Avian epidemic

Even as large parts of Asia reel under avian influenza or bird flu, there are fears that mutant species of the virus could transform the disease into a pandemic.

JUST when medical scientists came to believe that avian influenza (AI), or `bird flu' as it has come to be called, has been brought under control as a result of the preventive measures that were taken in the aftermath of the outbreak of the epidemic in Hong Kong in 1997, there has been a resurgence of the viral disease over the past one year. The latest outbreak, which seems to have begun around August-October 2003 and has since spread across ten Asian countries, appears to be the most severe.

The major cause for concern this time is that as in the 1997 outbreak, the epidemic has resulted in direct transmission of the infection from birds - essentially domestic poultry (chicken and ducks) - to humans. Since January, Vietnam and Thailand have reported cases of human beings affected by the disease and high mortality rates. This is evidence that the bird flu virus(es) is evolving and might soon jump the species barrier that was until recently believed to protect humans from contracting the lethal avian disease. AI, which was identified in Italy more than 100 years ago, normally infects birds and, less commonly, pigs. Until recently, it was not known to infect directly, or circulate in, humans.

More pertinently, while the 1997 one as well as the other recent outbreaks were localised, the latest one is extensive in its geographical spread. The reason for the occurrence of large and fatal outbreaks in a number of countries around the same time is unclear. The epidemic is occurring in Japan for the first time since 1925 and is the first ever to be documented in Vietnam and the Republic of Korea.

It is curious that India seems to have been spared even as Pakistan and probably Bangladesh have been affected. There might be reasons other than providence for this. In any case, a red alert has been sounded and the import of birds and poultry products from affected regions has been banned. According to Dr. Hare Krishna Pradhan, Director of the High Security Animal Disease Laboratory (HSADL) in Bhopal, surveillance measures have been put in place, particularly in States along the northeastern border and the western border. The only one of its kind in the country, the HSADL is among the 10 laboratories around the world that are equipped to identify highly virulent viruses.

While all birds are believed to be susceptible to AI, some are more resistant than others. A wide spectrum of symptoms are associated with the disease, whose severity might range from mild illness to a highly contagious condition that can lead to death, which can occur even within a day of the appearance of symptoms. The mortality rate of the highly pathogenic avian influenza (HPAI) forms of the infection can be as high as 100 per cent. Aquatic birds, most notably migratory waterfowl and wild duck, which are resistant to the infection, are the natural reservoirs of the virus. Domestic poultry, including chickens, ducks and turkeys, are known to be particularly susceptible to HPAI epidemics. They contract the virus through direct or indirect contact with aquatic birds. The virus can enter domestic and commercial poultry flocks through the droppings of infected migratory wild birds. The risk is the highest in places where wild and domestic birds are part of the same environment. Evidence suggests that AI viruses, which are mildly pathogenic in wild birds, mutate to highly virulent forms once they infect domestic poultry.

Once the infection sets in, it spreads easily from farm to farm. Birds shed large amounts of the virus through saliva, nasal secretions and faeces, which in turn contaminates the soil and the environment. Bird-to-bird transmission can also occur through the airborne virus. Contaminated farm equipment, feed, cages and so on are potential carriers of the virus, as are "mechanical vectors" such as rodents and farm animals. Live bird markets, known as `wet markets', where large numbers of birds are sold in overcrowded and unhygienic conditions, seem to be breeding grounds for the AI virus and major sources for the spread of the disease.

While the disease is extremely contagious as far as the bird population is concerned, there is very little evidence of the spread of the disease from person to person. A family of four in Vietnam is under investigation after two members who do not seem to have come into contact with poultry seem to have acquired the infection from the other two. Scientists believe that such an eventuality is not unlikely. In the Hong Kong outbreak of 1997 and the Netherlands outbreak of 2003, there was evidence of very limited person-to-person transmission.

Influenza viruses are highly unstable and tend to mutate rapidly. Studies have shown that mildly pathogenic forms, if allowed to circulate for sometime in a poultry population, mutate into highly pathogenic viruses. There is concern in the medical community and the World Health Organisation (WHO) that the pathogen could adapt itself into new virus types that are associated with human-to-human transmission. The co-circulation of HPAI viruses with human viruses could create opportunities for the swapping of genetic material. The infection might then spread rapidly among humans resulting in a pandemic (global outbreak). The most severe flu pandemic in recent times was the "Spanish Flu" outbreak in 1918-19, which killed an estimated 50 million people.

Influenza viruses belong to a family of viruses known as Orthomyxoviridae and are classified into three types - A, B and C. Type A is the most common and usually causes the most serious epidemic. Type B outbreaks can also cause epidemics but the infection is milder. Type C has never been implicated in a large epidemic. Type A viruses can infect several animal species, including birds, pigs, horses, seals and whales. Birds are a particularly important species because all known subtypes of type A viruses circulate among wild birds, which are considered the natural hosts for influenza A viruses.

The subtype classification of type A viruses is on the basis of their surface proteins: hemagglutinin (HA) and neuraminidase (NA). There are 14 HA subtypes and 9 NA subtypes. While all subtypes circulate in birds, only three subtypes of HA (H1, H2 and H3) and two subtypes of NA (N1 and N2) are known to circulate in humans. Human influenza is because of the different strains of viruses, H1N1, H2N2 and H3N2, which too have evolved from animal subtypes. However, the known HPAI viruses all belong to either the H5 or the H7 subtype. The classical fowl plague, typified by the 1955 outbreak, is because of the H7N7 virus and the major bird flu epidemic in the United States during 1983-84 was because of the H5N2 virus. However, not all H5 and H7 viruses are virulent for poultry.

The present AI outbreak is particularly alarming from the perspective of human health because the causative agent for most of these outbreaks is a highly pathogenic strain, H5N1, which is deadly to poultry, particularly chicken. Birds that survive infection shed the virus for at least 10 days, orally and through faeces, thus facilitating its spread. H5N1 also has the unique capacity to jump the species barrier. The virus, which was first isolated from terns in South Africa in 1961, mutates rapidly and has the propensity to acquire genes from influenza viruses, affecting other animal species.

The first incidence of human infection by H5N1 was reported during the Hong Kong outbreak, which resulted in the death of six of the 18 persons who had contracted the infection by coming into contact with infected poultry. The human cases coincided with the outbreak of AI due to H5N1. In February 2003, infection by the same strain resulted in the death of two of a family of three in Hong Kong, who had travelled to South China. Therefore, it is of serious concern that the death of two persons in Vietnam and Thailand has coincided with the current widespread epidemic of H5N1 avian influenza. The mechanism by which H5N1 is transmitted directly to humans and the cause of the strain's high virulence in humans are not well understood.

Two other AI strains have caused illness in human beings, but the infection was not as virulent as in the case of H5N1. The H9N2 strain, known to be highly pathogenic in birds, caused mild illness in two children in 1999 and in one child in mid-December 2003 in Hong Kong. The outbreak of the HPAI virus strain H7N7 in the Netherlands in February 2003 caused the death of one veterinarian and 83 poultry workers and six members of their families. In both the 1997 Hong Kong outbreak and the Netherlands outbreak, mild person-to-person transmission probably occurred, indicating the emergence of a new strain but with inefficient human-to-human transmission potential and possibly poor survivability.

There are possibly several H5N1 strains in circulation. In the current outbreak, the H5N1 strain from the Republic of Korea and Vietnam has been found to be slightly different. Also, the strain is different from the 1997 Hong Kong strain, thus rendering the vaccine developed earlier ineffective. More significantly, the genetic sequencing of the virus has shown that all its genes are of avian origin. This means that the virus has not acquired human influenza virus genes and person-to-person spread is unlikely.

The genetic instability of influenza type A viruses makes them change in two different ways: `antigenic drift' and `antigenic shift'. The former refers to small changes in the virus that happen over time because of the lack of efficient "proof reading" and error-repairing mechanisms even as it replicates itself in human beings and animals. Antigenic drift changes the genetic composition of the virus resulting in new virus strains that the body's immune mechanism cannot recognise. (This is one of the reasons why people get flu more than once because their antibodies no longer recognise the "newer" strains.) The latter is an abrupt, major change, resulting in new HA and/or NA proteins in the influenza A viruses. Antigenic shift, which occurs only occasionally, results in new virus subtypes. When this happens, there is little protection from the body's immune system.

One way in which influenza type A viruses undergo `antigenic shift' is by acquiring genetic material from subtypes characteristic of different species, "re-assorting" the genes and then merging. This re-assortment results in a novel subtype different from both parent subtypes. As populations lack immunity to the new subtype, antigenic shift has the potential to cause pandemics if the virus acquires genes from the human flu virus, making human-to-human transmission possible for a sustainable period.

Domestic pigs have been known to act as intermediate hosts and provide appropriate conditions for the `antigenic shift' to occur. Pigs can be infected with both human influenza viruses and AI viruses in addition to swine influenza viruses. This allows the possibility of pigs getting simultaneously infected by avian and human viruses; they then serve as a "mixing vessel" for the scrambling of genes and the forming of a new subtype. The new virus could have most of the genes from the human virus but an HA and/or an NA from the avian virus. The new virus will be able to infect humans and cause efficient person-to-person transmission, but it would have surface proteins (HA and/or NA) that have not been seen previously by the human immune system. (In the Netherlands outbreak, there is the likelihood of swine in the vicinity having served as the intermediate host.) With recent evidence of direct transmission to humans in some of the 15 avian subtypes, humans can, apparently, serve as the "mixing vessel". If a person is infected by both a human influenza virus and an avian influenza virus (such as H5N1), a re-assortment can occur, resulting in a new subtype that can be highly pathogenic to humans with the help of efficient inter-human transmission. This possibility has led experts such as Robert G. Webster to warn: "An influenza pandemic may be inevitable and probably imminent."

WHAT has led to an AI outbreak of such magnitude in Asia? As described earlier, domestic poultry forms the basis of entry, spread and mutation of viruses, which in the past were mostly mildly infectious and confined to aquatic birds, into highly pathogenic forms. According to the Food and Agriculture Organisation (FAO), the dramatic growth in poultry production and a massive concentration of poultry in the region is part of the reason (see map). It is estimated that the eastern and southeastern parts of Asia have a poultry population of nearly seven billion. More than half of the domestic bird population, according to the FAO, is in medium- to large-scale intensive poultry holdings where strict prevention and containment (`bio-security') measures are in place. However, a sizable part of the poultry population remains in small holdings belonging to an estimated total of 200 million farmers, each keeping about 15 birds, mainly comprising ducks, chicken, geese, turkeys and quails. The village poultry is composed of scavenging birds, which are exposed to viruses carried by wild birds.

A possible explanation for the observed geospatial distribution of the AI virus, according to the FAO, is the seasonal seeding of influenza viruses into backyard poultry systems by waterfowl migrating along the East and Central Asian flyways (recognised migration routes from northern China/Siberia to South-East Asia and South and West Asia). The rapid spread of AI within the poultry subsector, where live poultry movements or the transportation of infected materials occur, is believed to play an incriminating role. Prior to the 1997 outbreak, live poultry markets in Hong Kong (about 1,000) used to house all types of poultry for sale. Aquatic birds, including domestic ducks, geese, wild ducks and occasionally wild waterfowl, were kept in the same vicinity as chickens, pigeons, quail, pheasants and so on.

Scientists R.J. Webby and Webster believe that live poultry markets provided near-optimal conditions for perpetuating and amplifying AI viruses. According to them, the H5N1 strain of the 1997 outbreak resulted from an assortment that occurred in these markets resulting in the mixing of wild goose, quail and duck genes with the quail serving as the "mixing vessel". While post 1997, live poultry market practices in Hong Kong have changed vastly, and aquatic birds are no longer available in retail outlets, traditional sale practices have continued in mainland China and elsewhere in the region, providing an enabling environment for the emergence of new AI viruses in the region, the scientists point out.

The rapidity with which AI spreads in domestic birds makes it very difficult to control especially in the affected regions of Asia where there is a very high concentration of poultry. Mass "culling" (killing) and quarantining and disinfecting of infected farms are the only means of effective control and eradication of the disease. During the 1997 outbreak, the entire poultry population of Hong Kong (about 1.5 million chickens and other birds) was culled in three days. Similarly, during the 2003 outbreak in the Netherlands, 30 million birds (out of a total bird population of 100 million) were killed within a week. Experts believe that this was chiefly responsible for preventing the disease from spreading further as well as averting a human influenza pandemic.

In the current campaign against the epidemic, already 25 million poultry birds, across 10 affected countries in Asia have been slaughtered. Even so, concern has been expressed that mass culling is not taking place at a speed that is necessary for the rapid containment of the virus. In the absence of prompt control measures, AI epidemics can last for years, as it happened in the case of the H5N2 AI epidemic in Mexico in 1992. What began as an epidemic of low pathogenicity evolved to a highly fatal form and was not controlled until 1995. During the 1983-84 epidemic in the U.S. (which was largely confined to the State of Pennsylvania), the H5N2 virus initially caused low mortality but became highly pathogenic within six months, with the mortality rate approaching 90 per cent. Only the destruction of 17 million birds (to a loss of nearly $65 million) ended the outbreak. During the 1999-2001 epidemic in Italy, the initially lowly pathogenic H7N1 virus mutated to a highly virulent form within nine months. More than 13 million birds died or were destroyed.

In economic terms, an AI epidemic, especially if it is HPAI, is disastrous for the poultry industry and farmers of the affected countries. Even though the poultry population culled is less than 1 per cent of the total inventory of the region, the impact on local economies and both commercial poultry operations and small holders is severe. "The impact on local communities, small farmers and commercial poultry operations is devastating and will be worse if further culling is required," said Changchui, head of FAO's regional office in Bangkok. "It is essential that compensation and assistance are provided to producers, in particular small farmers who are dependent on a daily income from selling their poultry products," he added.

Interestingly, India seems to have escaped the spread of the HPAI infection, or infection by H5N1 or H9 and H7 subtypes, which have affected Pakistan. The possible reasons are that one, India does not quite fall in the migratory routes of waterfowl from the north, and two, Indian culinary practices do not include the consumption of exotic and wild birds. The live markets too do not stock such birds alongside domestic poultry. Indeed, according to Dr. Pradhan, the HPAI virus has never been seen even in the past among the Indian poultry.

The Indian poultry population is large (about 150 million) and if such an epidemic strikes it would be disastrous. While the virus may be present in the dormant form in wild bird populations, no surveillance of wild birds has been systematically carried out for AI viruses, according to Dr. T.S. Johri of the Central Avian Research Institute, Izatnagar. However, Dr. Pradhan says that 13,000-14,000 birds of all kinds were tested last year and no AI virus was found. There have been occasional alarms like the one last year when a suspected outbreak near Chandigarh turned out to be a bacterial infection. A mild strain, H9N7, was apparently detected in some chickens in a farm in north Gurgaon near Delhi.

Other infections of the poultry are, however, fairly high, indicating poor farming practices. The retail markets too leave much to be desired in terms of hygiene, sanitation and overcrowding. But effective surveillance and vaccination measures are very much in place to contain any infection, says Pradhan. Also, according to him, the country's poultry industry is, however, well developed with proper biosecurity measures implemented. "We have the technology and expertise to handle any eventuality," Pradhan added. In the Indian context, if not anything else, the Asian outbreak of the highly pathogenic bird flu has highlighted the importance of promoting and strengthening veterinary research and animal husbandry as a discipline.