Ocular Symptoms In COVID-19 Infection: A Survey Study

Abstract Background: Coronavirus disease 2019 (COVID-19) systemic symptoms and sequelae have been studied extensively, but less is known about the characterization, duration, and long-term sequelae of ocular symptoms associated with COVID-19 infection. The purpose of this study was to analyze the frequency, spectrum, and duration of ocular symptoms in participants with COVID-19 infection treated in inpatient and outpatient settings. Methods: A retrospective electronic survey was distributed to NIH employees and the public who reported testing positive for SARS-CoV-2. The anonymous survey collected information on demographics, past ocular history, systemic COVID-19 symptoms, and ocular symptoms. Results: A total of 229 (21.9% male and 78.1% female, mean age 42.5 ±13.9) survey responses were included. Ocular symptoms were reported by 165 participants with a mean of 2.31±2.42 symptoms. The most commonly reported ocular symptoms were light sensitivity (31.0%), itchy eyes (24.9%), tearing (24.9%), eye redness (24.5%), and eye pain (24.5%). Participants with ocular symptoms had a higher number of systemic symptoms compared to participants without ocular symptoms (mean 9.17 ± 4.19 vs 6.22 ± 3.63; OR: 1.21; 95% CI: 1.11 – 1.32; p<0.001). Ocular symptoms were more common in those who reported a past ocular history compared to those who did not (81.8% vs 67.1%; OR: 2.17; 95% CI: 1.08 – 4.37; p=0.03). Additionally, the onset of ocular symptoms occurred most frequently at the same time as systemic symptoms (47.5%), and 12.6% reported symptoms lasting ≥14 days. Conclusions: Ocular surface-related symptoms are the most frequent ocular manifestations, and systemic disease severity is associated with the presence of ocular symptoms. Additionally, our results show that ocular symptoms can persist post-COVID-19 infection. Further work is needed to better understand ocular symptoms in COVID-19 and long-term sequelae.

Currently, several theories exist regarding the pathogenesis of ocular symptoms associated with COVID- 19 infection. Notably, the ocular surface has been implicated as a potential route of entry of SARS-CoV-2 virus through the nasolacrimal system 8, 9 . Additionally, conjunctival expression of angiotensin-converting enzyme 2 (ACE2), which mediates viral entry into the host cell, and transmembrane serine protease 2 (TMPRSS2), which cleaves the virus's spike (S) protein, may facilitate an ocular route of viral entry 10 .
Although SARS-CoV-2 has also been detected via reverse transcription polymerase chain reaction (RT-PCR) on conjunctival swabs, evidence of spread via ocular secretions is still inconclusive 11, 12 . Despite these reports, more information is still needed on the frequency, timing, spectrum, and duration of SARS-CoV-2-associated ocular symptoms. Additionally, the majority of published reports describing ocular symptoms involve hospitalized patients, whereas comparatively less is known about those treated in the outpatient setting. Thus, the purpose of this study is to systematically characterize the range of ocular symptoms found in majority non-hospitalized individuals with COVID-19 infection. Our survey was designed to gather a large amount of information regarding ocular symptoms in COVID-19 infection. The study information was distributed to NIH employees who had tested positive for SARS-CoV-19, as well as the general public through social media and patient recruitment mailing lists. The survey queried participants about demographics, past ocular and medical history, details of their COVID-19 infection, and ocular symptoms. All responses were kept anonymous, and survey responses were collected from October 2020 through June 2021. In order to participate in the study, respondents were required to consent to completing the survey, con rm testing positive for SARS-CoV-2 via a polymerase chain reaction (PCR) test, and attest that they were 18 years of age or older. This study was approved as exempt by the NIH O ce of IRB Operations, and patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this project.

Methods
Only complete responses were included for analysis. For statistical analyses, SPSS v.17.0 statistical software for Windows (SPSS Inc., Chicago, IL) was used. For descriptive statistics, continuous variables are presented as means ± standard deviations, and categorical variables are presented as frequencies and proportions. Multivariable logistic regression models were used to identify signi cant predictors of clinical symptoms adjusted by age, gender and race. Comparisons of continuous variables between two variables were done by student t-test for normally distributed variables. For variables without normal distribution, Mann-Whitney U test was used for comparisons between two independent variables. A twotailed p value of < 0.05 was considered signi cant.
Notably, only 22 (13.3%) of respondents with ocular symptoms sought medical attention by an eye care professional (ophthalmologist or optometrist). Of those participants who sought care, 9 out of 22 (40.9%) respondents had their eye symptoms attributed to COVID-19 infection by their eye care professional.

Discussion
Our results demonstrate several points of interest, including 1) ocular surface related symptoms are the most frequently reported ocular symptoms in COVID-19 infection; 2) ocular symptoms are more frequent in those with a reported past ocular history; 3) systemic disease severity is associated with the presence of ocular symptoms; and 4) a proportion of participants reported post-COVID-19 persistent ocular symptoms.
In large-scale studies, the reported prevalence of ocular ndings in COVID-19 infection have varied from as low as 1.4% to as high as 11.2% 5,14,15 . However, Inomata and colleagues suggested that these numbers are likely an underestimation, as individuals with COVID-19 have a range of manifestations and may be unlikely to seek out ophthalmic evaluation when other life-threatening symptoms are present. The most frequently observed signs in a meta-analysis by La Distia Nora et al. were epiphora, conjunctival injection, and chemosis, which are commonly seen in other forms of viral conjunctivitis 16 . Other reported ocular ndings have included both anterior and posterior segment ndings such conjunctivitis, uveitis, acute macular neuroretinopathy, and retinopathy 17,18 . Notably, ocular manifestations have occasionally been described as the sole or initial presentation of SARS-CoV-2 infection [19][20][21] . The majority of large series studies that investigate ocular manifestations of COVID-19 are in hospitalized patients, and differentiating these manifestations from factors related to hospitalization rather than the infection itself, especially with intensive care, can be challenging. Thus, our study provides insight into ocular symptoms experienced by COVID patients who were -in large part -not hospitalized (90.0%).
Although survey and cross-sectional studies have reported varying frequencies of ocular symptoms, current literature points towards a predominance of ocular surface symptoms when eye symptoms are present. A recent meta-analysis by Soltani et al. found that the most prevalent ocular symptoms were dry eyes (23.8%) and eye pain (10.3%) 22 . Similarly, Nasiri et al., in their meta-analysis, found the most common ocular manifestations to be dry eyes/foreign body sensation (16.0%), redness (13.3%), tearing (12.8%), itching (12.6%), and eye pain (9.8%) 23 . Although varied, these analyses are largely consistent with the ocular symptoms most commonly reported in our study, including light sensitivity (31.0%), itchy eyes (24.9%), tearing (24.9%), and eye redness/pain (24.5%).
Corneal and conjunctival expression of ACE2 receptor, a known entry mechanism of the SARS-CoV-2, has been postulated as a potential mechanism for direct viral invasion of the ocular surface and subsequent ocular manifestations 10,24 . Additionally, Zhong and colleagues of revealed a pooled positivity rate of 3.9% from conjunctival swabs 16 ; however, there are numerous studies that have reported patients with positive conjunctival swabs but no ocular symptoms, and vice versa 1,12,25 . Further, a review by Douglas and colleagues concluded there is no clear relationship between conjunctival titers and transmissibility 2 .
Overall, current research indicates that the relationship between PCR positivity in conjunctival swabs, transmission, and ocular symptoms remains unclear.
Reports have also found that patients with more severe disease were more likely to have associated ocular manifestations, presumably due to a higher viral load leading to disseminated disease 16,26  There is a paucity of data in the literature regarding ocular symptoms associated with "long-haul" COVID- This study has several limitations: As with any survey study, there is unavoidable recall bias. There is also likely an inclusion bias towards respondents experiencing eye symptoms, as this survey was distributed by the National Eye Institute. This bias at least partially accounts for the high frequency of ocular symptoms in our study (72.1%). Another potential limitation is that our study reported ocular symptoms of COVID-19 experienced by patients, not diagnoses since the respondents were not examined by an ophthalmologist at the time of survey completion. Lastly, the results of this study would have been strengthened by a larger sample size.
In conclusion, our results show that ocular surface-related symptoms were more common and visionaffecting symptoms were rare. The majority of participants reported the onset of ocular symptoms at the same time as systemic symptoms, and over a fth of our respondents reported ocular symptoms lasting ≥ 14 days in duration. As vaccination rates increase, hospitalization rates fall, and outpatient cases rise; we believe these results are critical to the understanding of COVID-19 and its ocular manifestations, particularly in outpatient settings. Overall, further research is needed to fully comprehend the pathophysiology and sequalae of ocular symptoms associated with COVID-19 infection. Availability of data and materials -The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests -The authors declare that they have no competing interests.