Possible association between vaccination against SARS-CoV-2 and recurrence of macular edema due to branch retinal vein occlusion: a case report

Abstract

We herein describe a patient who developed recurrence of macular edema (ME) due to branch retinal vein occlusion (BRVO) 3 days after administration of the BNT162b2 vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A man in his early 50s visited our hospital because of vision loss in his right eye. His logarithmic best-corrected visual acuity (BCVA) was −0.79 in both eyes. ME due to superior temporal BRVO was observed in his right eye, and the central foveal thickness (CFT) was 486 µm. The patient was treated with an intravitreal aflibercept injection with logarithmic BCVA of −0.79, leading to resolution of the ME with a CFT of 299 µm. Three months after the initial visit, he received a fourth dose of an mRNA vaccine. Three days later, he developed vision loss in his right eye. Although the logarithmic BCVA was maintained at −0.79, ME recurred with a CFT of 507 µm. The patient was treated with an additional dose of intravitreal aflibercept injection. The ME resolved and the logarithmic BCVA in the right eye was maintained at −0.79. This case indicates a possible association between vaccination against SARS-CoV-2 and recurrence of ME due to BRVO.

Introduction

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) was detected in China at the end of 2019, ¹ and the associated respiratory syndrome was named coronavirus disease 2019 (COVID‑19). ² COVID-19 was declared a pandemic in March 2020. By January 2022, >9.5 billion doses of vaccine against COVID-19 had been administered worldwide. ³ BNT162b2 is an mRNA vaccine developed by Pfizer–BioNTech to prevent the disease caused by SARS-CoV-2. ⁴

Several ocular adverse events related to these vaccines have been reported.^3,5–14 For example, several reports described the occurrence of retinal vein occlusion (RVO) after vaccination.^3,6–14 Vujosevic et al. ¹⁰ stated that RVO can be considered a rare ophthalmic complication after vaccination against SARS-CoV-2.

RVO is a multifactorial vascular disease characterized by retinal blood stasis, increased venous tortuosity, intraretinal hemorrhage, and macular edema (ME), and it may cause loss of vision or blindness. ¹² Branch RVO (BRVO) occurs at arteriovenous crossing regions ¹⁵ and typically occurs in middle-aged and older patients (i.e., >50 years of age) with an equal sex distribution. ME is the main cause of vision loss in patients with BRVO. Anti-vascular endothelial growth factor agents are used as the first-line treatment of ME due to BRVO.

In this report, we describe a patient who developed recurrence of ME due to BRVO 3 days following vaccination against SARS-CoV-2 with BNT162b2 produced by Pfizer–BioNTech.

Case presentation

A man in his early 50s presented with decreased vision in his right eye. He had maintained good health for >12 years after quitting smoking, and he had no chronic systemic diseases. He had received two doses of the SARS-CoV-2 mRNA vaccine BNT162b2 (Pfizer–BioNTech) in 2021 as well as a third dose of the SARS-CoV-2 mRNA-1273 vaccine (Moderna) in March 2022. He experienced headache, muscle pain, and general fatigue 1 day after the fourth dose of the SARS-CoV-2 vaccine as well as during the previous vaccine administration. He had been previously diagnosed with ME due to BRVO in an eye clinic. On his initial visit to our hospital, the patient’s logarithmic best-corrected visual acuity (BCVA) was −0.79 in both eyes. Moreover, his intraocular pressure was 13 and 15 mmHg in the right and left eye, respectively. Slit-lamp biomicroscopy showed no abnormalities such as cataract, anterior chamber inflammation, or vitreous cells in either eye. Fundus examination revealed ME due to superior temporal BRVO in the right eye (Figure 1(a)). Optical coherence tomography confirmed the ME in the right eye (Figure 1(b)), and the central foveal thickness (CFT) was 486 µm. The hemoglobin A1c and homocysteine levels were 5.9% and 12.5 nmol/mL, respectively. Other blood test results were within normal limits, including the D-dimer concentration.

Figure 1.

(a) Fundus photograph showing widespread hemorrhage associated with venous occlusion of the superotemporal branch vein in the right eye. However, retinal hemorrhage was not observed in the left eye and (b) Optical coherence tomography of the macula showing substantial cystoid macular edema and accumulation of intraretinal fluid. These observations were associated with subfoveal neuroretinal detachment and a central macular thickness of 486 µm in the right eye.

The clinical diagnosis in this case was ME due to BRVO in the right eye. The patient was immediately treated with intravitreal aflibercept (IVA) injection. One month after the IVA injection, the CFT decreased to 299 µm (Figure 2).

Figure 2.

Cystoid macular edema in the right eye disappeared 1 month after treatment (central foveal thickness: 299 µm).

In January 2023, the patient received a fourth dose of the SARS-CoV-2 mRNA vaccine BNT162b2 (Pfizer–BioNTech) because the Japanese government recommended that people receive multiple doses of COVID vaccines. ¹⁶ Three days later, the patient noticed vision loss in his right eye. Although his logarithmic BCVA remained unchanged at −0.79, optical coherence tomography images showed recurrence of ME in his left eye (Figure 3). The CFT had increased to 507 µm (Figure 3). The patient was treated with an additional one-time dose of IVA injection. The ME resolved immediately (Figure 3), and the logarithmic BCVA was maintained at −0.79. Eight months after the additional IVA injection, the patient had developed no recurrence or new BRVO.

Figure 3.

Cystoid macular edema recurred after the fourth dose of an mRNA vaccine against severe acute respiratory syndrome coronavirus 2. The central foveal thickness had increased to 507 µm.

The patient provided written informed consent for administration of the treatment. The study protocol conformed to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Dokkyo Medical University Saitama Medical Center (approval number 23051). Because of the retrospective nature of this study, the requirement for informed consent for the publication of this report was waived by the Ethics Committee of Dokkyo Medical University Saitama Medical Center. All patient details have been de-identified. The reporting of this study conforms to the CARE guidelines. ¹⁷

Discussion

To the best of our knowledge, only one report to date has described recurrence of ME due to BRVO that had been previously under control following vaccination against SARS-CoV-2. ¹⁸ Therefore, the relevance and novelty of our case are high. Mani and Ojha ¹⁹ reported that thromboembolic events can occur following vaccination against SARS-CoV-2, most commonly after the administration of the vaccine produced by AstraZeneca. These thromboembolic events may be responsible for the development of RVO following vaccination against SARS-CoV-2. Tanaka et al. ¹¹ suggested that vaccination against SARS‑CoV‑2 may trigger an inflammatory response, microvascular disorders, and hypercoagulability, resulting in the development of BRVO. Majumder and Prakash ¹⁴ reported that RVO can occur because of inflammation-induced thrombosis following vaccination against SARS-CoV-2. Although the AstraZeneca vaccine was not used in the present case, the same mechanism may be responsible for the recurrence of ME. Tanaka et al. ¹⁸ hypothesized that vaccination against SARS-CoV-2 can lead to a systemic immunogenic response and secondary coagulative dysfunction similar to that induced by COVID-19. This coagulative dysfunction can result in BRVO recurrence. ¹⁸ In the present case, the retinal hemorrhage did not progress, and only recurrence of ME was observed. Although recurrence of ME may be caused by inflammation, no inflammation involving the anterior chamber or vitreous cells was observed in the present case. Therefore, the probability of inflammation in our patient seems low.

Tanaka et al. ¹⁸ reported that SARS-CoV-2 vaccination initiates a systemic inflammatory reaction that imitates the immunogenic reaction observed in patients with COVID-19. Although our patient developed no ocular local inflammation, such as that involving the anterior chamber or vitreous cells, he experienced headache, muscle pain, and general fatigue after the fourth dose of the SARS-CoV-2 vaccine. These symptoms may have been caused by a systemic inflammatory reaction and immune reaction. The vaccine administration seems to be a likely explanation because no indication of recurrence was observed 8 months after the additional IVA injection, and the patient had maintained good health for >12 years after quitting smoking and had no chronic systemic diseases.

Nevertheless, Feltgen et al. ¹⁵ reported that vaccination against SARS-CoV-2 was not associated with a higher risk of retinal vascular occlusive disease. Because our patient developed reduced vision 3 days after vaccination, we considered that vaccination might have been the cause of this phenomenon. However, it is possible that the reduced vision occurred because of unknown reasons. The ME may have started to worsen before the patient received the fourth dose of the vaccine. At present, the association between RVO and vaccination against SARS-CoV-2 remains unclear.

Recurrence of ulcerative colitis, ²⁰ glomerulonephritis, ²¹ multiple sclerosis, ²² nephrotic syndrome, ²³ uveitis, ²⁴ and Vogt–Koyanagi–Harada (VKH) disease ²⁵ may be associated with vaccination against SARS-CoV-2. Masuta et al. ²⁰ suggested that type I interferon responses due to mRNA sensing by pattern recognition receptors results in the exacerbation of ulcerative colitis. They described a 22-year-old woman who developed diarrhea, bloody stool, and abdominal pain 4 days after the first dose of BNT162b2 vaccination (Pfizer–BioNTech). ²⁰ Nabizadeh et al. ²² reported that vaccination against SARS-CoV-2 may trigger relapses in some patients with multiple sclerosis. In their study, 22 of 29 patients developed relapse after their first dose of the COVID-19 vaccine, 1 after the second dose, and 5 after the booster dose. ²² Twelve patients received the Oxford/AstraZeneca vaccine, 12 received the Pfizer–BioNTech vaccine, 2 received the Moderna vaccine, and 1 each received the Sputnik and Sinopharm vaccines. ²² Nakagawa et al. ²³ stated that the association between vaccination against SARS-CoV-2 and relapse of nephrotic syndrome remains unclear. They observed 18 cases of relapse following Pfizer–BioNTech vaccination, 2 following Moderna vaccination, and 1 following unknown vaccination. ²³ Seven cases occurred after the first dose and 14 occurred after the second dose. ²³ Zhong et al. ²⁴ reported that 39 uveitis relapse events occurred in 34 patients after COVID-19 vaccination. They reported that 19 episodes of relapse occurred after the first dose of the vaccine, 17 after the second dose, and 3 after the third dose. ²⁴ Papasavvas and Herbort ²⁵ reported that vaccination against SARS-CoV-2 can increase the risk of relapse of VKH disease that had been controlled for a long period of time. They reported that 6 weeks after the second dose of the Pfizer anti-SARS-CoV-2 vaccine, the patient developed severe recurrence of VKH disease. ²⁵ The mechanism underlying this relapse is unclear. Although the above diseases^20–25 are autoimmune or inflammatory systemic diseases, they are categorized differently from BRVO. Therefore, their comparison with our case may be difficult.^20–25

In summary, we managed a patient who developed recurrence of ME due to BRVO 3 days after the administration of a fourth dose of a vaccine against SARS-CoV-2. Despite the recurrence of ME, the BCVA was unaffected. It is not possible to identify the cause of this recurrence because the association between BRVO-induced ME and vaccination against SARS-CoV-2 is currently unclear. However, considering the widespread use of vaccines against SARS-CoV-2, ophthalmologists should consider the possibility of such an association.