History is supposed to teach lessons. But past flu pandemics, it turns out, don't teach much about whether today's bird flu will become a human mega-killer or just make some scientists and officials look like Chicken Little.
In a viral sense, the sky has fallen three times in the last century — 1918, 1957 and 1968 — when "super-flu" strains killed millions more people than annual flu epidemics routinely do.
Back then, there weren't surveillance systems or modern genetic tools to detect and document viruses as they evolved into killer strains. Because scientists don't know how that evolution happened or how long it took, they can't tell us whether what we're seeing with bird flu now is the run-up to a pandemic or a near miss.
"My crystal ball doesn't allow me to answer that," said Dr. Frederick Hayden, a University of Virginia flu expert.
Leading scientists now discount the notion that flu pandemics happen in regular intervals and that the world is overdue for a new one.
They don't even agree on how bad it is that bird flu has spread to more types of birds. Instead of an appetite for people, the germ is showing a growing fondness for birds, some say.
They do agree on the need to make vaccine, stockpile drugs and be prepared.
"We have to run scared" and be glad if precautions prove unneeded, said Dr. Edwin Kilbourne, a longtime microbiologist and flu virus expert at Cornell University who is now an emeritus professor at New York Medical College.
Nobody can say when the next pandemic will emerge — just ask Kilbourne. When "swine flu" appeared in 1976, following global flu epidemics in 1957 and 1968, he championed the idea that pandemics appear every 10 years or so. But swine flu didn't become a pandemic, and neither has anything else in the three decades since then. Clearly, Kilbourne says now, the notion of regularly timed pandemics is wrong.
The first documented cases of bird flu in people occurred in 1997 in Hong Kong, where six people died and the entire poultry population of about 1.5 million birds was slaughtered in three days to control the outbreak. The current flu virus strain, classified as H5N1 like the Hong Kong germ, appeared in people in 2003. More than 60 people in Asia have died, and more than 150 million chickens and ducks have died from the germ or been slaughtered.
Nearly all the human victims caught the virus from close contact with sick chickens, with only one confirmed case of a person infecting another person. The fear now is that H5N1 will acquire the ability to spread easily from person to person, sparking the worldwide outbreak known as a pandemic.
For a pandemic to occur, the virus "must make people sick and spread easily. Very few new influenza strains do those two things," said Dr. Dennis Maki, infectious diseases chief at the University of Wisconsin-Madison.
In fact, Maki takes some comfort in the fact that H5N1 has not yet acquired the genetic changes it needs to start spreading easily from person to person.
"It's been around for almost three years with lots and lots of opportunity to do so and it hasn't happened yet," Maki noted. "That suggests it's not an easy adaptation genetically."
Michael Osterholm, a government flu adviser from the University of Minnesota School of Public Health, still sees big dangers.
"There have been many, many mutations with this virus . . . and it only continues to march around the world" instead of abating, he said.
Scientists don't know the genetic changes needed to transform a bird flu virus into a pandemic killer of people, said Jeffery Taubenberger of the Armed Forces Institute of Pathology in Rockville, Md.
If they could build up a catalog of crucial genetic changes, scientists could screen flu viruses in birds to see which variants pose the most threat, and focus on wiping those germs out, he said.
Studies of past pandemics don't reveal how the switchover from bird virus to human scourge will happen in the next one. Instead, they illustrate there are two routes. The virus can make the genetic changes on its own. Or it can pick up genes from a human flu virus, perhaps in a person who became infected simultaneously with the bird and human viruses. This gene-swapping process is called reassortment.
Taubenberger, who is studying the genetic makeup of the 1918 pandemic virus, said that germ appears to have mutated on its own. In contrast, the viruses behind the other two pandemics of the 20th century were apparently products of reassortment, he said.
Kilbourne agreed that recent work suggests the 1918 virus mutated on its own, "but some of us have reservations about how strong that evidence is."
If it is true, it suggests the way a bird flu virus goes about making the changes could affect how deadly it becomes. The 1918 virus was by far the most lethal flu germ of the 20th century, killing 20 million to 50 million worldwide and more than 500,000 in the United States alone.
In contrast, the 1957 Asian flu killed 2 million around the world and the 1968 Hong Kong flu, 1 million. Maybe the human genes in these hybrid viruses made them more recognizable to the disease-fighting immune systems of people, thus producing milder pandemics, said Dr. William Schaffner, a Vanderbilt University infectious diseases expert and government flu adviser.
Of course, H5N1 has already killed some people, but even that gives no real indication of how deadly it is for humans. These few deaths have no context. There may be many less severely ill people going unnoticed.
The way to tell the real death rate is by taking blood samples from a large population to see how many have antibodies to the virus, indicating they had been infected. These serosurveys, as they are called, are standard operating procedure when a new germ appears. They were among the first things done when West Nile virus and SARS emerged. Yet they have not been done in a big way among poultry workers in Asia — the most likely people exposed to bird flu.
"I'm frankly a bit bamboozled by all that. I can't understand why that hasn't been done extensively," Schaffner said.
Without serosurvey information, the apparent human death rate for H5N1 infection of about 50 percent may be erroneous, said Craig Pringle, a viral diseases moderator for ProMed-mail, a blog operated by the International Society for Infectious Diseases. He's also a retired professor at the University of Warwick in England.
In any case, Kilbourne said the makeup of H5N1 itself might dampen its impact. The "N1" part of the virus refers to the classification of a certain protein on its surface. Another kind of N1 human flu virus has been widely circulating since 1977, so it's recognizable to the immune systems of many people.
When the "N" part of the flu virus didn't change between the pandemics of 1957 and 1968, the latter was a milder killer, Kilbourne noted.
So as for the current bird flu, "I am less concerned about all this business than others because I think the N1 immunity that everyone in this population has now . . . may well mitigate the effects," he said.
Of course, nobody is rooting for H5N1 to trigger a human pandemic. But if it doesn't do so in the next year or two, Taubenberger said, there could be another public health problem: anti-flu backlash.
"People will say . . . this was hyped and there really wasn't risk," ignoring the fact that future viruses could pose a threat as well, he said.
"I would hate to lose the momentum we have in terms of influenza surveillance and pandemic preparedness . . . and have a pandemic occur when your back is turned."