Saraceno et al. Int J Retin Vitr (2021) 7:49 https://doi.org/10.1186/s40942-021-00319-3 International Journal of Retina and Vitreous LETTER TO THE EDITOR Open Access Vogt-Koyanagi-Harada Syndrome following COVID-19 and ChAdOx1 nCoV-19 (AZD1222) vaccine Janaína Jamile Ferreira Saraceno1, Guilherme Macedo Souza2, Luciana Peixoto dos Santos Finamor2, Heloisa Moraes Nascimento2,3* and Rubens Belfort Jr2,3 Abstract The challenge of COVID-19 has rapidly changed medical management worldwide. The relatively small time from pan- demic to vaccines regulatory approval triggered a race toward vaccines development. However, important questions regarding SARS-CoV-2 vaccines remain. A case of complete Vogt-Koyanagi-Harada (VKH) Syndrome that occurred 4 days following SARS-CoV-2 vaccination and another patient that developed VKH 14 days post COVID-19 clinical onset are presented. A causal relationship between COVID-19 and uveitis may exist. Introduction Vogt-Koyanagi-Harada (VKH) syndrome is a multisys- tem disorder with chronic, bilateral, non-necrotizing, granulomatous panuveitis and exudative retinal detach- ment [1–5]. The etiology of VKH remains unknown, and the pathogenesis is thought to be multifactorial and pri- marily targets the choroidal layer. Many etiologies were previously reported, most of which were immunogenetic and environmental. It is a T-cell-mediated autoimmune response against one or more antigenic components of melanocytes [6–8]. Previous reports demonstrate VKH association with interferon-alpha, pembrolizumab and dabrafenib/ trametinib therapy, as well as after vaccination for influ- enza, yellow fever and BCG. Immunological mechanisms and dysregulation of the immune system may play a sig- nificant role in the association between VKH disease and COVID-19 [9–15]. Rare descriptions of post-COVID-19 immune-medi- ated conditions such as uveitis, Guillain-Barré syndrome *Correspondence: helomn@gmail.com 2 Department of Ophthalmology and Visual Science, Federal University of Sao Paulo, Sao Paulo, Brazil Full list of author information is available at the end of the article or systemic lupus erythematosus have been published. It is speculated that SARS-CoV-2 can disturb self-tolerance and trigger autoimmune responses through cross-reac- tivity with host cells [16–18]. A case of complete VKH that occurred 4  days follow- ing vaccination with ChAdOx1 nCoV-19 (AZD1222) and another patient that developed VKH 14  days post COVID-19 clinical onset are presented. To our knowl- edge, no previous reports have indicated that SARS- CoV-2 infection or the vaccine may be related to the VKH. Cases reports Patient 1 A 62-year-old healthy female patient developed a severe headache and tinnitus 2  days after receiving COVID-19 immunization with the Oxford-AstraZeneca Chimpan- zee Adenovirus Vectored Vaccine ChAdOx1 nCoV-19 (AZD1222). Two days later she developed an acute loss of vision in both eyes. BCVA was 20/600 in OD and 20/200 in OS, IOP was 14  mmHg OU and the slit-lamp examination showed a mild inflammation in the anterior chamber with 2+ cells and 1+ of vitreous cells OU. Fundus examination showed © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Saraceno et al. Int J Retin Vitr (2021) 7:49 Page 2 of 7 a serous retinal detachment and optic disc hyperemia OU (Fig. 1). OCT showed bilateral serous retinal detachment, bacillary layer detachment and subretinal hyperreflective dots (Fig. 2). Patient 2 A 37-year-old female patient with a 15  days history of blurred vision with metamorphopsia in both eyes, asso- ciated with tinnitus and no prior history of eye trauma or intraocular surgery was seen. Two weeks before she had experienced headache, anosmia and fever and tested positive for the SARS COV-2 on rt-PCR test. BCVA was hand motion in OU and intraocular pres- sure was normal. Slit-lamp examination showed granu- lomatous keratic precipitates (KP) in OD, and mild vitritis OU. Fundus examination showed serous retinal detachment with an inferior bullous detachment and optic disk hyperemia in OU (Fig.  3), fluorescein angi- ography revealed bilateral optic disk hyperfluorescence due to leakage and multiple hyperfluorescence pinpoints (Fig.  4), OCT revealed a bilateral serous retinal detach- ment with bacillary detachment (Fig.  5), characterizing initial onset. In both cases, systemic evaluation was nonspecific with mononuclear cells in the cerebrospinal fluid and infec- tious work-up was negative. Both were diagnosed as Fig. 2 (Patient 1) OCT of both eyes showing serous retinal detachment with bacillary layer detachment complete VKH syndrome, according to the Revised Diag- nostic Criteria (RDC) [3]. Patient 1 was treated with oral systemic prednisone (1.5 mg/kg/day)—intravenous therapy was avoided due to the severity of the pandemic at that time and the restric- tion of available hospital beds—and within 4  days the visual acuity improved to 20/60 OD and 20/80 OS. She continued to be followed up, using regressive oral corti- costeroid therapy, and after 3 weeks, evolved with BCVA of 20/20 OU, no signs of inflammatory activity and disap- pearance of the retinal detachment (Figs. 6 and 7). Fig. 1 (Patient 1) Fundoscopy and autofluorescence of both eyes showing serous retinal detachment and optic disc hyperemia Saraceno et al. Int J Retin Vitr (2021) 7:49 Page 3 of 7 Fig. 3 (Patient 2) Fundoscopy and autofluorescence of both eyes showing serous retinal detachment, optic disc hyperemia and choroidal inflammation Fig. 4 (Patient 2) Fluorescein angiography of both eyes Saraceno et al. Int J Retin Vitr (2021) 7:49 Page 4 of 7 Fig. 5 (Patient 2) OCT of both eyes showing serous retinal detachment with bacillary layer detachment Fig. 6 (Patient 1) Fundoscopy and autofluorescence of both eyes showing improvement of the serous retinal detachment Patient 2 was also treated with oral systemic pred- nisone (1  mg/kg/day, dose was taped by 10  mg every week). On the thirtieth treatment day her visual acuity achieved 20/25 OD and 20/50 OS, no signs of inflam- matory activity and improvement of retinal detachment (Figs. 8 and 9). Both patients have been followed up for the past 2 and 3 months respectively and have not had recurrence of the disease. Even with the COVID pandemic, these patients are being closely monitored due to the severity of the dis- ease, with potential visual impairment. Discussion Vogt-Koyanagi-Harada is a bilateral, autoimmune dif- fuse granulomatous uveitis associated with neurologi- cal, audiovestibular, and dermatological abnormalities. Although the exact pathogenesis is still uncertain, immunological and histopathological studies sug- gest that VKH is mediated by CD4+ T cells that target melanocytes. These activated T cells likely initiate the inflammatory process through generation of cytokines, IL-17 and IL23. Genetic factors and viral infections are likely involved [1–8]. Saraceno et al. Int J Retin Vitr (2021) 7:49 Page 5 of 7 Viral diseases may play a role in VKH development, as CMV seroprevalence is higher in VKH patients, and cross-reaction between tyrosinase peptides and cyto- megalovirus antigen by T cells from patients with VKH has already been stablished [8]. Other virus, as Influenza A, was described as a trigger to VHK in a positive for HLA-DR4 patient [9]. Wade and cols. described a case of a 14-year-old female, without evidence of active M. pneu- moniae infection, presented with elevated antibody titers and signs of VKH disease [19]. Bilateral uveitis with extraocular changes that were vir- tually identical to VKH was described in three patients with Hepatitis C (HCV). Two of them manifested the uveitis after the initiation of pegylated interferon–2b treatment. It suggests a possible association between the HCV infection and/or treatment with interferon and the development of VKH. The patients improved after Fig. 7 (Patient 1) OCT of both eyes showing improvement of the serous retinal detachment and bacillary layer detachment Fig. 8 (Patient 2) Fundoscopy and autofluorescence of both eyes showing improvement of the serous retinal detachment Saraceno et al. Int J Retin Vitr (2021) 7:49 Page 6 of 7 Fig. 9 (Patient 2) OCT of both eyes showing resolution of the serous retinal detachment and bacillary layer detachment corticosteroids and immunosuppressive treatment and suspension of the antiviral therapy [10, 11]. VKH can also associate with systemic autoimmune diseases, such as autoimmune polyglandular syndrome, Guillain-Barré immunoglobulin A nephropathy [20, 21]. syndrome, and Dogan et  al. described a case of VKH following BCG vaccination in a patient treating superficial transitional cell carcinoma (TCC) of the bladder, and another one with both VKH and tuberculosis. The authors speculated that M. tuberculosis and BCG proteins induce high Th1 responses causing uveitis by antigenic mimicry [13]. Reports described a case of VKH following influenza, hepatitis B and yellow fever vaccination. One proposed mechanism is related to the use of adjuvants in vaccines. Adjuvants enhance immunogenic activity by a combina- tion of mechanisms, including cytokine and chemokine release, sustained release of antigen (depot effect), activa- tion of antigen presenting cells, antibody production, and cellular recruitment. Adjuvants are also routinely used in experimental auto-immune uveitis models [9–15]. The Oxford-AstraZeneca ChAdOx1 nCoV-19 vaccine (AZD1222) consists in a replication-deficient adenoviral vector, containing the SARS-CoV-2 structural surface glycoprotein antigen gene, and there are no adjuvants used in its composition. This vaccine induces generation of binding and neutralizing antibodies, and interferon-γ enzyme-linked immunospot responses [22]. Patel et  al. describes a case of a 37-year-old man who was diag- nosed with Guillain–Barre syndrome (GBS) 3 weeks post the first dose of the ChAdOx1 vaccine, in the absence of any other triggering factors. There are a few cases, which have been published correlating COVID-19 infection with the development of GBS [18]. Recently a case of Citokine Release Syndrome that occurred 5  days after vaccination with BTN162b2 (tozi- nameran)—the Pfizer-BioNTech mRNA COVID-19 vac- cine—in a patient with colorectal cancer  was reported [23]. Although it is difficult to determine causality, our cases raise the possibility of ChAdOx1 nCoV-19 (AZD1222) vaccination and COVID-19 triggering—or even causing— VKH disease. This report of vaccine-induced VKH can enlighten possible causative mechanisms involved in VKH pathogenesis. Sir. Stewart Duke-Elder, in 1966, had already emphasized that the etiology of numerous obscure uveitis may be secondary to virus infections [24]. The possibility of identifying which Sars-CoV-2 viral particles—possible used in the vaccines, as the structural surface glycoprotein anti- gen—may trigger uveitis is an important path for scientific research. Acknowledgements Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (1270963774537698); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Authors’ contributions JJFS was the main writer of this paper and acquired data of the Patient 2; GMS was the second writer and acquired data of the Patient 1; LPSF was a reviewer and made substantial contributions to the conception of the paper; HMN was a reviewer, made substantial contributions to the conception of the paper and is the Corresponding Author; RBJ was a reviewer and made substantial contributions to the conception of the paper. All authors have approved the manuscript submission for publication. All authors read and approved the final manuscript. Funding Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Availability of data and materials All data generated during this study are included in this published article. Declarations Ethics approval and consent to participate Ethical approval for this study was obtained from Invitare—Pesquisa Clínica Auditoria e Consultoria LTDA (CAAE: 30764320.6.0000.8098). Written informed consent was obtained from all subjects before the study. Consent for publication Written informed consent was obtained from all subjects before the study. Competing interests The authors declare that there is no conflict of interest regarding the publica- tion of this paper. Author details 1 Department of Ophthalmology, Hospital Sao Rafael, Salvador, Brazil. 2 Depart- ment of Ophthalmology and Visual Science, Federal University of Sao Paulo, Sao Paulo, Brazil. 3 Research Department, Instituto Paulista de Estudos e Pesqui- sas em Oftalmologia/Instituto da Visão (IPEPO), Sao Paulo, Brazil. Received: 25 June 2021 Accepted: 17 August 2021 Saraceno et al. 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System of ophthal- Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. 12. Campos WR, Cenachi SPF, Soares MS, Gonçalves PF, Vasconcelos-Santos mology, vol. 9. London: Henry Kimpton Publishers Ltd; 1966. Ready to submit your research ? Choose BMC and benefit from: ? Choose BMC and benefit from: Ready to submit your research fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year • • • • • • At BMC, research is always in progress. Learn more biomedcentral.com/submissions