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From:

http://www.cfr.org/publication/9230/council_on_foreign_relations_conference_on_the_global_threat_of_pandemic_influenza_session_1.html

To the left is Amin Soebandrio; he's the assistant deputy for Medical and Health Sciences at the Ministry of Research and Technology of Indonesia. To the far right, Steven Wolinsky, chief of the Division of Infectious Diseases at Northwestern University Feinberg School of Medicine. And sitting right next to me is Dr. Robert Webster, professor in the Division of Virology in the Department of Infectious Diseases at St. Jude's children's hospital.

Later on, we'll include your questions and get some answers to things that may have been bugging you all along, and we'll try to get them settled today.

Dr. Webster, where do we stand? As people try to form some sort of understanding of what's moving where, what's percolating in the bloodstreams of animals large and small through the world's time zones, where do we stand?

DR. ROBERT WEBSTER: We're sitting on the knife-edge right now. The virus has spread across most -- from Asia to Central Asia to Europe. It's sitting on the knife-edge for spreading to Africa and next season probably to the U.S. And the situation in humans is growing by the day. The number of human cases keeps creeping. And the situation is extremely serious.

SUAREZ: What is the bio-break point, the threshold that gets crossed in the change in the virus itself that moves this from something that only affects a small number of humans, and a large number of birds, to something that really can be a worldwide problem?

WEBSTER: The answer to that is unknown. We are not there yet in terms of our understanding of transmissibility. The key question is sustained transmission between people. We've had small clusters of
humans infected in different countries, but there's no -- so far, thank God -- no sustained transmission from person to person. What is the basis of transmissibility, we don't know.

SUAREZ: When there is a human-to-human confirmed case, will that tell us something about the underlying health status of the humans involved, or will it tell us something that's changed fundamentally about the virus itself?

WEBSTER: One human-to-human won't tell us very much. And unfortunately, we don't get enough information from humans in Asia on what has happened to humans. The number of postmortems done is extremely small. The number of viruses we get to examine is extraordinarily small. And we will not know from one or two passages the molecular basis. We have to take this back into the laboratory to really
understand this, and we will know when we have sustained transmissibility; that's the breakpoint.

SUAREZ: Dr. Wolinsky, is there a situation that's created by human activity or a situation that's created by
bird activity, which is something sort of beyond our reach, that can make this a greater or lesser danger?

DR. STEVEN WOLINSKY: Well, certainly when, during the course of human events when we're put in greater proximity to animals that have other viruses, they do have a propensity to leap from their animal host to humans. This has gone on in many situations. HIV/AIDS is a perfect example of a virus that existed within a primate host for a long period of time until it actually was successful in its jump to humans. But that leap was preceded by many sort of tentative steps, as we're seeing now where it sort of makes a little dance forward; maybe there's a one or two person spread. It doesn't quite make it. And again, I would emphasize that we really do need to know what is going on at the molecular level. What really characterizes the virus that makes that leap? What are the underlying genetic factors that both the virus, the host and its immune response that makes this happen?

SUAREZ: Are there changes that happen in the virus that blunt any attempts to defend against it?

WOLINSKY: Well, in respect that the virus can have enhanced pathogenicity -- its ability to actually do greater damage to the host -- there may be aspects of the virus, per se. Witness the 1918 influenza virus. There's properties that we've seen in the animal models where it really has shown an enhanced ability to kill in a situation where other viruses, other influenza viruses did not -- its ability to incite an immune response that far outweighs what is needed for the host to be protected, and in fact, ravages the host, ravages the animal model. So there are some genetic variants that exist in particular and have been transmitted. What are the actual particular pathogenic factors that mediate this are still really not known.

SUAREZ: We tend to talk about mutation as if it's a discrete event which gets you from one place to a single new place. Could five or six or 10 or 100 variants be cooking right now in animal host bloodstreams and some just end up being mutational dead ends because they kill too quickly or don't kill at all or don't spread easily, and, in fact, it's only the one that's successful that catches our attention?

WOLINSKY: Well, certainly -- we can just go back to Darwin on this -- (inaudible) -- we're looking at dissent with modification.

SUAREZ: You can do that because we're in New York State. Okay? (Laughter.)

WOLINSKY: That's right. We're not in Kansas anymore. (Laughter.) And like other RNA viruses, flu is highly mutable, highly adaptable and capable of rapid evolution. And within the host, it's not a single virus that you have but actually a swarm of viruses. And they're all genetically related but yet distinctive. The virus is constantly mutating. And it's on a cycle that's akin to other RNA viruses that every time it replicates, it makes a mistake. And so basically you're left with this viral swarm. And how the swarm actually adapts to the host, how the immune system actually manages that is really up to an individual basis as well. And there are individual differences in terms of how people respond to infectious diseases, and there are differences because of their genetic makeup, because of their immune response, their underlying difficulties with immune response, how the virus is able to exploit these and the fact that certain ones become adapted, better able to grow in a certain environment.

SUAREZ: Dr. Soebandrio, what do we know about the situation, the state of Avian flu in Indonesia?

DR. AMIN SOEBANDRIO: Yes, as you are already aware that the first outbreak in Indonesia among birds was announced by the government in the middle of 2003 and the number of bird deaths increasing. But actually, we could control until the beginning of 2004; the number of bird death is decreasing very much.

But a few months after that increase, again we have a small peak. But what makes us so scared -- in end of June this year, we have the first human case. A small child was hospitalized with the symptoms fever and problem with the respiratory track, and when she was hospitalized, her sister also then developed same symptom, and also their father. They all died. That was the first cluster. But unfortunately, we couldn't find any source of contact because they don't live in area where close to poultry farm or something like this. It was the fist cluster.

A few weeks later appeared some other cases. And so far, we have nine confirmed human cases, five of them dead. And by virus isolation, helped by a Hong Kong laboratory, we then identified already now four clusters. The first cluster has three members, one family; second cluster, one young lady and then her nephew, a boy; and then third cluster, also a young lady and also one of her family; and then coming the fourth cluster. The other three -- the last three cluster only consist of two family members. But the last -- (inaudible) -- cluster we could identify the source, really. They have clear contact with birds. But still, for
the first cluster, it's unclear.

So with that situation, we realized that -- already a very serious situation happened in Indonesia especially -- (inaudible) -- Jakarta. As you know that most of the cases -- (inaudible) -- in Indonesia is in surrounding
area of Jakarta, in outskirts of Jakarta -- only one-hour drive from center of Jakarta. Why it happened in the area, one of the most important hypotheses -- dense human population and also dense chicken population. Human population is up to 12,000 per square kilometers, and chicken population up 5,000 head per square kilometers. And they are all in the same vicinity. So -- and also one more thing: yeah, we have to admit that the bio-security of most of the farm is still very low. So that's the situation -- current situation in Indonesia.

Of course, probably the nine confirmed cases just the tip of the iceberg, because we do receive reports from other parts of Indonesia. People develop similar clinical symptom, but the laboratory, unconfirmed. That is the situation with the human influenza situation. I meant human cases.

If you are talking about the situation in birds, so far we have already 10 million birds already killed or died.
As a comparison, in Indonesia we have 1.4 billion population of bird, compared to China about 4 billion birds. So quite a lot. And another interesting situation is after last year, we have the bird confirmed to be infected by Avian influenza virus, just localized in the western part of Indonesia -- Java, Sumatra, Borneo, not in the eastern part of Indonesia. But from this year, we could identify many places in eastern part of Indonesia already infected by Avian influenza.

SUAREZ: You've mentioned the number of birds killed. How do you know whether that really works? One of the most common features of the news stories concerning how governments respond to bird flu involve huge culls in Thailand, in Vietnam, in China; you mentioned Indonesia. We've been killing birds by the tens of millions, yet Dr. Webster talked about the virus now spreading to all points on the globe.

SOEBANDRIO: Actually, if we follow the procedure, the OEI procedure, we should have killed more than 10 million. But the problem is the government has not enough resources to pay the compensation to the farmer, because this time we have to kill birds or pigs or ducks. We have to give compensation to the farmer. That's the problem. Compared to other countries, if we find a case of bird -- a flock of birds infected by Avian influenza, we have to kill in the area of up to three kilometers from the farmer, from the
farm. But in fact, we didn't do that. Only we killed the bird in the same farm.

SUAREZ: Dr. Webster, do culls work? And in the case of limited culls like Dr. Soebandio just described, is sort of doing it halfway almost as good as doing nothing?

WEBSTER: Culling does work. The documentation -- the H5N2 outbreak in the United States in the early 1980s, that virus is gone. Japan got rid of H5N2. Korea got rid of it by culling. On the other hand, if you turn to other countries where the virus was widespread before culling began, as in Mexico in the early '90s, H5N2 was widespread before culling began, and then culling doesn't work. In China, in Indonesia, where the virus was widespread before it was recognized, then culling does not work. It is not possible to cull in China at this time and cull in some countries. So yes, culling does work in some countries if you act quickly but not after it has become widespread.

SUAREZ: But here's a case where we have a mixture of very biologically similar bird types -- domestic and wild fowl among ducks and geese, both large-hold farms, where you're supplying protein to market, and small-hold farms, where you're feeding a family. So you've got stratification of all kinds and, now, passage to migratory populations of non-domesticated species. I mean, can you kill everything?

WEBSTER: You raise an extremely important point. This virus is now endemic. H5N1 is now endemic in the wild birds in Asia. And if we take the case in Thailand, Thailand killed and killed and killed, and they had nearly a year almost free of bird flu, but it's back. There are human cases. The virus is spreading again. And that virus is being spread, presumably, again by wild birds. So at this point, we're beyond the point where culling will work. We really have to think in terms of culling. Tough vaccination is the only way forward at the agricultural level.

SUAREZ: Is it important to know, Dr. Wolinsky, how we got here, whether there was a change in conditions that suddenly lit a match to the tinder? People have been farming birds in very close quarters in Southeast Asia for a long time. They've been living in close quarters. If you look at, you know, temple paintings and ancient carvings, there are domesticated birds, birds tied to each other by the ankle that are held by people's houses. Was there something qualitatively different about this last decade that made it possible for this disease to do something that it either hasn't done before or only done cyclically?

WOLINSKY: Interesting question. We've basically been faced with influenza pandemics, at least three, four a century, so that there seems to be some juxtaposition of when the virus actually makes a leap into the human population and when the population has not really contained its spread. And part of that is because we have not had an immunological memory to that specific type. No one, really, has seen H5N1 before. So if the fact is -- if that virus actually takes hold and is sustained transmission, so there's person-to-person spread, what we had is a situation whereby it goes through a population bottleneck. We have not really seen this virus before. And even though these viruses are highly mutable and can change rapidly, there's no reason for it to change once it hits a population that has never been exposed to it before, and it can ravage through a population. That's really what makes this such a difficult disease and why we have to really put everything at the forefront to try and contain it.

Again, what is the particular event that leads to one particular case of transmission that leads to it? I would defer to the person on my right who studied that the most in terms of how that occurred.

WEBSTER: I would answer that in a slightly different way in what is different from what we've been -- what's happened before is globalization. And farming practices have changed. Previously, we had backyard poultry. I grew up on a farm in New Zealand. We had a few backyard chickens and ducks. The next-door neighbor was so far away it didn't matter. Now we put millions of chickens into a chicken factory next door to a pig factory, and this virus has the opportunity to get into one of these chicken factories and make billions and billions of these mutations continuously. And so what we've changed is the way we raise animals and our interaction with those animals. And so the virus is changing in those animals and now finding its way back out of those animals into the wild birds. That's what's changed."