Abstract: Coronavirus disease 2019 (COVID-19), a newly identified acute respiratory disease caused by a strain of novel coronavirus (SARS-CoV-2), has become a worldwide pandemic. From December 2019 to present, millions of cases have been reported, bringing unprecedented pressure on both health and epidemic prevention services in every country. As frontline healthcare workers, ophthalmologists face an increased threat of viral infection, not only because of close contact with patients during examinations or operations, but also due to evidence showing that ocular fluids such as tears or conjunctival secretions may carry the virus. The risk that healthcare workers face is emphasized by the loss of our colleagues who have sacrificed themselves in combating the virus. As a result, it is necessary to have a comprehensive understanding of the threats that we face. In the first part of this review, we start by explaining the structure of SARS-CoV-2 and examining its transmission and means of infection. Next, we summarize the latest scientific advancements of epidemiology, clinical presentations, and current treatments of COVID-19. In the second half of the review, we emphasize the ocular transmission, symptomatic manifestations, and the essential knowledge in an ophthalmology clinic setting. As the pandemic of COVID-19 continues to pose a threat to global health, we hope that this review makes a contribution to combating COVID-19.

Background

In December of 2019, a novel coronavirus strain named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified among pneumonia patients in Wuhan, China (Adam, 2020; Guan et al., 2020). During the first four months of this outbreak, novel coronavirus disease 2019 (COVID-19) has spread rapidly throughout China and subsequently worldwide, posing a critical threat to global health. While COVID-19 caused by SARS-CoV-2 can result in serious respiratory illness and even death, it may also manifest with mild symptoms. Additionally, recent studies have suggested that COVID-19 may be spread by asymptomatic carriers of the virus (Yongchen et al., 2020). No specific antiviral therapies are available, and many countries are under enormous pressure on their health systems, with a shortage of personal protective equipment (PPE) and medical resources. These factors allowed the outbreak to reach to the pandemic level (Rowan and Laffey, 2020). Statistically, since the identification of the first case of COVID-19, the disease has affected 185 countries and regions, with 3,767,744 confirmed cases and 259,593 total deaths worldwide (May 8, 2020).

In this review, we searched and gathered relevant literature to summarize the COVID-19 ophthalmic manifestation and transmission, and provide management principles in the ophthalmology clinic.

Introduction of SARS-CoV-2

Coronavirus (CoV) is a single-stranded, positive-sense RNA virus with a diameter of 80-160 nm. It is divided into four subgroups: α-, β-, δ-, and γ-coronavirus (Walls et al., 2020). Six coronaviruses were previously known to cause disease in humans, in which SARS-CoV-2, belonging to β-coronavirus, is the seventh member of the coronavirus family that infects human beings following SARS-CoV and MERS-CoV, which led to outbreaks of Acute Respiratory Syndrome (SARS) in 2002-2003 and Middle East Respiratory Syndrome (MERS) in 2012, respectively. Unlike the usually mild disease associated with other human coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2 viruses generally can result in severe lower respiratory disease requiring hospitalization. When compared to SARS-CoV and MERS-CoV, SARS-CoV-2 has higher transmissibility and infectivity, despite its lower mortality rate (Mahase, 2020). SARS-CoV-2 has a genome of about 30 kb encoding structural and unstructured proteins. Specifically, it consists of nucleocapsid protein (N), RNA, hemagglutinin-esterase (HE), spike protein (S), membrane glycoprotein (M), and envelope protein (E) (Walls et al., 2020) (Figure 1).

Among the structural units, the S protein mainly mediates target cell recognition, virus attachment, and invasion via binding the receptor angiotensin-converting enzyme 2 (ACE2) (Wang et al., 2020). S protein is constituted by two subunits: S1 contains the receptor-binding domain (RBD), mediating host cell attachment by forming a complex with the receptor ACE2, and S2 comprises basic fusion elements to mediate host cell membrane fusion. The binding affinity of SARS-CoV-2 with ACE2 is 10-20 times higher than that of the S-protein of SARS-CoV, leading to higher infectivity and transmissibility as aforementioned (Wrapp et al., 2020). These mechanisms provide us with key insights into the ways of disrupting the SARS-CoV-2 infection process. A recent study showed that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S protein mediated entry into cells, highlighting the S protein as a vital target for the development of vaccines, antibodies, and inhibitors (Wrapp et al., 2020). The RBD of the S protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor, which serves as the main receptor that SARS-CoV-2 uses to gain entry into target cells. ACE2 receptor binding can be blocked by a clinically proven inhibitor of transmembrane serine protease 2 (TMPRSS2). Intriguingly, it was found that a novel pathway in which S protein binds CD147, also referred to as extracellular matrix metalloproteinase inducer (EMMPRIN), which is an immunoglobulin superfamily transmembrane protein in humans that mediates the viral invasion, providing another key target for the development of specific drugs (Ulrich and Pillat, 2020; Ke Wang et al., 2020).

Thus far, cases of COVID-19 caused by SARS-CoV-2 have displayed clinical presentations varying from asymptomatic and mildly symptomatic forms to clinical conditions characterized by respiratory failure requiring mechanical ventilation, and even multi-organ and systemic manifestations in terms of sepsis, septic shock, and multiple organ dysfunction syndromes (MODS) (Huang et al., 2020). The severity of COVID-19 was defined according to the “Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment (7^th version)“: 1) Mild type: clinical symptoms are mild and chest imaging shows no sign of pneumonia. 2) Moderate type: fever and respiratory symptoms are developed, and pneumonia signs are found by medical imaging. 3) Severe type: Adults: Shortness of breath, respiratory rate (RR) ≥ 30/min; oxygen saturation ≤ 93% at rest, alveolar partial pressure/fraction of inspiration (PaO₂/FiO₂) ≤ 300 mmHg, or significant progression of pulmonary lesion > 50% within 24 to 48 hours. Children: Shortness of breath (< 2-month of age, RR>60/min; 2~12-month of age, RR ≥ 50/min; 1~5-year old, RR ≥ 40/min; > 5-year old, ≥ 30/min) excluding fever and crying. 4) Critically severe type: patients display any of the symptoms: respiratory failure, septic shock, or multiple organ dysfunction (MOD) or failure (MOF).

Besides the common symptoms previously highlighted, a cross-sectional study in the United States by Yan et al. (2020) reported that smell and taste loss occurred in 68% and 71% of COVID-19-positive subjects, respectively, compared to 16% and 17% of COVID-19-negative patients with influenza-like symptoms, indicating that chemosensory dysfunction is strongly associated with COVID-19 positivity and should be considered when screening symptoms. Based on available evidence, children presenting with mild or moderate symptoms are more likely to become the asymptomatic carriers, highlighting the risk of further infection within their closed family environment (Dong et al., 2020). Pregnancy-induced immunological changes and suppression by stress and anxiety may increase the susceptibility of pregnant women. Although no mutually-agreed-upon protocols exist for the SARS-CoV-2 treatment of pregnant women, doctors have resorted to all approaches they can to treat the infection as effectively as possible and avoid preterm labor, such as oxygen support, antiviral therapy, antibiotic therapy, and corticosteroid treatment (Chen et al., 2020; Dashraath et al., 2020).

Transmission of the virus occurs in a variety of methods. The confirmed transmission of SARS-CoV-2 includes respiratory droplets (>5-10 μm in diameter) and physical contact (Sohrabi et al., 2020). Additionally, some studies have suggested that other, less well-characterized methods of transmissions may also exist. Airborne aerosols (<5 μm) could potentially travel across far greater distances than respiratory droplets that are coughed or sneezed out; and compared with droplets, aerosols can more easily penetrate to the depths of the lungs, and are then deposited in the alveoli (Wilson et al., 2020). Studies compared the viability of SARS-CoV-2 in different environmental conditions, and they found that SARS-CoV-2 remained viable in aerosols for up to 3 hours; however, there’s a lack of consensus among investigators on the viability of SARS-CoV-2 in aerosols (Lewis, 2020; van Doremalen et al., 2020). Vertical transmission is defined as transmission from mother to infant occurring via ovaries, placenta, breast milk, or contact with the mother’s body fluids. While several studies suggested there are no clinical findings or experimental evidence on SARS-CoV-2 vertical transmission, there are outliers that show that vertical transmission of SARS-CoV-2 may exist. A newborn was delivered by C-section to her mother, a SARS-CoV-2 positive patient, and was isolated in a negative-pressure room. Blood samples taken two hours post-partum from the newborn showed elevated IgM. Additionally, inflammation and liver injury were found, supporting the possibility of vertical transmission; however, further investigation is needed (Dong et al., 2020). Other possible transmission methods such as fecal-oral transmission also need to be further elucidated, as researchers have detected the virus from patient fecal samples (Hindson, 2020). Although further exhaustive investigations of the means of SARS-CoV-2 transmission are both costly and time-consuming, an understanding of how the virus spreads from person to person is crucial in influencing both clinical treatment measures and containment measures such as social distancing.

Management, Therapeutic Intervention, and Vaccines

Currently, due to the absence of any clinically-approved vaccines or drugs that specifically target the SARS-CoV-2 proliferation mechanism, this infection is spreading rapidly. There is an urgent need to establish efficacious treatments in the form of repurposing existing drugs, the development of effective vaccines, and new drugs.

Management

At present, for patients presenting with only mild symptoms and without any underlying chronic conditions such as heart disease, pulmonary disease, and renal disease, self-isolation, and rest at home with daily monitoring of physical conditions may be the first choice when inpatient care is unavailable or unsafe. For hospitalized patients, symptomatic treatments and oxygen therapy are mainly used. For patients with aggravating symptoms including acute respiratory distress syndrome (ARDS), it was suggested that prone ventilation and extracorporeal membrane oxygenation (ECMO) may be administered, while fully considering the possible side effects such as lymphopenia (Henry, 2020).

Therapeutic intervention

Repurposing antiviral drugs

Remdesivir, an antiviral medication, was designed to combat the Ebola virus and other RNA viruses. Through the insertion of a nucleotide analog into viral RNA chains, it causes premature termination (Warren et al., 2016). As a result, it was recently suggested as a promising antiviral drug against SARS-CoV-2. Holshue et al. (2020) first reported that the treatment of a patient with COVID-19 by Remdesivir resulted in the improvement of the patient’s clinical condition. Additionally, Wang et al. (2020) reported that Remdesivir was effective in the control of 2019-nCoV infection in vitro. On April 10^th, a study of Remdesivir compassionate use cohort analysis published in the New England Journal of Medicine showed that most patients with severe complications of SARS-CoV-2 (68%) had clinical improvement, but approximately two-thirds of patients suffered side effects during follow-ups, such as hepatic enzyme increase, diarrhea, renal impairment, hypotension, acute kidney injury, and so on. The trial had limitations including a lack of randomized controls and a small sample size (Grein et al., 2020). Recently, an orally bioavailable broad-spectrum antiviral treatment named NHC/EIDD-2801 showed promising results against SARS-CoV-2 in vitro and in vivo. Moreover, NHC/EIDD-2801 is also effective against Remdesivir-resistant viruses, highlighting its usefulness as a possible drug candidate for the treatment of SARS-CoV-2 (Sheahan et al., 2020).

Chloroquine and Hydroxychloroquine are both used to treat Malaria and autoimmune conditions. An in vitro study indicated that Chloroquine is highly effective in the control of SARS-CoV-2 infection in Vero E6 cells (Liu et al., 2020). Additionally, a small sample size study conducted in France demonstrated that Hydroxychloroquine is capable of significantly reducing the viral load in patients with SARS-CoV-2 (Gautret et al., 2020). Based on limited in vitro and in vivo studies, Hydroxychloroquine and Chloroquine may serve as a possible drug candidate for the treatment of SARS-CoV-2 (Gao et al., 2020; Gautret et al., 2020). However, at the time of writing, both drugs lack randomized, reliable results to prove their efficacy, and are currently being tested in clinical trials. Furthermore, the side effects of Hydroxychloroquine and Chloroquine are pronounced, including serious cutaneous adverse reactions, fulminant hepatic failure, and ventricular arrhythmias, especially within patients treated with azithromycin (Juurlink, 2020).

Lopinavir and Ritonavir, a combination of protease inhibitors typically used in human immunodeficiency virus (HIV), were tested as a SARS-COV-2 treatment. However, the results obtained were not encouraging. A randomized, controlled, open-label trial containing 199 hospitalized patients with severe COVID-19 treated with Lopinavir and Ritonavir resulted in no significant improvement in clinical outcomes (Cao et al., 2020).

The safety and efficacy of these drugs mentioned above are not yet known. As a result, conclusive randomized clinical trials must be performed in order to evaluate whether they are a safe and effective treatment for SARS-CoV-2.

Convalescent plasma therapy

Convalescent plasma therapy (CPT), a classic adaptive immunotherapy approach, has been applied in the treatment of infectious diseases for over a century. Recent studies have suggested that CPT may prove to be an effective treatment for SARS-CoV-2. Transfusion of plasma to patients from people who have recovered from SARS-CoV-2 was shown to potentially improve the clinical outcomes with little to no side effects in a recent study (Duan et al., 2020). Although CPT also needs to be further evaluated for its safety and efficacy via additional clinical trials, this may be the better choice to treat the severe cases that require immediate intervention.

Immuno-modulation therapy

Cytokine storm, a severe incident in SARS and MERS patients, results in the rapid deterioration, tissue destruction, progressive organ failure, and death. These manifestations are also observed in SARS-CoV-2 cases, especially in young patients. Therefore, controlling cytokine storm manifestations will ultimately be an important strategy to treat and manage severe COVID-19 cases (Mehta et al., 2020). Although the mechanisms in which SARS-CoV-2 incites cytokine storms are still unclear, protocols for treatment of cytokine storms caused by other diseases with medications such as an IL-6 antagonist (Tocilizumab) or other antagonists, corticosteroids, stem cell therapy (Gerlach, 2016), and blood purification treatments (Monard et al., 2019) are well outlined. Tocilizumab is an immunosuppressive drug (antibody) that binds to the IL-6 receptor and blocks IL-6 production during cytokine storms observed in severe COVID-19 patients (Michot et al., 2020). Synthetic recombinant interferon α has proven to be effective in the treatment of SARS patients in clinical trials, which suggests that interferon α could be used in the treatment of COVID-19 (Lythgoe and Middleton, 2020). Immunoglobulin, the safest immunomodulator for long-term use in all ages, could help to inhibit the production of proinflammatory cytokines and increase the production of anti-inflammatory mediators (Mehta et al., 2020). Moreover, thymosin alpha-1 (Ta1) has been shown to be an immune booster for SARS patients, effectively controlling the severity of disease manifestation (Kumar et al., 2013). Therefore, intravenous immunoglobulin and Ta1 may also be considered as possible therapeutics for COVID-19.

Traditional Chinese Medicine (TCM) treatment

During the SARS-CoV epidemics in 2004, traditional Chinese medicine has seen some success in both treating patients with SARS-CoV and reducing the spread of the disease (Zhang et al., 2004). TCM approaches may also see some success in treating SARS-CoV-2. The National Health Commission of China has adopted some TCM prescriptions in their Guidelines on Diagnosis and Treatment of COVID-19 (Trial 6th edition) such as Qing fei pai du tang, Hua shi bai du fang, and Xuan fei bai du fang (Shi-xin Wang et al., 2020). At the time of writing, more and more countries are actively evaluating the effectiveness of TCM in the treatment of COVID-19 via experimental drug approaches.

Other treatments

As SARS-CoV-2 infiltration is dependent on binding to the ACE2 receptor, various biotechnology firms are developing ACE-related drugs for the treatment of COVID-19. Human recombinant soluble ACE2 has already undergone clinical phase I and phase II testing and is being considered for the treatment of COVID-19 (NCT04287686). Moreover, with the rapid development of gene-editing technology in recent years, such as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and RNA interference (RNAi), these methods have been used successfully in a variety of fields. Recently, researchers developed a CRISPR/Cas13 based therapy called PAC-MAN (Prophylactic Antiviral CRISPR in huMAN cells) that may degrade SARS-CoV-2 sequences effectively in human lung epithelial cells (Abbott et al., 2020). Approaches involving RNAi-based methods are also being tested (Hodgson, 2020).

Vaccine development for SARS-CoV-2

Based on the knowledge from SARS and MERS vaccine developments, approximately 70 SARS-CoV-2 vaccines are currently under development worldwide using several platforms including mRNA, DNA, adenoviral vectors, and recombinant proteins. The S protein or its subunit, S1, which contains its RBD, may serve as an appropriate vaccine binding antigen, as vaccines containing neutralizing antibodies will prevent host cell attachment and infection. Targeting these regions, nucleic acid-based and DNA vaccines have shown to be the most successful platform with three ongoing phase I and II clinical trials (NCT03721718, NCT03399578, NCT03615911).

Ocular Manifestation

As the COVID-19 pandemic continues, extensive systemic symptoms have been reported. Nevertheless, there is limited medical literature that identifies ocular manifestations in COVID-19 patients. Hence, we review the ocular abnormalities and clinical characteristics of COVID-19 patients to provide references for follow-up research, prevention, and treatment. Among 38 highly suspected or confirmed COVID-19 cases from Yichang, China, Wu et al. (2020) reported that 12 patients (31.6%) displayed conjunctivitis with conjunctival hyperemia, chemosis, epiphora, or increased secretions as the main ocular manifestations. In addition, 11 of 12 patients with ocular abnormalities (91.7%) were detected as positive results from nasopharyngeal swabs and 2 (16.7%) cases were detected as positive results from both conjunctival and nasopharyngeal swabs for SARS-CoV-2 by reverse-transcription polymerase chain reaction (RT-PCR). Another cross-sectional study performed in Wuhan, China with a larger sample size (534 confirmed cases) reported ocular characteristics including conjunctival congestion (3.8~5.5%), dry eye (11.1~31.2%), blurred vision (4.8~20.9%), and foreign body sensations (4.8~19%). Recently, a study from Marinho et al. (2020) reported that OCT results from 12 adult COVID-19 patients appeared to have hyperreflective lesions at layers of ganglion cells and inner plexiform in both eyes. However, OCT-angiography, ganglionar cell complex analysis, visual acuity, and papillary reflexes displayed normally without any signs of intraocular inflammation in all eyes, which suggests that the possibility of endophthalmitis is very small (Chen et al., 2020).

Although there is a variation of the incidence rate of “conjunctival congestion” or conjunctivitis in different studies (0.8-31.6%), the total number of COVID-19 patients presenting with conjunctivitis is over 20,000 (Chen et al., 2020; Guan et al., 2020; Sun et al., 2020), indicating a need for expanded investigation in the ocular manifestations of SARS-CoV-2. Next, we will expound the ocular manifestations from two perspectives.

(1) Initial symptoms: Conjunctivitis, or “pink eye,” may occur as one of the first symptoms of COVID-19. A health care worker presented with foreign body sensation, congestion of the bulbar conjunctiva, and abnormal respiratory symptoms, but did not show any abnormal appearances of the chest as observed by CT scan on the third day after contact with a confirmed SARS-CoV-2 patient. After Ganciclovir eye drop treatment for 3 days, the ocular symptoms subsided, but the patient subsequently suffered from fever and respiratory symptoms and tested positive for SARS-CoV-2 as determined by RT-PCR from nasopharyngeal swabs, but negative from conjunctival swabs. CT of the chest showed discrete, scattered, patchy shadows over both lungs (Li et al., 2020). Additional cases showed similar patterns of disease manifestations, which will not be discussed due to their similarity (Chen et al., 2020; Xu et al., 2020).

(2) Simultaneous phenomenon in severe patients: Statistics from a hospital center in Hubei province, China, highlighted the fact that 31.6% (12/38) patients had ocular abnormalities, and ocular symptoms were more likely to occur in patients with more severe cases of COVID-19: 50% (6/12) patients with ocular abnormalities were classified as critical, 16.7% (2/12) patients with ocular abnormalities were classified as severe, and 33.3% (4/12) patients with ocular abnormalities were classified as moderate severity (Wu et al., 2020).

Through these specific cases, we wish to highlight the following. (1) Compared with nasopharyngeal swabs, conjunctival swabbing is a very useful, easy, and non-invasive way to test for the presence of the virus. However, to obtain accurate results of viral presence in the conjunctival sac, the swab must be performed as soon as possible when conjunctivitis is observed. (2) The ocular symptoms in these cases seem to occur prior to SARS-CoV-2 systemic symptom, acting as a sort of ‘early warning,’ which should not be ignored before more serious symptoms manifest. (3) As conjunctivitis can often occur as the first symptom of SARS-CoV-2 infection, it can be utilized as an auxiliary indicator of patients who are symptom-free but virus carriers. (4) We should also pay attention to the potential risk of retinopathy induced by SARS-CoV-2. Overall, the ocular manifestations play a vital role at different stages of the SARS-CoV-2 disease.

Ocular Transmission

As seen from the two confirmed means of viral transmission, close contact with an infected person without wearing goggles or touching of the eyes without hand-washing can potentially cause an infection of the eyes with the virus. Due to human nature, it is common that we inadvertently rub our eyes, scratch our noses and mouths, and touch our faces, greatly contributing to the overall transmissibility of the virus between humans. Most of the patients with SARS-CoV-2 related ocular symptoms usually have a history of viral exposure to the eyes or a hand-eye contact history (Chen et al., 2020). Evidence has shown that viral RNA of SARS-CoV-2 can be detected by RT-PCR from the tears of infected patients despite having a low positive rate (Colavita et al., 2020; Seah et al., 2020; Xia et al., 2020). For ophthalmologists, the threat of contracting SARS-CoV-2 is an ever-present threat in the ophthalmology clinic. The physical distance between the patients and the ophthalmologists is very close in many ophthalmic examinations and procedures, such as slit lamp microscope examination, direct ophthalmoscope examination, intraocular injection, and even ophthalmologic operations (Seah et al., 2020). Therefore, it is worth noting the ocular transmission of SARS-CoV-2.

(1) Respiratory droplets and airborne aerosols can easily contaminate human conjunctiva and cornea. Deng et al. (2020) showed that mild interstitial pneumonia was found in conjunctival inoculated-macaques. Although they detected the SARS-CoV-2 in macaques’ conjunctiva via conjunctival swabs just after one day after inoculation, the virus was primarily distributed in the nasolacrimal system and ocular system (lacrimal gland, conjunctiva, optic nerve) on day seven after inoculation.

(2) In addition to their expression in the lungs, the receptors that SARS-CoV-2 binds to are also widely expressed in the eye. Firstly, several studies revealed that ACE2 is not only expressed in the aqueous humor and retina, but also in the conjunctival or corneal epithelia (Sun, 2020). Additionally, any ocular fluids, such as tears, that may be contaminated by SARS-CoV-2 can pass through the nasolacrimal duct due to the anatomy between the lacrimal puncta and nasal passage and then gain entry into the respiratory tract (Qing et al., 2020). Secondly, the CD147 receptor that also mediates host cell invasion is widely expressed in human ocular tissues, such as corneal epithelial cells, corneal stromal keratocytes, corneal endothelial cells, and retinal pigment epithelium (RPE) cells (Maatta et al., 2006). CD147 also participates and plays an important role in several ocular disorders (Hori et al., 2000; Mauris et al., 2015), with some researchers even regarding CD147 as a potential biomarker of angiogenesis in proliferative diabetic retinopathy (Abu El-Asrar et al., 2017).

From the above, we are able to conclude:

(1) The conjunctiva contains many receptors used by SARS-CoV-2 for host cell infiltration, and is a susceptible organ for infection.

(2) SARS-CoV-2 infection of the ocular system may allow for further invasion into the respiratory system via the movement of ocular fluids.

(3) Often, negative results for SARS-CoV-2 are obtained from conjunctival swabs of both patients and animals. The reasons for this may include the following. (1) The overall systemic concentration of the virus is low, as some patients or animal models with conjunctivitis did not show any severe systemic symptoms. (2) Tears may wash down and break up the virus, making each sampling a hit-and-miss affair. (3) Diagnostic sensitivity and the false-negative rate. (4) The means and time point of sampling (Sun et al., 2020). All these highlight the possible infectivity of ocular fluids and the importance of further understanding the ocular transmission route of the virus.

Essentials in Ophthalmology Clinic

Precautionary measures for ophthalmologists

Given the fact that SARS-CoV-2 may be able to survive as an aerosol and remain infective in asymptomatic and pre-symptomatic individuals (Asadi et al., 2020), in addition to the fact that SARS-CoV-2 patients may present to ophthalmologists with viral conjunctivitis as the initial symptom (Wei et al., 2020), the adequate use of PPE of ophthalmologists including gloves, face masks, air-purifying respirators, goggles, face shields, and gowns during the ongoing SARS-CoV-2 pandemic is critical (Huh, 2020). In addition, social distancing strategies are essential in the current time of pandemic in a clinical setting. It has been reported that the gas cloud and its payload of pathogen-bearing droplets of all sizes can travel 23 to 27 feet (7-8 m) (Bourouiba, 2020) given various combinations of an individual patient’s physiology and environmental conditions, such as humidity and temperature. Therefore, 27 feet will be considered as the minimum safe distance.

Further, an instant testing platform of SARS-CoV-2 is a necessity to offer healthcare providers in ophthalmology clinics a rapid result in order to guide frontline physicians in making quick diagnoses, taking protective measures accordingly, and making immediate decisions of treatment. To this end, a rapid and non-location limited testing methodology is in demand. On March 27, 2020, the Food and Drug Administration (FDA) issued emergency - use authorization for a rapid molecular in vitro diagnostic test instrument launched by Abbott utilizing isothermal nucleic acid amplification technology for the qualitative detection of the SARS-CoV-2 viral RNA sampled from nasal, nasopharyngeal, or throat swabs eluted in viral transport media. Since this methodology does not require a series of alternating temperature cycles needed in PCR, it can deliver positive results in as little as five minutes and negative results in 13 minutes, significantly faster than RT-PCR and serological testing which may take a few hours to two days. Although the testing specificity and sensitivity of this isothermal nucleic acid amplification based method have not been fully evaluated, it remains suitable thus far for outpatient care in the ophthalmology clinic.

Telemedicine in ophthalmology during SARS-CoV-2 pandemic

Telemedicine is defined as the incorporation of telecommunication technologies into therapeutic medicine. Ophthalmology is a specialty very suitable for telemedicine service delivery systems, as most diagnostic instruments can easily adapt to static and video cameras (Maa et al., 2017). As a routine practice of ophthalmology professionals, they regularly analyze photographic images to make inferences about various eye conditions, so disruption to the diagnostic process should be minimal. Teleophthalmology has emerged as a branch of telemedicine originally to increase access to eye care for remote and rural populations. It has successfully been applied in the diagnosis and care of diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, glaucoma, and orbital diseases. Nevertheless, with the SARS-CoV-2 pandemic putting frontline ophthalmologists under mounting pressure, teleophthalmology is occupying an increasingly important position for patient care in the current crisis. Herein, we reviewed the relevant literature regarding triage new patients and follow-up on existing patients and clinical trial subjects.

Virtual triage and real-time video consultation

Virtual triaging has been pioneered and applied in glaucoma patients referral at Moorfields Eye Hospital, U.K. by the Kotecha team (Kotecha et al., 2017). According to this study, a virtual clinic strategy was proven to significantly reduce the referral patient volume into the outpatient department. In addition, the triage system also has been utilized to effectively recognizing the urgency of ophthalmic conditions, and reducing unnecessary emergency load and waiting time in Saudi Arabia (AlSamnan et al., 2015). Therefore, during the current COVID-19 outbreak, “forward triage” potentially could serve as an efficient strategy for managing ophthalmology patients by sorting patients before they present physically to an ophthalmology clinic. In this way, reduced outpatient service load will protect all parties involved: patients, doctors, and the entire community.

A real-time video consultation system was originally designed and built up for areas or countries with an unevenly distributed population in order to deliver healthcare services to rural residents and remote communities, avoiding long delays and high transportation costs. The study performed in Western Australia demonstrates that there is a high level of overall satisfaction with ophthalmological video consultation, with a total of 94% of patients reporting they were ‘Satisfied’ or ‘Very satisfied’ (Host et al., 2018). Nevertheless, it holds great potential in the current COVID-19 outbreak to provide specialist eye services for patients remotely and reduce the chances of face-to-face consultation. During the early days, the connectivity used to be a major obstacle of real-time video consultation as the heavy data transmission. To date, the omnipresence of broadband Internet and 4G and 5G has overcome the barrier. This offers a powerful tool for teleophthalmology as detailed video could be transmitted in real-time with readily available equipment. NHS Forth Valley and Moorfields Eye Hospital have launched a teleophthalmology project performing the world’s first tele-examination of an eye in 4K resolution using 5G broadband, by which a video of a slit lamp examination can stream live between London and Edinburgh. NHS Forth Valley is also using the system to remotely examine patients in community optometry practice, while inside Moorfields Eye Hospital a senior specialist can perform remote examinations.

Home monitoring and communication

As an important component of teleophthalmology, home monitoring systems of visual acuity, visual fields, and intraocular pressure are being developed with safety and effectiveness (Chew et al., 2014; Ittoop et al., 2016; Anderson et al., 2017). For patients who have chronic eye diseases, such as dry age-related macular degeneration (AMD), chronic glaucoma or diabetic macular edema, especially in such a pandemic when individuals may have to go into quarantine or self-isolation unexpectedly, home monitoring of symptoms and timely communication is of great importance. In an interventional case study conducted by Starr et al. (2019), 59 patients with exudative AMD receiving intravitreal anti-vascular endothelial growth factor (VEGF) injections at local satellite clinic were able to be effectively managed using a telemedicine system with electronic consultation at Mayo Clinic over a period of 1.2 years. Throughout the study period, visual acuity was preserved stable. In addition, smartphone-based ocular imaging is a rapidly emerging area. With an appropriate app and slit-lamp adapter installed, it allows anterior and posterior photographs to be taken, further strengthening the diagnostic capabilities of teleophthalmology (Mohammadpour et al., 2017).

Management of ophthalmic perioperative period during SARS-CoV-2 pandemic

To reduce virus transmission and enhance nations’ ability to care for those who are desperately ill, the American Academy of Ophthalmology (AAO) has released the recommendation for triage of ophthalmology patients regarding urgent and non-urgent care, suggesting all ophthalmologists should cease providing procedures other than urgent or emergent care. For urgent and unavoidable procedures, a cross-sectional study has concluded that during the prevention and control period of the epidemic of SARS-CoV-2, strict adherence to the prevention and control measures proposed can effectively ensure the smooth implementation of the operation and the perioperative safety of all medical staff and patients involved (Wang et al., 2020).

Subjects and patients follow-up during SARS-CoV-2 pandemic

Clinical trial subjects follow-up

Principles for following up subjects enrolled in a clinical trial (Zhang et al., 2020) are as follows. (1) The Principle Investigator (PI) communicates with the sponsor and decides the subject’s visit method and time during the epidemic. It is advisable to try to follow up by either telephone or video conference. The researcher must truthfully record the remote follow-up process. The follow-up is carried out by the researcher or an institutional professional. The content and procedures should be unified. (2) All changes to the follow-up methods of the subject during the epidemic and any protocol violation (PV) events that occur must be reported to the ethics committee in accordance with the normal processes, and filed with the central office by mail. (3) For subjects who must physically go to the hospital for follow-up but cannot return to the hospital due to force majeure factors such as traffic congestion, the researcher should guide or arrange the subjects to seek medical treatment nearby and try to complete the relevant examinations required by the protocol. The researcher must use remote communication to collect and gauge all inspection results. (4) Special inspection requirements that cannot be completed at the moment can be classified as missing data. Supplementary inspections should be conducted as soon as conditions permit or after the epidemic, and the corresponding protocol deviation (PD) and PV records and corresponding records should be made. (5) Subjects who are able to come to the hospital for a follow-up after communication with the researcher must call in advance for the research team to understand the subject’s current condition and whether there is a history of contact within the epidemic area, in an effort to minimize the risk of transmission. Subjects must be made aware that in order for a follow-up visit to occur, their body temperature must be normal, and they must not exhibit any other symptoms related to the virus, in addition to wearing a mask. (6) The research team needs to make arrangements for visits in advance and disinfect the follow-up area promptly. (7) On the day of the visit, the researcher must carefully register and catalog the subjects who come to the hospital for follow-up. (8) The body temperature of the subjects should be taken immediately upon arrival at the hospital. Those with normal body temperature should be followed up as planned. Subjects with elevated body temperature must be moved to the fever clinic for investigation as required by the hospital. (9) The research team should reinforce the ideas of virus protection, isolation, and other precautionary measures the subjects can take. Furthermore, researchers should remind the subjects to actively maintain communication with the research doctor, and actively provide the research doctor with personal health status and medication information updates.

Patients follow-up

The follow-up of ophthalmological patients should meet the following requirements. (1) Telephone communication with the patients to ensure that the patients or any immediate family members have not been isolated for various reasons, and determine that the subjects and their families have no epidemiological history and no fever at present or do not have a cough or other symptoms. If the patient is displaying any viral symptoms, the patient’s follow-up visit should not be scheduled. Patients who are willing to come to the hospital for a follow-up should agree on the time of the visit in advance. If their physical condition does not allow for an independent visit to the hospital, only one family member is allowed to accompany them, and must be cautiously protected, wearing masks and hats. (2) On the day of the visit, the patient should be provided with a patient questionnaire and instructed to fill in and sign any relevant content. Additionally, the body temperature of both the patient and the accompanying person should be measured. Any protective measures for the patient and the accompanying person should also be evaluated at this time. (3) Guide for the referral of the subjects: any examinations of the patient should be conducted in as efficient a manner as possible. The patient should be transported throughout the hospital in the shortest and most reasonable route. (4) Personal protection during the inspection: the patient is strongly advised not to take off any protective PPE including masks unless necessary. If the patient has any discomfort, one should communicate in advance and be attended to accordingly.

In summary, the purpose of this review is to inform medical workers, especially ophthalmologists, and recognize the current situation and adopt the right approach to cope with COVID-19 during the pandemic. Clearly, the network connections we have today give us the tools to fight this pandemic, and measures built on this network platform will be crucial to ensure that the next outbreak never has a chance to turn from an epidemic to a global pandemic. This allows us to care and monitor patients and assess their progress across distance, which goes a long way towards reassuring people, preventing panic, and keeping medical centers and hospitals running. It is hoped all participants quickly and successfully adapt to the new routines of ophthalmology care that safeguard both patients and care professionals.

Acknowledgment

Shuo Sun was supported by China Scholarship Council (CSC).

Disclosure

No conflicting interest exists for any author.

Author Contribution

Shuo Sun, M.D., and Wenqi Su, M.D., contributed equally to this article.

Corresponding Authors

Bo Tian, M.D., Ph.D., and Haijiang Lin, M.D., Ph.D., Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, MA 01605, USA and Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA.

References

Abbott TR, Dhamdhere G, Liu Y, Lin X, Goudy L, Zeng L, Chemparathy A, Chmura S, Heaton NS, Debs R, Pande T, Endy D, La Russa M, Lewis DB, Qi LS. Development of CRISPR as an antiviral strategy to combat SARS-CoV-2 and influenza. Cell 181(4):865-876.e12, 2020.

Abu El-Asrar AM, Ahmad A, Alam K, Siddiquei MM, Mohammad G, Hertogh G, Mousa A, Opdenakker G. Extracellular matrix metalloproteinase inducer (EMMPRIN) is a potential biomarker of angiogenesis in proliferative diabetic retinopathy. Acta Ophthalmol 95(7):697-704, 2017.

Adam D. Special report: The simulations driving the world’s response to COVID-19. Nature 580(7803):316-318, 2020.

Alsamnan MS, Mousa A, Al-Kuwaileet S, Alsuhaibani AH. Triaging self-referred patients attending ophthalmic emergency room. Saudi Med J 36(6):678-684, 2015.

Anderson AJ, Bedggood PA, George Kong YX, Martin KR, Vingrys AJ. Can Home Monitoring Allow Earlier Detection of Rapid Visual Field Progression in Glaucoma? Ophthalmology 124(12):1735-1742, 2017.

Asadi S, Bouvier N, Wexler AS, Ristenpart WD. The coronavirus pandemic and aerosols: Does COVID-19 transmit via expiratory particles? Aerosol Sci Technol 54(6):635-638, 2020.

Bourouiba L. Turbulent Gas Clouds and Respiratory Pathogen Emissions: Potential Implications for Reducing Transmission of COVID-19. JAMA 323(18):1837-1838, 2020.

Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, et al. A trial of lopinavir- ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 382(19):1787-1799, 2020.

Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, Li J, Zhao D, Xu D, Gong Q, Liao J, Yang H, Hou W, Zhang Y. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet 395(10226):809-815, 2020.

Chen L, Deng C, Chen X, Zhang X, Chen B, Yu H, Qin Y, Xiao K, Zhang H, Sun X. Ocular manifestations and clinical characteristics of 535 cases of COVID-19 in China: A cross-sectional study. Acta Ophthalmol 10.1111/aos.14472, 2020.

Chew EY, Clemons TE, Bressler SB, Elman MJ, Danis RP, Domalpally A, Heier JS, Kim JE, Garfinkel R. Randomized trial of a home monitoring system for early detection of choroidal neovascularization home monitoring of the Eye (HOME) study. Ophthalmology 121(2):535-544, 2014.

Colavita F, Lapa D, Carletti F, Lalle E, Bordi L, Marsella P,Nicastri E, Bevilacqua N, Giancola ML, Corpolongo A, Ippolito G, Capobianchi MR, Castilletti C. SARS-CoV-2 Isolation From Ocular Secretions of a Patient With COVID-19 in Italy With Prolonged Viral RNA Detection. Ann Intern Med 173(3):242-243, 2020.

Dashraath P, Wong JLJ, Lim MXK, Lim LM, Li S, Biswas A, Choolani M, Mattar C, Su LL. Coronavirus Disease 2019 (COVID-19) Pandemic and Pregnancy. Am J Obstet Gynecol 222(6):521-531, 2020.

Deng W, Bao L, Gao H, Xiang Z, Qu Y, Song Z, Gong S, Liu J, Liu J, Yu P, Qi F, Xu Y, Li F, Xiao C, Lv Q, Xue J, Wei Q, Liu M, Wang G, Wang S, et al. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques. Nature Commun 11(1):4400, 2020.

Dong L, Tian J, He S, Zhu C, Wang J, Liu C, Yang J. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA 323(18):1846-1848, 2020.

Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, Tong S. Epidemiology of COVID-19 Among Children in China. Pediatrics 145(6):e20200702, 2020.

Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M, Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A 117(17):9490-9496, 2020.

Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 14(1):72-73, 2020.

Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honore S, Colson P, Chabriere E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J AntimicrobAgents 56(1):105949, 2020.

Gerlach H. Agents to reduce cytokine storm. F1000Res 5:2909, 2016.

Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, Feldt T, Green G, Green ML, Lescure FX, Nicastri E, Oda R, Yo K, Quiros-Roldan E, Studemeister A, Redinski J, Ahmed S, Bernett J, Chelliah D, Chen D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med 382(24):2327-2336, 2020.

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 382(18):1708-1720, 2020.

Henry BM. COVID-19, ECMO, and lymphopenia: a word of caution. Lancet Respir Med 8(4):e24, 2020.

Hindson J. COVID-19: faecal-oral transmission? Nat Rev Gastroenterol Hepatol 17(5):259-259, 2020.

Hodgson J. The pandemic pipeline. Nat Biotechnol 38(5):523-532, 2020.

Holshue ML, Debolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, Spitters C, Ericson K, Wilkerson S, Tural A, Diaz G, Cohn A, Fox L, Patel A, Gerber SI, Kim L, Tong S, Lu X, Lindstrom S, Pallansch MA, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med 382(10):929-936, 2020.

Hori K, Katayama N, Kachi S, Kondo M, Kadomatsu K, Usukura J, Muramatsu T, Mori S, Miyake Y. Retinal Dysfunction in Basigin Deficiency. Invest Ophthalmol Vis Sci 41(10):3128-3133, 2000.

Host BK, Turner AW, Muir J. Real-time teleophthalmology video consultation: an analysis of patient satisfaction in rural Western Australia. Clin Exp Optom 101(1):129-134, 2018.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395(10223):497-506, 2020.

Huh S. How to train health personnel to protect themselves from SARS-CoV-2 (novel coronavirus) infection when caring for a patient or suspected case. J Educ Eval Health Prof 17:10-10, 2020.

Ittoop SM, Soohoo JR, Seibold LK, Mansouri K, Kahook MY. Systematic Review of Current Devices for 24h Intraocular Pressure Monitoring. Adv Ther 33(10):1679-1690, 2016.

Juurlink DN. Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection. CMAJ 192(17):E450-E453, 2020.

Kotecha A, Brookes J, Foster PJ. A technician-delivered ‘virtual clinic’ for triaging low-risk glaucoma referrals. Eye (Lond) 31(6):899-905, 2017.

Kumar V, Jung YS, Liang PH. Anti-SARS coronavirus agents: a patent review (2008 - present). Expert Opin Ther Pat 23(10):1337-1348, 2013.

Lewis D. Is the coronavirus airborne? Experts can’t agree. Nature 580(7802):175, 2020.

Li X, Wang M, Dai J, Wang W, Yang Y, Jin W. Novel coronavirus disease with conjunctivitis and conjunctivitis as first symptom: Two cases report. Chin J Exp Ophthalmol 38(04):318-321, 2020.

Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, Li Y, Hu Z. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 6:16, 2020.

Lythgoe MP, Middleton P. Ongoing Clinical Trials for the Management of the COVID-19 Pandemic. Trends Pharmacol Sci 41(6):363-382, 2020.

Maa AY, Wojciechowski B, Hunt KJ, Dismuke C, Shyu J, Janjua R, Lu X, Medert CM, Lynch MG. Early Experience with Technology-Based Eye Care Services (TECS): A Novel Ophthalmologic Telemedicine Initiative. Ophthalmology 124(4):539-546, 2017.

Määttä M, Tervahartiala T, Kaarniranta K, Tang Y, Yan L, Tuukkanen J, Sorsa T. Immunolocalization of EMMPRIN (CD147) in the human eye and detection of soluble form of EMMPRIN in ocular fluids. Curr Eye Res 31(11):917-924, 2006.

Mahase E. Coronavirus covid-19 has killed more people than SARS and MERS combined, despite lower case fatality rate. BMJ 368:m641, 2020.

Marinho PM, Marcos AAA, Romano AC, Nascimento H, Belfort R, Jr. Retinal findings in patients with COVID-19. Lancet 395(10237):1610-1610, 2020.

Mauris J, Dieckow J, Schob S, Pulli B, Hatton MP, Jeong S, Bauskar A, Gabison E, Nowak R, Argüeso P. Loss of CD147 results in impaired epithelial cell differentiation and malformation of the meibomian gland. Cell Death Dis 6(4):e1726, 2015.

Mehta P, Mcauley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395(10229):1033-1034, 2020.

Michot JM, Albiges L, Chaput N, Saada V, Pommeret F, Griscelli F, Balleyguier C, Besse B, Marabelle A, Netzer F, Merad M, Robert C, Barlesi F, Gachot B, Stoclin A. Tocilizumab, an anti-IL-6 receptor antibody, to treat COVID-19-related respiratory failure: a case report. Ann Oncol 31(7):961-964, 2020.

Mohammadpour M, Heidari Z, Mirghorbani M, Hashemi H. Smartphones, tele-ophthalmology, and VISION 2020. Int J Ophthalmol 10(12):1909-1918, 2017.

Monard C, Rimmelé T, Ronco C. Extracorporeal Blood Purification Therapies for Sepsis. Blood Purif 47(Suppl 3):1-14, 2019.

Qing H, Li Z, Yang Z, Shi M, Huang Z, Song J, Song Z. The possibility of COVID-19 transmission from eye to nose. Acta Ophthalmol 98(3):e388, 2020.

Rowan NJ, Laffey JG. Challenges and solutions for addressing critical shortage of supply chain for personal and protective equipment (PPE) arising from Coronavirus disease (COVID19) pandemic - Case study from the Republic of Ireland. Sci Total Environ 725:138532, 2020.

Seah I, Su X, Lingam G. Revisiting the dangers of the coronavirus in the ophthalmology practice. Eye (Lond) 34(7):1155-1157, 2020.

Seah IYJ, Anderson DE, Kang AEZ, Wang L, Rao P, Young BE, Lye DC, Agrawal R. Assessing Viral Shedding and Infectivity of Tears in Coronavirus Disease 2019 (COVID-19) Patients. Ophthalmology 127(7):977-979, 2020.

Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, Leist SR, Schafer A, Dinnon KH, 3rd, Stevens LJ, Chappell JD, Lu X, Hughes TM, George AS, Hill CS, Montgomery SA, Brown AJ, Bluemling GR, Natchus MG, Saindane M, et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med 12(541), 2020.

Sohrabi C, Alsafi Z, O’neill N, Khan M, Kerwan A, Al-Jabir A, Iosifidis C, Agha R. World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19). Int J Surg 76:71-76, 2020.

Starr MR, Barkmeier AJ, Engman SJ, Kitzmann A, Bakri SJ. Telemedicine in the Management of Exudative Age-Related Macular Degeneration within an Integrated health care System. Am J Ophthalmol 208:206-210, 2019.

Sun CB, Wang YY, Liu GH, Liu Z. Role of the Eye in Transmitting Human Coronavirus: What We Know and What We Do Not Know. Front Public Health 8:155, 2020.

Ulrich H, Pillat MM. CD147 as a Target for COVID-19 Treatment: Suggested Effects of Azithromycin and Stem Cell Engagement. Stem Cell Rev Rep 16(3):434-440, 2020.

Van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, Tamin A, Harcourt JL, Thornburg NJ, Gerber SI, Lloyd-Smith JO, de Wit E, Munster VJ. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med 382(16):1564-1567, 2020.

Walls AC, Park YJ, Tortorici MA, Wall A, Mcguire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 181(2):281-292.e286, 2020.

Wang K, Chen W, Zhou YS, Lian JQ, Zhang Z, Du P, Gong L, Zhang Y, Cui HY, Geng JJ, Wang B, Sun XX, Wang CF, Yang X, Lin P, Deng YQ, Wei D, Yang XM, Zhu YM, Zhang K, et al. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. bioRxiv, 2020.

Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30(3):269-271, 2020.

Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, Lu G, Qiao C, Hu Y, Yuen KY, Wang Q, Zhou H, Yan J, Qi J. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell 181(4):894-904.e899, 2020.

Wang SX, Wang Y, Lu YB, Li JY, Song YJ, Nyamgerelt M, Wang XX. Diagnosis and treatment of novel coronavirus pneumonia based on the theory of traditional Chinese medicine. J Integr Med 18(4):275-283, 2020.

Wang XL, Wang Z, Yao CL, Li SY. Management of ophthalmic perioperative period during 2019 novel coronavirus disease outbreak. Chin J Exp Ophthalmol 38(03):200-203, 2020.

Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC, Larson N, Strickley R, Wells J, Stuthman KS, Van Tongeren SA, Garza NL, Donnelly G, Shurtleff AC, Retterer CJ, Gharaibeh D, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531(7594):381-385, 2016.

Wei WE, Li Z, Chiew CJ, Yong SE, Toh MP, Lee VJ. Presymptomatic Transmission of SARS-CoV-2 — Singapore, January 23-March 16, 2020. MMWR Morb Mortal Wkly Rep 69(14):411-415, 2020.

Wilson NM, Norton A, Young FP, Collins DW. Airborne transmission of severe acute respiratory syndrome coronavirus-2 to healthcare workers: a narrative review. Anaesthesia 75(8):1086-1095, 2020.

Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, Mclellan JS. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367(6483):1260-1263, 2020.

Wu P, Duan F, Luo C, Liu Q, Qu X, Liang L, Wu K. Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19) in Hubei province, China. JAMA Ophthalmol 138(5):575-578, 2020.

Xia J, Tong J, Liu M, Shen Y, Guo D. Evaluation of coronavirus in tears and conjunctival secretions of patients with SARS-CoV-2 infection. J Med Virol 92(6):589-594, 2020.

Xu M, Zhang H, Niu X. COVID-19 patient firstly visiting eye doctor due to tarsadenitis and subconjunctival hemorrhage: A case report. Chin J Exp Ophthalmol 4(38):374-376, 2020.

Yan CH, Faraji F, Prajapati DP, Boone CE, Deconde AS. Association of chemosensory dysfunction and Covid-19 in patients presenting with influenza-like symptoms. Int Forum Allergy Rhinol 10(7):806-813, 2020.

Yongchen Z, Shen H, Wang X, Shi X, Li Y, Yan J, Chen Y, Gu B. Different longitudinal patterns of nucleic acid and serology testing results based on disease severity of COVID-19 patients. Emerg Microbes Infect 9(1):833-836, 2020.

Zhang MM, Liu XM, He L. Effect of integrated traditional Chinese and Western medicine on SARS: a review of clinical evidence. World J Gastroenterol 10(23):3500-3505, 2004.

Zhang P, Lu YY, Song S, Yu XB, Dai H. Key points of serious adverse event and protection of patients in ophthalmic clinical trials during novel coronavirus pneumonia outbreak. Chin J Exp Ophthalmol 38(03):273-275, 2020.

Zhang X, Chen X, Chen L, Deng C, Zou X, Liu W, Yu H, Chen B, Sun X. The evidence of SARS-CoV-2 infection on ocular surface. Ocul Surf 18(3):360-362, 2020.

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