Ocular tropism of SARS‐CoV‐2 infection

COVID-19, caused by SARS-CoV-2, is still ravaging and has brought unprecedented challenges globally, which can lead to respiratory tract infections, pulmonary inflammation, and multiorgan involvement.1 More COVID-19 patients with conjunctivitis as the first or concomitant symptom have been observed since the optimization and adjustment of COVID-19 measures in China on December 7, 2022. The following are three typical cases: Case 1: An 8-year-old boy from Ningbo, Zhejiang, China. He was infected by SARS-CoV-2 and visited Ningbo Beilun Second People's Hospital on January 1, 2023, complaining of pain in both eyes, foreign body sensation, blurred vision, tearing, periocular erythema, and suspected drug allergy. Examination revealed no obvious signs of a food or drug allergy. Given the patient's clinical history and symptoms, an ophthalmology referral was required. Case 2: A 30-year-old male from Ningbo visited the above hospital the same day. The COVID-19 patient complained of swollen, sore eyes, increased tear production, and eye secretions the day after the high fever. Case 3: A 50-year-old male patient from Wuhan visited Tianyou Hospital on January 2, 2023, after a high fever accompanied by sore, congested eyes, blurred version and tearing. The three mild cases of COVID-19 presented no respiratory symptoms and developed ocular manifestations after the resolution of high fever. These ocular symptoms were similar, including conjunctival congestion, tearing, itching, foreign body sensation, eye pain, conjunctival follicles, and mild eyelid edema; on slit-lamp microscopy, both eyes exhibited conjunctival congestion and thin secretions in the conjunctival sac. Funduscopic examination revealed clear eye optic discs with normal color and retinal vascularity. The macular area showed no edema, exudation, or hemorrhage. Three cases were diagnosed with viral conjunctivitis in both eyes, and the ocular discomfort resolved after one week of treatment. The clinical symptoms for these 3 cases are similar to those of Ozturker et al.2 and Hong et al.3 Ozturker et al. reported a COVID-19 patient with only conjunctivitis and accompanying ocular symptoms without a fever. Hong et al. analyzed ocular symptoms in 15 COVID-19 patients. 6 developed ocular symptoms concurrently with fever or respiratory symptoms, 4 had ocular symptoms 1 to 7 days before fever or respiratory symptoms, and 2 with unknown timing. In contrast, our study found that patients experienced ocular symptoms within 1 to 2 days after the resolution of high fever. Possible mechanisms may include viral replication elsewhere in the body and subsequent spread to the eye, triggering immune responses leading to ocular inflammation or direct viral invasion of the ocular surface. Additionally, Case 1 exhibited both ocular and skin symptoms with erythema on the periocular skin. This phenomenon may involve changes in blood flow resulting from immune responses against the virus. A study found skin symptoms, including measles or erythema multiforme, with the latter more frequent in children.4 The red spots, in this case, resolved after treatment without serious symptoms. The cases above suggest that SARS-CoV-2 may have an ocular predisposition that could cause ocular pain and conjunctivitis. ACE2, the receptor mediating viral infection, is widely expressed in humans, including the respiratory tract, kidneys, intestines, heart, testicles, and central nervous system.5-7 ACE2 is also present in human ocular surface tissues, raising the possibility that droplets or aerosols carrying the virus may bind to ACE2 on the ocular surface, leading to conjunctivitis. Macaques can be infected with SARS-CoV-2 through their conjunctiva and those with relatively high viral loads in their nasolacrimal duct system but only mild and localized lung disease.8 Six days after intranasal infection, a study demonstrated that the SARS-CoV-2 preferentially infected the retinal ganglion cell layer in mouse models, causing enlarged retinas and a severe inflammatory response with high expression of proinflammatory markers. Direct eye injection did not result in brain or lung infection, with the viral load decreasing over time. However, other routes led to infection in the eye and brain via the trigeminal and optic nerves, indicating that the virus may migrate from the respiratory tract to the eyes through the brain.9 These findings further support the ocular tropism and neuroinvasive feature of SARS-CoV-2 and suggest that the eye and brain may be secondary susceptible organs for SARS-CoV-2. The ability of the virus to infect humans through the conjunctiva is still up for dispute. The fundamental mechanism by which the virus causes sickness needs to be confirmed by further research and evidence. The interaction between SARS-CoV-2 and eyes is still mostly unknown. Shuai Zhang, Jianguo Ju, Fang Yang, Chunfu Zheng, and Jingbo Zhai participated in conceptualizing, literature review, and drafting the letter. Chunfu Zheng and Jingbo Zhai critically revised the letter for final submission. All authors approved the final version for submission and publication. This work was supported by a grant from the National Natural Science Foundation of China (NO. 82160312), and Basic Scientific Research Project for Universities of Inner Mongolia Autonomous Region, and the 2023 Young Science and Technology Talent Development Project (Innovation Team) for the Key Technology Research Project of Zoonose Prevention and Control (NMGIRT2315) and Major science and technology projects of Inner Mongolia of China (2019ZD006). The authors declare no conflict of interest. Data availability is not applicable to this article as no new data were created or analyzed in this study.

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