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

深圳地鐵6號線民樂停車場出入線總長約2.6公里，隧道穿越強(qiáng)、中、微風(fēng)化花崗巖，采用TBM+局部礦山及明挖法施工。其中明挖段長71m，隧道上方為南坪快速牛咀大橋，共7根橋墩侵入隧道洞身，為不中斷南坪快速交通，隧道穿越橋梁基礎(chǔ)采用樁基托換。

通過BIM模型中，進(jìn)行安裝模擬：首先安裝YZL17；然后安裝YZL8，同時全灌漿套筒全部安裝在YZL8的甩出鋼筋上，移動到梁端一側(cè)，布置YZL8一側(cè)箍筋；最后，在YZL9就位前，將YZL9側(cè)箍筋先穿在梁甩出鋼筋上，安裝就位，移動全灌漿套筒，在移動箍筋間距控制在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.

嚴(yán)格按照規(guī)范標(biāo)準(zhǔn)，通過清淤疏浚降低河床底部標(biāo)高，拓寬河道，增大泄洪斷面，同時，加強(qiáng)河流堤防建設(shè)，正常發(fā)揮河道行洪、排澇的基本功能，提高抗御洪水的能力。對地籠、網(wǎng)絡(luò)子、過路壩、沉船等阻水障礙物進(jìn)行清理，并加強(qiáng)日常巡查管理，完善管理機(jī)制，確保水系暢通；對于水閘口停泊船只等社會問題，要根據(jù)實際情況制定專門的整治方案，整合水務(wù)、海事、漁政、邊防、屬地鄉(xiāng)鎮(zhèn)等部門的力量，通過宣傳教育，增強(qiáng)船民的安全意識，同時，加大船只的驅(qū)趕、自拆等聯(lián)合執(zhí)法力度，提高整個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.

對于擴(kuò)張后的系統(tǒng)(7)，運用反雙曲正弦函數(shù)建立新的擴(kuò)張狀態(tài)觀測器(Extended State Observer,ESO)為

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.

看上去年齡都不過十五。[注]烏其拉圖：《<江格爾> 中的歷史遺跡和波斯古經(jīng)》，載《蒙古語言文學(xué)》(蒙古文版)1997年第1期。論文為蒙古文，所引《江格爾》詩句采用了霍爾查所譯《江格爾》中的漢譯文(新疆人民出版社，1988年版，第3頁)；而《阿維斯塔》詩句采用了季羨林主編的《東方文學(xué)作品選》中的漢譯文(湖南人民出版社，1986年版，第408頁)江格爾

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.

教學(xué)目標(biāo)是教學(xué)活動的出發(fā)點和依據(jù)，也是教學(xué)達(dá)成的歸宿。好的教學(xué)目標(biāo)應(yīng)該緊扣課程標(biāo)準(zhǔn)、教材內(nèi)容、學(xué)情等因素進(jìn)行綜合性的考慮和設(shè)計，讓學(xué)生“跳得起，夠得著”，增強(qiáng)學(xué)習(xí)欲望，挖掘?qū)W習(xí)潛能，引導(dǎo)學(xué)生深度學(xué)習(xí)。同時，教學(xué)目標(biāo)更要明確、具體、簡約，不能含混籠統(tǒng)，模糊教學(xué)方向，造成教學(xué)目標(biāo)難以達(dá)成，課堂成效將大打折扣。如《楞次定律》的教學(xué)設(shè)計中的過程與方法目標(biāo)設(shè)計：培養(yǎng)學(xué)生總結(jié)、概括、抽象思維的能力，這一目標(biāo)就顯得空洞籠統(tǒng)，可以將此目標(biāo)設(shè)計得更明確，如：通過實驗體驗，引導(dǎo)學(xué)生分析現(xiàn)象，尋找現(xiàn)象共性，歸納內(nèi)在規(guī)律，培養(yǎng)學(xué)生的總結(jié)概括和思維能力。

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).

所謂大局，是指整個局面和整個形勢，以及與之密切相關(guān)的長遠(yuǎn)利益。具備團(tuán)結(jié)合作的大局觀念是黨政領(lǐng)導(dǎo)干部做好各項工作的重要前提。面對紛繁復(fù)雜的社會思潮和波云詭譎的政治形勢，黨的領(lǐng)導(dǎo)干部要善于從全局的高度、以長遠(yuǎn)的眼光，觀察形勢，分析問題，圍繞黨和國家的中心任務(wù)、長遠(yuǎn)利益，認(rèn)識和把握大局，團(tuán)結(jié)協(xié)作，創(chuàng)造性地做好本職工作。

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