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.

The COVID-19 Pandemic from an Ophthalmologist's Perspective.

The current coronavirus disease 2019 (COVID-19) pandemic is rapidly spreading around the world. The first doctor to report this new disease was an ophthalmologist: this exemplifies the role of ophthalmologists in an infectious disease pandemic. Here we review how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the eye and discuss implications for ophthalmologists.

COVID-19 and the Human Eye: Conjunctivitis, a Lone COVID-19 Finding - A Case-Control Study.

OBJECTIVES: COVID-19 has varied clinical manifestations, from asymptomatic to severe cases, and conjunctivitis is one of them, but sometimes a lone initial symptom is found to be present. The aim of this study was to identify the prevalence of conjunctivitis as the first symptom in COVID-19 patients in a primary healthcare unit. METHODOLOGY: A retrospective study was conducted, analyzing the presenting complains/symptoms and results of COVID-19-confirmatory tests. RESULTS: Out of the 672 cases that were sent for RT-PCR testing, only 121 (18%) were found to be positive. Among these, 2.67% patients had both conjunctivitis and COVID-19, 77.77% patients had unilateral eye affected, while 22.22% had bilateral conjunctivitis of varying degrees. Fifteen patients diagnosed to have both acute conjunctivitis and COVID-19 presented other symptoms associated with COVID-19 infection. Three patients had only acute conjunctivitis during their entire course of COVID-19. CONCLUSIONS: Conjunctivitis is a symptom of COVID-19 and may be the first sign of the infection, until the onset of the classical manifestations; such patients may continue to be a viral reservoir. Physicians should not miss unilateral conjunctivitis as it can be the only presenting complaint of COVID-19 during the initial phase, which might worsen if undetected and can aid in the spread of the contagion.

Case Report: A Re-Positive Case of SARS-CoV-2 Associated With Glaucoma.

The current pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has already become a global threat to the human population. Infection with SARS-CoV-2 leads to a wide spectrum of clinical manifestations. Ocular abnormalities have been reported in association with COVID-19, but the nature of the impairments was not specified. Here, we report a case of a female patient diagnosed with glaucoma on re-hospitalization for ocular complications two months after being discharged from the hospital upon recovery from COVID-19. Meanwhile, the patient was found re-positive for SARS-CoV-2 in the upper respiratory tract. The infection was also diagnosed in the aqueous humor through immunostaining with antibodies against the N protein and S protein of SARS-CoV-2. Considering the eye is an immune-privileged site, we speculate that SARS-CoV-2 survived in the eye and resulted in the patient testing re-positive for SARS-CoV-2.

Identification of SARS-CoV-2 on the ocular surface in a cohort of COVID-19 patients from Brazil.

In this cross-sectional study, we investigate the presence of Severe Acute Respiratory Syndrome Coronavirus 2 Ribonucleic Acid (SARS-CoV-2 RNA) in the tears of hospitalized COVID-19 patients. After laboratory confirmation of SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR) analysis, tear samples from both eyes of each patient were collected using conjunctival swab for RT-PCR. Detailed demographic profile, systemic and ocular symptoms, comorbidities, clinical, ancillary, and ocular manifestations were evaluated. Of the 83 patients enrolled in the study, 7 (8.43%) had SARS-CoV-2 RNA detected in the tear samples. Neutrophils' count, C-reactive protein, and D-dimer were higher in patients with SARS-CoV-2 detected in tears than in patients without virus in ocular surface samples. One patient with SARS-CoV-2 in tears showed mild ocular eyelid edema, hyperemia, and chemosis. No relevant ocular manifestations were detected in the other patients. Although the levels of viral RNA on ocular surface samples were low for most patients (5/7), with positivity only for gene N and CT higher than 30, two patients were positive for all viral targets tested (N, E, and RpRd), with viral load near 1 × 105 ePFU/mL, indicating that the ocular transmission of SARS-CoV-2 is a possibility that needs to be considered, especially in the hospital environment. Further studies need to be conducted to demonstrate whether infective viral particles could be isolated from tears.

Fluorescence of ocular surface in a Covid -19 patient after Favipiravir treatment: a case report.

BACKGROUND: Favipiravir is used in treatment of Covid-19 patients. We aimed to share of ocular surface fluorescence in a patient after Favipiravir treatment in this case report. CASE PRESENTATION: A 20-year-old male patient declared no known systemic disease prior to Covid-19. He applied to us with blurry vision and blue light reflection after Covid-19 treatment with Favipiravir. We observed bilateral fluorescence on his eyes and fluorescence of his nails. Biomicroscopic examination was insignificant. CONCLUSION: We investigated the fluorescence of favipiravir tablets under ultraviolet light. Drug demonstrated fluorescence. We recorded the favipiravir fluorescence in-vitro. This appears to be a strong evidence in terms of the linkage between the fluorescence of the ocular surface and favipiravir.

Value of anal swabs for SARS-COV-2 detection: a literature review.

Facing the unprecedented global public health crisis caused by coronavirus disease 2019 (COVID-19), nucleic acid tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are the gold standard for diagnosing COVID-19. The asymptomatic carriers were not suspected of playing a significant role in the ongoing pandemic, and universal nucleic acid screening in close contacts of confirmed cases and asymptomatic carriers has been carried out in many medium- and high-risk areas for the spread of the virus. Recently, anal swabs for key population screening have been shown to not only reduce missed diagnoses but also facilitate the traceability of infectious sources. As a specimen for the detection of viruses, the goal of this paper is to briefly review the transmission route of SARS-CoV-2 and the necessity of using anal swabs for SARS-CoV-2 screening to minimize transmission and a threat to other people with COVID-19.

Ocular findings in patients with coronavirus disease 2019 (COVID-19) in an outbreak hospital.

PURPOSE: The aim of this study was to investigate the ocular findings observed in patients with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 and to present the relationship between ocular involvement, systemic findings, and laboratory results. MATERIAL AND METHODS: This cross-sectional study was carried out between 1 May and 30 June 2020. The study included 359 patients diagnosed with COVID-19 and assessed by clinical evaluation, nasopharyngeal polymerase chain reaction, and lung computed tomography. RESULTS: One hundred ninety-seven (54.9%) of the patients were male and 162 (45.1%) were female. The mean age of the patients was 58.5 years (20-91). Two hundred ninety-four (81.9%) patients were treated in the inpatient clinic and 65 (18.1%) patients were treated in the intensive care unit. Various ocular diseases were observed in 16 (4.5%) of the patients. Although the rate of ocular disease was 12 out of 294 (4.1%) in patients followed up in the inpatient clinic, this rate was 4 out of 65 (6.2%) in intensive care patients. There was no systemic problem in one patient, in whom conjunctival hyperemia was the first and only reason for admission to the hospital. Four patients followed up in the inpatient clinic had conjunctivitis at the time of admission, and conjunctivitis occurred in three patients during hospitalization. Subconjunctival hemorrhage occurred in five patients and vitreous hemorrhage in one patient. CONCLUSION: Ocular diseases are uncommon in COVID-19 patients but may occur during the first period of the disease or during follow-up. Ocular diseases may be the initial or only sign of COVID-19 infection.

Ocular Assessments of a Series of Newborns Gestationally Exposed to Maternal COVID-19 Infection.

IMPORTANCE: Congenital viral infections leading to ocular abnormalities are frequent and devastating. As ophthalmological manifestations of COVID-19 in newborns are still unknown, it is important to clarify if SARS-CoV-2 could be associated with ocular abnormalities. OBJECTIVE: To determine whether exposure to SARS-CoV-2 is associated with outcomes in the eyes of newborns. DESIGN, SETTING, AND PARTICIPANTS: This case series enrolled newborns from April to November 2020 from 3 different maternity hospitals in São Paulo, Brazil. The diagnosis of COVID-19 in mothers and newborns was based on real-time reverse transcriptase-polymerase chain reaction assays with material obtained from oronasopharyngeal swab sample; positive IGM serology was also considered as a diagnostic test for mothers. Newborns were excluded if they had any evidence of another congenital infection. All infants underwent external ocular examination and binocular indirect ophthalmoscopy. EXPOSURES: Serology test for COVID-19 and detection of SARS-CoV-2 from oronasopharyngeal specimen using a real-time reverse transcriptase-polymerase chain reaction assay on both mothers and newborns. MAIN OUTCOMES AND MEASURES: Screening for ophthalmologic manifestation in newborns after maternal COVID-19 infection. RESULTS: A total of 165 newborns (age range at examination, 1 to 18 days) were evaluated. Of these, 123 (74.5%) were born at full term, and 42 (25.4%) were born preterm. Maternal gestational age at the time of COVID-19-positive test varied from first to 40th gestational weeks. Six newborns (3.6%) had positive polymerase chain reaction findings for SARS-CoV-2. One newborn tested positive within 18 days (horizontal transmission), and 5 newborns tested positive in the first day of life (possible vertical transmission). None had ocular abnormalities. Concerning exposed newborns with negative test results, 1 presented with venous engorgement and vascular tortuosity, 7 had intraretinal hemorrhages, and 2 were diagnosed as having retinopathy of prematurity. CONCLUSIONS AND RELEVANCE: In this uncontrolled case series of Brazilian newborns of mothers with COVID-19 infection, a low rate of COVID-19 infection was found among newborns, and none had ocular abnormalities. Additional controlled studies may be warranted to confirm these findings.

The Transmission of SARS-CoV-2 Infection on the Ocular Surface and Prevention Strategies.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health problem. Although the respiratory system is the main impaired organ, conjunctivitis is one of its common findings. However, it is not yet understood if SARS-CoV-2 can infect the eye and if the ocular surface can be a potential route of SARS-CoV-2 transmissions. Our review focuses on the viral entry mechanisms to give a better understanding of the interaction between SARS-CoV-2 and the eye. We highlighted findings that give evidence for multiple potential receptors of SARS-CoV-2 on the ocular surface. Additionally, we focused on data concerning the detection of viral RNA and its spike protein in the various ocular tissues from patients. However, the expression level seemed to be relatively low compared to the respiratory tissues as a result of a unique environment surrounding the ocular surface and the innate immune response of SARS-CoV-2. Nevertheless, our review suggests the ocular surface as a potential route for SARS-CoV-2 transmission, and as a result of this study we strongly recommend the protection of the eyes for ophthalmologists and patients at risk.

Can SARS-CoV-2 infect the eye? An overview of the receptor status in ocular tissue.

Is the new coronavirus SARS-CoV­2 able to infect ocular tissue and thus poses a risk of infection through the tissue in addition to the risk of contact? This is the question that has occupied ophthalmologists since the beginning of the outbreak. In order to infect a certain type of tissue specific receptors for each virus and sometimes also coreceptors or other proteins must be present. The aim of this review was to summarize and reflect the current state of research with the help of the currently available literature as of 28 May 2020. At the time of the research, angiotensin-converting enzyme 2 (ACE2) was clearly identified as the receptor and transmembrane serine protease 2 (TMPRSS2) as the necessary protease to enable the infection of human cells with SARS-CoV­2. In the eye both ACE2 and TMPRSS2 are expressed, although sometimes very weakly and with varying degrees in different tissues. It is noteworthy that very different results were obtained with different methods. Several reasons can account for this effect: Firstly, the method of detection or preservation of the tissue, secondly, the possibly different expression of the tested tissue samples and thirdly, a possibly rapid loss of receptor expression post-mortem. Therefore, an infection of the eye seems possible, which has already been reported in various publications. The amount of virus or receptor expression necessary to cause an infection is not known. According to current state of knowledge the eye is not considered to be a high-risk tissue due to the low ACE2 and TMPRSS2 expression. Nevertheless, appropriate protective measures are necessary for both medical personnel and patients. In cases of corneal transplantation an infection of the donor tissue with SARS-CoV­2 must be excluded.

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.

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.

Role of the Eye in Transmitting Human Coronavirus: What We Know and What We Do Not Know.

The outbreak of the current 2019 novel coronavirus (2019-nCoV, now named SARS-CoV-2) infection has become a worldwide health threat. Currently, more information is needed so as to further understand the transmission and clinical characteristics of 2019-nCoV infection and the infection control procedures required. Recently, the role of the eye in transmitting 2019-nCoV has been intensively discussed. Previous investigations of other highly infectious human CoVs, that is, severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), may provide useful information. In this review, we describe the genomics and morphology of human CoVs, the epidemiology, systemic and ophthalmic manifestations, and mechanisms of human CoV infection, and recommendations for infection control procedures. The role of the eye in the transmission of 2019-nCoV is discussed in detail. Although the conjunctiva is directly exposed to extraocular pathogens, and the mucosa of the ocular surface and upper respiratory tract are connected by the nasolacrimal duct and share the same entry receptors for some respiratory viruses, the eye is rarely involved in human CoV infection, conjunctivitis is quite rare in patients with 2019-nCoV infection, and the CoV RNA positive rate by RT-PCR test in tears and conjunctival secretions from patients with 2019-nCoV and SARS-CoV infection is also extremely low. This suggests that the eye is neither a preferred organ of human CoV infection nor a preferred gateway of entry for human CoVs for infecting the respiratory tract. However, pathogens that the ocular surface is exposed to might be transported to nasal and nasopharyngeal mucosa by constant tear rinsing through the lacrimal duct system and then cause respiratory tract infection. Considering that close doctor-patient contact is quite common in ophthalmic practice and is apt to transmit human CoVs by droplets and fomites, strict hand hygiene and proper personal protection are highly recommended for health care workers to avoid hospital-related viral transmission during ophthalmic practice.

Severe Acute Respiratory Syndrome Coronavirus 2 Nucleocapsid Protein in the Ocular Tissues of a Patient Previously Infected With Coronavirus Disease 2019.

Importance: Coronavirus disease 2019 (COVID-19) has been recognized as a pandemic by the World Health Organization. Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can also infect tissues besides the respiratory system, such as the ocular tissues, remains unclear. Objective: To determine whether SARS-CoV-2 exists intracellularly in the ocular tissues of a patient previously infected with COVID-19. Design, Setting, and Participants: This case study analyzed a patient previously infected with COVID-19 who had an acute glaucoma attack during her rehabilitation. Plasma samples and tissue specimens, including ones from the conjunctiva, anterior lens capsular, trabecular meshwork, and iris, were collected during phacoemulsification and trabeculectomy surgery. Specimens from another patient who had glaucoma but not COVID-19 were used as a negative control. Main Outcomes and Measures: Specimens were analyzed using hematoxylin-eosin staining. The nucleocapsid protein antigen of SARS-CoV-2 was measured in the conjunctiva, trabecular meshwork, and iris using immunofluorescence and immunohistochemistry. The expression of angiotensin-converting enzyme 2 receptor on the conjunctiva was measured using immunohistochemistry. Results: The patient with a previous COVID-19 infection was female and 64 years old, and the control patient without a COVID-19 infection history was male and 61 years old. The nucleocapsid protein antigen of SARS-CoV-2 was detected on the cells of the conjunctiva, trabecular, and iris of the patient infected with COVID-19 but not in the control participant, while angiotensin-converting enzyme 2 receptor proteins were detected on the conjunctiva of both patients. Conclusions and Relevance: The nucleocapsid protein antigen of SARS-CoV-2 existed intracellularly in the ocular tissues of a patient previously infected with COVID-19. Thus, SARS-CoV-2 can also infect ocular tissues in addition to the respiratory system.

Smart polymeric eye gear: A possible preventive measure against ocular transmission of COVID-19.

The angiotensin-converting enzyme 2(ACE-2) receptors with approx. 0.8% congestion in conjunctival surface, leads to increase susceptibility of Covid-19 transmission through ocular surface. It has been observed that prophylactic measures such as goggle or face shield are unable to offer complete protection against ocular transmission of SRS-CoV-2. Hence, it is hypothesized that topical ocular prophylaxis using biocompatible polymers with reported in-vitro and in-vivo evidence of ACE inhibition and antiviral activity appears to be a promising strategy for preventing ocular transmission of Covid-19 to healthcare workers. They are capable of binding to ACE-2 receptors which may provide highly potential trails to block virus entry to host cells. Further biopolymers imparting antiviral activities greatly improve their protective performance. They not only provide prolong protection but also are safe for long-term use. This article discusses the description of structural and functional attributes of ACE-2 to identify appropriate polymer with better binding affinity. Furthermore, potential polymers with appropriate concentration are suggested for evaluation through a hypothesis to consider them for Covid-19 implication.

[SARS-CoV-2, COVID-19 and the eye: An update on published data]. / SARS-CoV-2, COVID-19 et œil : le point sur les données publiées.

The COVID-19 pandemic has dramatically changed our daily lives as ophthalmologists. This general review firstly provides a better understanding of the virus responsible for the pandemic: the SARS-CoV-2, and the clinical manifestations of the COVID-19 disease. The second part is detailing the pathophysiology, clinical signs and challenges of ocular involvement, which seems rare and not functionally severe, but which may be a potential source of contamination. Finally, we discuss the preventive measures that need to be implemented in our daily practice to avoid any viral dissemination.