Ocular manifestations following COVID-19 vaccination

Background Immunologic and inflammatory adverse effects following vaccination against COVID-19 are being reported. While some reactions may develop denovo others concern its immunogenic effect in patients with pre-existing inflammatory conditions. Methods Retrospective consecutive patients diagnosed with ocular inflammatory manifestations within 8 weeks of receiving COVID-19 vaccination who presented to a tertiary eye care centre in South India. Results Ninety-eight eyes of 67 patients presenting with ocular inflammatory manifestations within 8 weeks following COVID-19 vaccination were studied. The mean age was 43 years (+/- 14.82; range 19–80 years). The most common presentations were anterior uveitis (n = 31, 31.7%), followed by panuveitis (n = 24, 24.5%). The mean time to onset of symptoms was 25 days (+/- 15.48; range 2–55 days) following a dose of vaccine. Among all patients, 39 (58.2%) had a previous history of ocular inflammation. Mean presenting visual acuity was 0.4 (0-4) logMAR units and mean final visual acuity was 0.2 (0-4) logMAR units. The causes for reduced vision included of cystoid macular edema (n=2, 2%), chorioretinal atrophy (n=2.2%), optic atrophy (n=1.1%), retinal vascular occlusion (n=1.1%) and acute retinal necrosis (n=1.1%). Conclusion Infective and immunogenic adverse events should be watched out for after COVID-19 vaccination. It is difficult to establish causality for such manifestations, nevertheless, most of them were mild and had good final visual outcomes. Supplementary Information The online version contains supplementary material available at 10.1186/s12348-023-00358-x.


Introduction
Anti-SARS CoV-2 (Severe acute respiratory syndrome coronavirus 2) vaccination has played a vital role in the control of the COVID-19 (Coronavirus disease 2019) pandemic.As of 26 February 2022, a total of 10,585,766,316 vaccine doses have been administered across the world [1].Similar to previous several other vaccines, COVID-19 vaccinations have not been without adverse effects, most of which have been reported largely from post-marketing surveillance phases [2].Hence it is critical to report any adverse effects occurring after vaccination for improving our understanding of not only de novo reactions but also its effects on previously existing illness such as autoimmune as well as infectious diseases.
Various vaccine models have been approved and each type of vaccine for COVID-19 works differently to introduce antigens, which are unique features of the SARS-CoV-2 virus, into the human body.These antigens trigger a specific immune response which ultimately is responsible for building immune memory and helps the body counter SARS-CoV-2 infections in the future.Currently, four types of COVID-19 vaccines are available, including the vector vaccines (Janssen Johnson & Johnson and Oxford-AstraZeneca, COVISHIELD ™ , SputnikV); the whole virus vaccines (Sinovac13, Sinop-harm14 and Covaxin); the messenger RNA (mRNA) vaccines (Pfizer-BioNTech and Moderna); and the protein subunit vaccines (Novavax, corbevax).Covovax SARS-CoV-2 rS Protein (COVID-19) recombinant spike protein Nanoparticle Vaccine.Inflammatory adverse events, including pericarditis, myocarditis and multisystem inflammatory syndrome, have been reported to occur following COVID-19 vaccination [3][4][5].The objective of this study is to describe the various ocular inflammatory manifestations associated with the administration of COVID-19 vaccination in an Indian population.

Methods
Retrospective case series of patients diagnosed with ocular inflammatory manifestations after receiving COVID-19 vaccination were collected from hospital medical records in the uveitis and ocular immunology department in a tertiary care referral eye hospital in South India over a 3-month period in 2021.The study was conducted with institutional ethical committee approval.A diagnosis of COVID-19 vaccination triggered ocular inflammation was established based on the onset of the symptoms within 8 weeks following COVID-19 vaccination.
The following data were retrieved from patients' medical records: age, gender, laterality, type of COVID-19 vaccination, doses of vaccination, time to onset of symptoms, past ocular history, type of ocular inflammatory manifestation (anatomical diagnosis) including anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, episcleritis, scleritis, sclerouveitis, sclerokeratouveitis, and keratouveitis, etiological diagnosis, treatment and outcome.Statistical data were analyzed using Excel and SSPS statistical program.Continuous variables were described as mean [range] while binary variables were described as numbers (%).A minimum follow-up for a period of 3 months was recorded in all patients.The study and data collection were conducted following the approval by the Institutional review board and ethics committee.

Results
Ninety-eight eyes of 67 patients presented with ocular inflammatory manifestations within 8 weeks following COVID-19 vaccination.Demographic distribution and vaccination data are described with details of ocular manifestations with anatomical diagnosis in   A large majority of patients, 56 cases (83.6%), had received one or more doses of COVISHIELD ™ vaccine.Among the remaining 11 patients, 9 had received Covaxin, while Sputnik and Pfizer vaccines had been administered to one patient each.The mean time to onset of symptoms following vaccination was 25 days (+/-15.48;range 2-55 days).Ocular inflammation was reported after the first dose of vaccination in 31 (55.2%)cases and after the second dose in 28 (41.8%)cases.Only 2 (3%) patients had developed symptoms after both doses of vaccination.
De novo inflammation was noted in 28 (41.7%)patients while 39 (58.2%) patients with a formerly diagnosed uveitis, had a recurrence of previously quiescent inflammation post vaccination.Among patients with first episode of ocular inflammation following COVID-19 (28 cases, 41.7%), infectious etiology comprised 10 cases (35%) cases of which viral disease was noted in 8 cases (80%) and tuberculosis in 2 cases (20%).First episode of autoimmune disease associated ocular inflammation was seen in only 3 cases of Vogt Koyanagi Harada disease.Among patients with recurrence of previously quiescent inflammation (39 cases, 58.2%), autoimmune disease association was noted in 20 cases (51.3%).HLA B27 associated  and one case of recurrence of tubercular uveitis was seen.Mean presenting visual acuity was 0.4 (0-4) logMAR units and mean final visual acuity was 0.2 (0-4) logMAR units.The causes for reduced vision included of cystoid macular edema, chorioretinal atrophy, optic atrophy, retinal vascular occlusion, retinoschisis, retinal detachment and acute retinal necrosis.

Discussion
Vaccines were manufactured to protect from SARS-CoV-2, the virus causing COVID-19.While vaccines can induce large quantities of high affinity virus-neutralizing antibodies to prevent infection, they haven't been able to avoid untoward side effects.Vaccination trials required detailed clinical management, complemented with precise evaluation of immune responses and safety.Since the introduction of COVID-19 vaccinations, there have been numerous reports on the adverse ocular events following vaccination Here, we reviewed the ocular inflammatory manifestations of different vaccines in patients who presented with de novo and recurrent ocular inflammation following vaccination against SARS-CoV-2.
Possible pathological mechanisms responsible for autoimmune responses in SARS-CoV-2 infected patients include molecular mimicry, bystander activation, epitope spreading, cryptic antigen presentation, B-cell polyclonal activation and the existence of the superantigens have been suggested as possible pathological mechanisms behind autoimmune responses in SARS-CoV-2 infected patients [6,7].Either of these mechanisms might have resulted in recurrence of inflammation in our cases.
Although the precise pathogenesis frequently remains unclear, different mechanisms have been hypothesized including changes in adaptive and innate immune system.Both arms of the immune system may be influenced by adjuvants via various mechanisms including the activation of.
Toll-like receptors, Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) etc., leading to downstream in cytokines generation.Moreover, the heightened adaptive immune response to antigen can occur following the activation of antigen presenting cells [16][17][18].Other mechanisms include the direct infection by the attenuated but active virus strain and inflammation induced by one or more adjuvants (such as aluminum salts), routinely used in inactivated or subunit/ conjugate vaccines [16,19].Patients with a personal or history of autoimmune disease may develop auto-inflammation or autoimmune conditions induced by adjuvants, known as Shoenfeld syndrome.[16,20].
Testi I et al. reported a multinational case series of 70 patients diagnosed with inflammatory adverse events following COVID-19 vaccination from 40 centres over a 3-month period [21].They found the mean age as 51 years (range 19-84 years).Most common events noted were anterior uveitis (58.6%) followed by posterior uveitis 12.9% and the mean time to adverse event was 5 days after the first vaccine and 6 days following the second dose of vaccine.
Bolletta E et al. reported 34 patients with uveitis and other ocular complications following COVID-19 vaccination.With a mean age of 49.8 years (range 18-83 years).Mean time between vaccination and the onset of ocular complication was 9.4 days (range 1-30 days) [24].Pang et al. reported 12 eyes of 9 cases of ocular adverse events following administration of inactivated COVID-19 vaccines, although the causal relationship could not be established in the study [25].The mean (SD) age was 44.7 ± 16.5 years (range, 19-78 years), with 77.8% female cases.The mean time of ocular adverse events was 7.1 days (range, 1-14 days) after receiving the inactivated COVID-19 vaccine.They described patients with choroiditis, optic disc vasculitis with sunset glow fundus, keratitis, scleritis, acute retinal necrosis and anterior uveitis [25].
Studies have reported ocular inflammation following most of the vaccines administered worldwide including Pfizer-BioNTech vaccination (BNT162b2 mRNA), Oxford-AstraZeneca vaccine (ChAdOx1 nCoV-19) which is similar to Covishield available in India, ModernaTX vaccination (mRNA-1273), and Janssen Johnson & Johnson vaccine (Ad26.COV2) [25].It is difficult comment on the comparative immunogenicity and safety of different vaccines due to the geographical distribution bias of vaccinations administered.Nevertheless, systemic and local side-effects after BNT162b2 and ChAdOx1 nCoV-19 vaccination that were studied prospectively using an app in the UK showed that the frequencies were lower than reported in phase 3 trials [26].
Episcleritis and scleritis have also been reported in patients within a mean of 5 days following the first dose of the inactivated COVID-19 vaccine (Sinopharm) [24,25].Renisi et al. reported a case of anterior uveitis 14 days after the second dose of Pfizer-BioNTech COVID-19 vaccine [27].One case of a 18-year-old female with a history of antinuclear antibody (ANA) positive oligoarticular juvenile idiopathic arthritis (JIA) developing bilateral anterior uveitis 5 days after the second dose of BBIBP-CorV has been reported [28].We also had a 19-year old patient with previously quiescent inflammation with JIA associated uveitis that recurred following both doses of vaccination.Increased IFN-I secretion by vaccine-induced immunological responses could potentially generate autoimmune manifestations in patients with a history of systemic autoimmunity disease has been the proposed hypothesis in such cases [24,28,29].
Vaccines can result in the reactivation of varicella zoster virus (VZV), has been previously described in patients receiving vaccines for rabies, hepatitis A, influenza, and Japanese encephalitis [30].There are cases reported in the literature describing VZV reactivation after vaccination with the mRNA COVID-19 vaccine, including cases with herpes zoster ophthalmicus (HZO) [31][32][33][34].We have reported a case of acute retinal necrosis in a 71 year male following COVISHIELD vaccination due to VZV reactivation [35].
Although unclear, the proposed hypothesis of stimulation of the immune system that induces a strong T-cell response following vaccination.This can lead to an increased CD8 + T cell and T helper type 1 CD4 + T cell population with relatively low VZV-specific CD8 + cells, that further allows VZV to escape its latent phase.Abrogation in TLR expression among vaccinated individuals is another possible explanation that has been linked with marked induction of type I interferon (IFN-I) and potentiation of pro-inflammatory cytokines.This may negatively modulate antigen expression and potentially contribute to VZV reactivation [33].Bolletta E et al. reported two cases of herpes keratitis reactivation in patients with a history of previous herpetic keratouveitis although under systemic antiviral treatment [24].There has also been a speculation regarding the preventive role of antiviral treatment in patients with prior history of herpes [34].
Recurrence of Toxoplasma retinochoroiditis have been described due to vaccination-induced CD8 T-cell exhaustion that may lead to parasite reactivation [25,36], however, we did not have any cases of toxoplasmosis in our study.Arora A et al. described two patients with recurrence of tubercular choroiditis 2-6 weeks following the first dose of Covishield vaccine.As both their patients had unilateral recurrence, they were managed with intravitreal injection dexamethasone (0.7 mg) (Ozurdex ® , Allergan, Inc., Irvine, CA, USA) [37].We had three patients with tubercular uveitis, one each with de novo intermediate uveitis, de novo serpiginous like choroiditis and recurrence of sclerouveitis.
We found a majority of HLA B27 related uveitis (60%) among the non-infective uveitis cases in our study.All 100% of these patients had developed a recurrence of their previous quiescent inflammation.There have been similar reports of vaccine triggered inflammation in HLA B27 positive cases by other authors [21,24].Furer V et al. reported mRNA BNTb262 vaccine as immunogenic in majority of patients with autoimmune inflammatory rheumatic diseases.Factors responsible for reduced immunogenicity included those on treatment with glucocorticoids, rituximab, MMF, and abatacept [38].
Other autoimmune pathologies included reactivation of inflammation in 6 patients with sarcoidosis and one patient with VKH.However, there were 3 patients with first episode of VKH within the study period.Dysregulation of the immune system and other immunological mechanisms may play a significant role in the association between VKH disease and COVID-19 vaccination [39][40][41].
Papasavvas I. and Herbort CP. also have reported a case of VKH disease which was completely under control for 6 years and on infliximab maintenance therapy that was reactivated 6 weeks after the second dose of the Pfizer vaccine administration [42].Saraceno JJF et described a case of a 62-year-old healthy female who developed complete Vogt-Koyanagi-Harada (VKH) Syndrome 4 days after a dose of ChAdOx1 nCoV-19 (AZD1222) vaccine [43].There have also been reports of exaggeration of VKH disease following Covid-19 vaccination where the close temporal relationship between the vaccine dose and the worsening of symptoms strongly suggested COVID-19 vaccination as the trigger of its exacerbation [44].
A recently reported retrospective study assessed the risk of vaccine associated uveitis (VAU) following SARS-CoV-2 vaccination in 1094 cases from 40 countries [54].They found most cases were reported in patients who received Pfizer-BioNTech vaccine.The mean age of patients with VAU was 46.24 ± 16.93 years, and majority were women (68.65%)Most cases were reported after the first dose (41.32%) and within the first week (54.02%) of the vaccination.
The major limitation of this study was its retrospective design.Other limitations include a relatively low number of cases, single tertiary referral centre bias and a limited period study.There is growing evidence in literature about the ocular complications following COVID-19 vaccination, although a definitive association has been difficult to demonstrate.
Inflammatory ocular manifestation in the anterior and posterior segments may be seen in following COVID-19 vaccine.Considering the growing number of COVID-19 vaccinations and the commencement of booster vaccines, increasing number of ocular inflammatory adverse effects may be seen from the various available vaccines.Even if causality remains presumed, caution must be warranted among physicians about the possibility of ocular inflammation following SARS-CoV-2 vaccination.

Conclusion
Improved reporting and enhanced understanding of mechanisms responsible for post-vaccination ocular inflammation can help in well-designed vaccination strategies.These are critical for establishing better guidelines and providing insights to limit harm while promoting assurance especially when a large population including pediatric age-group are yet to receive their vaccines.Nevertheless, we still consider vaccination as a vital public health tool in the containment of the COVID-19 pandemic.

Case no. Age Gender Vaccine Dose Days Eye Anatomical diagnosis Etiological diagnosis Occurance Presenting va Final va
Table providing information about all patients, type of vaccines, ocular manifestations disease was noted in 12 cases (60%), sarcoidosis in 6 cases (30%), JIA-related uveitis and VKH disease in 1 case each.Recurrence of old viral uveitis was seen in 6 cases(22.2%)