A Killer Takes Wing

Times Staff Writer

Beneath a dim morning sky, Jonathan Runstadler trudged across the ice with a long fiberglass tube, some gardening tools and a smattering of plastic lab bottles.

Months earlier, summer breezes had carried wild birds from Asia to this little pond. Now, with the temperature hovering at 9 degrees, Runstadler bored through the frozen surface in search of the seeds of a pandemic.

"Ground Zero is what's in birds," said the University of Alaska molecular biologist, who dropped hockey puck-shaped ice samples into a Ziploc bag.

This snowy patch of the Alaskan wilderness sits at the edge of a bird flu outbreak that emerged in Hong Kong in 1997 and has recently spread as far as Kazakhstan, Croatia and Siberia. The virus has ravaged farms in Thailand and felled wild birds from western China to Eastern Europe.

Turkey has become the latest hot spot, reporting at least two human deaths from bird flu since the start of the year -- the first human cases outside Asia.

Since 2003, the virus has killed 76 people in its march across the globe, according to the World Health Organization. More than half died in the last year.

What Americans once viewed as a distant scourge is now just across the Bering Strait. If it arrives in North America, scientists expect to find it first in Alaska, a breeding ground for many migratory birds from Asia.

The bird flu virus, known as H5N1, is the culmination of random mutations and countless viral mixings, producing a strain of influenza completely unfamiliar to the human immune system.

It could be just a few more mutations away from being able to easily infect and spread among people -- the raw ingredients needed to spark a global pandemic. Or it could evolve into a harmless strain.

Its future is uncertain.

The virus is not so different from the common flu that causes fevers and runny noses each winter. Yet it has provoked a degree of fear that belies its mundane origins.

Governments have slaughtered millions of chickens and other poultry. Hospitals are stockpiling Tamiflu and other antiviral medications. Scientists are racing to develop a vaccine.

In Alaska, scientists such as Runstadler are searching for traces of H5N1 in bird droppings left from the summer breeding season. They could be preserved in now-frozen water or soil.

"It's just a matter of time before H5N1 shows up everywhere," said George M. Happ, a biologist at the University of Alaska who is coordinating the state's pursuit of the virus.

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It arrived with little fanfare.

In May 1997, there was panic in Hong Kong over an outbreak of German measles that sickened more than 1,500 people, mostly teenagers.

Amid the commotion, a 3-year-old boy with fever, aches and a sore throat was admitted to a Kowloon hospital. He had typical flu symptoms, nothing unusual in a young child.

Yet as the days progressed, the boy's illness continued to worsen. His symptoms indicated viral pneumonia and Reye's syndrome, a rare disorder that causes brain inflammation.

He died six days after being admitted to the hospital.

Dr. Wilina Lim, a virologist with Hong Kong's Department of Health, tested a fluid sample from the boy's windpipe.

It was a puzzle. She confirmed it was an influenza virus but couldn't identify it.

Lim sent off samples to two of the top infectious disease laboratories in the world -- the U.S. Centers for Disease Control and Prevention in Atlanta and the National Influenza Centre in the Netherlands.

Three months later, she received a startling reply: The boy had been infected with a virus that had been found only in birds.

Kennedy Shortridge, a University of Hong Kong microbiologist, had identified a nearly identical virus a few months earlier as the cause of 4,500 chickens' deaths on farms in Hong Kong's Yuen Long district.

To the virologists on the case, the notion that bird flu could kill humans was preposterous.

At first, they suspected the samples had been contaminated by virus particles from Shortridge's lab. Only after ruling out that possibility did they realize the significance of the discovery.

It was the first documented case of bird flu jumping directly to humans with lethal consequences.

New patients came down with H5N1 in November 1997. All but one had visited Hong Kong's live poultry markets within several days of the onset of their symptoms.

Altogether, 18 people came down with severe respiratory illness. Six of them died.

Because the outbreak coincided with the onset of the regular flu season, health officials worried that H5N1 could mix with a human flu strain and morph into an easily transmissible virus.

Hong Kong's health director, Margaret Chan, ordered the culling of all poultry in the territory.

Secretaries, park rangers and dog catchers were drafted to help slaughter 1.6 million chickens, ducks, quails, partridges and geese. Workers in white suits and masks hauled the carcasses to a landfill.

There were no more human cases that season. Hong Kong cheered.

A pandemic, scientists believed, had been averted.

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The horrors of a global outbreak are still within living memory.

In the spring of 1918, while the world was at war, a mysterious bug sickened soldiers in Kansas and spread to other American military camps. Amid the global commotion, the virus propagated quickly, affecting healthy adults as well as children and the elderly.

The virus claimed the lives of 8 million Spaniards in May alone, giving the pandemic its name: the Spanish flu.

By the time it receded the following year, as many as 50 million people had died, including more than 500,000 in the United States. More soldiers of all nations were killed by the Spanish flu than by World War I combat.

Influenza probably has been known since ancient times. Hippocrates documented an outbreak likely to be influenza in the Greek city Perinthus in the 5th century BC. And some scholars believe the flu may have contributed to the downfall of Athens.

The first documented pandemic occurred in 1580, and there have been 30 more since.

In modern times, remnants of the Spanish flu virus mixed with a strain of avian influenza in China and became the 1957 Asian flu. It caused as many as 2 million deaths, including about 70,000 in the United States.

That gave way to another pandemic virus in 1968 known as the Hong Kong flu, which killed 34,000 Americans and about 70,000 people worldwide.

Scientists worry that the H5N1 virus could be next.

The virus resurfaced in Asia in 2001 and has been spreading steadily from its epicenter in southern China since 2003. Vietnam, Thailand, Cambodia, Indonesia and China reported 39 deaths last year, according to the WHO.

The influenza virus is a simple device. Each spherical flu particle contains eight strands of RNA, which have instructions for making 10 proteins.

One of them, hemagglutinin, forms spikes on the virus' outer shell to help it attach to a host cell. Once inside, the virus hijacks the cell's machinery to copy itself hundreds of times. Another protein on the outer shell, neuraminidase, helps the new virus particles detach from the host so they can find fresh cells to invade.

These two proteins define a flu's character. Scientists have identified 16 types of hemagglutinin, or H, and nine kinds of neuraminidase, or N. The particular combination is what gives a flu its name.

The power of influenza lies in its endless pursuit of change.

Unlike more complex organisms, whose genetic code is stored in DNA, flu viruses have RNA, which cannot copy itself reliably. Each mutation changes the shape of the H and N proteins, and over time, the immune system fails to recognize them.

This genetic "drift" is why the flu vaccine must be updated every year. Even small drifts enable viruses to sicken millions of Americans each winter and kill an average of 36,000.

A more dramatic event is a "shift," which occurs when two flu viruses infect a cell at the same time and swap entire strands of RNA. The mixing could involve two kinds of human flu, or it could include strains from birds, pigs, horses, seals, whales or other animals.

The most dangerous scenario is for a human virus to exchange its H -- or both its H and N -- with an animal equivalent. The combination probably would create a new strain, and no one would be immune. It would take months to develop a vaccine.

That is precisely the scenario that makes scientists fearful of H5N1.

There have been 146 documented human cases since 2003, the WHO said. Each new case increases the possibility of a deadly mutation.

H5N1 has already made a complex evolutionary journey.

Researchers have traced the ancestor of its H5 gene to a virus identified in geese in 1996. The N1 came from a teal duck carrying a harmless H6N1 strain. Both pieces, scientists believe, finally came together in a quail, which provided essential proteins from an H9N2 virus.

It was only a matter of time before it showed up in a Hong Kong live poultry market.

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Nine years later and 5,000 miles away is Chevak, Alaska.

The modest village is in the Yukon-Kuskokwim Delta in the southwestern portion of the state along the Bering Sea. The gray land is threaded by rivers and estuaries, making it an attractive breeding ground for migratory birds. The ground is a thick, squishy mud, and temperatures rarely reach 60 degrees in the summer. Most of its 816 residents are Eskimos.

Last year marked the first time researchers traveled to places like Chevak in search of H5N1. In July, Runstadler flew to the tidal flats to spend a week testing black brant geese for signs of H5N1. The birds were molting their feathers, making them easier to catch.

The researchers can't tell if an individual bird came from Asia, but they know that some of the species they are monitoring -- including brant geese, pintails, mallards and godwits -- migrate from the other side of the Pacific.

"It's good to get anything we can because we're starting from a knowledge base of essentially zero," Runstadler said.

Scientists surmise that migratory birds carrying H5N1 in their guts have transported the virus far from its origin in southern China as they traverse the vast aerial interstates that crisscross the globe. The eight major flyways cover nearly every speck of land on Earth -- with the exception of Antarctica -- and they all overlap.

Infected birds from China flying along the Central Asia flyway could have mixed with birds from the neighboring East Africa-West Asia flyway, bringing the virus to Kazakhstan in August. From there, it's an easy jump to the Black Sea-Mediterranean flyway, which encompasses Romania, Turkey and Croatia -- three countries where birds tested positive for H5N1 in October.

The East Asia-Australia flyway, which stretches from Australia to Siberia and over to Alaska, would be the likely culprit for bringing the virus to North America. Once in Alaska, migratory birds could pick it up and carry it south along the Pacific Americas flyway or the Mississippi Americas flyway, which encompass most of the Western Hemisphere.

There is no known way to stop it now.

Government officials thought they could contain the spread of H5N1 by culling millions of farm birds. That notion now seems quaint, as wild birds have become a permanent natural reservoir for the virus.

Detecting the first signs of H5N1's arrival here will give farmers and public health officials crucial time to ready their defenses, said Dr. John Clifford, chief veterinarian at the U.S. Department of Agriculture.

It is a painstaking vigil.

This summer, in the marshy land of Chevak, Runstadler and his fellow researchers corralled brant geese into a temporary pen. Then he began collecting samples from each bird's hindquarters with the gentle rub of a Dacron swab. The swabs were deposited in ethanol to preserve any virus that might be present.

The weeklong effort produced samples from more than 1,000 migratory birds. Similar efforts around the state yielded 4,000 more samples from mid-May to late September.

About 500 of the samples have been screened so far. More than 15% have tested positive for avian influenza.

So far, none of the strains are H5N1.

The birds, however, will return in the spring.

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(BEGIN TEXT OF INFOBOX)

On the move

History of influenza

412 BC - Hippocrates describes a disease that is probably influenza.

1580 - First recorded pandemic: An outbreak begins in Asia and spreads to Europe, Africa and the Americas.

1918 - H1N1 influenza: A pandemic known as the Spanish flu kills up to 50 million people worldwide.

1957 - H2N2: An Asian flu pandemic begins in China. It kills 70,000 people in the United States and up to 2 million people worldwide.

1968 - H3N2: Hong Kong flu pandemic kills 34,000 people in the United States and about 70,000 people worldwide.

1997 - H5N1: Bird flu infects 18 people in Hong Kong, killing six. The outbreak is the first known case of an avian flu being transmitted directly to people. Birds are slaughtered.

2001 - H5N1: Strains resurface in Hong Kong live poultry markets. Birds are slaughtered. There are no human cases.

2003 - H5N1: The virus begins spreading throughout Asia, causing at least one death in Hong Kong.

2004 - H5N1: Human infections reported in Vietnam and Thailand.

2005 - H5N1: Human infections also reported in Indonesia, Cambodia and China.

2006 - H5N1: Turkey reports first human cases outside of Asia.

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Sources: American Scientist, Institute of Medicine, Lancet, U.S. Centers for Disease Control and Prevention, Wetlands International, World Health Organization

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Graphics reporting by Rosie Mestel, Tom Reinken and Karen Kaplan

For The Record Los Angeles Times Saturday January 14, 2006 Home Edition Main News Part A Page 2 National Desk 1 inches; 67 words Type of Material: Correction Bird flu -- A front-page article Tuesday about avian influenza said 8 million Spaniards died from a virulent flu strain in May 1918. The number was based on a 1918 report in the British Medical Journal that was never substantiated. The true figure is unknown, but modern estimates place the death toll from the so-called Spanish flu that year at as many as 50 million people worldwide.
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