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Next Killer Flu

By Tim Appenzeller
Photographs by Lynn Johnson

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One reason you generally get over the flu after a few days' discomfort is that your immune system has seen it before and knows how to respond. This year's bug won't be a carbon copy of last year's, because the virus mutates constantly. But it will look similar enough that your body can almost always keep it in check.
Every so often, though, something new comes along from the animal world—a vast preserve of type A flu viruses, the ones that cause the most serious illness in humans. In far-flung studies in the late 1960s and 1970s, from Australia's Great Barrier Reef to lakes in northern Canada, Robert Webster and his colleagues tracked flu to its source. "Where do flu viruses come from?" he asks. "From the wild birds of the world, the wild aquatic birds—the waterfowl, the ducks, the shorebirds."
Dozens of flu subtypes inhabit the birds' guts, mostly harmless to their hosts or to any other creature. But occasionally one infects domestic poultry. Even more rarely, a bird virus or some of its genes slip into the much smaller pool of type A viruses that infect humans.
Normally a flu virus good at infecting birds can't attack humans because it isn't equipped to invade and grow in human cells. Until recently scientists thought avian viruses could gain that ability only by indulging in the viral equivalent of sex. Because flu viruses carry their genetic information on eight separate RNA segments, it's easy for different subtypes to swap genes if they happen to meet. The result: offspring with new abilities.
For an avian flu and a human flu to mix it up, they have to infect the same animal. Scientists have long considered the pig a likely mixing vessel, because pig cells have surface molecules that allow entry to both kinds of virus. A pig could conceivably catch a human flu from a farmer and a bird virus from, say, ducks at the same farm. The two viruses could then "reassort," creating a hybrid that—in the worst case—would now be able to infect human cells while still carrying bird-virus genes that would make it radically new to the immune system of the people who catch it, and unusually virulent.
Reassortment explains the two lesser flu pandemics of the 20th century, in 1957 and 1968. In each year a new flu subtype appeared, combining genes from the human virus that had been causing mild outbreaks in prior years with new genes from a bird virus. The new pandemic viruses raced around the world, together killing about two million people.
But in 1918, Taubenberger now believes, something different happened. "We think it's pretty likely that the virus was not derived from a previously circulating human virus," he says. All of its genes mark it as an animal virus, pure and simple, that somehow crossed to people without the help of genes from a previous human strain.
Now H5N1 is doing the same thing. So far, its steps across the species barrier are tentative, which is why it has caused tens of deaths, not millions. But as in 1918, doctors who have seen its effects close up are shaken.
The x-rays tell the story as Tran Tinh Hien, a doctor at the Hospital for Tropical Diseases in Ho Chi Minh City, clips them to a light box. In the first image, made the day the 18-year-old girl was admitted with bird flu, a whitish cloud appears at the base of her rib cage. Her lungs were partly filled with fluid. In a second film, four days later, the haze has spread throughout her chest. "All the lung tissue was destroyed," Hien says. "The process still happened when we treated." A week later the girl was dead.
So it went for Hien and his staff throughout January, when the latest bird-flu outbreak reached its peak in southern Vietnam. They cleared a 50-bed ward normally reserved for malaria and dengue fever and turned it into an isolation unit.
They sustained patients with oxygen masks and ventilators and treated them with oseltamivir, or Tamiflu, an expensive antiviral drug that can fight H5N1. Nurses worked 24-hour shifts, gowned, masked, and goggled for protection against the virus. As Hien says: "We were pushed to the wall."
He and his staff did everything they could for their nine bird-flu patients. "Unfortunately," he says, "we could not save any lives."
As an elite facility, the Hospital for Tropical Diseases saw the bleakest face of the disease. Only the sickest patients were sent there, and by then they may have been beyond help. In fact H5N1 doesn't always kill. Some infections may even be so mild that they go unnoticed. But every hospital that has treated people seriously ill with avian flu has recorded shocking death rates.
It has been that way since 1997, when an H5N1 virus strain—a cousin of the one now plaguing Asia—first jumped to humans. Early that year an outbreak of the virus killed chickens in Hong Kong's rural New Territories. At that point, no one thought bird viruses threatened people directly. But this one broke the rules.
In May 1997 a three-year-old boy was admitted to a Hong Kong hospital with a cough and fever. His symptoms worsened rapidly and he had trouble breathing. He was given a flood of antibiotics and put on a ventilator, but within six days he was dead. Flu experts were astonished when secretions from the boy's windpipe yielded an H5N1 virus. It turned out to be the same one that had killed the chickens.
Still, his death looked like it might be a fluke until late in the year, when another 17 people checked into hospitals around Hong Kong with similar symptoms, and tests confirmed infection with H5N1. Five died. Many of the victims had visited one of the island's live-poultry markets.
Public health experts converged on Hong Kong, fearing that a 1918-style pandemic was about to explode. They persuaded the Hong Kong government to kill every last bird—1.5 million of them—in the farms and markets. The mass slaughter worked. That particular H5N1 virus was never seen again, and a public health disaster had been averted.
But in 2001 another deadly strain of H5N1 cropped up in Hong Kong's markets, and the city again began killing poultry. This time the respite was shorter, and by the beginning of 2002 chickens were again dying of flu. The fact was, the drastic measures in Hong Kong had left the source of all these viruses untouched. They were coming from outside Hong Kong—just across the territorial border in southern China.
China's Guangdong Province teems with hundreds of millions of chickens, ducks, and geese, many wandering freely through gardens, farms, and ponds. Flu viruses that rain into this sea of poultry in wild-bird droppings can spread and swap genes with abandon. The result: new strains not found in the wild. Among them was the H5N1 virus that gave rise to the bird flu now plaguing Asia.
Year after year it swapped genes with other avian-flu viruses, generating a plethora of new H5N1 variants. Year after year they besieged Hong Kong, which imports poultry from the mainland. By the end of 2003, they were infecting and killing birds across half of Asia.
Radiating from China, H5N1 strains reached South Korea and Japan in the north; they swept through Southeast Asia as far as Indonesia. Some experts and officials have suggested that the viruses traveled in the guts of wild waterbirds—geese, ducks, herons—which might have picked up the infection from farms. Governments embarrassed by their failure to halt the flu's spread welcome that idea. "They get a free lunch," says Yi Guan, a virologist at the University of Hong Kong. "Each time there's an outbreak, they say, 'It's migratory birds. I cannot control them. I cannot lock my sky!'"
This summer the virus killed thousands of wild geese and gulls at a nature reserve in western China. It was the largest known outbreak in wild birds and a warning that in the future they might spread the disease far and wide. But Guan isn't ready to blame migratory birds for the spread so far. He thinks the virus has killed infected birds too quickly for them to fly long distances. Instead H5N1 probably hitchhiked across Asia in shipments of live poultry, in a disaster of our own making.
As it advanced, the virus began killing people again—by August the count stood at 40 in Vietnam, 12 in Thailand, 4 in Cambodia, and at least 1 in Indonesia. And it inflicted economic losses that, by one estimate, amounted to more than ten billion dollars in 2004 alone. Exports from Thailand's industrial chicken farms collapsed when the world learned of the outbreak there. In areas of Indonesia hit hard by the virus, more than 20 percent of the workers on commercial poultry operations lost their jobs.
Small farmers are suffering too. As one animal health official in Vietnam explains, "The birds are big treasures for the farmers." They scavenge for themselves, costing next to nothing to raise and putting good meat on the table. Vietnamese farmers lost some 40 million of these treasures in 2004, dead of flu or killed in control efforts. Even farms untouched by the disease were hit as fearful shoppers began avoiding poultry.
It may take a long time for Vietnam to regain its taste for chicken. At a riverside restaurant in the southern city of Can Tho, six veterinary officials—men responsible for keeping the district's poultry healthy—order prawns and a fish stew for lunch. They admit it: Not one of them will touch chicken these days.
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.

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