humans (Fouchier et al., 2004). Three out of four H5N1 human virus isolates from Vietnam had this mutation, but the human virus from Thailand did not, nor did any other avian influenza viruses tested. No recent H5N1 viruses characterized in this study had Glu 92 in the NS1 protein, which is reportedly associated with increased virulence in pigs (Seo et al., 2002).

The apparently simultaneous occurrence of H5N1 outbreaks across eastern Asia remains unexplained, but the presence of H5N1 viruses in dead migratory birds suggests that wild bird populations may be involved. In Hong Kong between late 2002 and the time of this report, genotype Z⁺ H5N1 virus was isolated from a dead little egret (Egretta garzetta), and genotype Z viruses were isolated from two dead grey herons (Ardea cinerea), a black-headed gull (Larus ridibundus), a feral pigeon (Columba livia), a tree sparrow (Passer montanus), and a peregrine falcon (Falco peregrinus). In the gene phylogenies, the H5N1 viruses isolated from wild birds have either an out-group or sister-group relation to recent Thailand and Vietnam H5N1 isolates (Figure 2-4; see also Supplementary Figs 1 and 2).¹³ The timing and distribution of the H5N1 infection in poultry in China from 2001 onwards (Figure 2-2) coincides with the general period of winter bird migration to southern China; however, it is not known whether the H5N1 virus has become established in wild bird populations. The potential role of wild birds in the maintenance and spread of H5N1 viruses must be considered in strategies for regional control.

H5N1 virus is now endemic in poultry in Asia (Table 2-1) and has gained an entrenched ecological niche from which to present a long-term pandemic threat to humans. At present, these viruses are poorly transmitted from poultry to humans, and there is no conclusive evidence of human-to-human transmission. However, continued, extensive exposure of the human population to H5N1 viruses increases the likelihood that the viruses will acquire the necessary characteristics for efficient human-to-human transmission through genetic mutation or reassortment with a prevailing human influenza A virus. Furthermore, contemporary human H3N2 influenza viruses are now endemic in pigs in southern China (Peiris et al., 2001) and can reassort with avian H5N1 viruses in this ‘intermediate host.’ Therefore, it is imperative that outbreaks of H5N1 disease in poultry in Asia are rapidly and sustainably controlled. The seasonality of the disease in poultry, together with the control measures already implemented, are likely to reduce temporarily the frequency of H5N1 influenza outbreaks and the probability of human infection. However, complacency would be

Front Matter (R1-R18)

Summary and Assessment (1-56)

1 The Story of Influenza (57-114)

2 Today (115-140)

3 Toward Preparedness: Opportunities and Obstacles (141-221)

4 Strategies for Controlling Avian Influenza Birds and Mammals (222-253)

5 Emerging Technical Tools (254-314)

6 Beyond Biomedical Response (315-372)

Appendix A: Pandemic Influenza: Assessing Capabilities for Prevention and Response (373-380)

Appendix B: Selected Bibliography (381-387)

Appendix C: The Critical Path to New Medical Products (388-389)

Appendix D: Forum Members, Speakers, and Staff Biographies (390-412)