Relations between the ocular surface and SARS-CoV-2 / Relações entre superfície ocular e SARS-CoV-2

ABSTRACT Introduction: The SARS-CoV-2 pandemic has been a major challenge for the international scientific community. Since its inception, studies aiming to describe pathophysiological aspects and clinical manifestations of the disease have been conducted, raising hypotheses and confirming possible associations. One aspect of this scientific medical production is the role of the ocular surface as a means of transmission and clinical presentation of viral syndrome. Objectives: To analyze the role of the ocular surface in transmission, pathophysiology, and clinical manifestations of SARS-CoV-2, by means of a systematic review. Methods: The search was carried out in three databases: Cochrane, PubMed Central Journals and MEDLINE, using the following descriptors: "COVID-19, ophthalmology". The filters last five years and studies on humans resulted in 32 studies; in that 12 were excluded for not meeting the purpose of the study. Results: There are still few published studies on the relation between SARS-CoV-2 and the ocular route. Most studies showed an association between the presence of nonspecific ocular manifestations and infection by the new coronavirus, with limitations in the number of patients analyzed and the methodology adopted. Hypotheses about the pathophysiological role are largely anchored in the association of SARS-CoV and the ocular surface evaluated in the past. Comments: The results found are still not sufficient to confirm the role of the ocular surface in the pathophysiology of the disease. Most of these preliminary studies are of considerable importance in raising hypotheses based on the medical analysis of the patients studied. However, larger studies with standardized methodology for diagnostic protocol and laboratory analysis of the individuals assessed are required.

RESUMO Introdução: A pandemia da SARS-CoV-2 tem sido um grande desafio para a comunidade científica internacional. Desde seu surgimento, estudos com a intenção de descrever os aspectos fisiopatológicos e as manifestações clínicas da doença vêm sendo conduzidos, levantando hipóteses e confirmando possíveis associações. Um dos temas dessa produção médica científica é o papel da superfície ocular como meio de transmissão e apresentação clínica da síndrome viral. Objetivo: Analisar o papel da superfície ocular na transmissão, na fisiopatologia e nas manifestações clínicas de SARS-CoV-2, através de uma revisão sistemática. Realizou-se a busca em três bancos de dados Cochrane Database, PubMed® e MEDLINE®, utilizando os descritores "COVID-19 e ophthalmology". Foram definidos como filtros o artigo ter sido publicado nos últimos 5 anos e estudo realizado em humanos, tendo sido encontrados 32 artigos. Destes, foram excluídos 12 por não corresponderem ao objetivo do estudo. Resultados: Ainda são poucos os estudos publicados sobre a relação entre o coronavírus 2 da síndrome respiratória aguda grave (SARS-CoV-2) e a via ocular. A maioria dos estudos mostrou associação entre a presença de manifestações oculares inespecíficas e a infecção pelo novo coronavírus, com limitações no número de pacientes analisados e na metodologia adotada. Hipóteses sobre o papel fisiopatológico se ancoram, em grande parte, na associação estudada entre o SARS-CoV-2 e a superfície ocular no passado. Comentários: Os resultados encontrados ainda não são suficientes para confirmar o papel da superfície ocular na fisiopatologia da doença. Grande parte desses estudos preliminares têm importância considerável ao levantar hipóteses baseadas na análise clínica dos pacientes estudados. No entanto, são necessários estudos maiores e com metodologia padronizada para protocolo diagnóstico e análise laboratorial dos indivíduos avaliados.

Long-Acting Protective Ocular Surface by Instilling Adhesive Dual-Antiviral Nanoparticles.

The eye is susceptible to viral infections, causing severe ocular symptoms or even respiratory diseases. Methods capable of protecting the eye from external viral invasion in a long-term and highly effective way are urgently needed but have been proved to be extremely challenging. Here, a strategy of forming a long-acting protective ocular surface is described by instilling adhesive dual-antiviral nanoparticles. Taking pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model virus, antiviral agent-loaded nanoparticles are coated with a "double-lock" hybrid cell membrane abundant with integrin-ß1 and angiotensin converting enzyme II (ACE2). After instillation, the presence of integrin-ß1 endows coated nanoparticles with steady adhesion via specific binding to Arg-Gly-Asp sequence on the fibronectin of ocular epithelium, achieving durable retention on the ocular surface. In addition to loaded inhibitors, the exposure of ACE2 can trap SARS-CoV-2 and subsequently neutralize the associated spike protein, playing a dual antiviral effect of the resulting nanoparticles. Adhesive dual-antiviral nanoparticles enabled by coating with a "double-lock" hybrid cell membrane could be a versatile platform for topical long-acting protection against viral infection of the eye.

Case Report: Rhino-orbital Mucormycosis Related to COVID-19: A Case Series Exploring Risk Factors.

There has been a surge of rhino-orbital mucormycosis cases in India in the wake of the second wave of the COVID-19 pandemic. It has been widely suggested that dysglycemia resulting from diabetes which is a common comorbidity in COVID-19 patients, and indiscriminate steroid use has resulted in this surge. We report a series of 13 cases of rhino-orbital mucormycosis in COVID-19 patients admitted to our center between mid-April and early June 2021. The cases showed a male preponderance, two patients had loss of vision, and four of them showed intracranial extension of disease. Twelve patients had received steroids and 12 had preexisting or newly diagnosed diabetes, both steroid use and diabetes being the most common identified risk factors. Considering other possible risk factors, immunosuppressed state, antiviral or ayurvedic (Indian traditional) medications, and oxygen therapy were not associated with a definite risk of mucormycosis, because they were not present uniformly in the patients. We propose that COVID-19 itself, through molecular mechanisms, predisposes to mucormycosis, with other factors such as dysglycemia or steroid use increasing the risk.

Pooled Prevalence Estimate of Ocular Manifestations in COVID-19 Patients: A Systematic Review and Meta-Analysis.

Background: There are reports of ocular tropism due to respiratory viruses such as severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Various studies have shown ocular manifestation in coronavirus disease-2019 (COVID-19) patients. We aimed to identify ophthalmic manifestations in COVID-19 patients and establish an association between ocular symptoms and SARS-CoV-2 infection. Methods: A systematic search of Medline, Scopus, Web of Science, Embase, and Cochrane Library was conducted for publications from December 2019 to April 2021. The search included MeSH terms such as SARS-CoV-2 and ocular manifestations. The pooled prevalence estimate (PPE) with 95% confidence interval (CI) was calculated using binomial distribution and random effects. The meta-regression method was used to examine factors affecting heterogeneity between studies. Results: Of the 412 retrieved articles, 23 studies with a total of 3,650 COVID-19 patients were analyzed. The PPE for any ocular manifestations was 23.77% (95% CI: 15.73-31.81). The most prevalent symptom was dry eyes with a PPE of 13.66% (95% CI: 5.01-25.51). The PPE with 95% CI for conjunctival hyperemia, conjunctival congestion/conjunctivitis, and ocular pain was 13.41% (4.65-25.51), 9.14% (6.13-12.15), and 10.34% (4.90-15.78), respectively. Only two studies reported ocular discomfort and diplopia. The results of meta-regression analysis showed that age and sample size had no significant effect on the prevalence of any ocular manifestations. There was no significant publication bias in our meta-analysis. Conclusion: There is a high prevalence of ocular manifestations in COVID-19 patients. The most common symptoms are dry eyes, conjunctival hyperemia, conjunctival congestion/conjunctivitis, ocular pain, irritation/itching/burning sensation, and foreign body sensation.

[Ophthalmological manifestations of post-COVID-19 syndrome]. / Oftal'mologicheskie proyavleniya postkovidnogo sindroma.

The review presents data on damage to the organ of vision in patients recovered from the new coronavirus infection reflecting on the results obtained by various researchers from examining patients with varying severity of the disease, both during the active stage and after recovery. Possible ways of transmission of the infectious agent into the organ of vision were analyzed. The most common ocular manifestation of COVID-19 is conjunctivitis, while lesions of the retina and optic nerve were noted less often. The article also outlines the strategy for treatment and describes infection prevention measures for doctors and patients.

Transcriptomic analysis revealed increased expression of genes involved in keratinization in the tears of COVID-19 patients.

Recent studies have focused their attention on conjunctivitis as one of the symptoms of coronavirus disease 2019 (COVID-19). Therefore, tear samples were taken from COVID-19 patients and the presence of SARS-CoV-2 was evidenced using Real Time reverse transcription polymerase chain reaction. The main aim of this study was to analyze mRNA expression in the tears of patients with COVID-19 compared with healthy subjects using Next Generation Sequencing (NGS). The functional evaluation of the transcriptome highlighted 25 genes that differ statistically between healthy individuals and patients affected by COVID-19. In particular, the NGS analysis identified the presence of several genes involved in B cell signaling and keratinization. In particular, the genes involved in B cell signaling were downregulated in the tears of COVID-19 patients, while those involved in keratinization were upregulated. The results indicated that SARS-CoV-2 may induce a process of ocular keratinization and a defective B cell response.

Association of Ocular Surface Diseases With SARS-CoV-2 Infection in Six Districts of China: An Observational Cohort Study.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses is mainly transmitted through respiratory droplets. Notably, some coronavirus disease 2019 (COVID-19) patients have ocular manifestations, including conjunctival hyperaemia, chemosis, epiphora, and increased secretions. However, the association between SARS-CoV-2 and ocular surface diseases is poorly described. Between May 2020 and March 2021, a total of 2, 0157 participants from six districts of China were enrolled. Serum samples were tested for immunoglobulin G and M (IgG and IgM) antibodies against the SARS-CoV-2 spike protein and nucleoprotein using magnetic chemiluminescence enzyme immunoassays. Throat swabs were tested for SARS-CoV-2 RNA using RT-PCR assays in a designated virology laboratory. Fisher exact, χ2 test, and logistic regression analysis were performed. Of 2, 0157 serum samples tested, 1, 755 (8.71%) were from ocular surface diseases, 1, 2550 (62.26%) from no-ocular surface diseases (ocular diseases except ocular surface diseases), 5, 852 (29.03%) from no-ocular diseases. SARS-CoV-2 prevalence for the combined measure was 0.90% (182/2, 0157). Seroprevalence of SARS-CoV-2 was significantly (p<0.05) higher in the population with ocular surface diseases (2.28%, 40/1755) compared with no-ocular surface diseases (0.70%, 88/1, 2550), and no-ocular diseases (0.92%, 54/5, 852). Similar results were also observed with respect to sex, age, time, and districts. Logistic regression analyses revealed that ocular surface diseases [ocular surface diseases vs. no-ocular diseases (p=0.001, OR =1.467, 95% CI=1.174-1.834); ocular surface diseases vs. no-ocular surface diseases (p<0.001, OR =2.170, 95% CI=1.434-3.284)] were associated with increased risk of susceptible to SARS-CoV-2 infection. In a word, there was a significant association between ocular surface disease and SARS-CoV-2 infection. Therefore, increasing awareness of eye protection during the pandemic is necessary, especially for individuals with ocular surface diseases.

SARS-CoV-2 and the Eyes: A Review of the Literature on Transmission, Detection, and Ocular Manifestations.

During the coronavirus disease 2019 (COVID-19) pandemic, numerous reports of ocular anomalies occurring in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged. The most frequently reported pathology is conjunctivitis, which may be the first or only clinical manifestation of the disease. Involvement of SARS-CoV-2 in development of alterations in other ocular structures was suggested, including the cornea, the retina, and blood vessels. Possible mechanisms include direct activity of the viral agent, as well as systemic inflammatory response with accompanying thromboembolic complications. Genetic material of SARS-CoV-2 was detected in ocular secretions of infected individuals, including asymptomatic patients. Moreover, angiotensin-converting enzyme 2 (ACE2), a receptor protein used by the virus to enter the cell, has been found on the surface of various structures of the eye, which indicates a risk of transmission through ocular tissues. Therefore, it is crucial to use eye protection by medical professionals having contact with potentially infected patients. This paper is a review of the literature regarding ocular manifestations of SARS-CoV-2 infection and a summary of the current state of knowledge about possibility of transmission from an ophthalmology point of view. For data collection, a thorough PubMed search was performed, using the key words: "COVID ocular", "COVID eye", "SARS-CoV-2 ocular", and "SARS-CoV-2 eye". Conclusions: SARS-CoV-2 infection may manifest itself in various ocular conditions. Eye protection should not be neglected, as recent studies suggest the eye as a potential route of transmission. Further search for adequate safety measures in ophthalmology practice is required.

Ophthalmology practice in Afghanistan during the COVID-19 pandemic.

This short communication described the actions taken in ophthalmic practice in Kabul, Afghanistan during the COVID-19 pandemic to effectively protect both patients and staff. By following World Health Organisation (WHO), international and local guidelines it has been possible to continue treating ophthalmic outpatients with minimum risk to both patients and staff. The changes which have been implemented may allow better overall infection control in the hospital which will continue to have benefits post-pandemic.

In the eye of the storm: SARS-CoV-2 infection and replication at the ocular surface?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged in December 2019 and spread quickly causing the coronavirus disease 2019 (COVID-19) pandemic. Recent single cell RNA-Seq analyses have shown the presence of SARS-CoV-2 entry factors in the human corneal, limbal, and conjunctival superficial epithelium, leading to suggestions that the human ocular surface may serve as an additional entry gateway and infection hub for SARS-CoV-2. In this article, we review the ocular clinical presentations of COVID-19 and the features of the ocular surface that may underline the overall low ocular SARS-CoV-2 infection. We critically evaluate the studies performed in nonhuman primates, ex vivo organ culture ocular models, stem cell derived eye organoids and the differences in infection efficiency observed in different parts of human ocular surface epithelium. Finally, we highlight the additional work that needs to be carried out to understand the immune response of the ocular surface to SARS-CoV-2 infection, which can be translated into prophylactic treatments that may be applied to other organ systems.

Eyes on coronavirus.

Recently, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has spread around the world and is receiving worldwide attention. Approximately 20% of infected patients are suffering from severe disease of multiple systems and in danger of death, while the ocular complications of SARS-CoV-2-infected patients have not been reported generally. Herein, we focus on two major receptors of SARS-CoV-2, ACE2 and CD147 (BSG), in human ocular cells, and interpret the potential roles of coronaviruses in human ocular tissues and diseases.

Evaluation of ocular symptoms in COVID-19 subjects in inpatient and outpatient settings.

PURPOSE: Evaluation of subtle ocular involvement and clinically significant conjunctivitis symptoms in a group of patients with COVID-19 in outpatient and inpatient settings. METHOD: Overall, 1083 patients infected with SARS-CoV-2 were recruited as subjects. Patients were divided into inpatients (group 1, n = 371) and outpatients (group 2, n = 712). Demographical and general medical data included age, sex, and comorbidities. Patients whose diagnosis was confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR) were called by phone, and their chronic ocular disease, previous ocular surgery, ocular medication, contact lens wear and ocular irritation symptoms were queried during the active disease period. RESULTS: The mean age of the patients was 44.2 ± 16.5 (19-97) years; 635 (58.6%) were male, and 448 (41.4%) were female. Comorbidity, chronic ocular disease, ophthalmic medication and previous ocular surgery rates were significantly higher in group 1 (p < 0.05), while contact lens wear was not significantly different between groups. The main complaints received from patients were sore eye or burning sensation, foreign body sensation, itching and red eye and were significantly higher in group 1. Clinically significant conjunctivitis symptoms, such as red eye, ocular discharge and eyelid edema, were observed in 28 patients (2.6%), with 14 (3.8%) patients in group 1 and 14 (2%) patients in group 2. CONCLUSION: Clinically significant conjunctivitis symptoms were detected in 28 subjects in the inpatient and outpatient groups. As systemic findings of COVID-19 intensify.

[Research progress on etiologic diagnosis of ocular viral diseases].

A large number of viruses have been found to be associated with ocular diseases, including human adenovirus, human herpesvirus (HHV), human T lymphotropic virus type-1 (HTLV-1), and newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This group of diseases is prone to be misdiagnosed or missed diagnosis, resulting in serious tissue and visual damage. Etiological diagnosis is a powerful auxiliary mean to diagnose the ocular diseases associated with human adenovirus, herpes simplex virus 1 and varicella-zoster virus, and it provides the leading diagnosis evidence of infections with herpes simplex virus 2, Epstein-Barr virus, cytomegalovirus, HHV-6/7, HHV-8, HTLV-1 and SARS-CoV-2. Virus isolation, immunoassay and genetic diagnosis are usually used for etiologic diagnosis. For genetic diagnosis, the PCR technique is the most important approach because of its advantages of rapid detection, convenient operation, high sensitivity and high specificity.

Ocular surface manifestations of coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis.

PURPOSE: This study was performed to determine the occurrence of ocular surface manifestations in patients diagnosed with coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: A systematic search of electronic databases i.e. PubMed, Web of Science, CINAHL, OVID and Google scholar was performed using a comprehensive search strategy. The searches were current through 31st May 2020. Pooled data from cross-sectional studies was used for meta-analysis and a narrative synthesis was conducted for studies where a meta-analysis was not feasible. RESULTS: A total of 16 studies reporting 2347 confirmed COVID-19 cases were included. Pooled data showed that 11.64% of COVID-19 patients had ocular surface manifestations. Ocular pain (31.2%), discharge (19.2%), redness (10.8%), and follicular conjunctivitis (7.7%) were the main features. 6.9% patients with ocular manifestations had severe pneumonia. Viral RNA was detected from the ocular specimens in 3.5% patients. CONCLUSION: The most common reported ocular presentations of COVID-19 included ocular pain, redness, discharge, and follicular conjunctivitis. A small proportion of patients had viral RNA in their conjunctival/tear samples. The available studies show significant publication bias and heterogeneity. Prospective studies with methodical collection and data reporting are needed for evaluation of ocular involvement in COVID-19.

Current Evidence of 2019 Novel Coronavirus Disease (COVID-19) Ocular Transmission: A Systematic Review and Meta-Analysis.

OBJECTIVE: To estimate the prevalence rate of ocular symptoms and the positive rate of conjunctival swab samples of patients diagnosed with 2019 Novel Coronavirus Disease (COVID-19). METHODS: We performed a systematic review and meta-analysis. A comprehensive literature search was done based on PubMed, Embase, MedRxiv, and the Cochrane Library. The primary outcomes are the prevalence rate of conjunctivitis/conjunctival congestion and the positive rate of conjunctival swab samples. Rates were expressed as proportions with 95% confidence intervals (CIs). RESULTS: A total of 12 studies with 1930 participants were included for meta-analysis. The pooled prevalence rate of conjunctivitis/conjunctival congestion was 8% (95% CI: 5%-12%). 1% (95% CI: 1%-4%) of COVID-19 patients were diagnosed with conjunctivitis/conjunctival congestion as the initial symptom. The pooled positive rate of conjunctival swab samples was 3% (95% CI: 2%-5%). We also assessed other ocular symptoms reported in the 12 studies, including foreign body sensation, increased secretion, and eye itching. The pooled prevalence rates were 6% (95% CI: 3%-10%), 10% (95% CI: 8%-12%), and 9% (95% CI: 7%-10%), respectively. CONCLUSIONS: The evidence on the positive rate of conjunctival swab samples and the prevalence rates of ocular symptoms indicated that COVID-19 ocular transmission was possible but less likely.

[A special on epidemic prevention and control: ophthalmologic research and prevention of 2019 novel coronavirus based on ocular manifestations of viral diseases].

This article was published ahead of print on the official website of Chinese Journal of Ophthalmology on February 24, 2020. In China, the fight against the 2019 novel coronavirus (2019-nCoV) has been at a critical stage. It has been confirmed that the transmission of 2019-nCoV is mainly through respiratory droplets and contact. Some scholars also pointed out that the possibility of transmission through the digestive system and eyes should not be ignored. Whether infection with 2019-nCoV will develop eye symptoms and whether the virus will spread through eyes are confusing to the medical workers and the general public, and it is ophthalmologists' responsibility to carry out in-depth discussions. Based on the ocular manifestations of viral diseases, this article analyzes whether the eye secretions and tears carry the virus, and whether ophthalmologists and patients are at a high risk for 2019-nCoV infection, and then presents the current research methods and the necessary prevention and control measures in the field of ophthalmology, with an aim to contribute to the fight against 2019-nCoV. ( Chin J Ophthalmol, 2020, 56: 414-417).

[Ocular manifestations of coronavirus infection COVID-19 (clinical observation)]. / Glaznye proyavleniya koronavirusnoi infektsii COVID-19 (klinicheskoe nablyudenie).

This paper describes possible clinical ocular manifestations of novel coronavirus infection COVID-19. Two clinical cases of conjunctivitis are examined. Due to the lack of ophthalmological approaches to the treatment of such patients, different management tactics are given based on the severity of local and systemic disease manifestations. Our research and practical management of these conditions showed the toxic and allergic nature of ocular surface manifestations in patients with COVID-19. Such cases are proposed to be treated similar to the conjunctivitis of "unclear origin" with components from antiviral and anti-allergic therapies.

The implication of ocular manifestation of COVID-19 for medical staff and patients - systematic review.

INTRODUCTION: SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) is a coronavirus that causes COVID-19 (coronavirus disease 2019) with mild to severe respiratory illness. It is a highly contagious disease transmitted through direct or indirect contact with infected people or contaminated surfaces, mainly through respiratory droplets, but other routes are being investigated. OBJECTIVE: It is known that coronaviruses (CoVs) can cause a variety of ocular pathologies in animals, including conjunctivitis, anterior uveitis, retinitis, and optic neuritis, many of which are severe. However, there is no evidence of the SARS-CoV-2 presence in the eye tissue of asymptomatic patients, even if the symptomatic incidence is low. This systematic review presents updated literature on this issue. ABBREVIATED DESCRIPTION OF THE STATE OF KNOWLEDGE: COVID-19 has now spread throughout the continents and poses a global threat to public health. The risk of rapidly overloading health care systems and causing substantial mortality worldwide is real. On 11 March 2020, the World Health Organization (WHO) announced coronavirus as a global pandemic. Several studies described a few cases with initial ocular symptoms followed by systemic symptoms of the disease. SUMMARY: Although the frequency of transmission of SARS-CoV-2 infection through the eye is low, ocular symptoms are not uncommon in COVID-19. In some cases, eye symptoms may be the first signs of illness. This implies the need for hygienic recommendations and use of personal protective equipment (PPE) for medical staff and other services to minimize COVID-19 infection of both health-care workers and patients. A triage for ophthalmic outpatient clinic is mandatory.