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·搜一搜.cn/《柳叶刀》最新“新冠”研究：有基础疾病的患者比例扩大 基因与“舟山蝙蝠”最相似

《柳叶刀》最新“新冠”研究：有基础疾病的患者比例扩大 基因与“舟山蝙蝠”最相似


《柳叶刀》最新“新冠”研究：有基础疾病的患者比例扩大 基因与“舟山蝙蝠”最相似

北京时间1月30日，《柳叶刀》在线发表（Published Online，January 29, 2020）两篇关于新型冠状病毒的最新论文。一篇为《99例武汉市新型冠状病毒性肺炎流行病学和临床特征》，一篇为《2019年新型冠状病毒的基因组表征和流行病学》。

99例患者分析
自2019年12月8日以来，中国湖北省武汉市报告了几例病因不明的肺炎。大多数患者在当地的华南海鲜批发市场工作或居住，该市场出售活体动物。在这种肺炎的早期阶段，发生了严重的急性呼吸道感染症状，一些患者迅速发展为急性呼吸窘迫综合征（ARDS），急性呼吸衰竭和其他严重并发症。1月7日，中国疾病预防控制中心（CDC）从患者的咽拭子样本中鉴定出一种新型冠状病毒，随后被WHO命名为2019-nCoV。冠状病毒可引起多种动物的多系统感染，主要是人的呼吸道感染，例如严重急性呼吸道综合症（SARS）和中东呼吸综合症（MERS）。大多数患者的症状较轻，预后良好。
到目前为止，一些2019-nCoV患者已经出现严重的肺炎、肺水肿、ARDS或多器官功能衰竭并死亡。2019-nCoV治疗的所有费用均由中国的医疗保险支付。目前，关于由2019-nCoV引起的肺炎的流行病学和临床特征的信息很少。在这项研究中，我们对99例确诊为2019-nCoV肺炎的患者的流行病学和临床特征进行了全面探索。由武汉金银潭医院收治，该院收治了首例2019-nCoV患者。此前一周，《柳叶刀》在线发表了41例“新冠”确诊感染的病例。新的文章所分析的病例数升至99例。在研究中，纳入了2020年1月1日至2020年1月20日在武汉市金银潭医院确诊的2019-nCoV病例。通过实时RT-PCR确诊病例，并对其流行病学，人口统计学，临床和放射学特征以及实验室数据。结果随访至2020年1月25日。
该研究在四个不同的机构完成了2019-nCoV的实验室确认：中国疾病预防控制中心，中国医学科学院，军事医学科学院和中国科学院武汉病毒学研究所。从入院时所有患者获得的上呼吸道咽拭子标本保存在病毒运输培养基中。使用之前描述的相同协议通过实时RT-PCR确认了2019-nCoV。这四个机构提供了RT-PCR检测试剂。还使用实时RT检测了其他呼吸道病毒，包括甲型流感病毒（H1N1，H3N2，H7N9），乙型流感病毒，呼吸道合胞病毒，副流感病毒，腺病毒，SARS冠状病毒（SARS-CoV）和MERS冠状病毒（MERS-CoV）。此外，所有患者均接受了胸部X光检查或胸部CT检查。
该研究纳入了99例2019-nCoV患者，其中两个是夫妻。研究结果显示：在99名患者中，有49名（49％）曾有过华南海鲜市场市场接触史。其中，有47名具有长期接触史，大多数是销售员或市场经理，还有两名具有短期接触历史的患者是购物者。所有患者均不是医务人员，大多数患者是男性，平均年龄为55.5岁，包括67名男性和32名女性。
50名（51％）患者患有慢性疾病。包括心脑血管疾病，内分泌系统疾病，消化系统疾病，呼吸系统疾病，恶性肿瘤和神经系统疾病。此前41例患者患有基础疾病的比例为32%，此次占比有所上升。入院时，大多数患者发烧或咳嗽，三分之一的患者呼吸急促。患者的临床表现为发烧（82 例，占83％），咳嗽（81例，82％），呼吸急促（31例，31％），肌肉疼痛（11例，11％），精神错乱（9例，9％），头痛（8例，8％），喉咙痛（5例，5％），鼻涕（4例，4％），胸痛（2例，2％），腹泻（2例，2％），恶心和呕吐（1例，1％）。
许多患者出现器官功能损害，包括17例（17％）的ARDS，8例（8％）的急性呼吸系统损伤，3例（3％）的急性肾损伤，4例（4％）的败血性休克和1例（1％）伴呼吸机相关性肺炎。根据影像学检查，有74例患者（75％）显示双侧肺炎，14名（14％）患者表现出多处斑驳和毛玻璃样混浊，并且一名患者患有气胸。17例（17％）患者发展为急性呼吸窘迫综合征，其中11例（11％）患者在短时间内恶化并死于多器官功能衰竭。
研究发现，新型冠状病毒更可能影响有综合病症的老年男性，并可能导致严重甚至致命的呼吸系统疾病。通常，死亡患者的特征与MuLBSTA评分相符，MuLBSTA评分是预测病毒性肺炎死亡率的预警模型。男性居多、年龄偏大、具有基础疾病的人群占比较高，这些结果与此前的分析一致。
与“舟山蝙蝠”相似度88%第二篇从新型冠状病毒的基因组序列分析，探讨了病毒起源问题。
研究者称，对来自9例住院患者的支气管肺泡灌洗液和培养分离物的样品进行了测序，其中8例曾去过武汉的华南海鲜市场。从这些个体获得了完整的和部分的2019-nCoV基因组序列。对这些2019-nCoV基因组和其他冠状病毒基因组进行了系统进化分析，以确定该病毒的进化史并有助于推断其可能的起源。进行同源性建模以探索病毒的可能的受体结合特性。
结果显示，从九名患者获得的十个2019-nCoV基因组序列极其相似，表现出超过99·98％的序列同一性。值得注意的是，2019-nCoV与2018年在中国东部舟山采集的两种蝙蝠源性严重急性呼吸综合征（SARS）样冠状病毒bat-SL-CoVZC45和bat-SL-CoVZXC21密切相关（同一性为88％），但与SARS-CoV（约79％）和MERS-CoV（约50％）距离较远，也就是没那么像。系统发育分析表明，2019-nCoV属于Betacoronavirus属的Sarbecovirus亚型，其最接近的亲属bat-SL-CoVZC45和bat-SL-CoVZXC21的分支长度相对较长，并且在遗传学上与SARS-CoV不同。值得注意的是，同源性建模显示，2019-nCoV具有与SARS-CoV相似的受体结合结构域结构，尽管某些关键残基处存在氨基酸差异。
2019-nCoV与SARS-CoV的差异很大，可以被认为是一种新型的人类感染性乙型冠状病毒。尽管我们的系统发育分析表明，蝙蝠可能是该病毒的原始宿主，但武汉海鲜市场上出售的动物可能是促进该病毒在人体内出现的中间宿主。重要的是，结构分析表明2019-nCoV可能能够与人类的血管紧张素转化酶2受体结合。该病毒的未来进化、适应和传播需要紧急调查。在最后的探讨部分，作者们给出了流行病学方面的认识：我们研究的9名患者中有8名有接触武汉华南海鲜市场的历史，表明他们可能与市场上的感染源密切接触。但是，尽管有一名患者在疾病发作之前就住在市场附近的一家旅馆里，但从未去过市场。该发现表明可能有当前未知的来源感染。
另一方面，尽管新型冠状病毒和蝙蝠中分离出的病毒序列相似度最高，但作者们认为不太可能直接从蝙蝠传染给人类，而是有中间宿主。“尽管蝙蝠很重要，但一些事实表明另一种动物正在充当蝙蝠与人类之间的中间宿主。”理由是，首先，该疫情爆发于2019年12月下旬，当时武汉大多数蝙蝠物种正在冬眠。其次，在华南海鲜市场上没有出售或发现蝙蝠，而有各种非水生动物（包括哺乳动物）可供购买。第三，2019-nCoV与其近亲bat-SL-CoVZC45和bat-SL-CoVZXC21之间的序列同一性小于90％，这反映在它们之间相对较长的分支上。因此，bat-SL-CoVZC45和bat-SL-CoVZXC21不是2019-nCoV的直接祖先。第四，在SARS-CoV和MERS-CoV中，蝙蝠都是天然的宿主，另一种动物（SARS-CoV35的果子狸和MERS-CoV的骆驼）则作为中间宿主，人类是末端宿主。
因此，根据目前的数据，造成武汉爆发的2019-nCoV病毒似乎也可能最初是由蝙蝠宿主的，并且可能已经通过在华南海鲜市场出售的目前未知的野生动物传播给了人类。感染家庭成员和医务人员的群集证据现已证实存在人际传播。显然，这种感染是主要的公共卫生问题，特别是因为这次暴发恰逢中国春节旅游高峰期，在此期间，成千上万人将穿越中国。
作为一种典型的RNA病毒，冠状病毒的平均进化速度约为每个位点每年10个核苷酸取代，每个复制周期都会产生突变。因此，令人惊讶的是，此处描述的来自不同患者的2019-nCoV序列几乎相同，具有大于99.9％的序列同一性。这一发现表明，2019-nCoV在很短的时间内就起源于一个来源，并且被相对迅速地检测到。但是，随着病毒传播给更多的人，需要对突变的不断监测。
总之，我们已经描述了第七种人类冠状病毒的基因组结构，它可以引起严重的肺炎，并阐明其起源和受体结合特性。更普遍的是，与2019-nCoV相关的疾病暴发再次凸显了野生动物中隐藏的病毒库以及它们偶尔扩散到人群中的潜力。

新浪财经APP  2020年01月30日 16:05 21世纪经济报道
原标题：《柳叶刀》最新“新冠”研究：有基础疾病的患者比例扩大 基因与“舟山蝙蝠”最相似
https://tech.sina.com.cn/roll/2020-01-30/doc-iimxxste7667841.shtml
 柳叶刀



Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding
Roujian Lu, Xiang Zhao, Juan Li, Peihua Niu, Bo Yang, Honglong Wu, and others
The Lancet
Published: January 30, 2020
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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.[/p]
Introduction

Viruses of the family Coronaviridae possess a single-strand, positive-sense RNA genome ranging from 26 to 32 kilobases in length.
1Coronaviruses have been identified in several avian hosts,2,  3 as well as in various mammals, including camels, bats, masked palm civets, mice, dogs, and cats. Novel mammalian coronaviruses are now regularly identified.1 For example, an HKU2-related coronavirus of bat origin was responsible for a fatal acute diarrhoea syndrome in pigs in 2018.4Among the several coronaviruses that are pathogenic to humans, most are associated with mild clinical symptoms,1 with two notable exceptions: severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), a novel betacoronavirus that emerged in Guangdong, southern China, in November, 2002,5 and resulted in more than 8000 human infections and 774 deaths in 37 countries during 2002–03;6and Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), which was first detected in Saudi Arabia in 20127 and was responsible for 2494 laboratory-confirmed cases of infection and 858 fatalities since September, 2012, including 38 deaths following a single introduction into South Korea.8,  9




Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study
Nanshan Chen, Min Zhou, Xuan Dong, Jieming Qu, Fengyun Gong, Yang Han, and others
The Lancet
Published: January 30, 2020
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Summary
Background
In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia.

Methods
In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020.

Findings
Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure.

Interpretation
The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection.

Funding
National Key R&D Program of China.

Introduction
Since Dec 8, 2019, several cases of pneumonia of unknown aetiology have been reported in Wuhan, Hubei province, China.1,  2,  3 Most patients worked at or lived around the local Huanan seafood wholesale market, where live animals were also on sale. In the early stages of this pneumonia, severe acute respiratory infection symptoms occurred, with some patients rapidly developing acute respiratory distress syndrome (ARDS), acute respiratory failure, and other serious complications. On Jan 7, a novel coronavirus was identified by the Chinese Center for Disease Control and Prevention (CDC) from the throat swab sample of a patient, and was subsequently named 2019-nCoV by WHO.4
Coronaviruses can cause multiple system infections in various animals and mainly respiratory tract infections in humans, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).5,  6,  7 Most patients have mild symptoms and good prognosis. So far, a few patients with 2019-nCoV have developed severe pneumonia, pulmonary oedema, ARDS, or multiple organ failure and have died. All costs of 2019-nCoV treatment are covered by medical insurance in China.
At present, information regarding the epidemiology and clinical features of pneumonia caused by 2019-nCoV is scarce.1,  2,  3 In this study, we did a comprehensive exploration of the epidemiology and clinical features of 99 patients with confirmed 2019-nCoV pneumonia admitted to Jinyintan Hospital, Wuhan, which admitted the first patients with 2019-nCoV to be reported on.[/p][p]

Methods
Study design and participants
For this retrospective, single-centre study, we recruited patients from Jan 1 to Jan 20, 2020, at Jinyintan Hospital in Wuhan, China. Jinyintan Hospital is a hospital for adults (ie, aged ≥14 years) specialising in infectious diseases. According to the arrangements put in place by the Chinese Government, adult patients were admitted centrally to the hospital from the whole of Wuhan without selectivity. All patients at Jinyintan Hospital who were diagnosed as having 2019-nCoV pneumonia according to WHO interim guidance were enrolled in this study.
4 All the data of included cases have been shared with WHO. The study was approved by Jinyintan Hospital Ethics Committee and written informed consent was obtained from patients involved before enrolment when data were collected retrospectively.
Research in contextEvidence before this study
We searched PubMed on Jan 25, 2020, for articles that describe the epidemiological and clinical characteristics of the 2019 novel coronavirus (2019-nCoV) in Wuhan, China, using the search terms “novel coronavirus” and “pneumonia” with no language or time restrictions. Previously published research discussed the epidemiological and clinical characteristics of severe acute respiratory syndrome coronavirus or Middle East respiratory syndrome coronavirus, and primary study for the evolution of the novel coronavirus from Wuhan. The only report of clinical features of patients infected with 2019-nCoV was published on Jan 24, 2020, with 41 cases included.Added value of this studyWe have obtained data on 99 patients in Wuhan, China, to further explore the epidemiology and clinical features of 2019-nCoV. This study is, to our knowledge, the largest case series to date of 2019-nCoV infections, with 99 patients who were transferred to Jinyintan Hospital from other hospitals all over Wuhan, and provides further information on the demographic, clinical, epidemiological, and laboratory features of patients. It presents the latest status of 2019-nCoV infection in China and is an extended investigation of the previous report, with 58 extra cases and more details on combined bacterial and fungal infections. In all patients admitted with medical comorbidities of 2019-nCoV, a wide range of clinical manifestations can be seen and are associated with substantial outcomes.Implications of all the available evidence
The 2019-nCoV infection was of clustering onset, is more likely to affect older men with comorbidities, and could result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. Early identification and timely treatment of critical cases of 2019-nCoV are important. Effective life support and active treatment of complications should be provided to effectively reduce the severity of patients' conditions and prevent the spread of this new coronavirus in China and worldwide.[/p][p]
Procedures
We obtained epidemiological, demographic, clinical, laboratory, management, and outcome data from patients' medical records. Clinical outcomes were followed up to Jan 25, 2020. If data were missing from the records or clarification was needed, we obtained data by direct communication with attending doctors and other health-care providers. All data were checked by two physicians (XD and YQ).
Laboratory confirmation of 2019-nCoV was done in four different institutions: the Chinese CDC, the Chinese Academy of Medical Science, Academy of Military Medical Sciences, and Wuhan Institute of Virology, Chinese Academy of Sciences. Throat-swab specimens from the upper respiratory tract that were obtained from all patients at admission were maintained in viral-transport medium. 2019-nCoV was confirmed by real-time RT-PCR using the same protocol described previously.3 RT-PCR detection reagents were provided by the four institutions. Other respiratory viruses including influenza A virus (H1N1, H3N2, H7N9), influenza B virus, respiratory syncytial virus, parainfluenza virus, adenovirus, SARS coronavirus (SARS-CoV), and MERS coronavirus (MERS-CoV) were also examined with real-time RT-PCR
Sputum or endotracheal aspirates were obtained at admission for identification of possible causative bacteria or fungi. Additionally, all patients were given chest x-rays or chest CT.[/p][p]

Outcomes
We describe epidemiological data (ie, short-term [occasional visits] and long-term [worked at or lived near] exposure to Huanan seafood market); demographics; signs and symptoms on admission; comorbidity; laboratory results; co-infection with other respiratory pathogens; chest radiography and CT findings; treatment received for 2019-nCoV; and clinical outcomes.[/p][p]

Statistical analysis
We present continuous measurements as mean (SD) if they are normally distributed or median (IQR) if they are not, and categorical variables as count (%). For laboratory results, we also assessed whether the measurements were outside the normal range. We used SPSS (version 26.0) for all analyses.[/p][p]

Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.[/p][/p][p]

Results
99 patients with 2019-nCoV were included in this study, two of whom were husband and wife. In total, 49 (49%) patients were clustered and had a history of exposure to the Huanan seafood market. Among them, there were 47 patients with long-term exposure history, most of whom were salesmen or market managers, and two patients with short-term exposure history, who were shoppers. None of the patients were medical staff. Most patients were men, with a mean age of 55·5 years (SD 13·1; table 1). 50 (51%) patients had chronic diseases, including cardiovascular and cerebrovascular diseases, endocrine system disease, digestive system disease, respiratory system disease, malignant tumour, and nervous system disease (table 1).[/p]

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30211-7/fulltext