Myocarditis and pericarditis risk after covid-19 vaccination

One of the main safety concerns associated with mRNA vaccines for covid-19 is the rare risk of myocarditis or pericarditis. Despite their large sample sizes,12 phase 3 clinical trials are unlikely to detect such rare events, especially those occurring in small subgroups. Population based studies or those using national surveillance systems are able to assess risk in much larger numbers. However, incidence rates reported in those studies can vary depending on the data source (passive versus active surveillance), geographical region, and outcome definition (eg, people admitted to hospital only or all individuals). Furthermore, the sheer number of published studies on this topic (7380 publications in Google Scholar from 1 January 2021 to 15 June 2022 alone) makes keeping up to date of the rapidly changing literature extremely challenging for clinicians.

In this context, Pillay and colleagues (doi:10.1136/bmj-2021-069445)3 conducted a systematic review to examine incidence rates, risk factors, short term clinical course, and longer term outcomes of myocarditis and pericarditis after covid-19 mRNA vaccination. Among thousands of database citations through to 10 January 2022, their team ultimately focused on 46 studies.

The authors report several important findings. First, their review provides evidence that the relative incidence of myocarditis is highest among young male individuals between the ages of 12 and 29 years after a second dose. Second, their study finds, with moderate certainty, that the incidence of myocarditis is probably higher after Moderna’s mRNA vaccine than after Pfizer-BioNTech’s vaccine. Third, with low certainty, they report that the risk of myocarditis or pericarditis might be lower when the second dose is administered more than 30 days after the first dose. Finally, the review finds that most patients are only briefly admitted to hospital and respond well to standard therapy, although long term follow-up is limited.

Despite the large numbers of studies reviewed, the overall certainty of the conclusions remains low, with a very wide range reported for myocarditis incidence. That we are now more than a year and a half into mass mRNA vaccination and still do not have strong certainty about the incidence of this clinically important outcome is disappointing. Because these events are rare, making precise estimates is difficult.

Additionally, ascertainment of the outcome or outcomes of interest differs from study to study, contributing to the uncertainty. For example, some studies might search using International Classification of Diseases-10-Clinical Modification codes whereas others rely on spontaneous reporting or a health system’s medical record. Some studies might confirm individuals with adverse events using the US Centers for Disease Control and Prevention case definition4 whereas others might use the Brighton Collaboration’s criteria,5 or expert consensus or opinion. Pillay and colleagues’ research focused on studies of confirmed cases of myocarditis or pericarditis. The range of incidence estimates would be far wider if additional studies without such confirmation were included, but accuracy would suffer. Clearly, the incidence of myocarditis is rare after vaccination. Just how rare remains a question of major importance.

This living evidence syntheses and review finds that the incidence of myocarditis is probably higher after Moderna’s vaccine than after Pfizer-BioNTech’s vaccine. This finding has led multiple countries to prefer use of the Pfizer-BioNTech over Moderna vaccine for young people.678 US agencies have so far declined to make this recommendation. In a recent meeting of the vaccine advisory committee of the US Food and Drug Administration, the FDA justified this position by use of its new data comparing risk between the two mRNA vaccines.9 This study used International Classification of Diseases-10 codes to ascertain myocarditis and pericarditis with no case confirmation. Although Moderna vaccine recipients had an estimated excess risk of 28 myocarditis cases per million doses relative to Pfizer-BioNTech’s vaccine, the 95% confidence interval spanned from 22 fewer cases to 77 more cases per million. The FDA concluded that insufficient evidence exists to confirm the higher risk, despite the international data reported in Pillay and colleagues’ systematic review.

A paucity of data exists regarding longer term outcomes among patients with vaccine associated myocarditis. The Pillay review identified only 38 cases from studies with more than 90 days of follow-up. So how frequently electrocardiographic changes or symptoms, such as chest discomfort, can persist remains unclear. The CDC is surveying patients at least 90 days after vaccine associated myocarditis; preliminary data from 360 respondents interviewed after a median of 143 days from diagnosis were presented to the US Advisory Committee on Immunization Practices in February.10 About a third of people still reported chest pain, although no control group was used and response bias is likely. Roughly 80% (n=309) of 380 patients were judged by clinicians to have fully or probably fully recovered but more data and longer term follow-ups are urgently needed.

Although the data for myocarditis risk after a second dose is incredibly important, its future relevance is uncertain as the vaccination rollout moves to younger children. Notably, the FDA recently amended the emergency use authorizations for both mRNA vaccines for children down to 6 months of age. Many adolescents and young adults eligible for the adult primary series have already been vaccinated (in the US, at least), and now need information about the risks associated with booster doses. Recent studies suggest a non-negligible myocarditis risk after boosters,1112 and this issue will remain salient as boosters for young people are discussed again later this year.

In summary, a large body of reviewed studies continues to suggest that mRNA covid-19 vaccines are associated with a rare but heightened risk of acute myocarditis and pericarditis. These risks are highest in young males shortly after the second dose. Key uncertainties remain, including risks associated with boosters, risks associated with primary vaccination of young children, and the long term outcomes of those who experience myocarditis. But these uncertainties must be placed in the context of the substantial and widely accepted benefits of vaccination.