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Seropositivity for avian influenza H6 virus among humans, China.

To the Editor: Influenza virus subtype H6 was first isolated from a turkey in 1965 in the United States (1) and was subsequently found in other parts of the world (2). Over the past several decades, the prevalence of H6 virus has dramatically increased in wild and domestic birds (2-4). In China, highly pathogenic influenza A(H5N1), low pathogenicity influenza (H9N2), and H6 are the most prevalent avian influenza viruses among poultry (5). Although only 1 case of H6 virus infection in a human has been reported worldwide (6), several biological characteristics of H6 viruses indicate that they are highly infectious to mammals. Approximately 34% of H6 viruses circulating in China have enhanced affinity to human-like receptors (a-2,6 NeuAcGal) (2). H6 viruses can also infect mice without prior adaptation (2,7), and some H6 viruses can be transmitted efficiently among guinea pigs (2). To evaluate the potential threat of H6 viruses to human health, we conducted a systematic serologic study in populations occupationally exposed to H6 viruses.

During 2009-2011, a total of 15,689 serum samples were collected from live poultry market workers, backyard poultry farmers, large-scale poultry farmers, poultry-slaughter factory workers, and wild bird habitat workers in 22 provinces in mainland China. A/chicken/Y94/ Guangdong/2011 (H6N2), a representative isolate of predominant H6 viruses in mainland China, was used for the serologic testing (online Technical Appendix Table 1, Figures 1, 2, Hemagglutination inhibition (HI) assay was performed for all serum samples, and samples with an HI titer [greater than or equal to] 20 were verified by a microneutralization (MN) assay, as indicated by World Health Organization guidelines (8). An MN result of [greater than or equal to] 20 was considered positive.

The HI result was [greater than or equal to] 20 for H6N2 virus in 298 of the 15,689 specimens, and the MN result was positive in 63 of the 298 specimens (overall seropositivity range 20-320, mean 32.7, 0.4%) (online Technical Appendix Table 2). The proportion of group members who were seropositive differed significantly according to occupational exposure (p = 0.0125). Seropositivity was highest among workers in live poultry markets, backyard poultry farmers, and workers in wild bird habitats (0.66%, 0.42%, and 0.51%, respectively) (Table). According to [chi square] test results, seropositivity among workers in live poultry markets was significantly higher than that among large-scale poultry farmers (p = 0.0015, adjusted [alpha] = 0.005. Analysis by unconditional logistic regression model showed that exposure to live poultry markets was a risk factor for human infection with avian influenza H6 virus (odds ratio 2.1, 95% CI 1.27-3.47).

Seropositivity did not differ significantly among male and female persons tested (p = 0.08) (Table). No children were positive for the H6N2 virus. For other age groups, seropositivity ranged from 0.25% to 0.45%, but differences were not significant (p > 0.05) (Table).

Of the 22 provinces from which serum specimens were collected, 11 were northern provinces and 11 were southern provinces. Positive specimens were detected in all southern provinces. In northern China, no seropositive results were detected in Henan, Liaoning, or Jilin Provinces. According to [chi square] test results, seropositivity in southern China was significantly higher than seropositivity in northern China (p = 0.0375) (Table).

Human infection with influenza H6 virus in mainland China has not been reported, but 63 serum specimens tested in our study were positive for the H6 virus. This level of seropositivity is much higher than that for highly pathogenic avian influenza A(H5N1) virus, for which only 2 of the serum specimens we tested were positive (data not shown), but much lower than the seropositivity level for low pathogenicity avian influenza A(H9N2) virus; 3.4% of the samples tested were positive for A/Chicken/Hong Kong/ G9/1997(H9N2)-like virus (data not shown). A previous US study has reported H6N2-positive antibodies in veterinarians (9). Our results and the veterinarian study indicate that the H6N2 virus could infect humans.

In our study, positive samples were detected in 19 of 22 provinces and in all tested worker populations, suggesting that the H6 virus has been broadly circulating in birds in China. Live poultry market exposure is the major risk factor for human infection with avian influenza H6 virus. The limitation of this study is that antigen selection may not accurately detect neutralization antibodies for different subtypes of H6 viruses. Surveillance of the H6 virus in birds and occupationally exposed populations should be strengthened for pandemic preparedness.

DOI: htpp://


This study was performed under the serology surveillance system of occupationally exposed populations in China. We are deeply thankful for the contributions of all National Influenza Surveillance Network members, including the China Centers for Disease Control and Prevention in the provinces and in the prefects, all of which collected samples for years. We also thank Ms. Qiao-hong Liao for providing consultation on statistical analysis.

This study was supported in part by the China-United States cooperation project "Developing sustainable influenza surveillance networks and response to avian and pandemic influenza in China" and by the China National Mega-projects for Infectious Diseases (2014ZX10004002).


(1.) Downie JC, Webster RG, Schild GC, Dowdle WR, Laver WG. Characterization and ecology of a type A influenza virus isolated from a shearwater. Bull World Health Organ. 1973; 49(6):559-66.

(2.) Wang G, Deng G, Shi J, Luo W, Zhang G, Zhang Q, et al. H6 influenza viruses pose a potential threat to human health. J Virol. 2014; 88:3953-64.

(3.) Jiao P, Yuan R, Wei L, Jia B, Cao L, Song Y, et al. Complete genomic sequence of a novel natural recombinant H6N2 influenza virus from chickens in Guangdong, Southern China. J Virol. 2012; 86:7717-8.

(4.) Zhao G, Lu X, Gu X, Zhao K, Song Q, Pan J, et al. Molecular evolution of the H6 subtype influenza A viruses from poultry in eastern China from 2002 to 2010. Virol J. 2011; 8:470.

(5.) Pepin KM, Wang J, Webb CT, Smith GJ, Poss M, Hudson PJ, et al. Multiannual patterns of influenza A transmission in Chinese live bird market systems. Influenza Other Respir Viruses. 2013; 7: 97-107.

(6.) Yuan J, Zhang L, Kan X, Jiang L, Yang J, Guo Z, et al. Origin and molecular characteristics of a novel 2013 avian influenza A(H6N1) virus causing human infection in Taiwan. Clin Infect Dis. 2013; 57:1367-8.

(7.) Gillim-Ross L, Santos C, Chen Z, Aspelund A, Yang CF, Ye D, et al. Avian influenza H6 viruses productively infect and cause illness in mice and ferrets. J Virol. 2008; 82:10854-63.

(8.) World Health Organization. Manual for the laboratory diagnosis and virological surveillance of influenza. Geneva: The Organization; 2011. p. 63-77.

(9.) Myers KP, Setterquist SF, Capuano AW, Gray GC. Infection due to 3 avian influenza subtypes in United States veterinarians. Clin Infect Dis. 2007; 45:4-9.

Li Xin, Tian Bai, Jian Fang Zhou, Yong Kun Chen, Xiao Dan Li, Wen Fei Zhu, Yan Li, Jing Tang, Tao Chen, Kun Qin, Jing Hong Shi, Rong Bao Gao, Da Yan Wang, Ji Ming Chen, Yue Long Shu

Author affiliations: National Institute of Viral Disease Control and Prevention, Beijing, China (L. Xin, T. Bai, J.F. Zhou, Y.K. Chen, X.D. Li, W.F. Zhu, Y Li, J. Tang, T Chen, K. Qin, J.H. Shi, R.B. Gao, D.Y. Wang, Y.L. Shu); China Animal Health and Epidemiology Center, Qingdao, China (J.M. Chen)

Address for correspondence: Yue Long SHU, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Key Laboratory for Medical Virology, Ministry of Health, Beijing, 102206, China; email:
Table. Seropositivity of occupationally exposed populations for the
influenza (H6N2) virus, China, 2009-2011 *

Population                               Total no.    Mean titer for
                                           serum     MN [greater than
                                          samples     or equal to] 20

Total                                     15,689          32.70
  Live poultry market                      3,950          43.08
  Poultry farm                             3,762          25.71
  Backyard poultry farm                    4,324          26.67
  Poultry slaughter factory                1,235          30.00
  Wild bird habitat                         788           20.00
  Other                                    1,630          23.33
  F                                        7,620          24.29
  M                                        8,069          39.39
Age group, y
  Children, [less than or equal to] 14      74              --
  Youth, 15-24                             1,168          20.00
  Adult, 25-59                            1,2450          34.07
  Elderly, [greter than or equal to] 60    1,748          13.33
  No age record                             249             --
Geographic distribution
  South                                   10,522          32.00
  North                                    5,167          35.38

Population                                  No. serum
                                           samples with
                                         MN [greater than
                                          or equal to]20
Total                                           63
  Live poultry market                           26
  Poultry farm                                  7
  Backyard poultry farm                         18
  Poultry slaughter factory                     2
  Wild bird habitat                             4
  Other                                         6
  F                                             28
  M                                             35
Age group, y
  Children, [less than or equal to] 14          0
  Youth, 15-24                                  3
  Adult, 25-59                                  54
  Elderly, [greter than or equal to] 60         6
  No age record                                 0
Geographic distribution
  South                                         50
  North                                         13

Population                               Seropositivity (95% CI)

Total                                       0.40 (0.40-0.41)
  Live poultry market                       0.66 (0.64-0.68)
  Poultry farm                              0.19 (0.18-0.19)
  Backyard poultry farm                     0.42 (0.40-0.43)
  Poultry slaughter factory                 0.16 (0.15-0.17)
  Wild bird habitat                         0.51 (0.47-0.54)
  Other                                     0.37 (0.35-0.39)
  F                                         0.37 (0.36-0.38)
  M                                         0.43 (0.42-0.44)
Age group, y
  Children, [less than or equal to] 14              0
  Youth, 15-24                              0.26 (0.24-0.27)
  Adult, 25-59                              0.43 (0.43-0.44)
  Elderly, [greter than or equal to] 60     0.34 (0.33-0.36)
  No age record                                     0
Geographic distribution
  South                                     0.48 (0.47-0.48)
  North                                     0.25 (0.24-0.26)

Population                               Odds ratiof (95% CI)

  Live poultry market                      2.10 (1.27-3.47)
  Poultry farm                             0.40 (0.18-0.87)
  Backyard poultry farm                    1.05 (0.61-1.82)
  Poultry slaughter factory                0.38 (0.09-1.57)
  Wild bird habitat                        1.28 (0.47-3.54)
  Other                                    0.91 (0.39-2.11)
  F                                           Reference
  M                                        1.18 (0.72-1.94)
Age group, y
  Children, [less than or equal to] 14          0 (0)
  Youth, 15-24                             0.75 (0.19-3.00)
  Adult, 25-59                             1.27 (0.54-2.94)
  Elderly, [greter than or equal to] 60       Reference
  No age record                                   --
Geographic distribution
  South                                       Reference
  North                                    0.59 (0.30-1.15)

* MN, microneutralization; --, not applicable.

([dagger]) Odds ratios were calculated by using unconditional logistic
regression model (SPSS 17.0, Armonk, NY, USA).
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Title Annotation:LETTERS
Author:Xin, Li; Bai, Tian; Zhou, Jian Fang; Chen, Yong Kun; Li, Xiao Dan; Zhu, Wen Fei; Li, Yan; Tang, Jing
Publication:Emerging Infectious Diseases
Article Type:Report
Date:Jul 1, 2015
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