Ophthalmic Presentations and Manifestations of COVID-19: A Systematic Review of Global Observations

As the presentations and complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to surface, the ocular manifestations have emerged as an area of interest. Research and reports conveyed the presence of several ophthalmic conditions observed in Coronavirus disease 2019 (COVID-19) patients. These publications documented a range of presentations varying from asymptomatic to serious impairments. The aim of this study is to characterize the ophthalmic pathologies and their frequencies observed due to COVID-19 in patients across different regions of the world. The goal is that the paper assists primary care physicians and healthcare providers. A systematic review of 31 articles published between January 1, 2021 to January 13, 2022, explored the presenting ocular symptoms of COVID-19, diagnosis, duration of ophthalmic complications, as well as pre-existing comorbidities. A total of 816 patients, 427 (52.3%) males and 389 (47.7%) females, from various regions of the world were investigated. Studies focusing on patients with a history of ocular pathologies, non-COVID-19 infections, complications associated with the COVID-19 vaccine, and pediatric patients were excluded from this study. Ocular complications were most commonly reported one to two weeks following the initial COVID-19 diagnosis. Analysis suggests that the “red” eye is the most prevalent presenting ophthalmologic symptom, followed by temporary vision loss. Conjunctivitis was also the most common clinical diagnosis reported, followed by neuro-retinal affection in the form of cotton wool spots (n=127 and n=9, respectively). This study summarizes ocular manifestations in COVID-19 patients and serves to help healthcare providers recognize common symptoms and their severity. This may lead to early diagnosis, treatment, and intervention of these manifestations.

While the pathological effects of COVID-19 were initially emphasized on the respiratory system, other organ systems are beginning to receive added attention. In particular, the eyes have become a particular organ of study. Initial research found that COVID-19 could be transmitted via the lacrimal ducts of the eye [34]. SARS-CoV-2 was found to bind angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease serine 2 (TMPRSS2). These receptors also exist in the tissue of the eyes and represent a possible route of entry via the eyes [35][36][37]. Beyond a potential vector for transmission, the eyes have also expressed an area of research for the manifestations and complications of this disease. Initial documentation has reported various symptoms from dry eye, foreign body sensation, itching, conjunctivitis, and visual acuity changes [38]. Most cases reported were transient and ocular abnormalities resolved following COVID-19 recovery.
Despite the increasing attention, there remains an incomplete understanding of the ocular manifestations and complications surrounding COVID-19 infection. Challenges are exacerbated by the unknown prevalence 1 1 1 1 1 1 of asymptomatic COVID-19 carriers that are unaware and not receiving medical care [40].

Literature Search Criteria
To identify eligible studies, a literature search was performed in PubMed for accessible articles with publication dates between January 1, 2021 and January 13, 2022. The following search terms were applied to identify publications available in English: "COVID-19" AND "ophthalmologic" OR "OPTIC" AND "anterior segment" OR "conjunctiva" OR "ocular surface" OR "retina" OR "retinitis" OR "retinal vein occlusion" OR "glaucoma" OR "conjunctivitis" OR "choroid" OR "uveitis" OR "neuro-ophthalmology" OR "cranial nerve palsy" OR "orbit" AND "manifestations" OR "complications." The initial search resulted in 170 studies using one database (PubMed) (Figure 1). Abstracts of the accessible studies were independently reviewed by two reviewers for eligibility per inclusion and exclusion criteria. Articles were selected for the final analysis if they observed any relationship between COVID-19 infection and ophthalmic manifestations, and infection was confirmed through positive diagnostic tests indicating either previous COVID-19 infection by antibody assay or active infection confirmed by viral reverse transcription-polymerase chain reaction testing (RT-PCR). Exclusion criteria included: studies on pediatric patients younger than 18 years of age, studies with a primary focus on ocular complications due to secondary infection such as mucor mycosis, herpes simplex virus (HSV), and cytomegalovirus (CMV), COVID-19 vaccine-related complications, and papers that focused on the viral-load detection of COVID-19 in conjunctival surfaces.

FIGURE 1: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart followed for inclusion and exclusion criteria
After applying the inclusion and exclusion criteria, 31 accessible papers were finalized to be included in this review . The 31 selected studies had a total of 816 subjects. Publications included 27 case reports, a case series, a cross-sectional study, and a cross-sectional cohort study.

Literature Review Process and Data Collection
Six reviewers extracted information from 31 publications. Each paper was initially examined by two independent reviewers and discrepancies were reevaluated by two other reviewers. The following data were extracted from each study: study design, sample size, country, patient characteristics such as age, gender, comorbidities, and past medical history when available, methodology of COVID-19 diagnosis, ophthalmic diagnosis, intraocular pressure when characterized, interventions, and treatments.

Results
A total of 31 papers were included in the final analysis. The study characteristics are summarized in Table 1

Disease Severity
Most patients included in this study were documented as being placed in the Intensive Care Unit (n=65) or generally admitted to the hospital (n=8). The extent of some COVID-19 infections was not reported, so the status of the patient was reported instead (e.g., hospitalized or home quarantined). Many other papers did not report or grade the severity of COVID-19 and those patients were not included in Table 3.

Reported Time of Ocular Manifestations
In relationship to COVID-19 infection, the reported time of ophthalmic manifestations varied between studies. Earliest reported manifestations were five weeks prior to positive COVID-19 test [27], and the latest reported manifestation was three months following their history of COVID-19 infection [25]. The most reported time of manifestation was approximately one to two weeks following COVID-19 onset or positive test (12 of 27 reported cases). Of note, five of the 27 reported cases reported COVID-19 diagnosis after evaluation or diagnosis of ocular complaints.

Ocular Manifestations
Presenting symptom terminology varied greatly between studies, so symptoms were aligned with the American Association of Ophthalmology's (AAO) list of symptoms to help with categorization of symptoms [42].
Inflammation of the eye, via conjunctivitis, was the most commonly documented presenting symptom with 56 (49.1%) documentations out of the 114 recorded [1,2]. Symptoms, such as eye irritation, redness, and conjunctival hyperemia, were characterized as conjunctivitis in the study by Öncül et al. [1]. Discharge from the eye (via increased secretions or lacrimation) was also documented in their findings and was the third most common presenting symptom documented in our review (  General vision loss (decreases in visual acuity and scotomas) was the second most common diagnosis and was documented 15 (13.2%) times. This vision loss was often temporary and 14 of 15 patients recovered to baseline vision [3,[6][7][8][9]12,16,22,24,[26][27][28][29]. The exception to this recovery was seen in the study done by Mabrouki et al., in which the patient experienced complete blindness due to optic demyelinating neuritis and optic atrophy. Of note, the COVID-19 infection was found incidentally after the patient presented with acute bilateral vision loss [30]. The patient's past medical history included an undocumented splenectomy, diabetes mellitus, and hypothyroidism [30].

Diagnosis
Conjunctivitis was the most common clinical diagnosis provided (n=127). The study conducted by Wasfy et al. accounted for 111 documented cases of diagnosed conjunctivitis [2]. All cases were temporary and resolved within 10 days of combined treatment of antibiotic, steroid, and artificial tears. Retinal affection, in the form of cotton wool spots, was also seen in this study but was temporary and resolved within five weeks. The study also documented six patients diagnosed with orbital fungal cellulitis, each documented as having recovered from COVID-19 infection with at least one pre-existing risk factor, e.g., diabetes [2].
The study conducted by Öncül et al. reported subconjunctival hemorrhage in five patients and vitreous hemorrhage in one patient [1]. In the patient who experienced vitreous hemorrhage, they were diagnosed with diabetes mellitus eight years prior. The patient did not receive routine diabetic eye examinations for four months as COVID-19 interfered with treatment. This patient was on anticoagulant drug therapy during the treatment period and had a severe cough beginning three days before the hemorrhage started [1].

Discussion
The initial reports concerning COVID-19 focused on respiratory manifestations. However, our research demonstrates there are ophthalmic manifestations as well. In this systematic review, we identified papers published on the topic of ocular manifestations of COVID-19 in order to provide healthcare professionals with an updated report. We hope this study aids with the rapid identification and treatment of ophthalmic manifestations associated with COVID-19 disease.
The review revealed a total number of 109 ophthalmic presenting symptoms, with the most common being general inflammation of the eye (n=56), followed by vision loss (n=15), discharge (n=10), and blurriness (n=6) (Figure 2). Overall, the most reported diagnosis was conjunctivitis with the majority reported in the study conducted by Wasfy et al. who reported 111 of the 127 cases of conjunctivitis [2]. Interestingly, all six reported diagnoses of secondary fungal orbital cellulitis were also reported by Wasfy et al. [2]. The time of onset of ocular manifestations in the context of COVID-19 illness is critical for healthcare professionals in consideration of care for infected patients. In our review, the time of ocular manifestations varied quite significantly and was not well documented between studies. The earliest manifestation was reported five weeks prior to a positive COVID-19 test and the latest was reported three months following a positive COVID-19 test. Although there are other causes of ocular pathologies, varying from viral to autoimmune, we are limited by the lack of disclosure of further investigation of other possible causes of ocular pathologies. Regardless, this gap of knowledge will open avenues for other future studies. Average time of presentation varied, with the most common timeframe being one to two weeks following a positive COVID-19 diagnosis, as reported for 12 out of 27 patients. This variability in the timeline of onset of ocular manifestations may be attributed to the methods of data collection which relied primarily on self-reporting of ocular manifestations by patients. The variable geographical health mandates prompted by local governments to prevent transmission of COVID-19 may have negatively disrupted the ability of ophthalmologists to conduct eye exams and other elective clinical services, which may have biased an accurate timeline of the onset of ocular manifestations.
In our systematic review, we found that 65 patients were placed in the ICU and eight patients were admitted to the hospital during the time of diagnosis of ocular manifestations. The association between severe COVID-19 illness and the prevalence of ocular manifestations has also been discussed in the literature with previous studies yielding variable data. Loffredo et al. found the rate of conjunctivitis to be 3% in severe and 0.7% in non-severe COVID-19 patients [45]. Similarly, Guan et al. [46], who retrospectively analyzed clinical characteristics of 1,099 COVID-19 patients, and Wu et al. [47], who retrospectively investigated the ocular characteristics of 38 COVID-19 patients, reported an increased incidence of conjunctivitis in patients with severe disease. In another study conducted by Layikh et al., conjunctivitis was significantly associated with severe COVID-19 illness [48]. However, Xia et al. did not find an increased incidence of conjunctivitis in severe COVID-19 in their prospective study of 30 COVID-19 patients that assessed the presence of the virus in tears [49].
Our findings add to the broader discussion of the association of conjunctivitis as a presenting symptom in severe COVID-19 illness. However, our study was limited by the fact that most manuscripts we reviewed did not document the severity of COVID-19 illness when documenting ocular manifestations, thus preventing us from studying a bigger sample size. Further studies with an emphasis on COVID-19 disease staging are necessary to better elucidate a potential association between the prevalence of ocular manifestations and COVID-19 severity.
Interestingly, Mabrouki et al. reported a case of complete blindness due to optic demyelinating neuritis and atrophy, but it is important to note the patient presented with acute bilateral vision loss before a confirmatory COVID-19 test was performed [30]. Though it is unclear if the patient's COVID-19 illness was the causative factor of the acute bilateral vision loss, the poor prognosis may suggest that COVID-19 could exacerbate symptoms in previously affected eyes.
It should be noted that most of the papers reviewed in this study did not discuss treatment of the ocular manifestations, and diagnoses were assumed to be self-resolving unless otherwise reported. The most common treatments were reported to be steroid use (n=16) and antimicrobial use (n=13) (Figure 3). The selfresolving nature of symptoms may suggest some association between ocular manifestations and active COVID-19 infection.

Limitations
Limitations of this study include the inability to control for potential medication-induced side effects, varying timelines in presentation post COVID-19 infection, and variations in workup of optic complications. Due to quarantine mandates and safety guidelines, patients may have opted to postpone doctor appointments that may have affected documentation of findings. Similarly, postponement of appointments may have exacerbated symptoms due to delayed treatments. Future studies that examine whether preexisting ocular pathologies influence the severity and duration of COVID-19 induced ocular manifestations would provide further understanding of presentations.
Another limitation includes lack of reported severity of COVID-19, either not mentioned or use of nonstandard reports (Table 3). Lastly, ophthalmic examination is often not feasible in ICU patients.
Lastly, there is potential for publication bias as our literature search utilized PubMed exclusively. However, the potential publication bias is offset by the importance of the topic for general providers' educational purposes surrounding COVID-19. Additionally, limiting our search allowed for filtering of false information from unreliable sources, which is particularly important for COVID-19 information.

Conclusions
Since the pandemic, it has been increasingly important to understand the signs and symptoms of COVID-19.
Our results suggest that ocular manifestations of COVID-19 are extensive and can be the presenting symptom of infection, which may be beneficial in timely detection. Therefore, understanding how COVID-19 can present in the eye can aid in its diagnosis and treatment, potentially reducing long-term complications.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.