Avian influenza viruses and human health

February 2004

The epidemic of avian influenza caused by a highly pathogenic strain of avian influenza A (H5N1) virus, which began in mid-December 2003 in the Republic of Korea and has spread to other countries in eastern Asia, is a potential threat to human health since humans have no immunity to H5-type influenza virus.

The epidemic is the first outbreak of highly pathogenic avian influenza (HPAI) in Japan since 1925, and the first ever-documented in Vietnam and the Republic of Korea. At the time of writing, seven cases of H5N1 infection in humans have been confirmed in Vietnam, six of them fatal, and two in Thailand. A very similar H5N1 type virus of avian origin directly infected a small number of humans in Hong Kong in 1997, causing severe respiratory illness in 18 people, six of whom died. Up to that time it had been considered that infection of humans by avian viruses carrying novel antigens would require a preliminary period of adaptation and/or genetic interaction with human or mammalian viruses in an intermediate susceptible host such as the pig.

In the Netherlands in 2003, a large outbreak of HPAI caused by a H7N7 type virus caused 83 cases of mild illness and one fatality. An H3N2 human influenza virus was present sporadically in Europe at the same time and there was perceived risk of genetic interaction between avian and human viruses and evolution of a new pandemic virus. In this outbreak, the neuraminidase inhibitor oseltamivir (Tamiflu, Roche) was used extensively to protect poultry workers and this may have played a role in reducing the risk.

The current epidemic of HPAI in eastern Asia is causing greater alarm because the three great influenza pandemics of the past century — H1N1 (Spanish flu) in 1918, H2N2 (Asian flu) in 1957, H3N2 (Hong Kong flu) in 1968 — are considered now to have originated in the Far East, possibly in southern China where the rural population still live in close proximity to domestic animals and birds. There is also molecular evidence that the HPAI H5N1 strain is genetically unstable (Guan et al., Proc Natl Acad Sci. 2002;99(13):8950-8955).

About avian influenza

Avian influenza is an infectious disease of birds that has been recognized as a distinct disease entity since 1878 and was described originally as “fowl plague” because of the severity of the disease associated with some strains of the virus.

By about 1955, it was apparent that the viruses associated with avian influenza were closely related to the mammalian influenza A viruses recovered from humans, equines, swine, mink and marine mammals. In fact, phylogenetic analysis of nucleoprotein gene sequences indicates that mammalian influenza viruses have originated directly or indirectly from avian virus ancestors. All birds are thought to be susceptible to infection with influenza viruses.

Avian influenza viruses are ubiquitous. Migratory and non-migratory waterfowl serve as reservoirs of antigenic and genetic variation that poses a direct threat to commercial poultry and a potential threat to humans. Migratory waterfowl — notably wild ducks — are the natural reservoirs of avian influenza viruses, since these birds are the most resistant to infection. By contrast, domestic poultry are susceptible to epidemics of rapidly fatal influenza.

The two major surface proteins of influenza viruses, the hemagglutinin (HA or H) and the neuraminidase (N), mediate attachment and release of influenza virus from the host cell. Immunologically, the hemagglutinin is the more important. Fifteen types of hemagglutinin and nine neuraminidases have been identified in birds. Although in principle any combination of the eight subunits of the influenza virus genome can arise by reassortment, only a limited number of combinations of the H and N antigens has been observed in non-avian hosts.

H7N7 and H3N8 type viruses have caused respiratory disease in horses, H1N1 and H3N2 have been isolated from swine, H7N7 and H4N5 have been associated with respiratory and systemic disease in seals, H10N4 has caused respiratory disease in mink, and H1N1, H2N2 and H3N2 have caused the three global pandemics of human influenza. (H9, H7 and N7 have appeared in humans transiently).

Infection causes a wide spectrum of symptoms in birds, ranging from mild illness to a highly contagious and rapidly fatal disease resulting in severe epidemics. Sudden onset, severe illness, and rapid death characterize HPAI, with a mortality that can approach 100%. To date, all outbreaks of HPAI have been caused by viruses of subtypes H5 and H7. The pathogenesis of avian influenza differs significantly from that in mammals in that viral replication occurs in the intestinal tract as well as the respiratory tract and as a consequence, transmission of infection occurs in part via environmental contamination.

Infectivity depends on cleavage of the hemagglutinin. The HA of both avirulent and virulent strains is cleaved in the superficial tissues of the respiratory and intestinal tracts, but only the HA of virulent strains is cleaved by the proteases present in more vulnerable internal tissues causing systemic disease and death.

All influenza A viruses can undergo genetic change by progressive accumulation of mutations (usually monitored as “antigenic drift”) or be reciprocal exchange (reassortment) of genome subunits when two genetically divergent viruses multiply in the same cells (usually monitored as “antigenic shift”).

Avian viruses of low pathogenicity have been observed occasionally to evolve to become highly pathogenic. For example, in the United States during 1983-84, an H5N2 virus over a period of six months exhibited increasing pathogenicity in domestic poultry and finally caused mortality approaching 90%. During a 1999-2001 epidemic in Italy, an H7N1 virus, initially of low pathogenicity, evolved over a period of nine months to become highly pathogenic causing the death of 13 million birds. Paradoxically, phylogenetic analysis indicates that wild aquatic birds appear to be in evolutionary stasis; whereby mutations accumulate with time at comparable rates to mammalian viruses, but the mutations are neutral and do not result in progressive amino acid changes.

Currently, epidemiological surveillance indicates that strains of HPAI virus can infect humans, but so far they have been unable to achieve person-to-person transmission. It can be conjectured that the evolution of a pandemic strain requires some degree of sequential mutational change, firstly to facilitate amplification of the avian virus in the mammalian host and then to achieve transmission of infection by the respiratory route.

Recent molecular genetic studies indicate that there is no inherent incompatibility regarding the reassortment of genome sub-units of avian and human viruses (Harvey et al., J Virol. 2004;78[1]:502-507). The uncontrolled spread of infection in domestic birds increases the opportunities for direct infection of humans and the probability of genetic interaction between avian and human viruses is increased. However, there are indicators that the evolution of a new pandemic strain is not imminent.

In the most recent appearance of H5N1 virus in Vietnam there is discordance between the geographical location of the avian and human outbreaks, with the human cases occurring in the north and the HPAI outbreak several hundred miles to the south. There have been no human cases in South Korea and Japan. Furthermore, influenza virologists have been predicting unsuccessfully the onset of the next global pandemic since 1976, when a drifted variant of the H1N1 Spanish flu virus appeared in swine in the U.S.A. but did not initiate a human pandemic. Nonetheless, there is no room for complacency, and the WHO is pre-emptively implementing a human vaccine development initiative (see: www.who.int/csr/don/2004_01_20/en/).

The progress of the HPAI outbreak can be followed at the FAO Web site www.fao.org/english/newsroom/news/2003/27419-en.html, and the OIE Web site www.oie.int/eng/en_index.htm.

Dr. Craig Pringle is emeritus professor of the University of Warwick, U. K., and currently serves as Virus Diseases moderator for ProMED-mail. His research career was concerned with defining the genetic properties of several viruses of both medical and veterinary importance. More recently he has carried out research in human RSV and related viruses. He also has served extended terms as Secretary of the International Committee on Taxonomy of Viruses and Editor-in-Chief of the Journal of General Virology. At the invitation of Dr. Don Kaye, he has prepared this informative discussion on yet another respiratory disease threat, avian influenza. — Theodore C. Eickhoff, MD

For more information:

• C.R. Pringle, PhD, is Emeritus Professor, University of Warwick, United Kingdom; currently ProMED-mail Virus Diseases Moderator.