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Next Killer Flu
OCTOBER 2005
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Next Killer Flu

By Tim Appenzeller
Photographs by Lynn Johnson

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H5N1 is all the more frightening because so much is unknown, starting with how it kills people. In a chicken, the virus spreads everywhere—gut, lungs, brain, muscle. In humans, like the 1918 flu, it devastates the lungs first and foremost.
 
Researchers at the University of Hong Kong have found that a victim's own immune system may be part of the problem. It reacts to the virus with a flood of chemical messengers that draw white blood cells into the lungs, where they trigger a massive inflammatory reaction. "It's kind of like inviting in trucks full of dynamite," says Malik Peiris, who led the work. Healthy tissue dies and blood vessels leak, filling the lungs with fluid.
 
But H5N1 may have more than one way to kill. This year researchers in Ho Chi Minh City, including Jeremy Farrar, detected H5N1 in a little boy who died in a coma, his brain inflamed but his lungs healthy until the very end. To Farrar it suggests that the virus can spread throughout the body. Others aren't sure.
 
It's one more bird-flu mystery.
 
Ask Keiji Fukuda and Tim Uyeki, flu epidemiologists at the Centers for Disease Control and Prevention (CDC) in Atlanta, what they would most like to know about the disease, and the questions come tumbling out. "How many people are infected? How many animals are infected?" Asks Fukuda. Since 2004 only four countries have reported human illnesses. "Have there been no others?" Uyeki asks. "It's pretty likely there have been, but we have no information about that."
 
Then there's the mystery of exactly how people get infected. "Right now we believe that most cases are related to people somehow being exposed to sick or dying or dead poultry," says Fukuda. "Well, what does that mean?" He asks, ticking off possibilities. Does that mean people touched it? Did they eat it? Did they breathe in dust containing chicken feces? He's frustrated at the often sketchy reports from Asia. "What is really going on?" He asks. "This has very practical implications" for fighting the disease.
 
The biggest question is whether the virus will start spreading like ordinary human flu. "Human to human—that's the one that we don't want to see," says Robert Webster. But already, H5N1 has given experts a few scares.
 
Nguyen Thanh Hung, a cement trader in Hanoi, says he feels well these days. He works, tends a small forest of potted plants, and spends hours a day jogging and doing breathing exercises. In his living room one day in February he shows off his hospital discharge papers as if they were his new lease on life. It's been just a month since Hung got over a serious bout of avian flu. "The doctor told me if I had been taken to the hospital one or two days later—no way," he says. His older brother, also infected, was not so lucky.
 
If Hung's survival is remarkable, so is the way he seems to have caught the disease. On a visit to their home village outside Hanoi he and his brother had shared a pudding made of raw duck blood, a Vietnamese delicacy. The duck must have been infected with H5N1, because Hung's brother came down with the flu a few days later. But Hung did not get sick for more than two weeks—not until the day after his brother died.
 
That's too late for the pudding to be the cause, Tim Uyeki believes. Hung probably got infected while caring for his brother in his final days.
 
H5N1 is also thought to have jumped from a girl dying of avian flu in Thailand to her mother and aunt, who nursed her. Several other cases of human-to-human transmission are suspected. But one step beyond the initial victim is all the virus seems to have managed. So far, sustained transmission—the chain-reaction spread of ordinary flu—is not in its repertoire.
 
It might gain that ability on its own, by mutating. Or it might swap genes with a human-flu virus. That could take place in an infected person who also catches ordinary flu, or in the classic flu mixing vessel, the pig. Still, no one knows whether the exchange would yield a nightmare virus or a dud.
 
Flu researchers at the CDC and in the Netherlands hope to find out in advance, by artificially breeding new viruses. In high-containment labs they are deliberately mixing and matching genes from H5N1 and human-flu viruses. Then they will test the hybrids to see whether any have inherited both the bird virus's virulence and the human virus's ability to spread. In effect, they are trying to create a pandemic flu strain in the lab.
 
Some critics think that's reckless, but Erich Hoffmann, a St. Jude researcher who helped develop a genetic engineering technique for flu, says the experiments are key to learning what we may eventually face. "It's basically the best simulation one could have in the lab of what possibly could happen in nature."
 
If we're lucky, he says, all the hybrid viruses will be harmless or won't thrive, suggesting that H5N1 may never spawn a pandemic. "That of course would be good news," says Hoffmann. And if the news is less reassuring? Then scientists monitoring H5N1 in Asia would have a clue about what to watch for—what genetic changes in the virus might signal big trouble ahead.
 
That knowledge might buy some warning time, but no one wants to sit and wait for H5N1 to make its move. And everyone agrees on the best way to head it off: Eradicate H5N1 in poultry, so people can't catch it. It's simple—but not easy.
 
Howard Wong, a senior veterinary officer in Hong Kong, knows what it takes. Since 2003, after multiple outbreaks and two wholesale poultry slaughters, the territory has kept its farms and markets free of H5N1. Wong is proud of his success. "We were very happy in 2004, when it was everywhere else, and we managed to hold it back."
 
Here are some steps Wong and other officials took: vaccinating every chicken in Hong Kong against H5N1; regularly testing chickens, pet birds, even wild birds; shutting down the hundreds of live-poultry stalls twice a month to disinfect them; and inspecting farms and markets obsessively. "We're almost at the limit of what we can do," says Wong. "It's like holding up this wall, and this wall just gets heavier all the time."
 
And as one aid official in Vietnam puts it, Hong Kong is rich, and an island. Vietnam is neither. In the winter of 2003-04, H5N1 broke out in most of the country's 64 provinces. To fight it, the country slaughtered tens of millions of chickens. The epidemic seemed to decline, and in March the government declared victory.
 
But in late 2004 avian flu roared back, infecting birds and people along the length of the country. Cooler weather, which favors the survival and spread of the virus, had apparently brought it out of hiding. By February of this year Anton Rychener, the representative of the United Nations Food and Agriculture Organization (FAO) in Hanoi, was beside himself. "Why the hell are we sitting here a year later with literally the same pattern of outbreak?" he asked a roomful of officials. A year of meetings and emergency initiatives had done little to change the conditions that made Vietnam ripe for viral spread.
 
In the countryside, chickens peck in yards and stalk through underbrush, mingling with birds from other farms. Poultry markets act as viral swap meets, and unsold birds are taken back home with any viruses they picked up. Farmers with sick birds have little incentive to speak up and see their flocks destroyed: The government can afford to pay less than half of a bird's market value as compensation. And then there are the ducks.
 
The duck, says Webster, is "the Trojan horse of this outbreak." His group has found that unlike chickens, infected ducks often seem healthy, able to waddle, swim—and spread the virus in their droppings. In Vietnam and other parts of Southeast Asia, they spread it far and wide because duck herders drive their flocks from one rice field to the next, following the harvest, so the birds can fatten on leftover grains.
 
Inefficiency, tradition, and scarce funds have all slowed Vietnam's efforts to change such practices. And although officials gamely declare that they are making progress, last year's confidence has faded. When asked whether he expects his district to be hit by bird flu again next year, a veterinary officer in Can Tho says, "It's not my expectation, but I think it will happen."
 
Thailand has made more headway. Wealthier and more developed than Vietnam, it reimburses farmers more generously when birds are slaughtered. It tests ducks for H5N1 and allows only virus-free flocks to move around the countryside. And it has enlisted nearly a million village volunteers to watch for unusual chicken die-offs. By early this year it had driven the virus back into just a handful of provinces.
 
Even so, Wantanee Kalpravidh, the FAO's regional coordinator for avian influenza in Southeast Asia, says the country cannot rest easy. It has long borders with Laos and Cambodia, destitute lands struggling with their own avian-flu outbreaks. Thailand's efforts could quickly be undone if a crate or two of infected poultry slipped in. As Kalpravidh points out, "Birds need no visa or passport."
 
Nor do viruses. Suppose H5N1 lives up to the fears and picks up a new talent for contagion. Somewhere, probably deep in the countryside, a pandemic spark would ignite. A person sick with bird flu would infect his family, who would pass the disease to friends and neighbors. Exponential spread might follow.
 
Computer simulations suggest that public health officials just might be able to douse the spark by flooding the region with antiviral drugs, treating the hundreds of thousands of people who are at highest risk for infection. But the strategy could succeed only if the outbreak were detected within a few weeks and the virus spread slowly at first. And the infrastructure and skills required are lacking in much of Asia.
 
If containment failed, in a few more weeks the newborn pandemic would hit major cities. There it would infect people with passports and plane tickets. The rest of the world would be hours away.
 
Richer countries are scrambling to prepare. Because Tamiflu can protect against H5N1 as well as treat it, governments are building up stockpiles, and drugmaker Roche is hard-pressed to keep up with demand. The U.K. has ordered enough for 15 million people, a quarter of its population, and France almost as much. The U.S. has opted for a smaller stockpile—just 2.3 million treatments so far. It is also pinning its hopes on a vaccine.
 
Ordinary flu vaccines contain flu virus, grown in fertilized chicken eggs, then killed and split into pieces. But because it's so deadly, H5N1 requires expensive safety measures and tends to kill the eggs needed to grow it.
 
So Webster's group turned to genetic engineering, altering one gene to tame the virus and splicing in others to speed its growth. By August human tests of a vaccine made from the altered virus showed early signs of success. The U.S. government has already ordered two million doses.
 
Two million doses would be scant protection for a country of nearly 300 million. But officials hope the vaccine formula will be fully tested and ready before it is ever needed. Makers would know how to produce it and could boost production fast, says Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases. At the first sign of a pandemic, "We'll be able to say: Go, take off the brakes and make millions and millions of doses."
 
But again comes the refrain, no one knows. No one knows whether an H5N1 pandemic strain—if it ever emerges—will be similar enough to the virus now stalking Asia for this vaccine to offer full protection. No one can even be sure H5N1 is the right threat to focus on. Several other bird-flu viruses have recently shown signs of infecting humans, though none has proved as deadly as H5N1.
 
Here is what we know for sure. One day a new flu pandemic will come, and one day it will pass. And then the killer strain, tamed by our immune systems and the passage of time, will fade into the background of nuisance flus.
 
It even happened to the worst of them all. Did you catch the flu last winter? There's a chance it was a direct descendant of the Spanish flu. If so, you were lucky. The heir to 1918 is one of the milder flu strains around today.


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