From the archives: Bird flu outbreak poses global threat

This article was originally published in Newsday on March 6, 2005

The disaster could begin with little more than an infected duck, a promiscuous virus and a well-timed sneeze.

Where it would end remains less certain, but the growing alarm over a disease known as avian influenza owes much to the peculiar properties of a virus quickly expanding its domain far beyond birds.

On its surface, each strain of influenza virus is stippled with different combinations of two main proteins, abbreviated H and N.

Some of these combinations are seen only in wild birds or poultry. Many produce only mild symptoms. But the H5N1 strain that has killed at least 46 people within the past 14 months and forced the slaughter of more than 140 million birds hadn't previously been seen in humans for at least a century, meaning that no one alive today is immune.

It is, scientists say, one of the worst combinations of all.

"I would say in my lifetime, this is the most threatening time I've ever seen, and I've spent my lifetime studying the flu," said Robert Webster, head of virology at St. Jude Children's Research Hospital in Memphis.

Webster, an avian influenza expert who has long warned of the potential for a worldwide flu epidemic, or pandemic, now finds himself surrounded by a growing chorus of agreement.

Dr. Shigeru Omi, the World Health Organization's Western Pacific regional director, sounded one of the latest alarms at a conference last month in Ho Chi Minh City, Vietnam, to assess the threat of a viral disease commonly called the bird flu.

"We at WHO believe that the world is now in the gravest possible danger of a pandemic," Omi told attendees, echoing comments earlier in the week by Dr. Julie Gerberding, director of the Centers for Disease Control and Prevention. Speaking in Washington, D.C., at the American Association for the Advancement of Science's annual conference, Gerberding characterized the virus as "the most important threat that we are facing right now."

She and other CDC officials later sought to downplay suggestions that the world is on the brink of a pandemic, stressing that no evidence has emerged to suggest that the H5N1 strain has achieved the ability to spread easily from person to person - a vital step in its transformation into a swift and proficient killer.

In January, the WHO released a 62-page report on the threat, commending researchers, health officials and governments for improving preparations for such an eventuality.

But the report and independent experts suggest there is still ample reason to be worried about a disease that once did little more than ruffle a few feathers in domestic chickens.

"I'm very concerned, because the virus is endemic in a large part of Asia and has the possibility of either mutating or recombining, re-assorting with human influenza viruses," said Dr. Thijs Kuiken, a veterinary pathologist at the Erasmus Medical Center in Rotterdam, the Netherlands.

The longer the H5N1 virus remains in circulation, health officials say, the graver the risk for catastrophe. In rural parts of Asia, poultry and other livestock are often housed together on land next to homes, meaning that human and avian flu strains could join forces to create a potent global assassin.

Most researchers have been loath to make death toll predictions for a potential H5N1 pandemic, citing the sheer unpredictability of the virus. But estimates have ranged from "best-case scenarios" of 2 million to 7.4 million, to "considerably worse" scenarios surpassing the estimated 1918-1919 pandemic toll of 40 million from "Spanish flu."

For a flu outbreak to become a pandemic, three conditions must be met:

A type A virus strain must arise with H and N proteins to which few, if any, people have acquired immunity.

Second, the virus must infect humans and be able to replicate easily - the process that leads to a severe disease.

And third, the virus must be easily spread from person to person in prolonged chains of casual contact.

The H5N1 strain already has achieved the first two requirements. When, or whether, it will meet the third remains anyone's guess, but Webster said the world needs to "get our act together" - and soon.

"It's going to happen sooner or later, probably sooner rather than later," he said. "The virus is making these changes, it's going from being pathogenic in domestic, terrestrial poultry to becoming pathogenic in waterfowl, and it's spread to tigers and domestic cats." The latter two animals were previously thought to be resistant to the virus, but research has shown that they too can fall seriously ill. Webster's group discovered they could experimentally infect ferrets with the virus as well, rapidly causing diarrhea, hind leg paralysis and death.

"Everything it does is rather frightening," he said.

Until 1997, only two people had ever fallen ill from the bird flu. In that year, however, a formerly mild version of the H5N1 strain mysteriously emerged in Hong Kong as a deadly disease - for both chickens and humans. Within a matter of weeks, 18 people had fallen ill.

Six of them died.

A slaughter of the city's 1.5 million birds over three days has been credited with averting a potential human health disaster.

But the virus didn't go away.

Beginning in late 2003, a more deadly version again washed over Asia, leading to poultry outbreaks in eight countries and a combined culling of at least 140 million birds in a desperate effort to control the outbreak.

But unlike in Hong Kong, those efforts may have come too late. Health officials are increasingly convinced that the virus is entrenched in poultry populations scattered throughout Thailand and Vietnam.

Over the past 14 months, successive waves of the H5N1 strain have unofficially infected 66 people, all but one in Vietnam or Thailand. So far, 46 of them have died, for a mortality rate of 70 percent. But recent reports have raised concerns that health officials may be missing even more cases.

Although no evidence of efficient person-to-person spread has emerged, experts believe some patients may have fallen ill not from contacting infected poultry but from prolonged exposure to an infected relative.

And there's something else: Last year, the average age of bird flu patients in Thailand was 20. In Vietnam, it was 15.

Close contact between poultry and children or young adults may be one explanation. But doctors also are seeing an exaggerated immune response in some cases - meaning a robust immune system may go overboard, worsening the illness.

"Why are some people susceptible? There has to be a genetic basis for it, but we don't have any knowledge of that yet," Webster said.

Last summer, Kuiken and other scientists at the Erasmus Medical Center made another surprising discovery. By infecting domestic cats with the H5N1 strain, they induced severe viral pneumonia in many of cats, as well as limited cat-to-cat spread of the virus.

Studies confirmed that leopards and tigers in a Thai zoo and reserve also had fallen ill after eating infected chicken carcasses - an indication the virus "produces disease in a greater range of species" than previous strains, Kuiken said.

Yet another species has been fingered as a "silent" viral reservoir: ducks.

"The ducks, the ducks, the ducks are the key to the whole damned thing," Webster agreed. Ducks, which are "everywhere in the south of Vietnam,"he said, have been shown to excrete large amounts of the virus through their feces, compounding the risk to humans who come into contact with it. Unlike chickens, however, most ducks have been symptom-free, meaning they could pass on the infection undetected.

If there is hope for dealing with the gathering threat, Webster said it may come from the place where it all began. Last year, he said, "there was no bird flu in Hong Kong, and it was all around it. They've cleaned up their act."

Domestic chickens are now vaccinated and twice a month the markets close for a thorough scrubbing. Webster said the efforts are a model for other nations.

"And they have had no bird flu, but unfortunately, the world hasn't shouted about that fact," he said.

Elsewhere, contingency plans are gathering steam. In the United States, health officials are scrambling to test an experimental vaccine against the H5N1 strain, based on an inactivated version of the virus from a Vietnamese patient. Clinical trials beginning this month will involve 4,000 volunteers.

But even if a vaccine proves safe and effective, how easily can the vaccine industry meet a global demand that could exceed hundreds of millions or billions of doses?

In the event of U.S. shortages, officials say an ethics panel to the CDC may determine who would receive vaccines first.

Other tests by the CDC have shown that the H5N1 strain is resistant to two of the four drugs cited as potential prophylactic or treatment options - leaving the less readily available and more expensive compounds oseltamivir and zanamivir (marketed as Tamiflu and Relenza, respectively) as the best options in a national stockpile.

So far, the United States has stockpiled enough oseltamivir for about 2.3 million people.

For now, experts say, the best approach may be to prepare for a reality that many foresee in the near future. In a post-9/11 world, the idea of imminent danger and pre-emptive action is finding a more receptive audience.

At a bio-security conference earlier this week in Lyon, France, Webster said he told attendees: "The greatest bio-terrorist at the moment is Mother Nature brewing something."

No one, he said, disagreed.

The avian flu

In 1997, a strain of bird flu known as H5N1 emerged in Hong Kong, killing chickens-and six humans. In the past year, the same viral strain has infected humans and poultry alike across Southeast Asia, raising fears of a global flu epidemic, or pandemic, that could kill millions.

WHAT A PANDEMIC REQUIRES:

1. A virus emerges to which the general population has little or no immunity.

2. The virus can replicate in humans and cause serious illness.

3. The virus can be easily spread among humans.

The current avian strain has met the first two criteria.

A few humans are believed to have spread it to other humans, but there is no evidence that the virus is easily spread.

MANY POSSIBILITIES

Flu viruses get their names from two sets of protein spikes that jut from the surface of the virus - the hemagglutinin, or H, spike and the neuraminidase, or N, spike.

There are 15 H subtypes, designated H1 to H15, and nine N subtypes, designated N1 to N9. The current avian flu strain is made up of H5 and N1; hence, the flu's name is H5N1. The unpredictability of how the two protein spikes will match up is why creating a vaccine causes headaches for health officials.

PANDEMICS AND ANIMALS

Flu pandemics often begin in Asia because many people tend to be in close contact with their food sources, meaning the virus is more easily transmitted. Humans can get the flu from animals by eating raw meat, handling the animals or coming into contact with their feces.

1918-19

The "Spanish flu'' pandemic killed 40 million people or more worldwide, including more than 650,000 Americans. The origins of the strain, known as H1N1, remain hotly debated.

1957

The "Asian flu'' pandemic killed an estimated 2 million people or more globally and about 70,000 in the United States. That milder strain, H2N2, is thought to be the product of a recombination between separate human and avian flu strains.

1968

The "Hong Kong flu'' pandemic killed about 1 million people worldwide and 34,000 in the United States. The strain, H3N2, was again likely formed through a recombination of human and avian strains.

The next one?

The avian flu strain currently in Asia, H5N1, is known to have infected such animals as chickens, ducks, hawks and other wild birds, and tigers and leopards. In experiments, scientists have successfully infected cats and ferrets. Most infected ducks have shown no symptoms, meaning they could spread the virus unbeknownst to human observers.

THE FLU VIRUS

NA - Neuraminidase

HA - Hemagglutinin