June 17, 2002 -- It happened three times in the last century -- and nearly happened again in 1997. Now experts say that another killer flu epidemic is brewing.

Will it emerge to kill millions -- as did the 1918 Spanish flu? Or will it be nipped in the bud, as in the 1997 emergence of chicken flu in humans? There are no easy answers. But now the same experts who led the successful effort to stop the 1997 virus in Hong Kong raise troubling new questions.

Those questions come from a report in the June 25 issue of the prestigious Proceedings of the National Academy of Sciences. The report shows that flu viruses similar to the killer 1997 strain reappeared in Hong Kong in 2001. It happened again this year, the authors now say.

"We don't want this in humans or the world will be in deep, deep trouble," researcher Robert G. Webster, PhD, tells WebMD. "What will you do if one of these gets away? You haven't got anything to do. Are we going to be prepared for this? It is going to happen sooner or later, and authorities are not stockpiling effective drugs. We have had two years of very mild flu, and now these drugs are in very short supply. If one of these viruses gets away, we are in for trouble."

And while none of the 2001 or 2002 viruses infected humans, they had acquired dangerous new genes. Lab mice exposed to some of these viruses quickly developed brain infections and died. Webster is director of the World Health Organization collaborating center on influenza viruses in lower animals and birds.

Flu viruses can change their genes to become more infectious and more deadly to humans. The new study shows that the potentially deadly Hong Kong flu virus known as H5N1 has been shifting in alarming ways.

"This time, this virus has picked up a whole set of new internal genes," Webster says. "What worries me is this shows it is possible for this virus to 'mate' with a number of different viruses and produce viruses highly [lethal] for poultry. The key question is, 'What is the potential in humans?' Can you afford to let the experiment happen? The worrying thing is that all these original viruses continue to circulate. If this virus mates with a virus that allows it to spread from human to human, it would be of great worry to me."

David L. Suarez, DVM, PhD, is lead scientist for avian influenza at the U.S. Department of Agriculture's Southeast Poultry Research Laboratory in Athens, Ga. He's the point man for U.S. efforts to track emerging flu epidemics in poultry.

"There is danger of human infection -- the risk is not zero," Suarez tells WebMD. "The major concern is that the genes that made up the 1997 outbreak are still circulating. Fortunately, we haven't seen a virus with the same set of genes as in 1997, but the fear is that we could always see something like that."

Another author of the PNAS study is J.S. Malik Peiris, MD, PhD, professor of microbiology at the University of Hong Kong. Peiris points out that none of the H5N1 viruses seen since 1997 had the right gene combination to let them infect humans.

But Peiris also says that we should not be concentrating solely on the H5N1 viruses as a possible cause of a global flu epidemic. A number of other influenza viruses -- some more widespread than H5N1 -- also deserve close attention, he says.

In 1997, Hong Kong authorities had all of the city's 3 million chickens slaughtered. While there were 18 human infections and eight deaths, all of these infections came directly from birds. Killing the poultry stopped the outbreak before the virus could learn to spread from human to human. It was a close call -- and the first time a human action prevented a worldwide epidemic.

In 2001, Hong Kong authorities again ordered the deaths of hundreds of thousands of chickens. They also established strict new rules for the area's poultry farmers and live-poultry markets. Affected chickens were killed this year, too, but a new poultry vaccine was used to prevent spread among uninfected birds. Unfortunately, no such safeguards are in place in mainland China.

Mainland China is still denying they have a problem, Saurez says. "For me it is a very big concern." Every year since 1997 we have seen flu viruses that cause severe disease -- the source for which was China, he says. "It is there. So obviously they are unable or unwilling to control it. It is a huge risk."