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鐘南山團隊新冠病毒最新論文:潛伏期最長24天,與肺炎關系待考

時間:2020-03-01 來源:新英格蘭醫學雜志 作者:鐘南山等 本文字數:17787字

  當地時間2月28日,由國家衛健委高級別專家組組長、中國工程院院士鐘南山領銜的“中國2019新型冠狀病毒疾病的臨床特征”研究論文在頂級醫學期刊《新英格蘭醫學雜志》(NEJM)上在線公開發表。該研究納入了來自2019年12月11日至2020年1月29日來自全國31個省(市)共552家醫院的1099例確診新冠肺炎患者。中英文全文如下,文后附英文原文免費下載!

Clinical characteristics of 2019 novel coronavirus infection in China

2019年中國新型冠狀病毒感染的臨床特點

Abstract

摘  要

  Background: Since December 2019, acute respiratory disease (ARD) due to 2019 novel coronavirus (2019-nCoV) emerged in Wuhan city and rapidly spread throughout China. We sought to delineate the clinical characteristics of these cases.

  背景:自2019年12月以來,武漢市出現了由2019年新型冠狀病毒(2019-nCoV)引起的急性呼吸系統疾病(ARD),并迅速在中國各地蔓延。我們試圖描述這些病例的臨床特征。

  Methods: We extracted the data on 1,099 patients with laboratory-confirmed 2019-nCoV ARD from 552 hospitals in 31 provinces/provincial municipalities through January 29th, 2020.

  方法:從31個省(市)的552家醫院抽取到2020年1月29日的1099例實驗室確診病例資料。

  Results: The median age was 47.0 years, and 41.90% were females. Only 1.18% of patients had a direct contact with wildlife, whereas 31.30% had been to Wuhan and 71.80% had contacted with people from Wuhan. Fever (87.9%) and cough (67.7%) were the most common symptoms. Diarrhea is uncommon. The median incubation period was 3.0 days (range, 0 to 24.0 days)。 On admission, ground-glass opacity was the typical radiological finding on chest computed tomography (50.00%)。 Significantly more severe cases were diagnosed by symptoms plus reverse-transcriptase polymerase-chain-reaction without abnormal radiological findings than non-severe cases (23.87% vs. 5.20%, P<0.001)。 Lymphopenia was observed in 82.1% of patients. 55 patients (5.00%) were admitted to intensive care unit and 15 (1.36%) succumbed. Severe pneumonia was independently associated with either the admission to intensive care unit, mechanical ventilation, or death in multivariate competing-risk model (sub-distribution hazards ratio, 9.80; 95% confidence interval, 4.06 to 23.67)。

  結果:中位年齡47.0歲,女性41.90%.只有1.18%的患者直接接觸過野生動物,31.30%的患者去過武漢,71.80%的患者接觸過武漢人。發熱(87.9%)和咳嗽(67.7%)是最常見的癥狀。腹瀉是不常見的。中位潛伏期為3.0天(0-24.0天)。入院時,磨玻璃樣陰影是胸部電腦斷層攝影的典型影像學表現(50.00%)。癥狀加逆轉錄聚合酶鏈反應無異常影像學表現的危重病例明顯多于非危重病例(23.87%對5.20%,P<0.001)。82.1%的患者出現淋巴細胞減少。55例(5.00%)進入重癥監護病房,15例(1.36%)死亡。在多元競爭風險模型中,重癥肺炎與重癥監護病房入院、機械通氣或死亡獨立相關(亞分布危險比,9.80;95%可信區間,4.06至23.67)。

  Conclusions: The 2019-nCoV epidemic spreads rapidly by human-to-human transmission. Normal radiologic findings are present among some patients with 2019-nCoV infection. The disease severity (including oxygen saturation, respiratory rate, blood leukocyte/lymphocyte count and chest X-ray/CT manifestations) predict poor clinical outcomes.

  結論:2019年nCoV疫情通過人傳人傳播迅速。部分2019例nCoV感染患者的影像學表現正常。疾病的嚴重程度(包括血氧飽和度、呼吸頻率、白細胞/淋巴細胞計數和胸部X線/CT表現)預示著不良的臨床結果。

  Key words: 2019 novel coronavirus; acute respiratory disease; transmission; mortality; risk factor

  關鍵詞:2019年新冠狀病毒;急性呼吸道疾病;傳染;死亡率;風險因素

  Abstract: 249 words; main text: 2677 words

  摘要:249字;正文:2677字

  Funding: Supported by Ministry of Science and Technology, National Health Commission, National Natural Science Foundation, Department of Science and Technology of Guangdong Province.

  經費來源:科技部、國家衛生委員會、國家自然科學基金、廣東省科技廳。

  Conflict of interest: None declared.

  利益沖突:未聲明。

  Running head: 2019-nCoV in China

  運行負責人:2019中國nCoV
 

鐘南山研究團隊
 

配圖:鐘南山研究團隊

  1. Introduction

  1、引言

  In early December 2019, the first pneumonia cases of unknown origins were identified in Wuhan city, Hubei province, China [1]. High-throughput sequencing has revealed a novel betacoronavirus that is currently named 2019 novel coronavirus (2019-nCoV) [2], which resembled severe acute respiratory syndrome coronavirus (SARS-CoV) [3]. The 2019-nCoV is the seventh member of enveloped RNA coronavirus (subgenus sarbecovirus, Orthocoronavirinae subfamily) [3]. Evidence pointing to the person-to-person transmission in hospital and family settings has been accumulating [4-8].

  2019年12月初,中國湖北省武漢市首次發現不明原因肺炎病例。高通量測序發現一種新型冠狀病毒,目前命名為2019年新型冠狀病毒(2019- ncov)[2],與嚴重急性呼吸綜合征冠狀病毒(SARS-CoV)[3]相似。2019-nCoV是包膜RNA冠狀病毒(sarbecvirus亞屬,Orthocoronavirinae亞科)[3]的第七成員。越來越多的證據表明,在醫院和家庭環境中存在人際傳播[4-8].

  The World Health Organization has recently declared the 2019-nCoV a public health emergency of international concern [9]. As of February 5th, 2020, 24,554 laboratory-confirmed cases have been documented globally (i.e., the USA, Vietnam, Germany) [5,6,9,10]. 28,018 laboratory-confirmed cases and 563 death cases in China as of February 6th, 2020 [11]. Despite the rapid spread worldwide, the clinical characteristics of 2019-nCoV acute respiratory disease (ARD) remain largely unclear. In two recent studies documenting the clinical manifestations of 41 and 99 patients respectively with laboratory-confirmed 2019-nCoV ARD who were admitted to Wuhan, the severity of some cases with 2019-nCoV ARD mimicked that of SARS-CoV [1,12]. Given the rapid spread of 2019-nCoV, an updated analysis with significantly larger sample sizes by incorporating cases throughout China is urgently warranted. This will not only identify the defining epidemiological and clinical characteristics with greater precision, but also unravel the risk factors associated with mortality. Here, by collecting the data from 1,099 laboratory-confirmed cases, we sought to provide an up-to-date delineation of the epidemiological and clinical characteristics of patients with 2019-nCoV ARD throughout mainland China.

  世界衛生組織最近宣布2019-nCoV為國際關注的突發公共衛生事件。截至2020年2月5日,全球共有24,554例實驗室確診病例(即,美國,越南,德國)[5,6,9,10].截至2020年2月6日,中國實驗室確診病例28018例,死亡病例563例。盡管在全球范圍內迅速傳播,但2019-nCoV急性呼吸道疾病(ARD)的臨床特征仍不清楚。最近的兩項研究分別記錄了實驗室確診的2019-nCoV ARD的41例和99例的臨床表現,其中部分2019-nCoV ARD的嚴重程度與SARS-CoV相似[1,12].鑒于2019-nCoV的迅速傳播,迫切需要通過納入中國各地的病例更新分析,使樣本量大大增加。這不僅將更精確地確定確定的流行病學和臨床特征,而且還將揭示與死亡率相關的危險因素。在此,通過收集1099例實驗室確診病例的數據,我們試圖為中國大陸2019-nCoV ARD患者的流行病學和臨床特征提供最新的描述。

  2. Methods Data sources

  2、研究方法與數據來源

  We performed a retrospective study on the clinical characteristics of laboratory-confirmed cases with 2019-nCoV ARD. The initial cases were diagnosed as having 'pneumonia of unknown etiology', based on the clinical manifestations and chest radiology after exclusion of the common bacteria or viruses associated with community-acquired pneumonia. Suspected cases were identified as having fever or respiratory symptoms, and a history of exposure to wildlife in Wuhan seafood market, a travel history or contact with people from Wuhan within 2 weeks [13]. Cases were diagnosed based on the WHO interim guidance [14]. A confirmed case with 2019-nCoV ARD was defined as a positive result to high-throughput sequencing or real-time reverse-transcriptase polymerase-chain-reaction (RT-PCR) assay for nasal and pharyngeal swab specimens [1]. Only the laboratory-confirmed cases were included the analysis. The incubation period was defined as the duration from the contact of the transmission source to the onset of symptoms. The study was approved by the National Health Commission and the institutional board of each participating site. Written informed consent was waived in light of the urgent need to collect clinical data.

  我們對2019-nCoV ARD實驗室確診病例的臨床特征進行了回顧性研究。在排除與社區獲得性肺炎相關的常見細菌或病毒后,根據臨床表現和胸片學,最初的病例被診斷為“病因不明的肺炎”.疑似病例經確認有發熱或呼吸道癥狀,有在武漢海鮮市場接觸野生動物的歷史,有2周內與來自武漢的人接觸或旅行史。病例是根據世衛組織臨時指南[14]診斷的。經鼻咽拭子標本[1]高通量測序或實時逆轉錄酶聚合酶鏈反應(RT-PCR)檢測,確診病例為2019-nCoV ARD陽性。只有實驗室確診病例納入分析。潛伏期定義為從接觸傳播源到出現癥狀的時間。這項研究得到了國家衛生委員會和每個參與站點的機構委員會的批準。鑒于迫切需要收集臨床數據,放棄了書面知情同意。

  The epidemiological characteristics (including recent exposure history), clinical symptoms and signs and laboratory findings were extracted from electronic medical records. Radiologic assessments included chest X-ray or computed tomography. Laboratory assessments consisted of complete blood count, blood chemistry, coagulation test, liver and renal function, electrolytes, C-reactive protein, procalcitonin, lactate dehydrogenase and creatine kinase. The severity of 2019-nCoV ARD was defined based on the international guidelines for community-acquired pneumonia [15].

  從電子病歷中提取流行病學特征(包括近期接觸史)、臨床癥狀和體征以及實驗室檢查結果。放射學評估包括胸部x光或計算機斷層掃描。實驗室評估包括全血計數、血液化學、凝血試驗、肝腎功能、電解質、c反應蛋白、降鈣素原、乳酸脫氫酶和肌酸激酶。2019-nCoV ARD的嚴重程度是根據國際社區獲得性肺炎[15]指南確定的。

  The primary composite endpoint was the admission to intensive care unit (ICU), or mechanical ventilation, or death. Secondary endpoints comprised mortality rate, the time from symptom onset to the composite endpoint and each of its component. Because clinical observations were still ongoing, fixed time frame (i.e. within 28 days) was not applied to these endpoints.

  主要的復合終點是重癥監護病房(ICU),或機械通氣,或死亡。次要終點包括死亡率、從癥狀出現到復合終點的時間及其各組成部分。由于臨床觀察仍在進行中,所以沒有對這些終點應用固定的時間范圍(即28天內)。

  All medical records were copied and sent to the data processing center in Guangzhou, under the coordination of the National Health Commission. A team of experienced respiratory clinicians reviewed and abstracted the data. Data were entered into a computerized database and cross-checked. If the core data were missing, requests of clarification were immediately sent to the coordinators who subsequently contacted the attending clinicians. The definition of exposure to wildlife, acute respiratory distress syndrome (ARDS), pneumonia, acute kidney failure, acute heart failure and rhabdomyolysis are provided in the Supplementary Appendix.

  在國家衛生健康委員會的協調下,所有的醫療記錄被復制并發送到廣州的數據處理中心。一組有經驗的呼吸臨床醫師回顧并提取數據。數據被輸入計算機化的數據庫并反復核對。如果核心數據丟失,立即向協調員提出澄清要求,協調員隨后聯系主治醫師。野生動物暴露、急性呼吸窘迫綜合征(acute respiratory distress syndrome, ARDS)、肺炎、急性腎衰竭、急性心力衰竭和橫紋肌溶解的定義見附錄。

  3. Laboratory confirmation

  3、實驗室確認

  Laboratory confirmation of the 2019-nCoV was achieved through the concerted efforts of the Chinese Center for Disease Prevention and Control (CDC), the Chinese Academy of Medical Science, Academy of Military Medical Sciences, and Wuhan Institute of Virology. The RT-PCR assay was conducted in accordance with the protocol established by the World Health Organization [16]. Further details are available in the Supplementary Appendix.

  通過中國疾病預防控制中心、中國醫學科學院、軍事醫學科學院和武漢病毒學研究所的共同努力,2019-nCoV的實驗室確認工作已經完成。RT-PCR檢測按照世界衛生組織[16]制定的方案進行。更多詳情見補充附錄。

  4. Statistical analysis

  4、統計分析

  Continuous variables were expressed as the means and standard deviations or medians and interquartile ranges (IQR) as appropriate. Categorical variables were summarized as the counts and percentages in each category. We grouped patients into severe and non-severe 2019-nCoV ARDaccording to the American Thoracic Society guideline on admission [15]. Wilcoxon rank-sum tests were applied to continuous variables, chi-square tests and Fisher's exact tests were used for categorical variables as appropriate. The risk of composite endpoints among hospitalized cases and the potential risk factors were analyzed using Fine-Gray competing-risk models in which recovery is a competing risk. The proportional hazard Cox model was used in sensitivity analyses. The candidate risk factors included an exposure history, greater age, abnormal radiologic and laboratory findings, and the development of complications. We fitted univariate models with a single candidate variable once at a time. The statistically significant risk factors, sex, and smoking status were included into the final models. The sub-distribution hazards ratio (SDHR) along with the 95% confidence interval (95%CI) were reported. All analyses were conducted with R software version 3.6.2 (R Foundation for Statistical Computing)。 Distribution map was plotted using ArcGis version 10.2.2.

  連續變量以均值和標準差或中位數和四分位數范圍(IQR)表示。分類變量被總結為每個類別中的計數和百分比。根據美國胸科協會關于入院[15]的指南,我們將患者分為嚴重和非嚴重2019-nCoV ARD.連續變量采用Wilcoxon秩和檢驗,分類變量適當采用卡方檢驗和Fisher精確檢驗。采用細灰色競爭風險模型分析住院患者的復合終點風險和潛在風險因素,其中康復是競爭風險。靈敏度分析采用比例危險系數Cox模型。可能的危險因素包括接觸史、年齡、異常的放射學和實驗室檢查結果,以及并發癥的發展。我們一次用一個候選變量擬合單變量模型。統計上顯著的危險因素、性別和吸煙狀況被納入最終的模型。報告了子分布危險率(SDHR)和95%置信區間(95% ci)。所有分析均使用R軟件版本3.6.2 (R統計計算基礎)進行。使用ArcGis version 10.2.2繪制分布圖。

  5. Results

  5、結果

  Demographic and clinical characteristics

  人口統計學和臨床特征

  Of all 1,324 patients recruited as of January 29th, 222 (16.8%) had a suspected diagnosis and were therefore excluded. The core data sets (including clinical outcomes and symptoms) of 3 patients were lacking due to the incompleteness of original reports, hence this report delineates 1,099 patients with 2019-nCoV ARD from 552 hospitals in 31 provinces/province-level municipalities (Fig. 1)。

  截至1月29日,1324名患者中,222名(16.8%)有疑似診斷,因此被排除在外。由于原始報告的不完整性,3名患者的核心數據集(包括臨床結果和癥狀)缺乏,因此本報告描述了31個省/直轄市552家醫院1099名2019年NCO患者(圖1)。

圖1

圖1

  The demographic and clinical characteristics are shown in Table 1. 2.09% were healthcare workers. A history of contact with wildlife, recent travel to Wuhan, and contact with people from Wuhan was documented in 1.18%, 31.30% and 71.80% of patients, respectively. 483 (43.95%) patients were local residents of Wuhan. 26.0% of patients outside of Wuhan did not have a recent travel to Wuhan or contact with people from Wuhan. The median incubation period was 3.0 days (range, 0 to 24.0)。

  人口統計學和臨床特征見表1.2.09%是醫療工作者。1.18%的患者有接觸野生動物史,31.30%有近期到過武漢,71.80%有接觸過武漢人。483例(43.95%)患者為武漢本地居民,26.0%的武漢以外地區患者近期未到武漢旅游或與武漢人接觸。潛伏期中位數為3.0天(范圍為0至24.0)。

  The median age was 47.0 years (IQR, 35.0 to 58.0), and 41.9% were females. 2019-nCoV ARD was diagnosed throughout the whole spectrum of age. 0.9% of patients were aged below 15 years. Fever (87.9%) and cough (67.7%) were the most common symptoms, whereas diarrhea (3.7%) and vomiting (5.0%) were rare. 25.2% of patients had at least one underlying disorder (i.e., hypertension, chronic obstructive pulmonary disease)。 On admission, 926 and 173 patients were categorized into non-severe and severe subgroups, respectively. The age differed significantly between the two groups (mean difference, 7.0, 95%CI, 4.4 to 9.6)。 Moreover, any underlying disorder was significantly more common in severe cases as compared with non-severe cases (38.2% vs. 22.5%, P<0.001)。 There were, however, no marked differences in the exposure history between the two groups (all P>0.05)。

  中位年齡47.0歲(IQR, 35.0 ~ 58.0歲),女性41.9%.2019-nCoV ARD的診斷跨越整個年齡譜。0.9%的患者年齡在15歲以下。發燒(87.9%)和咳嗽(67.7%)是最常見的癥狀,而腹瀉(3.7%)和嘔吐(5.0%)罕見。25.2%的患者至少有一種潛在的疾病(即、高血壓、慢性阻塞性肺病)。入院時分別將926例和173例患者分為非嚴重組和嚴重組。兩組間年齡差異有統計學意義(均值分別為7.0、95%CI、4.4 ~ 9.6)。此外,與非嚴重病例相比,嚴重病例(38.2%比22.5%,P<0.001)更常見。兩組患者的暴露史無明顯差異(P>0.05)。

  Radiologic and laboratory findings at presentation

  表現時的放射學和實驗室檢查結果

  Table 2 shows the radiologic and laboratory findings on admission. Of 840 patients who underwent chest computed tomography on admission, 76.4% manifested as pneumonia. The most common patterns on chest computed tomography were ground-glass opacity (50.0%) and bilateral patchy shadowing (46.0%)。 Figure E1 in the Supplementary Appendix demonstrates the representative radiologic findings of two patients with non-severe 2019-nCoV ARD and another two patients with severe 2019-nCoV ARD. Despite these predominant manifestations, 221 out of 926 (23.87%) in severe cases compared with 9 out of 173 non-severe cases (5.20%) who had no abnormal radiological findings were diagnosed by symptoms plus RT-PCR positive findings (P<0.001)。 Severe cases yielded more prominent radiologic abnormalities on chest X-ray and computed tomography than non-severe cases (all P<0.05)。

  表2顯示入院時的放射學和實驗室檢查結果。840名病人在入院時接受了胸部計算機斷層掃描,其中76.4%表現為肺炎。胸部計算機斷層最常見的模式是毛玻璃陰影(50.0%)和雙側斑片狀陰影(46.0%)。附錄中的圖E1顯示了2例非嚴重2019-nCoV ARD患者和2例嚴重2019-nCoV ARD患者的典型影像學表現。盡管有這些主要表現,926例(23.87%)重癥患者中有221例(23.87%),而在173例無放射學異常表現的非重癥患者中有9例(5.20%)通過癥狀和RT-PCR陽性結果確診(P<0.001)。嚴重病例在胸部x線及電腦斷層攝影上的影像異常較非嚴重病例更為明顯(P<0.05)

  On admission, 82.1% and 36.2% of patients had lymphopenia and thrombocytopenia, respectively. Overall, leukopenia was observed in 33.7% of patients. Most patients demonstrated elevated levels of C-reactive protein, but elevated levels of alanine aminotransferase, aspartate aminotransferase, creatine kinase and D-dimer were less common. Severe cases had more prominent laboratory abnormalities (i.e., leukopenia, lymphopenia, thrombocytopenia, elevated C-reactive protein levels) as compared with non-severe cases (all P<0.05)。

  入院時,82.1%的患者淋巴細胞減少,36.2%的患者血小板減少。總的來說,33.7%的患者出現白細胞減少。大多數患者c反應蛋白水平升高,但丙氨酸氨基轉移酶、天冬氨酸氨基轉移酶、肌酸激酶和d -二聚體水平升高較少見。嚴重的病例有更明顯的實驗室異常(即、白細胞減少、淋巴細胞減少、血小板減少、c反應蛋白水平升高(P均<0.05)。

  Treatment and complications

  治療和并發癥

  Overall, oxygen therapy, mechanical ventilation, intravenous antibiotics and oseltamivir therapy were initiated in 38.0%, 6.1%, 57.5% and 35.8% of patients, respectively. All these therapies were initiated in significantly higher percentages of severe cases (all P<0.05)。 Significantly more severe cases received mechanical ventilation (non-invasive: 32.37% vs. 0%, P<0.001; invasive: 13.87% vs. 0%, P<0.001) as compared with non-severe cases. Systemic corticosteroid was given to 18.6% of cases and more so in the severe group than the non-severe patients (44.5% vs 13.7%, p<0.001)。 Moreover, extracorporeal membrane oxygenation was adopted in 5 severe cases but none in non-severe cases (P<0.001)。

  總體而言,分別有38.0%、6.1%、57.5%和35.8%的患者開始接受氧療、機械通氣、靜脈注射抗生素和奧司他韋治療。所有這些治療方法在嚴重病例中均有顯著提高(P<0.05)。機械通氣(無創:32.37% vs. 0%, P<0.001;侵襲性:13.87% vs. 0%, P<0.001)。18.6%的患者使用了全身性皮質類固醇,重癥組比非重癥組更多(44.5% vs 13.7%, p<0.001)。5例重癥患者采用體外膜氧合,非重癥患者未采用體外膜氧合(P<0.001)。

  During hospital admission, the most common complication was pneumonia (79.1%), followed by ARDS (3.37%) and shock (1.00%)。 Severe cases yielded significantly higher rates of any complication as compared with non-severe cases (94.8% vs. 72.2%, P<0.001) (Table 3)。

  住院期間最常見的并發癥是肺炎(79.1%),其次是ARDS(3.37%)和休克(1.00%)。嚴重病例的并發癥發生率明顯高于非嚴重病例(94.8%比72.2%,P<0.001)(表3)。

  Clinical outcomes

  臨床結果

  The percentages of patients being admitted to the ICU, requiring invasive ventilation and death were 5.00%, 2.18% and 1.36%, respectively. This corresponded to 67 (6.10%) of patients having reached to the composite endpoint (Table 3)。

  需要有創通氣和死亡的ICU患者分別為5.00%、2.18%和1.36%.這相當于67例(6.10%)患者達到復合終點(表3)。

  Results of the univariate competing risk model are shown in Table E1 in Supplementary Appendix. Severe pneumonia cases (SDHR, 9.803; 95%CI, 4.06 to 23.67), leukocyte count greater than 4,000/mm3  (SDHR, 4.01; 95%CI, 1.53 to 10.55) and interstitial abnormality on chest X-ray (SDHR, 4.31; 95%CI, 1.73 to 10.75) were associated with the composite endpoint (Fig. 2, see Table E2 in Supplementary Appendix)。 Sensitivity analyses are shown in Figure E2 in Supplementary Appendix.

  單變量競爭風險模型的結果見附錄表E1.重癥肺炎病例(SDHR, 9.803;白細胞計數大于4000 /mm3 (SDHR, 4.01;胸部x線顯示95%CI, 1.53 ~ 10.55)及間質異常(SDHR, 4.31;95%CI, 1.73 ~ 10.75)與復合終點相關(圖2,見附錄表E2)。靈敏度分析見附錄圖E2.

圖2

圖2

  6. Discussion

  6、討論

  This study has shown that fever occurred in only 43.8% of patients with 2019-nCoV ARD on presentation but developed in 87.9% following hospitalization. Severe pneumonia occurred in 15.7% of cases. No radiologic abnormality was noted on initial presentation in 23.9% and 5.2% of severe and non-severe cases respectively while diarrhea was uncommon. The median incubation period of 2019-nCoV ARD was 3.0 days and it had a relatively lower fatality rate than SARS-CoV and MERS-CoV. Disease severity independently predicted the composite endpoint.

  本研究表明,2019-nCoV ARD患者中僅有43.8%出現發熱癥狀,但住院后出現發熱癥狀的占87.9%.重癥肺炎占15.7%.嚴重和非嚴重的病例中分別有23.9%和5.2%在最初的表現沒有發現放射學異常,而腹瀉則不常見。2019-nCoV ARD的中位潛伏期為3.0天,相對于SARS-CoV和MERS-CoV的致死率較低。疾病嚴重程度獨立預測復合終點。

  Our study provided further evidence of human-to-human transmission. Around only 1% of patients had a direct contact with wildlife, while more than three quarters were local residents of Wuhan, or had contacted with people from Wuhan. Most cases were recruited after January 1st, 2020.These findings echoed the latest reports, including the outbreak of a family cluster [4], transmission from an asymptomatic individual [6] and the three-phase outbreak patterns [8]. Our study cannot preclude the presence of 'super-spreaders'. The median incubation period was shorter than a recent report of 425 patients (3.0 days vs. 5.2 days) [8]. Our findings have provided evidence from a much larger sample size to guide the duration of quarantine for close contacts.

  我們的研究為人際傳播提供了進一步的證據。大約只有1%的患者與野生動物有過直接接觸,而超過四分之三的患者是武漢當地居民,或與來自武漢的人有過接觸。大多數病例是在2020年1月1日以后招募的。這些發現與最近的報告相呼應,包括一個家庭群集[4]的暴發、一個無癥狀個體[6]的傳播以及[8]的三階段暴發模式。我們的研究不能排除“超級傳播者”的存在。中位潛伏期較近期報告的425例患者(3.0天vs. 5.2天)短。我們的發現為指導密切接觸者的隔離期提供了來自更大樣本量的證據。

  Importantly, the routes of transmission might have contributed considerably to the rapid spread of 2019-nCoV. Conventional routes of transmission of SARS-CoV, MERS-CoV and highly pathogenic influenza consisted of the respiratory droplets and direct contact [17-19]. According to our latest pilot experiment, 4 out of 62 stool specimens (6.5%) tested positive to 2019-nCoV, and another four patients in a separate cohort who tested positive to rectal swabs had the 2019-nCoV being detected in the gastrointestinal tract, saliva or urine (see Tables E3-E4 in Supplementary Appendix)。 In a case with severe peptic ulcer after symptom onset, 2019-nCoV was directly detected in the esophageal erosion and bleeding site (Hong Shan and Jin-cun Zhao, personal communication)。 Collectively, fomite transmission might have played a role in the rapid transmission of 2019-nCoV, and hence hygiene protection should take into account the transmission via gastrointestinal secretions. These findings will, by integrating systemic protection measures, curb the rapid spread worldwide.

  重要的是,傳播途徑可能對2019-nCoV的迅速傳播有相當大的貢獻。SARS-CoV、MERS-CoV和高致病性流感的常規傳播途徑包括飛沫和直接接觸[17-19].根據我們最新的預試驗,4 62份糞便標本2019 - ncov(6.5%)陽性,在一個單獨的隊列和另外四個病人陽性2019 - ncov直腸拭子已經被發現在胃腸道,唾液或尿液在補充附錄E3-E4(見表)。出現癥狀后出現嚴重消化性潰瘍的病例,直接在食管糜爛出血部位檢測到2019-nCoV (Hong Shan and Jin-cun Zhao, personal communication)。綜上所述,2019-nCoV的快速傳播可能與污染物傳播有關,因此,衛生防護應考慮通過胃腸道分泌物的傳播。這些發現將通過綜合系統的保護措施,遏制全球范圍內的迅速蔓延。

  We have adopted the term 2019-nCoV ARD which has incorporated the laboratory-confirmed symptomatic cases without apparent radiologic manifestations. Pneumonia was not mandatory for inclusion. 20.9% patients have isolated 2019-nCoV infection before or without the development of viral pneumonia. Our findings advocate shifting the focus to identifying and managing patients at an earlier stage, before disease progression.

  我們采用了2019-nCoV ARD這一術語,它包含了實驗室確診的無明顯放射學表現的癥狀病例。肺炎并不是強制納入的。20.9%的患者在發生病毒性肺炎之前或未發生病毒性肺炎之前已分離出2019-nCoV感染。我們的發現主張將重點轉移到在疾病進展之前的早期階段識別和管理患者。

  In concert of recent publications [1,8,12], the clinical characteristics of 2019-nCoV ARD mimicked those of SARS-CoV. Fever and cough were the dominant symptoms whereas gastrointestinal symptoms were rare, suggesting the difference in viral tropism as compared with SARS-CoV, MERS-CoV and influenza [20-22]. Notably, fever occurred in only 43.8% of patients on initial presentation and developed in 87.9% following hospitalization. Absence of fever in 2019-nCoV ARD is more frequent than in SARS-CoV (1%) and MERS-CoV infection (2%) [19] and such patients may be missed if the surveillance case definition focused heavily on fever detection [14]. Consistent with two recent reports [1,12], lymphopenia was common and, in some cases, severe. However, based on a larger sample size and cases recruited throughout China, we found a markedly lower case fatality rate (1.4%) as compared with that reportedly recently [1,12]. The fatality rate was lower (0.88%) when incorporating additional pilot data from Guangdong province (N=603) where effective prevention has been undertaken (unpublished data)。 Our findings were consistent with the national official statistics, reporting the mortality of 2.01% in China out of 28,018 cases as of February 6th, 2020 [11,23]. Early isolation, early diagnosis and early management might have collectively contributed to the marked reduction in mortality in Guangdong. Furthermore, dilution of health workforce as a result of central management (i.e., Wuhan JinYinTan Hospital) might have led to increased mortality rate. These findings will inform the mass public, clinicians and policy makers the true transmissability of 2019-nCoV which has resulted in a major social panic.

  在近期發表的文獻[1,8,12]中,2019-nCoV ARD的臨床特征與SARS-CoV相似。發熱、咳嗽為主要癥狀,胃腸道癥狀少見,提示與SARS-CoV、MERS-CoV、流行性感冒相比,病毒向性有差異[20-22].值得注意的是,最初出現發熱癥狀的患者僅占43.8%,住院后出現發熱癥狀的患者占87.9%.2019-nCoV ARD的無發熱情況比SARS-CoV(1%)和MERS-CoV感染(2%)[19]更為常見,如果監測病例定義主要集中于發熱檢測[14],則此類患者可能會被遺漏。與最近的兩篇報道一致[1,12],淋巴細胞減少是常見的,在某些情況下是嚴重的。然而,基于更大的樣本量和中國各地招募的病例,我們發現與最近報道的相比,病死率顯著降低(1.4%)[1,12].納入廣東省的其他試點數據(N=603)時,死亡率較低(0.88%),廣東省采取了有效的預防措施(未發表的數據)。我們的研究結果與國家官方統計數據一致,截至2020年2月6日,中國28018例患者的死亡率為2.01%[11,23].早期隔離、早期診斷和早期治療可能共同有助于廣東死亡率的顯著降低。此外,由于中央管理(即可能導致了死亡率的上升。這些發現將告知大眾、臨床醫生和政策制定者2019-nCoV的真實傳播能力,該病毒已經導致了一場重大的社會恐慌。

  Our study has stratified patients with 2019-nCoV ARD based on the severity on admission according to international guidelines [15]. Severe cases had significantly higher risk of reaching the composite endpoint. The risk factors indicated the importance of taking into account the disease severity, laboratory findings, chest imaging findings in practice. The applicability of MuLBSTA score, an early warning model for predicting mortality in viral pneumonia, warrants further validation [25].

  根據國際指南[15],我們的研究根據入院時的嚴重程度對2019-nCoV ARD患者進行了分層。嚴重病例達到復合終點的風險明顯更高。危險因素表明,在實際工作中應考慮疾病的嚴重程度、實驗室檢查結果、胸部影像學檢查結果。MuLBSTA評分是預測病毒性肺炎死亡率的早期預警模型,其適用性值得進一步驗證。

  Despite the markedly high phylogenetic homogeneity as compared with SARS-CoV, there are some clinical characteristics that differentiated 2019-nCoV from SARS-CoV, MERS-CoV, and seasonal influenza which have been more common in respiratory out-patient clinics and wards. Table E5 in Supplementary Appendix highlights the defining characteristics of these viruses, enabling clinicians to differentiate these diagnoses.

  盡管與SARS-CoV相比具有明顯高的系統發育同質性,但仍有一些臨床特征可將2019-nCoV與SARS-CoV、MERS-CoV和季節性流感區分開來,這類流感在呼吸門診診所和病房中更為常見。附錄中的表E5強調了這些病毒的定義特征,使臨床醫生能夠區分這些診斷。

  Our study has some notable limitations. First, some cases had incomplete documentation of the exposure history, symptoms and laboratory testing given the variation in the structure of electronic database among different participating site and the urgent timeline for data extraction. Some cases were diagnosed in out-patient settings where medical information was briefly documented and incomplete laboratory testing was applied. There was a shortage of infrastructure and training of medical staff in non-specialty hospitals, which has been aggravated by the burn-out of local medical staff in milieu of a surge of cases. Second, because many patients still remained in the hospital, we did not compare the 28-day rate of the composite endpoint. To mitigate the potential bias, we have applied the competing-risk model for analysis. Third, we might have missed asymptomatic or mild cases managed at home, and hence our cohort might represent the more severe end of 2019-nCoV ARD. However, there were a minority of patients who had no apparent radiologic manifestations, suggesting that we had included patients at the early stage of disease. Last, we took reference on the existing international guideline to define the severity of 2019-nCoV because of its global recognition [15].

  我們的研究有一些明顯的局限性。首先,考慮到不同參與地點電子數據庫結構的差異和數據提取的緊急時間安排,一些病例的暴露史、癥狀和實驗室檢測記錄不完整。一些病例是在門診診斷的,那里的醫療信息被簡要地記錄下來,并且應用了不完整的實驗室檢測。非專科醫院缺乏基礎設施和醫務人員培訓,而在病例激增的情況下,當地醫務人員疲憊不堪,使情況更加嚴重。其次,由于許多患者仍在住院,我們沒有比較復合終點的28天生存率。為了減少潛在的偏差,我們采用了競爭風險模型進行分析。第三,我們可能錯過了在家治療的無癥狀或輕度病例,因此我們的研究對象可能代表2019-nCoV ARD的更嚴重結局。然而,有少數患者沒有明顯的放射學表現,這表明我們包括了早期的患者。最后,我們參考了現有的國際準則來定義2019-nCoV的嚴重性,因為它的全球認可度為[15].

  In summary, 2019-nCoV elicits a rapid spread of outbreak with human-to-human transmission, with a median incubation period of 3 days and a relatively low fatality rate. Absence of fever and radiologic abnormality occurs in a substantial proportion of patients on initial presentation while diarrhea is uncommon. The disease severity is an independent predictor of poor outcome. Stringent and timely epidemiological measures are crucial to curb the rapid spread. Ongoing efforts are needed to explore for an effective therapy (i.e., protease inhibitors, remdesivir, β interferon) for this emerging acute respiratory infection.

  綜上所述,2019-nCoV導致疫情迅速傳播,人際傳播,潛伏期中位數為3天,致死率相對較低。相當比例的患者在最初表現時沒有發熱和放射學異常,腹瀉則不常見。疾病嚴重程度是不良預后的獨立預測因子。嚴格和及時的流行病學措施對控制迅速蔓延至關重要。需要不斷的努力來探索一種有效的治療方法。、蛋白酶抑制劑、remdesivir β干擾素)這一新興急性呼吸道感染。

  7. Acknowledgment

  7、感謝

  We thank the hospital staff (see Supplementary Appendix for a full list of the staff) for their efforts in recruiting patients. We are indebted to the coordination of Drs. Zong-jiu Zhang, Ya-hui Jiao, Bin Du, Xin-qiang Gao and Tao Wei (National Health Commission), Yu-fei Duan and Zhi-ling Zhao (Health Commission of Guangdong Province), Yi-min Li, Zi-jing Liang, Nuo-fu Zhang, Shi-yue Li, Qing-hui Huang, Wen-xi Huang and Ming Li (Guangzhou Institute of Respiratory Health) which greatly facilitate the collection of patient's data. Special thanks are given to the statistical team members Prof. Zheng Chen, Drs. Dong Han, Li Li, Zheng Chen, Zhi-ying Zhan, Jin-jian Chen, Li-jun Xu, Xiao-han Xu (State Key Laboratory of Organ Failure Research, Department of Biostatistics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University)。 We also thank Li-qiang Wang, Wei-peng Cai, Zi-sheng Chen, Chang-xing Ou, Xiao-min Peng, Si-ni Cui, Yuan Wang, Mou Zeng, Xin Hao, Qi-hua He, Jing-pei Li, Xu-kai Li, Wei Wang, Li-min Ou, Ya-lei Zhang, Jing-wei Liu, Xin-guo Xiong, Wei-juna Shi, San-mei Yu, Run-dong Qin, Si-yang Yao, Bo-meng Zhang, Xiao-hong Xie, Zhan-hong Xie, Wan-di Wang, Xiao-xian Zhang, Hui-yin Xu, Zi-qing Zhou, Ying Jiang, Ni Liu, Jing-jing Yuan, Zheng Zhu, Jie-xia Zhang, Hong-hao Li, Wei-hua Huang, Lu-lin Wang, Jie-ying Li, Li-fen Gao,Jia-bo Gao, Cai-chen Li, Xue-wei Chen, Jia-bo Gao, Ming-shan Xue, Shou-xie Huang, Jia-man Tang, Wei-li Gu, Jin-lin Wang (Guangzhou Institute of Respiratory Health) for their dedication to data entry and verification.

  我們感謝醫院工作人員(完整的工作人員名單見附錄)為招募病人所做的努力。我們感謝Drs的協調。Zong-jiu張Ya-hui嬌,本·杜,Xin-qiang高和魏道(國家健康委員會),岳飛段和Zhi-ling趙(廣東省衛生委員會),李Yi-min Zi-jing Liang Nuo-fu張Shi-yue Li Qing-hui黃黃洗臉和李明(廣州呼吸衛生研究所)大大促進病人的數據的集合。特別感謝統計小組成員鄭晨教授。(南方醫科大學公共衛生學院廣東省熱帶病研究重點實驗室生物統計學系器官衰竭研究國家重點實驗室)Wei-peng Cai,我們還要感謝李強Wang Zi-sheng Chen Chang-xing Ou, Xiao-min Peng Si-ni崔,元王,諒解備忘錄曾慶紅,鑫,Qi-hua他Jing-pei Li Xu-kai Li Wei,李敏歐,亞雷,經緯Liu Xin-guo Xiong, Wei-juna Shi, San-mei Yu Run-dong秦,羊絨衫姚明,Bo-meng張蕭紅謝,謝Zhan-hong Wan-di Wang Xiao-xian張Hui-yin Xu Zi-qing周,應江,倪,晶晶元,鄭朱、張Jie-xia,洪濤,魏華黃Lu-lin王李潔英,高麗芬,高嘉波,李彩晨,陳學偉,高嘉波,薛明山,黃壽燮,唐家文,古偉立,王金林(廣州呼吸健康研究所),他們致力于數據錄入和驗證。
 

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