Here is a discussion of a study that was published in The Lancet Respiratory Medicine on 12 April 2022 which gave the reassuring news that myopericarditis following COVID-19 vaccination is rare.

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Myopericarditis

It has previously been linked only to smallpox vaccination. The side effects of vaccination are more often mild and self-limiting; However, a study from Israel suggested that mRNA COVID-19 vaccines significantly increase the risk of myocarditis, particularly in males and in people aged 16–39 years. More such disquieting reports followed.

History of myopericarditis

1. Scientists first identified SARS-CoV-2, the virus that causes COVID-19 in December 2019. Research to develop vaccines against coronaviruses has been an ongoing effort.
2. On December 11, 2020, the Food and Drug Administration gave emergency use authorisation against the virus to Pfizer vaccine. It was the first vaccine to achieve this distinction.
3. Soon, there were concerns as scientists found that myopericarditis is an adverse effect of vaccination.

Do they reflect a true increase in incidence or merely improved reporting and recall bias?

Researchers do not know the answer conclusively. They have postulated that "the mRNA in the vaccine might activate aberrant innate and acquired immune responses that potentially trigger myocardial inflammation as part of a systemic reaction".

Though they have suggested many mechanisms, they have not established the actual mechanism for the pathogenesis of post-vaccine myopericarditis. They could not identify any meta-analyses evaluating the proportion of people who develop myopericarditis following vaccination.

A press release from the journal concluded (verbatim):

1. A new analysis of over 11 studies covering 395 million COVID-19 vaccine doses reveals that the risk of heart inflammation (myopericarditis) following COVID-19 vaccination is comparable to or lower than the risk following non-COVID-19 vaccinations.
2. The overall incidence of myopericarditis following COVID-19 vaccination was 18 cases per million doses, compared to 56 cases per million doses for non-COVID vaccinations, such as influenza.
3. Higher risk factors for myopericarditis included being under the age of 30 (40.9 cases per million doses), being male (23 cases per million doses), receiving an mRNA vaccine (22.6 cases per million doses), and receiving a second dose of vaccine (31.1 cases per million doses) – compared to all COVID-19 vaccines in the general population.
4. The authors conclude that these findings should inform the public of the rarity of myopericarditis, highlighting that the benefits of vaccination far outweigh the risk of this rare adverse event.

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The study methods

1. Researchers reviewed four international databases for relevant studies, published in English from Jan 1, 1947, to Dec 31, 2021, using appropriate keywords.
2. Their exhaustive search covered observational studies reporting on people in the general population who had myopericarditis in temporal relation to receiving vaccines and even grey literature. They identified 4919 studies from the search strategy, of which 22 observational studies were relevant to their study.

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Results

1. They reviewed more than 400 million vaccination doses to compare the risk of myopericarditis following vaccination against COVID-19 and other diseases such as influenza and smallpox. Researchers analysed more than 20 studies. Of these, 11 studies looked specifically at COVID-19 vaccinations, covering over 395 million COVID-19 vaccine doses – nearly 300 million of which were mRNA vaccines. The rest of the studies covered other vaccinations such as smallpox (2.9 million doses), influenza (1.5 million doses), and others (5.5 million doses).

2. They found no statistically significant difference between the incidence of myopericarditis following the COVID-19 vaccination (18 cases per million doses) and other vaccinations (56 cases per million doses).

According to Dr. Kollengode Ramanathan, a cardiac intensivist at National University Hospital, Singapore, and corresponding author asserted in the press release from the journal.

“Our research suggests that the overall risk of myopericarditis appears to be no different for this newly approved group of vaccines against COVID- 19, compared to vaccines against other diseases. The risk of such rare events should be balanced against the risk of myopericarditis from infection and these findings should bolster public confidence in the safety of COVID-19 vaccinations,”

3. The rate of myopericarditis following COVID-19 vaccination was 18 cases per million doses. For all other viral vaccinations combined, the rate of myopericarditis was 56 cases per million doses. Among COVID-19 vaccinations, the risk of myopericarditis was higher for those who received mRNA vaccines (22.6 cases per million doses) compared to non-mRNA vaccines (7.9 cases per million doses). Reported cases were also higher in people below the age of 30 (40.9 cases per million doses), males (23 cases per million doses), and following the second dose of COVID-19 vaccine (31.1 cases per million doses).

4. In order to place the findings in context with the risk of myopericarditis following COVID-19 infection, the authors conducted a post-study analysis. Among 2.5 million patients who were hospitalised with COVID-19, many of whom had clinical or radiological suspicion of myopericarditis, 1.1% had myopericarditis.

5. However, while these figures provide a frame of reference, the authors note that the results are not directly comparable with the number of cases of myopericarditis following the COVID-19 vaccination due to different units of measurement. Dr Jyoti Somani, an infectious diseases specialist at National University Hospital, Singapore, and co-author noted that the occurrence of myopericarditis following non-COVID-19 vaccination could suggest that myopericarditis is a side effect of the inflammatory processes induced by any vaccination and is not unique to the SARS-CoV-2 spike proteins in COVID-19 vaccines or infection.

Dr Jyoti Somani added in the press release from the journal:

“This also highlights that the risks of such infrequent adverse events should be offset by the benefits of vaccination, which includes a lower risk of infection, hospitalisation, severe disease, and death from COVID-19.” 

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The authors acknowledge some limitations of this study

1. The findings include only a small proportion of children under the age of 12 who have only recently been eligible for vaccination, and the results of this study cannot be generalised to this age group.
2. Comparisons have been made across different times for different vaccines. Diagnostic tools might have differed or not been available leading to lower reporting of cases in earlier studies.

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Comments in the accompanying the paper

"Reports of unexpected adverse events – albeit rare and limited to a select subset of vaccine recipients – have the potential to damage vaccine confidence at a critical point in pandemic response. As if Ling and colleagues, all professionals who have described myocarditis following COVID-19 vaccination have emphasised that the benefits of vaccination far outweigh the risks in the midst of the current pandemic. Nonetheless, scientific knowledge and public health strategies must continue to evolve. Alternative vaccine platforms, vaccine doses, or vaccine schedules may reduce the risk of rare adverse events following immunisation, and must be explored in the context of changing infection risk.”

Writing in a linked comment, Margaret Ryan of the Defence Health Agency and Clinical Professor at the University of California San Diego, USA and Jay Montgomery, a medical director for the Defense Health Agency's Immunisation Healthcare Division's North Atlantic Region Vaccine Safety Hub who was not involved in the study cautioned.

They suggested that although there are common demographic and clinical features between the myopericarditis cases that followed the smallpox vaccine and those that followed the mRNA COVID-19 vaccines, a better understanding of the pathophysiology of these adverse events following vaccination is an important area for future research.

They clarified:

 "Because smallpox vaccination has very limited global application in the modern era, the experience of mRNA COVID-19 vaccination must now propel the field forward. Analyses of the pathology and immunological mechanisms behind these demographic-dependent adverse events following vaccination are likely to advance our understanding of cardiology and immunology. These advances could spur the development of safer vaccines or precision vaccination practices."

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Response from the corresponding author

Dr Kollencode R Ramanathan, the corresponding author answered the questions by e-mail.:

Q.1) With the current rates of vaccinations, how long it may take to get relevant data on statistically respectable numbers of vaccinated children under age 12?

Overall, the population of <12 years is incorporated/ embedded into the databases /studies, but the breakdown is currently unavailable from our data. Worldwide, we should already be there. In the US, at least 18.8% of 5-12 y have had two doses as of January 2022 and worldwide, many countries including Singapore have been vaccinating children between the ages of 5-12 years. Other countries including Italy, Germany, Ireland, and the UK have also initiated vaccination for 5–12- year-olds since 2022.

Q.2) Is there any ongoing internationally coordinated programme for this group of patients?

The Canadian and Singapore governments are tracking hospitalisations for children related to post COVID vaccination adverse events. Of course, The Centers for Disease Control and Prevention Vaccine Adverse Events Reporting System (CDC VAERS) is continuing to monitor adverse events in the pediatric age group, and they are also engaging in longer-term follow up of outcomes in children who had any adverse cardiac events.

Q.3) Are there any thoughts on why males have more rates of Myopericarditis than females?

The incidence of non-vaccine related myocarditis is also much higher in males than females in the general population. This difference narrows in post-menopausal females. It is postulated that testosterone mediated differences in the immune response may be the reason for this difference. Other mechanisms that have been postulated include molecular mimicry and immune-mediated inflammatory reactions.

Q.4) Margaret Ryan and Jay Montgomery who made the accompanying comments stated that the risk of myopericarditis in young males after their second dose of mRNA COVID-19 vaccine is remarkably higher than expected. Is there any explanation for this?

We have not read their article yet. However, our study shows the following pattern of myopericarditis in the general population after the second dose:

• Males <30 years: 59.7 cases per million
• Females <30 years: 5.3 cases per million
• Males >30 years: 4.0 cases per million
• Females >30 years: 1.7 cases per million

The incidence of myocarditis overall is higher in males than in females, and this is likely due to a testosterone-related effect on the immune response to an antigen (infection or vaccine or otherwise).

While the exact mechanisms are still unknown or being researched, the much higher risk in adolescent males after the 2nd dose is likely related to this same effect. Other proposed mechanisms include prior sensitisation with the first dose, cross-reactions with myocardial proteins and hypersensitivity reactions.

Disclaimer- The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of M3 India.

Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph. D. from the University of Leeds, UK, he is a medical physicist with a specialisation in radiation safety and regulatory matters. He was a Research Associate at the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member of some of its Technical and Advisory Committees.