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CHAPTER 1 - BACKGROUND TO AVIAN FLU

1.1 Key characteristics

Avian flu (or avian influenza, AI) is a viral infection. It is also known as fowl plague, and is caused by type A influenza viruses of the Orthomyxoviridae family. It was first recorded in Italy around 1878 and pathogenic AI was first recognised in the US in 1924-25. It re-occurred in 1929, but was eradicated both times.

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There are numerous strains of avian flu, and at least 144 have been identified. Many occur at low levels in wild birds, in particular in waterfowl. Most of these strains are benign. However, some are highly pathogenic, causing high mortality rates. AI is one of only 14 diseases accorded List A status – ‘capable of rapid spread with serious socio-economic consequences’ – by the OIE. It can cause major financial losses to intensive poultry producers. Although vaccines are available, flocks remain vulnerable to the emergence of new, virulent viral strains. These also present a challenge to vaccine manufacturers. It can only infect humans with difficulty (see below), but if it mutates and crosses the species barrier, it could cause a major pandemic, with significant financial and health consequences (see Chapter 1.5.2).

Present on a worldwide basis, AI can cause a range of clinical conditions in affected flocks, ranging from modest reductions in productivity to near-total mortality.

Respiratory signs are most common, and infection may be confused initially with bacterial respiratory infections. It can also induce immunosuppression, leaving birds susceptible to secondary infections. Sub-clinical viral infections are often implicated in subsequent outbreaks of bacterial disease.

AI is not related to Newcastle disease, an important viral infection that can also cause significant financial losses in commercial poultry flocks.

Classification and pathogenicity

Influenza A viruses are divided into categories, strains or subtypes based on two genes that they carry on their surface. These are termed haemaggluttinin (H) and neuraminidase (N). Scientists have found 15 types of haemaggluttinins and nine neuraminidases. Since these can be combined in any way such that there is one H gene and one N gene, this gives a theoretical total of 135 different combinations, all of which can be termed AI. But some Hs and Ns have never been found together, leading experts to hypothesize some combinations cannot be formed. The H5 and H7 strains are most frequently associated with high pathogenicity. Neuraminidase is less important in determining pathogenicity.

Birds have been shown to be infected by the full range of haemaggluttinins, ie from H1 to H15. humans are infected by far fewer (H1, 2, 3, 5, 7 and 9) Pigs are infected by only two (H1 and H3) and horses also by two (H3 and H7). There is no clear rationale behind the wide range of haemaggluttinin strains that infect birds. It is also of course possible that other H strains infect other species but have yet to be identified.

AI viruses have varying pathogenicity (ie the extent to which each subtype causes disease in infected hosts, often shortened to “path”). Viruses are classified according to whether they are highly pathogenic (HP), or low pathogenic (LP). The latter cause mild disease or none at all. The former have high mortality rates. 

Pathogenicity is also influenced by the cleavage sequence. Thus, in the outbreak in Canada in 2004, the original strain was identified as H7N3 with a cleavage sequence of PENPKTR*GLF. This was of low pathogenicity (IVPI = 0). Infection of a second flock a few days later was by a mutated strain which was still H7N3, but the cleavage site differed by possessing a 21 nucleotide/7 amino acid insert. It had an IVPI of 2.96 and was thus much more pathogenic.

The IVPI (intravenous pathogenicity index) indicates the degree of pathogenicity. It refers to a test in which the virus is inoculated into susceptible chickens that are then kept under observation. The higher the proportion of chickens that dies, the higher the IVPI. HP strains are defined as having an IVPI in 6-week old chickens of greater than 1.2; or cause at least 75% mortality in 4- to 8-week old chickens infected intravenously (OIE, 2005).

Between 1959 and 2001, a total of 18 primary outbreaks of HP AI in poultry were recorded (10 of H7 and eight of H5). Five were in the UK, five in Australia, three in other (ie non UK) European countries, and one each in Pakistan, Hong Kong, Canada, US and Mexico (see Table 1.2) the first infection in South America was in 2002 in Chile.

Some recent AI strains are detailed in Table 1.2. Low pathogenic strains leave infected chickens without symptoms, and only H5 and H7 are pathogenic enough to wipe out poultry stocks. However, even some H5 and H7 strains are low path – a low level outbreak of H5N2 in Mexico has been around for more than a decade without causing huge economic damage. There is also evidence that pathogenicity can alter over time in a single strain. Thus, an H5N2 virus in the US in 1983-84 initially caused low mortality, but within six months became highly pathogenic, with mortality approaching 90%. Control of the outbreak required destruction of more than 17 million birds at a cost of nearly $65 million.

The H5N1 strain of the virus that is responsible for the current outbreak first appeared in geese in 1996 in Guangdong Province in China (hence its original designation as Geese/GD/96). It adapted over a relatively short time period to the domestic duck population. The virus then spread to the domestic duck population in China, but caused little or no disease symptoms. By 2004, it was estimated that infected waterfowl were excreting the virus for up to 17 days following infection, causing a huge contamination of the environment. By 1997 it was found in domestic ducks. The first major outbreak was in Hong Kong in the same year when it infected poultry and humans, causing six deaths. The virus then mutated to form a genetically heterogeneous population of H5N1 strains that infected poultry, domestic and wild waterfowl. The majority of the viruses detected and characterised were of the “Z” genotype, which is now dominant in the region.

AI can infect most, if not all, birds. The following commercial species are at risk: chickens, turkeys, ducks, geese, guinea fowl, partridges, quail, pheasants, cassowaries, ostriches, emus, rheas and kiwis. Mortality rates are particularly high in turkeys. Ducks tend to show lower morbidity and mortality than chickens, but they become major virus shedders. This is a key issue in countries with large commercial/backyard duck populations, since the ducks as a reservoir for the AI virus, allowing re-infection. Moreover, the efficacy of vaccines in ducks has not been clearly established.

The incubation period for AI is 3-5 days. The virus replicates mainly in the respiratory tissues of chickens and turkeys, but in wild birds (in particular waterfowl) more commonly in the intestinal tract.

The signs of infection are normally presented suddenly. They can include oedema of the head, cyanosis of the comb and wattles, dullness, lack of appetite, respiratory distress, diarrhoea and drop in egg production. Birds will often die without any signs of disease being present. There can be considerable variation in the clinical picture and the severity of the symptoms.

Post mortem findings of infected birds can vary considerably. Congestion and haemorrhages affecting any organs are common. Necrotic foci many be found in the liver, lungs, spleen and kidneys. There may also be exudates in the air sacs and peritoneum and occasionally a fibrinous pericarditis. When the disease affects adult laying birds, an egg peritonitis is common.

Transmission in commercial flocks is through faecal and other secretions; and by contaminated feed, water, equipment and clothing. It is promoted by the population density of intensively-reared birds and the consequent close contact between birds. Chicks in incubators can become infected from broken contaminated eggs. In Southeast Asia, it has probably been spread largely by the movement of domestic poultry, eg to and from open markets. It is assumed that the long-distance spread of the virus is by wild birds (eg when migrating) and the level of contact between wild birds and commercial flocks is thus key in terms of new infections. In developed countries, free range poultry is more at risk. Where backyard farming is common (ie in much of Asia), it is easily spread from wild birds to home-reared poultry and vice versa. Infection can occur through direct contact between birds or via contaminated objects, clothes or vehicles. This has important consequences for restricting the spread of the virus between commercial flocks and regions.

Table 1.1: History of AI outbreaks in birds

Date	Flu strain	Country	Comments
C1878	Na	Italy	AI virus first recognised in Italy.
1924-1925	Na	US	Outbreak, later controlled.
1929	Na	US	Outbreak, later controlled.
1983-84	H5N2	US	Virus initially caused low mortality, but within six months became highly pathogenic, with a mortality approaching 90%. Control of the outbreak required destruction of more than 17 million birds at a cost of nearly $65 million.
1991	Na	UK	Infected a flock of 8,000 turkeys.
1995-2005	H5N2	Mexico	Lingering low path outbreak in poultry flocks for over a decade.
1997-1998	H5N2	Italy	HP AI outbreak between October 1997 and January 1998.
1997	H5N1	Hong Kong	Infected chickens and humans. The entire poultry flock was slaughtered to contain the outbreak. This was the first time an AI virus was proved to be transmitted directly from birds to humans.
1999	H9N2	Hong Kong/ China	AI strain H9N2 were confirmed in two children. Several additional human H9N2 infections were reported from mainland China in 1998-99.
1997	H7N4	Australia	Outbreak of HP AI near Tamworth, northern New South Wales. IVPI of 2.52-2.90.
1999-2001	H7N1	Italy	H7N1 virus, initially of LP, mutated within nine months to a HP form. More than 13 million birds died or were culled. Total costs were Euro 200 million.
2002-03	H7N3	Italy	45 million birds vaccinated.
2002	H7N3	Chile	Outbreak of LP AI in a broiler breeder flock. Later mutated into an HP AI.
2003-05	H5N1	SE & E Asia	Outbreaks of H5N1 confirmed among poultry in Cambodia, China, Hong Kong, Indonesia, Japan, Laos, South & North Korea, Thailand and Vietnam (see Table 1.3).
2003	H7N7	Netherlands	Outbreak among poultry. Infections among poultry workers and their families were confirmed. 30 million chickens killed. 89 humans infected, one person died. There were a few linked cases in Belgium and one in Germany.
2004	H2N2	US	H2N2 AI was diagnosed in a single Pennsylvania layer complex in early February.
	H7N2	US	Delaware & Maryland reported outbreaks of H7N2 among poultry.
	H5N2	US	H5N2 strain was detected in Texas. A highly pathogenic strain, it is the first such case in 20 years. No evidence of human transmission.
2004	H7N3	Canada	HP H7N3 on poultry farms in British Columbia (see Case Study).
2005	H5N1	Russia	Outbreak in Novosibirsk, eastern Russia. 18,500 birds culled by August 2005. Outbreaks were also recorded in Altai (in the southeast), Omsk, Tyumen and Kurgan (west).
2005	H5N1	Kazakhstan	Geese in Pavlodar region of Kazakhstan infected. 2,400 birds culled.
2005	H5N1	Romania	Deaths of whooping swans reported in October. Outbreak of AI in November in Scarlatesti, in the eastern region. 15,000 birds culled. Migratory birds on the Danube Delta suspected as source of infection.
2005	H5N1	Turkey	Deaths of domestic turkeys reported in October.
2005	Na	Mongolia	Outbreak confirmed by OIE.
2005	H5N2	Mexico	Outbreak in northern state of Coahuila. This was the same strain as identified in Texas (which is contiguous) in 2004.
2005	H9	Colombia	In October, the H9 strain was found in chickens at three farms in Tolima state, western Columbia.

Source: Animal Pharm Reports.

Formation of new strains

New strains are formed by mutation. These can be due to either antigenic drift (small mutations) or antigenic shift (large mutations). Antigenic drift is due to the fact that viruses lack the mechanism to “proofread” and repair errors that in the DNA during replication. These changes are constant and permanent, but usually small. Antigenic shift by contrast, is caused by viruses swapping (or “reassorting”) genetic material, or merging, in the host body. This results in a novel subtype that is different from both parents. Antigenic shift can result in a subtype for which there are no vaccines and can give rise to pandemics, whether in birds or humans.

There is a growing recognition that outbreaks of LP AI are an important source of HP AI (Halvorson, 2002), and that both commercial and wild bird flocks can act as a reservoir of LP AI. Currently, outbreaks of LP AI are ignored, or not identified, especially if their clinical effects are low or zero, they occur in wild birds, or in backyard poultry flocks. This suggests a policy of improved surveillance for LP AI, in particular in commercial flocks exposed to wild birds. Some authors also suggest that it argues for vaccination against non-H5 or non-H7 strains of LP AI, with the intention of removing them from the commercial bird population, so that HP strains do not develop. H1N1 vaccines are widely used in turkey flocks in the US in states with large swine populations. In Utah in 1995, a LP AI H7 outbreak was halted six weeks after initial infection of over 200 flocks with a killed H7 vaccine and the disease subsequently eliminated (Halvorson, 2002). Certainly laboratory tests show that viral shedding of vaccinated turkeys after exposure to the field virus is reduced by 99% to 99.99% compared to those that are not vaccinated (Karunakaran, 1987).

Jumping the species barrier

It is important to distinguish between an Influenza A virus infecting a host that it would not normally infect; and the virus mutating so that it “jumps the species barrier”, such that it becomes a highly pathogenic infection that is easily spread to new members of the same species. In the former case, the virus is unlikely to infect new members of the same species. In the latter case, a new virus is formed, and a pandemic may result.

A virus is thought more likely to jump the species barrier when an organism is infected with two viruses: one that normally infects the host, and one that normally infects another species. Thus, if a human is infected with a strain of AI at the same time as a human flu virus, the two can mix and mutate (through antigenic shift) to form a new strain that is highly pathogenic to humans. However, this mechanism (and indeed, the genetics of viruses in general) is poorly understood. The key point is that the AI virus can jump the species barrier to infect a range of other animals, at which point it may become highly pathogenic.

The H5N1 AI virus has been found in pigs. This was confirmed by Chinese authorities in August 2004. Chen Hualan, Director of the China National AI Reference Laboratory stated that in 2003 and 2004 Chinese scientists started finding the H5N1 virus in pigs in different regions of China. Surveys in Indonesia have also revealed the presence of HP AI in pigs. The Ministry of Agriculture conducted three surveys in the Bandung province of West Java between February 23 and April 26 2005. A total of 187 samples were taken from asymptomatic pigs using purposive and pooled sampling. Researchers identified the H5N1 strain of the virus. 

This has sparked renewed concern that the disease could mutate into a form transmissible between humans. Although pigs do not usually transmit the virus one to another, flu experts are concerned that pigs could act as a reservoir in which a human pandemic strain could evolve through antigenic shift.

In Thailand, the H5N1 strain has been reported in domestic cats, captive tigers and leopards (Tiensin et al, 2004). Fresh chicken carcasses fed to tigers in Sriracha Zoo in Chonburi Province were thought to be responsible for the infection there, which lead to the death or culling of 147 tigers.