The Spread of Avian Influenza

THE HISTORY OF THE AVIAN FLU

Influenza is a global threat with two dimensions: avian and human. Human influenza viruses cause epidemics every year, with millions of human illness cases and many thousands of deaths. Avian influenza viruses cause periodically large outbreaks in domestic fowl, with high commercial loss in the poultry industry. All influenza viruses, including the human ones, originally come from birds. Their natural hosts are wild aquatic birds, ducks, geese, gulls, and many others.

Influenza viruses occurring in this reservoir have a very high genetic variability defined by 16 hemagglutinin and nine neuraminidase subtypes—these are the proteins on the surface of the virus particles. We are therefore talking of H1N1 viruses, H3N2 viruses, H5N1 viruses, and so forth. Usually these influenza viruses are confined to their natural hosts, the wild aquatic birds, but occasionally they are transmitted to other species such as terrestrial birds, chickens, turkeys, pigs, and horses in which they cause disease without having changed their genetic makeup very much. This is where we are now with the human cases caused by the H5N1 bird flu virus, a very early stage in the transmission to another species.

However, on rare occasions the avian viruses adapt to their new hosts. Then, for example, a duck virus is converted into a pig virus that is then transmitted within the pig population. If this occurs in humans—if a virus with a new hemagglutinin or a new neuraminidase subtype is introduced by this mechanism into the human population—then we have a pandemic, a worldwide outbreak affecting the entire human population, with millions of deaths. In the last century, we had three such pandemics. The great Spanish flu of 1918 caused more than 40 million deaths and was probably the most devastating outbreak ever of an infectious disease within a limited time period. There were also two less severe pandemics in 1957 and in 1968.

Because of their importance as disease agents, influenza viruses have been studied in great detail. The structure of the virus particles has been elucidated, their replication strategies are known, and their genome has been sequenced. In fact, we can manipulate these viruses with gene technology, so we can convert a dangerous virus into a harmless virus and then use it as a vaccine. We can also convert a harmless virus into a dangerous one. As in many other fields we have a dual-use problem.

H5N1, the so-called bird flu virus, first caught our attention in 1997. Until that time we thought this particular virus was completely harmless for man, but in that year a large outbreak in poultry occurred in Hong Kong and 18 human infections, with six deaths, also occurred. The virus disappeared, but re-emerged in 2002, and since 2005 has been endemic in Southeast Asia, killing more than 200 million chickens. On rare occasions, the virus has also been found to spread to other species—monkeys, cats, tigers, leopards, civets, and martens—and though there have been very few cases, the virus caused very severe disease in these new species. So far, about 200 humans have been infected, about 100 of whom have died. But because there have been 200 human cases as opposed to 200 million chicken cases, this is still very much an animal disease and not yet a human disease.

In May 2005, however, something unusual happened. The virus was reintroduced from domestic fowl into wild birds, evident in a large outbreak in a nature reserve at Lake Qinghai in Northwest China, where thousands of wild geese, ducks, and gulls were killed. This was the start of the travel of the virus through large parts of the world, moving quickly to Siberia, southern Russia, the Black Sea countries, and Central and Western Europe, where it arrived by the end of 2005. Now it is also spreading in Africa.

THE GLOBAL OUTLOOK

What is the potential of H5N1 to cause human disease? Because the virus spreads quickly in poultry and wild birds, there is an enhanced chance of human exposure. The virus has the ability to cross the species barrier, to be transmitted to man and other species. It also is highly pathogenic for these other hosts, and of course the human population has no immune protection because it has never been exposed to this virus. But so far no man-to-man transmission has been observed although there have been some mutations in the virus that we may call humanizing mutations, since they are similar to features in present human viruses. Fortunately, they have not proved to be stable.

FIGHTING THE AVIAN FLU

Many countries have reacted to this threat—not only the H5N1 threat but also the threat of a pandemic in general—with preparedness plans that are very similar. One important part of these plans is having tight surveillance of influenza activity in man and in animals, implying close cooperation between medical surveillance organizations and veterinary surveillance organizations. However, in Third World countries, where the virus is often endemic, there may be a reasonable human medical system but a very weak or non-existent veterinary system, which is a big problem.

Another part of most of the preparedness plans is providing vaccines. However, a major problem with vaccines is that they are being aimed at a moving target, which means that we have to prepare vaccines against a virus that we still do not really know—the virus could be H5N1 in its present form, H5N1 in a modified form, or a completely different virus. So we need to develop new vaccine strategies that are different from the current vaccine production strategies and we have to make more vaccines, because the entire world should be vaccinated, and we have to prepare them in much less time than is required to prepare conventional vaccines. Another problem is that the world’s vaccine production capacity is far too low, so there needs to be a significant increase in vaccine production capabilities.

The first tool to be used in our fight against a pandemic is the so-called antivirals, such as Tamiflu or other neuraminidase inhibitors. But again there is a production problem: the production facilities are too small. While many countries have stockpiled these drugs, there is yet another problem with them: If we apply these drugs against the virus, then the virus will develop resistance and stop being sensitive to these drugs. So we need to develop a large variety of drugs as we have done with drugs against bacterial infections.

Another problem is the control of avian influenza. This must be handled by culling, animal vaccination, and sheltering of flocks, as is practiced now in Germany. We also must be prepared for patient management in the case of a pandemic. We need to be prepared to care for many thousands of seriously ill people who will come down with the disease in a very short time period and who will be highly infectious. Currently our hospital systems are not prepared for this.

CONCLUDING REMARKS

Right now we should keep in mind that avian influenza is still an animal disease; it is not yet a direct human threat. H5N1 outbreaks are under control in some of the countries in which the virus originally appeared—in Thailand and in Vietnam—but it is still active in Africa, Indonesia, and some parts of Central Asia. So we must be on continuous alert for a pandemic caused by H5N1 or another influenza virus.