致病性
甲型禽流感病毒株被分类为低致病性禽流感 (low-pathogenic avian influenza, LPAI) 或高致病性禽流感 (highly pathogenic avian influenza , HPAI),所使用的分类标准包括实验性受感染鸡禽中的分子分析和致病性评估。值得注意的是,术语 LPAI 和 HPAI 没有描述人类中感染引起的疾病严重程度,也不一定与之相关。
大多数甲型禽流感病毒是 LPAI 病毒,能在受感染家禽中引起无症状性感染或轻度疾病。LPAI 的 H6N1、H7N2、H7N3、H7N7、H7N9、H9N2、H10N7 和 H10N8 病毒株可以感染人类,导致结膜炎或非致命性上呼吸道和下呼吸道疾病,或者严重的下呼吸道疾病,甚至死亡(H7N9、H10N8)。[15]Skowronski DM, Tweed SA, Petric M, et al. Human illness and isolation of low-pathogenicity avian influenza virus of the H7N3 subtype in British Columbia, Canada. J Infect Dis. 2006 Mar 15;193(6):899-900.
https://academic.oup.com/jid/article/193/6/899/1032927
http://www.ncbi.nlm.nih.gov/pubmed/16479527?tool=bestpractice.com
[16]Peiris M, Yuen KY, Leung CW, et al. Human infection with influenza H9N2. Lancet. 1999 Sep 11;354(9182):916-7.
http://www.ncbi.nlm.nih.gov/pubmed/10489954?tool=bestpractice.com
[17]Uyeki TM, Chong YH, Katz JM, et al. Lack of evidence for human-to-human transmission of avian influenza A (H9N2) viruses in Hong Kong, China 1999. Emerg Infect Dis. 2002 Feb;8(2):154-9.
https://wwwnc.cdc.gov/eid/article/8/2/01-0148_article
http://www.ncbi.nlm.nih.gov/pubmed/11897066?tool=bestpractice.com
[18]Avian influenza A/(H7N2) outbreak in the United Kingdom. Euro Surveill. 2007 May 31;12(5):E070531.2.
http://www.ncbi.nlm.nih.gov/pubmed/17868584?tool=bestpractice.com
[19]Kurtz J, Manvell RJ, Banks J. Avian influenza virus isolated from a woman with conjunctivitis. Lancet. 1996 Sep 28;348(9031):901-2.
http://www.ncbi.nlm.nih.gov/pubmed/8826845?tool=bestpractice.com
[20]World Health Organization. Avian influenza A(H7N9) virus. 2019 [internet publication].
https://www.who.int/influenza/human_animal_interface/influenza_h7n9/en/
[21]Tong XC, Weng SS, Xue F, et al. First human infection by a novel avian influenza A(H7N4) virus. J Infect. 2018 Jun 10;77(3):249-57.
http://www.ncbi.nlm.nih.gov/pubmed/29898409?tool=bestpractice.com
迄今为止,所有已发现的 HPAI 病毒均属于 H5 或 H7 亚型,在家禽中可引起严重疾病。人类 HAPI 病毒感染的疾病表现可从无症状,到重症或威胁生命。罕见情况下,已经发现散发性人类 HPAI 病毒感染病例,例如 H5N1、H5N6、H7N3 和 H7N7,导致了广泛的疾病谱,从结膜炎(包括 H7N3 和 H7N7 病毒)到急性呼吸窘迫综合征,甚至是致死性结局(例如 H7N7 和 H5N1 病毒)。[22]Tweed SA, Skowronski DM, David ST, et al. Human illness from avian influenza H7N3, British Columbia. Emerg Infect Dis. 2004 Dec;10(12):2196-9.
https://wwwnc.cdc.gov/eid/article/10/12/04-0961_article
http://www.ncbi.nlm.nih.gov/pubmed/15663860?tool=bestpractice.com
[23]Nguyen-Van-Tam JS, Nair P, Acheson P, et al. Outbreak of low pathogenicity H7N3 avian influenza in UK, including associated case of human conjunctivitis. Euro Surveill. 2006 May 4;11(5):E060504.2.
http://www.ncbi.nlm.nih.gov/pubmed/16816456?tool=bestpractice.com
[24]International Society for Infectious Diseases. ProMED-mail. Avian influenza (59): China (SC) LPAI H5N6, human, first case, poultry. May 2014 [internet publication].
https://promedmail.org/promed-post/?id=2451125
在 2013-2016 年期间,所有人类甲型 (H7N9)病毒感染病例均由 LPAI 病毒引起。自 2017 年 2 月,在中国的 3 例人类病例以及环境和家禽样本中检测到了具有 HPAI 遗传特征的亚洲谱系甲型(H7N9)病毒。[2]World Health Organization. Human infection with avian influenza A(H7N9) virus - China. Feb 2017 [internet publication].
https://www.who.int/csr/don/27-february-2017-ah7n9-china/en/
[25]Zhou L, Tan Y, Kang M, et al. Preliminary epidemiology of human infections with highly pathogenic avian influenza A(H7N9) virus, China, 2017. Emerg Infect Dis. 2017 Aug;23(8):1355-9.
https://wwwnc.cdc.gov/eid/article/23/8/17-0640_article
http://www.ncbi.nlm.nih.gov/pubmed/28580900?tool=bestpractice.com
病毒学
亚洲谱系 A(H7N9) 是一种重组病毒,含有来自其他甲型禽流感病毒的遗传物质。亚洲 A(H7N9) 病毒的 LPAI 形式是第一种导致人类严重和致命疾病重大暴发的 LPAI 病毒。对血凝素进行编码的 RNA 片段来自在鸭禽中发现的欧亚 A(H7) 禽病毒,而对神经氨酸酶进行编码的片段类似于禽病毒 A(H11N9) 和其他禽病毒 A(H7N9),可能已感染候鸟。六个内部 RNA 片段与中国家禽中分离的 A(H9N2) 病毒密切相关,并且已发现至少两个 LPAI A(H7N9) 病毒亚型。[26]Liu D, Shi W, Shi Y, et al. Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses. Lancet. 2013 Jun 1;381(9881):1926-32.
http://www.ncbi.nlm.nih.gov/pubmed/23643111?tool=bestpractice.com
[27]Lam TT, Wang J, Shen Y, et al. The genesis and source of the H7N9 influenza viruses causing human infections in China. Nature. 2013 Oct 10;502(7470):241-4.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3801098/
http://www.ncbi.nlm.nih.gov/pubmed/23965623?tool=bestpractice.com
分析表明,由于多个连续的重组事件发生而形成了新的亚洲谱系 LPAI A(H7N9) 病毒,此情况可能发生在鸭和鸡中。已感染人类的亚洲谱系 A(H7N9) 病毒的动物宿主尚未得到确认,但在中国东部和南部活禽市场所售家禽的样本中已检测到该病毒。[5]Chen Y, Liang W, Yang S, et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet. 2013 Jun 1;381(9881):1916-25.
http://www.ncbi.nlm.nih.gov/pubmed/23623390?tool=bestpractice.com
[28]Lu J, Wu J, Zeng X, et al. Continuing reassortment leads to the genetic diversity of influenza virus H7N9 in Guangdong, China. J Virol. 2014 Aug;88(15):8297-306.
https://jvi.asm.org/content/88/15/8297.long
http://www.ncbi.nlm.nih.gov/pubmed/24829356?tool=bestpractice.com
亚洲谱系 A(H7N9) 病毒可以感染鸡、鸭、鹌鹑、鸽和鹅;实验性受感染的鹌鹑可将亚洲谱系 A(H7N9) 病毒传播给其他鹌鹑。[29]Pantin-Jackwood MJ, Miller PJ, Spackman E, et al. Role of poultry in the spread of novel H7N9 influenza virus in China. J Virol. 2014 May;88(10):5381-90.
https://jvi.asm.org/content/88/10/5381.long
http://www.ncbi.nlm.nih.gov/pubmed/24574407?tool=bestpractice.com
继实验性感染后,病毒在雪貂、小鼠和非人类灵长类动物中复制。尽管该病毒具有适应哺乳动物的遗传标记,但在雪貂实验模型的感染和传播中,亚洲谱系 LPAI A(H7N9) 病毒似乎比 A(H1N1)pdm09 病毒传染性更低。[26]Liu D, Shi W, Shi Y, et al. Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses. Lancet. 2013 Jun 1;381(9881):1926-32.
http://www.ncbi.nlm.nih.gov/pubmed/23643111?tool=bestpractice.com
[27]Lam TT, Wang J, Shen Y, et al. The genesis and source of the H7N9 influenza viruses causing human infections in China. Nature. 2013 Oct 10;502(7470):241-4.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3801098/
http://www.ncbi.nlm.nih.gov/pubmed/23965623?tool=bestpractice.com
自 2013 年出现以来,亚洲谱系 LPAI A(H7N9) 病毒已显示出遗传和抗原的进化,这对甲型流感病毒来说并不出乎意料或不同寻常。已有关于亚洲谱系 LPAI A(H7N9) 病毒的两个主要亚系的记录,展示了在中国不同地理位置,病毒的存在情况:长江三角洲亚系和珠江三角洲亚系。[3]Yang JR, Liu MT. Human infection caused by an avian influenza A (H7N9) virus with a polybasic cleavage site in Taiwan, 2017. J Formos Med Assoc. 2017 Mar;116(3):210-2.
https://www.sciencedirect.com/science/article/pii/S0929664617301493
http://www.ncbi.nlm.nih.gov/pubmed/28259506?tool=bestpractice.com
[30]Iuliano AD, Jang Y, Jones J, et al. Increase in human infections with avian influenza A(H7N9) virus during the fifth epidemic - China, October 2016-February 2017. MMWR Morb Mortal Wkly Rep. 2017 Mar 10;66(9):254-5.
https://www.cdc.gov/mmwr/volumes/66/wr/mm6609e2.htm
http://www.ncbi.nlm.nih.gov/pubmed/28278147?tool=bestpractice.com
此外,据 2017 年 2 月的报道,在病毒血凝素基因的多碱基剪切位点检测到插入突变,表明出现亚洲谱系 HPAI 甲型(H7N9)病毒。[2]World Health Organization. Human infection with avian influenza A(H7N9) virus - China. Feb 2017 [internet publication].
https://www.who.int/csr/don/27-february-2017-ah7n9-china/en/
[3]Yang JR, Liu MT. Human infection caused by an avian influenza A (H7N9) virus with a polybasic cleavage site in Taiwan, 2017. J Formos Med Assoc. 2017 Mar;116(3):210-2.
https://www.sciencedirect.com/science/article/pii/S0929664617301493
http://www.ncbi.nlm.nih.gov/pubmed/28259506?tool=bestpractice.com
经证实,HPAI A(H5N1) 病毒的切割位点是其在哺乳动物(包括人类)中的毒力因子;相比之下,A(H3N2) 病毒中 HPAI 切割位点的实验性诱导未在雪貂实验模型的感染中增加毒性。一些证据表明,与 LPAI A(H5N1) 病毒相比,HPAI A(H5N1) 病毒[31]Ocaña-Macchi M, Bel M, Guzylack-Piriou L, et al. Hemagglutinin-dependent tropism of H5N1 avian influenza virus for human endothelial cells. J Virol. 2009 Dec;83(24):12947-55.
https://jvi.asm.org/content/83/24/12947.long
http://www.ncbi.nlm.nih.gov/pubmed/19812146?tool=bestpractice.com
[32]Baigent SJ, McCauley JW. Influenza type A in humans, mammals and birds: determinants of virus virulence, host-range and interspecies transmission. Bioessays. 2003 Jul;25(7):657-71.
http://www.ncbi.nlm.nih.gov/pubmed/12815721?tool=bestpractice.com
的空气传播性可能有所降低,[33]Richard M, Herfst S, van den Brand JM, et al. Low virulence and lack of airborne transmission of the Dutch highly pathogenic avian influenza virus H5N8 in ferrets. PLoS One. 2015 Jun 19;10(6):e0129827.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129827
http://www.ncbi.nlm.nih.gov/pubmed/26090682?tool=bestpractice.com
[34]Richard M, Schrauwen EJ, de Graaf M, et al. Limited airborne transmission of H7N9 influenza A virus between ferrets. Nature. 2013 Sep 26;501(7468):560-3.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819191/
http://www.ncbi.nlm.nih.gov/pubmed/23925116?tool=bestpractice.com
并且涉及较低的病毒负荷。目前没有证据表明亚洲谱系 HPAI A(H7N9) 病毒与人类疾病严重程度增加有关或与禽鸟到人类、人类之间的传播性增加有关,但需要对这种不断进化的病毒进行其他研究和监测。
在亚洲谱系甲型(H7N9)病毒中偶尔也检测到与神经氨酸酶抑制剂抗病毒药物敏感性降低相关的氨基酸替代物,[35]Zhou J, Wang D, Gao R, et al. Biological features of novel avian influenza A (H7N9) virus. Nature. 2013 Jul 25;499(7459):500-3.
http://www.ncbi.nlm.nih.gov/pubmed/23823727?tool=bestpractice.com
[36]Hay AJ, Hayden FG. Oseltamivir resistance during treatment of H7N9 infection. Lancet. 2013 Jun 29;381(9885):2230-2.
http://www.ncbi.nlm.nih.gov/pubmed/23809549?tool=bestpractice.com
[37]Hu Y, Lu S, Song Z, et al. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet. 2013 Jun 29;381(9885):2273-9.
http://www.ncbi.nlm.nih.gov/pubmed/23726392?tool=bestpractice.com
[38]Liu X, Li T, Zheng Y, et al. Poor responses to oseltamivir treatment in a patient with influenza A (H7N9) virus infection. Emerg Microbes Infect. 2013 May;2(5):e27.
https://www.tandfonline.com/doi/full/10.1038/emi.2013.30
http://www.ncbi.nlm.nih.gov/pubmed/26038464?tool=bestpractice.com
[39]Marjuki H, Mishin VP, Chesnokov AP, et al. Neuraminidase mutations conferring resistance to oseltamivir in influenza A(H7N9) viruses. J Virol. 2015 May;89(10):5419-26.
https://jvi.asm.org/content/89/10/5419.long
http://www.ncbi.nlm.nih.gov/pubmed/25740997?tool=bestpractice.com
[40]Marjuki H, Mishin VP, Chesnokov AP, et al. Characterization of drug-resistant influenza A(H7N9) variants isolated from an oseltamivir-treated patient in Taiwan. J Infect Dis. 2015 Jan 15;211(2):249-57.
https://academic.oup.com/jid/article/211/2/249/2910585
http://www.ncbi.nlm.nih.gov/pubmed/25124927?tool=bestpractice.com
[41]Gao HN, Yao HP, Liang WF, et al. Viral genome and antiviral drug sensitivity analysis of two patients from a family cluster caused by the influenza A(H7N9) virus in Zhejiang, China, 2013. Int J Infect Dis. 2014 Dec;29:254-8.
https://www.ijidonline.com/article/S1201-9712(14)01695-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/25462187?tool=bestpractice.com
包括最近检测到的一些 HPAI 病毒。[2]World Health Organization. Human infection with avian influenza A(H7N9) virus - China. Feb 2017 [internet publication].
https://www.who.int/csr/don/27-february-2017-ah7n9-china/en/
对于已进行序列分析的病毒,其对药物敏感性降低的比例与不同年度之间亚洲谱系 A(H7N9) 病毒活性波动相似。[2]World Health Organization. Human infection with avian influenza A(H7N9) virus - China. Feb 2017 [internet publication].
https://www.who.int/csr/don/27-february-2017-ah7n9-china/en/
[42]European Centre for Disease Prevention and Control. Influenza A(H7N9) virus in China: implications for public health. Seventh update. Jul 2017 [internet publication].
https://www.ecdc.europa.eu/sites/portal/files/documents/2017-07-03-RRA-Disease-China_H7N9_0.pdf
针对 83 种亚洲谱系 A(H7N9) 病毒进行的遗传分析在三种病毒中发现了与药物敏感性降低相关的氨基酸替代物:两种具有 R292K,一种具有 A246T(N2 编号)。[2]World Health Organization. Human infection with avian influenza A(H7N9) virus - China. Feb 2017 [internet publication].
https://www.who.int/csr/don/27-february-2017-ah7n9-china/en/
具有 R292K 氨基酸替代物的病毒表现出对奥司他韦的耐药性和对扎那米韦和帕拉米韦的敏感性降低。[37]Hu Y, Lu S, Song Z, et al. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet. 2013 Jun 29;381(9885):2273-9.
http://www.ncbi.nlm.nih.gov/pubmed/23726392?tool=bestpractice.com
某些分离株展现出对奥司他韦的敏感性降低,但对帕拉米韦的敏感性不变。[43]Gao R, Cao B, Hu Y, et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013 May 16;368(20):1888-97.
https://www.nejm.org/doi/10.1056/NEJMoa1304459
http://www.ncbi.nlm.nih.gov/pubmed/23577628?tool=bestpractice.com
尽管相关临床数据的报告不完整,但是在受影响个体中使用神经氨酸酶抑制剂进行治疗之后或期间,某些病毒中似乎出现敏感性降低的情况。[42]European Centre for Disease Prevention and Control. Influenza A(H7N9) virus in China: implications for public health. Seventh update. Jul 2017 [internet publication].
https://www.ecdc.europa.eu/sites/portal/files/documents/2017-07-03-RRA-Disease-China_H7N9_0.pdf
几种降低神经氨酸酶抑制剂敏感性的氨基酸替代不会导致体外细胞系的病毒适应性降低(即,不会降低亚洲谱系甲型 HPAI [H7N9] 病毒的复制)。[44]Tang J, Zhang J, Zhou J, et al. Highly pathogenic avian influenza H7N9 viruses with reduced susceptibility to neuraminidase inhibitors showed comparable replication capacity to their sensitive counterparts. Virol J. 2019 Jul 2;16(1):87.
https://virologyj.biomedcentral.com/articles/10.1186/s12985-019-1194-9
http://www.ncbi.nlm.nih.gov/pubmed/31266524?tool=bestpractice.com
测序数据表明,所有亚洲谱系甲型(H7N9)病毒本身就对金刚烷抗病毒药物(金刚烷胺和金刚乙胺)具有耐药性,因为它们都存在 S31N 氨基酸取代。
应该注意的是,2017 年 3 月在美国田纳西州的商业禽类中检测到的北美野生禽鸟谱系 HPAI A(H7N9) 病毒在基因上与亚洲谱系 A(H7N9) 病毒不同。美国家禽中也检测出北美野生禽鸟谱系 LPAI A(H7N9) 病毒;到目前为止,在美国尚未发现 HPAI 病毒或 LPAI A(H7N9) 病毒的人类感染病例。在 2013 年亚洲谱系 A(H7N9) 病毒出现之前,在野生禽鸟中已检测到其他不同的 LPAI A(H7N9) 病毒。[45]Olson SH, Gilbert M, Cheng MC, et al. Historical prevalence and distribution of avian influenza virus A(H7N9) among wild birds. Emerg Infect Dis. 2013 Dec;19(12):2031-3.
https://wwwnc.cdc.gov/eid/article/19/12/13-0649_article
http://www.ncbi.nlm.nih.gov/pubmed/24274638?tool=bestpractice.com