Carditis following COVID-19 vaccination: balancing the risks and benefits

The coronavirus disease 2019 (COVID-19) pandemic has profoundly impacted the world. The uniquely expeditious development of vaccines was welcomed by the medical community due to the immense scale of the pandemic. The ongoing emergence of SARS-CoV-2 variants and waning immunity after vaccination called for repeated doses of vaccination to maintain immunity against COVID-19. While the side effects of vaccination were typically mild and self-resolving, there were emerging reports of serious adverse events, one of which was carditis.1Ling R.R. Ramanathan K. Tan F.L. et al.Myopericarditis following COVID-19 vaccination and non-COVID-19 vaccination: a systematic review and meta-analysis.Lancet Respir Med. 2022; 10: 679-688Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar In The Lancet Regional Health – Western Pacific, Dr Min Fan and colleagues report on a self-controlled case series (SCCS) and a case–control study in a Hong Kong cohort investigating whether homologous mRNA (BNT162b2) or inactivated (CoronaVac) vaccination against COVID-19 was associated with carditis.2Fan M. Lai F.T.T. Cheng F.W.T. et al.Risk of carditis after booster vaccination with mRNA (BNT162b2) or inactivated (CoronaVac) covid-19 vaccination: a self-control cases series and a case-control study.Lancet Reg health West Pacific. 2023; 35: 100745Summary Full Text Full Text PDF Scopus (1) Google Scholar From 15 million doses of vaccines, the authors found an increase in carditis following all doses of BNT162b2 vaccination; the risks were substantially higher for males than females, and those younger than 30 years compared to those 30 years or older. They did not find any associations between carditis and CoronaVac vaccines. These results were internally validated using a case–control study design. The SCCS has been used before in assessing the safety of vaccination, and specific modifications have been made to facilitate analyses in the context of COVID-19 vaccination.3Ghebremichael-Weldeselassie Y. Jabagi M.J. Botton J. et al.A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety.Stat Med. 2022; 41: 1735-1750Crossref PubMed Scopus (24) Google Scholar In an SCCS, individuals with an event act as their own control group, and comparisons are made within individuals rather than between groups,4Farrington P. The self-controlled case series method and covid-19.BMJ. 2022; 377: o625Crossref PubMed Scopus (4) Google Scholar accounting for time-fixed confounders. The authors then accounted for time-varying confounders by adjusting for the calendar month. This modified study design is particularly elegant when the event of interest (carditis) is rare, or one group (those who have not received the vaccine) is very small. In such situations, conventional cohort studies may yield imprecise estimates.5Petersen I. Douglas I. Whitaker H. Self controlled case series methods: an alternative to standard epidemiological study designs.BMJ. 2016; 354: i4515Crossref PubMed Scopus (260) Google Scholar In addition, a modified SCCS accounts for when patients do not receive subsequent vaccination following carditis. Similar efforts by the authors investigating other adverse events in COVID-19 vaccination have been published as well.6Ye X. Huang C. Wei Y. et al.Safety of BNT162b2 or CoronaVac COVID-19 vaccines in patients with heart failure: a self-controlled case series study.Lancet Reg Health West Pacific. 2023; : 30Google Scholar The authors also investigated the risk of carditis in a large cohort of patients receiving an inactivated vaccine (CoronaVac), which has not been extensively reported on thus far. Studying both vaccines in the same population provides more data and facilitates open and transparent conversations about the benefits and harms of various vaccines against COVID-19. Of note, the authors report on a population which is mostly ethnically Chinese, which is in contrast to the current published literature which reports on a mostly ethnically Caucasian population.1Ling R.R. Ramanathan K. Tan F.L. et al.Myopericarditis following COVID-19 vaccination and non-COVID-19 vaccination: a systematic review and meta-analysis.Lancet Respir Med. 2022; 10: 679-688Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar This is an important question to study in diverse populations, as the pre-pandemic incidence of carditis has been shown to vary based on geographical region. There are some limitations of this study. The SCCS only provides relative, and not absolute, measures of risk.4Farrington P. The self-controlled case series method and covid-19.BMJ. 2022; 377: o625Crossref PubMed Scopus (4) Google Scholar As such, a large incidence rate ratio could reflect a truly large increase in carditis, or be a result of very low baseline incidence rates of carditis. In this study, Dr Fan and colleagues report an incidence rate of 18.9 per million doses for BNT162b2 vaccination, and 5.22 per million doses for CoronaVac vaccination, which are comparable to previous studies.1Ling R.R. Ramanathan K. Tan F.L. et al.Myopericarditis following COVID-19 vaccination and non-COVID-19 vaccination: a systematic review and meta-analysis.Lancet Respir Med. 2022; 10: 679-688Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar It is therefore unclear if the absolute increase in the risk of carditis is clinically significant, which requires estimating the clinical morbidity and long-term complications of carditis post vaccination, and even comparing it to that of COVID-19 infection. Ultimately, the final decision to vaccinate does not solely depend on the risk of carditis. Other side effects of vaccines (arrhythmias7Shi A. Tang X. Xia P. et al.Cardiac arrhythmia after COVID-19 vaccination versus non–COVID-19 vaccination: a systematic review and meta-analysis.medRxiv. 2022; Google Scholar and thromboembolic events8Tu T.M. Yi S.J. Koh J.S. et al.Incidence of cerebral venous thrombosis following SARS-CoV-2 infection vs mRNA SARS-CoV-2 vaccination in Singapore.JAMA Netw Open. 2022; 5e222940Crossref Scopus (13) Google Scholar,9Fan B.E. Ling R.R. Ramanathan K. et al.COVID-19 mRNA vaccine-associated cerebral venous thrombosis: rare adverse event or coincidence?.Am J Hematol. 2023; 98: E4-e7Crossref PubMed Scopus (2) Google Scholar for example) and benefits including protection from serious SARS-CoV-2 infections, including ongoing morbidity, are also important considerations. There are certain points which remain unanswered despite the novelties of this study. First, the study was limited by sample size in drawing any meaningful inferences in the female population, and those of younger age groups. It is unclear whether this reflects a lack of association, or that carditis is so rare in these subpopulations that the study was underpowered to detect a risk signal. Second, this cohort may not reflect the baseline pre-pandemic incidence of carditis in a population who was not exposed to COVID-19. As such, increases in detection and surveillance of carditis during the observation period may confound the incidence rate ratios, and the increase in carditis risk may be larger than expected when compared to a pre-pandemic observation period. Importantly, the authors did not look at vaccine response or efficacy for either vaccine. Taken together, it would be unreasonable to enact blanket policies that mRNA COVID-19 vaccination should be avoided in the whole population in view of the excess risk of carditis. As this study shows, the incidence rate ratio of post-vaccination carditis depends on the baseline risk, and absolute risks are just as important when deciding on vaccination. Rather, there should be ongoing discussions at the physician and individual level for those who are at higher risk of carditis after vaccination. They need to balance their individual risk of morbidity from COVID-19 itself and the efficacy of the vaccine, against the side effects of vaccination. Avoiding mRNA COVID-19 vaccination and opting for alternative vaccines which confer a lower risk of carditis may be a solution. Ultimately, the decision for which vaccine to choose will evolve and will depend on many factors including: the circulating variant, the severity of COVID-19 for that individual and society, the efficacy of the vaccine, balanced against many short and long terms risks associated with COVID-19 infection (which include cardiovascular side effects10Xie Y. Xu E. Bowe B. Al-Aly Z. Long-term cardiovascular outcomes of COVID-19.Nat Med. 2022; 28: 583-590Crossref PubMed Scopus (629) Google Scholar), and the various side effects of each vaccine beyond carditis alone. Study design: RRL, JS, KR Drafting of manuscript: RRL, JS, KR Critical revision of manuscript for intellectually important content: RRL, JS, KR All authors provided critical conceptual input, read, and approved the final draft. KR was responsible for the decision to submit the manuscript. Not applicable. Not applicable. Not applicable. We declare no competing interests. Not applicable. Funding: There was no funding source for this study. Risk of carditis after three doses of vaccination with mRNA (BNT162b2) or inactivated (CoronaVac) covid-19 vaccination: a self-controlled cases series and a case–control studyLarge-scale comparative research exploring the risk after the third dose and after inactivated covid-19 vaccination is limited. This study aimed to assess the risk of carditis following three doses of BNT162b2 or CoronaVac. Full-Text PDF Open Access