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上海专家:2-4周大部分患者将被治愈 2个月结束/ 纽约市长记者会未雨绸缪

作者：change?  于 2020-1-26 11:27 发表于 最热闹的华人社交网络--贝壳村

通用分类:健康生活|已有8评论



纽约市长：冠状病毒将“赶早不赶晚”来袭纽约


Mayor de Blasio holds media availability at New York City Office of Emergency Management.

布拉西奥市长周五说：“我们必须根据这样的假设行事。
纽约—市长比尔·德·布拉西奥（Bill de Blasio）市长周五警告纽约人，这种神秘而致命的冠状病毒很可能正前往纽约市。
布拉西奥星期五早上说：“我们已经看到了如此迅速的传播。” “我们必须根据这样的假设采取行动，不幸的是，纽约市将比现在早，而不是晚。
市长说，周五早上，市政府官员进行了一次演习，因为有消息传出，这种病毒已经夺走了至少25人的生命，已经从中国武汉扩散到华盛顿州和芝加哥。
更新：根据州长安德鲁·库莫（Andrew Cuomo）办公室星期五发布的新闻，周五在纽约州对三人进行了冠状病毒检测。第四个人进行了测试，发现没有感染冠状病毒。

市长说，纽约很可能会收到病例报告，因为该城市是亚洲以外世界上任何城市中华人人口最多的城市。
de Blasio告诉记者，截至周五早上，纽约市尚未报告任何病例。但他要求在过去两周内到过武汉并出现流感样症状的任何人立即去看医生。
否则，市长说：“继续生活。”

市卫生局长 Barbot说，纽约处于低风险和高准备状态，但是该病毒需要保持警惕。
据Barbot说，目前尚不清楚该疾病如何在人与人之间传播，并且还没有疫苗或确定的治疗方法。
“这很令人担忧，”巴博特说。 “还有很多我们不知道的事情。”

===================

专家:2-4周大部分患者将被治愈 2个月结束武汉战役

（原标题：上海医疗救治专家组组长：控制武汉新冠病毒感染的主体战役应在1个月内结束，2个月内进入尾声）

除夕之夜，国家征召，全国数十支医疗队伍奔赴武汉，是壮举，是我们国家的体制优势再次展现——这是今天上海市医疗救治专家组组长张文宏教授发在华山感染微信公众号中提到的一句话，对于疫情的变化趋势、热点问题及相关注意事项，张文宏做了进一步解读。

张文宏认为，华山医院感染科感染重症病房徐斌主任医生和全国数千名的医生通道奔赴武汉，这种精神无疑给了大家战胜新冠状肺炎的必胜信念。

武汉的著名感染病专家华中科技大学附属同济医院感染科主任宁琴教授告诉他，“今晚接紧急任务，同济医院汉阳中法新城院区，明天整体搬迁腾出1200张床为收治发热病人众志成城一夜腾出'小汤山'。"至此，国家在击溃”新冠肺炎“的一盘大棋拉开序幕。不出意外，这是2003年成功控制传染性非典（又称SARS）的成功经验将再次在中国上演。

他认为，中国不到一个月获得了新冠病原体的基因信息，这是科学的胜利；但是控制病毒蔓延，我们还是要回到最古老的办法，那就是“隔离救治”。就像美国医学会杂志在1918年全球大流感的时候所说的，“在这场流行病中，病毒对生命构成严重威胁，必须给每个病人实施最完善的隔离治疗才能保证人们的安全”。

这几天，大家的微信圈中充斥着武汉医院内拥挤的病人，求一床而不得，民众又因为武汉限行萌生了不安与恐惧。那么，如今一夜之间，一所1200张的医院腾出来了，据我所知，如果床位不够，政府还可能在一周之内再打造一所新的1000多张床位的“武汉小汤山”。这样，再加上目前武汉已经存在的各家定点医院，收入所有的不明原因发热病人已经不成问题。

至此，全国各地医疗志愿军逆向而行进入武汉的“阳谋”已经跃然而出。我们已经不是2003年的中国了。控制武汉新冠病毒感染的主体战役应该在1个月内结束，2个月内进入尾声。

英雄逆向而行。百姓怎样过年？微信圈被钟南山院士的过年微信刷屏。据说，钟南山院士呼吁：“解决疫情最快，成本最低的方式就是全中国人民在家隔离两周，这样对全国经济影响最小，对生命健康最有利。强烈建议全中国人民都在家过春节，不要走亲访友。

张文宏进一步说，其实，从分离出新冠病毒之后，就已经知道这是一种以急性感染为表现的病毒性疾病，一般不会出现长期慢性带毒的情况。对于这样的病毒，只要足够时间的隔离，完全覆盖掉潜伏期（目前所知该病毒最长潜伏期为2周），那么所有潜在的病人将自动被筛选出进入医院隔离治疗，部分免疫力较强的患者则会自愈。两周之后，社会将重归秩序与繁荣。

所以对于武汉，已经采取了限行、停止公交、科普教育等措施，备足了床位与来自全国各地的医疗力量 那么可以预见，2周内，所有已经发病或者即将发病的患者将会顺利进入医疗点救治。经过2-4周治疗，大部分患者将被治愈。这样的话，2个月内结束武汉战役不是一场梦。

武汉进入紧急状态，病毒控制在即。2周内发病病例数势必会出现下降。但是，刚刚进入输入性疾病早期的全国各地呢？能否遵从“在家两周”，过个“健康春节”呢？估计很难，不到最后关头，能够遵从健康建议的人只是少数，君不见控烟行动从未真正奏效吗？那么其他全国各地减少活动的困难可想而知。

“从全国各地英雄往武汉逆向奔袭之际，我们相信武汉战役从一开始就是从胜利走向胜利。反之，我们下一步的目光更应该投向武汉之外的城市，我们决不允许武汉发生的新冠传播和爆发再上演一次。”张文宏说。

=============

中国时评作家王亚军（王歪嘴）刚刚为武汉募捐物资就被湖北XX威胁

最後一段話 真的讓人鼻酸 如果哪天中國人民起來反抗政府了 相信各界都會給予支持 畢竟你們的政府 太霸道了 對國外的人霸道就算了 還時常欺負自己人民?

看了这个视频真的很心酸，泪在眼眶打转，正义善举反而被打击，老哥一定要保重，国人都应该向您学习

看了好难过，真的。我自己在家族群发些境外的视频，我表弟说要举报我，我表哥逼我退群还说我造谣，再继续传播就抓我。哎

這有來自香港同胞的直持 都21世紀了，還有這麼一個無恥、流氓政府⋯

共产党根本心思不在控制疫情上，到现在还忙着维稳

我一个最底层最底层都因言被喝过茶，何况你们这些有影响力的了。

他應該自豪，當收到老共的威脅時，就証明他是頂天立地的人





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3 回复 change? 2020-1-26 11:54
novel coronavirus, designated as 2019-nCoV, emerged in Wuhan, China, at the end of 2019. As of January 24, 2020, at least 830 cases had been diagnosed in nine countries: China, Thailand, Japan, South Korea, Singapore, Vietnam, Taiwan, Nepal, and the United States. Twenty-six fatalities occurred, mainly in patients who had serious underlying illness.1 Although many details of the emergence of this virus — such as its origin and its ability to spread among humans — remain unknown, an increasing number of cases appear to have resulted from human-to-human transmission. Given the severe acute respiratory syndrome coronavirus (SARS-CoV) outbreak in 2002 and the Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak in 2012,2 2019-nCoV is the third coronavirus to emerge in the human population in the past two decades — an emergence that has put global public health institutions on high alert.

China responded quickly by informing the World Health Organization (WHO) of the outbreak and sharing sequence information with the international community after discovery of the causative agent. The WHO responded rapidly by coordinating diagnostics development; issuing guidance on patient monitoring, specimen collection, and treatment; and providing up-to-date information on the outbreak.3 Several countries in the region as well as the United States are screening travelers from Wuhan for fever, aiming to detect 2019-nCoV cases before the virus spreads further. Updates from China, Thailand, Korea, and Japan indicate that the disease associated with 2019-nCoV appears to be relatively mild as compared with SARS and MERS.

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Table 1.

Pathogenicity and Transmissibility Characteristics of Recently Emerged Viruses in Relation to Outbreak Containment.
Figure 1.

Surveillance Pyramid and Its Relation to Outbreak Containment.
After initial reports of a SARS-like virus emerging in Wuhan, it appears that 2019-nCoV may be less pathogenic than MERS-CoV and SARS-CoV (see table). However, the virus’s emergence raises an important question: What is the role of overall pathogenicity in our ability to contain emerging viruses, prevent large-scale spread, and prevent them from causing a pandemic or becoming endemic in the human population? Important questions regarding any emerging virus are, What is the shape of the disease pyramid? What proportion of infected people develop disease? And what proportion of those seek health care? These three questions inform the classic surveillance pyramid (see diagram).4 Emerging coronaviruses raise an additional question: How widespread is the virus in its reservoir? Currently, epidemiologic data that would allow us to draw this pyramid are largely unavailable (see diagram).

Clearly, efficient human-to-human transmission is a requirement for large-scale spread of this emerging virus. However, the severity of disease is an important indirect factor in a virus’s ability to spread, as well as in our ability to identify those infected and to contain it — a relationship that holds true whether an outbreak results from a single spillover event (SARS-CoV) or from repeated crossing of the species barrier (MERS-CoV).

If infection does not cause serious disease, infected people probably will not end up in health care centers. Instead, they will go to work and travel, thereby potentially spreading the virus to their contacts, possibly even internationally. Whether subclinical or mild disease from 2019-nCoV is also associated with a reduced risk of virus spread remains to be determined.

Much of our thinking regarding the relationship between transmissibility and pathogenicity of respiratory viruses has been influenced by our understanding of influenza A virus: the change in receptor specificity necessary for efficient human-to-human transmission of avian influenza viruses leads to a tropism shift from the lower to the upper respiratory tract, resulting in a lower disease burden. Two primary — and recent — examples are the pandemic H1N1 virus and the avian influenza H7N9 virus. Whereas the pandemic H1N1 virus — binding to receptors in the upper respiratory tract — caused relatively mild disease and became endemic in the population, the H7N9 virus — binding to receptors in the lower respiratory tract — has a case-fatality rate of approximately 40% and has so far resulted in only a few small clusters of human-to-human transmission.

It is tempting to assume that this association would apply to other viruses as well, but such a similarity is not a given: two coronaviruses that use the same receptor (ACE2) — NL63 and SARS-CoV — cause disease of different severity. Whereas NL63 usually causes mild upper respiratory tract disease and is endemic in the human population, SARS-CoV induced severe lower respiratory tract disease with a case-fatality rate of about 11% (see table). SARS-CoV was eventually contained by means of syndromic surveillance, isolation of patients, and quarantine of their contacts. Thus, disease severity is not necessarily linked to transmission efficiency.

Even if a virus causes subclinical or mild disease in general, some people may be more susceptible and end up seeking care. The majority of SARS-CoV and MERS-CoV cases were associated with nosocomial transmission in hospitals,5 resulting at least in part from the use of aerosol-generating procedures in patients with respiratory disease. In particular, nosocomial super-spreader events appear to have driven large outbreaks within and between health care settings. For example, travel from Hong Kong to Toronto by one person with SARS-CoV resulted in 128 SARS cases in a local hospital. Similarly, the introduction of a single patient with MERS-CoV from Saudi Arabia into the South Korean health care system resulted in 186 MERS cases.

The substantial involvement of nosocomial transmission in both SARS-CoV and MERS-CoV outbreaks suggests that such transmission is a serious risk with other newly emerging respiratory coronaviruses. In addition to the vulnerability of health care settings to outbreaks of emerging coronaviruses, hospital populations are at significantly increased risk for complications from infection. Age and coexisting conditions (such as diabetes or heart disease) are independent predictors of adverse outcome in SARS-CoV and MERS-CoV. Thus, emerging viruses that may go undetected because of a lack of severe disease in healthy people can pose significant risk to vulnerable populations with underlying medical conditions.

A lack of severe disease manifestations affects our ability to contain the spread of the virus. Identification of chains of transmission and subsequent contact tracing are much more complicated if many infected people remain asymptomatic or mildly symptomatic (assuming that these people are able to transmit the virus). More pathogenic viruses that transmit well between humans can generally be contained effectively through syndromic (fever) surveillance and contact tracing, as exemplified by SARS-CoV and, more recently, Ebola virus. Although containment of the ongoing Ebola virus outbreak in the Democratic Republic of Congo is complicated by violent conflict, all previous outbreaks were contained through identification of cases and tracing of contacts, despite the virus’s efficient person-to-person transmission.

We currently do not know where 2019-nCoV falls on the scale of human-to-human transmissibility. But it is safe to assume that if this virus transmits efficiently, its seemingly lower pathogenicity as compared with SARS, possibly combined with super-spreader events in specific cases, could allow large-scale spread. In this manner, a virus that poses a low health threat on the individual level can pose a high risk on the population level, with the potential to cause disruptions of global public health systems and economic losses. This possibility warrants the current aggressive response aimed at tracing and diagnosing every infected patient and thereby breaking the transmission chain of 2019-nCoV.

Epidemiologic information on the pathogenicity and transmissibility of this virus obtained by means of molecular detection and serosurveillance is needed to fill in the details in the surveillance pyramid and guide the response to this outbreak. Moreover, the propensity of novel coronaviruses to spread in health care centers indicates a need for peripheral health care facilities to be on standby to identify potential cases as well. In addition, increased preparedness is needed at animal markets and other animal facilities, while the possible source of this emerging virus is being investigated. If we are proactive in these ways, perhaps we will never have to discover the true epidemic or pandemic potential of 2019-nCoV.

Disclosure forms provided by the authors are available at NEJM.org.

This article was published on January 24, 2020, at NEJM.org.

Author Affiliations
From the Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT (V.J.M., N.D., E.W.); and the Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands (M.K., D.R.).
4 回复 change? 2020-1-26 11:56
A Novel Coronavirus from Patients with Pneumonia in China, 2019
List of authors.
Na Zhu, Ph.D., Dingyu Zhang, M.D., Wenling Wang, Ph.D., Xinwang Li, M.D., Bo Yang, M.S., Jingdong Song, Ph.D., Xiang Zhao, Ph.D., Baoying Huang, Ph.D., Weifeng Shi, Ph.D., Roujian Lu, M.D., Peihua Niu, Ph.D., Faxian Zhan, Ph.D., et al., for the China Novel Coronavirus Investigating and Research Team
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed another clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)

Emerging and reemerging pathogens are global challenges for public health.1 Coronaviruses are enveloped RNA viruses that are distributed broadly among humans, other mammals, and birds and that cause respiratory, enteric, hepatic, and neurologic diseases.2,3 Six coronavirus species are known to cause human disease.4 Four viruses — 229E, OC43, NL63, and HKU1 — are prevalent and typically cause common cold symptoms in immunocompetent individuals.4 The two other strains — severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) — are zoonotic in origin and have been linked to sometimes fatal illness.5 SARS-CoV was the causal agent of the severe acute respiratory syndrome outbreaks in 2002 and 2003 in Guangdong Province, China.6-8 MERS-CoV was the pathogen responsible for severe respiratory disease outbreaks in 2012 in the Middle East.9 Given the high prevalence and wide distribution of coronaviruses, the large genetic diversity and frequent recombination of their genomes, and increasing human–animal interface activities, novel coronaviruses are likely to emerge periodically in humans owing to frequent cross-species infections and occasional spillover events.5,10

In late December 2019, several local health facilities reported clusters of patients with pneumonia of unknown cause that were epidemiologically linked to a seafood and wet animal wholesale market in Wuhan, Hubei Province, China.11 On December 31, 2019, the Chinese Center for Disease Control and Prevention (China CDC) dispatched a rapid response team to accompany Hubei provincial and Wuhan city health authorities and to conduct an epidemiologic and etiologic investigation. We report the results of this investigation, identifying the source of the pneumonia clusters, and describe a novel coronavirus detected in patients with pneumonia whose specimens were tested by the China CDC at an early stage of the outbreak. We also describe clinical features of the pneumonia in two of these patients.

Methods
VIRAL DIAGNOSTIC METHODS
Four lower respiratory tract samples, including bronchoalveolar-lavage fluid, were collected from patients with pneumonia of unknown cause who were identified in Wuhan on December 21, 2019, or later and who had been present at the Huanan Seafood Market close to the time of their clinical presentation. Seven bronchoalveolar-lavage fluid specimens were collected from patients in Beijing hospitals with pneumonia of known cause to serve as control samples. Extraction of nucleic acids from clinical samples (including uninfected cultures that served as negative controls) was performed with a High Pure Viral Nucleic Acid Kit, as described by the manufacturer (Roche). Extracted nucleic acid samples were tested for viruses and bacteria by polymerase chain reaction (PCR), using the RespiFinderSmart22kit (PathoFinder BV) and the LightCycler 480 real-time PCR system, in accordance with manufacturer instructions.12 Samples were analyzed for 22 pathogens (18 viruses and 4 bacteria) as detailed in the Supplementary Appendix. In addition, unbiased, high-throughput sequencing, described previously,13 was used to discover microbial sequences not identifiable by the means described above. A real-time reverse trans**tion PCR (RT-PCR) assay was used to detect viral RNA by targeting a consensus RdRp region of pan β-CoV, as described in the Supplementary Appendix.

ISOLATION OF VIRUS
Bronchoalveolar-lavage fluid samples were collected in sterile cups to which virus transport medium was added. Samples were then centrifuged to remove cellular debris. The supernatant was inoculated on human airway epithelial cells,14 which had been obtained from airway specimens resected from patients undergoing surgery for lung cancer and were confirmed to be special-pathogen-free by NGS.13

Human airway epithelial cells were expanded on plastic substrate to generate passage-1 cells and were subsequently plated at a density of 2.5×105 cells per well on permeable Transwell-COL (12-mm diameter) supports. Human airway epithelial cell cultures were generated in an air–liquid interface for 4 to 6 weeks to form well-differentiated, polarized cultures resembling in vivo pseudostratified mucociliary epithelium.13

Prior to infection, apical surfaces of the human airway epithelial cells were washed three times with phosphate-buffered saline; 150 μl of supernatant from bronchoalveolar-lavage fluid samples was inoculated onto the apical surface of the cell cultures. After a 2-hour incubation at 37°C, unbound virus was removed by washing with 500 μl of phosphate-buffered saline for 10 minutes; human airway epithelial cells were maintained in an air–liquid interface incubated at 37°C with 5% carbon dioxide. Every 48 hours, 150 μl of phosphate-buffered saline was applied to the apical surfaces of the human airway epithelial cells, and after 10 minutes of incubation at 37°C the samples were harvested. Pseudostratified mucociliary epithelium cells were maintained in this environment; apical samples were passaged in a 1:3 diluted vial stock to new cells. The cells were monitored daily with light microscopy, for cytopathic effects, and with RT-PCR, for the presence of viral nucleic acid in the supernatant. After three passages, apical samples and human airway epithelial cells were prepared for transmission electron microscopy.

TRANSMISSION ELECTRON MICROSCOPY
Supernatant from human airway epithelial cell cultures that showed cytopathic effects was collected, inactivated with 2% paraformaldehyde for at least 2 hours, and ultracentrifuged to sediment virus particles. The enriched supernatant was negatively stained on film-coated grids for examination. Human airway epithelial cells showing cytopathic effects were collected and fixed with 2% paraformaldehyde–2.5% glutaraldehyde and were then fixed with 1% osmium tetroxide dehydrated with grade ethanol embedded with PON812 resin. Sections (80 nm) were cut from resin block and stained with uranyl acetate and lead citrate, separately. The negative stained grids and ultrathin sections were observed under transmission electron microscopy.

VIRAL GENOME SEQUENCING
RNA extracted from bronchoalveolar-lavage fluid and culture supernatants was used as a template to clone and sequence the genome. We used a combination of Illumina sequencing and nanopore sequencing to characterize the virus genome. Sequence reads were assembled into contig maps (a set of overlapping DNA segments) with the use of CLC Genomics software, version 4.6.1 (CLC Bio). Specific primers were subsequently designed for PCR, and 5′- or 3′- RACE (rapid amplification of cDNA ends) was used to fill genome gaps from conventional Sanger sequencing. These PCR products were purified from gels and sequenced with a BigDye Terminator v3.1 Cycle Sequencing Kit and a 3130XL Genetic Analyzer, in accordance with the manufacturers’ instructions.

Multiple-sequence alignment of the 2019-nCoV and reference sequences was performed with the use of Muscle. Phylogenetic analysis of the complete genomes was performed with RAxML (13) with 1000 bootstrap replicates and a general time-reversible model used as the nucleotide substitution model.

Results
PATIENTS
Figure 1.

Chest Radiographs.
Three adult patients presented with severe pneumonia and were admitted to a hospital in Wuhan on December 27, 2019. Patient 1 was a 49-year-old woman, Patient 2 was a 61-year-old man, and Patient 3 was a 32-year-old man. Clinical profiles were available for Patients 1 and 2. Patient 1 reported having no underlying chronic medical conditions but reported fever (temperature, 37°C to 38°C) and cough with chest discomfort on December 23, 2019. Four days after the onset of illness, her cough and chest discomfort worsened, but the fever was reduced; a diagnosis of pneumonia was based on computed tomographic (CT) scan. Her occupation was retailer in the seafood wholesale market. Patient 2 initially reported fever and cough on December 20, 2019; respiratory distress developed 7 days after the onset of illness and worsened over the next 2 days (see chest radiographs, Figure 1), at which time mechanical ventilation was started. He had been a frequent visitor to the seafood wholesale market. Patients 1 and 3 recovered and were discharged from the hospital on January 16, 2020. Patient 2 died on January 9, 2020. No biopsy specimens were obtained.

DETECTION AND ISOLATION OF A NOVEL CORONAVIRUS
Three bronchoalveolar-lavage samples were collected from Wuhan Jinyintan Hospital on December 30, 2019. No specific pathogens (including HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1) were detected in clinical specimens from these patients by the RespiFinderSmart22kit. RNA extracted from bronchoalveolar-lavage fluid from the patients was used as a template to clone and sequence a genome using a combination of Illumina sequencing and nanopore sequencing. More than 20,000 viral reads from individual specimens were obtained, and most contigs matched to the genome from lineage B of the genus betacoronavirus — showing more than 85% identity with a bat SARS-like CoV (bat-SL-CoVZC45, MG772933.1) genome published previously. Positive results were also obtained with use of a real-time RT-PCR assay for RNA targeting to a consensus RdRp region of pan β-CoV (although the cycle threshold value was higher than 34 for detected samples). Virus isolation from the clinical specimens was performed with human airway epithelial cells and Vero E6 and Huh-7 cell lines. The isolated virus was named 2019-nCoV.

Figure 2.

Cytopathic Effects in Human Airway Epithelial Cell Cultures after Inoculation with 2019-nCoV.
To determine whether virus particles could be visualized in 2019-nCoV–infected human airway epithelial cells, mock-infected and 2019-nCoV–infected human airway epithelial cultures were examined with light microscopy daily and with transmission electron microscopy 6 days after inoculation. Cytopathic effects were observed 96 hours after inoculation on surface layers of human airway epithelial cells; a lack of cilium beating was seen with light microcopy in the center of the focus (Figure 2). No specific cytopathic effects were observed in the Vero E6 and Huh-7 cell lines until 6 days after inoculation.

Figure 3.

Visualization of 2019-nCoV with Transmission Electron Microscopy.
Electron micrographs of negative-stained 2019-nCoV particles were generally spherical with some pleomorphism (Figure 3). Diameter varied from about 60 to 140 nm. Virus particles had quite distinctive spikes, about 9 to 12 nm, and gave virions the appearance of a solar corona. Extracellular free virus particles and inclusion bodies filled with virus particles in membrane-bound vesicles in cytoplasm were found in the human airway epithelial ultrathin sections. This observed morphology is consistent with the Coronaviridae family.

To further characterize the virus, de novo sequences of 2019-nCoV genome from clinical specimens (bronchoalveolar-lavage fluid) and human airway epithelial cell virus isolates were obtained by Illumina and nanopore sequencing. The novel coronavirus was identified from all three patients. Two nearly full-length coronavirus sequences were obtained from bronchoalveolar-lavage fluid (BetaCoV/Wuhan/IVDC-HB-04/2020, BetaCoV/Wuhan/IVDC-HB-05/2020|EPI_ISL_402121), and one full-length sequence was obtained from a virus isolated from a patient (BetaCoV/Wuhan/IVDC-HB-01/2020|EPI_ISL_402119). Complete genome sequences of the three novel coronaviruses were submitted to GASAID (BetaCoV/Wuhan/IVDC-HB-01/2019, accession ID: EPI_ISL_402119; BetaCoV/Wuhan/IVDC-HB-04/2020, accession ID: EPI_ISL_402120; BetaCoV/Wuhan/IVDC-HB-05/2019, accession ID: EPI_ISL_402121) and have a 86.9% nucleotide sequence identity to a previously published bat SARS-like CoV (bat-SL-CoVZC45, MG772933.1) genome. The three 2019-nCoV genomes clustered together and formed an independent subclade within the sarbecovirus subgenus, which shows the typical betacoronavirus organization: a 5′ untranslated region (UTR), replicase complex (orf1ab), S gene, E gene, M gene, N gene, 3′ UTR, and several unidentified nonstructural open reading frames.

Figure 4.

Phylogenetic Analysis of 2019-nCoV and Other Betacoronavirus Genomes in the Orthocoronavirinae Subfamily.
Although 2019-nCoV is similar to some betacoronaviruses detected in bats (Figure 4), it is distinct from SARS-CoV and MERS-CoV. The three 2019-nCoV coronaviruses from Wuhan, together with two bat-derived SARS-like strains, ZC45 and ZXC21, form a distinct clade in lineage B of the subgenus sarbecovirus. SARS-CoV strains from humans and genetically similar SARS-like coronaviruses from bats collected from southwestern China formed another clade within the subgenus sarbecovirus. Since the sequence identity in conserved replicase domains (ORF 1ab) is less than 90% between 2019-nCoV and other members of betacoronavirus, the 2019-nCoV — the likely causative agent of the viral pneumonia in Wuhan — is a novel betacoronavirus belonging to the sarbecovirus subgenus of Coronaviridae family.

Discussion
We report a novel CoV (2019-nCoV) that was identified in hospitalized patients in Wuhan, China, in December 2019 and January 2020. Evidence for the presence of this virus includes identification in bronchoalveolar-lavage fluid in three patients by whole-genome sequencing, direct PCR, and culture. The illness likely to have been caused by this CoV was named “novel coronavirus-infected pneumonia” (NCIP). Complete genomes were submitted to GASAID. Phylogenetic analysis revealed that 2019-nCoV falls into the genus betacoronavirus, which includes coronaviruses (SARS-CoV, bat SARS-like CoV, and others) discovered in humans, bats, and other wild animals.15 We report isolation of the virus and the initial des**tion of its specific cytopathic effects and morphology.

Molecular techniques have been used successfully to identify infectious agents for many years. Unbiased, high-throughput sequencing is a powerful tool for the discovery of pathogens.14,16 Next-generation sequencing and bioinformatics are changing the way we can respond to infectious disease outbreaks, improving our understanding of disease occurrence and transmission, accelerating the identification of pathogens, and promoting data sharing. We describe in this report the use of molecular techniques and unbiased DNA sequencing to discover a novel betacoronavirus that is likely to have been the cause of severe pneumonia in three patients in Wuhan, China.

Although establishing human airway epithelial cell cultures is labor intensive, they appear to be a valuable research tool for analysis of human respiratory pathogens.14 Our study showed that initial propagation of human respiratory secretions onto human airway epithelial cell cultures, followed by transmission electron microscopy and whole genome sequencing of culture supernatant, was successfully used for visualization and detection of new human coronavirus that can possibly elude identification by traditional approaches.

Further development of accurate and rapid methods to identify unknown respiratory pathogens is still needed. On the basis of analysis of three complete genomes obtained in this study, we designed several specific and sensitive assays targeting ORF1ab, N, and E regions of the 2019-nCoV genome to detect viral RNA in clinical specimens. The primer sets and standard operating procedures have been shared with the World Health Organization and are intended for surveillance and detection of 2019-nCoV infection globally and in China. More recent data show 2019-nCoV detection in 830 persons in China.17

Although our study does not fulfill Koch’s postulates, our analyses provide evidence implicating 2019-nCoV in the Wuhan outbreak. Additional evidence to confirm the etiologic significance of 2019-nCoV in the Wuhan outbreak include identification of a 2019-nCoV antigen in the lung tissue of patients by immunohistochemical analysis, detection of IgM and IgG antiviral antibodies in the serum samples from a patient at two time points to demonstrate seroconversion, and animal (monkey) experiments to provide evidence of pathogenicity. Of critical importance are epidemiologic investigations to characterize transmission modes, reproduction interval, and clinical spectrum resulting from infection to inform and refine strategies that can prevent, control, and stop the spread of 2019-nCoV.

This work was supported by grants from the National Key Research and Development Program of China (2016YFD0500301) and the National Major Project for Control and Prevention of Infectious Disease in China (2018ZX10101002).

Drs. Zhu, Zhang, W. Wang, Li, and Yang contributed equally to this article.

This article was published on January 24, 2020, at NEJM.org.

We thank Dr. Zhongjie Li, Dr. Guangxue He, Dr. Lance Rodewald, Yu Li, Fei Ye, Li Zhao, Weimin Zhou, Jun Liu, Yao Meng, Huijuan Wang, and many staff members at the China CDC for their contributions and assistance in this preparation and submission of an earlier version of the manus**t.

Author Affiliations
From the MHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (N.Z., W.W., J.S., X.Z., B.H., R.L., P.N., X.M., D.W., W.X., G.W., G.F.G., W.T.), and the Department of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University (X.L.) — both in Beijing; Wuhan Jinyintan Hospital (D.Z.), the Division for Viral Disease Detection, Hubei Provincial Center for Disease Control and Prevention (B.Y., F.Z.), and the Center for Biosafety Mega-Science, Chinese Academy of Sciences (W.T.) — all in Wuhan; and the Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China (W.S.).

Address reprint requests to Dr. Tan at the NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, China CDC, 155 Changbai Road, Changping District, Beijing 102206, China; or at tanwj@ivdc.chinacdc.cn, Dr. Gao at the National Institute for Viral Disease Control and Prevention, China CDC, Beijing 102206, China, or at gaof@im.ac.cn, or Dr. Wu at the NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, China CDC, Beijing 102206, China, or at wugz@ivdc.chinacdc.cn.
4 回复 change? 2020-1-26 11:58
Another Decade, Another Coronavirus
List of authors.
Stanley Perlman, M.D., Ph.D.

or the third time in as many decades, a zoonotic coronavirus has crossed species to infect human populations. This virus, provisionally called 2019-nCoV, was first identified in Wuhan, China, in persons exposed to a seafood or wet market. The rapid response of the Chinese public health, clinical, and scientific communities facilitated recognition of the clinical disease and initial understanding of the epidemiology of the infection. First reports indicated that human-to-human transmission was limited or nonexistent, but we now know that such transmission occurs, although to what extent remains unknown. Like outbreaks caused by two other pathogenic human respiratory coronaviruses (severe acute respiratory syndrome coronavirus [SARS-CoV] and Middle East respiratory syndrome coronavirus [MERS-CoV]), 2019-nCoV causes respiratory disease that is often severe.1 As of January 24, 2020, there were more than 800 reported cases, with a mortality rate of 3% (https://promedmail.org/. opens in new tab).

As now reported in the Journal, Zhu et al.2 have identified and characterized 2019-nCoV. The viral genome has been sequenced, and these results in conjunction with other reports show that it is 75 to 80% identical to the SARS-CoV and even more closely related to several bat coronaviruses.3 It can be propagated in the same cells that are useful for growing SARS-CoV and MERS-CoV, but notably, 2019-nCoV grows better in primary human airway epithelial cells than in standard tissue-culture cells, unlike SARS-CoV or MERS-CoV. Identification of the virus will allow the development of reagents to address key unknowns about this new coronavirus infection and guide the development of antiviral therapies. First, knowing the sequence of the genome facilitates the development of sensitive quantitative reverse-trans**tase–polymerase-chain-reaction assays to rapidly detect the virus. Second, the development of serologic assays will allow assessment of the prevalence of the infection in humans and in potential zoonotic sources of the virus in wet markets and other settings. These reagents will also be useful for assessing whether the human infection is more widespread than originally thought, since wet markets are present throughout China. Third, having the virus in hand will spur efforts to develop antiviral therapies and vaccines, as well as experimental animal models.

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Much still needs to be learned about this infection. Most important, the extent of interhuman transmission and the spectrum of clinical disease need to be determined. Transmission of SARS-CoV and MERS-CoV occurred to a large extent by means of superspreading events.4,5 Superspreading events have been implicated in 2019-nCoV transmission, but their relative importance is unknown. Both SARS-CoV and MERS-CoV infect intrapulmonary epithelial cells more than cells of the upper airways.4,6 Consequently, transmission occurs primarily from patients with recognized illness and not from patients with mild, nonspecific signs. It appears that 2019-nCoV uses the same cellular receptor as SARS-CoV (human angiotensin-converting enzyme 2 [hACE2]),3 so transmission is expected only after signs of lower respiratory tract disease develop. SARS-CoV mutated over the 2002–2004 epidemic to better bind to its cellular receptor and to optimize replication in human cells, enhancing virulence.7 Adaptation readily occurs because coronaviruses have error-prone RNA-dependent RNA polymerases, making mutations and recombination events frequent. By contrast, MERS-CoV has not mutated substantially to enhance human infectivity since it was detected in 2012.8

It is likely that 2019-nCoV will behave more like SARS-CoV and further adapt to the human host, with enhanced binding to hACE2. Consequently, it will be important to obtain as many temporally and geographically unrelated clinical isolates as possible to assess the degree to which the virus is mutating and to assess whether these mutations indicate adaptation to the human host. Furthermore, if 2019-nCoV is similar to SARS-CoV, the virus will spread systemically.9 Obtaining patient samples at autopsy will help elucidate the pathogenesis of the infection and modify therapeutic interventions rationally. It will also help validate results obtained from experimental infections of laboratory animals.

A second key question is identification of the zoonotic origin of the virus. Given its close similarity to bat coronaviruses, it is likely that bats are the primary reservoir for the virus. SARS-CoV was transmitted to humans from exotic animals in wet markets, whereas MERS-CoV is transmitted from camels to humans.10 In both cases, the ancestral hosts were probably bats. Whether 2019-nCoV is transmitted directly from bats or by means of intermediate hosts is important to understand and will help define zoonotic transmission patterns.

A striking feature of the SARS epidemic was that fear played a major role in the economic and social consequences. Although specific anticoronaviral therapies are still in development, we now know much more about how to control such infections in the community and hospitals, which should alleviate some of this fear. Transmission of 2019-nCoV probably occurs by means of large droplets and contact and less so by means of aerosols and fomites, on the basis of our experience with SARS-CoV and MERS-CoV.4,5 Public health measures, including quarantining in the community as well as timely diagnosis and strict adherence to universal precautions in health care settings, were critical in controlling SARS and MERS. Institution of similar measures will be important and, it is hoped, successful in reducing the transmission of 2019-nCoV.
3 回复 change? 2020-1-26 12:17
摘要
2019年12月，一群原因不明的肺炎患者与中国武汉的海鲜批发市场有关。通过对肺炎患者样本进行无偏测序，发现了先前未知的β冠状病毒。人类气道上皮细胞被用于分离一种新型冠状病毒，命名为2019-nCoV，该冠状病毒在sarbecovirus亚属Orthocoronavirinae亚科内形成了另一个进化枝。与MERS-CoV和SARS-CoV不同的是，2019-nCoV是感染人类的​​冠状病毒家族的第七个成员。加强监视和进一步调查正在进行中。 （由中国国家重点研究发展计划和中国国家传染病预防控制重大项目资助。）

新兴和重新出现的病原体是公共卫生面临的全球挑战。1冠状病毒是被包膜的RNA病毒，广泛分布于人类，其他哺乳动物和鸟类中，并引起呼吸系统，肠道，肝脏和神经系统疾病。2,3已知六种冠状病毒引起人类疾病。4四种病毒-229E，OC43，NL63和HKU1-普遍存在，通常会在具有免疫能力的个体中引起普通感冒症状。4其他两种病毒株-严重急性呼吸综合征冠状病毒（SARS-CoV）和中东呼吸道病毒综合征冠状病毒（MERS-CoV）—起源于人畜共患病，有时与致命疾病相关。5SARS-CoV是2002年和2003年中国广东省严重急性呼吸道综合症暴发的病因。6-8MERS -冠状病毒是导致2012年中东地区严重呼吸道疾病暴发的病原体。9由于冠状病毒的高流行和广泛分布，大规模的基因潜水由于其频繁发生的跨物种感染和偶然的外溢事件，其基因组的稀有性和频繁的重组以及人类与动物之间的界面活动不断增加，新型冠状病毒很可能会定期在人体内出现。5,10

2019年12月下旬，几家当地卫生机构报告了一群原因不明的肺炎，这些流行病学与中国湖北省武汉市的海鲜和湿动物批发市场有关.11 2019年12月31日，中国疾病预防控制中心疾病预防控制中心派出了一个快速反应小组，陪同湖北省和武汉市卫生部门开展流行病学和病因学调查。我们报告了这项调查的结果，确定了肺炎簇的来源，并描述了在疾病爆发早期由中国疾病预防控制中心检测其标本的肺炎患者中检测到的新型冠状病毒。我们还描述了其中两名患者的肺炎的临床特征。

方法
病毒诊断方法
从2019年12月21日或以后在武汉发现的，原因不明的肺炎患者中收集了四个下呼吸道样本，包括支气管肺泡灌洗液，这些样本在他们离开时已出现在华南海鲜市场临床表现。从北京医院因已知原因引起的肺炎患者中收集了七个支气管肺泡灌洗液样本作为对照样本。如制造商（Roche）所述，用高纯病毒核酸试剂盒从临床样品（包括用作阴性对照的未感染培养物）中提取核酸。根据制造商的说明，使用RespiFinderSmart22kit（PathoFinder BV）和LightCycler 480实时PCR系统，通过聚合酶链反应（PCR）对提取的核酸样品进行病毒和细菌测试.12根据分析，对样品中的22种病原体进行了分析（18病毒和4种细菌），如补充附录中所述。此外，先前所述的无偏，高通量测序[13]用于发现无法通过上述方法鉴定的微生物序列。如补充附录中所述，通过靶向泛β-CoV的共有RdRp区，使用实时逆转录PCR（RT-PCR）分析来检测病毒RNA。

病毒隔离
在无菌杯中收集支气管肺泡灌洗液样品，并向其中加入病毒转运介质。然后将样品离心以除去细胞碎片。将上清液接种在人气道上皮细胞上，14这是从接受肺癌手术的患者切除的气道标本中获得的，并经NGS确认不含特殊病原体。13

将人气道上皮细胞在塑料基质上扩增以产生第1代细胞，然后以每孔2.5×105个细胞的密度接种在可渗透的Transwell-COL（直径12毫米）支持物上。人气道上皮细胞培养物在气液界面上产生4到6周，形成分化良好的极化培养物，类似于体内假复层粘膜纤毛上皮。13

感染前，用磷酸盐缓冲液将人气道上皮细胞的顶端表面清洗三遍；将150μl来自支气管肺泡灌洗液样品的上清液接种到细胞培养物的顶表面上。在37°C下孵育2小时后，用500μl磷酸盐缓冲液洗涤10分钟以去除未结合的病毒；人的气道上皮细胞保持在气液界面，并在37°C与5％的二氧化碳温育。每48小时，将150μl磷酸盐缓冲盐水施加到人气道上皮细胞的顶表面，并在37°C孵育10分钟后，收集样品。伪分层的粘膜纤毛上皮细胞保持在这种环境中。顶端样品以1：3稀释的小瓶原液传代至新细胞。每天用光学显微镜监测细胞的细胞病变作用，并用RT-PCR监测上清液中病毒核酸的存在。经过三次传代，准备了顶端样品和人气道上皮细胞用于透射电子显微镜。

透射电子显微镜
收集显示出细胞病变作用的人气道上皮细胞培养物的上清液，用2％多聚甲醛将其灭活至少2小时，然后超速离心以沉淀病毒颗粒。将富集的上清液在膜包被的格栅上进行负染以进行检查。收集显示出细胞病变作用的人气道上皮细胞，并用2％多聚甲醛–2.5％戊二醛固定，然后用1％四氧化固定，其中四氧化经PON812树脂包埋的等级乙醇脱水。从树脂块上切下切片（80nm），并分别用乙酸铀酰和柠檬酸铅染色。在透射电子显微镜下观察到负染色的网格和超薄切片。

病毒基因组测序
从支气管肺泡灌洗液和培养上清液中提取的RNA被用作模板来克隆和测序基因组。我们结合使用Illumina测序和纳米孔测序来表征病毒基因组。使用CLC Genomics软件4.6.1版（CLC Bio）将序列读数组装成重叠群图（一组重叠的DNA片段）。随后设计了特异性引物用于PCR，并使用5'-或3'-RACE（cDNA末端的快速扩增）填补了传统Sanger测序的基因组空白。这些PCR产物已从凝胶中纯化，并按照制造商的说明使用BigDye Terminator v3.1循环测序试剂盒和3130XL基因分析仪进行测序。

使用Muscle对2019-nCoV和参考序列进行多序列比对。用具有1000个自举重复的RAxML（13）和完整的时间可逆模型作为核苷酸取代模型，进行了完整基因组的系统发育分析。

结果
患者
图1。

胸部X光片。
三名患有严重肺炎的成年患者于2019年12月27日入武汉医院。患者1是一名49岁的女性，患者2是61岁的男性，患者3是32岁的男性岁的男人。患者1和2可获得临床资料。患者1报告于2019年12月23日无基础慢性疾病，但报告有发烧（温度37°C至38°C）和咳嗽伴有胸部不适。疾病，咳嗽和胸部不适加剧，但发烧减少；肺炎的诊断基于计算机断层扫描（CT）扫描。她的职业是海鲜批发市场的零售商。患者2最初于2019年12月20日报告发烧和咳嗽;发病后7天出现呼吸窘迫，并在接下来的2天内恶化（见胸部X线片，图1），此时开始进行机械通气。他是海鲜批发市场的常客。患者1和3已康复，并于2020年1月16日出院。患者2于2020年1月9日死亡。未获得活检标本。

新型冠状病毒的检测与分离
2019年12月30日，从武汉金银滩医院收集了3份支气管肺泡灌洗液样本。 。从患者的支气管肺泡灌洗液中提取的RNA用作模板，结合Illumina测序和纳米孔测序对基因组进行克隆和测序。从单个标本中获得了超过20,000个病毒读数，并且大多数重叠群与beta冠状病毒属B的基因组相匹配-与蝙蝠SARS样冠状病毒（bat-SL-CoVZC45，MG772933.1）的同一性超过85％基因组先前已发表。使用实时RT-PCR测定RNA靶向泛β-CoV的共有RdRp区也获得了积极的结果（尽管对于检测到的样品，其循环阈值高于34）。使用人气道上皮细胞以及Vero E6和Huh-7细胞系从临床标本中分离病毒。分离出的病毒命名为2019-nCoV。

为了确定是否可以在2019-nCoV感染的人气道上皮细胞中看到病毒颗粒，接种后6天每天用光学显微镜和透射电子显微镜检查模拟感染和2019-nCoV感染的人气道上皮培养物。接种人气道上皮细胞表面层96小时后观察到细胞病变作用。用光学显微镜在焦点中心观察到缺乏纤毛的跳动（图2）。直到接种后6天，在Vero E6和Huh-7细胞系中都没有观察到特异性的细胞病变作用。

图3。

用透射电子显微镜可视化2019-nCoV。
负染色的2019-nCoV粒子的电子显微照片通常是球形的，具有一些多态性（图3）。直径在约60至140nm之间变化。病毒颗粒具有非常独特的尖峰，大约9至12 nm，并且使病毒体具有太阳日冕的外观。在人气道上皮超薄切片中发现细胞外游离病毒颗粒和在细胞质膜结合囊泡中充满病毒颗粒的包涵体。该观察到的形态与冠状病毒科一致。

为了进一步表征病毒，通过Illumina和纳米孔测序获得了临床标本（支气管肺泡灌洗液）和人气道上皮细胞病毒分离株的2019-nCoV基因组从头序列。从所有三名患者中鉴定出新的冠状病毒。从支气管肺泡灌洗液中获得了两个接近全长的冠状病毒序列（BetaCoV /武汉/ IVDC-HB-04 / 2020，BetaCoV /武汉/ IVDC-HB-05 / 2020 | EPI_ISL_402121），并且获得了一个全长序列。分离自患者的病毒（BetaCoV / Wuhan / IVDC-HB-01 / 2020 | EPI_ISL_402119）。将三种新型冠状病毒的完整基因组序列提交给GASAID（BetaCoV / Wuhan / IVDC-HB-01 / 2019，登录号：EPI_ISL_402119; BetaCoV /武汉/ IVDC-HB-04 / 2020，登录号：EPI_ISL_402120; BetaCoV / Wuhan / IVDC-HB-05 / 2019，登录号：EPI_ISL_402121），与先前发布的蝙蝠SARS样冠状病毒（bat-SL-CoVZC45，MG772933.1）基因组具有86.9％的核苷酸序列同一性。三个2019-nCoV基因组聚集在一起并在sarbecovirus亚属内形成一个独立的亚群，显示了典型的β冠状病毒组织：5'非翻译区（UTR），复制酶复合体（orf1ab），S基因，E基因，M基因，N基因，3'UTR和一些不确定的非结构性开放阅读框。

尽管2019-nCoV与在蝙蝠中检测到的某些β-冠状病毒相似（图4），但它与SARS-CoV和MERS-CoV不同。来自武汉的三种2019-nCoV冠状病毒，以及两种蝙蝠衍生的SARS样菌株ZC45和ZXC21，在sarbecovirus亚类B系中形成了独特的进化枝。来自人类的SARS-CoV病毒株和从中国西南地区收集的蝙蝠的遗传相似的SARS样冠状病毒形成了sarbecovirus亚属内的另一个进化枝。由于保守复制酶结构域（ORF 1ab）中的序列同一性在2019-nCoV和乙型冠状病毒的其他成员之间小于90％，因此2019-nCoV-武汉病毒性肺炎的可能病原体-是一种新的乙型冠状病毒，属于冠状病毒科的sarbecovirus亚属。

讨论
我们报告了一种新的CoV（2019-nCoV），该病毒已于2019年12月和2020年1月在中国武汉的住院患者中鉴定出。该病毒的存在包括通过全基因组测序在三名患者的支气管肺泡灌洗液中进行鉴定，直接PCR和培养。该冠状病毒可能引起的疾病被称为“新型冠状病毒感染的肺炎”（NCIP）。完整的基因组已提交给GASAID。系统发育分析表明，2019-nCoV属于beta冠状病毒属，其中包括在人，蝙蝠和其他野生动物中发现的冠状病毒（SARS-CoV，蝙蝠SARS状CoV等）15。对其特定细胞病变效应和形态的初步描述。

分子技术已成功用于鉴定传染原已有多年。无偏倚的高通量测序是发现病原体的有力工具。14,16下一代测序和生物信息学正在改变我们应对传染病暴发的方式，加深了我们对疾病发生和传播的理解，加速了对病原体的识别。病原体，促进数据共享。我们在本报告中描述了分子技术和无偏DNA测序的使用，以发现一种新型的β冠状病毒，该病毒可能已在中国武汉的三名患者中引起严重的肺炎。

尽管建立人呼吸道上皮细胞培养物是劳动密集型的，但它们似乎是分析人呼吸道病原体的有价值的研究工具。14我们的研究表明，人呼吸道分泌物最初在人气道上皮细胞培养物中的传播，然后是透射电子显微镜和培养物上清液的全基因组测序已成功用于可视化和检测新的人类冠状病毒，这可能无法通过传统方法进行鉴定。

仍然需要进一步发展准确快速的方法来鉴定未知的呼吸道病原体。在对本研究中获得的三个完整基因组进行分析的基础上，我们设计了针对2019-nCoV基因组的ORF1ab，N和E区域的几种特异性和灵敏测定法，以检测临床标本中的病毒RNA。引物组和标准操作程序已与世界卫生组织共享，目的是在全球和中国范围内监视和检测2019-nCoV感染。最新数据显示，中国830人中2019-nCoV的检测17。

尽管我们的研究未能满足科赫的假设，但我们的分析提供了与武汉爆发的2019-nCoV有关的证据。证实2019-nCoV在武汉爆发中的病因学意义的其他证据包括通过免疫组织化学分析鉴定患者肺组织中的2019-nCoV抗原，两次检测患者血清样品中的IgM和IgG抗病毒抗体证明血清转化，并通过动物（猴子）实验提供致病性证据。至关重要的是流行病学调查，以表征感染导致的传播方式，繁殖间隔和临床范围，以告知和完善可以预防，控制和阻止2019-nCoV传播的策略。

这项工作得到了中国国家重点研究发展计划（2016YFD0500301）和中国国家传染病控制与预防重大项目（2018ZX10101002）的资助。

博士Zhu，Zhang，W。Wang，Li和Yang对本文做出了同样的贡献。

本文于2020年1月24日在NEJM.org上发布。

我们感谢李忠杰博士，何光学博士，兰斯·罗德瓦尔德博士，于立，叶飞，李立，赵为民，周军，刘军，孟瑶，王慧娟以及中国疾控中心的许多工作人员所做的贡献和感谢。协助编写和提交较早版本的手稿。

作者单位
来自中国疾病预防控制中心国家疾病预防控制中心病毒疾病预防控制中心MHC生物安全重点实验室（NZ，WW，JS，XZ，BH，RL，PN，XM，DW，WX，GW，GFG，WT ），以及首都医科大学附属北京地坛医院传染病科-都在北京；武汉市金银潭医院（D.Z.），湖北省疾病预防控制中心病毒病检测科和中国科学院（W.T.）生物安全大科学中心-都在武汉;以及山东第一医科大学和山东医学科学院，中国济南。

在北京市疾病预防控制中心病毒疾病预防控制所国家卫生总局生物安全重点实验室，中国北京昌平区昌百路155号，向谭博士致函转载请求102102；或发送至tanwj@ivdc.chinacdc.cn，中国疾病预防控制中心国家病毒性疾病预防控制研究所的高博士，北京102206，或gaof@im.ac.cn，或NHC Key的吴博士。中国疾病预防控制中心，国家疾病预防控制中心，生物安全实验室，北京102206，或发送电子邮件至wugz@ivdc.chinacdc.cn。
3 回复 change? 2020-1-26 12:36
中国出现的新型冠状病毒—影响评估的关键问题
作者列表。
Vincent J.Munster博士，Marion Koopmans博士，Neeltje van Doremalen博士，Debby van Riel博士和Emmie de Wit博士

于2019年底，在中国武汉出现了新型的冠状病毒，命名为2019-nCoV。截至2020年1月24日，在九个国家（中国，泰国，日本，韩国，新加坡，越南，台湾，尼泊尔和美国。发生了26例死亡，主要是在患有严重基础疾病的患者中发生的。1尽管这种病毒的出现的许多细节（例如其起源和在人类中传播的能力）仍然未知，但似乎导致这种情况的病例越来越多从人与人之间的传播。考虑到2002年爆发的严重急性呼吸系统综合症冠状病毒（SARS-CoV）和2012年发生的中东呼吸系统综合症冠状病毒（MERS-CoV）2，2019-nCoV是过去二十年来人类中出现的第三种冠状病毒-这种现象使全球公共卫生机构倍受戒备。

中国迅速做出反应，将疫情通报世界卫生组织（WHO），并在发现病原体后与国际社会共享序列信息。世卫组织通过协调诊断发展迅速作出反应；发布有关患者监测，标本采集和治疗的指南； 3该地区的几个国家以及美国正在对来自武汉的旅行者进行发烧筛查，目的是在病毒进一步传播之前发现2019-nCoV病例。来自中国，泰国，韩国和日本的最新消息表明，与SARS和MERS相比，与2019-nCoV相关的疾病似乎相对较轻。

在武汉出现SARS样病毒的初步报道之后，看来2019-nCoV的致病性可能低于MERS-CoV和SARS-CoV（见表）。但是，这种病毒的出现提出了一个重要的问题：总体致病性在我们遏制新兴病毒，防止大规模传播并防止其在人类中引起大流行或成为地方性流行的能力方面起什么作用？关于任何新兴病毒的重要问题是，疾病金字塔的形状是什么？有多少比例的感染者患上疾病？当中有百分之几的人寻求医疗保健？这三个问题代表了经典的监视金字塔（见图）。4新兴的冠状病毒提出了另一个问题：病毒在其储存库中的传播程度如何？当前，尚无可用来绘制金字塔的流行病学数据（见图）。

显然，有效的人际传播是这种新兴病毒大规模传播的要求。但是，疾病的严重性是病毒传播能力以及我们识别感染者并加以控制的能力的重要间接因素。这种关系对于爆发是否是由单个外溢事件引起的（SARS- CoV）或物种壁垒的反复穿越（MERS-CoV）。

如果感染没有引起严重的疾病，被感染的人可能最终不会进入医疗中心。取而代之的是，他们将去上班和旅行，从而有可能将病毒传播给他们的联系人，甚至可能传播到国际上。从2019-nCoV开始的亚临床或轻度疾病是否也与病毒传播风险降低相关，尚待确定。

我们对呼吸道病毒的可传播性和致病性之间关系的许多思考都受到我们对甲型流感病毒的理解的影响：禽流感病毒在人与人之间有效传播所必需的受体特异性的变化会导致从降低至上呼吸道，从而降低疾病负担。大流行的H1N1病毒和禽流感H7N9病毒是两个主要的（也是最近的）例子。大流行的H1N1病毒（与上呼吸道的受体结合）引起相对较轻的疾病并在人群中流行，而H7N9病毒（与下呼吸道的受体结合）的病死率约为40％，迄今为止，仅导致了少数人与人之间的传播。

试图假定这种关联也适用于其他病毒，但并没有给出这样的相似性：使用相同受体（ACE2）的两种冠状病毒-NL63和SARS-CoV-引起不同严重程度的疾病。 NL63通常会引起轻度的上呼吸道疾病，并且在人类中很流行，而SARS-CoV会导致严重的下呼吸道疾病，病死率约为11％（参见表）。 SARS-CoV最终通过症状监测，隔离患者以及隔离他们的接触者而得到遏制。因此，疾病的严重程度不一定与传播效率有关。

即使病毒通常引起亚临床或轻度疾病，某些人也可能更易感染并最终寻求治疗。大多数SARS-CoV和MERS-CoV病例与医院的院内传播有关，5至少部分是由于在呼吸系统疾病患者中使用了产生气溶胶的程序。特别是，医院内超级传播事件似乎已导致卫生保健机构内部和之间的大规模爆发。例如，一名SARS-CoV患者从香港到多伦多的旅行在当地医院导致128例SARS病例。同样，沙特阿拉伯将一名MERS-CoV患者引入韩国卫生保健系统，导致186例MERS病例。

院内传播大量参与SARS-CoV和MERS-CoV暴发表明，这种传播是其他新兴呼吸道冠状病毒的严重危险。除了医疗机构容易受到新兴冠状病毒爆发的影响外，医院人群感染并发症的风险也大大增加。年龄和并存疾病（例如糖尿病或心脏病）是SARS-CoV和MERS-CoV不良后果的独立预测因子。因此，由于健康人缺乏严重疾病，可能无法发现的新兴病毒可能会对处于基础疾病中的脆弱人群造成重大风险。

缺乏严重的疾病表现会影响我们遏制病毒传播的能力。如果许多感染者无症状或轻度有症状（假设这些人能够传播病毒），则鉴定传播链和随后的接触者追踪要复杂得多。通常，可通过症状（发烧）监视和接触者追踪有效地遏制更多在人类之间传播的病原性病毒，例如SARS-CoV和最近的埃博拉病毒。尽管暴力冲突使刚果民主共和国持续控制埃博拉病毒爆发变得复杂，但尽管该病毒能有效地进行人与人之间的传播，但以前的所有爆发都是通过病例鉴定和接触者追踪来控制的。

我们目前尚不知道2019-nCoV在人与人之间的传播能力范围之内。但是可以肯定地说，如果这种病毒有效地传播，与SARS相比，其看起来较低的致病性，在特定情况下可能与超级传播者事件相结合，可以大规模传播。以这种方式，在个人层面上对健康构成低威胁的病毒可能在人口层面上构成高风险，并有可能造成全球公共卫生系统中断和经济损失。这种可能性保证了当前的积极反应，旨在追踪和诊断每个感染患者，从而打破了2019-nCoV的传播链。

需要通过分子检测和血清监测获得的有关该病毒的致病性和传播性的流行病学信息，以填写监视金字塔中的详细信息并指导对这种暴发的反应。此外，新型冠状病毒易于在医疗中心传播，这表明还需要外围医疗设施随时待命，以识别潜在病例。另外，在动物市场和其他动物设施上需要提高防范能力，同时正在研究这种新兴病毒的可能来源。如果我们以这些方式积极进取，也许我们将永远不必去发现2019-nCoV的真正流行或大流行潜力。

本文于2020年1月24日在NEJM.org上发布。

作者单位
来自美国国立卫生研究院国家过敏和传染病研究所病毒学实验室，密歇根州汉密尔顿（V.J.M.，N.D.，E.W.）;荷兰鹿特丹伊拉斯姆斯医学中心病毒科学系（M.K.，D.R.）。
3 回复 change? 2020-1-26 12:42
社论

又一个十年，又一个冠状病毒
作者列表。
斯坦利·珀尔曼（Stanley Perlman），医学博士

人畜共患冠状病毒已经是三十年来的第三次跨物种感染人类。该病毒临时称为2019-nCoV，最初在中国武汉被发现于暴露于海鲜或潮湿市场的人群中。中国公共卫生，临床和科学界的迅速反应促进了对临床疾病的认识和对感染流行病学的初步了解。最初的报道表明人与人之间的传播是有限的或不存在的，但是我们现在知道发生了这种传播，尽管在何种程度上尚不清楚。就像其他两种致病性人类呼吸道冠状病毒（严重急性呼吸综合征冠状病毒[SARS-CoV]和中东呼吸综合征冠状病毒[MERS-CoV]）引起的暴发一样，2019-nCoV引起的呼吸道疾病也很严重。1截至1月24日到2020年，报告的病例超过800个，死亡率为3％（https://promedmail.org/。在新标签中打开）。

正如《华尔街日报》报道的那样，Zhu等人2已经确定并表征了2019-nCoV。已对病毒基因组进行了测序，这些结果与其他报告一起显示，它与SARS-CoV的同源性为75％至80％，并且与几种蝙蝠冠状病毒的亲缘关系更为密切。3它可以在与有助于SARS-CoV和MERS-CoV的生长，但值得注意的是，与SARS-CoV或MERS-CoV不同，2019-nCoV在原代人气道上皮细胞中的生长要好于标准组织培养细胞。病毒的鉴定将允许开发试剂来解决有关这种新冠状病毒感染的关键未知因素，并指导抗病毒疗法的发展。首先，了解基因组序列有助于开发灵敏的定量逆转录酶-聚合酶链反应测定法，以快速检测病毒。其次，血清学检测方法的发展将允许评估在潮湿市场和其他环境中人类以及潜在的人畜共患病毒感染的流行率。由于整个中国都存在湿货市场，因此这些试剂也可用于评估人类感染是否比最初想象的更为广泛。第三，掌握病毒将刺激开发抗病毒疗法和疫苗以及实验动物模型的努力。

关于这种感染，仍然需要学习很多知识。最重要的是，需要确定人际传播的程度和临床疾病的范围。 SARS-CoV和MERS-CoV的传播在很大程度上是通过超级传播事件发生的。4,5超级传播事件与2019-nCoV传播有关，但它们的相对重要性未知。 SARS-CoV和MERS-CoV感染肺上皮细胞的程度均高于上呼吸道细胞[4,6]。因此，传播主要是从已确诊疾病的患者而不是轻度，非特异性体征的患者发生的。看来2019-nCoV使用与SARS-CoV相同的细胞受体（人类血管紧张素转换酶2 [hACE2]）3，因此只有在出现下呼吸道疾病的迹象后才有望传播。 SARS-CoV在2002-2004年的流行中发生了突变，可以更好地与其细胞受体结合并优化在人类细胞中的复制，从而提高毒力。7由于冠状病毒具有易于出错的RNA依赖性RNA聚合酶，因此容易发生适应，从而使突变和重组事件频繁发生。相比之下，自2012年被检测到以来，MERS-CoV并未发生实质性突变以增强人类感染力。

2019-nCoV的行为可能更像SARS-CoV，并通过增强与hACE2的结合进一步适应人类宿主。因此，重要的是要获得尽可能多的时间和地理上无关的临床分离株，以评估病毒突变的程度并评估这些突变是否表明对人宿主的适应性。此外，如果2019-nCoV与SARS-CoV相似，则该病毒会全身传播。9进行尸检时获取患者样本将有助于阐明感染的发病机制，并合理地调整治疗干预措施。它还将有助于验证从实验动物的实验性感染获得的结果。

第二个关键问题是病毒的人畜共患病源的鉴定。由于其与蝙蝠冠状病毒非常相似，因此蝙蝠可能是该病毒的主要宿主。 SARS-CoV是从湿市场中的外来动物传播给人类的，而MERS-CoV是从骆驼传播给人类的。10在这两种情况下，祖先的宿主都可能是蝙蝠。了解2019-nCoV是直接从蝙蝠传播还是通过中间宿主传播，对理解这一点很重要，这将有助于定义人畜共患病的传播方式。

SARS流行的一个显着特征是恐惧在经济和社会后果中起着重要作用。尽管仍在开发特定的抗冠状病毒疗法，但我们现在对如何控制社区和医院中的此类感染了解更多，这应该可以减轻这种恐惧。根据我们对SARS-CoV和MERS-CoV的经验，2019-nCoV的传播可能通过大液滴和接触发生，较少通过气溶胶和毒气传播.4,5公共卫生措施，包括隔离社区以及及时诊断和严格遵守医疗机构中的普遍预防措施，对于控制SARS和MERS至关重要。采取类似措施非常重要，希望能够成功减少2019-nCoV的传播。


该社论于2020年1月24日在NEJM.org上发布。

作者单位
来自爱荷华市爱荷华大学微生物学和免疫学系。
3 回复 change? 2020-1-26 12:59
Coronavirus Infections—More Than Just the Common Cold
Catharine I. Paules, MD1; Hilary D. Marston, MD, MPH2; Anthony S. Fauci, MD2
Author Affiliations Article Information
JAMA. Published online January 23, 2020. doi:10.1001/jama.2020.0757
Human coronaviruses (HCoVs) have long been considered inconsequential pathogens, causing the “common cold” in otherwise healthy people. However, in the 21st century, 2 highly pathogenic HCoVs—severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV)—emerged from animal reservoirs to cause global epidemics with alarming morbidity and mortality. In December 2019, yet another pathogenic HCoV, 2019 novel coronavirus (2019-nCoV), was recognized in Wuhan, China, and has caused serious illness and death. The ultimate scope and effect of this outbreak is unclear at present as the situation is rapidly evolving.

Coronaviruses are large, enveloped, positive-strand RNA viruses that can be divided into 4 genera: alpha, beta, delta, and gamma, of which alpha and beta CoVs are known to infect humans.1 Four HCoVs (HCoV 229E, NL63, OC43, and HKU1) are endemic globally and account for 10% to 30% of upper respiratory tract infections in adults. Coronaviruses are ecologically diverse with the greatest variety seen in bats, suggesting that they are the reservoirs for many of these viruses.2 Peridomestic mammals may serve as intermediate hosts, facilitating recombination and mutation events with expansion of genetic diversity. The surface spike (S) glycoprotein is critical for binding of host cell receptors and is believed to represent a key determinant of host range restriction.1

Until recently, HCoVs received relatively little attention due to their mild phenotypes in humans. This changed in 2002, when cases of severe atypical pneumonia were described in Guangdong Province, China, causing worldwide concern as disease spread via international travel to more than 2 dozen countries.2 The new disease became known as severe acute respiratory syndrome (SARS), and a beta-HCoV, named SARS-CoV, was identified as the causative agent. Because early cases shared a history of human-animal contact at live game markets, zoonotic transmission of the virus was strongly suspected.3 Palm civets and raccoon dogs were initially thought to be the animal reservoir(s); however, as more viral sequence data became available, consensus emerged that bats were the natural hosts.

Common symptoms of SARS included fever, cough, dyspnea, and occasionally watery diarrhea.2 Of infected patients, 20% to 30% required mechanical ventilation and 10% died, with higher fatality rates in older patients and those with medical comorbidities. Human-to-human transmission was documented, mostly in health care settings. This nosocomial spread may be explained by basic virology: the predominant human receptor for the SARS S glycoprotein, human angiotensin-converting enzyme 2 (ACE2), is found primarily in the lower respiratory tract, rather than in the upper airway. Receptor distribution may account for both the dearth of upper respiratory tract symptoms and the finding that peak viral shedding occurred late (≈10 days) in illness when individuals were already hospitalized. SARS care often necessitated aerosol-generating procedures such as intubation, which also may have contributed to the prominent nosocomial spread.

Several important transmission events did occur in the community, such as the well-characterized mini-outbreak in the Hotel Metropole in Hong Kong from where infected patrons traveled and spread SARS internationally. Another outbreak occurred at the Amoy Gardens housing complex where more than 300 residents were infected, providing evidence that airborne transmission of SARS-CoV can sometimes occur.4 Nearly 20 years later, the factors associated with transmission of SARS-CoV, ranging from self-limited animal-to-human transmission to human superspreader events, remain poorly understood.

Ultimately, classic public health measures brought the SARS pandemic to an end, but not before 8098 individuals were infected and 774 died.2 The pandemic cost the global economy an estimated $30 billion to $100 billion.1 SARS-CoV demonstrated that animal CoVs could jump the species barrier, thereby expanding perception of pandemic threats.

In 2012, another highly pathogenic beta-CoV made the species jump when Middle East respiratory syndrome (MERS) was recognized and MERS-CoV was identified in the sputum of a Saudi man who died from respiratory failure.3 Unlike SARS-CoV, which rapidly spread across the globe and was contained and eliminated in relatively short order, MERS has smoldered, characterized by sporadic zoonotic transmission and limited chains of human spread. MERS-CoV has not yet sustained community spread; instead, it has caused explosive nosocomial transmission events, in some cases linked to a single superspreader, which are devastating for health care systems. According to the World Health Organization (WHO), as of November 2019, MERS-CoV has caused a total of 2494 cases and 858 deaths, the majority in Saudi Arabia. The natural reservoir of MERS-CoV is presumed to be bats, yet human transmission events have primarily been attributed to an intermediate host, the dromedary camel.

MERS shares many clinical features with SARS such as severe atypical pneumonia, yet key differences are evident. Patients with MERS have prominent gastrointestinal symptoms and often acute kidney failure, likely explained by the binding of the MERS-CoV S glycoprotein to dipeptidyl peptidase 4 (DPP4), which is present in the lower airway as well as the gastrointestinal tract and kidney.3 MERS necessitates mechanical ventilation in 50% to 89% of patients and has a case fatality rate of 36%.2

While MERS has not caused the international panic seen with SARS, the emergence of this second, highly pathogenic zoonotic HCoV illustrates the threat posed by this viral family. In 2017, the WHO placed SARS-CoV and MERS-CoV on its Priority Pathogen list, hoping to galvanize research and the development of countermeasures against CoVs.

The action of the WHO proved prescient. On December 31, 2019, Chinese authorities reported a cluster of pneumonia cases in Wuhan, China, most of which included patients who reported exposure to a large seafood market selling many species of live animals. Emergence of another pathogenic zoonotic HCoV was suspected, and by January 10, 2020, researchers from the Shanghai Public Health Clinical Center & School of Public Health and their collaborators released a full genomic sequence of 2019-nCoV to public databases, exemplifying prompt data sharing in outbreak response. Preliminary analyses indicate that 2019-nCoV has some amino acid homology to SARS-CoV and may be able to use ACE2 as a receptor. This has important implications for predicting pandemic potential moving forward. The situation with 2019-nCoV is evolving rapidly, with the case count currently growing into the hundreds. Human-to-human transmission of 2019-nCoV occurs, as evidenced by the infection of 15 health care practitioners in a Wuhan hospital. The extent, if any, to which such transmission might lead to a sustained epidemic remains an open and critical question. So far, it appears that the fatality rate of 2019-nCoV is lower than that of SARS-CoV and MERS-CoV; however, the ultimate scope and effects of the outbreak remain to be seen.

Drawing on experience from prior zoonotic CoV outbreaks, public health authorities have initiated preparedness and response activities. Wuhan leaders closed and disinfected the first identified market. The United States and several other countries have initiated entry screening of passengers from Wuhan at major ports of entry. Health practitioners in other Chinese cities, Thailand, Japan, and South Korea promptly identified travel-related cases, isolating individuals for further care. The first travel-related case in the United States occurred on January 21 in a young Chinese man who had visited Wuhan.

Additionally, biomedical researchers are initiating countermeasure development for 2019-nCoV using SARS-CoV and MERS-CoV as prototypes. For example, platform diagnostic modalities are being rapidly adapted to include 2019-nCoV, allowing early recognition and isolation of cases. Broad-spectrum antivirals, such as remdesivir, an RNA polymerase inhibitor, as well as lopinavir/ritonavir and interferon beta have shown promise against MERS-CoV in animal models and are being assessed for activity against 2019-nCoV.5 Vaccines, which have adapted approaches used for SARS-CoV or MERS-CoV, are also being pursued. For example, scientists at the National Institute of Allergy and Infectious Diseases Vaccine Research Center have used nucleic acid vaccine platform approaches.6 During SARS, researchers moved from obtaining the genomic sequence of SARS-CoV to a phase 1 clinical trial of a DNA vaccine in 20 months and have since compressed that timeline to 3.25 months for other viral diseases. For 2019-nCoV, they hope to move even faster, using messenger RNA (mRNA) vaccine technology. Other researchers are similarly poised to construct viral vectors and subunit vaccines.

While the trajectory of this outbreak is impossible to predict, effective response requires prompt action from the standpoint of classic public health strategies to the timely development and implementation of effective countermeasures. The emergence of yet another outbreak of human disease caused by a pathogen from a viral family formerly thought to be relatively benign underscores the perpetual challenge of emerging infectious diseases and the importance of sustained preparedness.

Back to topArticle Information
Corresponding Author: Anthony S. Fauci, MD, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, 31 Center Dr, MSC 2520, Bldg 31, Room 7A-03, Bethesda, MD 20892-2520 (afauci@niaid.nih.gov).

Published Online: January 23, 2020. doi:10.1001/jama.2020.0757
3 回复 change? 2020-1-26 13:03
冠状病毒感染—不仅仅是普通感冒
凯瑟琳·鲍尔斯（MD1）；希拉里·马斯顿（Hilary D.Marston），医学博士，MPH2；安东尼·福西（MD2）
作者所属文章信息
贾玛在线发布于2020年1月23日。doi：10.1001 / jama.2020.0757
人类冠状病毒（HCoV）长期以来一直被认为是无关紧要的病原体，在原本健康的人中引起“普通感冒”。然而，在21世纪，动物蓄水池中出现了2种高致病性HCoV，即严重的急性呼吸综合症冠状病毒（SARS-CoV）和中东呼吸综合症冠状病毒（MERS-CoV），导致全球流行，其发病率和死亡率令人震惊。 2019年12月，另一种致病性HCoV，即2019年新型冠状病毒（2019-nCoV）在中国武汉被确认，已造成严重的疾病和死亡。随着局势的迅速发展，目前尚不清楚该暴发的最终范围和影响。

冠状病毒是大型的，有包膜的正链RNA病毒，可分为4个属：α，β，δ和γ，其中已知α和βCoV感染人类。1四种HCoV（HCoV 229E，NL63，OC43 ，和HKU1）是全球性流行病，占成年人上呼吸道感染的10％至30％。冠状病毒在生态上是多样的，在蝙蝠中观察到的种类最多，表明它们是这些病毒中许多病毒的贮藏库。2周生哺乳动物可作为中间宿主，促进重组和突变事件，并扩大遗传多样性。表面刺突糖蛋白对宿主细胞受体的结合至关重要，被认为是限制宿主范围的关键因素。1

直到最近，由于HCoV在人类中的表型较轻，因此受到的关注相对较少。这种情况在2002年发生了变化，当时在中国广东省描述了严重的非典型肺炎病例，引起了全世界的关注，因为该疾病是通过国际旅行传播到2多个国家/地区。2这种新疾病被称为严重急性呼吸道综合症（SARS）， β-HCoV（称为SARS-CoV）被确定为病原体。由于早期病例在现场游戏市场上有人类-动物接触的历史，因此强烈怀疑该病毒的人畜共患性传播。3最初认为棕榈c和狗是动物的水库。然而，随着更多病毒序列数据的出现，人们逐渐达成共识，蝙蝠是自然宿主。
SARS的常见症状包括发烧，咳嗽，呼吸困难，偶尔还有水样腹泻。2在感染患者中，有20％至30％的患者需要机械通气，有10％死亡，老年患者和患有合并症的患者死亡率更高。人与人之间的传播已有记录，主要是在卫生保健机构中。这种医院传播可能是由基本病毒学解释的：SARS S糖蛋白的主要人类受体，即人类血管紧张素转换酶2（ACE2），主要在下呼吸道而不是上呼吸道中发现。受体的分布可能既解释了上呼吸道症状的缺乏，又解释了当患者已经住院时，病毒的高峰释放发生在疾病的晚期（约10天）。 SARS护理通常需要气雾生成程序（例如插管），这也可能导致医院内广泛传播。

社区确实发生了几起重要的传播事件，例如，在香港大都会酒店中，特征鲜明的小型暴发流行，受感染的顾客从那里传播并在国际上传播SARS。另一个暴发发生在淘大花园住宅区，有300多名居民受到感染，这提供了有时可发生SARS-CoV空中传播的证据。4近20年后，与SARS-CoV传播有关的因素包括自有限的从动物到人类的传播给人类超级传播者的事件仍然知之甚少。

最终，经典的公共卫生措施终结了SARS的大流行，但在8098人被感染并造成774人死亡之前未曾发生。2大流行使全球经济损失了300亿至1000亿美元。1SARS-CoV证明动物冠状病毒可能会跳跃物种屏障，从而扩大了对大流行威胁的认识。

2012年，另一种高致病性的β-CoV在识别出中东呼吸综合症（MERS）并在一名因呼吸衰竭而死亡的沙特男子的痰液中发现了MERS-CoV时使该物种跳跃。3与SARS-CoV迅速MERS散布在全球各地，并在相对较短的时间内被遏制和消除，其特征是零散的人畜共患病传播和有限的人类传播链。 MERS-CoV尚未持续传播社区；相反，它引起了爆炸性的医院传播事件，在某些情况下与单个超级吊具有关，这对医疗保健系统造成了灾难性的破坏。根据世界卫生组织（WHO）的数据，截至2019年11月，MERS-CoV总共造成2494例病例和858例死亡，其中大部分在沙特阿拉伯。 MERS-CoV的天然库被认为是蝙蝠，但人类传播事件主要归因于中间宿主，即单峰骆驼。
MERS与SARS具有许多临床特征，例如严重的非典型肺炎，但主要区别显而易见。患有MERS的患者具有明显的胃肠道症状，并常常出现急性肾功能衰竭，这可能是由于MERS-CoV S糖蛋白与下呼吸道以及胃肠道和肾脏中存在的二肽基肽酶4（DPP4）结合所致。中东呼吸综合征需要50％至89％的患者进行机械通气，病死率为36％.2

尽管MERS并未引起SARS引起的国际恐慌，但第二种高致病性人畜共患病毒HCoV的出现说明了该病毒家族的威胁。 2017年，世卫组织将SARS-CoV和MERS-CoV列入其优先病原体名单，希望借此激发研究和制定针对CoV的对策。

世卫组织的行动证明是有先见之明的。 2019年12月31日，中国当局报告了中国武汉市发生的一系列肺炎病例，其中大多数病例报告有暴露于出售许多活体动物的大型海鲜市场的患者。怀疑另一种致病性人畜共患病毒HCoV的出现，到2020年1月10日，上海公共卫生临床中心和公共卫生学院的研究人员及其合作者向公共数据库发布了完整的2019-nCoV基因组序列，证明了在爆发反应。初步分析表明，2019-nCoV与SARS-CoV具有某些氨基酸同源性，并且可能能够使用ACE2作为受体。这对于预测大流行潜力的发展具有重要意义。 2019-nCoV的情况正在迅速发展，目前案件数已增加到数百个。武汉市一家医院的15名医疗保健从业人员感染证明了2019-nCoV的人际传播。这种传播可能导致持续流行的程度（如果有的话）仍然是一个悬而未决的关键问题。到目前为止，看来2019-nCoV的死亡率低于SARS-CoV和MERS-CoV的死亡率;但是，爆发的最终范围和影响尚待观察。

借鉴先前人畜共患病暴发的经验，公共卫生当局已启动了备灾和应对活动。武汉市领导关闭并消毒了第一个确定的市场。美国和其他几个国家已经开始对主要入境口岸武汉的旅客进行入境检查。其他中国城市（泰国，日本和韩国）的卫生从业人员迅速发现了与旅行有关的病例，隔离了个体以进行进一步护理。美国首例与旅行有关的案件发生在1月21日，发生在一名年轻的中国男子，他去了武汉。
此外，生物医学研究人员正在以SARS-CoV和MERS-CoV为原型开始针对2019-nCoV的对策开发。例如，平台诊断模式正在迅速适应包括2019-nCoV的功能，从而可以及早识别和隔离病例。广谱抗病毒药，例如remdesivir，一种RNA聚合酶抑制剂以及lopinavir / ritonavir和干扰素beta在动物模型中显示出抗MERS-CoV的前景，并正在评估其对2019-nCoV.5疫苗的活性。也正在追求用于SARS-CoV或MERS-CoV的方法。例如，美国国家过敏和传染病研究所疫苗研究中心的科学家已经使用了核酸疫苗平台方法。6在SARS期间，研究人员从获得SARS-CoV的基因组序列转向了DNA疫苗的1期临床试验。自20个月以来，对于其他病毒性疾病，该时间表已缩短为3.25个月。对于2019-nCoV，他们希望使用Messenger RNA（mRNA）疫苗技术更快地发展。类似地，其他研究人员也准备构建病毒载体和亚单位疫苗。

尽管无法预测这种暴发的轨迹，但要从经典的公共卫生策略的角度出发，要迅速采取行动，就必须及时采取行动，并及时制定和实施有效的对策。以前被认为是相对良性的病毒家族病原体引起的另一次人类疾病暴发凸显了新兴传染病的长期挑战以及持续防备的重要性。

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通讯作者：美国国家过敏和传染病研究所免疫调节实验室Anthony S.Fauci博士，MSC 2520中心博士，MSC 2520，Bldg 31，Bethesda，7A-03室，MD 20892-2520（afauci@niaid.nih。 gov）。

在线发布：2020年1月23日。doi：10.1001 / jama.2020.0757

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