Next Killer Flu
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By Tim Appenzeller
Photographs by Lynn Johnson
In Southeast Asia a virus that kills chickens is now also killing people. The race is on to keep the bird flu from ravaging the world.
Little Ngoan was buried behind her parents' hut three weeks ago. Her grave, a bulky concrete tomb like others dotting the Vietnamese countryside, rests on high ground between a fishpond and yellow-green rice fields. At one end her family laid out her cherished possessions: a doll's chair, a collection of shells, plastic sandals. They painted her tomb powder blue.
While Ngoan's parents are off helping with the rice harvest, other relatives share their memories. "She was so small, just ten years old," says her grandmother, sitting on a hammock. "She was very gentle and a good student. If you look at her older sister"—the 17-year-old hangs back shyly—"you can imagine what she was like." Ngoan's grandfather, silent with grief, lights a stick of incense at her grave.
The loss of a beloved child has hit this family hard. But ordinarily, the wider world would pay little attention to a child's death from infectious disease in this remote corner of Vietnam's Mekong Delta. Old scourges like dengue fever and typhoid still take a toll here, and HIV/AIDS is on the rise.
Yet Ngoan's death and more than 50 others in Southeast Asia over the past two years have raised alarms worldwide. Affected countries are struggling to take action; other nations are sending aid and advisers while stockpiling drugs and developing vaccines at home. And scientists have stepped up their research into the fateful traffic of disease between animals and people.
Why? Because Ngoan died of the flu.
To most of us, flu is a nuisance disease, an annual hassle endured along with taxes and dentists. Some people think a flu shot isn't worth the bother. But flu is easy to underestimate. The virus spreads so easily via tiny droplets that 30 million to 60 million Americans catch it each year. Some 36,000 die, mostly the elderly. It mutates so fast that no one ever becomes fully immune, and a new vaccine has to be made each year.
That's ordinary flu. But the disease that is taking lives in Southeast Asia is no ordinary flu. Its primary victims have been chickens, more than a hundred million of them, killed either by the virus or in often futile control efforts. It's not unusual for chickens to get flu; in fact, avian-flu viruses far outnumber human ones. But Robert Webster of St. Jude Children's Research Hospital in Memphis has studied flu viruses for 40 years and has never seen the likes of the one that killed Ngoan.
"This virus right from scratch is probably the worst influenza virus, in terms of being highly pathogenic, that I've ever seen or worked with," Webster says. Not only is it frighteningly lethal to chickens, which can die within hours of exposure, swollen and hemorrhaging, but it kills mammals from lab mice to tigers with similar efficiency. Here and there people have come down with it too, catching it from infected poultry like the chickens that died on Ngoan's farm a few days before she fell ill. Half the known
cases have died.
In those deaths many public health experts hear the distant rumblings of a catastrophe. So far this virus—classified as H5N1 for two proteins that stud its surface like spikes on a mace—isn't good at passing from birds to people, let alone from one person to the next. "It can make that first step across, but then it doesn't spread easily from human to human," says Webster. "Thank God. Or else we'd be in big trouble."
Maybe H5N1 will never learn the trick of racing from person to person like the milder flus that empty offices and classrooms each year. Maybe it simply can't. Or maybe efforts to eradicate the virus—largely fitful and underfunded so far—will succeed. But experts are urging the world to prepare for the worst.
What is known about flu viruses' remarkable capacity to change and jump species has led to a sense of inevitability, a conviction that even if this menacing animal flu doesn't explode into a global pandemic that kills millions, another one will. "It's going to happen, at some point, that a virus like this changes to be able to transmit from one person to another," says Jeremy Farrar, an Oxford University doctor who works on the front lines of avian flu at the Hospital for Tropical Diseases in Vietnam's Ho Chi Minh City. "It's bound to happen. And when it does, the world is going to face a truly horrible pandemic."
After all, it has happened before.
In 1918, the final year of the savage trench fighting of World War I, something else began felling the soldiers. No one knows for sure when or where the Spanish flu emerged, though it certainly wasn't in Spain. As a neutral country, Spain had no wartime censorship, and the flu apparently got its false pedigree from news reports about outbreaks there in May 1918. In fact the disease was already spreading on both sides of the European front, laying low entire divisions through the spring and early summer. Then it seemed to subside.
In late summer, though, the Spanish flu returned, and this time its virulence was unmistakable. The sick took to their beds with fever, piercing headache, and joint pain. Many were young adults, exactly the group that normally shrugs off the flu. About 5 percent of the victims died, some in just two or three days, their faces turning a ghastly purple as they essentially suffocated to death. Doctors who opened the chests of the dead were horrified: The lungs, normally light and elastic, were as heavy as waterlogged sponges, clogged with bloody fluid.
After flashing through crowded military camps and troopships in Europe and the United States, the flu leaped out of uniform to ports and industrial cities. In Philadelphia, historian Alfred Crosby found, 12,000 people died of flu and pneumonia in October—759 in a single day. Schools and businesses were shut down and church services cancelled. Morgues overflowed.
By then the sickness had spread to the far corners of the planet, from the South Pacific to the Arctic. "Everybody on Earth breathed in the virus, and half of them got sick," says Jeffery Taubenberger of the Armed Forces Institute of Pathology in Maryland, who is trying to learn what made it such a killer. More than 50 million people died—at least three times as many as in the war. The best medical minds of the day could hardly believe that this was flu.
It was flu all right, but with a crucial difference that scientists are only beginning to understand. Scattered across Taubenberger's desk are translucent wax blocks the size of matchboxes. Borrowed from a pathology archive, they hold fingernail-size scraps of purplish tissue, sliced from the lungs of flu victims in U.S. military hospitals almost 90 years ago. In the mid-1990s Taubenberger and his colleagues realized that a sample from someone who died quickly, lungs still seething with virus, might still hold genetic traces of the killer. They were right: In 1996 lung tissue from a soldier who died in September 1918 at Fort Jackson, South Carolina, yielded pieces of the virus's genes.
The pickings soon got better. Inspired by Taubenberger's discovery, a retired pathologist named Johan Hultin traveled to a remote Alaska village and excavated a mass grave that had been hacked into the permafrost after the Spanish flu swept through in November 1918. One female body still contained intact lung tissue, preserved by the cold and sheer luck. Bit by bit, Taubenberger's group teased out the entire genetic sequence of the virus. They plan to finish publishing it this year.
So far this genetic blueprint hasn't revealed exactly what made the Spanish flu so deadly. No single gene or protein is the obvious culprit. But comparing the 1918 sequence to those of the flu viruses that wreak mild havoc each winter has confirmed what was long suspected: The Spanish flu virus had recently crossed into people from some unknown animal, leaving victims with little immunity to this new threat.
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.
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