In the questionnaire answered by 3,289 participants, a discrepancy was observed between the proportion of individuals who tested positive for COVID-19 antigens (29.25%) and those who exhibited COVID-19-related systemic symptoms (83.27%). Various factors may contribute to this lower positive rate of COVID-19 testing. First, changes in testing policies. Following the opening of the epidemic policy on December 7, 2022, regular nucleic acid testing was no longer mandatory and may have led to fewer individuals being tested, potentially declining the detection rate of COVID-19 cases. Second, testing methodologies. Some individuals might have been tested for COVID-19 using antigen strip tests, which are quicker and more convenient but have lower sensitivity compared with nucleic acid tests, especially in individuals with low viral loads or during the early stages of infection. Finally, variability in symptom presentation and disease course. The patients with mild or asymptomatic COVID-19 may test negative for the virus, particularly during the early stages of infection when viral loads are lower. These variabilities can lead to false-negative results, further contributing to the discrepancy between symptom prevalence and positive test rates.
To address this issue during Phase A of this study, which coincided with the COVID-19 pandemic, a comprehensive approach was adopted. Regardless of whether individuals undergoing COVID-19 testing received positive or negative results if they exhibited COVID-19-related systemic symptoms, they were classified as having a COVID-19 infection. This approach acknowledged the limitations and potential inaccuracies of testing methodologies and ensured that individuals with symptomatic presentations were not excluded from analysis solely based on testing results. This inclusive approach possibly provided a more comprehensive understanding of the effect of COVID-19 on our study population during the pandemic phase.
Since the onset of the COVID-19 outbreak, many studies and meta-analyses highlighted the presence of ocular symptoms associated with the virus. These symptoms varied widely in prevalence (range = 0.05–31.6%).17–22 Conjunctival congestion has emerged as one of the most frequently reported ocular presentations.23,24 Additionally, patients have been presenting other ocular symptoms such as increased discharge, ocular pain, photophobia, dry eye, tearing, foreign body sensation, irritation/itching/burning sensation, and temporary vision loss.19–23,25−28 In our study, among participants with systemic symptoms of COVID-19, approximately one-third presented ocular discomfort, indicating a high incidence. Interestingly, the incidence of conjunctival congestion was not the highest. This may be because the data of this study was obtained from an online questionnaire survey, the median age of participants was 32 (20), and all individuals presented only mild systemic or ocular symptoms, with none requiring hospital treatment. Notably, 77.73% of participants with ocular discomfort reported spontaneous resolution of their symptoms without any treatment, suggesting that the condition was transient, mild, and reversible.
The data of this study revealed that the number of ophthalmic outpatient visits notably declined within 1 month after the opening of the epidemic policy (Phase A) and more than 75% of patients exhibited COVID-19-related systemic symptoms, contrasting with zero infected case in the preceding month (Phase B) and the corresponding period the previous year (Phase C). Possibly because of the heightened concerns regarding potential COVID-19 exposure in hospitals during this period and considering the fact that many ocular conditions can be managed at a later, non-urgent time.
During the pandemic Phase A, distinct changes were observed in the spectrum of ocular diseases presented in the ophthalmic clinic compared with that of Phases B and C. The proportion of visits for some conditions reduced, including optometry, conjunctival diseases, dry eye, and lens diseases. These changes likely mirrored the overall decrease in ophthalmic outpatient visits. These conditions shared the following common characteristics: slow progression, minimal short-term effects on the vision, and they did not lead to considerable ocular discomfort.
The diseases that showed an increased proportion of visits included trauma, cornea/keratitis, glaucoma/acute angle-closure glaucoma (AACG), vitreoretinal disease/RVO/AMN, and strabismus. Notably, keratitis-related visits increased two-fold, whereas AACG-related visits increased eight-fold. Some cases of keratitis during this period presented typical herpes simplex virus (HSV)-associated dendritic lesions with corneal fluorescent staining. Studies have linked a small number of HSV keratitis cases in patients with COVID-19 since the pandemic outbreak.29–32
The immune system characteristics in patients with COVID-19, such as immunosuppression and cytokine storm syndrome, may promote the reactivation of latent viral infections such as HSV.33,34 The association between HSV and COVID-19 infections suggests that COVID-19 may pose a risk factor for developing or potentially triggering HSV keratitis.29,35,36 Studies have shown an increased prevalence of herpes keratitis during the peak of the COVID-19 period, which is consistent with our observations.29 However, a systematic review and meta-analysis evaluating active human herpesvirus infections in patients with COVID-19 reported no significant difference in the prevalence of active herpesvirus infections between patients with COVID-19 and non-COVID-19 controls, including those with HSV infections and HSV keratitis.30 This underscores the need for large cohort studies to systematically investigate the reactivation of herpesviruses in patients with COVID-19.
As China downgraded its prevention and control measures for novel coronavirus pneumonia from Grade A to Grade B in January 2023, AACG cases notably increased, which has been reported at various ophthalmic academic conferences.37 A retrospective study examining the morbidity characteristics and risk factors for glaucoma in Huizhou City, China, during the COVID-19 pandemic, revealed that although the overall number of ophthalmic clinic visits decreased during the pandemic period, the proportion of AACG cases increased considerably, indicating that testing positive for COVID-19 increased the risk of developing AACG.7 This observation is consistent with our findings and suggests the contribution of the COVID-19 pandemic to the increase in AACG occurrence.
The underlying mechanisms for the increase in AACG during the COVID-19 pandemic remain unclear. Various factors, including lifestyle alteration-related physiological and psychological changes during the pandemic, may play a role. For example, reduced levels of physical exercise,38,39 decreased sleep quality,40,41 lower ambient light exposure because of increased indoor living,42 changes in body posture, with more time spent sitting or lying down,43,44 and increased screen time.45 Additionally, an increase in mental health issues such as anxiety and depression was reported during the COVID-19 pandemic.46 These psychological states can lead to autonomic nervous system disorders and stimulate the hypothalamic–pituitary–adrenal axis, causing increased adrenaline secretion, pupil dilation, vasomotor dysfunction, ciliary body edema, and other changes.47,48 When the above physiological and psychological changes occur in the population with some special ocular anatomy (such as shallow anterior chambers, narrow chamber angles, or short ocular axes) can lead to increased intraocular pressure, impeding aqueous humor outflow, and ultimately triggering an acute episode of AACG.
Various other relevant factors have been reported, including studies on COVID-19-induced hyponatremia leading to angle-closure glaucoma in individuals with shallow anterior chamber angles,49 cases of bilateral acute angle-closure glaucoma following prone ventilation for pneumonia,50 and instances of over-the-counter oral cold and flu medications triggering AACG.37 Additionally, delayed hospital visits because of epidemic control policies may have contributed to advanced AACG in patients seeking medical attention. The findings of this study revealed that 5.71% of patients with AACG onset at the time of admission to the hospital more than 1 month, underscoring the potential effects of delayed medical care during the pandemic.
This study showed a notable increase in RVO and AMN prevalence during the COVID-19 pandemic compared with those during control periods, with Phases A and C showing particularly notable differences.
To date, many studies on retinal vascular occlusions in association with COVID-19, which are limited to case reports) have reported an increase in the incidence of retinal vascular occlusions after COVID-19 infection, including retinal artery occlusion (RAO), RVO, and AMN, suggesting that retinal vascular damage due to abnormal clotting and thromboembolic events caused by Covid-19 infection may be one of the clinical manifestations of COVID-19.51–55 However, in the absence of randomized controls, a complete and sufficient cause-and-effect relationship remains unelucidated. Two cohort studies concerning the incidence of retinal vascular occlusions in the COVID-19 period reported different trends.56,57 Bobeck et al. reported an association between COVID-19 infection and RVOs but not with RAOs.56 Ahmad et al. reported that the percentages of new cases of RAO and RVO concerning all new diagnoses in retina clinics remained stable for most of the COVID-19 period.57 Further large-scale epidemiologic studies are needed to fully elucidate the relationship between retinal thromboembolic events and COVID-19 infection.
This study found no statistically significant differences regarding the age and sex distribution of patients visiting the ophthalmology clinic during Phases A, B, and C. However, the analysis of age distribution revealed a notable decrease in the number of patients < 18 and > 60 years old during the epidemic period compared with the prevention and control periods. David et al. reported that the incidence and detection rates of COVID-19 were highest in the elderly age group, which may be linked to more extensive testing. Adjusting for testing frequency revealed a reduced infection risk among children and individuals over 70 years old.58 This may be because of behavioral factors affecting risk (such as adherence to social distancing, mask-wearing, and other protective measures), variations in detection methods, or differences in awareness levels among different age groups.59–62
This study has several limitations, including a retrospective, nonconsecutive study design, a relatively short observation period, the presence of unadjusted confounding variables such as past medical history and local or systemic factors, and the lack of serological evidence confirming COVID-19 infection in some patients. It must be acknowledged that establishing a causal relationship between systemic symptoms and ocular manifestations associated with COVID-19 is challenging. However, given the normalization, polymorphism, and persistence of the COVID-19 epidemic, humanity's battle against the virus is far from over. As such, our study holds significant implications and can contribute to enhancing our understanding of the characteristics and changes in the spectrum of ocular diseases under varying COVID-19 epidemic conditions.