Discussion
Vogt-Koyanagi-Harada (VKH) disease is a severe bilateral granulomatous panuveitis frequently associated with a series of systemic and ocular manifestations. It manifests clinically in four stages: prodromal stage, acute stage, convalescent stage, and chronic recurrent stage. The prodromal phase is characterized by flu-like symptoms, including fever, headache, nausea, tinnitus, periorbital pain and so on. In this patient, extraocular manifestations, including fever and headache, have resolved by time of examination. Following the prodromal phase, bilateral posterior uveitis occurs, characterized by multiple exudative retinal detachment, optic disc swelling and choroidal thickening. Our patient presented with typical signs, in which inflammation is limited to the posterior segment of the eye. Based on Revised Diagnostic Criteria (RDC) for VKH disease4, our patient was diagnosed as incomplete VKH disease.
Studies indicated that the clinical manifestations of VKH disease are caused by an inflammatory autoimmune response, which is mediated by CD4+ cytotoxic T-lymphocyte against melanocyte-related antigens in the target organs, such as the eye, inner ear, meninges and skin1,6. VKH-derived lymphocytes recognize synthetic peptides derived from tyrosinase which is an enzyme uniquely expressed by melanocytes and involved in melanin synthesis, and are activated to initiate the immune response in VKH disease. Furthermore, it is widely accepted that genetic factors and exogenous or environmental trigger may play important role in the initial stage of VKH disease. Although the definitive mechanisms involved need further detailed research, the hypothesis that virus may play a triggering role in the disease is widely accepted. Meningeal manifestations including fever, headache, and EBV DNA discovered in the cerebrospinal fluid (CSF)7or vitreous8 from patients with VKH disease provided evidence for the triggering role of a viral infection resulting in this disease. However, other studies could not verify these results, and EBV is a common virus in humans. According to evidence accumulated during past decades with the rapid advancement in several domains of basic science, a mechanism of molecular mimicry was proposed. Exogenous antigens encoded by viruses may resemble proteins from pigmented cells which can be recognized by specific HLA-class II molecules, subsequently activating the immune reaction. Sugita et al found the similarity between a cytomegalovirus-associated peptide and tyrosinase peptide, and suggested that some T cells from patients with VKH disease responded strongly to both peptides9,10. Furthermore, microbial immune products can be recognized by Toll-like receptors (TLRs), consequently triggering the innate immune responses. Currently, the increased expression of TLR3 and TLR4 in macrophages from active VKH patients compared to controls provided evidence for the role of TLRs in the pathogenesis of VKH disease11.
According to early studies, Mycoplasma pneumoniae12and influenza A virus13 have been reported to be associated with the development of VKH disease. In our report, this patient presented with VKH symptom 2 weeks after SARS CoV-2 infection. Thus, we hypothesized that SARS CoV-2 may play a triggering role in initiating the VKH disease.
COVID-19 typically manifests as an acute respiratory disease with inflammatory and vascular complications caused by SARS CoV-2. However, the SARS-CoV-2 is known to cause various clinical symptoms in multiple organ systems including respiratory organ, neurological system, cardiovascular, gastrointestinal tract, immune, eye and so on14. Most patients presented with fever, headache, cough, sore throat, and fatigue. While, severe COVID-19 may progress to acute respiratory distress syndrome, cytokine storm and multiorgan failure15. Our patient, confirmed SARS-CoV-2 infection by PCR, presented with fever, cough, and headache, and she presented with VKH symptom 2 weeks after COVID-19 infection onset.
A growing number of studies indicated that ocular manifestations were pre-existing or occurred as a result of SARS-CoV-2 infection. Aggarwal reported that ocular manifestations were observed in 11.64% COVID-19-infected patients in the meta-analysis16. There is evidence that conjunctivitis is the most common ocular pathology. Furthermore, retinal vascular occlusions, optic neuritis and uveitis have also been associated with COVID-192. To our best knowledge, there have been some cases of VKH disease after COVID-19 vaccination reported17-19. However, the case of VKH disease associated with SARS-CoV-2 was rare. For the first time, Santamaria et al described the possible associations between SARS-CoV-2 infection and VKH disease20. Eatz reported a case of VKH disease 2 weeks after COVID-19 infection onset, and suggested that SARS-CoV-2 may be a immunological trigger of VKH if COVID-19 infection onset was prior to the 2-week history of VKH symptom onset, or during the prodromal VKH phase21. With all these facts, the triggering role of COVID-19 infection in the development of VKH disease is widely accepted but still uncertain. Based on the analysis above, SARS-CoV-2 infection may directly provoke VKH disease, and also may indirectly lead to VKH disease via molecular mimicry, but further research is need to elucidate the specific mechanism of these two hypotheses. As we all known, the SARS-CoV-2 enters the host cells via binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Several researchers have confirmed that ACE2 receptor is expressed in the eye, specifically on the conjunctiva, choroid, vascular endothelium, and nerves22. Thus, it is proposed that the SARS-CoV-2 may attack the choroid resulting in the development of VKH disease. In addition, SARS-CoV-2 may cause dysfunction of immune responses characterized by lymphopenia and an activated lymphocyte profile or dysfunction23. T cells can not only express some cell markers which may confer susceptibility to VKH disease, but also product a certain profile of cytokines which may have an effect on the differentiation of naïve T cells, forming a complicated immune environment23,24. Under the specific immune environment, activated effector T cells and other effector immune cells may attack tissue with pigment including the choroid, ear, skin and meninges. However, we need to provide additional insight into the definitive underlying mechanism explaining the triggering role of SARS-CoV-2 infection in the VKH disease.
This study has some limitations. Because genetic testing is expensive and cannot be popularized at that time, genetic testing was not performed in our patient. So we cannot confirm the genetic role the pathogenesis of VKH disease. As a case report, the relationship between SARS-CoV-2 infection and the VKH disease cannot be generalized in this study. Further studies are needed to reveal the exact pathogenesis that could be an aid to manage the VKH disease. Clinically, ophthalmologists and physicians should be aware of this possible association between VKH disease and COVID-19. Based on studies reviewed above, SARS‑CoV‑2 virus could be a possible trigger for VKH disease.