eight patients were examined with cardiac magnetic resonance imaging (MRI) at the acute phase of illness, thus clinically confirming myocarditis. Notably, managed care was brief, with rapid recovery in all patients.