What you need to know about avian influenza (Proceedings)

Influenza virus is an ancient virus that has affected man for many centuries. Every year, influenza causes the deaths of thousands of people. Throughout history, there have been pandemics that have lead to the deaths of millions. The natural reservoir of influenza virus is birds, particularly waterfowl; however, various mammalian species, including man, are also susceptible to infection. A hallmark characteristic of influenza viruses is their ability to mutate rapidly, and sometimes dramatically, which has contributed to their importance as a human pathogen.

In most species, influenza virus is spread by aerosol and droplet transmission. It replicates primarily in the epithelia lining the respiratory tract. The virus damages and ultimately kills the cells in which it replicates, leading to the typical symptoms of influenza, including cough, fever, muscle ache, and fatigue. Pneumonia, either due directly to the virus or secondary bacterial infection, may occur, in some cases leading to death.

The virus

To understand the threat from influenza, we first we need to understand the virus. Influenza virus is classified by its antigenicity, or how it is seen by the immune system. The types of influenza (A, B, and C) are based on the antigenicity of internal viral proteins. Subtype classification is based on the antigenicity of two important surface proteins, hemagglutinin (HA, or H) and neuraminidase (NA, or N), which are given numeric designations (H1-16; N1-9). While nearly all combinations of these two proteins may occur in birds, a limited number of combinations are seen in mammals. For example, the seasonal influenza of humans is usually H3N2, or H1N1.

The virus itself is encased in a lipid membrane, making it easy to inactivate with any common detergent. The genetic material of the virus is single-stranded RNA, and, uniquely, this genetic material is in separate segments, with each segment encoding a different protein. This unique structure allows this virus to have a high mutation rate. Mutations may be small, within a single virus, termed antigenic drift; or they may involve the exchange of entire genes between different influenza viruses, termed antigenic shift.

Antigenic drift, while small, can lead to important changes in the virus. These include changes in antigenicity, allowing it to escape the immune response, and changes in viral protein properties which can lead to increased virulence of the virus or drug resistance. Antigenic shift occurs when two distinct viruses infect the same host, allowing mixing of the genomic segments. This ability of influenza virus to mutate in small and large ways makes it a potential threat.

Epidemiology

As stated above, waterfowl are the natural reservoir of influenza viruses. In these animals, the virus replicates in both respiratory and gastrointestinal tracts, with shedding in respiratory droplets and feces. These hosts can potentially spread the virus to a variety of hosts and geographic locales. In its natural host, avian influenza is often asymptomatic. In domestic fowl, disease may vary from mild respiratory disease to severe systemic disease with high mortality. These latter strains are referred to as highly pathogen, or HP strains, and are reportable in the USA.

The host susceptibility to the many different influenza viruses is determined by several viral proteins. The surface protein HA, which is responsible for attachment of the virus to its target cell of infection, is a major determinant of host susceptibility. This protein attaches to sugar residues on cellular surface proteins. It is these structures that determine in part host susceptibility. These cell surface structures differ between birds and mammals, which in turn leads to differences in virus susceptibility. Other virus proteins also play a role in host susceptibility, though the mechanism is not well understood.

Another property of the HA protein that affects the tissue tropism of the virus is its requirement for proteolytic cleavage: If the HA protein is not cleaved into 2 subunits, virus entry into the cell for replication cannot occur. This cleavage is done by cellular proteases; thus, the virus requires the presence of this cellular enzyme in order for viral replication to occur. In mammals, this leads replication in the respiratory tract where the necessary enzyme is present. The easier the HA protein is able to be cleaved, the more pathogenic, or lethal the virus is. Thus, many HP strains have a HA protein that is easily cleaved, allowing them to spread systemically, beyond the respiratory tract.

Pandemic influenza

Influenza pandemics have occurred throughout history. The most notable perhaps is the pandemic of 1918, which killed 20-40 million people. Analysis of this virus in recent years revealed relatively minor changes in that virus as compared to some avian viruses. Other examples of influenza's mutability have been seen more recently. In 2004, an equine influenza virus infected and became adapted to dogs. Only a few amino acid changes appear responsible for this adaptation. Highly pathogenic avian strains have also arisen from low pathogenic strains, leading to devastating outbreaks in domestic poultry. Thus, the ability of influenza viruses to mutate can lead to changes in host susceptibility, virulence, and spread.

So why are we so worried about H5N1???

There are several reasons. For one, it appears to be a highly pathogenic strain, in both birds and mammals. In the human infections that have occurred, a mortality rate over 50% has been observed. In addition, in these cases, evidence of infection beyond the respiratory tract has been documented, including intestines, and central nervous system. This virus possesses an easily cleavable HA protein, making it highly virulent.

The H5N1 seems to be particularly contagious as well, with shedding of up to a month documented in recovered birds. This variant originated in Asia where live bird markets, little biosecurity, significant movement of birds, and close contact between humans and birds has led to spread of this virus within domestic poultry, as well as occasional infections in humans. While some species of birds, including many wild as well as domestic fowl, also suffer severe disease with high mortality following H5N1 infection, other birds, such as ducks may remain asymptomatic. This could allow spread via wild bird migration. While possible, it is more likely that trade and movements of birds and bird products, both legal and illegal is a major contributor to the spread of this virus.

Other mammalian species have also been infected with this virus, including dogs and cats. While rare, these infections have led to severe disease with mortality. Thusfar, spread to humans and other mammals has been restricted primarily to those exposed to high doses of the virus through contact with infected poultry. Efficient spread from human to human, or between other mammalian hosts has not occurred. If the H5N1 does acquire this ability, a pandemic could result. And because of its apparent high lethality, the consequences could be significant mortality. Thus, surveillance and preparation are needed.

And if it's not H5N1, history tells us that a future pandemic is virtually certain. The potential impact is not known, but erring on the side of caution is warranted. Currently, H5N1 does not occur in the USA, and clients do not need to worry for the welfare of their pets. There is reason for concern, monitoring, preparation, but no need for hysteria. Cool heads must prevail, and veterinary technicians are an integral part not only of the preparation, but client education as well.

References

Alexander, D. J. 2007. An overview of the epidemiology of avian influenza. Vaccine 25 (2007) 5637–5644.

Capua, I., and D. J. Alexander. 2006. The challenge of avian influenza to the veterinary community. Avian Pathology (June 2006) 35(3):189-205

de Jong M. D., and T. T. Hien. Review: Avian influenza A (H5N1). 2006. Journal of Clinical Virology 35 (2006) 2–13.

Peiris, J. S. M., M. D. de Jong, and Y. Guan. 2007. Avian Influenza Virus (H5N1): a Threat to Human Health. CLINICAL MICROBIOLOGY REVIEWS, Apr. 2007, p. 243–267.

Sandrock, C. and T. Kelly. 2007. Clinical review: Update of avian influenza A infections in humans. Critical Care 2007, 11:209.

Thomas, J. K., and J. Noppenberger. 2007. Avian influenza: A review. Am J Health-Syst Pharm—Vol 64 Jan 15, 2007 149-165.