Reactivation of previously controlled Vogt–Koyanagi–Harada disease more than 46 years following COVID-19 vaccination: a case study

Abstract

We report a case of Vogt–Koyanagi–Harada (VKH) disease that recurred 46 years after initial treatment. A 59-year-old woman presented with a 2-month history of bilateral vision blurring. She had received her third dose of coronavirus disease 2019 (COVID-19) vaccination 4 months before the onset of blurring. The best-corrected visual acuity (BCVA) was 1.0 in the right eye and 0.15 in the left eye at the initial visit. Iritis and synechia were observed between the lens and iris bilaterally. A sunset glow fundus was found in both eyes with no serous retinal detachments or disc hyperemia. The patient had a history of VKH disease and had been treated with whole-body corticosteroid administration at another hospital when she was 13 years old. The patient was diagnosed with VKH disease recurrence, and oral corticosteroid therapy and corticosteroid eyedrop treatment were initiated. The treatment response was good. At the time of this writing, recurrence had not been observed for 14 months, and the BCVA was 1.0 in both eyes. To our knowledge, this case represents the longest recorded interval of VKH disease recurrence in the literature to date. COVID-19 vaccination might be the cause of long-term well-controlled disease recurrence.

Introduction

Vogt–Koyanagi–Harada (VKH) disease is a chronic systemic inflammatory disorder characterized by bilateral panuveitis. ¹ It is associated with serous retinal detachments, disk edema, and vitritis with eventual development of sunset glow fundus. Although not all patients present with the full constellation of these extraocular findings, ² tinnitus, hearing loss, vertigo, meningismus, poliosis, and vitiligo may also be associated with VKH disease.

Although VKH disease has a good prognosis with adequate treatment, autoimmune responses to melanocytes frequently play a role in its occurrence. ³ Several reports have described the recurrence of VKH disease after coronavirus disease 2019 (COVID-19) vaccination^4–7; therefore, this disease necessitates long-term monitoring. Additionally, several reports have stated that VKH disease recurrence and VKH disease itself may be correlated with COVID-19 vaccination.^8–10

The optimal duration of careful observation is unclear. Kondo et al. ¹¹ reported a case of VKH disease that recurred 21 years later. According to the results of a search of the PubMed and CiNii Research databases (keyword: “VKH,” search years: 2000–2022), the report by Kondo et al. ¹¹ describes the longest period from the initial attack to recurrence in the literature until the present case.

We herein report a case of VKH disease that recurred 46 years after the initial attack and 2 months after the third dose of COVID-19 vaccination.

Case presentation

A 59-year-old woman presented to the Imaizumi Eye Hospital with blurred vision in both eyes. She recalled receiving oral corticosteroid therapy and subconjunctival steroid injection for VKH disease 46 years previously at Fukushima Medical University. The patient’s treatment records had not been preserved because of limitations on record retention. Although the patient’s clinical findings from 46 years previously were unknown, she remembered the diagnosis and treatment methods. Before the current presentation, she had received three doses of the BNT162b2 vaccine (Pfizer-BioNTech) and subsequently noticed blurred vision. At a medical checkup at another eye clinic 2 months after administration of the third dose of the Pfizer COVID-19 vaccine, she was diagnosed with refractory uveitis. Her best-corrected visual acuity (BCVA) was 1.0 in the right eye and 0.15 in the left eye on her initial visit to Imaizumi Eye Hospital. Both eyes had normal intraocular pressure, and slit-lamp biomicroscopy revealed iritis, iris–lens synechia, and vitreous cavity cells in both eyes. Furthermore, fine keratic precipitates were found in both eyes, with an anterior chamber cell grade of 1+ in the right eye and 3+ in the left eye. The grade of keratic precipitates was 1+ in the right eye and 2+ in the left eye.

A sunset glow fundus was found in both eyes (Figure 1(a)). Blood test results were nearly normal, and fluorescein angiography showed no specific abnormalities (Figure 1(b)). However, optical coherence tomography revealed fractional choroidal thickening in both eyes (Figure 2). The patient’s serum high-density lipoprotein and creatinine levels were slightly increased, but her hemoglobin A1c level was 5.3%. Her angiotensin-converting enzyme level was within the normal range. Furthermore, her serum viral antibody titers of Epstein–Barr virus, human T-cell leukemia virus type 1, cytomegalovirus, and herpes virus were negative, and tests for syphilis and toxoplasma antibodies yielded negative results. Chest X-ray examination revealed no abnormalities such as bilateral hilar lymphadenopathy.

Figure 1.

Fundus photographs at initial visit. (a) Sunset glow fundus in both eyes. The photograph is slightly unclear because of inflammation in the anterior chamber and vitreous opacity in the left eye and (b) No characteristic findings of Vogt–Koyanagi–Harada disease were observed in either eye.

Figure 2.

Optical coherence tomography images at initial visit. Despite the absence of characteristic findings such as serous retinal detachment and retinal pigment epithelium undulations, fractional choroidal thickening was observed in both eyes. The choroidal thickness was 366 and 327 µm in the right and left eye, respectively.

The clinical diagnosis was recurrence of VKH disease based on the patient’s history and absence of abnormal findings in other tests. The patient was immediately treated with betamethasone sodium phosphate (Sanbetason ophthalmic and otorhinologic 0.1% solution; Santen Pharmaceutical, Osaka, Japan) and prednisolone (Predonine; Shionogi, Osaka, Japan) at 10 mg daily with gradual tapering over the following 2 months. The betamethasone sodium phosphate eye solution was started at three times a day in the right eye and six times a day in the left eye for the first 3 weeks. It was then decreased to two times a day in the right eye and four times a day in the left eye for the next 3 weeks. Finally, it was decreased to once a day in the right eye and three times a day in the left eye for the last 3 weeks. Similarly, the prednisolone administration started at 10 mg/day for the first 30 days and was then decreased to 5 mg/day for the last 30 days. Tropicamide and phenylephrine hydrochloride (Ophmic ophthalmic solution; Wakamoto Pharmaceutical, Tokyo, Japan) were used to release the synechia between the lens and iris.

The iritis disappeared in both eyes 2 weeks after steroid therapy, with gradual disappearance of the opacity in the vitreous cavity. The synechia in the left eye persisted for 1 month after therapy; however, the synechia between the lens and iris of the right eye soon resolved (Figure 3). The BCVA had improved by 1.0 in both eyes by 4 months after the initial visit. The synechia between the lens and iris of the left eye was still present 14 months after the initial visit, and the BCVA was consistently 1.0 in both eyes. The sunset glow fundus remained unchanged throughout the follow-up period (Figure 4), with no recurrence of ocular inflammation and or treatment-related side effects.

Figure 3.

Synechia between iris and lens 1 month after initial visit. The pupil was round in the right eye and distorted in the left eye because of synechia between the iris and lens after mydriasis.

Figure 4.

Fundus photograph 10 months after the initial visit. The sunset glow fundus was unchanged and the transparency of the left eye had improved because of reduction of inflammation.

Written informed consent for publication and treatment was obtained from the patient. The study protocol conformed to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Imaizumi Eye Hospital (approval No. 202202). The reporting of this study confirms to the CARE guidelines. ¹²

Discussion

Only Japanese reports^11,13–15 are available on the recurrence of VKH disease >10 years after initial treatment. Ocular symptoms, such as photophobia, eye pain, and decreased vision, were not experienced by our patient for 46 years. Therefore, we diagnosed her with recurrence of VKH disease 46 years after the initial attack, which is the longest period reported worldwide to date. Thus, the novelty of our case is high.

The ocular abnormalities in this case of recurrence included refractory iritis and vitritis. The patient was referred to Imaizumi Eye Hospital because the ocular inflammation could not be controlled with the steroid eye solution prescribed by the previous eye clinic. We therefore used oral prednisolone therapy in addition to a steroid eye solution. Although a sub-Tenon’s triamcinolone acetonide injection was initially considered, the patient declined this treatment. The presence of a sunset glow fundus, ¹⁶ bilateral recurrent granulomatous anterior uveitis, ¹⁶ multifocal chorioretinal atrophy, ¹⁶ and slight choroidal thickening ¹⁶ ; the response to treatment with oral prednisolone and steroid eye solution; and the blood test and chest X-ray results led to the diagnosis of VKH disease recurrence.

Papasavvas and Herbort ⁴ reported a case involving the post-COVID-19 vaccination recurrence of VKH disease that had been controlled for >6 years; the recurrence developed 6 weeks after administration of the second dose of the Pfizer COVID-19 vaccine. Accorinti et al. ⁵ reported a case of recurrence of well-controlled VKH disease 11 days after the first dose of the Pfizer COVID-19 vaccine. Bolletta et al. ⁶ reported that the mean time between vaccination and onset of ocular complications was 9.4 days (median, 7 days; range, 1–30 days). Rujkorakarn and Patamatamkul ⁷ reported the recurrence of VKH disease 1 week after the third dose of an mRNA-based vaccine (mRNA-1273; Moderna). Our patient developed blurred vision 2 months after the third dose of the Pfizer COVID-19 vaccination, whereas Yasaka et al. ¹⁷ defined ocular complications as the development of ocular inflammatory events within 14 days after COVID-19 vaccination.

Zhong et al. ¹⁸ suggested that concomitant treatment with systemic glucocorticoids for uveitis at the time of COVID-19 vaccination was associated with a dose-dependent lower risk of uveitis relapse after vaccination. Our patient did not receive systemic glucocorticoids after COVID-19 vaccination. If she had received systemic glucocorticoids after vaccination, the VKH disease may not have recurred. Furthermore, Zhong et al. ¹⁹ showed that compared with the recommendation for deferred vaccination, the recommendation for patients with inactive uveitis to receive early non-mRNA COVID-19 vaccination led to earlier self-reported worsening of symptomatic uveitis. The authors found no evidence that uveitis activity or visual acuity at 3 months differed substantially based on the recommendation. ¹⁹ Because our patient received an mRNA COVID-19 vaccine, simple comparison is difficult; however, the results of this earlier study may be useful.

Hirooka et al. ²⁰ and Accorinti et al. ²¹ reported that 9 (23.1%) of 39 eyes and 17 (44.7%) of 38 patients treated with systemic corticosteroids, respectively, developed sunset glow fundus, which frequently occurs after treatment in patients with VKH disease. Additionally, Nakayama et al. ³ observed sunset glow fundus in 110 (49.5%) eyes treated with pulse intravenous corticosteroids. According to Hirooka et al., ²⁰ a significantly higher number of recurrences were observed within more than 12 months in patients with than without sunset glow fundus; our patient developed recurrence after 46 years. The correlation between sunset glow fundus and recurrence after a long duration is expected to be elucidated in future research.

Iwahashi et al. ²² reported recurrent inflammation in approximately 25% of patients with VKH disease. Poor initial visual acuity and rapid tapering of the corticosteroid were associated with posterior segment recurrence. ²² Nakayama et al. ³ reported that anterior and/or posterior segment recurrence of inflammation was observed in 25 (22.5%) of 111 patients. Accorinti et al. ²¹ reported lower recurrence in patients who received intravenous than oral corticosteroids. Our patient’s treatment was not maintained because it had been initiated 46 years previously.

VKH disease can recur a very long time after initial treatment (up to 46 years later according to the present case). Thus, ophthalmologists must remain vigilant of this possibility considering the increasing number of people developing COVID-19 and receiving COVID-19 vaccinations. Furthermore, recurrence should be considered if a patient has ocular symptoms and a history of treatment for VKH disease.