key: cord-0826074-77ossmom
authors: Badawi, Amani E.; Elsheikh, Sara S.; Addeen, Sarah Zaher; Soliman, Mostafa A.; Abd-Rabu, Rami; Abdella, Walid Shaban; Gad, Elham A.
title: An Ophthalmic Insight into Novel Coronavirus 2019 Disease: A Comprehensive Review of the Ocular Manifestations and Clinical Hazards
date: 2020-12-12
journal: J Curr Ophthalmol
DOI: 10.4103/joco.joco_255_20
sha: 69d2babe1d230d96f6f4b69c4ee23ef80b2141a2
doc_id: 826074
cord_uid: 77ossmom

PURPOSE: To discuss the ocular manifestations provoked by novel coronavirus 2019 (COVID-19) disease in humans, the natural history of the disease in the eye, and its treatment. METHODS: We designed a narrative review of the ocular manifestations of COVID-19 based on the literature published till July 30, 2020. The databases were PubMed, Scopus, Cochrane Library, Google Scholar, and ScienceDirect. The inclusion criteria were (1) all types of clinical studies and (2) the topic was COVID-19 and its association to the eye regarding the current guidelines. RESULTS: From 168 abstracts screened, 61 papers fully filled the inclusion criteria after the full-text screening. The 61 records include 13 case reports, 17 prospective (case series or cross-sectional) studies, 8 retrospective studies, 12 literature reviews (one systematic review), and 11 letters to the editor. The majority of the papers agreed that ophthalmic manifestations due to COVID-19 were few and rarely encountered. The main ocular pathology seemed to be conjunctivitis, where the viral polymerase chain reaction also happened to be most detectable. Posterior segment or neuro-ophthalmic manifestations were scarce. Viral genome detection in the eye as well as viral portal of entry to the globe is still vague. CONCLUSION: The exact incidence of ocular manifestations in COVID-19 disease is uncertain. Conjunctivitis is the most prevalent ocular manifestation. It is still a debate whether the eye is a portal of entry for infection.

apart from the respiratory tract, including the ocular tissues and gastrointestinal tract. 4 Although the majority of studies are focused on the respiratory tract because of its life-threatening nature, manifestations of COVID-19 in other systems should not be ignored as they may represent an alternative mode of transmission. 5 A recent study stated that SARS-CoV-2 also uses the cell entry receptor, angiotensin-converting enzyme 2 (ACE2). 6 Moreover, the activity and expression of ACE2 can be noticed in the ocular surface, including the cornea and conjunctiva, which provides transocular entry a possibility for COVID- 19. 7 Ocular manifestations of COVID-19 are reported in the form of increased conjunctival secretion, epiphora, and diminution of vision. Many infected cases were first presented by conjunctivitis before pneumonia occurred. 8, 9 Several concerns among the ophthalmologists have been raised about the potential ophthalmic manifestations associated with COVID-19. Hence, the focus has now been shifted toward evaluating the studies from China and other countries that highlight this association. Many imperative and indispensable queries need to be clarified, including the detailed ocular presentation, course, and its incidence in COVID-19 disease, the possibility of COVID-19 transmission through the tear, and the incidence of the disease among the contact lens (CL) users.

The available studies differ in their content and significance, causing further dilemmas among professionals. Hence, we designed this review to evaluate the currently available evidence for COVID-19 infection of ocular tissue in humans, as well as its ocular manifestations and treatment. Furthermore, we attempt to bridge the gap of knowledge in this field and put the base for further research from an ophthalmic point of view.

We conducted a review of association between COVID-19 and the ocular manifestations, as well as the available therapeutic options and potential ocular toxicity in humans, based on the literature published till July 30, 2020, including the preprint and peer-reviewed studies. The following keywords used in various combinations were adapted for each search: "Coronaviruses" and "Ocular Implications", "Ocular findings in coronavirus patients", "Conjunctival infection in coronavirus patient", "Coronavirus transmission by tears", "Ocular manifestation for coronavirus", "Coronavirus in tears", "Coronavirus and eye", "Coronaviruses and Ocular complications", "COVID-19 and eye", "Ophthalmic manifestation and COVID19", "Contact lens and COVID-19", and "Retina and COVID-19". These search keywords were adapted for use in different databases: PubMed, Cochrane Library, ScienceDirect, Scopus, and Google scholar.

The search strategy was used to get the titles and the abstracts of the pertinent studies in any language as the first stage of search by two independent authors (S.S.E. and M.A.S.). Then, they retrieved the abstracts. In the second stage of the search, they reviewed the full text of articles to determine the suitability of implication. Dispute ruling was done by a third author (R.A.), and the final decision was taken by the first author (A.E.B.). The full-text articles were screened based on the following inclusion and exclusion criteria. The inclusion criteria were (1) clinical studies (case-control, case series, case report, or a cohort design). We also included reviews, viewpoints, commentaries, opinions, or letters to the editor. ( 2) The exposure of interest was COVID-19 and its association to the eye. We excluded the following: (1) papers studying in vitro ophthalmic manifestations and (2) studies with ocular manifestations but without the development of a complete clinical picture of COVID-19 or confirmation of coronavirus regarding the current guidelines. All authors collaborated in data extraction for further data analysis to convey the relevant data.

We started with a database of 168 papers in total. In Phase 1 screening (title and abstract screening), a total of 63 papers were excluded following the pre-established eligibility criteria. In Phase 2 screening (full-text screening), a total of 44 papers were excluded as they did not fulfill the criteria we were searching for. They did not report cases with ocular manifestations but mainly precautions and control measures for ophthalmologists to follow during this pandemic. Figure 1 The 61 records  include 13 case reports, 17 prospective (case series or  cross-sectional) studies, 8 retrospective studies, 12 literature  reviews (1 systematic review, and 11 letters to the editor) . Table 1 shows all included primary studies with the main findings of each study. Out of 18 secondary studies, we sufficed by just listing the important results of systematic reviews and meta-analysis studies in Table 2 .

Among the 43 original studies we came upon on the final search, we found 29 about conjunctivitis, which seems to be the most prevalent ocular manifestation. Most of these studies also examined the positivity of polymerase chain reaction (PCR) of conjunctival swab/tear samples. Five studies reported mainly the viral PCR on tear film swabs, ocular transmission of SARS-CoV-2, and ACE2 expression in the conjunctiva. Other ocular manifestations were rarely encountered and reported in only 8 studies (2 studies reported keratoconjunctivitis/keratitis, 1 study reported acute nodular scleritis, 2 studies reported neuro-ophthalmic manifestations, and 2 studies reported the retinal and optic nerve findings). Besides ophthalmic medications, trial and side effects showed up in one study, while two studies confirmed the absence of ocular manifestations in COVID-19 patients.

Contact lens practice is one that can be greatly impacted by an infectious and transmissible disease. Although we did not find any original articles mentioning this dilemma, we addressed this issue based on the data in two review articles. The other secondary research (reviews and letters to the editor) dealt with ocular manifestations and ocular transmissions of SARS-CoV-2 comprehensively, and it was hard to classify them.

Consistent with previous studies, most patients with COVID-19 present with various respiratory symptoms, such as fever, dry cough, and chest tightness, that may rapidly progress to pneumonia. 56, 57 However, COVID-19 disease could present with distinguished extrapulmonary manifestations including diarrhea, headache, myalgia, or arthralgia. Some patients even present with asymptomatic infection. 58 Yet, there is a large controversy about the relationship between SARS-CoV-2 virus and ocular pathology -conjunctivitis, in particular -as well as the infectivity and transmissibility of the virus from ocular surfaces. The authors categorized the virus impacts and the possible ocular manifestations in essential points based on the current literature.

Conjunctivitis has been convened to be the most prevalent ocular manifestation in COVID-19-infected patients. Authors depended on clinical examination and conjunctival swabs to detect the viral ribonucleic acid (RNA) by quantitative reverse transcription-polymerase chain reaction (RT-PCR). 10, 14, 15 The exact pathogenesis of conjunctivitis is unclear. It may be purely a synchronous disease unrelated to the infection, or it may be correlated to SARS-CoV-2 infection. 59 It could be through an exogenous mechanism. At the early phase of the disease, the local inflammatory invasion occurs and does not exceed 1 week. At the late stages, keratoconjunctivitis exacerbates due to cytokine surge. 41 To date, the precise incidence of ocular manifestations in COVID-19 disease is uncertain. It ranges from 0.8% 17 to 64% 33 in different published studies. However, it could be stated that the majority recorded a percentage close to 3%, 9, 15, 25 while other studies listed relatively far results (5% 20 and 8% 13 ). In contrast, some authors have emphasized that the ocular manifestation is an infrequent finding in COVID-19. 46, 50 The overall pooled prevalence of ocular manifestations among COVID-19 infected patients ranged from 4% 54 to 5.5%, 52 using the random-effects model, whereas the incidence of conjunctivitis varies in the pediatric population, reaching 15%. 49 Pediatric ocular manifestations seem to be milder than that in adults. However, there is a possible existence of viral load in pediatric conjunctival secretions and therefore a risk of transmission. The different prevalence may be due to variations in population characteristics, sample size, study designs, and severity of COVID-19 cases.

Conjunctivitis could be unilateral 10 53 This controversial issue may require further investigation.

The spectrum of acute conjunctivitis' signs and symptoms fluctuated reportedly from mild, such as foreign body sensation, conjunctival hyperemia, and tearing, 11, 22 to more severe photophobia, swollen eyelid, mucus secretions, chemosis, dry eye, and follicular reaction in forniceal conjunctiva. 10, 11, 20, 32, 34, 35 In addition, pseudomembranes of fibrin and inflammatory cells on the tarsal conjunctiva were noted by Salducci and La Torre 22 and Navel et al., 26 who described follicles, petechiae, tarsal hemorrhages, chemosis, mucus filaments, and tarsal pseudomembranes. Systemic correlations were mostly preauricular, submaxillary, or cervical lymphadenopathy, 10, 11, 17, 22 in addition to the now well-known constitutional and respiratory symptoms of COVID-19 infection.

Laboratory findings were generally normal in COVID-19 patients with ocular signs. Whereas, Wu et al reported higher and April 30, 2020

Cross-sectional study 21.5% had at least one ocular manifestation: most common findings included hyperemia (20) , epiphora (9) , increased secretion (6), chemosis (3), follicular conjunctivitis (2), and episcleritis (2) The most common symptom was photophobia (15) Abrishami et al. 33 Iran 142 white blood cell (WBC) counts, neutrophils counts, and higher levels of procalcitonin, C-reactive protein, and lactate dehydrogenase in patients with ocular symptoms than in those without symptoms. 14 The timing of conjunctivitis appearance throughout the COVID-19 course is still uncertain. Some authors reported late-onset conjunctivitis (10-13 days). 11, 35, 41 Others reported synchronous conjunctivitis along with the systemic manifestations. 12, 14, 40 Some authors described that acute conjunctivitis was the sole presenting sign without any systemic manifestations as an atypical presentation of COVID-19 disease, 36, 37, 40, 42 while it was the initial symptom in other reports. 14, 20, 21, 24, 39 Usually, conjunctivitis resolves within 1-2 weeks without any complications. 35, 42, 45, 54 However, Guo et al. 41 published a case report of relapsing bilateral keratoconjunctivitis 5 days after full recovery.

Corneal affection was seldom noticed. Mainly, superficial punctate keratitis was observed. 26 Small pseudodendrites and small localized subepithelial infiltrates with overlying epithelial defects were remarked as well. They look like herpetic keratitis and evolved later into over 50 discrete areas of subepithelial infiltrates with overlying diffusely, spreading epithelial defects throughout the whole cornea. 10 Episcleritis Episcleritis was reported as a possible ocular complication of COVID-19. 32,38 It may be due to immune-vascular inflammation and coagulation/thrombotic complications recorded in COVID-19 patients. 38

There are almost no rigorous and satisfactory data on how the disease affects the retina or the optic nerve except for a recent study by Marinho et al. 18 Retinal and optical coherence tomography (OCT) findings have been perceived in 12 cases; 9 confirmed by PCR (using nasal and oral swabs), and 2 tested positive in antibody tests for COVID-19. All patients appeared to have hyperreflective lesions at the level of ganglion cell and inner plexiform layers, especially at the papillomacular bundle zone in both eyes. OCT-angiography and ganglion cells complex analysis seemed ordinary. Besides, four patients had subtle cotton wool spots and microhemorrhages along the arterial arcades. The author suggested a potential association between ganglion cell and plexiform layer findings and central nervous system (CNS) manifestations. 18 Another study illustrated unilateral papillophlebitis as a possible ocular complication of COVID-19. The condition started 6 weeks after the disease onset without macular edema. One week later, the macular edema developed and visual acuity (VA) decreased. There are three essential agents implicated the coagulopathy and venous occlusions in patients with COVID-19: endotheliitis, which leads to mechanical vasoconstriction, cytokine storm which activates 

Resolution of conjunctivitis was after 3-5 days clotting factors, and finally, stasis and hypoxia that stimulate coagulation mechanisms as well. 51 The presence of SARS-CoV-2 in the retinal cells has been demonstrated in three human retinal biopsies out of 14 deceased COVID-19 patients. Retinal biopsies were prepared from the enucleated eyes. It is still unknown whether the virus replicates in the retina and in which retinal structures it is exactly located, as there is no evidence if SARS-CoV-2 is present in the choroid or vitreous. Blood is another probable source of the virus that cannot be fully excluded. 62 Further studies are warranted to detect the existence of the SARS-CoV-2 virus in different ocular tissues to clarify this query.

Interestingly, Dinkin et al. 31 reported two COVID-19 patients with ophthalmoplegia within a few days of respiratory symptoms and the disease onset. Hence, they concluded worthy theories related to SARS-CoV-2 infection. They described a case of unilateral third nerve palsy that began partially before it was fully paralyzed. The condition was accompanied by leg paresthesia and bilateral sixth nerve palsy. They attributed this to an acute direct infection rather than demyelinating inflammatory neuropathy secondary to a virus-mediated immune response, based on the time of occurrence of neurological symptoms within a few days of disease onset. The second case was unilateral sixth nerve palsy with lacking radiological evidence of abducens nerve involvement and the presence of optic nerve sheath enhancement. They hypothesized that the viral leptomeningeal invasion or ischemic process was the cause. Both cases showed lymphopenia that seemed to be prevalent in patients with CNS manifestations. 31

Another report declared eight cases of ophthalmoplegia in COVID-19 patients: three cases with unilateral sixth nerve palsy, one case of bilateral sixth nerve palsy, and two cases of unilateral fourth nerve palsy, and two cases of unilateral third nerve palsy. 43

The majority of the reviewed literature established that VA was within normal. In fact, few studies denoted a decline in VA that could be justified by viral keratitis. 10 Other reasonable associated etiologies such as senile lens opacity or dry eye disease might vindicate. 12 So far, neither pupillary light reflex anomalies nor relative afferent pupillary defect has been designated. Intraocular inflammation also appears implausible. 10, 18, 26, 61 

Notably, COVID-19 is not correlated with CLs; however, it has been suggested that silicone lenses are more prone to bind the pathogen than hydrogels. 63 Nevertheless, in the pandemic of coronavirus, CL practice has become more sophisticated to reduce the transmission rate of COVID-19 in CL users. 64

A variety of treatments have been applied to treat ophthalmic manifestations, mainly antiviral drugs such as ganciclovir eye drop 15, 20, 25 or gel combined with artificial tears, 22, 38 ribavirin eye drop, 11 oral acyclovir 500 mg in conjunction with moxifloxacin eye drop based on a presumed diagnosis of herpetic keratoconjunctivitis. 10, 37 Topical antibiotics and corticosteroids have been used, 21,38 azithromycin eye drops with low-dose dexamethasone and pseudomembranes debridement have been used as well. 26 However, the majority of cases resolved spontaneously.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been recommended in the treatment of COVID-19 infection in many protocols. Suggested doses for the treatment of COVID-19 (1000 mg/day for 10 days, CQ; 800 mg 1 st day and then 400 mg/day for 5 days, HCQ) in many guidelines worldwide are considerably higher than the maximum recommended daily safe doses of both drugs (2.3 mg/kg/day, CQ; 5.0 mg/kg/day, HCQ). Otherwise, the development of retinal toxicity is potential. Irreversible retinal damage can occur if the exposure to the safe doses is for more than 5 years, Letter to the editor A meta-analysis was conducted The prevalence of ocular manifestations among COVID-19-infected patients ranged from 2% to 32% Liu et al. 53 Letter to the editor A meta-analysis of 62 studies Significant increased probability of conjunctivitis in non-severe stages of COVID-19 compared to severe subjects Lawrenson and Buckley 54

Letter to the editor A meta-analysis of selected 9 studies Conjunctivitis is a rare complication of COVID-19, with an estimated pooled prevalence of 4% or less. Virus presents in approximately 3% of tear/conjunctival swab samples Aiello et al. 55 Systematic review of 11 studies

Conjunctivitis was demonstrated to be as high as 32% in one study, three patients had conjunctivitis with a positive tear-PCR, 8 patients had positive tear-PCR in the absence of conjunctivitis, and 14 had conjunctivitis with negative tear-PCR The majority of the available data regarding SARS-CoV-2 colonization of ocular tissues and secretions have to be considered controversial *Secondary studies mean studies on secondary results and involve the analysis of research which have already been performed and published. COVID-19: Novel coronavirus 2019, SARS-CoV: Severe acute respiratory syndrome coronavirus, SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus-2, PCR: Polymerase chain reaction and visual loss despite ceasing prescription is inevitable. Nevertheless, Leung et al. found that two of seven cases of COVID-19 who were treated with the high dose of HCQ showed abnormalities of the macula on the retinal imaging and multifocal electroretinogram without visual symptoms. 19 It is worth mentioning that the newest investigations fight against the use of those two agents in the treatment protocols due to their ineffectiveness and impending harm. 65, 66 

Another important structure that seemingly holds the virus is the tear film. The ocular surface may represent a portal of entry for the SARS-CoV-2 in the human body. 50 The isolation of SARS-CoV-2 in the tear samples in patients with confirmed COVID-19 has prompted concerns that the virus could be transmitted through ocular secretions as well as by fomite transmission to the eyes via contaminated hand. 67 Conjunctival swabs for RT-PCR showed positivity in concurrence with conjunctivitis 61 or in isolation. 9 In a study on 67 patients, conjunctival swab samples from one patient showed positive RT-PCR results, and two other patients had probable positive results lacking ocular symptoms. 24 Another study of 72 COVID-19 patients concluded that SARS-CoV-2 was spotted in the conjunctival secretions' samples of only one patient who was an emergency department nurse. 25 On the contrary, a case series in Singapore disclosed the absence of SARS-CoV-2 RNA in conjunctival secretions through RT-PCR, where multiple tear samples were collected from 17 cases. 30 In agreement, others have concluded the absence of COVID-19 virus in tears samples. 12, 16, 23, 27, 28, 63 Evidence of viral particles in tears/conjunctiva is low. It presents in approximately 3% of tear/conjunctival swab samples 54 and ranges from 0% to 7.14%. 68 Studies have been conducted to isolate the virus from conjunctival and tear swabs, [13] [14] [15] 25 the above studies confirmed positive SARS-CoV-2 RT-PCR results from very few patients' tears, but the isolation of the virus was unsuccessful. This could be due to the hardness of collecting tears and further analysis. Besides, the virus has a large size and usually difficult to secrete via exocrine gland. 46 Some patients showed ocular symptoms during the disease course without evidence of SARS-CoV-2 in the tear samples, thus hypothesizing that SARS-CoV-2 can exist in tears or the conjunctival sac. 55 Otherwise, viral shedding in the ocular secretions has been demonstrated in asymptomatic patients without ocular disease. 55, 69 Although the ocular transmission of SARS-CoV-2 is theoretically possible, it remains uncertain, and there is a debate over its spread via tears. 20, 52 Some authors have emphasized that the eye could be an important window for infection via respiratory droplets, as well as the possibility of ocular transmission by infected tears or secretions. 67, 70, 71 On the other hand, others have asserted that SARS-CoV-2 is unlikely to be transmitted via the conjunctiva or ocular secretions. 69, 72 Moreover, the high positivity rate of nasopharyngeal swabs by RT-PCR in contrary to its conjunctiva/tear counterpart makes the estimation that the nasolacrimal duct is an important entry gate for the virus doubtful. 67 The pooled sensitivity of the ocular tissue/fluid in identifying SARS-CoV-2 is still very low (0.6%) compared with standard sample collection from nasopharyngeal swab/sputum. 52 On the other hand, some critical points should be kept in mind. First, although PCR is a widely accepted means to spot viral genome, the shedding loads of the SARS-CoV-2 are perhaps below the sensitivity of the test, even with repeated sampling, 9 or are actually not shedding at the time of sampling. 30 Second, most studies sampled ocular tissue/secretions after the onset of respiratory and systemic disease. However, ocular manifestations have been reported to begin few hours 8 or days before respiratory symptoms instigate. 21, 23, 25 Furthermore, conjunctival swabs have occurred to regain positivity after nasopharyngeal swabs were negative and conjunctivitis regressed, 16 suggesting that nasopharyngeal and conjunctival swabs should be obtained in concurrence. 30 Third, since COVID-19 patients have viremia during the acute phase, the positivity of SARS-CoV-2 RNA is probably the result of viral exudation in the conjunctiva rather than actual replication. 60 Fourth, SARS-CoV-2 is anticipated to bind its spikes to ACE2 as a cellular receptor to gain entry into cell's insides as other SARS-CoV strains. 28 Current evidence on whether conjunctival epithelium can express ACE2 is still scarce. ACE2 is expressed in the conjunctival samples at a low level (range, 0.26-1% of elongation factor 1α [El1α]) and at a lower expression level in the cornea (0.1% of El1α). 73 However, upper respiratory tract epithelia, such as the oral, nasal, and nasopharynx mucosa did not express ACE2 receptors on the epithelial surface, proposing that these tissues are not entrance gateways for SARS-CoV-2. 5, 74 The same debate is applied for the contribution of sialylated ocular mucins to host defense against viral pathogens as well as the role of the interdependence of the ocular mucosal immune system with nasal cavity-associated lymphoid tissue in the nasolacrimal ducts. These topics merit further investigations. 61 Fifth, the conjunctiva and the cornea can adopt antiviral countermeasures. 73 Lactoferrin in tears can inhibit the virus binding as may decoy receptors such as 9-O-acetylated sialic acid on tear glycoproteins, which may explain the low prevalence of eye involvement. 75 In conclusion, conjunctivitis or keratoconjunctivitis is the most customary ocular manifestation in COVID-19. Nonetheless, in the pandemic of COVID-19, the occurrence of other ocular manifestations as a retinal impact or ophthalmoplegia should pay concerns to SARS-CoV-2 infection even in patients with mild symptoms or signs. In addition, the deficient and imprecise ophthalmic data call attention to the necessity of ophthalmologists in evaluating and screening COVID-19 patients with neuro-ophthalmic manifestation. Further studies are required urgently to understand the natural course of ocular hazers during COVID-19 pandemics as well as prognostic significance of used treatment.

Nil.

There are no conflicts of interest.

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