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Blunderov
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RE: virus: The Silence of the Chickens
« on: 2004-11-09 01:56:19 »
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[Blunderov] A long article but well worth the read. Once again, the
recurring theme; politics takes precedence over science.
Best Regards.

November 7, 2004
The Flu Hunters
By GRETCHEN REYNOLDS

Dr. Keiji Fukuda is, by nature, composed. His voice is soft and
measured. He rarely employs exclamations, never swears.

At 49, Fukuda, the top influenza epidemiologist at the Centers for
Disease Control and Prevention, looks distinguished in a scruffy,
academic way and reassuring. His face is unlined. His gray hair is
close-cropped around his ears, making the top of his head rise like a
pale dome above the timberline. He smiles often and gently. So when
Keiji Fukuda admits to being as concerned as ''I have ever been,''
people who know him start really worrying.

In the past year, Fukuda has watched from his office in Atlanta as
events overseas have seemed poised to spiral out of control. Between
January and the end of October, 32 people have died from avian influenza
in Vietnam and Thailand. Tens of millions of chickens have succumbed.
Millions of others have been slaughtered. More nations have admitted to
outbreaks among birds in more provinces than would have been conceivable
even 18 months ago. All of this, Fukuda says, ''certainly increases the
possibility'' of a much larger outbreak of avian flu among people.

Dr. Tim Uyeki, 45, one of the top epidemiologists who works with Fukuda
at the C.D.C., is more excitable and blunt than his boss. ''You have the
ingredients in Asia right now for a public health disaster,'' he says.
Of long-term concern to him and Fukuda is that the region may be brewing
a worldwide flu pandemic. ''It's a mess,'' Uyeki says. He is quiet. ''It
would be nice,'' he continues, choosing his words with care, ''to be in
the field, to be in Asia, to see firsthand what is going on.'' But he
and the other C.D.C. scientists must be invited by other nations to help
in disease investigations. Some countries prefer to do the work
themselves. Others would like to keep the news of any outbreak off the
world's radar screen, a difficult feat in the presence of a large
international medical team.

Uyeki and Fukuda are 21st-century epidemiologists, and their job is not
an easy one. They see themselves first and foremost as scientists. But
in a globalized world where peripatetic germs hitch rides in the lungs
or luggage of unwitting airline passengers, where sick chickens in Asia
can threaten to topple third-world governments, where the role of
politics and money can obscure the free flow of medical information,
they cannot do their job -- preventing the spread of deadly flu viruses
-- by being scientists only. They are medical monitors sitting at their
desks, reading e-mail messages, Web sites, faxes and reports in order to
track the varieties of flus in the United States and around the world.
They are investigators who are prepared to jump on a plane to an
outbreak site -- if invited -- and delicately interview the families of
flu victims, trying to piece together how and why particular people fell
ill and what the implications are for the rest of us. And less formally,
they are diplomats, lobbyists, policy advocates, pressing for measures
that governments would often prefer not to embrace.

While the United States has grappled this fall with a shortage of the
human flu vaccine, Fukuda and Uyeki have been preoccupied with broader
and more haunting questions. They and the 70 or so other members of the
C.D.C. influenza team are the nation's first -- and in a worst-case
scenario, last -- line of defense against an influenza pandemic. And as
is inherent in such a task, they act from a position of pessimism. They
live with the specter of the 1918 flu pandemic, which killed somewhere
between 20 million and 50 million people around the world and 500,000 in
this country, and with the assumption that another pandemic is
inevitable.

In their eyes, the vaccine shortage will almost certainly not be what
history remembers about influenza from this year and next. The vaccine
situation will probably be transitory. It is a matter for lawmakers and
regulators. Fukuda, Uyeki and their colleagues fear that influenza
itself won't be so amenable. Events in Asia, in particular, are
escalating almost daily, with more human deaths, more different species
becoming infected and more questions arising about how the virus there
behaves. At the same time, some governments in the region are remaining
closemouthed about what is happening within their borders. This
reticence exponentially increases the difficulty of epidemiologists'
work. Flu hunters are expected to forestall any big outbreak. But Fukuda
and Uyeki's real fear is that they might not know one is starting until
it is too advanced to stop.

''It's spooky,'' Fukuda says, the verbal equivalent for him of rushing
about shouting.

September was one of those periods that remind scientists why influenza
both compels and worries them. Early in the month, a death announcement
appeared on the World Health Organization's Disease Outbreak News, a Web
site that typically contains the first official report of unusual flu
cases. Fukuda and Uyeki dutifully scanned it. A young man died in
Thailand the previous day of avian flu. ''The case,'' the posting read,
''was an 18-year-old male who'd been exposed to sick chickens.''

In a follow-up posting that day, on ProMED-mail, the infectious-disease
world's invaluable blog, things got more intriguing. The posting
originated from the Thai Department of Disease Control and said that the
boy had ''had very close contact to . . . fighting cocks by carrying and
helping to clear up the mucous secretion from the throat of the cock
during the fighting game by using his mouth.''

That is, the young man -- in a move not uncommon in cockfighting circles
-- had cleared the cock's airway by sucking his rooster's beak and then
swallowing the spit and mucus. ''That was a risk factor for avian flu
that we hadn't really considered before,'' Uyeki told me dryly when we
discussed the recent outbreaks this fall. Few people in the world know
as much about how influenza can be expected to behave as Uyeki and
Fukuda. The two have been on a dozen or so field investigations, jointly
and separately, to Hong Kong, Vietnam, Madagascar, Mongolia, the
Philippines and China, as well as aboard cruise ships and at hospitals
and nursing homes here in this country. Scott Harper, an epidemiologist
who works with Fukuda at the C.D.C. said that Fukuda is a brilliant
scientist. ''His knowledge of influenza epidemiology is unparalleled.''
Fukuda and Uyeki feel a proprietary fascination for the disease that
even their colleagues at the C.D.C. call ''your bug,'' especially when
it does something novel.

In its announcement about the teenager's death, the Thai Department of
Disease Control said that the national and local health authority in the
province where the young man had lived would study the case. Village
chickens would be slaughtered. The young man's neighbors and the doctors
and nurses who had cared for him would be put under close observation in
case he had passed the infection to them. Another local teenager, whose
fighting rooster had become sick and died, was hospitalized with vague
symptoms. (He didn't have the flu -- just understandable anxiety.)

Uyeki, who has been in the C.D.C.'s influenza branch since 1998, has an
18-page C.V. of a senior scientist but the heavy, beveled black bangs,
darty energy and wardrobe of a bright undergraduate. A practicing
pediatrician as well as an epidemiologist (many of those at the C.D.C.
have M.D.'s and graduate degrees in epidemiology or public heath), he is
constitutionally restive, speaking in fast, emphatic sentences.

Uyeki is the point man for day-to-day updates on the avian flu in Asia.
He reads and files the postings and checks in with friendly colleagues
on the ground overseas, one of the benefits of having done fieldwork in
several countries. ''I know the scientists in many parts of Asia,''
Uyeki said. ''They know me.''

Epidemiology is a beat-reporter's science. Those who are good at it
collect tidbits of information and unofficial rumors. They cultivate
confidential sources. They squirrel away everything. But when it came to
Thailand this fall, Uyeki felt stymied because he had never been asked
to do fieldwork in the country and because the avian flu is such a
potent issue there. Until early this year, Thailand was the world's
fourth-largest chicken exporter. Its industrial poultry producers employ
hundreds of thousands of people. But after it reported on Jan. 23 to the
World Organization for Animal Health that avian influenza had been
detected in a poultry flock, nations began to bar the import of its
birds. There were calls for the prime minister and other officials to
resign.

As the weeks went by this fall, the Thai government did not release any
further report on the cockfighter's death. The previous winter, as Uyeki
was well aware, people in Vietnam and Thailand had fallen ill at about
the same time as had chickens. Within the space of two months, at least
35 people had developed severe respiratory distress; 23 had died.

But the number of new human infections mysteriously sputtered and then
ceased. The last death came in Vietnam in March. ''There had not been
any obvious sustained person-to-person transmission'' during this
outbreak, Uyeki said, a requisite for a pandemic to take hold.

Then in June, Indonesia reported an outbreak of avian influenza in
poultry flocks to the World Organization for Animal Health. Vietnam and
Thailand followed in July. China, Cambodia and Malaysia joined them in
rapid succession. That same month, the virus popped up again in humans
as mysteriously as it had disappeared before. There were reports of
human infections in Vietnam, with the first death in early August. Two
more deaths followed soon afterward in Vietnam, and then the
cockfighting boy in Thailand died on Sept. 8. Uyeki craved details.
''Anytime there's evidence of a developing outbreak, you want to know as
much as possible,'' he said.

On Sept. 27, Thai health authorities reported that a 26-year-old woman
living in the Bangkok suburbs had, to all appearances, contracted avian
flu from her 11-year-old daughter. The girl, who had been living in a
village with her aunt, had helped to dispose of sick chickens. She had
then become ill and been hospitalized. Her mother had rushed to tend to
her child. She stayed with her, holding and comforting her. The girl
died, and the day after her funeral, the mother returned home, started
to feel ill and, after severe illness, died. The girl's aunt, who had
also been with her at the hospital, got sick too, but she survived. Both
the mother and aunt tested positive for avian influenza.

Uyeki avidly read the case postings on ProMED. He itched to be doing the
legwork himself, but settled for calling and e-mailing colleagues. Soon
he found out the exact dates of the onset of disease in the daughter and
mother and of their hospitalizations and deaths. He learned that the
mother had spent about an hour in the village before going to the
hospital. Had she picked up a chicken, touched a knife used to slaughter
a chicken, walked through a chicken pen? Was there any way she could
have contracted the disease from sick poultry?

''Possible person-to-person transmission grabs our attention,'' he said.
When a virus is able to spread easily between people, it also can move
rapidly around the world. It could arrive in the United States within
the space of one long airplane ride. (Uyeki and his colleagues were
called repeatedly last flu season and over the summer when travelers
from Asia arrived in the United States with flu symptoms and were
suspected by state health departments of having avian influenza. None of
them did.) ''It's something that needs to be thoroughly investigated,''
Uyeki said.

Both Uyeki and Fukuda joined the C.D.C. through its Epidemic
Intelligence Service. This program brings in eager physicians, nurses,
veterinarians and Ph.D.'s who want to be involved in public health and
sends them into the field. Uyeki, whose appointment was in the influenza
branch, spent his first two months on the job in 1998 investigating an
outbreak of flu among thousands of tourists in Alaska and the Yukon
territory.

After Fukuda's time with the epidemic service -- his stint, like
Uyeki's, was two years -- he studied chronic fatigue syndrome and other
illnesses among gulf-war veterans. This was fascinating and worthy work,
but his primary interest was in disease control.

When a full-time slot opened in the influenza branch, Fukuda was hired.
This was in 1996. Until that point, influenza had been a backwater in
infectious disease. ''Not many people were interested in influenza in
1996,'' Fukuda said. ''Diseases like H.I.V. had the world's attention.''
That was about to change.

A year after starting in the flu branch, Fukuda was completing a
clinical rotation at a hospital in San Francisco, which he does every
year to keep his medical skills up to date. It was now August 1997. ''I
got a phone call'' -- saying a 3-year-old boy had tested positive for
avian influenza in Hong Kong -- ''a highly unusual event,'' he recalled.
''I thought, Wow.''

To understand how staggering this news was, you must understand
something of the physiognomy of flu. Influenza viruses are divided into
three types: A, B or C, depending on the virus structure. Humans can be
infected with all three, although C-class flus are uncommon and
influenza B doesn't usually cause severe illness except among children.

Influenza A is the monster, in both animals and people, causing, by and
large, the most virulent illness. Type A influenzas (unlike B's or C's)
have multiple subtypes, identified with maddeningly cryptic names: H3N2,
H1N1, H7N2. The ''H'' is for hemagglutinin, a spiky protein on the
surface of the influenza molecule. In human flu viruses, the spikes of
hemagglutinin connect, like sinister Legos, with matching receptors on
the outside of healthy respiratory-system cells. The virus then melds
with the healthy cell and begins replicating. Neuraminidase, the ''N''
in the flu name, another protein, uncouples the virus from its host,
tearing the cell membrane and allowing the progeny to escape, killing
the cell. Loosed, they start repeating the process deeper and deeper
into the respiratory tract.

The little boy in Hong Kong seven years ago had a type A influenza,
H5N1, a bird flu. H5N1 wasn't unfamiliar to flu watchers. It had been
isolated in wild birds as far back as the early 1960's. But this avian
flu had never been known to infect a human being. An avian flu can
occasionally jump from a bird to a person. Nature is fluky. The
resulting infection is a nasty shock for the patient, but not much of a
threat to the rest of us.

To cause a pandemic, an entirely new human influenza subtype must
emerge, one that most people would never have been exposed to and would
not have immunities to. This flu also must be able to be transmitted
efficiently from person to person. In recent history, three main types
of influenza A have circulated freely in humans. (Many more exist in
birds.) Each of these strains caused a pandemic when they were
introduced into the human race. The catastrophic 1918 Spanish flu
pandemic was caused by H1N1. The 1957 Asian flu pandemic, which killed
70,000 in the United States, was brought about by H2N2. And the 1968
pandemic of Hong Kong flu introduced H3N2. That outbreak killed about
34,000 people in the United States.

Science doesn't quite understand how a nonhuman flu virus adapts and
becomes a human flu, and why more, in fact, don't. But they do suspect
that it is a process of gene swapping. If an avian flu infects a person
who, coincidentally, suffers from a human flu, the two bugs might
exchange genetic material. The resulting virus could be essentially
avian, but possessing genetic components of the human flu that would
allow it to be easily transmitted from person to person. This is how the
Asian flu and the Hong Kong flu pandemics began.

Shortly after hearing about the 3-year-old boy with the avian flu,
Fukuda took part in an intense conference call between the C.D.C. and
the Hong Kong health department. He was, he said, trying to be
judicious, to keep his anxiety and slightly guilty but undeniable
excitement in check. ''There was a surge of adrenaline,'' he said. ''But
at that point, we had one case. It was an extremely interesting case,
but only one.'' He and several C.D.C. colleagues soon left for Hong
Kong.

For an epidemiologist, fieldwork is grueling, grimy, sometimes dangerous
and captivating. It is also, when everything clicks, the surest way to
understand the progress of a disease and, in the best of circumstances,
to stop it cold.

When Fukuda arrived in Hong Kong, he studied the chart of the dead boy.
His had been a hard death, which shook Fukuda, the father of two young
children. The child had a breathing tube inserted down his air passage
and was in great pain. ''As I went over his chart, the case became very
unabstract,'' he said. ''It drove home for me how much suffering there
might be behind the numbers if this bug took off.''

Fukuda soon learned that chickens had been dying in the New Territories
region of northern Hong Kong. Routine testing of the poultry had turned
up H5N1 infection.

Delicately, Fukuda had his local colleagues talk to the boy's parents
and ask if they had visited the affected region lately or if they had
been to a live poultry market. ''This was quite difficult for
everyone,'' he said. ''The parents were still very, very upset, as you
can imagine.'' But they managed to confirm that there had been no trips
to the territories or to markets.

The boy had attended day care, however, and when Fukuda and some of the
Hong Kong scientists visited the school, they found that the teachers
had kept chicks as playthings for the children. Some of the birds had
died. None now remained, so no testing of the animals was possible.

Though Fukuda surmised that the boy caught the disease from a chicken
with H5, the epidemiologists never could establish with certainty how
the boy had become ill. There were many other unanswered questions too:
Why didn't other children get sick? Had this boy played differently with
the bird? At a different time? Fukuda returned home. ''There was a
sense, I guess, of incompletion,'' he said, ''of dissatisfaction and
some concern. It simply wasn't clear at that time whether this had been
a unique, transitory event.''

Then, three months later, an e-mail message arrived at the C.D.C. from
Hong Kong. There was another H5 case. The health authorities there asked
Fukuda and his colleagues to return. He readily agreed to go.

It was now early December. By the time Fukuda and a colleague arrived at
the airport, a second human case of avian flu had been confirmed in this
new outbreak -- then a third and a fourth. Fukuda and his team of seven
others from the C.D.C. set up a war room at the department of health.
Each morning, they would tally the new cases. The total kept growing.
''None of us were sleeping much,'' Fukuda recalled. ''The adrenaline was
really flowing at this point. A pandemic was suddenly not this misty
historical possibility. It seemed very current.''

The investigators mapped out the homes and haunts of the sick. There was
little overlap among the flu victims. The contagion didn't seem to be
passing from one person to another. The team checked in with its
agricultural counterparts. Veterinarians had found evidence of a recent
outbreak of H5N1 in dying chickens in one region of Hong Kong. But few,
if any, of the human patients had visited that region. Fukuda and the
others determined, however, that most of them had been to a local live
poultry market the week before falling ill.

On Dec. 28, a Sunday, Fukuda and senior department of health staff
members were summoned to an emergency meeting. For weeks, their
veterinary counterparts had been working on a frantic, parallel
investigation of their own, taking samples of bird feces and blood. The
findings, presented now, chilled those assembled. H5N1 appeared to have
spread throughout the nation's live poultry markets. ''You have to
understand this news within the context of the human-disease
situation,'' Fukuda said. Small outbreaks among poultry in May preceded
the first case. Now the infection was widespread.

''The solution was obvious but not easy,'' Fukuda said. Hong Kong should
slaughter every bird within its borders.

There was hesitancy among the scientists at the Sunday meeting. If
chicken markets were not the direct cause of the current outbreak -- a
possibility that couldn't be shrugged off -- killing poultry would be an
enormous economic waste. If, however, Hong Kong opted not to kill the
birds and the disease spread . . . this outcome hung in the air. ''When
looked at that way, the conclusion became clearer,'' Fukuda said.

The scientists decided to recommend that all poultry in Hong Kong be
slaughtered. Government ministers were called. Remarkably, they didn't
balk. Within hours, preparations started. Poultry markets were shut down
and disinfected. Culling began the next morning and was completed in
three days.

Overnight, new human infections ceased. ''I remember it as the most
satisfying investigation of my life,'' Fukuda said.

But five years later, everything would be different. In early 2003,
Fukuda and Uyeki began hearing rumors from colleagues in Asia of people
in southern China falling ill with a mysterious respiratory illness.
China's health ministers didn't confirm the outbreak at first. Not until
many people had died did officials report to the World Health
Organization, saying the country was experiencing an outbreak of what
seemed to be a mild type of pneumonia.

Soon after, the respiratory illness cropped up at a hospital in Hanoi.
In March of that year, Uyeki went to Vietnam as the C.D.C.'s top
representative on a W.H.O.-led outbreak team, after that country
urgently requested that a group study the unknown pathogen quickly
spreading through the hospital. Many at the C.D.C. and elsewhere
believed it was flu and possibly H5N1. (Uyeki wasn't among them, he
said. He always thought the incubation period and symptoms were wrong.)
As it turned out, it was Severe Acute Respiratory Syndrome. SARS, which
is not as contagious as human influenza, is a different virus.
Relatively few people became infected, except in hospitals and a couple
of buildings, which made the disease much easier to contain than flu
would have been.

The worldwide news media, however, repeatedly showed disconcerting
images of empty sidewalks and shops and of cities where people who did
venture out wore surgical masks. Tourism to the affected areas dried up.
Other countries halted or slowed imports from the affected nations. The
Hong Kong stock market fell.

''SARS,'' Fukuda said, ''was the next step up in showing how
consequential an outbreak could be.'' The virus became, he said mildly,
''interpolated with economic and political concerns.''

Fukuda is reflexively polite. But as he recalls the course of the SARS
investigation, his diffidence is tipped with acid. China did not
cooperate in a useful way with the international investigators, as its
own health ministers have since acknowledged. Chinese officials released
little information about cases among its citizens and declined to have
outsiders visit the affected areas. One frustration for modern
epidemiologists is that although viruses don't respect borders, doctors
must.

''When political considerations begin to outweigh the interests of
epidemiology,'' Fukuda said, ''it affects the quickness with which we
can respond and our ability to respond at all. It affects how much of
the response is built on science versus how much is dictated by other
concerns.''

As Uyeki said, ''We were in some ways very lucky that SARS was SARS.''
If it had been a more infectious disease, he explained, like a new
strain of human flu, and if the outbreak had developed in the same
fashion, with early denials, delayed release of information and
continuing confusion, it could have been disastrous. ''Pandemic flu
would have dwarfed SARS. It would have made SARS look like a vacation.''


Fukuda is less heated but agrees. ''The H5 outbreak in Hong Kong in 1997
caught everybody by surprise,'' he said. ''Politics couldn't keep up
with biology. So public health could respond. Now we've seen SARS, and
the world is sensitized in a way it wasn't before. It's increasingly
difficult to respond to infectious disease in a way that is
predominantly science driven. This is a big problem. We can use
political responses to deal with political problems. That is not the
best way to deal with biological events.''

He paused, then added, ''If we look at the recent avian flu in Asia, we
have a really good example of how much more complicated things are
now.''

On Dec. 29 of last year, Uyeki was at his desk in Atlanta when he
received an e-mail message that made him blink. It was a private,
informal request for advice from a virologist at the National Institute
of Hygiene and Epidemiology in Hanoi. ''We have some childrent [sic]
patients with respirator symtomes [sic],'' she wrote. ''We need to know
what's causative of it.'' Several children throughout Vietnam had become
so ill that they had been brought to a pediatric hospital in Hanoi.

Uyeki, as a pediatrician, has a particular interest in influenza's
effect on the young. It is one of his specialties, and in the months
just past, a number of children in the United States had died after
getting the flu. These distressing pediatric deaths had brought him to
the office that day during the Christmas holiday to read case reports.
When he received the e-mail message from Hanoi, he thought that Vietnam
might be dealing with the same virulent human flu and suggested that the
virologist test the youngsters for human influenza.

He might have urged her to test for bird flu had he had confirmation of
any substantial numbers of chicken deaths in the region. There had been
rumors circulating among influenza scientists that chickens were sick in
Vietnam, Thailand and elsewhere. But no Asian country, except South
Korea, on Dec. 17, had reported poultry deaths from influenza to the
World Organization for Animal Health. Reporting to this world
organization is strictly voluntary. It is also inevitably
self-punishing, triggering export restrictions.

Though Thai officials had admiited in regional newspaper stories that
about 68,000 chickens had died in one of its provinces, they blamed fowl
cholera, a disease that rarely makes people sick.

The silence from Asia didn't necessarily mean people were covering up
chicken flu there, Fukuda said (although that charge has since been
publicly leveled by journalists and local activists against highly
placed government officials in both Thailand and Vietnam). Most Asian
nations don't have sophisticated veterinary surveillance systems for
detecting and reporting sickness in animals. Perhaps, too, ''people
don't want to know,'' Fukuda said, ''because of the economic and
political consequences.''

Near midnight on Dec. 29, Uyeki received another e-mail message from the
Vietnamese virologist: ''Dear Tim . . . these childrens . . . have
fever, cough, difficult breath . . . some of them have diahrea [sic]
after few days of onset and died quickly.''

This was the first he had heard of deaths. Uyeki pressed her again to
test further for human flu.

On Jan. 8, Vietnam reported for the first time that it had cases of
avian flu in chickens, some of which were thought to have occurred as
early as Dec. 27. Uyeki shipped the virologist specialized tests to
check for a wide variety of influenza A subtypes, including H5. He also
sent masks, gloves and gowns, which are sometimes in short supply in
Vietnam.

A few days later, the children's illness was confirmed. They had H5N1,
avian flu. By then, 11 children and 1 adult had died.

It is impossible to say, in retrospect, whether a speedier diagnosis
could have saved lives, although the thought runs through Uyeki's mind.
Like many influenzas, H5N1 can be treated with a new antiviral called
oseltamivir, though it is still unclear exactly how effective the drug
will be against this virus. But Vietnam has limited supplies of
oseltamivir. And it is thought that to be effective, the drug must be
administered within 48 hours of a person's first symptoms. Many of the
children were from outlying provinces. By the time they arrived at the
hospital in Hanoi, they had been sick for days. Many worsened and died
rapidly. Had doctors known what to look for, perhaps some of them could
have been helped or, at least, their suffering eased.

In any emerging outbreak, as Uyeki points out, there are two levels of
medical concern. The first is for those patients who are falling ill at
the moment: What can be done for them? The other is for the broader
public: What is this bug? How does it move? Is it doing anything
scientists wouldn't expect? Could it explode into a pandemic? To answer
any of these questions, epidemiologists must have full, accurate
disclosure about what, in effect, the bug is doing.

On Jan. 12, Japan reported to the World Organization for Animal Health
that it had found H5N1 in one flock of hens. Eleven days later, Thailand
reported that nearly 9,000 chickens on one farm were infected with H5N1.
The following week, it reported that almost 10 million chickens were
infected. That same month, Cambodia and Laos reported poultry outbreaks.
China and Indonesia soon followed suit. Throughout that time, human
cases continued to stream into hospitals in Vietnam and then Thailand.

Vietnam asked the W.H.O. to help investigate. Outbreak investigations
have changed since Fukuda went to Hong Kong in 1997. On Jan. 18, when he
and Uyeki left for Hanoi, they and four C.D.C. colleagues were part of
an international team that over the next six weeks swelled to include
scientists from France, Japan, Sweden, Holland, England, the
Philippines, Switzerland and Vietnam. There were also many Vietnamese
bureaucrats interested in the investigation. ''In Vietnam, you have
national, regional, provincial, city, district and commune level
governments,'' Uyeki said. ''We had to work with all of them.''

The scientists were operating under the umbrella of the W.H.O. The days
when the C.D.C. would send investigators directly to another country are
gone. This change was driven by the realization that outbreaks are
global threats, and it has had a laudable outcome, Uyeki said: ''We can
pool so much knowledge.'' The new global approach, however, has also
ensured that investigations now tend to be unwieldy and politicized.

Soon after Fukuda and Uyeki arrived in Vietnam, they split up. Fukuda
remained in Hanoi, where he was ''providing input on how to do some of
the investigations and how to interpret events.'' He was also
negotiating various issues with his Vietnamese counterparts. He would
help brief government ministers worried about what the scientists were
finding (and how the information would be released publicly). He talked
with reporters. He conducted conference calls with top flu people in
Atlanta and Geneva, who, even from their far vantages, were eager to be
involved in operations and decisions.

Uyeki went into the field. He joined up with a W.H.O. team investigating
cases in the southern part of the country, where several of the H5N1
patients had been infected.

One of the first concerns of epidemiology is why a particular person
gets sick and not another. If you can identify the behaviors that put
someone at risk, you may be able to keep other people from repeating
them. Specificity matters. The inquiry is tougher when the flu victim is
young or dead. In Vietnam, they often were both.

The ramifications of their investigation were also a stumbling block.
Vietnam isn't a major poultry exporter. Chickens tend to be raised for
local consumption. If avian flu is confirmed in a village, all of the
local flocks are slaughtered and burned. Few villagers were eager to
talk about sickness and the town's birds.

''It's easy when you're on the outside to say these people should do
this or that,'' said Fukuda, who advised Uyeki during the investigation.
''It's different when you're actually in Asia and realize resources are
so limited. When people open their doors to us, it can have profound
impacts. You realize, boy, this is an ethical dilemma.''

But Uyeki pressed on. By the end of his stay, he and his colleagues had
uncovered poultry contact for most of the sick people in the region. A
13-year-old boy, for instance, had been secretly involved in
cockfighting. Another child, a girl, had bought a duckling from a
village vendor. The duckling died. The girl got sick but survived. Her
little brother, who also played with the duckling, didn't get sick. Why?
The team was only able to speak with the girl's grandmother, who said
that the girl buried the duck herself. That was about all they learned.

His most frustrating moment came in a dusty village. A 17-year-old local
girl had died of avian flu. Uyeki said he had hoped to interview her
mother quietly. But when he and his team arrived in full protective gear
(gowns, gloves, goggles and masks), bewildered villagers crowded around
to watch. At the dead girl's house, an elderly woman came to the door,
recoiled and started shouting. She demanded to be left alone. She yelled
to her neighbors that her granddaughter had not died of avian flu. She
died of natural causes.

''I can't blame her, but it did put us in a bind,'' Uyeki said.
Wandering up the road and speaking with wide-eyed neighbors, he and his
group learned that the girl had prepared chickens for eating after they
had become sick and died.

But their informants were too far removed to provide other relevant
details: Had the girl washed her hands? What kind of knife had she used?
Did she pluck the feathers? Did her relatives help?

Her family might have known. But the mother and grandmother never did
cooperate.

In mid-March, Uyeki left Vietnam. Shortly after, for reasons that he
didn't understand, the outbreak simply stopped. It would inexplicably
reappear in humans this summer and fall.

"It's troubling to me that we still don't really know much more about
this virus than we did in 1997,'' Keiji Fukuda said about the current
state of avian flu research. Fukuda's Hong Kong investigation proved
that close contact with sick poultry was a significant risk factor for
H5N1 infection. But there is still a lengthy list of fundamental
questions that he, Uyeki and their colleagues have about the H5N1 virus.


Why haven't poultry workers become ill, for one? Hundreds of thousands
of people labor in Asia's live-chicken markets or have helped in the
chicken-culling process. ''But hundreds of thousands of people have not
died,'' Uyeki said. ''Thousands haven't died. Thousands haven't even
been hospitalized. Most of us in influenza think that there have been
more cases and more deaths from H5N1 than we've heard about. But there
haven't been huge numbers of undiscovered deaths. That's not the kind of
thing that could be missed.''

''Where are the studies being done to learn more about'' transmission?
Fukuda asked wearily. ''There's so much ambivalence'' about studying the
virus.

A 1997 study of blood samples from poultry workers in Hong Kong found
that 10 percent had developed antibodies to H5N1.

In 2001, Vietnamese scientists, with help from Uyeki, took blood from
200 poultry workers. The data haven't been published or updated.

''We also don't know how the bird virus managed to infect so much of
Asia so quickly,'' he said. Not long ago, H5N1 was confined to Hong
Kong. But this year, it has spread through chicken flocks so far and so
pervasively that the possibility of eradicating it anytime soon seems
slight. As New Scientist reported, it is possible that the virus's
explosion may be a result of a misbegotten poultry vaccination campaign
thought to have been carried out after 1997 in China. In order for avian
vaccination to be effective, virtually every bird needs to be immunized,
using a vaccine matched as closely as possible to the circulating avian
flu virus. The work is extensive and demands standardized veterinary
science. Inadequate, unregulated vaccines can create flocks in which
some chickens may not look sick but may harbor the virus and, if
exported to other countries, may carry the virus with them.

Another possible explanation for the virus's march, Fukuda said, is that
migratory birds picked up the virus in one country and deposited it in
another. Or that people unwittingly moved it from place to place. It is
thought that under the right climatic conditions, the virus can live for
days or weeks in bird feces, even after an entire flock has been culled.
If pens and surrounding areas aren't fully disinfected, the flu may be
able to hitchhike out on workers' boots or truck tires.

Another factor might be that bird smuggling is lucrative business in
parts of Asia. Some of the living booty could have harbored H5N1. (In
late October, a man from Thailand was detained in Belgium after
illegally smuggling two eagles in his luggage; they were infected with
H5N1. Although he was hospitalized and tested and the birds destroyed
without any apparent spread of the virus, it is exactly this kind of
occurrence that keeps Fukuda and his colleagues awake at night.)

And there are other daunting questions: Is today's H5N1 changing?
Influenza viruses mutate constantly. They are unpredictable. But H5N1
seems to be altering in ways that are disturbing, Fukuda said. Another
influenza expert, Dr. Robert G. Webster, a virologist at St. Jude
Children's Research Hospital in Memphis, a top academic institute that
studies catastrophic diseases among children, worries about how the
affect of avian flu is changing in certain birds. In the past, waterfowl
lived with avian flu without getting sick. In 2002, they began to die of
it. Now the virus appears to have altered and birds appear to be living
with this more lethal strain. Webster's concern is that they may spread
it. (At the end of October, migratory birds in Russia were reported to
have avian flu; it was thought that they flew from Southeast Asia.)

The flu strain has also infected and killed house cats and pigs. This
fall, it swept through a zoo in eastern Thailand, killing more than 20
tigers. It has been shown to be transmittable cat to cat, which no avian
flu has ever been before. This movement into other species concerns flu
hunters for many reasons, but principally because it suggests that H5N1
is becoming highly capable of infecting mammals. Also, some of the
infected animals, like swine, can catch both human flus and avian flus
simultaneously. So the gene shuffling required to make the avian flu
better adapted to humans could take place within a pig.

Fukuda and his colleagues also worry that as H5N1 mutates, it will be
difficult to make an effective vaccine against it. In May, the National
Institutes of Health contracted with companies in the United States to
make an H5N1 human vaccine using the avian flu strain that killed people
in Vietnam last winter. The vaccine is scheduled to go into trials early
next year. But if the circulating H5N1 strain changes significantly
between now and then, the vaccine could be rendered less effective
before it's even ready.

In October, scientists in the C.D.C.'s flu labs genetically sequenced
the virus that killed the 18-year-old Thai cockfighter and found that it
remains structurally similar to the strain used in the vaccine. Fukuda
said that he feels reassured, at least for the moment.

Some scientists outside the C.D.C. are less concerned about H5N1
mutating into a true human flu. If it could have, it would have, they
argue. There may be something in its genetic structure, they say, that
makes the move impossible. Fukuda shrugged. ''That would be nice,
wouldn't it?'' he said. ''We have no way of knowing.''

The worst-case scenarios are what haunt Fukuda, Uyeki and their
colleagues. ''There's so much reluctance in Asia to look'' for avian
flu, Fukuda said, that the particular moment when an epidemic passes
into a pandemic may go unnoticed. ''It's quite possible for us to miss
the fundamental event.'' The first sustained human-to-human
transmissions might start insidiously, perhaps within one family whose
infections aren't immediately identified as H5N1. It could spread
through their village, reach the nearest city and balloon around the
world from there, leaving science no chance to catch up.

The impact would be unimaginable, said Fukuda, who imagines it all the
time. ''In the beginning of any pandemic,'' he said, ''we would have no
way of knowing if it were going to be mild or severe. There would be
panic.'' The United States had glimpses of the possible impact last
winter and again this fall, when word got out of vaccine shortages.
People overwhelmed their doctors' offices, even though last year's
influenza season turned out to be only moderately severe and this year's
season hasn't even really begun.

During an actual flu pandemic, America's emergency rooms would be
overrun by frightened people, Fukuda said. Everyone with the sniffles
would rush in, convinced they had been infected. It would be physically
impossible to hospitalize all the patients who developed acute flu.
''The United States medical system has been moving toward fewer hospital
beds, less unused capacity,'' Fukuda said. ''This makes sense from a
business standpoint.'' His voice drops to a softer, sadder register. ''I
come from a generation of doctors who didn't think of what we do as
first and foremost a business. But I suppose we're dinosaurs. We have to
operate in the real world where medicine is run on a cost-benefit
basis.'' Most hospitals won't add beds and ventilators in anticipation
of ''a surge in patients that may not come for months or decades,''
Fukuda said.

By the end of October, at least 44 people had been infected since late
last year with H5N1 in Thailand and Vietnam and more than 30 had died.
Additional infections almost certainly have gone undetected or
unreported. ''I find it very curious that only Thailand and Vietnam have
had human cases, when the virus is in so many other countries,'' Uyeki
said.

In early October, 20,000 chickens died in two southern provinces of
Vietnam, and farmers were reportedly urged to burn the birds' carcasses.
But officials in Hanoi denied rumors that the cause was bird flu. When
samples from one commune did show H5N1 in dead birds, a spokesman for
the Ministry of Agriculture told a Ho Chi Minh City paper that it was
''impossible'' that thousands of birds could have died in the area.
Vietnam had announced earlier that month that bird flu was under
control.

At about the same time, Thailand's prime minister declared (in response
to the case of the mother who appeared to have caught the disease from
her child) that his country would be free of avian flu by Oct. 31. To
achieve this, he said, he would send out almost a million Thai
volunteers to check every household in the nation for sick chickens or
people. The patients would be hospitalized; the flocks destroyed. Almost
inevitably the volunteers would tromp through village chicken pens. They
would stir up bird droppings. They would most likely not have protective
clothing. Uyeki winces at the thought.

Fukuda, for his part, dismisses the whole enterprise. ''Nice goal,'' he
said, ''silly declaration.'' As of the beginning of November, bird flu
was still widespread among chickens.

''As a scientist,'' Fukuda explained, ''I am fascinated by viruses and
by how to figure out what is going on. That's fun. But when I put on my
public health hat and ask, What is the best way to be prepared for bad
things? . . .'' He paused. ''Preparedness has to be done as part and
parcel of scientific investigations, and that is really vexing now.''

He would like to be setting up studies in Asia, he admitted. But, like
Uyeki, he has to be asked. The amount of virus circulating in the region
will likely increase as the weather cools.

''I am,'' Fukuda said, ''more anxious than I would like to be.''

Gretchen Reynolds is a writer living in Santa Fe, N.M. Her last article
for the magazine was about monkeypox.
Copyright 2004 The New York Times Company


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