中华流行病学杂志  2020, Vol. 41 Issue (0): 0-0   PDF    
http://dx.doi.org/10.3760/cma.j.cn112338-20200806-01027
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文章信息

杨孝坤, 李昱, 赵宏婷, 李志丽, 耿梦杰, 王文玲, 秦颖, 余建兴, 彭质斌, 谭文杰, 郑建东, 李中杰, 冯子健.
Yang Xiaokun, Li Yu, Zhao Hongting, Li Zhili, Geng Mengjie, Wang Wenling, Qin Ying, Yu Jianxing, Peng Zhibin, Tan Wenjie, Zheng Jiandong, Li Zhongjie, Feng Zijian
新型冠状病毒感染不同阶段的传染性研究进展
Advance on the infectivity of Coronavirus 2019 infection at different stages
中华流行病学杂志, 2020, 41(0): 0-0
Chinese Journal of Epidemiology, 2020, 41(0): 0-0
http://dx.doi.org/10.3760/cma.j.cn112338-20200806-01027

文章历史

收稿日期: 2020-08-06
新型冠状病毒感染不同阶段的传染性研究进展
杨孝坤1 , 李昱1 , 赵宏婷1 , 李志丽1 , 耿梦杰1 , 王文玲2 , 秦颖1 , 余建兴3 , 彭质斌1 , 谭文杰2 , 郑建东1 , 李中杰1 , 冯子健4     
1. 中国疾病预防控制中心传染病管理处, 北京 102206;
2. 中国疾病预防控制中心病毒病预防控制所, 北京 102206;
3. 中国疾病预防控制中心传染病预防控制所, 北京 102206;
4. 中国疾病预防控制中心, 北京 102206
摘要: 新型冠状病毒(新冠病毒)感染不同阶段的传染性特征是调查病例感染来源、确定密切接触者范围和病例隔离时间等防控措施的重要基础。本文通过对国内外文献、技术报告与专业指南等资料进行综述,基于病原学和流行病学两个维度的研究结果,探讨新冠病毒感染者在潜伏期、临床症状期和恢复期阶段的传染性特征。现有研究提示,新冠病毒感染者在潜伏期末和发病期均可分离到具有感染性病毒,发病4~6d后在上呼吸道样本中病毒载量达到高峰,随后开始下降,提示在潜伏期末和发病1周内的传染性相对较强。个别病例在恢复期尽管可再次检出新冠病毒核酸,但未发现具有传染性的证据。
关键词: 新型冠状病毒    潜伏期    临床症状期    恢复期    传染性    
Advance on the infectivity of Coronavirus 2019 infection at different stages
Yang Xiaokun1 , Li Yu1 , Zhao Hongting1 , Li Zhili1 , Geng Mengjie1 , Wang Wenling2 , Qin Ying1 , Yu Jianxing3 , Peng Zhibin1 , Tan Wenjie2 , Zheng Jiandong1 , Li Zhongjie1 , Feng Zijian4     
1. Division of Infectious Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China;
2. National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China;
3. National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China;
4. Chinese Center for Disease Control and Prevention, Beijing 102206, China
Abstract: The study of characteristics of Coronavirus 2019 infection at different stages are an important basis for the establishment of relevant prevention and control measures, investigating the source of infection, and determining the scope of close contacts and the time of case isolation. This paper will discuss the infectivity characteristics of Coronavirus 2019 infected cases in the incubation period, clinical symptoms period and convalescent period by reviewing national and international papers, technical and professional guidelines. Existing researches suggested that the infectious viruses were isolated from the end of the incubation period and clinical symptoms onset period of Coronavirus 2019 cases, and the peak viral load in upper respiratory tract swabs appeared to occur on day 4-6 after symptom onset then began to decline, which indicated the infectivity was strong at the end of incubation period and about one week after symptom onset. Although there were cases that tested positive for Coronavirus 2019 after recovery, no evidence of infectivity was found.
Key words: Coronavirus 2019    Incubation period    Clinical symptoms period    Convalescent period    Infectivity    

新型冠状病毒(新冠病毒)的传播能力强,截至2020年6月底,已在200多个国家引起传播,导致全球1 000多万人发病、50多万患者死亡[1]。新冠病毒感染者不同阶段是否具有传染性、传染性强弱以及传染期长短等,是调查感染来源、确定密切接触者范围和病例隔离时间等防控措施的重要参数。本文以“COVID-19”“SARS-CoV-2”“pre-symptomatic transmission”“incubation period”“infectivity”“convalescent period”和“新型冠状病毒”“症状前传播”“潜伏期” “传染性”和“复阳”等关键词在PubMed和中国知网等检索2020年7月1日前发表的文献,以及国内外专业机构发布的技术报告和专业指南,对新冠病毒感染者在不同病程阶段的传染性研究进展进行综述,旨在明确新冠病毒传播特征,为制定相关防控措施提供依据。

一、相关概念及意义

参考国内外传染病学相关教材[2-3],本文新型冠状病毒肺炎(新冠肺炎)感染者病程相关的定义如下:

潜伏期(incubation period):指新冠病毒侵入感染宿主到该宿主出现临床症状和体征的间隔期。潜伏期可用于制定监测或病例搜索的定义、推断可疑的暴露时间、确定密切接触者医学观察期限、判断疫情传播是否终止等。

潜隐期(latent period):指新冠病毒侵入感染宿主到该宿主可以排出新的病原体的间隔期,可用于明确病例传染期开始的时机。若潜伏期长于潜隐期,说明病例在潜伏期时感染宿主已具有排出病原体的能力,可作为判断潜伏期是否具有传染性的依据。

传染期(infectious period):指新冠肺炎感染者可以持续排出具有传染能力的新冠病毒时期,感染宿主在传染期具有传染性,是作为制定隔离期限的依据。

临床症状期(clinical symptoms period):指新冠肺炎感染者持续表现出临床症状和体征的时期。

恢复期(convalescent period):指新冠肺炎感染者的临床症状及体征基本消失,至恢复至疾病前状态的时期。在此期间新冠肺炎感染者体内可能还有残余的病理改变或生化改变,新冠病毒尚未被完全清除。

代间距(serial interval):是指原发病例的发病日期与其传染导致的续发病例发病日期的间隔时间。代间距越短说明新冠肺炎有效传播速度越快,在人群中能够快速扩散。若代间距小于潜伏期,提示新冠肺炎感染者在潜伏期具有传染性。

二、传染期测量方法

理论上,新冠病毒感染者发病前(潜伏期)、发病期间和感染症状消失后(恢复期)均可能具有传染性。受感染者体内病原繁殖时间、病原排出方式与排出数量等因素影响,不同病原的传染期长短不同[4]。即使在具有传播能力的传染期内,新冠病毒在不同临床进展中的传染性强弱也有所差异。新冠病毒感染者能够向体外持续排出具有感染性病毒的时间段,是判断疾病传染期的最主要依据;感染者样本中病毒核酸检测阳性并不能代表其存在具有感染性的病毒[5],但在样本中存在病毒的情况下,患者核酸阳性持续时间可间接反映传染期的长短,病毒核酸载量或循环阈值(cycle threshold, Ct)可间接反映传染性强弱[6]。在具有明确“感染者-被感染者”关系的传播链中,对续发病例暴露于原发病例的时间点进行分析,也可推算疾病传染期。此外,也有研究通过比较潜伏期和代间距等指标大小差异来判断潜伏期具有传染性的概率。

三、潜伏期传染性

目前普遍认为新冠病毒的潜伏期为1~14d,平均潜伏期为5d左右[7-11],97.5%的感染者会在11.5d内出现临床症状[10]

病原学研究结果显示,感染者在潜伏期末具有传染能力。Pan等[12]对确诊病例的2名密切接触者的研究发现,在症状出现前1d的咽拭子和痰液样本核酸检测即呈阳性,且病毒载量较高(>1×105 RNA copies/ml),提示感染者在潜伏期即可排毒。同时,韩国的研究发现有3名感染者发病前2d的鼻咽拭子核酸检测阳性,其中2名感染者标本病毒载量较高(Ct<20.0)[13]。此外,美国研究者对一家养老机构的调查,也发现在潜伏期传播的现象[14],26例感染者潜伏期鼻咽拭子和咽拭子样本中的病毒载量(中位Ct=24.0,IQR:20.4~28.5)与8例发病≥7d感染者的病毒载量(中位Ct=25.0,IQR:21.3~28.2)相似;此外,24例处于潜伏期的感染者中有17例从咽拭子样本中分离培养到病毒,最早从发病前6d的标本中分离培养出病毒(2例),并且观察到有1例感染者在发病前7d核酸检测已呈阳性。

通过比较潜伏期与代间距可推断疾病在潜伏期是否具有传染性,若代间距小于潜伏期,提示病例在潜伏期具有传染性。Du等[15]对468例确诊病例的研究发现,59例(12.6%)是在首发病例的潜伏期内发生感染,经过正态分布拟合后推算出平均代间距为3.96(95% CI:3.53~4.39)d,推测12.6%的病例在潜伏期就开始传播病毒。Yang等[16]利用152对具有明确暴露日期和发病日期的传播链经正态分布拟合后推算的平均代间距为4.6(95%CI:3.7~5.5)d。以上研究发现新冠肺炎的平均代间距略低于平均潜伏期(5d),提示新冠病例在潜伏期具有传染性。

德国研究者对传播链不明确的聚集性疫情病例标本进行病毒全基因组测序,结果表明潜伏期具有传染性[17]:续发病例(病例4)在1月20-22日与首发病例(病例0)接触,24日出现症状;另一方面续发病例(病例5)未接触首发病例,但在1月22日与病例4在食堂近距离就餐。基因测序结果显示病例4和5的病毒序列中出现一个非同义的核苷酸多态性(G6446A替代),但病例1~3的序列中均未发现,此后出现的感染者均可追溯到病例5。详细的序列分析排除了病例4被病例5感染的可能性:病例4的咽拭子样本中检测到新的G6446A病毒序列,并在痰液中检测到原始的6446G病毒序列,而病例5的咽喉拭子中仅含有G6446A替代的同质病毒群序列。

Ren等[18]对80个“首发-续发”病例的传播链进行分析,发现9个传播链条中续发病例的暴露感染早于首发病例发病;采用蒙特卡罗模型的分析结果提示,在该80起传播链中,32起(40%)传播链的续发病例感染可能(50%的概率)发生在首发病例的潜伏期。He等[19]建立了基于77条聚集性疫情传播链的流行病学模型,研究结果提示新冠病毒感染者可能在发病前2.3(95%CI:0.8~3.0)d就具有传染性,并且推算潜伏期传播导致感染的比例可能高达44%(95%CI:25%~69%)。

基于以上研究结果,可以确定在病例的潜伏期可检测到病毒核酸,也能分离培养到病毒,提示在潜伏期具有传染能力。然而,发病前具有传染性的最长时间及其传染性的强弱目前尚无定论;此外,感染剂量、个体免疫状态、个人行为等因素也可影响其潜伏期传染性的强弱。因此,目前尚难以准确估计潜伏期内的传染期长短。综合现有的病原学和流行病学研究结果,目前WHO、美国、欧盟以及中国的相关防控技术指南,均采用发病前2d传染性较强的标准,并将此作为判断密切接触者的起始时间点[20-23]

四、临床症状期传染性

感染者的临床症状期持续时间受诸多因素的影响,如患者的基础疾病、年龄、治疗的及时性和治疗方法等,目前对临床症状期的持续时间尚无统一的认识。Chang等[24]对16例轻症新冠肺炎患者的观察发现,临床症状持续的时间平均为8d(IQR:6.3~11.5);新加坡一项研究对疫情初期18例新冠肺炎患者(12例轻症,6例重症)临床研究发现[25],轻症患者症状持续时间中位数为12(5~24)d,重症患者为16(10~20)d;Chen等[26]对上海市249例新冠肺炎患者临床特征的研究显示,235例(94.3%)患者具有发热症状,发热症状的持续时间平均为10(95%CI: 8~11)d,但ICU病房患者发热症状持续时间平均为31 d,非ICU病房患者为9d。

多项研究发现,新冠肺炎患者在临床症状初期上呼吸道标本中病毒载量较高,1周之内达到峰值,随后的1~3周缓慢下降[12, 14, 19, 27-38],这与SARS病例在发病后10 d左右体内病毒载量达到最高略有不同[39-40]。另有研究表明,新冠肺炎病例粪便、下呼吸道样本中病毒载量达到峰值时间与上呼吸道标本不同,粪便样本中的病毒载量通常在发病后2~3周达到峰值[13, 27, 41-47],而下呼吸道痰液样本中的病毒载量在发病后2周内达到高峰,且病毒载量高于上呼吸道样本[12, 32, 35, 45, 47-49]。多项研究提示,发病期间的排毒量与疾病严重程度也有关,病毒载量的高低可能成为预测疾病进展的指标[12, 28-29, 32, 47, 50-53],Liu等[29]研究发现,重症患者的鼻咽拭子病毒载量比轻症患者的高60倍。Yu等[50]对92例住院患者痰液病毒载量进行测定,发现高病毒载量与疾病严重性成正相关。

病毒核酸检测阳性持续时间不等同于传染性持续时间,检测出病毒载量的高低也不等同于传染性的强弱[5, 6, 54]。美国对某养老机构暴发病例的46份鼻咽拭子和咽拭子进行病毒分离培养[14],结果显示发病第9d后的样本不能分离培养出病毒。德国研究者对9例病例的研究发现[37],尽管痰液中病毒载量很高(105 copies/ml),但在发病8d后就不能从痰液中分离培养出病毒,据此建议在发病后10d、痰液病毒载量 < 105 copies/ml时患者可以出院,进行居家隔离观察。加拿大研究者对90份发病期核酸检测阳性的鼻咽拭子标本进行病毒分离[55],发现轻症患者在发病后8d或Ct>24时核酸阳性的鼻咽拭子样本不能分离培养出病毒。Bernard等[56]收集155例新冠肺炎患者183份鼻咽拭子进行病毒分离培养,其中129份样本能培养分离到病毒,病毒载量高(Ct:13~17)的样本中都能分离培养出病毒,病毒载量较低时(Ct > 34)不能分离出病毒,据此该研究认为Ct > 34时患者不再具有传染性,可以考虑解除隔离。此外,中国台湾地区报道一名50岁女性慢性带毒者[49],其痰液和咽拭子样本病毒核酸持续检测阳性≥63d,但在发病18 d后阳性样本中不能再分离出病毒。

基于感染者临床症状期的研究结果,WHO于5月27日更新了新冠肺炎患者临床管理指南[57],并在6月17日的科学简报中提出了基于症状确定解除隔离的策略[58],建议医疗卫生资源紧张的地区,无论患者的临床严重程度如何,症状消失后再观察3d,如仍无症状即可解除隔离。而对于长期出现症状的高危患者,仍可采用2次连续采样(间隔≥1d)核酸检测阴性作为解除隔离的标准。目前,为将疫情扩散风险降到最低,我国最新版诊疗方案提出的出院标准[59]:患者体温恢复正常 > 3d,呼吸道症状明显好转,肺部影像学显示急性渗出性病变明显改善,连续2次呼吸道标本核酸检测阴性(采样时间间隔≥1d)。同时满足上述条件方可解除住院隔离。

五、恢复期传染性

国内外陆续出现新冠肺炎患者恢复期检测出核酸阳性情况(复阳),研究者对这一群体是否具有传染性进行了研究。从恢复期患者的咽拭子、鼻咽拭子、痰液、肛拭子、粪便样本中均再次检测病毒核酸,肛拭子核酸阳性时间长于其他样本[35, 48, 56, 60-69]。其中,有个别恢复期感染者因发热、咳嗽等症状再次被收治入院,有些恢复期患者甚至发展为重症[70]。但至今尚无复阳患者引起密切接触者感染和再次传播的报道。武汉市全民核酸筛查结果显示[71],34 424例康复者中有107例(0.31%)咽拭子样本核酸阳性,而这107例复检阳性者的标本均未分离到病毒。

现有研究显示,尽管患者恢复期标本中检测到新冠病毒核酸,但未曾分离到病毒,也无流行病学证据显示其引起续发病例。因此,目前可认为新冠肺炎患者在恢复期具有传染性的可能性极低。

六、小结

现有研究结果显示,新冠病毒感染者潜伏期末和发病初期的传染性相对较强,其传染期特征与季节性流感和2009年甲型H1N1流感相似。甲型流感患者一般在发病后1~2d排毒达到高峰,此时传染性最强,在随后的1周排毒量逐渐减少。乙型流感患者在发病前2d就具有传染性,持续6~7d并形成2个排毒高峰[72]。SARS患者在发病前和发病初期的传染性不强,至发病后6~11d的传染性最强[39-40]。与SARS不同,新冠病毒感染者从开始发病到医疗机构就诊被准确诊断,一般需要数天甚至更长时间[7],这表明在新冠病例被发现并采取隔离措施之前,引起续发病例的概率较高。这种传染期特征的差异,一定程度解释了新冠的传播阻断比SARS更难,防控难度更大[73]

目前未发现恢复期感染者具有传染性的证据,但对于潜在长期携带病毒的特殊人群仍需关注。尽管目前对于新冠病毒传染特征的认识不断增加,但新冠病毒感染者在潜伏期的传播能力及其公共卫生意义,不同感染者在发病期传染性强弱的影响因素,以及新冠病毒核酸阳性与传染性的关系等内容仍有待进一步深入研究。

利益冲突  所有作者均声明不存在利益冲突

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