COVlD-19 infection with keratitis as the first clinical manifestation

INTRODUCTION

Almost all countries in the world do not mandate their residents to get COVID-19 test. COVID-19 symptoms are the only way to indicate that a person gets infected. Thus, how early a patient is quarantined depends on how early the symptoms appear. The early symptoms of COVID-19 include fever,cough, shortness of breath, persistent pain or pressure in the chest, confusion or inability to arouse, and bluish lips or face.However, this symptom list is not all-inclusive. It is critically important to identify any symptom of the infection as early as possible so that the infected people can 1) be directed to stay at home to stop the virus from exponentially spreading,and 2) get tested and treated immediately to reduce the lung damages. Considering no effective antivirals for the overwhelming infections, the most effective way of prevention is self-quarantine as soon as a COVID-19 symptom(s) is/are identified. Therefore, reporting a new symptom associated with COVID-19 infection is of both social and clinical significance.Here we report a case, in which keratitis is the first clinical manifestation of COVID-19 that occurred 3d earlier than the common COVID-19 symptoms.

P er the latest date from the World Health Organization,there were a total of 93 217 287 COVID-19 cases confirmed in more than 100 courtiers and 2 014 957 deaths globally (2.16% death rate), and this disease is rapidly spreading (https://www.who.int). This rapid spread is due to the virus’s high contagion. The reproduction number (R0)of COVID-19 is roughly 3, indicating that this disease could spread exponentially. The incubation period of COVID-19 is 2-14d, and the serial interval of COVID-19 is roughly 4.6d.Reasonably assuming that COVID-19 transmissions among people only happen during the incubation period (because once a person has symptoms, he would be quarantined so that he could not transmit virus to others). During the incubation period,, 10d, 1 person infects 3 “R0” people. If COVID-19 symptoms are identified and patients are quarantined at home one day earlier, the R0 would be reduced to 3×9/10=2.7. This 0.3 (3.0-2.7) difference in R0 makes exponentially difference in the numbers of infected people (infected people =R0,: the generation of the infection; Table 1). If an infected patient is quarantined one day early, it will prevent roughly 1140 people from being infected in 32d, and roughly 1 190 000 people from being infected in 60d (Table 1). Therefore, even one day early to identify COVID-19 symptoms will significantly decrease the number of infected patients.

A 35-year-old male ophthalmologist suddenly suffered pain, photophobia, and tears in his right eye for one day. No systemic COVID-19 symptoms.

SUBJECTS AND METHODS

This study was performed at the Department of Ophthalmology, the Hubei Provincial Hospital of Traditional Chinese Medicine and Department of Integrated Traditional Chinese and Western Medicine, Union Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China. The study was approved by the hospital ethics committee. All participating individuals signed the informed consent.

Microsoft Excel2010 was used for establishing the COVID-19 spread model and calculating the numbers of patients infected.

A 35-yearold male suddenly suffered pain, photophobia, and tearing in his right eye and was seen physicians at the Hubei Provincial Hospital of Traditional Chinese Medicine (Medical ID:3897813) and the Union Hospital in Wuhan on January 8, 2020(Medical ID: 3794961). Regular slit lamp examination, corneal scraping test, and chest computed tomography (CT) were performed. The ophthalmologic treatment included ganciclovir eye drop (50 mg/mL, 6 times/d). The treatment for diarrhea included Guifu Lizhong pills (Honey pills, a traditional medicine, 3 times a day for a total of 2d). The antiviral therapy consisted of oseltamivir 75 mg capsule Q12H; therapyThe serial interval of COVID-19 is roughly 4.6d. The reproduction number (R0) of COVID-19 is roughly 3.0. If the patient is quarantined at home one day earlier, R0=2.7; 2d earlier, R0=2.4; 3d earlier,R0=2.1.preventing bacterial infection consisted of azithromycin 250 mg tablet QD and moxifloxacin 0.4 g tablet Q12H; and therapy for cough relief and fever prevention consisted of Chinese herbal decoction (Maxing Shigan Tang from the) 100 mL Q12H.

RESULTS

深圳地铁6号线民乐停车场出入线总长约2.6公里，隧道穿越强、中、微风化花岗岩，采用TBM+局部矿山及明挖法施工。其中明挖段长71m，隧道上方为南坪快速牛咀大桥，共7根桥墩侵入隧道洞身，为不中断南坪快速交通，隧道穿越桥梁基础采用桩基托换。

通过BIM模型中，进行安装模拟：首先安装YZL17；然后安装YZL8，同时全灌浆套筒全部安装在YZL8的甩出钢筋上，移动到梁端一侧，布置YZL8一侧箍筋；最后，在YZL9就位前，将YZL9侧箍筋先穿在梁甩出钢筋上，安装就位，移动全灌浆套筒，在移动箍筋间距控制在200mm。

He was diagnosed with keratitis, which was seemingly different from common keratitis under a slit lamp microscope(Figure 1A). Specifically, it seemed like a viral keratitis,and the corneal inflammation looked distinct from common keratitis (Table 2). In the lower part of the right eye cornea, a shallow white turbid focus could be seen, which was similar to ground glass, with a clear boundary, and a large number of fine particles could be seen on the surface of the focus. Ganciclovir eye drop was initiated (6 times/d). The corneal scraping test for COVID-19 was positive (Table 3), and patient was quarantined at home. Patient started to feel fatigue.

Slit lamp examination showed that the white turbidity in the lower part of corner of the right eye cornea became slightly paler, and the fine particles on the surface of the lesion were significantly reduced. The keratitis the symptoms were significantly relieved 24h later ganciclovir was initiated. Pain,photophobia and tearing were also significantly relieved.Patient continued feeling fatigue and started to suffer fever,cough, and discomforts.

No ophthalmology symptoms. Dry cough.

严格按照规范标准，通过清淤疏浚降低河床底部标高，拓宽河道，增大泄洪断面，同时，加强河流堤防建设，正常发挥河道行洪、排涝的基本功能，提高抗御洪水的能力。对地笼、网络子、过路坝、沉船等阻水障碍物进行清理，并加强日常巡查管理，完善管理机制，确保水系畅通；对于水闸口停泊船只等社会问题，要根据实际情况制定专门的整治方案，整合水务、海事、渔政、边防、属地乡镇等部门的力量，通过宣传教育，增强船民的安全意识，同时，加大船只的驱赶、自拆等联合执法力度，提高整个河道水系的行洪能力。

It has been clear that transmissions of COVID-19 were through respiratory tract and digestive tract. Recently, researchers modeled the spike protein and identified the receptor for COVID-19, and indicated that angiotensin-converting enzyme 2 (ACE2) could be the receptor for this virus. It was found that the expression of ACE2 is positive in cornea and conjunctiva, and ACE2 can bind to the spike proteins of severe acute respiratory coronavirus virus 2 (SARS-CoV). In addition,previous studies detected the SARS coronavirus from tears.However, there is no evidence indicating that the cornea and conjunctiva are one of the transmission routes of COVID-19.In this case report, we described a distinct keratitis that was the first clinical manifestation in COVID-19 infection. It was not until 3d later that common symptoms of COVID-19 appeared.These pieces of evidence indicate that indeed the cornea and conjunctiva are one of the transmission routes of COVID-19,and support the use protective goggles.

No ophthalmology symptoms. Patient experienced nausea and diarrhea (water-like, 2 to 3 times/d). Patient took 50 pills of Guifu Lizhong pills three times a day for a total of 2d,during which the daily number of diarrhea gradually decreased,normal stool formed, and nausea disappeared during these 2d.

Slit lamp examination showed that the white turbidity in the lower part of corner of the right eye cornea became significantly smaller and paler, and the fine particles on the surface of the lesion disappeared (Figure 1B).The eye symptoms disappeared. Patient experienced fever,headaches, and fatigue. The body temperature was 37.5°C.After drinking a lot of boiled water and sweating, fever and headache were slightly relieved. By that time, it was officially reported that viral pneumonia of unknown etiology, whose symptoms includes fever and cough, might break out in Wuhan, Hubei Province, China. The patient received chest CT.The CT results showed no abnormalities (Figure 2A).

No ophthalmology symptoms. The systemic symptom was significantly aggravated. The chest CT images (Figure 2B) were abnormal confirming the diagnosis of COVID-19infection. Patient claimed that he had not gone to the Huanan Seafood Market. The antiviral therapy consisted of oseltamivir 75 mg capsule Q12H; therapy preventing bacterial infection consisted of azithromycin 250 mg tablet and moxifloxacin 0.4 g tablet Q12H; and therapy for cough relief and fever prevention consisted of Chinese herbal decoction (Maxing Shigan Tang from the) 100 mL Q12H.

No ophthalmology symptoms. CT showed no enlargement of the lung lesion (Figure 2C). Dry cough was alleviated. The therapies remained unchanged.

No ophthalmology symptoms. Oseltamivir,azithromycin, and moxifloxacin were discontinued.

对于扩张后的系统(7)，运用反双曲正弦函数建立新的扩张状态观测器(Extended State Observer,ESO)为

No ophthalmology symptoms. Dry cough disappeared.The pharynx was still itchy, and the lung lesions were obviously reduced and faded (Figure 2D). Maxing Shigan Tang was discontinued (all the medications were discontinued).

DISCUSSION

No ophthalmology symptoms. Ganciclovir eye drop was discontinued. Fever, headaches, fatigue disappeared.

看上去年龄都不过十五。[注]乌其拉图：《<江格尔> 中的历史遗迹和波斯古经》，载《蒙古语言文学》(蒙古文版)1997年第1期。论文为蒙古文，所引《江格尔》诗句采用了霍尔查所译《江格尔》中的汉译文(新疆人民出版社，1988年版，第3页)；而《阿维斯塔》诗句采用了季羡林主编的《东方文学作品选》中的汉译文(湖南人民出版社，1986年版，第408页)江格尔

There are 3 clinically established types of viral keratitis(Table 2). However, our case is distinct from these established types prompting us to perform a COVID-19 corneal scraping examination (Table 3). Our initial assessment on this case was that it was most likely and most reasonably a COVID-19 infection. The positive result from the corneal scraping examination confirmed our assessment. Our case was consistent with the report by Cheema, in which keratoconjunctivitis is the initial medical presentation of COVID-19. Further, Sansome and Linfound that there has been a surge in eye care following the COVID-19 outbreak.

All coronaviruses are positive-sense single-strand RNA viruses that replicate their genomes using an RNA-dependent RNA polymerase (RdRp). The RdRp in coronaviruses is a wellestablished drug target; the active site of the RdRp is highly conserved among positive-sense RNA viruses. These RdRps have low fidelity allowing them to be recognized by a variety of modified nucleotide analogues as substrates. Thus, such nucleotide analogues were often used as anti-virals to inhibit RNApolymerase, which catalyzes RNA replication.Recent study showed that the ganciclovir triphosphate from ganciclovir completely terminated the polymerase reaction in coronaviruses using the RdRp. This potency in inhibiting coronaviruses replication, we believe, is the underneath mechanism that the symptoms in our case were relieved after using ganciclovir.

The limitation of our study is that we did not sequence the COVID genome, which otherwise would be among the few COVID-19 genomes sequenced at the beginning of the pandemic in Wuhan. Such sequence could provide clinical insight into the treatment, especially at that time, no lab protocols, no established therapies, and no clinical experiences could be followed. Nevertheless, we used our professional judgment to treat our patient based on several aspects. The results from corneal scraping examination confirmed our initial prediction, and the recent evidence on ganciclovir lends support to our use of ganciclovir in this case. In conclusion,a new type of keratitis, atypical keratitis, is a clinical manifestation of COVID-19, and this clinical manifestation could appear 3d earlier than fever and cough. The earlier a COVID-19 symptom is identified, the earlier can a patient be directed to stay at home, and significantly fewer people would be infected.

教学目标是教学活动的出发点和依据，也是教学达成的归宿。好的教学目标应该紧扣课程标准、教材内容、学情等因素进行综合性的考虑和设计，让学生“跳得起，够得着”，增强学习欲望，挖掘学习潜能，引导学生深度学习。同时，教学目标更要明确、具体、简约，不能含混笼统，模糊教学方向，造成教学目标难以达成，课堂成效将大打折扣。如《楞次定律》的教学设计中的过程与方法目标设计：培养学生总结、概括、抽象思维的能力，这一目标就显得空洞笼统，可以将此目标设计得更明确，如：通过实验体验，引导学生分析现象，寻找现象共性，归纳内在规律，培养学生的总结概括和思维能力。

Study concept and design: Zuo DM,Fan H, and Xiao J; Acquisition of data: Zuo DM, Xue LP, Yang SL, Li LC, Luo JH; Analysis and interpretation of data: Zuo DM, Fan H, Zang S, Xiao J; The in-depth literature review:Xiao J; Drafting of the manuscript: Fan H, Xiao J; Statistical analysis: Xiao J; Obtained funding: Fan H; Administrative,technical, or material support: Zuo DM, Xue LP, Yang SL, Li LC, Luo JH, Zang S; Study supervision: Fan H, Xiao J; All authors have read and approved the manuscript.

Supported by the Tongji-Rockcheck Life Science and Medicine Research Center (No.202014).

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