a greater risk of bird flu infecting humans

[Guest guest]

Bird flu: the front line

Winter flu season has begun — and that means a greater risk of bird

flu infecting humans. Anjana Ahuja reports on the fight against a

killer

If you have the stomach for it, go to

www.who.int/csr/disease/avian_influenza/en/ and click on " frequently

asked questions " . Here, courtesy of the World Health Organisation

(WHO), you will find everything you ever wanted to know about H5N1,

the avian influenza virus — and plenty that you wished you didn't.

That the potential for H5N1 to fuel a human influenza pandemic " is

serious and has increased " ; that once a pandemic is under way it

is " considered unstoppable " ; that the best way to prevent one is to

eliminate H5N1 in birds but that this is seen as " increasingly

doubtful " .

There have been more deaths from bird flu — 73 — in 2006 than in any

previous year of the current outbreak, which kicked off in 2003. The

virus is creeping closer to Europe, with several countries —

Azerbaijan, Djibouti, Egypt, Iraq and Turkey — reporting human cases

for the first time this year. And now winter lies around the corner.

Cold weather brings a sharp rise in human influenza, heightening the

possibility that bird flu could infect a person already infected with

human flu. The resulting viral brew may permit H5N1 to snatch from

human flu the ability to jump from person to person (at present,

infection requires close contact with an infected bird). In WHO

parlance, the emergence of a transmissible virus takes us from phase

3 to phase 4, just two phases away from showtime.

But if you want to get a real feel for how the influenza community

perceives the threat, you have to join doctors and researchers on the

front line of the war against H5N1. For the past ten years Professor

Farrar has been director of the Oxford University Clinical

Research Unit at the Hospital for Tropical Diseases in Ho Chi Minh

City (formerly Saigon) in Vietnam. Many of the country's 93 confirmed

H5N1 cases have spent their final, suffocating hours here in the

hospital, built in the 19th century. Along with a Vietnamese medical

team headed by Dr Tran Tinh Hien, Farrar has cared for many victims

and is tracking the survivors.

" I don't necessarily share all the doom and gloom of the global

community, " he says, as we sit down to green tea in his large

office. " But I do think influenza is probably the only infectious

disease we know about that has the potential to cause a global

nightmare.

" There are very few infectious diseases that can affect everybody,

whether you're rich or poor, whether you live in San Francisco,

London, or Ho Chi Minh City, that can potentially kill a lot of

people, and that in reality you can't do much about. " For the moment,

H5N1 — or, to give its full name, HPAI A(H5N1): highly pathogenic

avian influenza virus of type A of subtype H5N1 — remains very much a

local nightmare, plaguing few people but tormenting them terribly.

The virus ravages the lungs — X-rays show the black of the lungs

replaced by a ghostly white cloud — to cause pneumonia. The virus can

also spread elsewhere in the body, even to the brain, to cause

multiple organ failure.

The pathogen appears to latch on to receptors in the lower lung. This

part of the body is relatively inaccessible — which may explain why,

even though the virus is endemic in poultry, human infection is so

rare. Human flu, in contrast, hooks on to receptors in the upper

respiratory tract, meaning that coughs and sneezes disperse the virus

easily. Scientists have warned that H5N1 could mutate and begin to

favour receptors in the upper tract, which would raise the threat

level.

" Avian influenza is a horrible disease, and people can deteriorate

incredibly quickly, " says Farrar, 45. " I remember one patient having

breakfast and talking and by the next morning she was dead. Seeing

fit healthy young people, and especially children, go from being very

well to very sick and then dying in a short space of time, is always

traumatic. " But to see Hn (a bird flu survivor, see opposite) coming

in every six months — she always remembers you and has got that

gorgeous smile — makes life worthwhile. She should have died. "

Each person that the virus infects — 256 worldwide since 2003, of

whom 151 have died — acts as a reservoir in which H5N1 can replicate

and mutate. What scientists fear most is that the virus maintains its

lethality — it kills around 60 per cent of people it infects — while

acquiring the capability to jump from person to person. Were this to

happen, the resulting pandemic could relegate the Spanish flu

outbreak of 1918 to the footnotes of history. The 1918 virus, H1N1,

killed only 1 per cent of those it infected. This is why clusters of

H5N1 victims within families or neighbourhoods cause palpitations

among scientists — fortunately, outbreaks within families have been

due to common exposure rather than to transmission between relatives.

Reassuringly, it is predicted that a rise in transmissibility will go

hand-in-hand with a decrease in virulence — as happened with later

milder pandemics, such as the 1957 episode of H2N2 that killed two

million people, and the 1968 outbreak of H3N2 that killed one

million. The logic is that a virus that wipes out its host also wipes

out its main vehicle for replication and transmission, so for a virus

to be " successful " — such as HIV, which is still with us 25 years

after emerging — it cannot be too virulent.

Farrar, though, sees no reason to smile: " The fear factor has gone a

little bit but my guess is that if a pandemic were to happen it would

happen explosively anyway. The virus would gain this

transmissibility, and if the climate was right, say in urban Manila,

or Shanghai, or Jakarta, then I think it would take off explosively. "

His unit has produced a wealth of research about H5N1, much of which

has earned global headlines. One of the most promising projects, a

collaboration between the unit and the National Institutes of Health

in land, involves isolating antibodies to H5N1 in the blood of

bird-flu survivors. Mice that are first immunised with these

antibodies and then infected with the virus survive the ordeal,

raising the prospect that the antibodies could form the basis of a

future vaccine. The Wellcome Trust, which is fast-tracking influenza

research and has funded much of the unit's work, has awarded the

project £385,000.

" We believe that part of surviving H5N1 involves individuals making

antibodies capable of killing the virus, " explains Dr Cameron

, who is leading the unit's involvement with the project.

But, says, antibodies are not the only key to survival: " It's

partly how soon you get medical care and Tamiflu, how much virus you

got initially, how old you are, and what your flu infection history

is. Although H5N1 is very different from human flu, parts of it are

very similar. So adults who have a long history of flu exposure could

potentially have an immune response that helps them to fight H5N1. "

The idea of mining survivors' blood for lifesaving chemicals dates

back to 1918, when doctors transfused the blood of flu survivors into

new patients. This roughly doubled the chances that the recipient

would survive. The technique was also employed on a smaller scale

during the Sars outbreak, although success rates are hard to pin

down. Latterly, however, the threat from blood-borne diseases such as

HIV and hepatitis B dampened enthusiasm for serum therapy. Some

British academics are arguing for British laws governing blood

products — tightened in the wake of " mad cow " disease — to be relaxed

ahead of any flu pandemic.

has isolated the H5N1-killing antibodies from the blood of

four survivors. He says: " We've shown that if you give these

antibodies to mice before they're infected,you can protect the animal

from what is rapidly lethal. "

The antibodies can quash the strain of H5N1 circulating in Vietnam

(this strain is also circulating in Thailand and Cambodia)but are

only partially effective against the other major strain of H5N1,

which has cornered China, Indonesia, Japan and South Korea. Any mass-

produced vaccine using this method would need to contain antibodies

to both strains.

The mice are also protected if the antibodies are given 24 hours

after infection. The researchers are now trying to gauge how long the

delay between infection and immu-nisation can be. The atmosphere in

the unit, says, is one of measured optimism: " It's difficult

to extrapolate from a mouse to a human, so there's doubt as to what

our experiments will mean for people.

" But it's exciting because although influenza has been a significant

disease for decades and the risk of a pandemic is a real one, we have

only one or two existing drugs. Our antibodies are another treatment

option for H5N1 that can be made on an industrial scale and

potentially very cheaply. "

Another of Farrar's colleagues, Dr Menno de Jong, has been studying

the impact of H5N1 on the immune system of patients. He recently

reported, in Nature Medicine, that the patients who died displayed a

particularly fierce immune response. Flu experts are now wondering

whether this ability to provoke an " immune storm " in the lungs

accounts for the virus' deadliness. Immunosuppressants might be

another therapeutic prospect.

De Jong, who helped to define the WHO's diagnostic criteria for H5N1,

is now trying to discover whether some individuals are immune to it.

Together with health officials in Ho Chi Minh City, he has collected

the blood of hundreds of poultry workers and individuals involved

with culling infected birds. It has been noted, anecdotally, that no

poultry workers or cullers have ever come down with H5N1. The plan is

to test the blood for H5N1 antibodies, to see whether these workers

actually encounter the virus but don't succumb to it.

Bleakly, De Jong believes that a human flu pandemic is inevitable,

although the culprit may not be H5N1: " If you look at history, every

now and then we do get a pandemic. My fear is that there is already a

pandemic under way in poultry. " Unlike chickens, ducks and geese can

carry H5N1 without ill effect; they are often described as Trojan

horses. Influenza researchers would like to see long-term strategic

planning for a human pandemic, plus basic research into the H5N1, as

a matter of urgency. A vaccine cannot be produced until a pandemic

strain emerges (to ensure the best match) but then, production

capacity is limited by the fact that the vaccine would need to be

cultured in chick eggs (and is thus dependent on egg supply). All the

while, H5N1 remains a moving target: it has already diverged into two

clades (families), with each family further split into various

subtypes.

Farrar says: " I'm not saying we will or won't have a pandemic, but if

we do, then we have to recognise that we don't have great vaccines,

we don't have the global capacity to produce them, and we have only

two drugs (Tamiflu and Relenza), neither of which is brilliant,

because you can't get them directly into the bloodstream. From a

public health perspective, that's not a great position to be in. "

He also points out that while an international effort is called

for, " pontificating in Washington or Geneva (the site of WHO's HQ) or

Oxford will get you only so far. It's local doctors who'll be seeing

patients, who will need to identify what's going on. If we rely on

people flying in from Geneva, we're stuffed. " The 2003 severe acute

respiratory syndrome (Sars) outbreak, which killed 774 people, was

popularly viewed as a dress rehearsal for a flu pandemic; alas, it

wasn't a realistic one. Sars sickened people immediately, making

victims easily identifiable, and containable, while they were

infectious. This allowed a prospective pandemic to be reined in with

relative ease (although not before losing the Asian economy an

estimated £22 billion; the World Bank reckons a flu pandemic could

cost 20 times that).

Human influenza is a stealthier foe, taking around three days to make

people ill, thus giving them ample time to infect others. Should H5N1

mutate into a transmissible form, this time lag between infection and

the appearance of symptoms may persist. In this case, the likelihood

of an H5N1 pandemic depends on how infectious the disease becomes.

Very roughly, if a person carrying H5N1 went on to infect two or more

people, it would be virtually impossible to contain a pandemic.

Mathematical simulations by Professor Neil Ferguson, at Imperial

College, London, shows that if each flu case infects an average of

1.8 people or fewer, a combination of containment strategies and pre-

vaccination offers hope. Ferguson has predicted that a pandemic could

cost up to 200 million lives.

Farrar, though, believes that such simulations depict an unreal

world; how likely is it, he asks, that people will overcome the

natural urge to flee a disaster zone and obey quarantine

orders: " What do you do then? Do you shoot them? Put them in

prisons? "

The death from Sars in 2003 of one of Farrar's friends, Dr Carlo

Urbani, has also brought home the risks of serving on the pandemic

frontline. Dr Urbani, the WHO's representative in Hanoi, was one of

the first specialists to raise the alarm on Sars. Tragically, Urbani,

who had been treating Sars-infected patients, fell ill on a flight to

Bangkok, and died in the city.

Farrar, who is married to Dr Christiane Dolocek, a researcher at the

unit specialising in typhoid and malaria, recalls: " Carlo persuaded

the hospital in Bangkok to close and he stayed in it and died. He had

three little kids and was a lovely guy. So when Dr Hien, a brilliant

doctor here, identified an H5N1 case in December 2003, it was

terrifying. I've got three little kids as well.

" When you're dealing with an unknown agent and you don't know whether

it's going to be like Sars, where a high proportion of healthcare

workers came down with it, and you don't know if you've got a

treatment for it, it's very scary. But how different is it from

Londoners living with terrorism? Here in Ho Chi Minh City, that seems

quite frightening to me. Things are always worse when you're not used

to dealing with them.

" Doctors here and elsewhere are treating people with far more

infectious diseases with bigger risks to themselves, like multi-drug-

resistant tuberculosis. Yes, people are frightened, but they don't

lose sleep over it. "

In the influenza community, it seems, there is neither hysteria nor

complacency — just a chilling acceptance that the risk of a pandemic

is a game of chance.

`I BOUGHT THE DUCKLING AS A PET' — A SURVIVOR'S STORY

Hn Diem Hong Nguyen, 11, puts one hand on her hip, thrusts her chin

out and sashays barefoot across her parents' living room. Then, all

charm and poise in her white ruched blouse and pink combat trousers,

she swivels round and sashays back. She does this under the eyes of

her proud parents — mother Chau, 38, and taxi-driver father, Drung

Ngoc, — and the watchful gaze of numerous Jesus figurines. As well as

her passions for drawing and painting, she explains through an

interpreter, she wants to become a model.

Hn and her 14-year-old brother Druong Suan live, like so many

Vietnamese city-dwellers, in a two-bedroom apartment in a narrow,

crowded alley with their parents and extended family. The living

room, which contains depictions of the Last Supper and photos of Pope

Benedict, opens on to the alley and provides welcome shelter from the

hammering downpours of southern Vietnam's rainy season. The living

room doubles up as a bedroom for Hn's aunt.

In December 2003 this pretty, slightly built schoolgirl was fighting

for her life in the city's Hospital for Tropical Diseases (HTD). She

caught H5N1 from a duckling that she bought outside her school. It

seemed an innocuous addition to the family's domestic menagerie: a

monkey, a dog, birds and fish. Hn says: " I bought the duckling as a

pet. It was so small and cute and I loved it. I fed it rice and

vegetables three times a day, just as my mother feeds me, and when I

came home from school, I played with it and hugged it. After a week

it got sick and died. I decided to bury it at the end of the alley

outside my house and went off alone with a dinner spoon. I felt sad

but I didn't cry. About three days later a neighbour asked me to dig

it up because it smelt. So I dug it up and went with two friends to

bury it in a nearby cemetery. I had wrapped the duck's legs in paper,

so that I didn't have to touch it. After burying it, I came home and

washed my hands without soap. "

The next day, Hn developed a fever. Her mother Chau recalls: " After

two days, the fever hadn't come down, so we took her to a paediatric

hospital. The doctor admitted her immediately. Within five days her

fever had worsened and she needed oxygen to breathe. I cried a lot. I

was so afraid that she would die. Doctors isolated her and told me

that her lungs were getting worse every day. They sent a blood sample

to the Pasteur Institute (in Ho Chi Minh City).

" One morning they told me that it was bird flu and that afternoon she

was transferred to the HTD. I was scared because I'd read in a

newspaper of bird flu in the north and the person died. The doctors

told me that my daughter was the first bird flu case in the south,

and that I should pray. I prayed every day before bed and we went to

church every day. I think God heard my prayers — that's why my

daughter survived. " Hn's father recalls seeing around 15 other cases

of bird flu during his daughter's recuperation; most died within

three days of arrival.

He remembers that his daughter was given Tamiflu an hour after

reaching the HTD. By this time she was unconscious, only one third of

one lung was functioning, and her immune system had almost shut down

(recent research suggests that this shutdown may have saved her life

as H5N1 appears to trigger a potentially lethal " immune storm " ).

Her father adds: " We had to wait 24 hours to see if Tamiflu worked. I

stayed with her the whole time and stopped working. Then we saw her

fever had come down — we were so happy that it was working. She had

half a Tamiflu pill a day and was fed intravenously. She stayed in

hospital for a month and three days. Ten days before she came home

the doctors said that there was no virus in her body and that she'd

survive. We just thanked God. I hugged the doctors. We thought we

were luckiest people alive. "

One of Hn's most vivid memories was that her father bought her a pair

of pink slippers to help her to walk again — she'd been bedridden for

so long. " I couldn't walk because I was so weak. When I came home, I

couldn't wait to go to school. My friends had collected money to send

toys to the hospital. " The family will never keep pets again (the

city has banned the keeping of domestic poultry). " We wouldn't dare, "

says Chau. " It is too scary. "

Hn's recovery has come at a financial cost in a country where

healthcare is not free (except for children under 6) and the average

income is £320. Her parents estimate their medical costs at about

$4,000 (£2,140), half of which covered drugs and hospital care. The

other half went on medical transportation plus other expenses, such

as a large donation to the local church which held a special ceremony

to pray for Hn, and gifts to doctors. Hn's illness coincided with the

Tet, or Vietnamese New Year, during which it is customary to give to

others.

As our meeting draws to a close, Hn smiles serenely and reaches for

her mother's hand — and pledges to pay her parents back with proceeds

from the catwalk.

MY FAMILY CAME TO SAY GOODBYE

Oanh Duong Thi Kieu Duong, 27, is tall and slim, dressed in dark

jeans and a pink T-shirt, and her black hair is in a ponytail. She

sits nervously in a room at the Hospital for Tropical Diseases (HTD),

a place that she once feared she would never leave alive.

A tailor — she sews coats in a clothing factory for export to Taiwan —

Oanh rents a single room in Ho Chi Minh City, returning once a month

to her husband and eight-year-old daughter, who live in a one-room

hut in a province 170km (105 miles) away. Oanh's husband is a poor

farmer. She describes her ordeal: " It was December 2004 and we had

about 50 chickens in the house. I saw that some of them were ill and

dying. I buried the small ones and kept the biggest one to cook and

eat. I cleaned and plucked it but, because I had a headache, I left

it for my husband to cook when he came from work.

" That afternoon I started feeling dizzy. The next morning I felt so

bad that I went to the local health centre. I felt as if my head

would explode. They gave me tablets. I wrapped myself in a blanket

and went to my sister's house so she could perform a

treatment, `rubbing wind', on me, which involves taking a coin and

rubbing it on the head, to get the poisoned wind, or bad chi, out of

my body. It didn't make me better so my brother came over and took me

to a provincial hospital on the back of his motorbike. I could barely

hold on for the hour-long journey. A doctor diagnosed a respiratory

infection and I told my brother to buy all the medicines he

prescribed. I took them all in one go.

" I still didn't feel better so I contacted my cousin, who works as a

doctor there. She admitted me and X-rayed my chest. They asked if I'd

eaten chicken. I said yes, even though I hadn't. I lied because I was

scared, the pain was so horrible. All the doctors went to get masks.

As soon as I saw the masks, I thought that I was dying. I asked the

doctor if I was going to be OK and she said that she didn't know. I

heard the doctors tell my husband it was bird flu — it was first time

I'd heard of it. "

Oanh was transferred to the HTD in Ho Chi Minh City, where she stayed

for ten days. " All I remember is that I didn't know the faces of the

doctors who treated me, and that when I had a high fever I was

unconscious. I remember thinking that, because I was isolated and

wearing a mask, if I died, nobody would hear my last words. I didn't

know if I would be around to be a mother to my daughter. I prayed

every day. My family came to say goodbye to me. My poor daughter

could not eat — someone gave her money to buy breakfast and instead

she saved it for me. "

The memories make Oanh cry. But the drama did not end after going

home. She discovered she had been pregnant throughout her illness.

Six months into the pregnancy, a scan showed the foetus had an

abnormally swollen belly. She was advised to abort to avoid the

foetus dying inside her and causing a fatal infection. She agreed.

She believes that the many medicines she took — which saved her life —

cost her the baby. Sadly, Oanh suffered another miscarriage earlier

this year.

Professor Farrar says that the effects of an aggressive course

of anti-flu medication on developing foetuses remains unknown but,

given the deadliness of bird flu, the mother must be the priority.

Oanh is grateful to be alive: " If it wasn't for my cousin, I'd be

dead. I saw so many people come here and die of bird flu. And I

survived because of my faith and because I am the youngest in my

family (she has 11 siblings). I needed to survive so that I could

mourn my parents when they die. "

She no longer eats poultry or eggs or keeps chickens. She has run up

4 million dong (£132) in debts, and has sold a piece of farmland to

pay her medical bills. Her hopes for the future? " I hope that I can

pay all my debts and have a second child. "

http://www.timesonline.co.uk/article/0,,25149-2425837,00.html