Ocular manifestations of COVID-19: A systematic review of current evidence

Introduction COVID-19 caused by SARS-CoV-2, commonly presents with symptoms such as fever and shortness of breath but can also affect other organs. There is growing evidence pointing to potential eye complications. In this article, we aim to systematically review the ocular manifestations of COVID-19. Methods We conducted a systematic review to explore the ocular manifestations of COVID-19. We searched online databases including PubMed, Embase, Scopus, and Web of Science up to September 4, 2023. After a two-stage screening process and applying inclusion/exclusion criteria, eligible articles were advanced to the data extraction phase. The PRISMA checklist and Newcastle-Ottawa Scale (NOS) were used for quality and bias risk assessments. Results We selected and extracted data from 42 articles. Most of the studies were cross-sectional (n = 33), with the highest number conducted in Turkey (n = 10). The most frequent ocular manifestation was conjunctivitis, reported in 24 articles, followed by photophobia, burning, chemosis, itching, and ocular pain. Most studies reported complete recovery from these manifestations; however, one study mentioned visual loss in two patients. Conclusion In general, ocular manifestations of COVID-19 appear to resolve either spontaneously or with supportive treatments. For more severe cases, both medical treatment and surgery have been employed, with the outcomes suggesting that complete recoveries are attainable.

The most common symptoms in COVID-19 are fever and shortness of breath (Wiersinga et al., 2020).While the virus primarily targets the lungs and immune system, it can also damage other organs, with the severity varying among patients (Chen and Jungang, 2020).COVID-19 complicates the clinical diagnosis process due to the absence of unique pathognomonic symptoms (Jin et al., 2020).Additionally, some patients may present with gastrointestinal (Han et al., 2020), renal and even ocular symptoms (Renu et al., 2020).The eye is an organ that plays a very important role in the transmission process of COVID-19, and protecting the eyes and doing this correctly during the epidemic is a must.On the other hand, it should be taken into account that sometimes eye manifestations can be the first or even the only manifestation of COVID-19, sometimes eye manifestations are a set of symptoms that can show themselves at any stage of the disease or even after recovery (Domínguez-Varela et al., 2021;Qu et al., 2021).
Most studies have emphasized respiratory symptoms, yet there is evidence pointing to potential eye complications (Seah and Agrawal, 2020).Research indicates that keratoconjunctivitis (Hutama et al., 2022), conjunctivitis (Chen et al., 2020;Maychuk et al., 2020;Wu et al., 2020), conjunctival irritation, diplopia and cotton wool patches are among the most prevalent ophthalmic symptoms in COVID-19 patients (Khan et al., 2021).Notably, viral conjunctivitis has been observed to affect men more frequently than women (Al-Namaeh, 2021).In some instances, these ophthalmic symptoms have been among the initial clinical manifestations of COVID-19 (Baig, 2020).Most reported cases were linked to acute manifestations of COVID-19, although some chronic instances have also been documented (Mahayana et al., 2020).
Understanding the frequency and nature of ocular symptoms related to COVID-19 can assist physicians in making more accurate and timely diagnoses.This study underscores the significance of recognizing the prevalence and ocular manifestations of COVID-19 to facilitate better and earlier detection of the disease.Hence, we aim to systematically examine the ocular manifestations of COVID-19 in this article.

Methods
In this systematic review, we provide a comprehensive overview of the ocular manifestations associated with COVID-19 infection, drawing from the current literature.The authenticity and reliability of our findings are enhanced through adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.Bias risk is also minimized by exploiting the Newcastle-Ottawa Scale (NOS) bias assessment tool.

Data sources
We searched for specified keywords and their combinations in the online databases of PubMed, Embase, Scopus, and Web of Science.All literature published in English up until September 4, 2023, were harvested for further investigations and data extraction processes.Below are the examples of keywords and their combinations used in our database searches: A. "COVID-19" OR "SARS-CoV-2" OR "coronavirus disease 2019" OR "severe acute respiratory syndrome coronavirus 2" [Title/Abstract] B. "Ocular" OR "Ophthalmic"

Study selection
Screening and selection of the retrieved publications occurred in two steps.In the initial step, the titles and abstracts were assessed.In this step, four researchers (R.S., A.M., A.D., M.A.H.) identified relevant articles based on their titles and abstracts to be considered for the subsequent, more detailed stage.In this second stage, five other researchers (A.P., I.A.F., S.S.T.Z., P.M., A.M.V.) scrutinized the full texts of the screened articles and proceeded with extraction of necessary data.
Included publications met the following criteria: they were being original article, case series, or case reports, published in English, and underwent peer review process before publication.We excluded the papers that met any of the following criteria: nonhuman such as animal or in vitro studies, experiments with insufficient published data, publications without accessible full texts, conference abstracts, duplicated papers, and editorial letters.

Data extraction
Five researchers (A.P., I.A.F., S.S.T.Z., P.M., A.M.V.) carried out extraction of essential data.This step was undertaken after the completion of the second selection phase, during which full texts were thoroughly reviewed.The extracted data is presented in Table 2.Additional checks for possible duplicate papers and extracted data were performed by other research members.

Quality assessment and bias risk evaluation
As mentioned above, to enhance the reliability and soundness of our research, we employed the items of PRISMA checklist in this review study.Moreover, we assessed the risk of bias in the included studies using the Newcastle-Ottawa Scale (NOS).The criteria of this tool, which include selection, comparability, and exposure/outcome, have respective values of 4, 2, and 3 for individual studies, as shown in Table 1.The sum of these values gives a maximum possible score of nine for each included study.

Results
In this review, we investigated the ocular manifestations in COVID-19 patients by examining available evidence.We initially identified 5,595 articles.After eliminating 3,227 duplicates, we screened 2,368 articles based on their titles and abstracts.In the first phase of screening, 1,816 articles were excluded based on our inclusion and exclusion criteria.During the second phase of screening, 552 articles were reviewed, from which we extracted data from 42 articles.The selection process is illustrated in the PRISMA diagram (Fig. 1).Most of the studies were cross-sectional (n = 33), followed by case-control studies (n = 3), cohort studies (n = 3), case-report (n = 2), and case-series (n = 1).Most of studies have been conducted in Turkey (n = 10); followed by China (n = 7), Italy (n = 4), India (n = 6), the USA (n = 4), with two studies each from Brazil, and Switzerland.Single studies were conducted in France, Spain, Germany, Iraq, Egypt, Iran, and a multi-country study was undertaken in both Turkey and the USA.
Comorbidities were reported as follow: hypertension in 14 articles, Diabetes Mellitus in 12 articles, obesity and cerebrovascular in 4 articles, cancer and asthma in 3 articles; and cardiovascular, cataract, renal disease, respiratory system disease, and dyslipidemia were each mentioned in 2 articles.Autoimmune disease, hyperlipidemia, chronic liver disease, CKD, COPD, Hashimoto disease, diabetic retinopathy, CRF, glaucoma, nephritis, thyroid disorders, and neurological disorders were each discussed in one article.Ocular manifestations were reported in the majority of the studies and were significantly more prevalent in COVID-19 patients compared to control groups.The most common ocular manifestation was conjunctivitis, mentioned in 24 articles, followed by photophobia, burning, chemosis, itching, and ocular pain in fourteen, seven, seven, six, and five articles, respectively.Less prevalent manifestations were as follows: tearing, red eyes, irritation, eye pain, blurry vision, and retinal hemorrhage.Some studies reported treatments for these manifestations, with most patients recovering fully (Giampietro et al., 2023;Silveira et al., 2022;Pirraglia et al., 2020;Wang et al., 2021;Reinhold et al., 2021;Wan et al., 2022;Abrishami et al., 2020).However, one study noted visual loss in two patients (Chen et al., 2020).
Based on a cross-sectional study of 104 COVID-19 patients of which 36 exhibited ocular symptoms, it was observed that ocular manifestations related to COVID-19 can manifest at various stages.Among those with ocular symptoms, 77.7 % developed them within three weeks of the onset of COVID-19 symptoms.Specifically, 50 % exhibited ocular symptoms concurrently with general symptoms.Additionally, 41.6 % showed ocular symptoms before the onset of COVID-19 symptoms, with 11.11 % presenting them one day before flu-like symptoms and another 11.11 % displaying them three days afterward (Silveira et al., 2022).
Conjunctivitis symptoms appeared as particular ocular manifestations at various times, with 28.5 % of patients exhibiting them during the first week of disease onset and 71.4 % exhibiting them during the second.Some individuals developed conjunctival congestion 0-3 days after developing clinical symptoms, while others developed it 15-28 days after developing clinical symptoms (Jidigam et al., 2022).Overall, the timing and presentation of ocular symptoms in COVID-19 patients varied, indicating that ocular involvement can happen at various times over the course of the illness (Giampietro et al., 2023;Sharma et al., 2022;Oren and Kocabas, 2022;Riotto et al., 2022;Dag Seker and Erbahceci Timur, 2021).
According to the findings, conjunctivitis is a rare and self-limited consequence in adults with COVID-19.However, the presence of coronavirus receptors on the surface of the human eye and the lacrimal glands of mice raises concerns about SARS-CoV-2 infection.Individuals with ocular pain had thinner peripapillary retinal nerve fiber layers, and those with fever and ocular involvement typically had greater levels of CRP, neutrophil counts, and ESR, while having lower levels of lymphocytes.Also, the inpatient group of patients had a higher prevalence of ocular symptoms, comorbidities, chronic ocular disease, and prior ocular surgery.Also, patients with signs or symptoms had greater plasma levels of interleukin-6 and red cell distribution width, and patients with retinal abnormalities were more likely to have a history of diabetes (Baig, 2020;Firat and Kobat, 2021;Ganesh and Mohanan-Earatt, 2022;Shaikh et al., 2022;Shen et al., 2021;Sindhuja et al., 2020;Pirraglia et al., 2020;Ranzenigo et al., 2021;Dag Seker and Erbahceci Timur, 2021;Jidigam et al., 2022;Wan et al., 2022;Abdelkader et al., 2021), be overweight (Baig, 2020;Sindhuja et al., 2020;Ranzenigo et al., 2021;Dag Seker and Erbahceci Timur, 2021), or have raised C-reactive protein levels (Pirraglia et al., 2020).

Overview of findings
Evidence indicates that COVID-19 exhibited a wide range of signs and symptoms.Although ocular manifestations in COVID-19 patients are typically infrequent, our systematic review aimed to evaluate these symptoms, potentially aiding in the disease's earlier diagnosis.In this systematic review, the authors encompassed 42 studies, with conjunctivitis emerging as the most frequently reported ocular symptom (n = 24 papers), followed by photophobia (n = 14), burning (n = 7), chemosis (n = 7), itching (n = 6), and ocular pain (n = 5).Some less common manifestations were as follows: tearing, red eyes, irritation, eye pain, blurry vision, and retinal hemorrhage.
In our study, conjunctivitis emerged as the most frequently observed ocular symptom, reported in 24 articles.Aligned with our findings, N. Shaikh et al. (Shaikh et al., 2022), reported that 33.3 % of COVID-19 patients exhibited conjunctivitis, making it the predominant ocular manifestation, followed by eye pain at 23.1 %.Another study showed that 13.4 % of patients experienced conjunctivitis, which significantly correlated with disease severity (Shen et al., 2021).The underlying pathogenic pathways of conjunctival COVID-19 infection remain unclear.The ocular surface might serve as an entry point for the virus, either through hand-to-eye contact or exposure to aerosolized droplets.Two critical components facilitating the virus's entry into host cells are the cell surface protease enzyme (TMPRSS2) and the ACE-2 receptor.The presence of these receptors on the ocular surface is a subject of debate.However, research utilizing immunohistochemistry analysis has indicated the ACE-2 receptor's distinct presence in the conjunctiva, cornea, and limbus.Additionally, conjunctival samples have shown expression of TMPRSS2 (Zhou et al., 2020).The research showing that SARS-CoV-2 RNA may be found in the conjunctival mucosa and tears of COVID-19 patients reinforces the idea that the eye may be a potential site of infection (Mohammad Alrawashdeh et al., 2021).SARS-CoV-2 is thought to spread via the conjunctival sac tears and nasolacrimal ducts and finally proceed to the respiratory system (Qing et al., 2020).Additionally, it has been suggested that the direct viral assault from the eyes could be maintained by a strong immune response that may result in significant tissue injury.As a result, autoimmune and autoinflammatory responses may both be at play (Gulati et al., 2020).The symptoms of conjunctivitis associated with COVID-19 are comparable to those of other viral types.Most often, the patients have chemosis, epiphora, follicular response of the tarsal conjunctiva, minor eyelid edema, watery discharge, and swollen submaxillary and preauricular lymph nodes (Bertoli et al., 2020).The COVID-19 conjunctival symptoms seem to be self-limiting.Some patients have shown symptom relief after the application of topical treatments like ganciclovir and ribavirin (Sen et al., 2021).Regarding ocular chemosis, a notable symptom observed in various studies, G.  patients with ocular complications and found that 58.2 % exhibited chemosis (Sehgal et al., 2021).Another study revealed that 15.5 % out of 142 COVID-19 patients presented chemosis as an ocular symptom (Abrishami et al., 2020).Factors such as decreased venous return and elevated hydrostatic pressure resulting from positive pressure ventilation or tight endotracheal tube tape, mainly due to prolonged recumbency, are potential risk factors for conjunctival chemosis (Sen et al., 2021).Some other manifestations such as photophobia, ocular pain, itching, and burning have also been reported as ocular manifestations of COVID-19 patients (Shaikh et al., 2022;Rodriguez-Ares et al., 2021;Abrishami et al., 2020).Therefore, medical personnel in close contact with COVID-19 patients should wear face shield or eye protection glasses, given the virus's ability to adhere to the ocular surface and enter the respiratory system through the eye (Qing et al., 2020).
In addition to the direct effects of the virus on the eyes, its treatments and immunizations have similar impacts.Some medications for COVID-19, such as chloroquine and hydroxychloroquine-commonly used treatments-may pose risks to ocular health.Prolonged use of these drugs can lead to retinal toxicity, although short-term use seems safe.Interferon, another treatment option, has been linked to side effects including retinopathy, conjunctivitis, corneal ulcers, optic neuropathy, and epithelial abnormalities (Asili et al., 2021;Eissa et al., 2022).Ribavirin is also identified to have side effects such as serous retinal detachment, retinopathy, retinal vein occlusion, and ischemic optic neuropathy.Corticosteroids also have known ocular side effects in systemic treatment, which comprise glaucoma, cataracts, and central serous chorioretinopathy (Samaranayake et al., 2020).
In regards to protective measures and ocular transmission of COVID-19, Samaranayake et al. in their systematic review of 21 papers found that using layered, masks/respirators that fit on face, and protectiveeyewear can curb COVID-19 transmission among healthcare workers.They also specified that a combination of intervention such as face mask and a face shield, can resist aerosol inhalation more effectively than either alone (Matos et al., 2021).Similarly, a review showed that SARS-CoV-2 can be transmitted effectively through the eyes which signifies the importance of eye-protection tools like goggles for health care workers or potential carriers of the virus (Chu et al., 2020).One study supported by the WHO for guidelines establishment on social distancing also proposed that eye protection can be effective in transmission prevention in the community setting and provides additional benefits (Davis et al., 2022).Another review also asserted that eyes are an additional entry route for SARS-CoV-2, and found that SARS-CoV-2 is most probable to be extracted from the ocular secretions of high-viral load patients that have conjunctivitis, as the ocular fluid can serve as a source of viral replication and transmission vector to corneal, conjunctival, and nasolacrimal tissue.Thus they also have signified the rule of protective eye-wear for prevention of COVID-19 transmission (Masiá et al., 2021).

Time of onset
In terms of ocular manifestation timeline, several studies have shown a correlation with the timing of the increase in immunoglobulin levels.In essence, high IgG concentrations, early seroconversion, and an elevated viral load have all been linked to severe COVID-19.It has been demonstrated that a mild infection results in delayed seroconversion and longer viral shedding.Due to the longer time being exposed to viral antigens, there is a delayed viral clearance and also increased serum levels of IgG at 6-8 weeks (Jin et al., 2020;Danthuluri and Grant, 2020).In an assessment of 27 COVID-19 patients, the onset of ocular symptoms spanned a broad timeline.For some, ocular manifestations were the initial symptom of the COVID-19 infection, while for others, these symptoms appeared anywhere from 0 to 28 days after the onset of clinical symptoms (Chen et al., 2020).Another study found that ophthalmological symptoms manifested between one and seven days following the appearance of clinical symptoms (Boz et al., 2021).The ocular symptoms may appear at any stage of the disease.Conjunctivitis, as a medical sign of COVID-19, usually appears at the beginning of the disease.If ocular pathology develops later in the clinical phase, it seems to be linked to COVID-19 being more severe.Although early detection of COVID-related ocular symptoms should limit the spread of the illness in general, evidence for direct transmission through eye mucosa is currently lacking (Danthuluri and Grant, 2020).

Outcome
Unfortunately, 26 out of 42 articles neither reported the outcome of patients nor did followed patients.However, the majority of studies that included a short follow-up reported that most of the ocular manifestations resolved spontaneously within few days or with supportive treatments.In cases of severe conditions, patients underwent medical treatments such as Vit-A/healing ointment, antibiotic eye drops, topical steroids, IV steroids, etc. and even surgery, leading to clinical improvement and complete recovery.While most symptoms disappeared and patients became symptom-free, some individuals continued to experience ocular discomfort, such as eye rubbing, for several months.

Limitation
The present study has some limitations.Firstly, the study design of included studies did not allow for reliable causal inferences.Additionally, there were few studies on some of the discussed matters, which may reduce the validity and reliability of reported outcomes.Nevertheless, this study may provide relevant insights for future research to conduct original studies and/or meta-analyses to precisely determine the association between COVID-19 and ocular manifestations.Furthermore, our recommendation for future studies is to continuously monitor patients in order to identify long-term effects of COVID-19 on eyes.

Conclusion
Although ocular manifestations of COVID-19 appear to be infrequent, they present a broad spectrum of symptoms, ranging in severity from mild eye redness or itching that may need no or only supportive treatment, to severe cases requiring medical intervention and possibly surgery.While there have been few reports of severe conditions resulting in visual loss, the majority of patients responded favorably to treatments, with full recoveries being attainable.These findings highlight the need for a comprehensive clinical assessment, encompassing not just the commonly recognized respiratory symptoms, but also potential ocular complications.Clinicians should be aware of the possibility of ocular symptoms as an early or concurrent presentation of COVID-19.Regular ophthalmic examinations, particularly for hospitalized patients, can aid in early detection and management and future policies should consider updating guidelines to include routine eye examinations for COVID-19 patients, particularly those exhibiting severe respiratory symptoms, as this could be indicative of systemic disease severity.

Future research
Few studies have investigated the ocular manifestations of COVID-19 among the children or the elderly, or the potential differences between sexes.In order to fill that gap in literature, the ocular symptoms among specific age or gender sub groups, more studies are needed.In addition, the exact mechanism of SARS-CoV-2 transmission via tear is unknown and uncertain thus further studies can be conducted to shed light on that part.

Table 1
Bias Risk Assessment of Included Studies Based on Newcastle-Ottawa Scale (NOS).

Table 2
Description of the findings reported in eligible studies.