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.