Ocular Complications Following COVID-19 Vaccination – Coincidence, Correlation, or Causation?

As of September 2022, the World Health Organization (WHO) had collected over 600 million confirmed cases of coronavirus disease 2019 (COVID-19) that resulted collectively in roughly 6.5 million deaths worldwide. More than two-thirds of the world’s population, or about 5.4 billion people, have received at least one COVID-19 immunization since the introduction of the first mRNA-based vaccines in December 2020. Remarkably, the first effective COVID-19 vaccines were available for widespread use less than 9 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was declared to be pandemic in March of that same year. Such unprecedentedly rapid development and delivery of what are now more than two dozen SARS-CoV-2-targeted vaccines has reduced COVID-19-related morbidity and mortality dramatically – an amazing achievement for biomedical research, the pharmaceutical industry, and international regulatory authorities. While the benefits of commercially available vaccines are clear, targeted activation of the immune system to help prevent severe infectious diseases and their complications is not without risks. Mild, yet manageable, side-effects of vaccination are well-recognized, including localized injection site reactions and constitutional signs and symptoms such as headache, fatigue, fever, chills, arthralgias, myalgias, and rashes. Ocular complications, including uveitis, can occur within days to weeks of immunization as well, and such events have been reported following COVID-19 vaccination with varying levels of evidence. Whether such descriptions represent coincidence or chance, correlation—which is best thought of as a mathematical or statistical association yet to be demonstrated to be causal, or true causation remains unclear in the vast majority of cases. Many have proposed, and we support, the use of the Naranjo approach for assessing suspected associations between the administration of a given therapeutic agent or vaccine and suspected adverse reactions, wherein the greatest weight is given to elimination of alternate causes or risk factors for each complication or adverse event, close temporal association, and, most notably, recurrence on rechallenge (Table 1). This issue of Ocular Immunology and Inflammation (OII) contains 20 additional reports of ocular complications following administration of one or more COVID-19 vaccine doses. Ferrand et al. retrospectively reviewed 25 subjects who developed uveitis following COVID-19 vaccination at one of four tertiary referral centers in Germany (n = 14), Italy (n = 8), or India (n = 3) between February and July 2021. Most patients (n = 19; 76.0%) received two immunizations, and among the total 44 delivered doses 30 were Pfizer/BioNTech (BNT162b2 mRNA), five were Moderna (mRNA-1273), seven were AstraZeneca (ChAdOx1 nCoV-19), and two were Bharat Biotech (Covaxin; BBV-152). Patient age ranged from 20 to 72 years (mean 43.2 years), 19 of the 25 subjects (76.0%) were female, and the time from vaccination to onset of uveitis ranged from 6 hours to 27 days (mean 10.7 days; median 12 days). Nineteen patients (76.0%) had a prior history of uveitis. Presentations included anterior uveitis in 14 (56.0%; four of which were bilateral, three of which were due to recurrent, unilateral herpes simplex-associated keratouveitis, and two of which had unilateral granulomatous features), intermediate uveitis in three (12%; one bilateral), posterior uveitis in four (16.0%; all bilateral), and panuveitis in one (4%; recurrence of prior Vogt-Koyanagi-Harada disease). While the likelihood of causality was graded using the aforementioned Naranjo algorithm, wherein a grade of 1 to 4 reflects a possible association, 5–8 a probable, and 9 or greater is definite (Table 1), the authors did not indicate specifically which components of the algorithm lead them to categorize 16 cases (64.0%) as possible and 9 (36.0%) as probable. Uveitis occurred after the first immunization in 21 patients (84.0%), after the second in two (8.0%) and after both in two (8%). These last two patients, each of whom received serial AstraZeneca vaccines, provide perhaps the strongest evidence for causality. Both had a history of anterior uveitis and developed similarly localized inflammation following immunization. Of note, however, none of the 17 other subjects who received two immunizations and who developed uveitis following the first dose were noted to develop uveitis after a second immunization. All patients responded well to traditional therapy, leading the authors to conclude that the benefits of COVID-19 vaccination far outweigh the risks of either recurrent or de novo uveitis. Nanji and Fraunfelder described two patients reported to the National Registry for Drug-Induced Ocular Side Effects who were found to have evidence of anterior uveitis 3 weeks and 3 days, respectively, after their first dose of the Moderna vaccine. The first patient, who had a history of bilateral anterior uveitis following hepatitis B vaccination, was found to have new posterior synechiae formation in her left eye at the threeweek visit, but showed no signs of keratic precipitates or anterior chamber cell or flare and so received no treatment. The second patient, who was found to have mild unilateral anterior uveitis with fibrin and posterior synechiae formation 3 days after immunization, responded promptly to local therapy. The authors identified an additional 59 cases of anterior uveitis in the WHO global database collected from over 140 member countries, including the United States. This cohort ranged in age from 24 to 88 years, 80% were female, and the time from vaccination to onset of symptoms ranged from 0 to 31 days, OCULAR IMMUNOLOGY AND INFLAMMATION 2022, VOL. 30, NO. 5, 1031–1034 https://doi.org/10.1080/09273948.2022. 2125763