专题讲座

从SARS冠状病毒到新型动物及人冠状病毒

Published at: 2014年第1卷第14期

Kelvin K. W. To 1 , Ivan F. N. Hung 2 , Jasper F. W. Chan 1 , Kwok-Yung Yuen 3
1 State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Hong Kong Special Administrative Region, China
2 State Key Laboratory of Emerging Infectious Diseases, Department of Medicine, the University of Hong Kong, Hong Kong Special Administrative Region, China
3 State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Hong Kong Special Administrative Region, China

引言

2003年,严重急性呼吸道综合征冠状病毒(SARS病毒)因其高毒性及人际传播的高效性而震惊世界(1-3),导致了21世纪的第一个大规模疫情。全世界超过8000名患者感染,导致774人死亡。除了加重医疗保健系统负担外,SARS也因为减少国内需求和国际旅行而对经济产生了不利影响(4)。据估计,由于SARS-CoV导致的全球经济损失约为400亿美元(5)。SARS被发现不久,又有两种新型人类冠状病毒(HCoV)——HCoV-HKU1和HCoV-NL63(6,7),这两种病毒均是自限性上呼吸道感染的病因(8,9)但在老年人及免疫功能低下患者中也偶有死亡案例报道(10-13)。另一方面,早在2012年4月就在中东地区引起人致命性感染并在最近蔓延到欧洲和北非的新型中东呼吸综合征冠状病毒(MERS-CoV)——以前也称人类β冠状病毒2C EMC/2012和人类冠状病毒EMC(HCoV-EMC)——及时提醒全球卫生界关注作为一种致命性人类呼吸道病原体的冠状病毒的重要性(14-16)。截止2013年5月30日,已有50例实验室确诊MERS-CoV人感染病例,其中27人死亡(17)。

冠状病毒属于包膜RNA病毒科冠状病毒,可导致人类和动物患病。它含有单股正链基因组,目前根据其蛋白质序列的不同分为4个属(15)。HCoV-229E和HCoV-NL63为α冠状病毒。HCoV-OC43和HCoV-HKU1为A系β冠状病毒,而SARS-CoV和MERS-CoV分别属于β冠状病毒的B和C谱系。目前,γ冠状病毒和δ冠状病毒尚未见报道引起人类疾病。SARS-CoV和MERS-CoV两种病毒在系统发育上均与蝙蝠冠状病毒密切相关(18-20)。在这篇文章中,我们从临床角度综述在过去十年中确定的新型人类冠状病毒,并讨论这些人类冠状病毒与其源头动物冠状病毒之间的关系(视频1)。

视频1 From SARS coronavirus to novel animal and human coronaviruses

人冠状病毒感染的临床特点

在SARS-CoV发现之前,已知致人呼吸道感染的冠状病毒仅有HCoV-229E和HCoV-OC43,占普通感冒15-30%,病情严重者罕见(21)。2002年11月,SARS-CoV导致的非典型肺炎在中国广东省佛山市发现(2)。2003年2月,感染蔓延到香港,然后蔓延到越南、北美和欧洲。该病毒由香港一名65岁的医生通过肺活检首次分离成功,患者从广州来港的53岁男性(3)。初步的临床研究和体外研究均满足修订版科赫假设的前三个标准,即从患病宿主体内分离出病毒、在宿主细胞中培养以及具有可滤过性(3,22-24),而病毒发现后不久,在食蟹猴中进行的研究满足了后三个标准,包括在相关物种中引起类似的疾病、病毒的再分离和检测到对病毒的特异性免疫应答(25)。SARS-CoV感染以急进性肺炎为特点(3)。虽然粪口传播也可能是传播途径(3),但SARS-CoV传播的主要方式似乎是通过呼吸道飞沫(26)。除了超级传播者,据统计,每位感染者传染给2-4位患者(27)。中位潜伏期估计为4-7天(28),病毒载量在病程的第10天达到峰值(3)。SARS-CoV能感染所有年龄段人群。以医护人员和免疫功能低下患者最为危险(29)。普遍会出现发热,肌痛和不适是常见的早期症状。后期往往出现咳嗽、呼吸困难、呼吸急促、胸膜炎、腹泻等症状(3)。常可见到淋巴细胞减少、肝功能异常以及肌酸激酶升高等实验室检查异常(3)。虽然早期胸片多正常,但胸部计算机断层扫描(CT)扫描常可见到毛玻璃样改变。约2/3的患者在病程的第2周病情恶化,以持续发热、呼吸困难加重、血氧饱和度下降为特点。此时胸部CT扫描显示进展为多灶性气腔,偶尔出现纵隔气肿(3)。约20-30%的患者后来需要重症监护和机械通气。尸体肺活检病理分析发现存在弥漫性肺泡损伤、肺上皮脱屑以及炎性浸润伴肺透明膜形成(30)。

2004年1月,在1名71岁社区获得性肺炎香港男子中检出新型病毒HCoV-HKU1(6),随后在全球范围均有发现。儿童和有基础疾病的老年人都有感染风险(8,31)。除了社区获得性肺炎,HCoV-HKU1还与急性细支气管炎和哮喘发作相关(31)。HCoV-HKU1感染者热性惊厥发生率高与其他人冠状病毒感染者(31)。在1位脑膜炎患者也发现了HCoV-HKU1(32)。大多数病例发生在流感高发的冬季和春季(31-34)。

HCoV-NL63最早报告于荷兰(7)。首位病人是一名7个月大,因存在发热、鼻炎和结膜炎,胸部影像学检查存在细支气管炎而住院的儿童。HCoV-NL63与喉气管炎有关(20,35),并且还有糖尿病患者进展为心包炎和横纹肌溶解症的报道(11)。另一方面,HCoV-NL63与川崎病的相关性仍然存在争议(36)。发病高峰在热带和亚热带地区如香港为初夏和秋季(31,37),在欧洲国家如荷兰和英国为冬季(7,32)。有时可能会出现合并感染其他呼吸道病毒,尤其是呼吸道合胞病毒(32)。

2012年首次发现MERS-CoV,不久使用猕猴模型满足了科赫假设(38)。报道的所有患者均是成年人,中位年龄56岁(39)。其临床特征与2003年爆发的SARS相似(13),以快速进展的急性肺炎为特点。与SARS相反,许多MERS-CoV感染患者还发生急性肾功能衰竭(14)。一名患者具有发热、腹泻和腹痛症状,但无呼吸道症状(40)。严重并发症包括急性呼吸窘迫综合征、消耗性凝血病和心包炎。虽然大部分实验室确诊病例来自中东(沙特阿拉伯、卡塔尔、约旦和阿联酋),但是密切接触者受到传染的输入性病例在英国、德国、法国、意大利和突尼斯均有报道。在至少六个家庭内或医疗保健群体中怀疑存在人际传染(41,42)。MERS-CoV在人类有超过50%的高致死率,与体外实验呈现出的快速病毒复制和在细胞系中广泛嗜人体组织细胞特性相一致(43,44)。

通过病毒培养来进行实验室确诊冠状病毒感染受到限制,因为这些病毒中的大部分在细胞培养中难以生长,常规的临床实验室缺乏处理SARS-CoV和MERS-CoV的适当的生物安全设施。对HCoV-HKU1,已有使用人呼吸道纤毛上皮细胞培养的报道,但尚未被广泛应用(45)。其它诊断方法包括直接抗原检测、血清学检测和RT-PCR测定。例如,已有报道在SARS-CoV和HCoV-HKU1中针对核衣壳蛋白使用单克隆抗体直接测定呼吸道标本的抗原(33,46,47)。采用中和法进行血清学检测可以比较急性期和恢复期血清样品,如果抗体滴度增加4倍,则确诊感染。然而,测试需要重复采样,据报道还存在抗体交叉反应。例如,虽然SARS-CoV和HCoV-HKU1在系统发育上不同,但在60.7%的SARS患者中存在对SARS-CoV中和抗体的交叉反应(48)。这可能与刺突蛋白七肽重复区2相似性有关,这是一个显著的B细胞表位。针对感染通过这些病毒进行宿主免疫应答的进一步研究可能有助于理解这种现象。

目前,还没有批准用于临床的特异性抗冠状病毒感染药物。许多化合物具有体外活性,但没有经过随机安慰剂对照试验验证(2)。没有1个抗病毒药物或免疫调节剂包括恢复期血浆,被认为是有效的。据报道,利巴韦林和糖皮质激素有可能产生不利影响(49)。已经证明环孢菌素A、干扰素a、干扰素a-2b和利巴韦林对MERS-CoV具有体外抗病毒活性(50,51)。配备机械通气和体外膜肺氧合支持的重症监护仍然是治疗的主要方式(52)。

人冠状病毒的人畜共患起源

流行病学研究发现,最初的SARS患者有宠物接触史。血清流行病学研究表明,动物售卖商SARS-CoVIgG的感染率高于一般人群(53)。携带SARS-CoV样病毒的首个动物是活禽市场中的喜马拉雅果子狸和貉(54)。随后在香港野外地区进行的野生动物监测研究中搜索天然动物宿主时发现,1种密切相关的蝙蝠冠状病毒,SARS相关性菊头蝠冠状病毒HKU3(SARSr-RH-BatCoV HKU3)中国马蹄蝙蝠(菊头蝠属)中(20)。系统发育分析表明,CoV-NL63可能起源于563-822年前分化的蝙蝠冠状病毒(55),而CoV-HKU1也有可能起源于蝙蝠冠状病毒(56)。MERS-CoV复制酶基因的初步系统发育分析表明,该病毒与蝙蝠CoV-HKU4和CoV-HKU5最密切相关(14,15,57)。最近使用部分复制酶序列的系统发育分析表明,MERS–CoV与来自欧洲和非洲的蝙蝠β冠状病毒更密切相关(58,59)。截至发稿时止,相关冠状病毒还没能从中东的动物中分离出来。继续寻找自然界存在的中间动物宿主有助于控制目前的疫情。

在蝙蝠被确定为SARS-CoV的天然宿主后,开始加速在蝙蝠中寻找新型冠状病毒。蝙蝠作为唯一飞行的哺乳动物能够长途跋涉,这有利于病毒的传播(60,61)。除了SARSr-RH-BatCoV HKU3,在香港发现的蝙蝠冠状病毒还包括菊头蝙蝠CoV-HKU2(62)、扁颅蝠冠状病毒CoV-HKU4(18)、伏翼蝙蝠CoV-HKU5(18)、鼠耳蝠蝙蝠CoV-HKU6(18)、折翅蝙蝠CoV-HKU7(18)和CoV-HKU8(18),蹄和棕果蝠COV-HKU10(63)。其他蝙蝠冠状病毒也已经在世界不同地区发现(64,65)。除了蝙蝠,鸟类也是新出现的造成人类感染病毒的一个重要起源,如禽源流感病毒(61)。多个冠状病毒也在多种鸟类中发现(66)。在香港发现的鸟类冠状病毒包括鹎CoV-HKU11、画眉COV-HKU12、文鸟COV-HKU13、绣眼COV-HKU16、麻雀COV-HKU17、鹊鸲COV-HKU18、夜鹭COV-HKU19、赤颈鸭CoV-HKU20和黑水鸡冠状病毒-HKU21。多数蝙蝠冠状病毒属于a冠状病毒和β冠状病毒,而鸟冠状病毒属于γ和δ冠状病毒(67)。除了蝙蝠和鸟类,冠状病毒还在许多其他的家畜和野生哺乳动物中发现,如狗、猫、猪、鲸和羊驼(66,68-70)。骆驼被怀疑是MERS-CoV的宿主,因为病毒起源自中东,部分患者在发病前曾经接触过骆驼。事实上,以前已在骆驼中发现肠道冠状病毒(71)。

结论

在过去的16年中,包括SARS-CoV和MERS-CoV在内的冠状病毒,与禽流源流感病毒H5N1和H7N9(72,73),导致人类流行病的高达10-60%的病死率。人畜共患的起源在SARS-CoV、A型流感H5N1和H7N9中发现,而系统发育分析表明,MERS-CoV有可能起源于蝙蝠冠状病毒。在哺乳动物和鸟类中持续监测将能够更好地了解冠状病毒的生态学,并可能在将来帮助预防疾病从动物到人类的传染和爆发。由于在多个MERS-CoV感染群体中存在人际传播,应在医院对疑似或确诊感染者实施严格的感染控制措施。具有呼吸道症状、有疫区旅行史或与在症状发作10至12天内的MERS-CoV者接触史的患者,应当隔离并及早进行测试以避免疾病的院内传播。在一些严重的病例中机械通气和体外膜肺氧合似乎有效。迫切需要开发1种有效的疫苗以及对潜在的特异性抗病毒制剂进行随机对照临床试验。

致谢

声明:作者宣称没有利益冲突。

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(译者:司磊)

Cite this article as: To KK, Hung IF, Chan JF, Yuen KY. From SARS coronavirus to novel animal and human coronaviruses. J Thorac Dis 2013;5(S2):S103-S108. doi: 10.3978/j.issn.2072-1439.2013.06.02 

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