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      Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China

      brief-report
      , MD 1 , , MD 2 , , MD 1 , , MD 1 , , MD 1 , , MD 1 , , MD 2 ,
      JAMA Ophthalmology
      American Medical Association

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          Key Points

          Question

          What are the ocular manifestations and conjunctival viral prevalence in patients from Hubei province, China, with coronavirus disease 2019 (COVID-19)?

          Findings

          In this case series including 38 patients with COVID-19, 12 patients had ocular manifestations, such as epiphora, conjunctival congestion, or chemosis, and these commonly occurred in patients with more severe systemic manifestations. Reverse transcriptase–polymerase chain reaction results were positive for severe acute respiratory syndrome coronavirus 2 in 28 nasopharyngeal swabs and 2 conjunctival swabs, and more significant changes in blood test values appeared in patients with ocular abnormalities.

          Meaning

          These data may assist ophthalmologists and others to understand the ocular manifestations of COVID-19, thus enhancing the diagnosis and prevention of the transmission of the disease.

          Abstract

          This case series investigates the ocular manifestations and viral prevalence in the conjunctiva of patients with coronavirus disease 2019 (COVID-19).

          Abstract

          Importance

          While the outbreak of coronavirus disease 2019 (COVID-19) has resulted in more than 100 000 infected individuals in China and worldwide, there are few reports on the association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with ocular abnormalities. Understanding ocular manifestations of patients with COVID-19 by ophthalmologists and others may facilitate the diagnosis and prevention of transmission of the disease.

          Objective

          To investigate ocular manifestations and viral prevalence in the conjunctiva of patients with COVID-19.

          Design, Setting, and Participants

          In this case series, patients with COVID-19 treated from February 9 to 15, 2020, at a hospital center in Hubei province, China, were retrospectively reviewed for ocular manifestations. During the period of treatment, the ocular signs and symptoms as well as results of blood tests and reverse transcriptase–polymerase chain reaction (RT-PCR) from nasopharyngeal and conjunctival swabs for SARS-CoV-2 were noted and analyzed.

          Main Outcomes and Measures

          Ocular signs and symptoms as well as results of blood tests and RT-PCR for SARS-CoV-2.

          Results

          Of the 38 included patients with clinically confirmed COVID-19, 25 (65.8%) were male, and the mean (SD) age was 65.8 (16.6) years. Among them, 28 patients (73.7%) had positive findings for COVID-19 on RT-PCR from nasopharyngeal swabs, and of these, 2 patients (5.2%) yielded positive findings for SARS-CoV-2 in their conjunctival as well as nasopharyngeal specimens. A total of 12 of 38 patients (31.6%; 95% CI, 17.5-48.7) had ocular manifestations consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, or increased secretions. By univariate analysis, patients with ocular symptoms were more likely to have higher white blood cell and neutrophil counts and higher levels of procalcitonin, C-reactive protein, and lactate dehydrogenase than patients without ocular symptoms. In addition, 11 of 12 patients with ocular abnormalities (91.7%; 95% CI, 61.5-99.8) had positive results for SARS-CoV-2 on RT-PCR from nasopharyngeal swabs. Of these, 2 (16.7%) had positive results for SARS-CoV-2 on RT-PCR from both conjunctival and nasopharyngeal swabs.

          Conclusions and Relevance

          In this study, one-third of patients with COVID-19 had ocular abnormalities, which frequently occurred in patients with more severe COVID-19. Although there is a low prevalence of SARS-CoV-2 in tears, it is possible to transmit via the eyes.

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          Most cited references5

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          Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

          Summary Background In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. Methods We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. Findings The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. Interpretation 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. Funding National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
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            Evidence of SARS-CoV-2 Infection in Returning Travelers from Wuhan, China

            To the Editor: As the number of cases of infection with the novel coronavirus (SARS-CoV-2) has continued to increase, many countries have established restrictions regarding travelers who have recently visited China. 1 With lockdown measures imposed in Hubei Province, China, 2 and a public health emergency of international concern declared by the World Health Organization, 3 foreign nationals have sought to return to their home countries from China, and public health authorities are racing to contain the spread of Covid-19 (the disease caused by SARS-CoV-2 infection) around the world. This process is complicated by epidemiologic uncertainty regarding possible transmission of the virus by asymptomatically or subclinically symptomatic infected persons. It is unclear whether persons who show no signs or symptoms of respiratory infection shed SARS-CoV-2. In this context, a group of predominantly German nationals who had stayed in Hubei Province was evacuated to Frankfurt, Germany, on February 1, 2020. They were to be transferred to Germersheim, Germany, and quarantined for 14 days, since this period is thought to be the upper limit of the incubation period of SARS-CoV-2. Screening for symptoms and clinical signs of infection was performed before their departure from China. A total of 126 travelers were allowed to board an aircraft operated by the German air force (Figure 1). During the flight, 10 passengers were isolated. Two passengers had had contact with 1 person who had a confirmed case of SARS-CoV-2 infection, 6 had reported symptoms, were deemed to be clinically symptomatic, or both, and 2 passengers had accompanied family members who had been isolated on the flight because of suspected SARS-CoV-2 infection or because of other symptoms (i.e., symptoms related to pregnancy). These 10 passengers were transferred to University Hospital Frankfurt immediately after arrival. All 10 tested negative for SARS-CoV-2 by real-time reverse-transcription–polymerase-chain-reaction (RT-PCR) assays 4 of throat swabs and sputum. The remaining 116 passengers (5 months to 68 years of age), including 23 children, were sent to the medical assessment center at Frankfurt Airport, where each was evaluated by a medical team of physicians. Each passenger was asked to report current symptoms of fever, fatigue, sore throat, cough, runny nose, muscle aches, and diarrhea, and each one was screened for signs of infection in the nose and throat. The temperature of all passengers was taken. All were afebrile except for 1 passenger who had a temperature of 38.4°C and reported dyspnea and cough. He was transferred to University Hospital Frankfurt for evaluation. However, testing to detect SARS-CoV-2 by RT-PCR of a throat swab and sputum was negative. In addition to the preplanned multistep process of screening for signs and symptoms of infection and observing the asymptomatic cohort in quarantine, we decided to offer a throat swab to test for SARS-CoV-2 in each of the 115 travelers who had passed triage. A total of 114 passengers consented to the test. Two of the 114 persons (1.8%) in this cohort of travelers who had passed the symptoms-based screening tested positive for SARS-CoV-2 by RT-PCR (cycle threshold value in the two samples, 24.39 and 30.25, respectively). Testing with a second protocol consisting of two commercial sets (LightMix Modular SARS and Wuhan CoV E-gene, and LightMix Modular Wuhan CoV RdRP-gene, both produced by TIB MOLBIOL) and retesting of the positive samples at the Institute of Virology, Philipps University Marburg, in Marburg, Germany, confirmed the results. In addition, the isolation of SARS-CoV-2 from both samples in cell culture of Caco-2 cells indicated potential infectivity (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). These two persons were subsequently isolated from the cohort and transferred to the Infectious Disease Unit at University Hospital Frankfurt for further evaluation and observation on the following day. After a thorough evaluation in the hospital ward, a faint rash and minimal pharyngitis were observed in one patient. Both patients remained well and afebrile 7 days after admission. In this effort to evacuate 126 people from Wuhan to Frankfurt, a symptom-based screening process was ineffective in detecting SARS-CoV-2 infection in 2 persons who later were found to have evidence of SARS-CoV-2 in a throat swab. We discovered that shedding of potentially infectious virus may occur in persons who have no fever and no signs or only minor signs of infection.
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              The severe acute respiratory syndrome coronavirus in tears.

              Severe acute respiratory syndrome (SARS) is a new infectious disease that caused a global outbreak in 2003. Research has shown that it is caused by a novel coronavirus. A series of cases is reported where polymerase chain reaction (PCR) testing on tears had demonstrated the presence of the virus. Detection of ocular infection from tears using the PCR technique has been widely used by ophthalmologists to diagnose infections for other viruses. This is a case series report from cases classified as probable or suspect SARS cases. Tear samples were collected from 36 consecutive patients who were suspected of having SARS in Singapore over a period of 12 days (7-18 April 2003), and analysed by PCR using protocols developed by the WHO network of laboratories. Three patients with probable SARS (one female and two male patients) had positive results from their tear samples. Tear samples were used to confirm SARS in the female patient, who was positive only from her tears. The positive specimens were found in cases sampled early in their course of infection. This is the first case series reported with the detection of the SARS coronavirus from tears, and has important implications for the practice of ophthalmology and medicine. The ability to detect and isolate the virus in the early phase of the disease may be an important diagnostic tool for future patients and tear sampling is both simple and easily repeatable. Many healthcare workers are in close proximity to the eyes of patients and this may be a source of spread among healthcare workers and inoculating patients. Ophthalmic practices may need to change as more stringent barrier methods, appropriate quarantine, and isolation measures are vital when managing patients with SARS.
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                Author and article information

                Journal
                JAMA Ophthalmol
                JAMA Ophthalmol
                JAMA Ophthalmol
                JAMA Ophthalmology
                American Medical Association
                2168-6165
                2168-6173
                May 2020
                31 March 2020
                31 March 2020
                : 138
                : 5
                : 575-578
                Affiliations
                [1 ]Department of Ophthalmology, The First College of Clinical Medical Science, Yichang Central People’s Hospital, China Three Gorges University, Yichang, China
                [2 ]Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-Sen University, Guangzhou, China
                Author notes
                Article Information
                Accepted for Publication: March 17, 2020.
                Published Online: March 31, 2020. doi:10.1001/jamaophthalmol.2020.1291
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Wu P et al. JAMA Ophthalmology.
                Corresponding Author: Liang Liang, MD, Department of Ophthalmology, The First College of Clinical Medical Science, Yichang Central People’s Hospital, China Three Gorges University, 183 Yiling St, Yichang 443003, China ( liangliang419519@ 123456163.com ); Kaili Wu, MD, Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, 54 S Xianlie Rd, Guangzhou 510060, China ( wukaili@ 123456maill.sysu.edu.cn ).
                Author Contributions: Drs Liang and K. Wu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs P. Wu and Duan contributed equally to this study. Drs Luo, Liu, and Qu contributed equally as senior authors.
                Study concept and design: Liang, K. Wu.
                Acquisition, analysis, or interpretation of data: P. Wu, Duan, Luo, Liu, Qu, Liang.
                Drafting of the manuscript: P. Wu, Duan, Liang.
                Critical revision of the manuscript for important intellectual content: P. Wu, Luo, Liu, Qu, Liang, K. Wu.
                Statistical analysis: P. Wu.
                Obtained funding: Liang, K. Wu.
                Administrative, technical, or material support: Duan, Luo, Liu, Qu, Liang.
                Study supervision: Liu, Liang, K. Wu.
                Conflict of Interest Disclosures: None reported.
                Funding/Support: This study was supported by grants 81770896 (Dr K. Wu) and 81770920 (Dr Liang) from the National Natural Science Foundation of China.
                Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Additional Contributions: We thank Haijiang Zhang, MD, Minxing Wu, MD, and Min Liu, MD (Yichang Central People’s Hospital, Yichang, China), for collecting the data and preparing the Table. None of these individuals received compensation for their contributions.
                Article
                ebr200003
                10.1001/jamaophthalmol.2020.1291
                7110919
                32232433
                ac4eb218-3a54-4e6a-a556-ff1d735d116c
                Copyright 2020 Wu P et al. JAMA Ophthalmology.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 29 February 2020
                : 17 March 2020
                Funding
                Funded by: National Natural Science Foundation of China
                Categories
                Research
                Research
                Brief Report
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