Myopericarditis risk after COVID-19 vaccine not greater than after other vaccines

The risk of myopericarditis after COVID-19 vaccination is not greater than that following other non–COVID-19 vaccinations, according to a systematic review and meta-analysis conducted by researchers in Singapore.

“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,” remarked corresponding author Dr Kollengode Ramanathan, Senior Consultant in the Department of Cardiac, Thoracic & Vascular Surgery at the National University Heart Centre, Singapore (NUHCS).

“Nonetheless, certain subpopulations – those of male sex or younger age and those receiving an mRNA vaccine, particularly the second dose – appear to be at increased risk of myopericarditis following COVID-19 vaccination,” added co-author Ryan Ruiyang Ling, a medical student at NUS Medicine, Singapore.

The researchers reviewed four international databases and identified 22 observational studies (405,272,721 vaccine doses) in English that reported on temporal post-vaccination myopericarditis between 1947 and 2021. Eleven of these studies were on COVID-19 vaccines (395,361,933 doses) and 11 were on non–COVID-19 vaccines (9,910,788 doses; six, two, and three studies on smallpox, influenza, and other non–COVID-19 vaccines, respectively). Randomized controlled trials, case reports, studies reporting on a specific patient subpopulation, non-human studies, and studies without information on number of doses were excluded. Nine studies specified COVID-19 vaccine type, identifying 290,730,653 doses of mRNA vaccines and 51,969,677 doses of non-mRNA vaccines.

Overall, the rate of myopericarditis following vaccination was 33.3 cases per million vaccine doses.

The incidence of myopericarditis after COVID-19 vaccination did not significantly differ from that following receipt of non–COVID-19 vaccines (18.2 vs 56.0 cases per million vaccine doses; p=0.20). [Lancet Respir Med 2022;doi:10.1016/S2213-2600(22)00059-5]

In particular, myopericarditis incidence was not significantly different following the COVID-19 compared with influenza vaccination (1.3 per million vaccine doses; p=0.43) or other non-smallpox vaccinations (57.0 per million vaccine doses; p=0.58).

Conversely, myopericarditis incidence was higher following smallpox vaccination (132.1 per million vaccine doses) than COVID-19 vaccination (p<0.0001 vs COVID-19 vaccine).

The authors noted that the studies of smallpox vaccination were primarily conducted among individuals in the US military (eg, mostly young men), which could explain the elevated incidence in this group.

“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,” said co-author Dr Jyoti Somani, specialist in infectious diseases at the National University Hospital, Singapore.

There was no significant difference in myopericarditis incidence between the adult and paediatric populations (26.0 vs 18.4 per million vaccine doses; p=0.67).

In terms of myocarditis specifically, incidence was significantly lower among COVID-19 than non–COVID-19 vaccine recipients (8.9 vs 79.4 per million doses; p<0.0001), while pericarditis incidence did not significantly differ between COVID-19 and non–COVID-19 vaccine recipients (10.1 vs 20.0 per million doses; p=0.64).

 

Factors influencing myopericarditis in COVID-19 vaccine recipients

Among COVID-19 vaccine recipients, myopericarditis more commonly occurred in males vs females (23.0 vs 5.1 per million doses; p=0.0019) and individuals aged <30 years vs ≥30 years (40.9 vs 2.9 per million doses; p<0.0001). In recipients aged <30 years, myopericarditis incidence in males was approximately tenfold than in females (59.7 vs 5.3 per million doses; p<0.0001), and also higher in males vs females aged ≥30 years (4.0 vs 1.7 per million doses; p=0.034).

Myopericarditis was also significantly more frequent following receipt of an mRNA vs non-mRNA vaccine (22.6 vs 7.9 per million doses; p=0.0010) and after a second vs first or third dose of a vaccine (31.3 vs 7.2 or 3.0 per million doses; p<0.0001).

In general, symptoms of myopericarditis emerged about 1–2 weeks after vaccination.

Meta-regression of five studies showed that decreasing age (excluding individuals aged <12 years) was tied to increased myopericarditis incidence (regression coefficient -0.069; p=0.0030).

 

In context of COVID-19

Post-hoc analysis of 2,453,491 patients hospitalized with COVID-19 with radiological or clinical suspicion for myopericarditis showed an incidence rate of 1.1 percent in this population.

Overall mortality did not differ following receipt of COVID-19 or non–COVID-19 vaccines (8.4 vs 7.2 per million doses; p=0.93).

 

Benefits outweigh risks

“The risk of such rare events [of myopericarditis] should be balanced against the risk of myopericarditis from infection and these findings should bolster public confidence in the safety of COVID-19 vaccinations,” said Ramanathan.

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

The authors acknowledged the possibility of underreporting of myopericarditis in the past following non–COVID-19 vaccinations, given the enhanced scrutiny received by COVID-19 vaccines. “Being aware of a possible association between COVID-19 vaccination and myopericarditis, clinicians might have had an inherently lower threshold for investigating a patient with non-specific chest pain after COVID-19 vaccination, eventually leading to a diagnosis of myopericarditis,” they said.

Moving forward, these findings could impact vaccination policy, they said. “[R]easonable policies—such as preferentially offering a non-mRNA vaccine to males, particularly those younger than 18 years—could be considered to manage the risk of myopericarditis, while considering the overall benefits and harms of the vaccines,” the authors said.

However, these strategies need to take into account multiple factors including morbidity risk in the particular population, local epidemiology, and availability of non-mRNA vaccines. “It is also important to interpret the risks and benefits in the context of the background incidence of myopericarditis across subpopulations—ie, the risk of myopericarditis will depend on the prevailing prevalence of COVID-19 locally and at the time of vaccination,” the authors said.

They called for further research into assessing myopericarditis incidence in COVID-19 vaccine recipients aged <12 years who were underrepresented in this analysis and for whom the present results may not apply.

“The impact of booster vaccines will require further research as well,” concluded Ramanathan.