Discussion
In this report, we present a case of scleritis after the third dose of COVID-19 vaccination with inactivated Sinopharm vaccine. Recently, Pichi and colleagues reported four cases of scleritis and episcleritis following the first dose of COVID-19 Sinopharm vaccination (8). There also has been few reports of mild scleritis or episcleritis caused by live virus vaccination previously (9-12).
Scleritis is a severe inflammatory eye disease, which may present unilaterally or bilaterally, and is differentiated into posterior and anterior involvement with diffuse, nodular, and necrotizing forms. The inflammation may be idiopathic or secondary to infections, malignancies, autoimmune diseases responsible for at least 50% of cases, vasculopathies, trauma, or surgically induced, and medication side effects (13). In this case, we firstly investigated the patient for a possible rheumatologic underlying cause. She did not have any history of skeletal involvement, furthermore, all the laboratory tests were within normal limits. Besides, she did not have signs and symptoms related to infectious disease or B symptoms related to malignancies. After ruling out all the possible causes, she was diagnosed with COVID-19 vaccination-induced scleritis. Testi et al. reported different ocular complications of COVID-19 vaccination (14). In another report, none out of 7 patients (10%) with scleritis were vaccinated with Sinopharm. Moreover, to our knowledge, all the reports underlined that the first scleritis manifestations initiated after the first and second dose. Pichie et al. reported an anterior scleritis after the first dose of COVID-19 inactivated vaccination in a patient with history of rheumatoid arthritis, well controlled with topical steroid after a week (8). Similar to our case, the participant had no other involvements in slit lamp examination; however, the vaccine complication was induced after the first dose. There are handful reports of anterior scleritis after Sinopharm injection, let alone after the booster dose with no previous complications (9-12, 15-17). Further investigations should clarify whether booster doses could induce more new additional immune reactions.
Although various reports of ocular adverse events developed after COVID-19 vaccination, the pathogenesis and mechanism of this immune response, remains the question. There have been certain studies demonstrating an association between COVID-19 vaccination and an increased risk of autoimmune diseases or related adverse reactions, such as autoimmune hepatitis, autoimmune glomerulitis, autoimmune rheumatism, and autoimmune scleritis (18-20). The most frequently proposed mechanism include molecular mimicry between scleral and vaccine peptides as well as hypersensitivity due to antigen-specific cell and antibody reactions (21). Through cross-reactivity, the immune system falsely targets human proteins which trigger autoimmune reactions (22). Kanduc et al., also showed same heptapeptides between the SARS-CoV-2 Spike glycoprotein and human proteins (23). Moreover, although safe in most of the population, vaccine adjuvants that were added to achieve the desired protection, led to autoinflammatory syndromes particularly connective tissue disorders due to different nucleic acid metabolism (24). Adjuvants could mimic Toll-like receptor (TLR) ligands, and stimulate immune responses (25). The addition of alum as an adjuvant also aggravated immunopathologic reactions (26). Noteworthy, inactivated COVID-19 vaccines stimulate T helper 2 cell reactions causing inflammation. In vaccines with adjuvants, T cells could be activated through bystander pathways. The auto-reactivated immune cells, migrate to inflammation site, produce cytokines and induce autoimmunity (6). We recommend that further longitudinal large population studies investigate risk factors of post COVID-19 vaccination autoimmune reactions, to elucidate the need for further restrictions in patients with autoimmune disease or even high-risk healthy population.
The genes for immunity, inflammation, and coagulation are part of X chromosome, so we may suspect that viral interactions associated with human genes could induce an abnormal immune response in COVID-19. Besides, according to Manzo et al., the presence of excess antigen and the formation of relatively resistant soluble antigen-antibody immune complexes after exposure to SARS-CoV-2 may cause persistent inflammation in organs (27). There are several reported cases of ocular inflammation and related conditions following COVID-19 vaccination. These include anterior uveitis, scleritis, episcleritis (7), multiple evanescent white dot syndrome, Vogt-Koyanagi-Harada disease (28), panuveitis (29), choroiditis (30), and central serous chorioretinopathy (31). Most cases were successfully treated with corticosteroid therapy, including topical, intravitreal, and/or systemic administration, and many patients achieved complete recovery of their baseline visual acuity. A case series of orbital inflammation following mRNA vaccines was also described, successfully treated with oral prednisolone (32). It is important for healthcare providers to be aware of these potential ocular reactions to COVID-19 vaccination and to monitor patients closely for any signs or symptoms of ocular inflammation or related conditions.
As mentioned, our patient didn’t show any serious reaction to previous doses of inoculation until the first booster. These reactions were found to be induced by activation of the secondary immune response; the memory cells (33). Comparing to the first and second doses of vaccinations, Rahmani et al. reported that booster doses are more probable to stimulate rare AEs including neurological symptoms (34). Moreover, authors suggested hormonal, genetic, and behavioral factors along with the time between the primary cycle to the first booster dose. The more the time between the booster dose and the first administration, the higher the immunogenic effect after the third shot (34). Consequently, further studies could elucidate the proper time of the booster inoculations, particularly for high-risk patients in order to prevent serious reactions. Future investigations could also assess long-term effects of COVID-19 vaccination on ocular health, especially in relation to autoimmune conditions like scleritis.
Clinicians should always be aware of possible adverse events of vaccines, even inactivated types such as Sinopharm. Autoimmune reactions should always be considered however, before reaching the diagnosis, all further potential and life-threatening causes must be excluded. All organ functions should also be investigated, autoimmunity is not limited to one side or even one time. Thus, patients with auto-immune reactions are susceptible to further involvements and long-term follow-up is necessary.
This study had some limitations. We did not evaluate her ocular symptoms with magnetic resonance imaging (MRI) for possible further involvements. In addition, follow-up more than one year could also be valuable in this case. Unfortunately, we did not have access to slit lamp and IOP records.