Science Tuesday - AVIAN FLU EDITION
Mar. 28th, 2006 07:00 am![[personal profile]](https://www.dreamwidth.org/img/silk/identity/user.png){kind=small}
brdgt
Q&A: How Serious Is the Risk?
By DENISE GRADY and GINA KOLATA, The New York Times, March 27, 2006
Over the last year, it has been impossible to watch TV or read a newspaper without encountering dire reports about bird flu and the possibility of a pandemic, a worldwide epidemic. First Asia, then Europe, now Africa: like enemy troops moving into place for an attack, the bird flu virus known as A(H5N1) has been steadily advancing. The latest country to report human cases is Azerbaijan, where five of seven people have died. The virus has not reached the Americas, but it seems only a matter of time before it turns up in birds here.
Even so, a human pandemic caused by A(H5N1) is by no means inevitable. Many researchers doubt it will ever happen. The virus does not infect people easily, and those who do contract it almost never spread it to other humans. Bird flu is what the name implies: mostly an avian disease. It has infected tens of millions of birds but fewer than 200 people, and nearly all of them have caught it from birds.
But when A(H5N1) does get into people, it can be deadly. It has killed more than half of its known human victims—an extraordinarily high rate. Equally alarming is that many who died were healthy, not the frail or sickly types of patients usually thought to be at risk of death from influenza.
The apparent lethality of A(H5N1), combined with its inexorable spread, are what have made scientists take it seriously. Concern also heightened with the recent discovery that the 1918 flu pandemic was apparently caused by a bird flu that jumped directly into humans.
In addition, A(H5N1) belongs to a group of influenza viruses known as Type A, which are the only ones that have caused pandemics. All those viruses were originally bird flus. And given the timing of the past pandemics — 1918, 1957, 1968 — some researchers think the world is overdue for another. It could be any Type A, but right now (A)H5N1 is the most obvious.
The virus lacks just one trait that could turn it into a pandemic: transmissibility, the ability to spread easily from person to person. If the virus acquires that ability, a pandemic could erupt.
Everything hangs on transmissibility. But it is impossible to predict whether A(H5N1) will become contagious among people. The virus has been changing genetically, and researchers fear that changes could make it more transmissible, or that A(H5N1) could mix with a human flu virus in a person, swap genetic material and come out contagious.
But most bird flu viruses do not jump species to people. Some experts say that since A(H5N1) has been around for at least 10 years and the shift has not occurred, it is unlikely to happen. Others refuse to take that bet.
The A(H5N1) strains circulating now are quite different from the A(H5N1) strain detected in Hong Kong in 1997, which killed 6 of 18 human victims. Over time, A(H5N1) seems to have developed the ability to infect more and more species of birds, and has found its way into mammals—specifically, cats that have eaten infected birds.
The actual number of human cases may well exceed the number that have been reported, and may include mild cases from which victims recovered without even seeing a doctor. If that is true, the real death rate could be lower. But no one knows whether mild cases occur, or whether some people are immune to the virus and never get sick at all.
In the absence of more information, health officials must act on what they see — an illness that apparently kills half its victims.
Q. How will we know if the virus starts spreading from person to person and becomes a pandemic?
A. If there is a pandemic, it would be everywhere, not in just one city or one country. To detect such an event as early as possible there is an international surveillance system, involving more than 150 countries, that searches for signs that a new flu strain is taking hold in humans. One hallmark of a pandemic flu would be an unusual pattern of illnesses — lots of cases, possibly cases that are more severe than normal and, possibly, flu infections outside the normal flu season.
Ordinary human flu viruses, for reasons that are not entirely understood, circulate only in winter. But pandemics can occur at any time. A pandemic would also involve a flu virus that was new to humans, meaning that no one would have immunity from previous infections.
Q. If bird flu reaches the United States, where is it likely to show up first?
A. Although health officials expect bird flu to reach the United States, it is impossible to predict where it may show up first, in part because there are several routes it could take. If it is carried by migrating birds, then it may appear first in Alaska or elsewhere along the West Coast.
But if the virus lurks in a bird being smuggled into the United States as part of the illegal trade in exotic birds, it could land in any international airport. Bird smuggling is a genuine problem: in 2004, a man was caught at an airport in Belgium illegally transporting eagles from Thailand, stuffed into tubes in his carry-on luggage. The birds turned out to be infected with A(H5N1), and they and several hundred other birds in a quarantine area at the airport had to be destroyed.
In theory, an infected human could also bring bird flu into the United States, and that person could fly into just about any international airport and go unnoticed if the virus had yet to produce any symptoms.
Q. Does bird flu affect all birds?
A. No one knows the full story. Scientists say A(H5N1) is unusual because it can infect and kill a wide variety of birds, unlike a vast majority of bird flus, which are usually found in wild birds, not domestic fowl, and which cause few symptoms.
Some researchers suspect that wild ducks, or perhaps other wild birds, are impervious to A(H5N1), and may be the Typhoid Marys of bird flu — getting the virus, spreading it to other birds but never becoming ill themselves. No one has good evidence of this yet, but that may be because the way scientists discovered A(H5N1) infections was by finding birds that had gotten the flu and died.
As virologists like to point out, dead birds don't fly. So migratory birds cannot spread the virus if they are dying shortly after being infected. That is why some researchers say that if wild birds are spreading the A(H5N1) virus, it must be a bird species that can be infected but does not become ill.
Q. When people die from avian flu contracted from birds, what kills them?
A. Like victims of severe pneumonia, many patients die because their lungs give out. The disease usually starts with a fever, fatigue, headache and aches and pains, like a typical case of the flu. But within a few days it can turn into pneumonia, and the patients' lungs are damaged and fill with fluid.
In a few cases, children infected with A(H5N1) died of encephalitis, apparently because the virus attacked the brain. A number of people have also had severe diarrhea — not usually a flu symptom — meaning that this virus may attack the intestines as well. Studies in cats suggest that in mammals the virus attacks other organs, too, including the heart, liver and adrenal glands.
But more detailed information about deaths in people is not available because very few autopsies have been done. In some countries, like Vietnam, where many of the deaths occurred, autopsies are frowned upon. Researchers say they may glean useful information from autopsies, but fear that pressing for them would alienate the public in some areas.
Q. When experts refer to bird flu as A(H5N1), what does that mean?
Q. If I got bird flu, how would I know?
A. There is no reason to suspect the disease unless you may have been exposed to it. Since the virus has not reached North America, doctors do not look for bird flu in people unless they have traveled to affected regions or have been exposed to sick or dead birds.
The early stages of the illness in people are the same as those of ordinary flu: fever, headache, fatigue, aches and pains. But within a few days, people with bird flu often start getting worse instead of better; difficulty breathing is what takes many to the hospital.
In any case, patients with flulike symptoms that turn severe or involve breathing trouble are in urgent need of medical care.
Q. Can I be tested for avian flu?
A. There is no rapid test for bird flu. There is a rapid test for Type A influenza viruses, the group that A(H5N1) belongs to, but the test is only moderately reliable, and it is not specific for A(H5N1).
State health departments and some research laboratories can perform genetic testing for A(H5N1) and give results within a few hours, but they do not have the capacity to perform widespread testing.
Because of the limited availability of testing and the extremely low probability of A(H5N1) in people in the United States, the test is recommended only for patients strongly suspected of having bird flu, like travelers with flulike symptoms who were exposed to infected birds.
Q. Do any medicines treat or prevent bird flu?
A. Two prescription drugs, Tamiflu and Relenza, may reduce the severity of the disease if they are taken within a day or two after the symptoms begin. But Relenza, a powder that must be inhaled, can irritate the lungs and is not recommended for people with asthma or other chronic lung diseases.
Both drugs work by blocking an enzyme — neuraminidase, the "N" part of A(H5N1) — that the virus needs to escape from one cell to infect another. But just how effective these medicines are against A(H5N1) is not known, nor is it clear whether the usual doses are enough. Also unknown is whether the drugs will help if taken later in the course of the disease. Although government laboratories and other research groups are trying to develop vaccines to prevent A(H5N1) disease in people, none are available yet.
Q. If there is an epidemic of flu in humans, how can I protect myself?
A. If there is a vaccine available, that would be the best option. But if there is no vaccine it may be hard to avoid being infected. Flu pandemics spread quickly, even to isolated regions. The 1918 flu reached Alaskan villages where the only way visitors could arrive was by dog sled.
The vaccines produced every year to prevent seasonal flu are unlikely to be of any use in warding off a pandemic strain. But a flu shot could provide at least some peace of mind, by preventing the false alarm that could come from catching a case of garden-variety flu.
Similarly, people over 65 and others with chronic health problems should consult their doctors about whether they should be vaccinated against pneumococcal pneumonia, a dangerous illness that can set in on top of the flu. Again, that vaccine will not stop bird flu, but it may prevent complications.
Some health officials have recommended stockpiling two to three months’ worth of food, fuel and water in case a pandemic interferes with food distribution or staffing levels at public utilities, or people are advised to stay home.
Many health experts have advised against stockpiling Tamiflu or Relenza, the prescription-only antiviral drugs that may work against bird flu. Doctors say the drugs are in short supply and hoarding may keep them out of reach of people who genuinely need them.
Also, they say, self-prescribing may lead to waste of the drugs or misuses that spur the growth of drug-resistant viruses. But people may not trust the government to distribute these drugs, and may want their own supplies. Doctors say people can take precautions like avoiding crowds, washing their hands frequently and staying away from those who are sick. Masks may help, but only if they are a type called N-95, which has to be carefully fitted. So far, masks and gloves have been recommended only for people taking care of sick patients.
Avoiding the flu can be hard because it is not always possible to spot carriers. Many people get and spread flu viruses and but never know they are infected.
Q. Is the government prepared for a bird flu pandemic?
A. No. The nation does not have an approved flu vaccine for people or enough antiviral drugs or respirators for all who would need them. The best protection in any flu pandemic will come from a vaccine, but scientists cannot tell ahead of time what strain the vaccine should protect against.
Efforts are under way to make a vaccine for A(H5N1). But the virus could mutate in a way that makes experimental vaccines ineffective, requiring more than one vaccine.
Moreover, there is no assurance that the next pandemic will even involve A(H5N1). It may involve a different strain of bird flu, and an A(H5N1) vaccine would not work for it. Recent efforts to develop a sort of universal flu vaccine that would work across strains have failed.
For now, the hope is to spot a pandemic early and quickly make a vaccine. Investigators are developing new and better ways to make vaccines — a bird flu, for example, cannot be grown in fertilized eggs like other flu viruses because it kills the chicken embryos — but these new methods must first be approved by the Food and Drug Administration.
Preparations also include government plans to stockpile drugs to protect people who were exposed to the flu and to reduce the severity of the disease in those who are ill. But the one antiviral drug that everyone wants to buy and stockpile, Oseltamivir, also sold by Roche as Tamiflu, is in short supply.
In retrospect, scientists say, maybe the nation should have started preparing sooner. But until the current bird flu appeared, there was little interest in such expensive and extensive preparations.
Q. If bird flu reaches the United States, will it be safe to eat poultry or to be around birds or other animals?
A. Poultry is safe to eat when it is cooked thoroughly, meaning that the meat is no longer pink and has reached a temperature of 180 degrees Fahrenheit. The risk is not from cooked meat — cooking kills viruses. Instead, it is from infected birds that are still alive or have recently died. So the person who killed an infected chicken, butchered it or put it in the pot would be at greater risk than the one who ate it.
It's not clear how long the virus lives on a dead bird, but it is unlikely to survive more than a couple of days. And it seems unlikely that infected chicken will find its way to supermarkets.
If the bird flu strikes poultry farms, the farmers will know there is a problem. Before they die, the birds develop major hemorrhages, with blood streaming from their cloacas and beaks. When the flu gets to a poultry farm, farmers have to destroy their flocks, and poulgreater risk than the one who ate it.
It's not clear how long the virus lives on a dead bird, but it is unlikely to survive more than a couple of days. And it seems unlikely that infected chicken will find its way to supermarkets.
If the bird flu strikes poultry farms, the farmers will know there is a problem. Before they die, the birds develop major hemorrhages, with blood streaming from their cloacas and beaks. When the flu gets to a poultry farm, farmers have to destroy their flocks, and poultry from infected farms cannot be sold for meat.
As for contact with healthy birds or animals, there is no need to panic. The A(H5N1) virus is a nasty one. If chickens or other animals became infected they would get sick and die, and you would know the virus was present.
But animals can carry many diseases besides influenza, and whenever you are around animals it is a good idea to wash your hands afterward. Because cats in Europe have caught A(H5N1), apparently from eating infected birds, health officials there advise keeping pet cats indoors, but no such recommendation has been made in the United States.
For now, officials at the Centers for Disease Control and Prevention say it is safe to have bird feeders, and they note that even if the virus does arrive here, the kinds of birds that perch at feeders are far less likely to carry A(H5N1) than are aquatic birds like ducks and geese.
Q. Is it safe to buy imported feather pillows, down coats or comforters and clothing or jewelry with feathers?
A. Imported feathers may not be safe. There is a risk to handling products made with feathers from countries with outbreaks of bird flu, according to the Centers for Disease Control and Prevention. Feathers from those countries are banned in the United States unless they have been processed to destroy viruses.
The Skeptic: On the Front: A Pandemic Is Worrisome but 'Unlikely'
By ELISABETH ROSENTHAL, The New York Times, March 28, 2006
OXFORD, England — The Hospital for Tropical Diseases in Ho Chi Minh City, where Dr. Jeremy Farrar works, has treated about two dozen people with avian influenza in the last three years.
With that tiny number, Dr. Farrar and his Vietnamese colleagues probably have more clinical experience than any other doctors with the A(H5N1) virus — the dreaded germ that international health officials fear may ignite the next flu pandemic.
Yet, Dr. Farrar notes, this trickle of humans infected with bird flu — 186 in all since 2003 — has provoked a flood of scientific meetings on pandemics, accelerating in recent months.
"The ratio of meetings to patients is probably 10 to 1: Hawaii tomorrow. Geneva and Singapore next week," said Dr. Farrar, in jeans and carrying a red backpack, on a break from a conference where he was — naturally — speaking on the topic.
"The interest is phenomenal," he said, clicking at his popular PowerPoint presentation.
Still, Dr. Farrar is not sure that this intensity is entirely rational:
Having observed A(H5N1) for many years in Asia, he thinks it is unlikely that the virus is poised to jump species, becoming readily transmissible to humans or among them. Nor does he believe the mantra that a horrific influenza pandemic is inevitable or long overdue. He points out that the only prior pandemic with a devastating death toll was in 1918, and he says that may have been "a unique biological event."
"For years, they have been telling us it's going to happen — and it hasn't," said Dr. Farrar, director of the Oxford University Clinical Research Unit at the hospital in Vietnam. "Billions of chickens in Asia have been infected and millions of people lived with them — we in Asia are intimate with our poultry — and less than 200 people have gotten infected.
"That tells you that the constraints on the virus are considerable," he continued. "It must be hard for this virus to jump."
Still, a part of Dr. Farrar is terrified of A(H5N1) — "a very nasty virus," he calls it — which he has watched kill healthy young people, devouring their lungs.
In the last year, the virus has extended its range in birds from Eastern China to Western Africa. Over time, it has expanded the variety of species it can infect, including ferrets and cats.
"That is alarming," he acknowledges in the understated British way.
Like all responsible scientists, Dr. Farrar believes the world should prepare. But schooled in places where people die of real and present diseases like malaria and tuberculosis, he finds the "doomsday" predictions sketched out by some international officials unhelpful, more fantasy than fact.
And even if these officials' dire forecasts were to come true, he says, many of their elaborate pandemic preparedness plans are unworkable in developing countries, which do not have the resources or medical facilities to comply.
"I think you have to say we really don't know the odds of pandemic, and people are not comfortable with that," Dr. Farrar said. "It could fizzle out and kill 98 people — one more than the number dead today. Or it could be something like 200 million," closer to an estimate once made by Dr. David Nabarro, chief avian flu coordinator for the United Nations.
"It's terrifying if it happens, but it is very, very unlikely, I think — and it is difficult to balance those facts."
At the Tropical Disease Hospital in Vietnam, doctors have been doing just that, bracing for a pandemic that may never come, since long before it became fashionable in the West.
Before Vietnam began vaccinating poultry in mid-2005, the disease was rampant among birds there. Of the world's 186 confirmed human cases, 93 are from Vietnam. There have been no new cases this year.
But in the Tropical Diseases Hospital, doctors and nurses still don full bio-protective gear when they evaluate suspected cases, because "you don't know if the next one will mark the start of human to human transmission," Dr. Farrar said.
With each new patient, they assiduously try to follow international scientific recommendations. But their on-the-ground experience reveals holes in the neat strategies coming from United Nations experts in Geneva and Rome.
The World Health Organization suggests that it might be possible to contain a pandemic by quickly diagnosing index cases, identifying contacts, prescribing all antiviral drugs, and quarantining, for example.
In response, Dr. Farrar shows a picture of the home of a patient: a hut on stilts by the Mekong River. When that patient fell ill, he took a boat to the local health station, and was transferred to the district hospital, Dr. Farrar says. Later, an ambulance took him to Ho Chi Minh City, where genetic analysis showed that he had avian influenza, instead of typical pneumonia. If bird flu ever gained the ability to spread easily among humans, that patient would have infected thousands before diagnosis.
"You've got to act quickly, but the process now takes many days," Dr. Farrar said, suggesting that more money for clinics, labs and experts should be flowing to developing nations.
"Then you're supposed to go back to the village and saturate it with oseltamivir?" he asks, using the generic name for the antiviral drug Tamiflu. "What do the villagers do when they hear the man has bird flu? They don't sit still; they get on buses and flee and stay with relatives in other villages," potentially spreading it there.
For doctors in Vietnam, human cases of avian influenza have been a frightening reality for more than three years, and Dr. Farrar vividly remembers the initial terror of the devoted hospital staff, unsure if they could catch bird flu from patients.
"Look at this lung — there's nothing there," he said pulling up the X-ray of a patient who is back at the university, but whose left chest shows a vast empty cavern. Studies from the hospital have taught the world much about A(H5N1): humans took longer to clear this virus than normal influenza, for example, and Tamiflu can quickly breed resistant strains.
But, to Dr. Farrar's chagrin, the treatment options have not really improved.
Flu vaccines are still manufactured by an "ancient strategy" that involves injecting eggs with virus, he complained, even as other vaccines rely on more sophisticated methods. As a result, flu vaccines — including experimental versions aimed at A(H5N1) — are cumbersome to produce, and target just one strain.
"What we need is a vaccine that is effective across strains because the virus can be different each year," he said. "My mom in the U.K. can get a shot every year, but that is not realistic in rural Asia."
More remarkable still, he said, Tamiflu is still the only drug useful against avian influenza, "and we all know that one drug is not adequate to treat any viral disease," he said, noting that multiple drugs are used in AIDS.
Patients at Dr. Farrar's Hospital are given Tamiflu, and it appears to help some. "It's all that we have," he said. "So if I was sick, I'd certainly want to get it."
But, he rues the lack of international research and coordination to tackle a disease that has been in Asia for nearly 10 years. For example, he said, although Vietnam has greatly reduced the number of bird flu outbreaks by vaccinating poultry, no one knows if the vaccine puts pressure on A(H5N1) to mutate to develop resistance to the shot, which could cause a rebound of disease in the coming years.
Personally, Dr. Farrar remains optimistic, believing a pandemic will not come. If A(H5N1) changed so that it readily infected people, it would probably become less deadly, he said.
But if disaster happens, he says: "People will look back and say: 'This was a nasty virus that you knew could sometimes infect other species. Why didn't you do something? All you had was a single effective drug and no vaccine?' "
The 1918 Flu Killed Millions. Does It Hold Clues for Today?
By GINA KOLATA, The New York Times, March 28, 2006
Flu researchers know the epidemic of 1918 all too well.
It was the worst infectious disease epidemic ever, killing more Americans in just a few months than died in World War I, World War II, the Korean War and the Vietnam Wars combined. Unlike most flu strains, which kill predominantly the very old and the very young, this one — a bird flu, as it turns out — struck young adults in their 20's, 30's and 40's, leaving children orphaned and families without wage earners.
So now, as another bird flu spreads across the globe, killing domestic fowl and some wild birds and, ominously, infecting and killing more than 100 people as well, many scientists are looking back to 1918. Did that flu pandemic get started in the same way as this one? Will today's bird flu turn into tomorrow's human pandemic?
And what, if anything, does that nearly century old virus and the pandemic it caused reveal about what is happening today?
The answer is: a lot and not enough. The 1918 pandemic showed how quickly an influenza virus could devastate American towns and cities and how easily it could spread across the globe, even in an era before air travel.
It showed that a flu virus could produce unfamiliar symptoms and could kill in unprecedented ways. And it showed that a bird flu could turn into something that spreads among people.
But the parallels go only so far, researchers say. For now, they are left with as many questions as answers.
In the fall of 1918 flu struck the United States and parts of Europe hard and traveled to every corner of the world except Australia and a few remote islands. A few months later, it vanished, burning itself out after infecting nearly everyone who could be infected.
The virus arrived at even the most improbable places, like isolated Alaskan villages. In one such village, Wales, 178 of its 396 residents died during one week in November, after a mailman arrived by dog sled, bringing the virus along with the mail.
Public health officials tried in vain to contain its spread. In Philadelphia, people were exhorted not to cough, sneeze or spit in public.
But the virus spread anyway. On Oct. 3, Philadelphia closed all of its schools, churches, theaters and pool halls. Still, within a month, nearly 11,000 Philadelphians died of influenza.
Anyone who doubts that flu deaths can be horrific need only read the memoirs of physicians like Dr. Victor C. Vaughan, who treated influenza victims in 1918.
Dr. Vaughan, a former president of the American Medical Association, was summoned by the surgeon general to Camp Devens, near Boston, where the flu struck in September. He later described the scene in his memoirs.
The men, Dr. Vaughan wrote, "are placed on the cots until every bed is full, yet others crowd in."
"Their faces soon wear a bluish cast; a distressing cough brings up the blood stained sputum," he continued.
"In the morning, the dead bodies are stacked about the morgue like cord wood," Dr. Vaughan said. "This picture was painted on my memory cells at the division hospital, Camp Devens, in the fall of 1918, when the deadly influenza virus demonstrated the inferiority of human inventions in the destruction of human life."
Still, scientists are left with an abiding mystery: Where did the 1918 virus come from?
Investigators know more than they once did. They know exactly what the virus looked like, thanks to Dr. Jeffrey Taubenberger, chief of the division of molecular pathology at the Armed Forces Institute of Pathology, and his colleagues, who obtained snippets of preserved lung tissue from three victims of the 1918 flu and managed to fish out shards of the virus and piece together its genes. Although the 1918 virus was a strain different from the A (H5N1) virus that is now killing birds, it was, Dr. Taubenberger found, a bird flu.
What is not known is how the 1918 virus moved from birds to humans.
One clue could come from knowing what flu viruses existed before the 1918 pandemic. Perhaps the 1918 virus entered the human population before 1918 in a more benign form then mutated to become a killer. Or perhaps it suddenly showed up in humans, jumping directly from birds to people.
To find out, Dr. Taubenberger and Dr. John Oxford of the Royal London Hospital are looking for human flu viruses that existed before 1918. London Hospital has a collection of human tissue obtained from 1908 to 1918. Dr. Taubenberger is searching for flu viruses in lung tissue from people who died of pneumonia in those years, hoping to use the same methods that allowed him to piece together the 1918 virus to resurrect a flu virus that was in humans before 1918.
The 1918 virus also is teaching researchers about experimental vaccines that scientists hope will protect against a variety of influenza strains. The plan had been to make a sort of universal flu vaccine that would protect against various flu viruses. Then people would not need a flu shot each year, and the vaccine might stop pandemic flu strains from ever gaining a toehold.
But, says Dr. Terrence Tumpey, a microbiologist at the Centers for Disease Control and Prevention, although the experimental vaccines protect against ordinary human flu viruses, they do not protect against the 1918 virus. Nor do they protect against today's A(H5N1) bird flu virus.
That leaves scientists with a puzzle. If they are worried about a 1918-like flu, they want a universal vaccine to protect against it, and they wonder what makes these bird flus so impervious? At this point, no one knows, Dr. Tumpey says.
Another abiding mystery is that neither the 1918 influenza pandemic nor any other human influenza pandemic began with a flu pandemic that killed birds. And, scientists add, if the 1918 pandemic had begun that way, it would have been noticed. Even if the deaths of wild birds went undetected, the deaths of domestic fowl would have been recorded.
Wild birds are inured to most flu viruses — clouds of the viruses normally infect them, living in their gastrointestinal tracts but causing little or no disease. Sometimes, those flu viruses infect poultry and, while they usually cause little illness, some flu strains can be lethal to fowl and economically devastating to farmers.
That, Dr. Taubenberger says, "has been recognized for 150 years." In the 1920's, scientists even isolated viruses from what they used to call fowl plague and what is now known to be bird flu. They were not the same viruses that infected humans.
The problem is in deciding what all this means.
The history of the 1918 flu can take scientists only so far, Dr. Taubenberger said.
"We don't know how the 1918 pandemic evolved and how the virus emerged into a form that was the finished product," he said. "What we sequenced was a virus that was ready for prime time, not its precursor."
"Ultimately," Dr. Taubenberger said, "the answer to the big question is, We don't know. There is no historical precedent for what is going on today."
Making a Ferret Sneeze for Hints to the Transmission of Bird Flu
By DENISE GRADY, The New York Times, March 28, 2006
ATLANTA — One way to collect nasal secretions from a ferret is to anesthetize it, hold a petri dish under its snout and squirt a little salt water up its nose so that it will sneeze into the dish.
At the Centers for Disease Control and Prevention, ferret sneezes are frozen in tiny vials and locked up in a high-security chamber called an enhanced biosafety Level 3 laboratory. It takes a fingerprint scan to get in, and an iris scan to open the freezer. Scientists wear scrub suits, gowns, double gloves and hoods, breathe filtered air and open vials only by reaching into a safety cabinet designed to keep germs from escaping into the air.
The vials are in this lab because the animals have been exposed to A(H5N1), the notorious avian flu virus that has swept across Asia, Europe and Africa, wiping out flocks of poultry and sometimes killing people as well. Researchers at the disease centers and in other labs are studying the transmission and virulence of bird flu in ferrets and mice, trying to answer questions that take on more urgency as the virus advances.
"We have never had a situation like the world is experiencing today, such an unprecedented spread among poultry," said Dr. Timothy Uyeki, an epidemiologist and influenza expert at the disease centers. "The geographic spread is unprecedented, and the mortality unprecedented as well, and this virus has been clearly confirmed to transmit directly from poultry to people and to cause severe and fatal illness."
The big question is, will A(H5N1) cause a human pandemic? Many scientists think the world is overdue for one and find it worrisome that this dangerous virus has popped up now. Even so, in its present form this flu does not seem to be a pandemic germ because it does not spread easily from birds to humans, and because infected people rarely transmit it to others. But everything could change if the virus were to mutate in a way that made it easier for people to catch and spread.
"Why would a particular virus be transmitted easily human to human, and another not?" asked Dr. Peter Palese, chairman of microbiology at the Mount Sinai School of Medicine in New York. "Even though I am 35 years in this field, we do not have molecular parameters or signatures which make that clear, although many groups, including my own, are working on this exact question."
The virus is a moving target, and two distinct subsets of it have developed, one from Vietnam and one from Indonesia, that differ enough to make scientists think separate vaccines will be needed. Scientists are trying to understand how a virus can be wildly contagious among birds but almost impossible to spread in mammals — and what type of mutation could change that. They are also comparing different strains of A(H5N1) to see if it is becoming more virulent, and they are examining the structure of the virus in hopes of figuring out what makes it so deadly.
Ferrets are used for some studies because, unlike mice, they easily catch human flu viruses and get sick, and so are considered a better model for people. At the disease centers, Taronna Maines and Terrence Tumpey have infected ferrets with A(H5N1) and then monitored them to see if the severity of the disease varies by strain and by dose, and to see if the infected animals cough up the virus or sneeze it out and spread it to healthy ones.
It turns out that ferrets do not transmit the disease easily, though some healthy animals develop antibodies to the virus, indicating that they have been exposed. If a strain comes along that is contagious in ferrets, it might be bad news for people.
Research like this may help determine whether (A)H5N1 is heading down the path to becoming a pandemic strain, and may also help to guide the development of vaccines and drugs.
Aside from the virus's recent horrible track record, several other things about it can help explain why some scientists worry that it has pandemic potential. The A means it belongs to a larger group known as Type A influenza viruses, which cause many of the human flu epidemics that occur every winter. But more ominously, Type A also includes the only viruses ever known to have caused human pandemics, in 1918, 1957 and 1968.
Flu viruses mutate a lot, and pandemics occur when a Type A virus undergoes a big genetic change to produce a new type of virus to which people have little or no resistance. Sometimes the change occurs when a person or a pig acts as a "mixing vessel" for two flu viruses — maybe a human one and a bird one — which swap genes to produce a new virus. That kind of change is believed to have caused the 1957 and 1968 pandemics. But the 1918 pandemic, the worst by far, is thought to have occurred without a gene swap, when a bird flu somehow mutated enough to jump into humans.
All Type A viruses are found in birds. They probably originated in wild birds and usually do them little or no harm. Only a few evolved into strains that could easily infect people. A(H5N1) is not adapted to people, and researchers suspect that human victims so far may have been infected because they were exposed to enormous amounts of the virus from birds.
The letters H and N stand for two proteins on the outside of all Type A viruses. The H, hemagglutinin, helps the virus get into cells, which it must do to reproduce. The N, neuraminidase, helps it get back out to infect more cells. There are 16 kinds of H and 9 kinds of N; they mix and match, and so can produce 144 possible Type A strains. The worrisome thing about H5 is that H5 viruses are avian flus and have not been known to cause human epidemics, so many people may have little or no resistance to them.
Not long ago, A(H5N1) may well have been what scientists call a perfect parasite, meaning one that does little harm to its host, Dr. Ruben Donis, a flu expert at the disease centers. said. Some wild ducks seem to carry it without getting sick at all, so scientists think that ducks were probably its original host and that the two evolved together into a peaceful coexistence: the virus did not hurt the duck, and the duck's immune system ignored the virus. Thriving in the bird's intestines, the virus multiplied rapidly and was spread far and wide by droppings. Other aquatic birds may have adapted in a similar way.
Not so for chickens or other domestic fowl: A(H5N1) attacks their lungs and other organs, and it quickly kills them. But the chicken's immune system tries to fight back, and that battle may alter the virus. The bird may fight off some viruses, ones with certain mutations. Other viruses survive, multiply and become more common. And since they have beaten out the chicken's immune system, they may also be nastier.
It is just a theory, but some scientists suspect that its forays into huge poultry flocks may have brought out more virulent forms of A(H5N1), which may explain why the virus now seems to be killing off more wild birds than in the past. At the same time, the virus has begun to invade more species, including mammals — infected cats, pigs and dogs have been reported. Researchers consider that a bad sign.
"The more opportunities this virus has to mutate during replication in a mammalian host, the more likely it is to mutate," said Dr. Nancy Cox, director of the influenza branch at the disease centers.
In the laboratory, Dr. Maines and Dr. Tumpey have found that the virus seems to have become more virulent over time. With some strains, an unbelievably small amount of virus will kill a mouse, Dr. Tumpey said. Last September, in the Journal of Virology, they reported that viruses from people infected in 2003 and 2004 were more deadly in mice and ferrets than were samples taken from 1997 victims. But there is not enough information about the human cases to tell whether the disease in people has gotten more severe.
Recent studies by several research teams have focused on hemagglutinin. The virus can attach only to cells that have the right receptors — compatible molecules on their surfaces. Many scientists think hemagglutinin, and mutations that change its structure, may control where the virus can go and what it can do. For instance, hemagglutinin may determine which species the virus can infect and which tissues it can invade.
The more organs and tissues a virus can attack, the more likely it is to cause severe disease. Scientists are especially interested in a part of the hemagglutinin that sets A(H5N1) apart from many other bird flu viruses by enabling it, in some species at least, to latch onto many types of cells and thus to cause systemic disease.
Studies published recently in Science and Nature by two research groups suggested that one reason A(H5N1) is not transmissible among people is that the virus can latch on only to cells deep in the respiratory tract, too far down to be coughed up or sneezed out to infect other people. They discovered that only the deeper cells had the right type of receptors.
But if the virus were to mutate so that it could connect with cells higher in the respiratory tract, then it might become transmissible. Several mutations would be needed, and virologists disagree about whether they are likely to occur.
Another major unanswered question concerns how severe bird flu really is in people. Based on cases in hospitals, it looks like a horrific disease with a 50 percent death rate.
But what if some people get infected and recover without seeing a doctor, or never get sick at all, and so are not counted? Then, the death rate would be lower.
A study published in January in The Archives of Internal Medicine suggests that there may be mild, unreported bird flu cases. Over a three-month period in 2004, researchers studied 45,478 residents in a rural district in Vietnam that had A(H5N1) outbreaks to find out how many had contact with sick birds and how many had flulike illnesses.
They found that statistically, those exposed to sick birds were most likely to have gotten sick, and of 8,149 who had a flulike illness, 650 to 750 probably caught it from birds. The study was not conclusive because the researchers did not test their subjects to find out for sure whether they had A(H5N1).
But if human cases are more common than previously thought, it could be both good news and bad news: good if not everyone becomes deathly ill, but not good if more people are infected and might act as the dreaded "mixing vessels" that could let A(H5N1) trade genes with an ordinary human flu virus and produce a new, highly contagious strain that could turn into a pandemic.
"The viruses are changing, and in ways of concern to me and other scientists," Dr. Cox said.
She said scientists had a unique window of opportunity now, in which they could see the disease in both birds and people and try to stop it or at least slow it down.
"Could we quench an incipient pandemic?" Dr. Cox asked. "I don't know, but we could try."
The Doctor's World: With Every Epidemic, Health Officials Face Tough Choices
By LAWRENCE K. ALTMAN, M.D., The New York Times, March 28, 2006
To warn. Or not to warn.
That classic dilemma in public health has been brought into sharp focus by the A(H5N1) avian influenza virus that is spreading around the world and has led to the death of tens of millions of birds in Asia and Europe.
For health officials, few decisions can be as crucial as deciding if and when to sound early warnings when they believe that an epidemic is possible but do not know whether it will become a real catastrophe.
The dilemma often concerns the influenza virus because it continually mutates, leading to human pandemics that predictably occur unpredictably. Although scientists lack the knowledge to predict when and what strain will cause the next influenza pandemic, they say they are convinced that another one is inevitable and so preparation must start as soon as a threat is detected.
That kind of immediate action occurred in 1976 after four cases of swine influenza were detected at Fort Dix, a military base in New Jersey. Fearing that the cases represented an early warning of an impending pandemic of influenza, Public Health Service officials rushed President Gerald R. Ford, who was running for re-election, into recommending a swine influenza shot for every American.
Mr. Ford proposed a $135 million program to make enough vaccine to immunize 200 million people, about 95 percent of the United States population at the time. It was the government's first effort to immunize all Americans against one disease in one program, and Congress authorized it.
But the effort was suspended shortly after it began because a paralyzing ailment, Guillain-Barré syndrome, occurred among a small number of the 42 million vaccine recipients.
A few cases of the syndrome had been linked to influenza vaccine, but government officials failed to mention the risk in the consent form or to discuss it publicly.
The feared killer disease never came. But by the time the effort ended, 535 cases of Guillain-Barré had been diagnosed, including 23 deaths, outnumbering the mostly mild 230 cases of swine flu at Fort Dix. The virus did not spread. The immunization plan was a fiasco. Health officials were dismissed, some say unfairly.
The episode has become a textbook case in training a new generation of health officials about the dangers of sounding warnings too early without having a well-thought-out plan.
The opposite problem — failing to warn about preparations for an outbreak — occurred in 2001.
Shortly after Sept. 11, Tommy G. Thompson, then the secretary of health and human services, went on national television to assure Americans that the government was fully prepared to respond to any bioterrorism attack.
Within days, the deliberate release of anthrax spores through the postal system proved him wrong. The outbreak was small — 22 cases, including 5 deaths. But it showed how poorly the government communicated in a timely way to doctors and the public. It left many government officials wanting never to be perceived as underreacting to a health threat.
The two episodes led many people to lose trust in government health warnings, or in the lack of them.
Warnings about A(H5N1) avian influenza began in 1997, when scientists in Hong Kong discovered that that strain of virus had jumped directly to cause disease in humans without first mixing in pigs, which had been the pattern until then. With the spread of the virus among birds, officials have warned that it could mutate, combine with a human influenza virus and create a new one to cause a human pandemic.
That has not happened, although 105 of the 186 people in the world who have developed A(H5N1) avian influenza have died.
Should health officials risk issuing stern warnings that may frighten people? Or should officials play it safe, going about their business and informing the public only when a pandemic becomes real?
If officials do issue early warnings, and nothing happens, they stand to lose credibility among people who say that scientists promoted the worst possibilities to grab more grants and waste taxpayer dollars.
If officials do not issue early or timely warnings, and a pandemic occurs, critics will say the public was not informed and protected in time.
The situation also leaves health officials vulnerable to charges of "I told you so," even though there is often no way to prove that the Monday morning quarterbacks actually made their criticisms known at the time key decisions had to be made.
Two types of dilemmas are often involved in deciding when and what warning to give, said Dr. Harvey V. Fineberg, who wrote a book with Richard E. Neustadt in 1978 analyzing the government's and industry's responses to the swine flu immunization program.
One is like a Category 5 hurricane with long odds on its occurring, but with devastating consequences if it does.
"In such cases, the naysayer is most often going to be right," said Dr. Fineberg, president of the Institute of Medicine of the National Academy of Sciences, said in an interview, referring to those who contend preparation is unnecessary.
The second dilemma involves a tension that can arise when scientists believe that political leaders and the public do not understand risk as well as scientists do. Problems can arise if an expert believes action is needed because the risk of an outbreak is, say, 10 percent, but perceives that government officials will consider 10 percent to be too low for action to be taken.
So the scientist may choose a way to present the facts and estimates to persuade government officials to do what the scientist believes is correct.
In deciding whether to warn and act, the tendency is often "reluctance to do something that may cause harm as opposed to allowing nature to create its own harm," Dr. Fineberg said.
Last year, the Bush administration released a comprehensive plan to counter an influenza pandemic. Even with it, the dilemma of when to warn will remain.
By DENISE GRADY and GINA KOLATA, The New York Times, March 27, 2006
Over the last year, it has been impossible to watch TV or read a newspaper without encountering dire reports about bird flu and the possibility of a pandemic, a worldwide epidemic. First Asia, then Europe, now Africa: like enemy troops moving into place for an attack, the bird flu virus known as A(H5N1) has been steadily advancing. The latest country to report human cases is Azerbaijan, where five of seven people have died. The virus has not reached the Americas, but it seems only a matter of time before it turns up in birds here.
Even so, a human pandemic caused by A(H5N1) is by no means inevitable. Many researchers doubt it will ever happen. The virus does not infect people easily, and those who do contract it almost never spread it to other humans. Bird flu is what the name implies: mostly an avian disease. It has infected tens of millions of birds but fewer than 200 people, and nearly all of them have caught it from birds.
But when A(H5N1) does get into people, it can be deadly. It has killed more than half of its known human victims—an extraordinarily high rate. Equally alarming is that many who died were healthy, not the frail or sickly types of patients usually thought to be at risk of death from influenza.
The apparent lethality of A(H5N1), combined with its inexorable spread, are what have made scientists take it seriously. Concern also heightened with the recent discovery that the 1918 flu pandemic was apparently caused by a bird flu that jumped directly into humans.
In addition, A(H5N1) belongs to a group of influenza viruses known as Type A, which are the only ones that have caused pandemics. All those viruses were originally bird flus. And given the timing of the past pandemics — 1918, 1957, 1968 — some researchers think the world is overdue for another. It could be any Type A, but right now (A)H5N1 is the most obvious.
The virus lacks just one trait that could turn it into a pandemic: transmissibility, the ability to spread easily from person to person. If the virus acquires that ability, a pandemic could erupt.
Everything hangs on transmissibility. But it is impossible to predict whether A(H5N1) will become contagious among people. The virus has been changing genetically, and researchers fear that changes could make it more transmissible, or that A(H5N1) could mix with a human flu virus in a person, swap genetic material and come out contagious.
But most bird flu viruses do not jump species to people. Some experts say that since A(H5N1) has been around for at least 10 years and the shift has not occurred, it is unlikely to happen. Others refuse to take that bet.
The A(H5N1) strains circulating now are quite different from the A(H5N1) strain detected in Hong Kong in 1997, which killed 6 of 18 human victims. Over time, A(H5N1) seems to have developed the ability to infect more and more species of birds, and has found its way into mammals—specifically, cats that have eaten infected birds.
The actual number of human cases may well exceed the number that have been reported, and may include mild cases from which victims recovered without even seeing a doctor. If that is true, the real death rate could be lower. But no one knows whether mild cases occur, or whether some people are immune to the virus and never get sick at all.
In the absence of more information, health officials must act on what they see — an illness that apparently kills half its victims.
Q. How will we know if the virus starts spreading from person to person and becomes a pandemic?
A. If there is a pandemic, it would be everywhere, not in just one city or one country. To detect such an event as early as possible there is an international surveillance system, involving more than 150 countries, that searches for signs that a new flu strain is taking hold in humans. One hallmark of a pandemic flu would be an unusual pattern of illnesses — lots of cases, possibly cases that are more severe than normal and, possibly, flu infections outside the normal flu season.
Ordinary human flu viruses, for reasons that are not entirely understood, circulate only in winter. But pandemics can occur at any time. A pandemic would also involve a flu virus that was new to humans, meaning that no one would have immunity from previous infections.
Q. If bird flu reaches the United States, where is it likely to show up first?
A. Although health officials expect bird flu to reach the United States, it is impossible to predict where it may show up first, in part because there are several routes it could take. If it is carried by migrating birds, then it may appear first in Alaska or elsewhere along the West Coast.
But if the virus lurks in a bird being smuggled into the United States as part of the illegal trade in exotic birds, it could land in any international airport. Bird smuggling is a genuine problem: in 2004, a man was caught at an airport in Belgium illegally transporting eagles from Thailand, stuffed into tubes in his carry-on luggage. The birds turned out to be infected with A(H5N1), and they and several hundred other birds in a quarantine area at the airport had to be destroyed.
In theory, an infected human could also bring bird flu into the United States, and that person could fly into just about any international airport and go unnoticed if the virus had yet to produce any symptoms.
Q. Does bird flu affect all birds?
A. No one knows the full story. Scientists say A(H5N1) is unusual because it can infect and kill a wide variety of birds, unlike a vast majority of bird flus, which are usually found in wild birds, not domestic fowl, and which cause few symptoms.
Some researchers suspect that wild ducks, or perhaps other wild birds, are impervious to A(H5N1), and may be the Typhoid Marys of bird flu — getting the virus, spreading it to other birds but never becoming ill themselves. No one has good evidence of this yet, but that may be because the way scientists discovered A(H5N1) infections was by finding birds that had gotten the flu and died.
As virologists like to point out, dead birds don't fly. So migratory birds cannot spread the virus if they are dying shortly after being infected. That is why some researchers say that if wild birds are spreading the A(H5N1) virus, it must be a bird species that can be infected but does not become ill.
Q. When people die from avian flu contracted from birds, what kills them?
A. Like victims of severe pneumonia, many patients die because their lungs give out. The disease usually starts with a fever, fatigue, headache and aches and pains, like a typical case of the flu. But within a few days it can turn into pneumonia, and the patients' lungs are damaged and fill with fluid.
In a few cases, children infected with A(H5N1) died of encephalitis, apparently because the virus attacked the brain. A number of people have also had severe diarrhea — not usually a flu symptom — meaning that this virus may attack the intestines as well. Studies in cats suggest that in mammals the virus attacks other organs, too, including the heart, liver and adrenal glands.
But more detailed information about deaths in people is not available because very few autopsies have been done. In some countries, like Vietnam, where many of the deaths occurred, autopsies are frowned upon. Researchers say they may glean useful information from autopsies, but fear that pressing for them would alienate the public in some areas.
Q. When experts refer to bird flu as A(H5N1), what does that mean?
Q. If I got bird flu, how would I know?
A. There is no reason to suspect the disease unless you may have been exposed to it. Since the virus has not reached North America, doctors do not look for bird flu in people unless they have traveled to affected regions or have been exposed to sick or dead birds.
The early stages of the illness in people are the same as those of ordinary flu: fever, headache, fatigue, aches and pains. But within a few days, people with bird flu often start getting worse instead of better; difficulty breathing is what takes many to the hospital.
In any case, patients with flulike symptoms that turn severe or involve breathing trouble are in urgent need of medical care.
Q. Can I be tested for avian flu?
A. There is no rapid test for bird flu. There is a rapid test for Type A influenza viruses, the group that A(H5N1) belongs to, but the test is only moderately reliable, and it is not specific for A(H5N1).
State health departments and some research laboratories can perform genetic testing for A(H5N1) and give results within a few hours, but they do not have the capacity to perform widespread testing.
Because of the limited availability of testing and the extremely low probability of A(H5N1) in people in the United States, the test is recommended only for patients strongly suspected of having bird flu, like travelers with flulike symptoms who were exposed to infected birds.
Q. Do any medicines treat or prevent bird flu?
A. Two prescription drugs, Tamiflu and Relenza, may reduce the severity of the disease if they are taken within a day or two after the symptoms begin. But Relenza, a powder that must be inhaled, can irritate the lungs and is not recommended for people with asthma or other chronic lung diseases.
Both drugs work by blocking an enzyme — neuraminidase, the "N" part of A(H5N1) — that the virus needs to escape from one cell to infect another. But just how effective these medicines are against A(H5N1) is not known, nor is it clear whether the usual doses are enough. Also unknown is whether the drugs will help if taken later in the course of the disease. Although government laboratories and other research groups are trying to develop vaccines to prevent A(H5N1) disease in people, none are available yet.
Q. If there is an epidemic of flu in humans, how can I protect myself?
A. If there is a vaccine available, that would be the best option. But if there is no vaccine it may be hard to avoid being infected. Flu pandemics spread quickly, even to isolated regions. The 1918 flu reached Alaskan villages where the only way visitors could arrive was by dog sled.
The vaccines produced every year to prevent seasonal flu are unlikely to be of any use in warding off a pandemic strain. But a flu shot could provide at least some peace of mind, by preventing the false alarm that could come from catching a case of garden-variety flu.
Similarly, people over 65 and others with chronic health problems should consult their doctors about whether they should be vaccinated against pneumococcal pneumonia, a dangerous illness that can set in on top of the flu. Again, that vaccine will not stop bird flu, but it may prevent complications.
Some health officials have recommended stockpiling two to three months’ worth of food, fuel and water in case a pandemic interferes with food distribution or staffing levels at public utilities, or people are advised to stay home.
Many health experts have advised against stockpiling Tamiflu or Relenza, the prescription-only antiviral drugs that may work against bird flu. Doctors say the drugs are in short supply and hoarding may keep them out of reach of people who genuinely need them.
Also, they say, self-prescribing may lead to waste of the drugs or misuses that spur the growth of drug-resistant viruses. But people may not trust the government to distribute these drugs, and may want their own supplies. Doctors say people can take precautions like avoiding crowds, washing their hands frequently and staying away from those who are sick. Masks may help, but only if they are a type called N-95, which has to be carefully fitted. So far, masks and gloves have been recommended only for people taking care of sick patients.
Avoiding the flu can be hard because it is not always possible to spot carriers. Many people get and spread flu viruses and but never know they are infected.
Q. Is the government prepared for a bird flu pandemic?
A. No. The nation does not have an approved flu vaccine for people or enough antiviral drugs or respirators for all who would need them. The best protection in any flu pandemic will come from a vaccine, but scientists cannot tell ahead of time what strain the vaccine should protect against.
Efforts are under way to make a vaccine for A(H5N1). But the virus could mutate in a way that makes experimental vaccines ineffective, requiring more than one vaccine.
Moreover, there is no assurance that the next pandemic will even involve A(H5N1). It may involve a different strain of bird flu, and an A(H5N1) vaccine would not work for it. Recent efforts to develop a sort of universal flu vaccine that would work across strains have failed.
For now, the hope is to spot a pandemic early and quickly make a vaccine. Investigators are developing new and better ways to make vaccines — a bird flu, for example, cannot be grown in fertilized eggs like other flu viruses because it kills the chicken embryos — but these new methods must first be approved by the Food and Drug Administration.
Preparations also include government plans to stockpile drugs to protect people who were exposed to the flu and to reduce the severity of the disease in those who are ill. But the one antiviral drug that everyone wants to buy and stockpile, Oseltamivir, also sold by Roche as Tamiflu, is in short supply.
In retrospect, scientists say, maybe the nation should have started preparing sooner. But until the current bird flu appeared, there was little interest in such expensive and extensive preparations.
Q. If bird flu reaches the United States, will it be safe to eat poultry or to be around birds or other animals?
A. Poultry is safe to eat when it is cooked thoroughly, meaning that the meat is no longer pink and has reached a temperature of 180 degrees Fahrenheit. The risk is not from cooked meat — cooking kills viruses. Instead, it is from infected birds that are still alive or have recently died. So the person who killed an infected chicken, butchered it or put it in the pot would be at greater risk than the one who ate it.
It's not clear how long the virus lives on a dead bird, but it is unlikely to survive more than a couple of days. And it seems unlikely that infected chicken will find its way to supermarkets.
If the bird flu strikes poultry farms, the farmers will know there is a problem. Before they die, the birds develop major hemorrhages, with blood streaming from their cloacas and beaks. When the flu gets to a poultry farm, farmers have to destroy their flocks, and poulgreater risk than the one who ate it.
It's not clear how long the virus lives on a dead bird, but it is unlikely to survive more than a couple of days. And it seems unlikely that infected chicken will find its way to supermarkets.
If the bird flu strikes poultry farms, the farmers will know there is a problem. Before they die, the birds develop major hemorrhages, with blood streaming from their cloacas and beaks. When the flu gets to a poultry farm, farmers have to destroy their flocks, and poultry from infected farms cannot be sold for meat.
As for contact with healthy birds or animals, there is no need to panic. The A(H5N1) virus is a nasty one. If chickens or other animals became infected they would get sick and die, and you would know the virus was present.
But animals can carry many diseases besides influenza, and whenever you are around animals it is a good idea to wash your hands afterward. Because cats in Europe have caught A(H5N1), apparently from eating infected birds, health officials there advise keeping pet cats indoors, but no such recommendation has been made in the United States.
For now, officials at the Centers for Disease Control and Prevention say it is safe to have bird feeders, and they note that even if the virus does arrive here, the kinds of birds that perch at feeders are far less likely to carry A(H5N1) than are aquatic birds like ducks and geese.
Q. Is it safe to buy imported feather pillows, down coats or comforters and clothing or jewelry with feathers?
A. Imported feathers may not be safe. There is a risk to handling products made with feathers from countries with outbreaks of bird flu, according to the Centers for Disease Control and Prevention. Feathers from those countries are banned in the United States unless they have been processed to destroy viruses.
The Skeptic: On the Front: A Pandemic Is Worrisome but 'Unlikely'
By ELISABETH ROSENTHAL, The New York Times, March 28, 2006
OXFORD, England — The Hospital for Tropical Diseases in Ho Chi Minh City, where Dr. Jeremy Farrar works, has treated about two dozen people with avian influenza in the last three years.
With that tiny number, Dr. Farrar and his Vietnamese colleagues probably have more clinical experience than any other doctors with the A(H5N1) virus — the dreaded germ that international health officials fear may ignite the next flu pandemic.
Yet, Dr. Farrar notes, this trickle of humans infected with bird flu — 186 in all since 2003 — has provoked a flood of scientific meetings on pandemics, accelerating in recent months.
"The ratio of meetings to patients is probably 10 to 1: Hawaii tomorrow. Geneva and Singapore next week," said Dr. Farrar, in jeans and carrying a red backpack, on a break from a conference where he was — naturally — speaking on the topic.
"The interest is phenomenal," he said, clicking at his popular PowerPoint presentation.
Still, Dr. Farrar is not sure that this intensity is entirely rational:
Having observed A(H5N1) for many years in Asia, he thinks it is unlikely that the virus is poised to jump species, becoming readily transmissible to humans or among them. Nor does he believe the mantra that a horrific influenza pandemic is inevitable or long overdue. He points out that the only prior pandemic with a devastating death toll was in 1918, and he says that may have been "a unique biological event."
"For years, they have been telling us it's going to happen — and it hasn't," said Dr. Farrar, director of the Oxford University Clinical Research Unit at the hospital in Vietnam. "Billions of chickens in Asia have been infected and millions of people lived with them — we in Asia are intimate with our poultry — and less than 200 people have gotten infected.
"That tells you that the constraints on the virus are considerable," he continued. "It must be hard for this virus to jump."
Still, a part of Dr. Farrar is terrified of A(H5N1) — "a very nasty virus," he calls it — which he has watched kill healthy young people, devouring their lungs.
In the last year, the virus has extended its range in birds from Eastern China to Western Africa. Over time, it has expanded the variety of species it can infect, including ferrets and cats.
"That is alarming," he acknowledges in the understated British way.
Like all responsible scientists, Dr. Farrar believes the world should prepare. But schooled in places where people die of real and present diseases like malaria and tuberculosis, he finds the "doomsday" predictions sketched out by some international officials unhelpful, more fantasy than fact.
And even if these officials' dire forecasts were to come true, he says, many of their elaborate pandemic preparedness plans are unworkable in developing countries, which do not have the resources or medical facilities to comply.
"I think you have to say we really don't know the odds of pandemic, and people are not comfortable with that," Dr. Farrar said. "It could fizzle out and kill 98 people — one more than the number dead today. Or it could be something like 200 million," closer to an estimate once made by Dr. David Nabarro, chief avian flu coordinator for the United Nations.
"It's terrifying if it happens, but it is very, very unlikely, I think — and it is difficult to balance those facts."
At the Tropical Disease Hospital in Vietnam, doctors have been doing just that, bracing for a pandemic that may never come, since long before it became fashionable in the West.
Before Vietnam began vaccinating poultry in mid-2005, the disease was rampant among birds there. Of the world's 186 confirmed human cases, 93 are from Vietnam. There have been no new cases this year.
But in the Tropical Diseases Hospital, doctors and nurses still don full bio-protective gear when they evaluate suspected cases, because "you don't know if the next one will mark the start of human to human transmission," Dr. Farrar said.
With each new patient, they assiduously try to follow international scientific recommendations. But their on-the-ground experience reveals holes in the neat strategies coming from United Nations experts in Geneva and Rome.
The World Health Organization suggests that it might be possible to contain a pandemic by quickly diagnosing index cases, identifying contacts, prescribing all antiviral drugs, and quarantining, for example.
In response, Dr. Farrar shows a picture of the home of a patient: a hut on stilts by the Mekong River. When that patient fell ill, he took a boat to the local health station, and was transferred to the district hospital, Dr. Farrar says. Later, an ambulance took him to Ho Chi Minh City, where genetic analysis showed that he had avian influenza, instead of typical pneumonia. If bird flu ever gained the ability to spread easily among humans, that patient would have infected thousands before diagnosis.
"You've got to act quickly, but the process now takes many days," Dr. Farrar said, suggesting that more money for clinics, labs and experts should be flowing to developing nations.
"Then you're supposed to go back to the village and saturate it with oseltamivir?" he asks, using the generic name for the antiviral drug Tamiflu. "What do the villagers do when they hear the man has bird flu? They don't sit still; they get on buses and flee and stay with relatives in other villages," potentially spreading it there.
For doctors in Vietnam, human cases of avian influenza have been a frightening reality for more than three years, and Dr. Farrar vividly remembers the initial terror of the devoted hospital staff, unsure if they could catch bird flu from patients.
"Look at this lung — there's nothing there," he said pulling up the X-ray of a patient who is back at the university, but whose left chest shows a vast empty cavern. Studies from the hospital have taught the world much about A(H5N1): humans took longer to clear this virus than normal influenza, for example, and Tamiflu can quickly breed resistant strains.
But, to Dr. Farrar's chagrin, the treatment options have not really improved.
Flu vaccines are still manufactured by an "ancient strategy" that involves injecting eggs with virus, he complained, even as other vaccines rely on more sophisticated methods. As a result, flu vaccines — including experimental versions aimed at A(H5N1) — are cumbersome to produce, and target just one strain.
"What we need is a vaccine that is effective across strains because the virus can be different each year," he said. "My mom in the U.K. can get a shot every year, but that is not realistic in rural Asia."
More remarkable still, he said, Tamiflu is still the only drug useful against avian influenza, "and we all know that one drug is not adequate to treat any viral disease," he said, noting that multiple drugs are used in AIDS.
Patients at Dr. Farrar's Hospital are given Tamiflu, and it appears to help some. "It's all that we have," he said. "So if I was sick, I'd certainly want to get it."
But, he rues the lack of international research and coordination to tackle a disease that has been in Asia for nearly 10 years. For example, he said, although Vietnam has greatly reduced the number of bird flu outbreaks by vaccinating poultry, no one knows if the vaccine puts pressure on A(H5N1) to mutate to develop resistance to the shot, which could cause a rebound of disease in the coming years.
Personally, Dr. Farrar remains optimistic, believing a pandemic will not come. If A(H5N1) changed so that it readily infected people, it would probably become less deadly, he said.
But if disaster happens, he says: "People will look back and say: 'This was a nasty virus that you knew could sometimes infect other species. Why didn't you do something? All you had was a single effective drug and no vaccine?' "
The 1918 Flu Killed Millions. Does It Hold Clues for Today?
By GINA KOLATA, The New York Times, March 28, 2006
Flu researchers know the epidemic of 1918 all too well.
It was the worst infectious disease epidemic ever, killing more Americans in just a few months than died in World War I, World War II, the Korean War and the Vietnam Wars combined. Unlike most flu strains, which kill predominantly the very old and the very young, this one — a bird flu, as it turns out — struck young adults in their 20's, 30's and 40's, leaving children orphaned and families without wage earners.
So now, as another bird flu spreads across the globe, killing domestic fowl and some wild birds and, ominously, infecting and killing more than 100 people as well, many scientists are looking back to 1918. Did that flu pandemic get started in the same way as this one? Will today's bird flu turn into tomorrow's human pandemic?
And what, if anything, does that nearly century old virus and the pandemic it caused reveal about what is happening today?
The answer is: a lot and not enough. The 1918 pandemic showed how quickly an influenza virus could devastate American towns and cities and how easily it could spread across the globe, even in an era before air travel.
It showed that a flu virus could produce unfamiliar symptoms and could kill in unprecedented ways. And it showed that a bird flu could turn into something that spreads among people.
But the parallels go only so far, researchers say. For now, they are left with as many questions as answers.
In the fall of 1918 flu struck the United States and parts of Europe hard and traveled to every corner of the world except Australia and a few remote islands. A few months later, it vanished, burning itself out after infecting nearly everyone who could be infected.
The virus arrived at even the most improbable places, like isolated Alaskan villages. In one such village, Wales, 178 of its 396 residents died during one week in November, after a mailman arrived by dog sled, bringing the virus along with the mail.
Public health officials tried in vain to contain its spread. In Philadelphia, people were exhorted not to cough, sneeze or spit in public.
But the virus spread anyway. On Oct. 3, Philadelphia closed all of its schools, churches, theaters and pool halls. Still, within a month, nearly 11,000 Philadelphians died of influenza.
Anyone who doubts that flu deaths can be horrific need only read the memoirs of physicians like Dr. Victor C. Vaughan, who treated influenza victims in 1918.
Dr. Vaughan, a former president of the American Medical Association, was summoned by the surgeon general to Camp Devens, near Boston, where the flu struck in September. He later described the scene in his memoirs.
The men, Dr. Vaughan wrote, "are placed on the cots until every bed is full, yet others crowd in."
"Their faces soon wear a bluish cast; a distressing cough brings up the blood stained sputum," he continued.
"In the morning, the dead bodies are stacked about the morgue like cord wood," Dr. Vaughan said. "This picture was painted on my memory cells at the division hospital, Camp Devens, in the fall of 1918, when the deadly influenza virus demonstrated the inferiority of human inventions in the destruction of human life."
Still, scientists are left with an abiding mystery: Where did the 1918 virus come from?
Investigators know more than they once did. They know exactly what the virus looked like, thanks to Dr. Jeffrey Taubenberger, chief of the division of molecular pathology at the Armed Forces Institute of Pathology, and his colleagues, who obtained snippets of preserved lung tissue from three victims of the 1918 flu and managed to fish out shards of the virus and piece together its genes. Although the 1918 virus was a strain different from the A (H5N1) virus that is now killing birds, it was, Dr. Taubenberger found, a bird flu.
What is not known is how the 1918 virus moved from birds to humans.
One clue could come from knowing what flu viruses existed before the 1918 pandemic. Perhaps the 1918 virus entered the human population before 1918 in a more benign form then mutated to become a killer. Or perhaps it suddenly showed up in humans, jumping directly from birds to people.
To find out, Dr. Taubenberger and Dr. John Oxford of the Royal London Hospital are looking for human flu viruses that existed before 1918. London Hospital has a collection of human tissue obtained from 1908 to 1918. Dr. Taubenberger is searching for flu viruses in lung tissue from people who died of pneumonia in those years, hoping to use the same methods that allowed him to piece together the 1918 virus to resurrect a flu virus that was in humans before 1918.
The 1918 virus also is teaching researchers about experimental vaccines that scientists hope will protect against a variety of influenza strains. The plan had been to make a sort of universal flu vaccine that would protect against various flu viruses. Then people would not need a flu shot each year, and the vaccine might stop pandemic flu strains from ever gaining a toehold.
But, says Dr. Terrence Tumpey, a microbiologist at the Centers for Disease Control and Prevention, although the experimental vaccines protect against ordinary human flu viruses, they do not protect against the 1918 virus. Nor do they protect against today's A(H5N1) bird flu virus.
That leaves scientists with a puzzle. If they are worried about a 1918-like flu, they want a universal vaccine to protect against it, and they wonder what makes these bird flus so impervious? At this point, no one knows, Dr. Tumpey says.
Another abiding mystery is that neither the 1918 influenza pandemic nor any other human influenza pandemic began with a flu pandemic that killed birds. And, scientists add, if the 1918 pandemic had begun that way, it would have been noticed. Even if the deaths of wild birds went undetected, the deaths of domestic fowl would have been recorded.
Wild birds are inured to most flu viruses — clouds of the viruses normally infect them, living in their gastrointestinal tracts but causing little or no disease. Sometimes, those flu viruses infect poultry and, while they usually cause little illness, some flu strains can be lethal to fowl and economically devastating to farmers.
That, Dr. Taubenberger says, "has been recognized for 150 years." In the 1920's, scientists even isolated viruses from what they used to call fowl plague and what is now known to be bird flu. They were not the same viruses that infected humans.
The problem is in deciding what all this means.
The history of the 1918 flu can take scientists only so far, Dr. Taubenberger said.
"We don't know how the 1918 pandemic evolved and how the virus emerged into a form that was the finished product," he said. "What we sequenced was a virus that was ready for prime time, not its precursor."
"Ultimately," Dr. Taubenberger said, "the answer to the big question is, We don't know. There is no historical precedent for what is going on today."
Making a Ferret Sneeze for Hints to the Transmission of Bird Flu
By DENISE GRADY, The New York Times, March 28, 2006
ATLANTA — One way to collect nasal secretions from a ferret is to anesthetize it, hold a petri dish under its snout and squirt a little salt water up its nose so that it will sneeze into the dish.
At the Centers for Disease Control and Prevention, ferret sneezes are frozen in tiny vials and locked up in a high-security chamber called an enhanced biosafety Level 3 laboratory. It takes a fingerprint scan to get in, and an iris scan to open the freezer. Scientists wear scrub suits, gowns, double gloves and hoods, breathe filtered air and open vials only by reaching into a safety cabinet designed to keep germs from escaping into the air.
The vials are in this lab because the animals have been exposed to A(H5N1), the notorious avian flu virus that has swept across Asia, Europe and Africa, wiping out flocks of poultry and sometimes killing people as well. Researchers at the disease centers and in other labs are studying the transmission and virulence of bird flu in ferrets and mice, trying to answer questions that take on more urgency as the virus advances.
"We have never had a situation like the world is experiencing today, such an unprecedented spread among poultry," said Dr. Timothy Uyeki, an epidemiologist and influenza expert at the disease centers. "The geographic spread is unprecedented, and the mortality unprecedented as well, and this virus has been clearly confirmed to transmit directly from poultry to people and to cause severe and fatal illness."
The big question is, will A(H5N1) cause a human pandemic? Many scientists think the world is overdue for one and find it worrisome that this dangerous virus has popped up now. Even so, in its present form this flu does not seem to be a pandemic germ because it does not spread easily from birds to humans, and because infected people rarely transmit it to others. But everything could change if the virus were to mutate in a way that made it easier for people to catch and spread.
"Why would a particular virus be transmitted easily human to human, and another not?" asked Dr. Peter Palese, chairman of microbiology at the Mount Sinai School of Medicine in New York. "Even though I am 35 years in this field, we do not have molecular parameters or signatures which make that clear, although many groups, including my own, are working on this exact question."
The virus is a moving target, and two distinct subsets of it have developed, one from Vietnam and one from Indonesia, that differ enough to make scientists think separate vaccines will be needed. Scientists are trying to understand how a virus can be wildly contagious among birds but almost impossible to spread in mammals — and what type of mutation could change that. They are also comparing different strains of A(H5N1) to see if it is becoming more virulent, and they are examining the structure of the virus in hopes of figuring out what makes it so deadly.
Ferrets are used for some studies because, unlike mice, they easily catch human flu viruses and get sick, and so are considered a better model for people. At the disease centers, Taronna Maines and Terrence Tumpey have infected ferrets with A(H5N1) and then monitored them to see if the severity of the disease varies by strain and by dose, and to see if the infected animals cough up the virus or sneeze it out and spread it to healthy ones.
It turns out that ferrets do not transmit the disease easily, though some healthy animals develop antibodies to the virus, indicating that they have been exposed. If a strain comes along that is contagious in ferrets, it might be bad news for people.
Research like this may help determine whether (A)H5N1 is heading down the path to becoming a pandemic strain, and may also help to guide the development of vaccines and drugs.
Aside from the virus's recent horrible track record, several other things about it can help explain why some scientists worry that it has pandemic potential. The A means it belongs to a larger group known as Type A influenza viruses, which cause many of the human flu epidemics that occur every winter. But more ominously, Type A also includes the only viruses ever known to have caused human pandemics, in 1918, 1957 and 1968.
Flu viruses mutate a lot, and pandemics occur when a Type A virus undergoes a big genetic change to produce a new type of virus to which people have little or no resistance. Sometimes the change occurs when a person or a pig acts as a "mixing vessel" for two flu viruses — maybe a human one and a bird one — which swap genes to produce a new virus. That kind of change is believed to have caused the 1957 and 1968 pandemics. But the 1918 pandemic, the worst by far, is thought to have occurred without a gene swap, when a bird flu somehow mutated enough to jump into humans.
All Type A viruses are found in birds. They probably originated in wild birds and usually do them little or no harm. Only a few evolved into strains that could easily infect people. A(H5N1) is not adapted to people, and researchers suspect that human victims so far may have been infected because they were exposed to enormous amounts of the virus from birds.
The letters H and N stand for two proteins on the outside of all Type A viruses. The H, hemagglutinin, helps the virus get into cells, which it must do to reproduce. The N, neuraminidase, helps it get back out to infect more cells. There are 16 kinds of H and 9 kinds of N; they mix and match, and so can produce 144 possible Type A strains. The worrisome thing about H5 is that H5 viruses are avian flus and have not been known to cause human epidemics, so many people may have little or no resistance to them.
Not long ago, A(H5N1) may well have been what scientists call a perfect parasite, meaning one that does little harm to its host, Dr. Ruben Donis, a flu expert at the disease centers. said. Some wild ducks seem to carry it without getting sick at all, so scientists think that ducks were probably its original host and that the two evolved together into a peaceful coexistence: the virus did not hurt the duck, and the duck's immune system ignored the virus. Thriving in the bird's intestines, the virus multiplied rapidly and was spread far and wide by droppings. Other aquatic birds may have adapted in a similar way.
Not so for chickens or other domestic fowl: A(H5N1) attacks their lungs and other organs, and it quickly kills them. But the chicken's immune system tries to fight back, and that battle may alter the virus. The bird may fight off some viruses, ones with certain mutations. Other viruses survive, multiply and become more common. And since they have beaten out the chicken's immune system, they may also be nastier.
It is just a theory, but some scientists suspect that its forays into huge poultry flocks may have brought out more virulent forms of A(H5N1), which may explain why the virus now seems to be killing off more wild birds than in the past. At the same time, the virus has begun to invade more species, including mammals — infected cats, pigs and dogs have been reported. Researchers consider that a bad sign.
"The more opportunities this virus has to mutate during replication in a mammalian host, the more likely it is to mutate," said Dr. Nancy Cox, director of the influenza branch at the disease centers.
In the laboratory, Dr. Maines and Dr. Tumpey have found that the virus seems to have become more virulent over time. With some strains, an unbelievably small amount of virus will kill a mouse, Dr. Tumpey said. Last September, in the Journal of Virology, they reported that viruses from people infected in 2003 and 2004 were more deadly in mice and ferrets than were samples taken from 1997 victims. But there is not enough information about the human cases to tell whether the disease in people has gotten more severe.
Recent studies by several research teams have focused on hemagglutinin. The virus can attach only to cells that have the right receptors — compatible molecules on their surfaces. Many scientists think hemagglutinin, and mutations that change its structure, may control where the virus can go and what it can do. For instance, hemagglutinin may determine which species the virus can infect and which tissues it can invade.
The more organs and tissues a virus can attack, the more likely it is to cause severe disease. Scientists are especially interested in a part of the hemagglutinin that sets A(H5N1) apart from many other bird flu viruses by enabling it, in some species at least, to latch onto many types of cells and thus to cause systemic disease.
Studies published recently in Science and Nature by two research groups suggested that one reason A(H5N1) is not transmissible among people is that the virus can latch on only to cells deep in the respiratory tract, too far down to be coughed up or sneezed out to infect other people. They discovered that only the deeper cells had the right type of receptors.
But if the virus were to mutate so that it could connect with cells higher in the respiratory tract, then it might become transmissible. Several mutations would be needed, and virologists disagree about whether they are likely to occur.
Another major unanswered question concerns how severe bird flu really is in people. Based on cases in hospitals, it looks like a horrific disease with a 50 percent death rate.
But what if some people get infected and recover without seeing a doctor, or never get sick at all, and so are not counted? Then, the death rate would be lower.
A study published in January in The Archives of Internal Medicine suggests that there may be mild, unreported bird flu cases. Over a three-month period in 2004, researchers studied 45,478 residents in a rural district in Vietnam that had A(H5N1) outbreaks to find out how many had contact with sick birds and how many had flulike illnesses.
They found that statistically, those exposed to sick birds were most likely to have gotten sick, and of 8,149 who had a flulike illness, 650 to 750 probably caught it from birds. The study was not conclusive because the researchers did not test their subjects to find out for sure whether they had A(H5N1).
But if human cases are more common than previously thought, it could be both good news and bad news: good if not everyone becomes deathly ill, but not good if more people are infected and might act as the dreaded "mixing vessels" that could let A(H5N1) trade genes with an ordinary human flu virus and produce a new, highly contagious strain that could turn into a pandemic.
"The viruses are changing, and in ways of concern to me and other scientists," Dr. Cox said.
She said scientists had a unique window of opportunity now, in which they could see the disease in both birds and people and try to stop it or at least slow it down.
"Could we quench an incipient pandemic?" Dr. Cox asked. "I don't know, but we could try."
The Doctor's World: With Every Epidemic, Health Officials Face Tough Choices
By LAWRENCE K. ALTMAN, M.D., The New York Times, March 28, 2006
To warn. Or not to warn.
That classic dilemma in public health has been brought into sharp focus by the A(H5N1) avian influenza virus that is spreading around the world and has led to the death of tens of millions of birds in Asia and Europe.
For health officials, few decisions can be as crucial as deciding if and when to sound early warnings when they believe that an epidemic is possible but do not know whether it will become a real catastrophe.
The dilemma often concerns the influenza virus because it continually mutates, leading to human pandemics that predictably occur unpredictably. Although scientists lack the knowledge to predict when and what strain will cause the next influenza pandemic, they say they are convinced that another one is inevitable and so preparation must start as soon as a threat is detected.
That kind of immediate action occurred in 1976 after four cases of swine influenza were detected at Fort Dix, a military base in New Jersey. Fearing that the cases represented an early warning of an impending pandemic of influenza, Public Health Service officials rushed President Gerald R. Ford, who was running for re-election, into recommending a swine influenza shot for every American.
Mr. Ford proposed a $135 million program to make enough vaccine to immunize 200 million people, about 95 percent of the United States population at the time. It was the government's first effort to immunize all Americans against one disease in one program, and Congress authorized it.
But the effort was suspended shortly after it began because a paralyzing ailment, Guillain-Barré syndrome, occurred among a small number of the 42 million vaccine recipients.
A few cases of the syndrome had been linked to influenza vaccine, but government officials failed to mention the risk in the consent form or to discuss it publicly.
The feared killer disease never came. But by the time the effort ended, 535 cases of Guillain-Barré had been diagnosed, including 23 deaths, outnumbering the mostly mild 230 cases of swine flu at Fort Dix. The virus did not spread. The immunization plan was a fiasco. Health officials were dismissed, some say unfairly.
The episode has become a textbook case in training a new generation of health officials about the dangers of sounding warnings too early without having a well-thought-out plan.
The opposite problem — failing to warn about preparations for an outbreak — occurred in 2001.
Shortly after Sept. 11, Tommy G. Thompson, then the secretary of health and human services, went on national television to assure Americans that the government was fully prepared to respond to any bioterrorism attack.
Within days, the deliberate release of anthrax spores through the postal system proved him wrong. The outbreak was small — 22 cases, including 5 deaths. But it showed how poorly the government communicated in a timely way to doctors and the public. It left many government officials wanting never to be perceived as underreacting to a health threat.
The two episodes led many people to lose trust in government health warnings, or in the lack of them.
Warnings about A(H5N1) avian influenza began in 1997, when scientists in Hong Kong discovered that that strain of virus had jumped directly to cause disease in humans without first mixing in pigs, which had been the pattern until then. With the spread of the virus among birds, officials have warned that it could mutate, combine with a human influenza virus and create a new one to cause a human pandemic.
That has not happened, although 105 of the 186 people in the world who have developed A(H5N1) avian influenza have died.
Should health officials risk issuing stern warnings that may frighten people? Or should officials play it safe, going about their business and informing the public only when a pandemic becomes real?
If officials do issue early warnings, and nothing happens, they stand to lose credibility among people who say that scientists promoted the worst possibilities to grab more grants and waste taxpayer dollars.
If officials do not issue early or timely warnings, and a pandemic occurs, critics will say the public was not informed and protected in time.
The situation also leaves health officials vulnerable to charges of "I told you so," even though there is often no way to prove that the Monday morning quarterbacks actually made their criticisms known at the time key decisions had to be made.
Two types of dilemmas are often involved in deciding when and what warning to give, said Dr. Harvey V. Fineberg, who wrote a book with Richard E. Neustadt in 1978 analyzing the government's and industry's responses to the swine flu immunization program.
One is like a Category 5 hurricane with long odds on its occurring, but with devastating consequences if it does.
"In such cases, the naysayer is most often going to be right," said Dr. Fineberg, president of the Institute of Medicine of the National Academy of Sciences, said in an interview, referring to those who contend preparation is unnecessary.
The second dilemma involves a tension that can arise when scientists believe that political leaders and the public do not understand risk as well as scientists do. Problems can arise if an expert believes action is needed because the risk of an outbreak is, say, 10 percent, but perceives that government officials will consider 10 percent to be too low for action to be taken.
So the scientist may choose a way to present the facts and estimates to persuade government officials to do what the scientist believes is correct.
In deciding whether to warn and act, the tendency is often "reluctance to do something that may cause harm as opposed to allowing nature to create its own harm," Dr. Fineberg said.
Last year, the Bush administration released a comprehensive plan to counter an influenza pandemic. Even with it, the dilemma of when to warn will remain.
