Anterior uveitis has been reported to occur after coronavirus disease 2019 (COVID-19) and its vaccination.[1-8] Post-systemic viral infection can also cause anterior uveitis. We herein report a unique case who developed anterior uveitis after COVID-19, its vaccination, and dengue hepatitis.[9,10]
Case Report
A 36-year-old Asian Indian male presented with redness and pain in his right eye (OD) of 1 week duration. He had been diagnosed with dengue hepatitis a month earlier and was admitted in the hospital for low platelet counts.
He was on subcutaneous adalimumab 40 mg every 3 weeks, oral methotrexate 20 mg, and cyclo-oxygenase inhibitors (etorcoxib 60 mg) for his human leucocyte antigen (HLA) B27-associated spondyloarthropathy and recurrent anterior uveitis as recommended by his consulting rheumatologist. The patient was receiving adalimumab every 3 weeks because of financial issues.
In 2020, he developed anterior and intermediate uveitis in OD 3 weeks after he developed COVID-19.[1] He was re-started on topical and systemic steroids (35 mg) and referred back to the rheumatologist to re-start oral methotrexate and injection adalimumab 40 mg subcutaneously, and topical and systemic steroids were tapered over a month.
He had two doses of COVID-19 vaccination (COVAXIN®) 5 weeks apart in 2021 and had developed anterior uveitis in OD 1 week after the second dose. He had taken a dose of subcutaneous adalimumab 40 mg between the vaccinations but had skipped the weekly dose of oral methotrexate before the vaccination, which is unlikely to cause re-activation.
The investigations performed for the patient are as shown in Table 1.
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Table 1: Investigations done for our patient
The anterior chamber inflammation was controlled with topical steroids (prednisolone acetate 1%) and cycloplegic homatropine 2%, which were tapered over a month. Concurrently, oral methotrexate 20 mg was resumed.
In mid-2022, the patient was diagnosed with dengue fever and subsequently developed hepatitis with deranged liver enzymes [Table 1]. Ultrasound abdomen showed prominent portal vein with reduced velocity (hepato-petal flow) with increased periportal echogenicity with diffuse circumferential enlargement of gall bladder with mild to moderate ascites. Ultrasound chest showed bilateral lower zone pneumonitis and right mild pleural effusion. He was treated with intravenous fluids and ceftriaxone 1000 mg for 5 days, dexamethasone 4 mg, and ondansetron 2 mg intramuscularly. The patient had stopped his oral methotrexate 20 mg during the week at the local hospital. He had received a subcutaneous dose of adalimumab 40 mg the previous week before the diagnosis of dengue hepatitis.
He resumed his 20 mg of weekly methotrexate a week later and with a subcutaneous dose of adalimumab 40 mg 2 weeks later. He developed anterior uveitis 2 weeks later in OD before his scheduled adalimumab dose. The patient was treated with topical prednisolone acetate 1% and homatropine 2% drops and tapered over a month with complete resolution of anterior chamber inflammation.
Discussion
Our patient had re-activation of his anterior chamber inflammation on three distinct occasions.
Hyper-inflammatory syndrome with anterior uveitis also has been reported following COVID-19.[2,3] Re-activation of anterior uveitis which had been in remission for 13 years has been reported after COVID-19.[4]
Pereira et al. reported a patient of acute anterior uveitis following COVID-19. His ocular inflammatory panel was positive for HLA-B27. They postulated that initial anterior uveitis attack in the setting of COVID-19 was dysregulation of inflammatory cells and mediators in a patient with baseline elevated risk for ocular inflammation.[11]
Anterior uveitis has also been reported following COVID-19 vaccination.[5,6] In a series assessing the COVID-19 vaccination and uveitis, Ferrand et al.[6] found that the majority were anterior uveitis and had a previous history of anterior uveitis, and 15.8% of cases needed an increase in their systemic therapy. Our patient was re-started on his methotrexate, and anterior uveitis was controlled with topical steroids.
Testi et al.[7] in their multi-national study on ocular inflammatory events following COVID-19 vaccination noted that 41 of their patients had anterior uveitis and the majority of them had received Pfizer vaccine. On an average, the anterior uveitis occurred 5.5 (1–14) days after the first dose. The majority of them had unilateral anterior uveitis similar to our patient and were in remission for more than 3 months. The majority of them resolved with topical steroids.[7]
Similarly, a 35-year-old Asian Indian female previously diagnosed with bilateral anterior uveitis and on oral methotrexate developed bilateral anterior uveitis following the first/second dose of COVID-19 vaccination. The authors postulated that COVID-19 or its vaccination may presumably play a role in triggering the immune system and can cause recurrent ocular inflammation even in the absence of an extra-ocular inflammation.[8]
Gupta et al.[9] have reported six patients with serological evidence of prior dengue fever who had presented with uveitis not attributable to any other disease. Seven eyes of six patients were affected. Anterior uveitis without any evidence of posterior segment involvement was present in the six eyes of five patients, whereas one patient had severe vitritis also.[9] Our patient developed recurrence of anterior uveitis 3 weeks after dengue hepatitis. It may be argued that skipping of a single dose of methotrexate may have predisposed to recurrence but is very unlikely.
The potential mechanism underlying the ocular inflammation response following COVID-19 vaccination is not known, and multiple mechanisms have been postulated.[12-17] In all these instances, there is a possibility of viruses/their components breaking down the self-tolerance by “molecular mimicry” and “bystander activation.” Viruses carry structurally similar antigens to self-antigens that activate B- and T-cells and lead to a cross-reactive response against both self- and non-self-antigens, and this mechanism is known as “molecular mimicry.”[12-17] Non-specific and an over-reactive anti-viral immune response create a localized pro-inflammatory environment, leading to the release of self-antigens from the damaged tissue. These self-antigens are subsequently taken up and presented by antigen presenting cells to stimulate the auto-reactive T-cells in the vicinity, triggering auto-immunity called “bystander activation.”[12-17] Inflammatory damage induced by adjuvants included in the vaccines stimulating innate immunity through endosolic or cytoplasmic nucleic acid receptors may be one of the other mechanisms.[13-17]
After the second dose of COVID-19 vaccine, the severe acute respiratory syndrome coronavirus (SARS-CoV-2) receptor binding domain (RBD) antibodies IgG were non-reactive, but anti-SARS-CoV-2 spike protein (S1/S2) IgG antibody was raised. However, after the recurrence of anterior uveitis following dengue hepatitis, SARS-CoV-2 RBD antibodies IgG were raised. This raises an important view as both dengue and SARS-CoV-2 result in a systemic infection, with some similar clinical presentations such as fever, headache, myalgia, and gastro-intestinal symptoms. Similarities are seen in the clinical presentation, risk factors for development of severe illness, cytokine storms, endothelial dysfunction, and multi-organ failure.[18,19] Both infections are characterized by a delayed and impaired type I interferon response and a pro-inflammatory immune response. Furthermore, although high levels of potent neutralizing antibodies are associated with protection, poorly neutralizing and cross-reactive antibodies have been proposed to lead to immuno-pathology by different mechanisms, associated with an exaggerated plasmablast response. The virus-specific T-cell responses are also shown to be delayed in those who develop severe illness, whereas varying degrees of endothelial dysfunction lead to increased vascular permeability and coagulation abnormalities.
Conclusion
In conclusion, patients with auto-immune diseases can have recurrent ocular inflammation after either COVID-19 or its vaccination or dengue as seen in our patient. It is important to treat the ocular inflammation with topical steroids, which alone may be sufficient without the need of titrating immuno-suppression. Complex immune mechanisms may play a role in re-activation of anterior uveitis, even when the patient is on adalimumab. Skipping a dose of methotrexate may not necessarily lead to re-activation.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
1. Sanjay S, Kawali A, Mahendradas P, Shetty R. Lockdown effects on a patient receiving immunosuppression for unilateral HLA- B27 associated uveitis during COVID-19 pandemic. Indian J Ophthalmol 2021;69:1351–3.
2. Sanjay S, Singh YP, Roy D, Mahendradas P, Kawali A, Shetty R. Recurrent bilateral idiopathic anterior uveitis with vitritis post Coronavirus Disease 2019 infection. Indian J Rheumatol 2021;16:460–3.
3. Sanjay S, Rao VKR, Mutalik D, Mahendradas P, Kawali A, Shetty R. Post corona virus Disease-19 (COVID-19):Hyper inflammatory syndrome-associated bilateral anterior uveitis and multifocal serous retinopathy secondary to steroids. Indian J Rheumatol 2021;16:451–5.
4. Sanjay S, Mutalik D, Gowda S, Mahendradas P, Kawali A, Shetty R. Post coronavirus disease (COVID-19) reactivation of a quiescent unilateral anterior uveitis. SN Compr Clin Med 2021;3:1843–7.
5. Sanjay S, Kawali A. Comment on:COVID-19 vaccine-associated reactivation of uveitis. Indian J Ophthalmol 2022;70:342–3.
6. Ferrand N, Accorinti M, Agarwal M, Spartalis C, Manni P, Stuebiger N, et al.
COVID-19 vaccination and uveitis:Epidemiology, clinical features and visual prognosis. Ocul Immunol Inflamm 2022;30:1265–73.
7. Testi I, Brandão-de-Resende C, Agrawal R, Pavesio C
COVID-19 Vaccination Ocular Inflammatory Events Study Group. Ocular inflammatory events following
COVID-19 vaccination:A multinational case series. J Ophthalmic Inflamm Infect 2022;12:4.
8. Sanjay S, Yathish GC, Singh Y, Kawali A, Mahendradas P, Shetty R.
COVID-19 vaccination and
recurrent anterior uveitis. Indian J Ophthalmol 2022;70:4445–8.
9. Gupta A, Srinivasan R, Setia S, Soundravally R, Pandian DG. Uveitis following dengue fever. Eye (Lond) 2009;23:873–6.
10. Mahendradas P, Kawali A, Luthra S, Srinivasan S, Curi AL, Maheswari S, et al. Post-fever retinitis-Newer concepts. Indian J Ophthalmol 2020;68:1775–86.
11. Pereira A, Murtaza F, Kaplan AJ, Yan P. Initial anterior uveitis event associated with recent novel SARS-CoV-2 (COVID-19) infection in the setting of HLA-B27. Am J Ophthalmol Case Rep 2022;26:101565.
12. Smatti MK, Cyprian FS, Nasrallah GK, Al Thani AA, Almishal RO, Yassine HM. Viruses and autoimmunity:A review on the potential interaction and molecular mechanisms. Viruses 2019;11:762.
13. Cunningham ET Jr, Moorthy RS, Fraunfelder FW, Zierhut M. Vaccine-associated uveitis. Ocul Immunol Inflamm 2019;27:517–20.
14. Watad A, De Marco G, Mahajna H, Druyan A, Eltity M, Hijazi N, et al. Immune-mediated disease flares or new- onset disease in 27 subjects following mRNA/DNA SARS-CoV-2 vaccination. Vaccines (Basel) 2021;9:435.
15. Teijaro JR, Farber DL. COVID-19 vaccines:Modes of immune activation and future challenges. Nat Rev Immunol 2021;21:195–7.
16. Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation:The type I interferonopathies, a conceptual overview. J Exp Med 2016;213:2527–38.
17. Cunningham ET Jr, Moorthy RS. Vaccine-associated posterior uveitis. Retina 2020;40:595–8.
18. Malavige GN, Jeewandara C, Ogg GS. Dengue and COVID-19:Two sides of the same coin. J Biomed Sci 2022;29:48.
19. Harapan H, Ryan M, Yohan B, Abidin RS, Nainu F, Rakib A, et al. Covid-19 and dengue:Double punches for dengue-endemic countries in Asia. Rev Med Virol 2021;31:e2161.
