Ocular manifestations after COVID-19 vaccination | Journal of Ophthalmic Inflammation and Infection

Vaccines are produced to protect against SARS-CoV-2, the virus that causes COVID-19. While vaccines can induce large numbers of high-affinity virus-neutralizing antibodies to prevent infection, they are not immune to adverse side effects. Vaccine trials require detailed clinical management, supported by precise assessment of immune response and safety. Since the introduction of COVID-19 vaccines, there have been numerous reports of adverse ocular events following vaccination. Here, we review the ocular inflammatory manifestations of different vaccines in patients with new and recurrent ocular inflammation after vaccination with SARS-CoV. 2.

Possible pathological mechanisms causing autoimmune responses in patients with SARS-CoV-2 infection include molecular mimicry, bystander activation, epitope spreading, cryptic antigen presentation, B cell polyclonal activation and the presence of superantigens that have been implicated as autoimmune responses. Possible pathological mechanisms behind SARS-CoV-2 infection in patients (6, 7). In our case, any of these mechanisms could have contributed to the recurrence of inflammation.

uveitis and Other ocular inflammatory events – rubella (MMR), yellow fever, and typhoid (8, 9, 10, 11, 12, 13, 14, 15). Additionally, various ocular adverse events have been reported following COVID-19 vaccination.

Although the exact pathogenesis often remains unclear, different mechanisms have been postulated, including changes in the adaptive and innate immune systems. Both branches of the immune system may be affected by adjuvants through various mechanisms, including activation.

Toll-like receptors, nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), etc., lead downstream of cytokine production. In addition, upon activation of antigen-presenting cells, an enhanced adaptive immune response to the antigen can occur (16, 17, 18). Other mechanisms include direct infection with attenuated but active viral strains and inflammation induced by one or more adjuvants (e.g., aluminum salts), typically used in inactivated or subunit/conjugate vaccines (16, 19). Patients with a personal or medical history of autoimmune disease may develop adjuvant-induced autoinflammatory or autoimmune disease known as Shoenfeld syndrome. (16, 20).

Testi et al. reported a multinational case series that included 70 patients from 40 centers over a 3-month period who were diagnosed with inflammatory adverse events after COVID-19 vaccination (21). They found that the mean age was 51 years (range 19-84 years). The most common event was anterior uveitis (58.6%), followed by posterior uveitis (12.9%), with the average time to occurrence of adverse events being 5 days after the first vaccination and 6 days after the second vaccination.

Rabinovich et al. described 21 cases of uveitis following administration of the BNT162b2 mRNA vaccine in Israel, of which 19 (90.5%) were diagnosed as anterior uveitis (22). Peach et al. Seven reported patients were diagnosed with acute macular neuroretinopathy (AMN) (2), paracentral acute neutrophilic macular degeneration (PAMM) (1), subretinal fluid (1), and superficial macular degeneration shortly after receiving an inactivating dose. Scleritis (1) and anterior scleritis (2) COVID-19 vaccination (Sinopharm) (23).

Boletta E et al. Thirty-four patients have been reported to have developed uveitis and other eye complications after receiving the COVID-19 vaccine. The mean age was 49.8 years (range 18-83 years). The mean time between vaccination and development of ocular complications was 9.4 days (range 1-30 days) (24). Pang et al. reported 9 cases of 12 eyes with ocular adverse events after vaccination with an inactivated COVID-19 vaccine, although causality 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% of cases being female. The mean duration of ocular adverse events after receiving the inactivated COVID-19 vaccine was 7.1 days (range, 1-14 days). They described patients with choroiditis with sunset fundus optic disc vasculitis, keratitis, scleritis, acute retinal necrosis, and anterior uveitis ( 25 ).

Studies report that ocular inflammation occurs after most vaccines around the world, including Pfizer-BioNTech vaccine (BNT162b2 mRNA), Oxford-AstraZeneca vaccine (ChAdOx1 nCoV-19) (similar to Covishield in India), ModernaTX vaccine ( mRNA-1273) and the Janssen & Johnson vaccine (Ad26.COV2) (25). Due to the biased geographical distribution of vaccinations, it is difficult to comment on the relative immunogenicity and safety of different vaccines. However, a prospective study of systemic and local side effects following BNT162b2 and ChAdOx1 nCoV-19 vaccination using an application in the United Kingdom showed that their frequency was lower than reported in phase 3 trials (26).

Episcleritis and scleritis have also been reported in patients an average of 5 days after the first dose of the inactivated COVID-19 vaccine (Sinopharm) (24, 25). Renici et al. Cases of anterior uveitis occurring 14 days after the second dose of the Pfizer-BioNTech COVID-19 vaccine have been reported (27). An 18-year-old female with a history of antinuclear antibody (ANA)-positive oligoarticular juvenile idiopathic arthritis (JIA) was reported to develop bilateral anterior uveitis 5 days after the second dose of BBIBP-CorV (28) . We also have a 19-year-old patient who previously had JIA-associated uveitis but relapsed after two doses of vaccine. Increased IFN-I secretion in vaccine-induced immune responses may produce autoimmune manifestations in patients with a history of systemic autoimmune disease, which has been a hypothesis proposed in such cases (24,28,29) .

Vaccines can cause reactivation of varicella zoster virus (VZV), which has been previously described in patients receiving rabies, hepatitis A, influenza, and Japanese encephalitis vaccines (30). Several cases have been reported in the literature describing VZV reactivation after vaccination with mRNA COVID-19 vaccines, including cases of herpes zoster ophthalmicus (HZO) (31, 32, 33, 34). We report a case of acute retinal necrosis due to VZV reactivation in a 71-year-old man after vaccination with the COVISHIELD vaccine (35).

Although unclear, the proposed hypothesis is that the immune system is stimulated to induce a strong T-cell response following vaccination. This may result in an increased CD8 + T cell and type 1 helper T cell CD4 + T cell population with a relatively low VZV-specific CD8 + cell population, which further allows VZV to escape its latency. The loss of TLR expression in vaccinated individuals is another possible explanation, which is associated with the significant induction of type I interferon (IFN-I) and the enhancement of proinflammatory cytokines. This may negatively regulate antigen expression and may lead to VZV reactivation (33). Boletta E et al. reported two cases of reactivation of herpetic keratitis despite systemic antiviral therapy in patients with a previous history of herpetic keratitis (24). There is also speculation that antiviral therapy has a preventive effect in patients with a past history of herpes (34).

It has been described that recurrence of Toxoplasma retinochoritis is due to vaccination-induced CD8 T cell depletion, possibly leading to parasite reactivation (25, 36), however, there were no cases of toxoplasmosis in our study. Arora A et al. Two patients were described who experienced recurrence of tuberculous choroiditis 2-6 weeks after the first dose of Covishield vaccine. Since both patients experienced unilateral recurrence, they were treated with intravitreal dexamethasone (0.7 mg) (Ozurdex®, Allergan, Inc., Irvine, CA, USA) (37). We had three patients with tuberculous uveitis, one with new-onset intermediate uveitis, one with new-onset prostrate choroiditis, and recurrent scleritis.

In our study, we found the majority of HLA B27-associated uveitis (60%) among non-infectious uveitis cases. Relapse of previously quiescent inflammation occurred in 100% of all patients. Other authors have similarly reported vaccine-induced inflammation in HLA B27-positive cases (21, 24). Fuller V et al. The mRNA BNTb262 vaccine has been reported to be immunogenic in most patients with autoimmune inflammatory rheumatic diseases. Factors leading to reduced immunogenicity include those associated with treatment with glucocorticoids, rituximab, MMF, and abatacept (38).

Other autoimmune pathologies included reactivation of inflammation in 6 patients with sarcoidosis and 1 patient with VKH. However, 3 patients had their first episode of VKH during the study period. Dysregulation of the immune system and other immune mechanisms may play an important role in the association between VKH disease and COVID-19 vaccination (39,40,41).

Papasavas I. and Herbert CP. A case of VKH disease was also reported that was completely controlled within 6 years with maintenance infliximab therapy but was reactivated 6 weeks after the second dose of the Pfizer vaccine (42). Saraceno JJF et al described the case of a 62-year-old healthy woman who developed full Vogt-Koyanagi-Harada (VKH) syndrome 4 days after vaccination with ChAdOx1 nCoV-19 (AZD1222) vaccine (43). Exacerbations of VKH disease have also been reported following Covid-19 vaccination, with a close temporal relationship between vaccine dose and symptom exacerbation strongly suggesting that COVID-19 vaccination is a trigger for exacerbation (44).

Regarding thrombosis after vaccination, central retinal vein occlusion, branch retinal vein occlusion, and superior ophthalmic vein thrombosis have been reported (24,45,46,47,48). In addition to major vessel occlusions, capillary plexus occlusions have also been reported, including cases of AMN following Covid-19 vaccination (49,50,51,52) . Likewise, Bohler AD et al. A case of AMN was reported in a young woman who was taking an estrogen-progestin combined oral contraceptive pill 2 days after vaccination with ChAdOx1 nCoV-19 vaccine (44). We also report here a 25-year-old female patient who developed bilateral sequential AMN after two doses of vaccine (53).

A recently reported retrospective study evaluated the risk of vaccine-associated uveitis (VAU) following SARS-CoV-2 vaccination in 1094 cases from 40 countries (54). They found that most cases were reported in patients who received the Pfizer-BioNTech vaccine. The mean age of VAU patients was 46.24±16.93 years, the majority were female (68.65%), and most cases were reported after the first dose of vaccine (41.32%) and within the first week after vaccination (54.02%).

The main limitation of this study is its retrospective design. Other limitations include the relatively small number of cases, single tertiary referral center bias, and limited study period. There is growing evidence in the literature of ocular complications following COVID-19 vaccination, but a clear association is difficult to prove.

Inflammatory ocular manifestations of the anterior and posterior segments may occur after COVID-19 vaccination. Given the increasing number of COVID-19 vaccinations and the onset of use of booster vaccines, it is likely that an increasing number of adverse effects of ocular inflammation will be seen with the various available vaccines. Even if a causal relationship remains presumed, physicians must be cautious about possible ocular inflammation following SARS-CoV-2 vaccination.