Bird flu: the front line
http://www.timesonline.co.uk/article/0,,7-2425837,00.html
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 Jeremy 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 Maryland, 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 Simmons, who is leading the unit’s involvement with the project.
But, Simmons 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.
Simmons 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, Simmons 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 Jeremy 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.”
