Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 28, Number 7—July 2022
Research

Epidemiologic, Clinical, and Genetic Characteristics of Human Infections with Influenza A(H5N6) Viruses, China

Wenfei Zhu1, Xiyan Li1, Jie Dong1, Hong Bo, Jia Liu, Jiaying Yang, Ye Zhang, Hejiang Wei, Weijuan Huang, Xiang Zhao, Tao Chen, Jing Yang, Zi Li, Xiaoxu Zeng, Chao Li, Jing Tang, Li Xin, Rongbao Gao, Liqi Liu, Min Tan, Yuelong Shu, Lei YangComments to Author , and Dayan WangComments to Author 
Author affiliations: National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China (W. Zhu, X. Li, J. Dong, H. Bo, J. Liu, Jiaying Yang, Y. Zhang, H. Wei, W. Huang, X. Zhao, T. Chen, Jing Yang, Z. Li, X. Zeng, C. Li. J. Tang, L. Xin, R. Gao, L. Liu, M. Tan, Y. Shu, L. Yang, D. Wang); Chinese Center for Disease Control and Prevention, Beijing (C. Li); World Health Organization Collaborating Centre for Reference and Research on Influenza, Beijing (W. Zhu, X. Li, J. Dong, H. Bo, J. Liu, Jiaying Yang, Y. Zhang, H. Wei, W. Huang, X. Zhao, T. Chen, Jing Yang, Z. Li, X. Zeng, J. Tang, L. Xin, R. Gao, L. Liu, M. Tan, Y. Shu, L. Yang, D. Wang); Key Laboratory for Medical Virology, National Health and Family Planning Commission, Beijing (W. Zhu, X. Li, J. Dong, H. Bo, J. Liu, Jiaying Yang, Y. Zhang, H. Wei, W. Huang, X. Zhao, T. Chen, Jing Yang, Z. Li, X. Zeng, J. Tang, L. Xin, R. Gao, L. Liu, M. Tan, Y. Shu, L. Yang, D. Wang); Sun Yat-sen University, Guangzhou, China (Jiaying Yang, Y. Shu)

Main Article

Table 3

Comparison of characteristics of laboratory-confirmed cases of human infection with avian influenza A(H5N6) virus before and during 2021, China*

Characteristic No. case-patients before 2021, n = 29 No. case-patients during 2021, n = 36 p value
Sex
M 12 (41.4) 21 (58.3) 0.17
F
 17 (58.6)
 15 (41.7)
Median age, y (IQR)
 40 (25-50)
 54 (49.5–60.5)
 <0.001
Age group, y <0.05
0–15 6 (20.7) 2 (5.6)
16–59 21 (72.4) 24 (66.7)
>60
 2 (6.9)
 10 (27.8)
Rural residence
 10 (34.5)
 21 (58.3)
 0.06
Fatality
 18 (62.1)
 18 (53.0)
 0.47
Poultry exposure <10 d before illness onset
Any exposure to poultry 25 (86.2) 36 (100.0) <0.05
Visited live poultry market 18 (78.3) 20 (58.8) 0.13
Exposure to backyard poultry 8 (34.8) 20 (58.8) 0.07
Exposure to sick or dead poultry 7 (30.4) 16 (45.7) 0.24
Processed poultry: slaughtered, cleaned, depilated, cooked
 11 (50.0)
 17 (51.5)
 0.91
Comorbidities†
Any‡ 11 (44.0) 20 (66.7) 0.09
Hypertension 3 (12.0) 11 (36.7) <0.05
Diabetes 2 (8.0) 2 (6.7) 1.00
Coronary heart disease 3 (12.0) 5 (16.7) 0.72
Cancer 4 (16.0) 2 (6.7) 0.39
Chronic renal disease
 0 (0.0)
 4 (13.3)
 0.12
Median time from illness onset to hospital admission, d (IQR) 5 (2.0–6.0) 4 (2.5–6.0) 0.61
Median time from illness onset to laboratory 
confirmation, d (IQR) 9 (7.0–12.0) 8.5 (7.0-12.0) 0.90
Median time from illness onset to oseltamivir treatment, d (IQR) 5 (3.0–9.0) 6 (2.0-8.0) 0.94
Median time from illness onset to ICU admission, d (IQR) 6 (5.0–7.0) 6 (4.5-8.0) 0.60
Median time from hospital admission to death, d (IQR) 16 (3.0–24.0) 12 (8.0–26.0) 0.50
Mean time from hospital admission to discharge, d (SD) 26.0 + 19.0 30.7 + 19.3 0.68

*Values are no. (%) except as indicated. IQR, interquartile range. †Only underlying diseases associated with a high risk for influenza complications (32) were counted here, including chronic respiratory disease, asthma, chronic cardiovascular disease, diabetes, chronic liver disease, chronic kidney disease, immunosuppressed status, and neuromuscular disorders. ‡Ten cases for which existence of comorbidities was unknown were excluded.

Main Article

References
  1. Pan  M, Gao  R, Lv  Q, Huang  S, Zhou  Z, Yang  L, et al. Human infection with a novel, highly pathogenic avian influenza A (H5N6) virus: Virological and clinical findings. J Infect. 2016;72:52–9. DOIPubMedGoogle Scholar
  2. Chen  H, Yuan  H, Gao  R, Zhang  J, Wang  D, Xiong  Y, et al. Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection: a descriptive study. Lancet. 2014;383:714–21. DOIPubMedGoogle Scholar
  3. Gao  R, Cao  B, Hu  Y, Feng  Z, Wang  D, Hu  W, et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013;368:1888–97. DOIPubMedGoogle Scholar
  4. Wang  D, Zhu  W, Yang  L, Shu  Y. The epidemiology, virology, and pathogenicity of human infections with avian influenza viruses. Cold Spring Harb Perspect Med. 2021;11:a038620. DOIPubMedGoogle Scholar
  5. Yang  L, Zhao  X, Li  X, Bo  H, Li  D, Liu  J, et al. Case report for human infection with a highly pathogenic avian influenza A(H5N6) virus in Beijing, China 2019. Biosafety and Health. 2020;2:49–52. DOIGoogle Scholar
  6. World Health Organization. Cumulative number of confirmed human cases for avian influenza A(H5N1) reported to WHO, 2003–2021, 1 October 2021 [cited 2021 Nov 19]. https://www.who.int/publications/m/item/cumulative-number-of-confirmed-human-cases-for-avian-influenza-a(h5n1)-reported-to-who-2003-2021-1-october-2021
  7. Li  KS, Guan  Y, Wang  J, Smith  GJ, Xu  KM, Duan  L, et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature. 2004;430:209–13. DOIPubMedGoogle Scholar
  8. Jeong  J, Kang  HM, Lee  EK, Song  BM, Kwon  YK, Kim  HR, et al. Highly pathogenic avian influenza virus (H5N8) in domestic poultry and its relationship with migratory birds in South Korea during 2014. Vet Microbiol. 2014;173:249–57. DOIPubMedGoogle Scholar
  9. Lee  DH, Torchetti  MK, Winker  K, Ip  HS, Song  CS, Swayne  DE. Intercontinental spread of Asian-origin H5N8 to North America through Beringia by migratory birds. J Virol. 2015;89:6521–4. DOIPubMedGoogle Scholar
  10. Butler  J, Stewart  CR, Layton  DS, Phommachanh  P, Harper  J, Payne  J, et al. Novel reassortant H5N6 influenza A virus from the Lao People’s Democratic Republic is highly pathogenic in chickens. PLoS One. 2016;11:e0162375. DOIPubMedGoogle Scholar
  11. Yang  L, Zhu  W, Li  X, Bo  H, Zhang  Y, Zou  S, et al. Genesis and dissemination of highly pathogenic H5N6 avian influenza viruses. J Virol. 2017;91:e02199–16. DOIPubMedGoogle Scholar
  12. Chu  DH, Okamatsu  M, Matsuno  K, Hiono  T, Ogasawara  K, Nguyen  LT, et al. Genetic and antigenic characterization of H5, H6 and H9 avian influenza viruses circulating in live bird markets with intervention in the center part of Vietnam. Vet Microbiol. 2016;192:194–203. DOIPubMedGoogle Scholar
  13. Bi  Y, Chen  Q, Wang  Q, Chen  J, Jin  T, Wong  G, et al. Genesis, evolution and prevalence of H5N6 avian influenza viruses in China. Cell Host Microbe. 2016;20:810–21. DOIPubMedGoogle Scholar
  14. Xu  W, Li  X, Bai  T, Zhao  X, Zhao  X, Zhang  Y, et al. A fatal case of infection with a further reassortant, highly pathogenic avian influenza (HPAI) H5N6 virus in Yunnan, China. Infect Genet Evol. 2016;40:63–6. DOIPubMedGoogle Scholar
  15. Yang  L, Zhu  W, Li  X, Bo  H, Zhang  Y, Zou  S, et al. Genesis and dissemination of highly pathogenic H5N6 avian influenza viruses. J Virol. 2017;91:e02199–16. DOIPubMedGoogle Scholar
  16. Cui  Y, Li  Y, Li  M, Zhao  L, Wang  D, Tian  J, et al. Evolution and extensive reassortment of H5 influenza viruses isolated from wild birds in China over the past decade. Emerg Microbes Infect. 2020;9:1793–803. DOIPubMedGoogle Scholar
  17. Zhang  Y, Chen  M, Huang  Y, Zhu  W, Yang  L, Gao  L, et al. Human infections with novel reassortant H5N6 avian influenza viruses in China. Emerg Microbes Infect. 2017;6:e50. DOIPubMedGoogle Scholar
  18. Sun  W, Li  J, Hu  J, Jiang  D, Xing  C, Zhan  T, et al. Genetic analysis and biological characteristics of different internal gene origin H5N6 reassortment avian influenza virus in China in 2016. Vet Microbiol. 2018;219:200–11. DOIPubMedGoogle Scholar
  19. Chen  Z, Wang  Z, Zhao  X, Guan  Y, Xue  Q, Li  J, et al. Pathogenicity of different H5N6 highly pathogenic avian influenza virus strains and host immune responses in chickens. Vet Microbiol. 2020;246:108745. DOIPubMedGoogle Scholar
  20. Sun  H, Pu  J, Hu  J, Liu  L, Xu  G, Gao  GF, et al. Characterization of clade 2.3.4.4 highly pathogenic H5 avian influenza viruses in ducks and chickens. Vet Microbiol. 2016;182:116–22. DOIPubMedGoogle Scholar
  21. Li  Y, Li  M, Li  Y, Tian  J, Bai  X, Yang  C, et al. Outbreaks of highly pathogenic avian influenza (H5N6) virus subclade 2.3.4.4h in Swans, Xinjiang, Western China, 2020. Emerg Infect Dis. 2020;26:2956–60. DOIPubMedGoogle Scholar
  22. Sun  H, Pu  J, Wei  Y, Sun  Y, Hu  J, Liu  L, et al. Highly pathogenic avian influenza H5N6 Viruses exhibit enhanced affinity for human type sialic acid receptor and in-contact transmission in model ferrets. J Virol. 2016;90:6235–43. DOIPubMedGoogle Scholar
  23. Bi  Y, Liu  H, Xiong  C, Di Liu , Shi  W, Li  M, et al. Novel avian influenza A (H5N6) viruses isolated in migratory waterfowl before the first human case reported in China, 2014. Sci Rep. 2016;6:29888. DOIPubMedGoogle Scholar
  24. Koutsakos  M, Wheatley  AK, Laurie  K, Kent  SJ, Rockman  S. Influenza lineage extinction during the COVID-19 pandemic? Nat Rev Microbiol. 2021;19:741–2. DOIPubMedGoogle Scholar
  25. World Health Organization. Assessment of risk associated with highly pathogenic avian influenza A(H5N6) virus [cited 2021 Nov 19]. https://cdn.who.int/media/docs/default-source/influenza/avian-and-other-zoonotic-influenza/a(h5n6)-risk-assessment.pdf
  26. Yu  L, Wang  Z, Chen  Y, Ding  W, Jia  H, Chan  JF, et al. Clinical, virological, and histopathological manifestations of fatal human infections by avian influenza A(H7N9) virus. Clin Infect Dis. 2013;57:1449–57. DOIPubMedGoogle Scholar
  27. Zhou  B, Donnelly  ME, Scholes  DT, St George  K, Hatta  M, Kawaoka  Y, et al. Single-reaction genomic amplification accelerates sequencing and vaccine production for classical and Swine origin human influenza a viruses. J Virol. 2009;83:10309–13. DOIPubMedGoogle Scholar
  28. McGinnis  J, Laplante  J, Shudt  M, George  KS. Next generation sequencing for whole genome analysis and surveillance of influenza A viruses. [Erratum in: J Clin Virol. 2017;93:65]. J Clin Virol. 2016;79:44–50. DOIPubMedGoogle Scholar
  29. Stamatakis  A. RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics. 2014;30:1312–3. DOIPubMedGoogle Scholar
  30. Drummond  AJ, Rambaut  A. BEAST: Bayesian evolutionary analysis by sampling trees. BMC Evol Biol. 2007;7:214. DOIPubMedGoogle Scholar
  31. Drummond  AJ, Rambaut  A, Shapiro  B, Pybus  OG. Bayesian coalescent inference of past population dynamics from molecular sequences. Mol Biol Evol. 2005;22:1185–92. DOIPubMedGoogle Scholar
  32. Fiore  AE, Shay  DK, Broder  K, Iskander  JK, Uyeki  TM, Mootrey  G, et al.; Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep. 2008;57(RR-7):1–60.PubMedGoogle Scholar
  33. Influenza  HE. In: Epidemiology and prevention of vaccine-preventable diseases, 14th edition. 2021 [cited 2022 Apr 21]. https://www.cdc.gov/vaccines/pubs/pinkbook/flu.html#impact
  34. Shi  Y, Zhang  W, Wang  F, Qi  J, Wu  Y, Song  H, et al. Structures and receptor binding of hemagglutinins from human-infecting H7N9 influenza viruses. Science. 2013;342:243–7. DOIPubMedGoogle Scholar
  35. Xu  R, de Vries  RP, Zhu  X, Nycholat  CM, McBride  R, Yu  W, et al. Preferential recognition of avian-like receptors in human influenza A H7N9 viruses. Science. 2013;342:1230–5. DOIPubMedGoogle Scholar
  36. Ramos  I, Krammer  F, Hai  R, Aguilera  D, Bernal-Rubio  D, Steel  J, et al. H7N9 influenza viruses interact preferentially with α2,3-linked sialic acids and bind weakly to α2,6-linked sialic acids. J Gen Virol. 2013;94:2417–23. DOIPubMedGoogle Scholar
  37. Guo  H, de Vries  E, McBride  R, Dekkers  J, Peng  W, Bouwman  KM, et al. Highly pathogenic influenza A(H5Nx) viruses with altered H5 receptor-binding specificity. Emerg Infect Dis. 2017;23:220–31. DOIPubMedGoogle Scholar
  38. Yang  ZY, Wei  CJ, Kong  WP, Wu  L, Xu  L, Smith  DF, et al. Immunization by avian H5 influenza hemagglutinin mutants with altered receptor binding specificity. Science. 2007;317:825–8. DOIPubMedGoogle Scholar
  39. Steel  J, Lowen  AC, Mubareka  S, Palese  P. Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathog. 2009;5:e1000252. DOIPubMedGoogle Scholar
  40. Li  Z, Chen  H, Jiao  P, Deng  G, Tian  G, Li  Y, et al. Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. J Virol. 2005;79:12058–64. DOIPubMedGoogle Scholar
  41. Subbarao  EK, London  W, Murphy  BR. A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol. 1993;67:1761–4. DOIPubMedGoogle Scholar
  42. Gabriel  G, Dauber  B, Wolff  T, Planz  O, Klenk  HD, Stech  J. The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci U S A. 2005;102:18590–5. DOIPubMedGoogle Scholar
  43. Lan  Y, Zhang  Y, Dong  L, Wang  D, Huang  W, Xin  L, et al. A comprehensive surveillance of adamantane resistance among human influenza A virus isolated from mainland China between 1956 and 2009. Antivir Ther. 2010;15:853–9. DOIPubMedGoogle Scholar
  44. Cowling  BJ, Jin  L, Lau  EH, Liao  Q, Wu  P, Jiang  H, et al. Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: a population-based study of laboratory-confirmed cases. Lancet. 2013;382:129–37. DOIPubMedGoogle Scholar
  45. Fiore  AE, Fry  A, Shay  D, Gubareva  L, Bresee  JS, Uyeki  TM; Centers for Disease Control and Prevention (CDC). Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011;60:1–24.PubMedGoogle Scholar
  46. Pyankova  OG, Susloparov  IM, Moiseeva  AA, Kolosova  NP, Onkhonova  GS, Danilenko  AV, et al. Isolation of clade 2.3.4.4b A(H5N8), a highly pathogenic avian influenza virus, from a worker during an outbreak on a poultry farm, Russia, December 2020. Euro Surveill. 2021;26:26. DOIPubMedGoogle Scholar

Main Article

1These authors contributed equally to this article.

Page created: April 16, 2022
Page updated: June 18, 2022
Page reviewed: June 18, 2022
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external