Appendicitis has been reported as a potential adverse event after immunization with mRNA-based COVID-19 vaccines, based on trial data,1 adverse event report data,2 and observational data.3 We evaluated the risk of appendicitis after receiving an mRNA COVID-19 vaccination and after diagnosis of SARS-CoV-2 infection compared with the risk of appendicitis in unvaccinated individuals.
In this cohort study, we used Danish nationwide registers to identify recipients of the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine and all individuals aged 12 years and older with SARS-CoV-2 confirmed by polymerase chain reaction (PCR) test from December 27, 2020, to November 30, 2021. For comparison, we analyzed an unvaccinated reference group of Danish individuals aged 12 years and older tested for SARS-CoV-2 infection (89% of Danish population aged 12 years and older) until November 30, 2021, by assigning each individual a random index date between January 1 and June 30, 2021. Weighting was then applied to adjust for potential confounders. By law, registry-based studies are exempt from ethical review and informed consent in Denmark. The study followed the STROBE reporting guideline.
We excluded individuals with a previous appendicitis or appendectomy, individuals immunized with non-mRNA COVID-19 vaccines, and individuals with PCR-confirmed SARS-CoV-2 before study inclusion.
The main exposures were first doses of the BNT162b2 or mRNA-1273 vaccine, which were evaluated as a combined exposure and separately for each vaccine. We evaluated the risk of study outcomes after the second vaccine dose or SARS-CoV-2 infection. The main outcome was a composite of a first-ever hospital contact with an appendicitis or appendectomy diagnosis code. Individuals were followed up for 21 days after inclusion (entry date included) and were censored at the end of the follow-up period, occurrence of the outcome, death, or SARS-CoV-2 infection. Individuals in the unvaccinated and SARS-CoV-2 infected groups were further censored if immunized against COVID-19 during follow-up.
We constructed cumulative incidence curves and obtained risk ratios and risk differences (per 100 000 individuals). Estimates were adjusted for age, sex, municipality, immigration status, history of inflammatory bowel disease, diabetes, and the number of antibiotic prescription fills during the past 2 years using propensity score–derived standardized morbidity ratio weights.
Among 4 048 883 individuals immunized with mRNA COVID-19 vaccines, 330 episodes of appendicitis occurred within 21 days of the first dose, corresponding with 8.1 episodes per 100 000 individuals vaccinated (Figure). The rate after the second dose was 8.6 per 100 000 individuals (340 cases among 3 944 408 individuals). Compared with the unvaccinated reference group, we found no increased risk of appendicitis after mRNA COVID-19 vaccination, with an adjusted risk ratio of 0.93 (95% CI, 0.79-1.11) after the first dose and 0.99 (95% CI, 0.84-1.18) after the second dose. This null association was stable across age groups, sexes, and vaccine types (Table). In analyses of the risk of appendicitis after SARS-CoV-2 infection vs the unvaccinated reference group, the adjusted risk ratio was 1.25 (95% CI, 0.79-1.99).
In this nationwide study comprising 4 million vaccinated individuals, we found no association between immunization with mRNA-based COVID-19 vaccines and appendicitis. The safety signal was raised when BNT162b2 vaccine trials showed higher numbers of appendicitis cases in vaccinated than placebo groups; the US Food and Drug Administration then listed appendicitis as an adverse effect of special interest.1,4 This suspicion was backed by disproportional reporting of adverse events2 and an Israeli cohort study estimating an excess risk of appendicitis of 5.0 episodes per 100 000 individuals after vaccination.3 However, an interim analysis of US surveillance data found no association.5 Limitations of the study include the nonrandomized observational design, accuracy of register-based identification of appendicitis,6 and inability to detect possible risks beyond the predefined risk interval. Further studies from different settings will be needed to fully eliminate appendicitis as an mRNA COVID-19 vaccination safety concern.
Accepted for Publication: March 6, 2022.
Published Online: April 25, 2022. doi:10.1001/jamainternmed.2022.1222
Corresponding Author: Helene Kildegaard, MD, Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 19/2, DK-5000 Odense C (hckildegaard@health.sdu.dk).
Author Contributions: Dr Kildegaard and Mr Pottegård had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Kildegaard, Rasmussen, Pottegård.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Kildegaard.
Critical revision of the manuscript for important intellectual content: Ladebo, Andersen, Jensen, Rasmussen, Damkier, Pottegård.
Statistical analysis: Kildegaard, Andersen, Jensen.
Obtained funding: Pottegård.
Administrative, technical, or material support: Ladebo.
Supervision: Pottegård.
Conflict of Interest Disclosures: Ms Rasmussen reported receiving support through the University of Southern Denmark from Novo Nordisk outside the submitted work. Mr Pottegård reported receiving grants from Alcon, Almirall, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Servier, and LEO Pharma outside the submitted work. No other disclosures were reported.
Additional Contributions: We thank Lars Christian Lund, MD, and Jesper Hallas, MD, from the University of Southern Denmark for valuable input into the methods used in this work. They were not compensated for their contributions.