1、,北京地坛医院感染中心 王凌航 Mar 28th，2018,Human-Avian influenza 人禽流感,概述,1900年首次发现禽流感病毒，被命名为“真性鸡瘟病毒”(fowl plague virus) 1955年，才正式确定其为甲型流感病毒，并在以后命名为禽流感病毒 人禽流感是由禽流感病毒中的某些亚型（H5、H7、H9、H10等）引起的人急性呼吸道传染病，临床表现随亚型差异而有不同，从轻微卡他症状、结膜炎到ARDS、MOF甚至死亡 H5N1，H7N2，H7N3，H7N7，H9N2均属于高致病性禽流感病毒（HPAI） 致病性最强的首推H5N1,HPAI,高致病性 高致病性禽流感因其传
2、播快、危害大，被世界动物卫生组织列为A类动物疫病，我国将其列为一类动物疫病，多为H5和H7型病毒 低致病性 低致病性禽流感可使禽类出现轻度呼吸道症状，食量减少、产蛋量下降，出现零星死亡 非致病性 不会引起明显症状，仅使染病的禽鸟体内产生病毒抗体,近年来流行的禽流感,病原学,流感病毒分型,流感病毒基因组均含有8个节段 ，在病毒RNA的第5节段上含有一种编码长度为498个氨基酸的蛋白，称为NP蛋白 根据病毒NP蛋白抗原性的不同，把流感病毒分为甲、乙、丙三型,禽流感病毒抵抗力,对热敏感 65,30min；100，2min可使病毒灭活 22感染性最稳定 4保存数月，-70保存数年 对紫外线敏感 在水中
3、存活的时间长(1个月) 酸性环境可破坏病毒的感染性 中性和弱碱性环境中其感染性稳定 许多消毒剂均敏感(乙醚、氯仿、丙酮、氯化剂、十二烷基硫酸钠、漂白粉、碘、高锰酸钾、酒精等),流感病毒命名,H and N,H：红细胞凝集素,能与红细胞发生凝集 在感染靶细胞、决定宿主范围等方面起重要作用 能诱导机体产生保护性中和抗体 在病毒感染和复制过程中也具有作用 分型的主要依据，共16个H亚型（H1-H16）,N：神经氨酸酶,具有保证病毒从感染细胞中释放的能力 能防止病毒从宿主细胞释放后形成聚集体 具有唾液酸酶活性，通过切除呼吸道黏液中的神经氨酸，防止病毒失活并提高病毒进入呼吸道上皮细胞的穿透力 神经氨酸酶
4、抗体不具有中和病毒感染的能力，但能减轻流感的症状 病毒神经氨酸酶氨基酸的变化是产生耐药性及新型病毒形成的一个重要根源 9个N亚型（N1-N9）,传染源,主要传染源：病禽和带病毒禽（鸡、火鸡、鸭、鹅、鹌鹑、野鸭、鸵鸟、鸽、孔雀及各种鸟类） 另外也可借助于猪、马类等其他哺乳类动物传播,传播途径,病毒在禽类的呼吸道和肠道内繁殖，可从呼吸道、结膜通过分泌物排出，或通过肠道从粪便中排出，粪便中排出的病毒量最大 禽类动物可通过呼吸道、消化道感染 呼吸道：鸡舍、猪圈等处的病毒以气溶胶的形式存在于空气中，经呼吸道感染 直接接触：通过皮肤接触，粪便、羽毛、分泌物中的病毒感染人体 消化道：进食未煮熟的病禽或被病毒
5、污染的食物 禽感染在先，突然发生，传播迅速，呈流行性；人感染在后，呈散发性,传播途径,For human influenza A (H5N1) infections, bird-to-human is the predominant route of transmission; limited, nonsustained human-to-human transmission has also occurred, environment-to-human spread is thought to be possible,易感人群,人群普遍易感 无性别差异 任何年龄均可患病，儿童较多见,Tiss
6、ue tropism,Human influenza viruses preferentially bind to host cells via HA by attaching to sialic acid molecules containing alpha 2-6 galactose receptors that are found on epithelial cells of the human upper respiratory tract. Avian influenza viruses, including H5N1, prefer sialic acid molecules co
7、ntaining alpha 2-3 galactose receptors, which are common in the respiratory tracts of birds but have also been detected throughout the human respiratory tract, particularly in alveoli and distal airways. This observation supports in vitro studies that demonstrate binding of H5N1 to tissue extracted
8、from the lower airways of humans. This pattern of binding is also consistent with post mortem examination of H5N1-infected patients that shows heavy damage to the lower lungs but not the upper airways.,H5N1,More than 840 clinical cases of H5N1 influenza infection have been reported in humans since 2
9、003, although the actual number of infections transmitted from birds to humans may be considerably higher. Two features of recent avian influenza H5N1 outbreaks are striking: the predominance of children and young adults and the high mortality rate. the case-fatality rate is approximately 53%; Howev
10、er, seroprevalence studies have found that some exposed individuals may have had a subclinical or mild infection, suggesting that the reported case-fatality rate may be an overestimate Highly pathogenic avian H5N1 influenza viruses are endemic among bird and poultry populations in Eurasia. Sporadic
11、transmission to humans raises concern that the H5N1 virus may mutate or combine with genetic material from coinfecting human influenza viruses to generate a novel strain capable of sustained human-to-human transmission with pandemic potential.,H7N9,In late March and April 2013, human cases of novel
12、avian influenza A H7N9 infection in China were reported to WHO. The earliest cases occurred in eastern China, but additional cases have been detected in other parts of mainland China as well as in Hong Kong, Taiwan, Malaysia, and Canada. The initial wave occurred from February to May 2013, during wh
13、ich 133 cases were detected. Some of the affected patients had exposures to poultry before becoming ill. To date, there is no evidence of sustained human-to-human transmission. Several genetic characteristics of avian influenza A H7N9 viruses isolated from humans suggest that it may have potential f
14、or high virulence. As an example, mutations at the receptor-binding site suggest that it has adapted to be able to bind to human-type (alpha 2-6 galactose) receptors in the respiratory tract. Patients have presented with respiratory tract infections, many of which have progressed to severe pneumonia
15、. Other clinical features have included acute respiratory distress syndrome, septic shock, multiorgan failure, rhabdomyolysis, and encephalopathy,H7N9,其他类型禽流感,Avian influenza H5N6 In 2014, a man in China developed pneumonia and respiratory failure caused by a novel avian influenza H5N6 virus. He req
16、uired a long hospital stay but eventually recovered. He regularly purchased and handled live poultry in poultry markets. Avian influenza H9N2 In Hong Kong in 1999, 2003, 2007, and 2009, influenza H9N2 viruses were isolated mainly from children with mild, self-limited respiratory infection. In a sero
17、logic study, 99 of 2191 poultry workers in China (4.5 %) had anti-H9 antibodies, suggesting that subclinical infection occurs .The highest rate of seropositivity was observed in poultry retailers in food markets (16 %), suggesting that direct contact with live birds and/or slaughtering poultry may b
18、e risk factors for acquisition. Avian influenza H7N7 Avian influenza H7 viruses have also been linked to occasional human disease . Extensive outbreaks of H7N7 occurred among poultry in the Netherlands in 2003. Among workers involved in the control of these outbreaks, including culling of poultry, t
19、here were 83 virologically confirmed cases of H7 conjunctivitis (of which five had influenza-like illness), and two cases of isolated respiratory illness,其他类型禽流感,Avian influenza H6N1 In May 2013, a previously healthy 20-year-old woman in Taiwan presented to a hospital with fever, nonproductive cough
20、, and shortness of breath and was found to have pneumonia and to be infected with avian influenza A H6N1, an influenza subtype known to circulate in wild and domestic avian species Avian influenza H10N8 and H10N7 In December 2013, the first human infection with avian influenza H10N8 was detected in
21、a 73-year-old woman in China who had several comorbidities, including thymectomy for myasthenia gravis. The patient had visited a live-bird market four days before the onset of illness. She developed severe pneumonia and died several days after being hospitalized. A second case in China was detected
22、 in a 55-year-old woman with severe pneumonia who had also visited a live-bird market. Avian influenza A H10N8 has been detected previously in wild and domestic birds in China as well as in South Korea, Japan, the United States, Canada, Italy, and Sweden.,临床表现,一般表现 潜伏期多为3-4天，一般在7天以内 急性起病，早期表现与其它流感非常
23、相似，以持续高热最常见 同时可有呼吸道、消化道和眼结膜炎的症状和体征 半数患者有肺炎 重症表现 病毒毒力强，患者抵抗力弱，可发展为重症 病情进展快，肺部炎症进行性加重，并发ARDS、肺出血、反应性胸腔积液、全血细胞减少、肾衰、败血症休克、Reye综合征、多脏器衰竭等,实验室检查,血白细胞计数多数降低，少数因继发细菌感染而升高，淋巴细胞降低，血小板正常 咽拭子细菌培养阴性 骨髓穿刺示细胞增生活跃，反应性组织细胞增生伴出血性吞噬现象 部分患者 ALT升高 半数患者胸部X线摄像显示单侧或双侧肺炎，少数伴胸腔积液,影像学检查,Radiographic findings of H5N1 avian in
24、fluenza include diffuse, multifocal, or patchy infiltrates; interstitial infiltrates; and segmental or lobular consolidation. Pleural effusions are usually not seen. Progression to respiratory failure is associated with diffuse bilateral ground-glass infiltrates,影像学检查,病理学检查,以反应性噬血细胞综合征为突出特征 伴有纤维化的弥漫
25、性肺泡损伤 广泛肝小叶中心坏死 急性肾小管坏死 淋巴功能衰竭 可溶性IL-2受体、IL-6、干扰素升高,禽流感病原及免疫诊断,病毒核酸检测 病毒分离 血清禽流感抗体,禽流感诊断及病例定义,根据流行病学史、临床表现和相关实验室检查综合判断 流行病学史：发病前1周内与禽类及其分泌物、排泄物等有接触史。 诊断标准 （1）疑似病例：符合上述临床表现，甲型流感病毒抗原阳性，或有流行病学接触史。 （2）确诊病例：符合上述临床表现，或有流行病学接触史，并且呼吸道分泌物标本中分离出禽流感病毒或禽流感病毒核酸检测阳性或动态检测双份血清禽流感病毒特异性抗体水平呈4倍或以上升高。 重症病例：肺炎合并呼吸功能衰竭或其
26、他器官功能衰竭者为重症病例。,MERS诊断及病例定义,根据流行病学史、临床表现和相关实验室检查综合判断 确诊病例：（具备下述4项之一） 至少双靶标PCR检测阳性。 单个靶标PCR阳性产物，经过基因测序确认。 从呼吸道标本中分离出中东呼吸综合征冠状病毒。 恢复期血清中东呼吸综合征冠状病毒抗体较急性期血清抗体水平阳转或呈4倍以上升高。,鉴别诊断,季节性流感（含甲型H1N1流感） 细菌性肺炎 传染性非典型肺炎（SARS） 新型冠状病毒肺炎 腺病毒肺炎 衣原体肺炎 支原体肺炎等,鉴别诊断,治疗,抗病毒治疗,Although the optimal dose and duration are unkno
27、wn, oseltamivir is typically administered to patients with uncomplicated disease at a dose of 75 mg twice daily for five days. Patients with pneumonia or clinical worsening on the lower dose should be given 150 mg twice daily for 10 days 帕拉米韦（ Peramivir ）注射液在疗效上优于磷酸奥司他韦，能够有效对抗耐奥司他韦的流感病毒，且剂型为注射液，适应流感
28、危重病人和对其它神经氨酸酶抑制剂疗效不佳患者的救治；成人用量为300-600mg，静脉滴注，每日1次，疗程1-5天。 实验室资料提示金刚烷胺（Amantadine）和金刚乙胺（Rimantadine）耐药，不建议单独使用,其他治疗,如出现低氧血症或呼吸衰竭的情况，应及时给予相应的治疗措施，包括吸氧、无创机械通气或有创机械通气等 出现其他脏器功能损害时，给予相应支持治疗 对病情严重者（如出现感染中毒性休克合并急性呼吸窘迫综合征），可考虑给予小剂量糖皮质激素治疗。不推荐使用大剂量糖皮质激素 合并细菌感染时，给予相应抗菌药物治疗,出院标准,因基础疾病或合并症较重，需较长时间住院治疗的患者，待人感染禽
29、流感病毒核酸检测连续2次阴性后，可转出隔离病房至相应病房或科室进一步治疗。 体温正常，临床症状基本消失，呼吸道标本人感染禽流感病毒核酸检测连续2次阴性，可以出院。,预防-PEP,The World Health Organization recommends that household contacts of patients with H5N1 avian influenza should receive postexposure prophylaxis with 75 mg of oseltamivir once daily for seven to ten days. Individuals who have been exposed to a proven or potential case of avian influenza should monitor their temperature,疫苗,
