Authors: Li Xuejie1 Wang Ming2 Chen Changzheng3 Yang Anhuai3 Jin Wei3
1 The First Clinical School of Wuhan University, Wuhan 430060, China;
2Clinical Laboratory Center, Renmin Hospital of Wuhan University，Wuhan 430060, China;
3Ophthalmic Center, Renmin Hospital of Wuhan University，Wuhan 430060, China;
Corresponding author:Jin Wei,Email: firstname.lastname@example.org
[Abstract] China is currently in a critical stage of controlling the outbreak of novel coronavirus pneumonia (COVID-19). As ophthalmologists working in the center of Wuhan city, the virus’s front line, we recently found conjunctivitis in five COVID-19 patients of a total of 92 COVID-19 patients.One of these five patients had conjunctivitis as the first symptom and was then diagnosed with COVID-19.These observations suggest: the mechanism and pathway of transmission of the novel coronavirus need to be further clarified; the symptoms of conjunctivitis accompanying novel coronavirus infection and conjunctiva as an important entrance point of the virus need to be further verified; early diagnosis, implementation of medical isolation, and giving appropriate treatment to patients with asymptomatic and mild-symptom conjunctivitis are essential to prevent the spread of the epidemic; those with conjunctivitis symptoms should be distinguished from other types of viral conjunctivitis; strict personal protection measures should be taken; and more sensitive techniques should be developed as soon as possible for virus detection in tear and conjunctiva swabs.
[Key words] Novel coronavirus pneumonia; Viral conjunctivitis; Eye protect glasses; Medical protection; Eye doctor
Characteristics and differentiation of viral conjunctivitis
2019-nCoV belongs to the family of coronavirus. It is an enveloped RNA virus with spherical particles and certain pleomorphism. Current research shows it has more than 85% homology with SARS-CoV (bat-SL-CoVZC45). At present, the diagnosis of COVID-19 mainly depend on clinical features: (1) fever, dry cough, dyspnea. (2) Typical CT/X-ray imaging manifestation, including multiple, patchy, sub-segmental or segmental ground-glass density shadows in both lungs. Severe cases could present as “white lung”. (3) normal or reduced white blood cell count, or reduced lymphocyte count in the early stages of the disease onset. Those with pathogenic evidence are the confirmed cases: positive for the 2019-nCoV by the real-time PCR test for nucleic acid in respiratory samples (nasopharyngeal swab). However, in the actual clinical work, many patients have extremely insidious onset. Some patients start with minor clinical signs or even no clinical symptoms . In addition, in the emergency department of our hospital, we found that some patients did not have fever, cough or other typical respiratory symptoms, but only had ophthalmic symptoms (such as conjunctivitis) as the first clinical feature, which brought great difficulties and hidden dangers to early diagnosis and timely isolation.
The proportion of COVID-19 patients with conjunctivitis is not high, and there are no specific ocular signs. In fact, ocular symptoms are common non-respiratory features after influenza virus infection in humans , and roughly 80% of documented human infections with H7 subtype viruses have been associated with ocular complications . This suggests that ophthalmologists should correctly distinguish viral conjunctivitis correctly with herpes conjunctivitis, bacterial conjunctivitis and allergic conjunctivitis . Viruses cause up to 80% of all cases of acute conjunctivitis, among which 65% to 90% of viral conjunctivitis is associated with adenovirus . Viral conjunctivitis presents with watery discharge, hyperemia and chemosis. Besides, viral infection may be always associated with fever and swelling of preauricular lymph nodes. Although no effective treatment exists, artificial tears, topical antihistamines, or cold compresses may be useful in alleviating some of the symptoms . Herpes conjunctivitis caused by herpes simplex virus is usually unilateral. The discharge is thin and watery, and accompanying vesicular eyelid lesions may be present. Topical and oral antivirals are recommended to shorten the course of the disease . Signs and symptoms of bacterial conjunctivitis include red eye, purulent or mucopurulent discharge, and chemosis. There is often accompanying eyelid swelling, eye pain on palpation, and preauricular adenopathy. Staphylococcus is the most common pathogen of adult bacterial conjunctivitis, followed by Streptococcus pneumoniae and Haemophilus influenzae. Most bacterial conjunctivitis can be effectively controlled in the early stage with topical broad-spectrum antibiotics such as Levofloxacin, Moxifloxacin and Tobramycin eye drops . Allergic conjunctivitis occurs mostly in spring. Common allergens include pollen, cosmetics and paint. Redness and eye itching are the main symptom, but with no vision loss. In terms of treatment, allergens should be removed first. Topical decongestants, antihistamines, mast cell stabilizers, nonsteroidal anti-inflammatory drugs, and corticosteroids may be useful to control the symptoms 
The transmission route of 2019-nCoV
The source of the virus and its route how it spreads between people remain unclear. In addition to respiratory droplet and contact transmission which were recognized previously, Holshue et al  reported in the “New England Journal of Medicine” in January, 2020 that 2019-nCoV nucleic acid was tested positive in the feces of COVID-19 patients, which suggested that 2019-nCoV may have the possibility of fecal-oral transmission. At a press conference on February 8th, 2020, experts from the Center for Disease Control and Prevention revealed aerosol transmission as a new transmission of 2019-CoV. Actually, we have observed a very few patients with conjunctivitis as the first symptom in the clinical practice. However, the ocular surface (notably the corneal and conjunctival epithelia) represents as an often overlooked mucosal surface that, like the respiratory tract, bears permissive receptors for influenza virus, which are host epithelial cell glycoproteins with terminal sialic acid (SA), primarily in an α-2-3 linkage . In addition, the functional receptor of SARS-CoV S protein, angiotensin-converting enzyme 2(ACE2), also expressed in human conjunctiva and cornea, suggesting a possible ocular invasion of 2019-nCoV . In 2004, Singaporean scholars reported in the “British Journal of Ophthalmology” that PCR was used to detect the tears of eight patients who were diagnosed with SARS-CoV, three of whom were positive for SARS virus RNA, and all three samples were collected in the early stage (9 days after the fever). Therefore, we speculate that SARS-Cov-2 may also be transmitted through the eyes: (1) droplets splash directly into the eyes when the patient coughs and sneezes. (2) rubbing the eyes with hands or in other ways to infect the whole body after contacting with the patient’s body fluid or blood. In addition, a study from Wake Forest University in 2008 found that after exposure to aerosols made from the live attenuated influenza vaccine (LAIV), three of four participating subjects’ nasal washes were positive for LAIV. This study indicates a very high rates of transocular transmission in subjects exposed to aerosols containing LAIV and LAIV can quickly reach the nasopharynx through the nasolacrimal duct . However, in other studies with lower exposure to influenza viruses, influenza viruses were not detected in subjects’ nasal washes . This suggests that factors such as specific virus characteristics (enveloped vs nonenveloped) or exposure amounts may influence transocular delivery. This is a strong warning for health care workers at the front lines who have to deal with large numbers of COVID-19 patients every day.
In fact, during the severe acute respiratory syndrome (SARS) and H1N1flu outbreaks, questions about eye exposure risks for health care workers have been raised . Multiple studies have demonstrated that there is no significant differences between subjects wearing surgical masks and those wearing N95 respirators . However, adding eye protection (eye and nose goggles  or goggles with a mask ) to personal protective equipment can effectively prevent cross-infection among workers. By studying the transmission of SARS-CoV, Yassi et al  showed that combining effective respirator types (such as surgical masks or N95 respirator) with eye goggles could successfully block aerosol-borne influenza. The eyes could be an entry route for 2019-nCoV, allowing viral particles easy and fast access to the upper respiratory tract. Therefore, National Health Commission suggests that in operations like respiratory specimens collecting, endotracheal intubation, bronchoscopy, airway nursing and sputum suction which may cause aerosols or splash, medical staff should wear goggles in addition to medical protective mask, wear overalls and isolation gown .
Proper use and disinfection of medical safety goggles
It is currently believed that indirect-ventilated goggles provide the most reliable and practical protection for the eye. When wearing goggles, do not touch the front and sides of the goggles. These surfaces are most likely to be contaminated with droplets. Remove the goggles from the head only by touching the relatively “clean” places such as the plastic temples, elastic bands, and cable ties. Non-disposable goggles should be placed in designated recycling containers after use for subsequent cleaning and disinfection. In clinical applications, one of the biggest disadvantages of protective goggles is that they are prone to fog, and goggles are more likely to fog than face masks . Some scholars believe that the face mask can be used as a substitute for goggles, but it does not mean that the face mask can be used alone as the main protective tool . Currently, it is recommended to use the combination of protective mask and goggles for protection during invasive surgery. However, the combination form may affect visual clarity and limit peripheral visual field to some extent, which should be considered before use.
In view of the current shortage of medical equipment, on January 30th, the State Council ’s Medical Materials Protection Unit of the Joint Prevention and Control Mechanism for Pneumonia Epidemic of Novel Coronavirus Infection issued a “Notice on Protective Suit Import and Other Related Issues During the Epidemic Period”, which stated that disposable medical safety goggles can be reused after strict disinfection in emergency situations with insufficient supply . However, if disinfection is not in place, the risk of contracting the virus comes not only from others, but also from repeated infections. Given that 2019-CoV is sensitive to UV and heat, and 30 minutes at 56 ° C, ether, 75% ethanol, chlorine-containing disinfectant, peracetic acid and chloroform can effectively inactivate the virus , the goggles can be immersed in acidic oxidation water (the main ingredient is hypochlorous acid), 3% hydrogen peroxide or 70% isopropyl alcohol for 5 minutes , rinsed and air-dried to achieve a clean surface and clear vision effect. As one of the new chlorine-containing disinfectants, EOW has the advantages of rapid, broad-spectrum sterilization, no irritation of eyes and skin and mucous membrane, no pollution residue and no damage to the natural environment. So it has been widely used in cleaning and disinfection of medical and pharmaceutical industry . In addition, it can be sterilized by autoclaving at 121 ° C for 30 minutes, reaching the standard of reuse.
Protection strategies for ophthalmologists
During the epidemic, ophthalmologists are high-risk groups that need protection. Appropriate personal protection should be taken at different levels of exposure risk. For contactless consultations or rounds, wear work clothes or gowns, medical surgical masks and work caps. However, be vigilant when facing patients with suspected conjunctivitis and wear goggles during consultations. Medical face shield/goggles and gloves should be added when directly contacting the patient for specialist examinations such as slit lamps, ophthalmoscopes, punctures, injections. When participating in surgery, it is recommended to take level 3 Protection including disposable work caps, medical protective masks (N95), medical safety goggles, medical face shield, disposable protective suit/disposable impermeable isolation clothes, disposable medical gloves and disposable long-shoe covers . Professor Zhang  also provided detailed instructions on the disinfection of ophthalmic examination instruments during the epidemic. It is particularly easy to overlook that when a non-contact tonometer measures intraocular pressure, tears on the ocular surface can form aerosol particles under the impact of air pressure. As the number of measurements increases, the concentration near the point of measurement increases, which is a risk of cross-infection for both patients and medical staff. Therefore, during the epidemic, patients with suspected viral conjunctivitis should try to avoid measure IOP. If necessary, the operator must clean and disinfect the possible contaminated area of the equipment and the patient contact area, ventilate as much as possible to dilute the aerosol particles around the measurement point . In addition, reducing the number of hospital visits is also an important measure to prevent cross-infection and control the spread of the epidemic. For patients who are not infected with 2019-nCoV but have to see a doctor for other diseases, telemedicine and AI-assisted diagnosis are a good choice. Our hospital has opened an online consultation platform, providing diagnosis and treatment services for a large number of patients through the Internet and official account platform, which greatly reduces the chance of cross-infection brought by patients’ face-to-face consultation. In addition, most of the hospitals participating in the construction of the medical consortium in China have telemedicine centers, and they should encourage the use of remote consultation, remote care, remote training, medical information services and other technologies to meet the needs of most patients . For patients who must go to the hospital, ophthalmologists can use more testing methods such as panretinal fundus color photography, optical coherence tomography and optical coherence tomography angiography instead of ophthalmoscope in direct contact with patients. Ophthalmic surgery should also strengthen protection and avoid general anesthesia ophthalmic surgery as far as possible. Patients with fever or any systemic symptoms (fever, dry cough, myalgia, diarrhea, vomiting) should temporarily postpone the ophthalmic examination and complete a complete medical evaluation in advance. In particular, on February 13th, 2020, Ontario authorities in Canada said that although two 2019-nCoV-infected patients confirmed in Toronto had been discharged from home quarantine, 2019-nCoV could still be detected in their nasopharynx. Although they are not yet able to determine whether the remaining virus is invasive, it suggests that personal protection and disinfection of appliances should be done even when receiving convalescent or recovered COVID-19 patients.
Although the diagnosis rate of suspected patients with COVID-19 has been greatly improved, the most commonly used chest CT scan has certain limitations for special populations such as pregnant women. Additionally, and we found that suspected patients often have to undergo 3 or 7 repeated tests of nasopharyngeal swabs to produce 2019-nCoV nucleic acid positive results, which may be related to the false negative results of reverse transcriptional PCR test. In 2017, Dona et al used the next-generation sequencing (NGS) technology to quickly and accurately detect the corresponding virus in the conjunctival sac and tears of patients infected with influenza or rubella virus . This technology can not only correctly identify the pathogens of known infections, but also identify unknown viruses that are difficult to detect with conventional detection methods such as PCR . Our center has successfully used NGS technology to diagnose 110 cases of infectious eye diseases including uveitis, endophthalmitis, cytomegalovirus retinitis, and ocular archworm disease for unknown pathogens. Therefore, we believe that using the NGS technology to detect the novel coronavirus in the conjunctival sac swabs or tears which are collected under the level 2 protection is expected to become a reliable auxiliary diagnosis for the suspected COVID-19 patients with asymptomatic or mild infections, especially those with conjunctivitis as the first symptom. This method is not only convenient for obtaining materials but also non-invasive, which is advantageous to early diagnosis, controlling familial clustering, and preventing the epidemic from spreading. However, the limitation of this technology lies in the high requirements for the testing platform and technical personnel of the testing department, which can only be carried out in a few large-scale hospitals and can not be widely popularized in a short period of time.
We believe that ophthalmologists should have a high degree of professional sensitivity in the face of this infectious disease, strengthening self-protection measures, and maintaining high vigilance to patients with viral conjunctivitis during the epidemic. We should neither despise the disease nor feel panic. The standard procedure of epidemic prevention should be followed in any medical operation.
Conflict of interest statement
The work is original, and there is no conflict of interest to disclose.
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