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The lethal 1918 “Spanish flu” virus was probably descended from an avian virus and shares some genetic features with today's H5N1 bird flu, but its exact origin remains mysterious, according to molecular pathologist Jeffery K. Taubenberger. He and his research team at the Armed Forces Institute of Pathology recently reconstructed the deadly virus from frozen tissue samples.
Their genetic analysis, published in October 2005, suggested that all eight genes of the 1918 flu came directly from a bird virus and moved into humans after gradually mutating. Federal health officials said at the time that H5N1 flu has already acquired some of the genetic-sequence changes that apparently allowed the 1918 virus to become easily transmissible among humans.
Of the more than 140 people infected with H5N1, most had contact with infected poultry. The potential similarities between the catastrophic 1918 flu and the H5N1 flu — which has caused at least 75 deaths so far — have put the global public health community on edge.
If, as Taubenberger suggests, the 1918 flu was a completely novel virus to which humans had never been exposed — and therefore had developed no immunity — that might help explain why so many people became sick and died. By contrast, the milder pandemics of 1957 and 1968 are believed to have been the combined product of a human flu and an avian virus that exchanged genes after either a human or a pig caught both viruses.
However, this explanation for the greater lethality of the 1918 flu is not universally accepted. It's also possible that the 1918 virus or versions of it had circulated in humans or other animals before it became pandemic, skeptics argue. Because no genetic information exists about any pre-1918 human viruses, no one can know for sure whether the 1918 virus was unique in makeup or whether it may have infected humans at some earlier point.
One of the skeptics, Mount Sinai School of Medicine microbiologist Peter Palese, says, “I don't think we can say [the 1918 flu] was an avian virus that jumped into humans.” It's “equally likely” that the 1918 flu was a product of both human and avian viruses, like the 1957 and 1968 pandemics, he says.
Palese is one of several scientists who are not convinced that H5N1 will become a human virus, citing research dating from 1992 indicating that many Chinese already have antibodies to it. “The H5 virus has had ample opportunity to jump from avian populations into humans,” he says.
What about mounting reports of humans contracting bird flu since 2003, half of whom have died? Palese thinks the widespread perception from media reports that there has been a jump in cases and a high fatality rate is erroneous. Many bird flu cases probably are not being reported, he says, because they are either mild or asymptomatic (in the case of people with antibodies). So the fatality rate is probably much lower than the apparent 50 percent rate, he says.
Many other scientists also suspect that cases of bird flu are being underreported, especially in China. For example, by the end of 2005, Vietnam had announced more than 90 cases of bird flu, while China — vastly larger than Vietnam — had reported only seven. Some experts, like Palese, suspect that the numbers infected in China are actually in the hundreds.
Nevertheless, the U.S. government is planning for a worst-case scenario with a 2.5 percent death rate, as experienced in 1918. Since influenza viruses also tend to lose lethality over time, some scientists argue that any increase in transmissibility will produce a massive drop in virulence, because killing the host (i.e. humans) impedes a virus' evolution into a more lethal strain.
No one can predict whether the virus will become humanly transmissible, or how virulent it will be, including Robert G. Webster, the scientist at St. Jude Children's Research Hospital in Memphis, Tenn., who has been warning of its potential dangers for years. When asked how serious it might be, all he can do is “hand wave” a guess. “My hand-waving would be if it does go human-to-human, the first wave will be a catastrophe for the world — for two, three, four months,” he suggests. “The second wave will be less pathogenic and the third wave will go back to being somewhat benign.” This is similar to the pattern observed in ducks, Webster says.
This month, however, Taubenberger and epidemiologist David M. Morens of the National Institutes of Health played down the similarities between the 1918 flu and H5N1. They noted that while the 1918 virus is “avianlike,” researchers have been unable to trace the 1918 virus to any particular bird and that there is no historical data indicating that a precursor virus attacked domestic poultry in large numbers, as H5N1 has. No highly pathogenic avian virus has ever been known to cause a human pandemic, they noted. And despite Taubenberger's genetic-sequencing work, the biological basis for converting a virus into a humanly transmissible form — the prerequisite for a human pandemic — remains “unknown,” they said.
“The 1918 virus acquired this trait, but we do not know how, and we currently have no way of knowing whether H5N1 viruses are now in a parallel process of acquiring human-to-human transmissibility,” they wrote. “Despite an explosion of data on the 1918 virus during the past decade, we are not much closer to understanding pandemic emergence in 2006 than we were in understanding the risk of H1N1 'swine flu' emergence in 1976,” which turned out to be a false alarm.
On the reassuring side, if H5N1 were to become a pandemic flu, the availability of modern antibiotics, which did not exist in 1918, would combat secondary bacterial infections, which caused many of the deaths in 1918.
But other unprecedented aspects of the virus worry scientists. The infection now has been found in tigers and domestic cats and in migratory birds, previously considered safe from such viruses. “We have to accept the fact that we're watching the evolution of this virus,” says Webster. “Will it ever go human-to-human? Let's hope not. But we'd better be prepared for it.”
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