Special feature: The bird flu threat
07 January 2006
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Debora MacKenzie
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How Flu invades cells and multiplies
Flu is no big deal. Why are we suddenly being warned about a deadly pandemic?
They won't like this in Kansas, but it's all down to evolution. Flu is such a successful virus that each year almost everyone on Earth is exposed, and about a third of us get sick.
It is by no means harmless - it kills between 50 and 200 people per million every year, especially the elderly. Flu can kill in several ways. It can destroy your lungs or damage them so much that bacteria run riot and finish the job. Your immune response to the virus can trigger a crisis such as a heart attack or even spiral out of control and kill you.
Despite these dangers, most of us fight off a flu virus every year and become immune to that particular strain. But flu keeps coming back. Like all viruses with genes made of RNA, its replication is error-prone, and every infection produces swarms of mutants.
Once most people have become immune to the surface proteins on a strain, this virus cannot spread further. Then a mutant offspring, one that is different enough to partly evade the immune reaction directed against its parent, takes over and dominates the next year's epidemic.
And so each year many of us get sick again, but not very sick, because our immunity to past viruses gives us some protection against each new, slightly different virus.
Every now and then, however, a flu virus appears with surface proteins so different that our immunity to past infections does not help us. This is when a pandemic occurs.
So flu is no big deal only because past infections provide some protection?
Right. But there's more to it than that. Some flu viruses are also inherently more deadly than others, for reasons we do not yet understand. Dangerous mutations can appear at any time, which is why some years the flu is much nastier than others.
Luckily for us, viruses often evolve to become less dangerous as they circulate in one species. A virus that quickly kills every creature it infects tends to be less successful than one that leaves its host not only alive but well enough to walk or fly about and spread the virus to others.
Descendants of the deadly 1918 flu, caused by an H1N1 virus from birds, circulated until 1957. But they became far less dangerous, partly because people developed immunity, but also because the viruses evolved into a milder form. In 1957 H1N1 was replaced by the H2N2 virus that caused the Asian pandemic that year. This also became milder and circulated until the H3N2 virus that caused the 1968 Hong Kong pandemic took over. The last time you got flu, a mild descendant of the 1968 virus was probably to blame.
?The lethal 1918 flu, caused by a virus jumping into humans from birds, did not suddenly disappear. Its descendants circulated in people until 1957?
The flu viruses that infect aquatic birds such as ducks and geese are even better adapted to their hosts: they infect the birds' guts without causing any obvious symptoms, and spread by defecation in water.
The real trouble starts when a flu virus from another species jumps into humans, or when human flu viruses pick up genes from a flu virus that usually infects another species.
And flu could be about to jump species again?
Yes. Most flu viruses circulate among aquatic birds but they occasionally mutate and infect other species. Right now, we're worried because one bird virus, called H5N1 (see Diagram), has become able to infect and kill people.
Two problems occur when a flu virus jumps species, as H5N1 is doing. One, its surface proteins are different from those on human flu virus, so our immunity to past flu will not help us. Two, the tricks that allowed the virus to evade the immune system of its previous host without much fuss can provoke the immune systems of its new host into a fatal overreaction. Such a virus can be deadly until we develop immunity, and it evolves into a milder form.
Some H5 bird flus have long been able to infect humans exposed to lots of the virus, but these strains do not appear to have been particularly dangerous. In 1992, up to 7 per cent of Chinese poultry workers surveyed had antibodies to viruses with H5. But at some point the far more lethal H5N1 virus evolved.
The strain of H5N1 circulating now, called the Z genotype, has been traced back to geese in Guangdong, China, in 1996. Since then H5N1 has appeared more and more in a new host, chickens, in which it is changing very rapidly. For reasons we don't understand, this evolution has also steadily made it more deadly to mammals.
?H5N1 bird flu has spread to a new host, chickens. For reasons we don't understand, this is making it become more deadly to mammals?
In 1997, H5N1 shocked virologists when it killed 6 out of 18 people infected by poultry in Hong Kong. That outbreak was stopped when all 1.2 million poultry in Hong Kong were slaughtered. But H5N1 continued to circulate in Chinese poultry and by 2003 had spread with the meat and cockfighting businesses across east Asia. In 2004, Vietnam began reporting human cases. Crucially, though, H5N1 is still unable to pass from person to person with the same ease with which it spreads from bird to bird.
But it could start to spread from person to person?
That's the big fear. The arrival of H5N1 in European birds sparked a media frenzy last year. But human cases are very rare even in countries with massive poultry outbreaks.
The main risk to us from this virus is not the odd person catching it directly from birds - it's that the virus could evolve into a form capable of spreading from person to person and thus causing a human pandemic.
The last steps in its adaptation to humans are most likely to occur in a human. So what matters is how many human infections there are: the more people are infected, the more likely it is that such a mutation will occur. In east Asia, there have been around 130 confirmed cases of H5N1 infecting humans since the start of 2004. In western Europe, outbreaks in poultry are unlikely to get out of hand as they have in Asia, and even if they did fewer people would be exposed to sick birds.
It could be a different story if H5N1 arrives in Africa, though, where human contact with poultry is if anything closer than in Asia. The scarcity of veterinary services in Africa makes it unlikely that poultry outbreaks will be controlled, plus many people's immune systems are weakened by HIV. It is there, and in impoverished parts of Asia, that H5N1 is most likely to evolve into a pandemic form.
Why is this happening now? And why can't we stop H5N1 before it turns into a pandemic strain?
Because as China and other east Asian countries have grown wealthier, there has been an explosion in meat production, especially of chicken. There are billions of chickens in crowded battery farms on offer to any flu virus capable of infecting them. And the many small farms where geese, ducks and chickens intermingle offer numerous opportunities for flu viruses to jump species.
Massive slaughtering campaigns have failed to eradicate H5N1 in poultry. This is partly because countries such as Indonesia do not compensate people whose poultry is slaughtered, so outbreaks often aren't reported. The virus can also lurk undetected in ducks, because they show no obvious symptoms.
China has tried vaccinating birds, but vaccines do not always prevent low-level infections, allowing the virus to spread widely without any obvious mass deaths of birds. The virus's persistence in vaccinated birds can also drive it to evolve into new forms.
The sheer mass of the virus in Asia has allowed it to push its way into wild bird species. This, along with the trade in birds, has helped it spread as far as Europe and possibly Africa. It is now the biggest outbreak of an animal disease ever recorded.
How bad would a human pandemic be?
Past pandemics have varied in severity. The worst was in 1918, when 98 per cent of all people in the world were exposed, about 28 per cent got sick and 3 per cent of those died. There were more than 40 million deaths, over 1 per cent of everyone alive at the time. Yet the next pandemic, the Asian flu of 1957, killed only 2 million in a more populous world, and the Hong Kong flu of 1968 was only slightly worse than normal flu.
?In 1918, 98 per cent of all people were exposed to the virus, about 28 per cent got sick and 3 per cent of those died: 1 per cent of everyone alive?
What made the difference? The 1918 pandemic was caused by an H1N1 bird flu virus becoming able to spread from person to person. By contrast, the two later pandemics arose when a flu virus circulating in humans picked up genes from a bird flu virus.
Flu viruses contain eight strands of RNA. If a cell is infected by two different strains at the same time, they can swap strands, or re-assort, to form new viruses containing a mixture of genes from the two parents.
The 1957 and 1968 pandemics were caused by human flu strains picking up one or two surface proteins from bird flu viruses, allowing them to evade the immune system. That made them nastier than usual, but their human-adapted half seems to have taken the edge off.
So if H5N1 re-assorts with a human virus, it might mean a rerun of 1957, with perhaps a few million dead. If, however, it doesn't re-assort but mutates so it can spread easily among people, as in 1918, the resulting pandemic could be far worse - after all, H5N1 seems to kill a third of the people it infects.
Before you panic, it is possible that some people infected with H5N1 suffer few or no symptoms, meaning the death rate is far lower than we think (although there is little evidence of this). More probably, mutations that make H5N1 more likely to spread from person to person might also make it less deadly, but there is no guarantee of this. And if we spot an emerging pandemic early enough, we might be able to nip it in the bud by treating all exposed people with antiviral drugs.
If a pandemic virus does emerge, much will depend on how quickly it evolves and whether it becomes less deadly. In today's crowded global village a lethal virus might not run out of hosts so fast that it must rapidly evolve to become milder.
What a typical scientific non-answer - we don't know for sure, but maybe, yadda yadda. How do you expect us to prepare for that?
Well, here's some certainty: there will be another flu pandemic. We don't know when it will happen or how severe it will be, but it is usually best to prepare for the worst.
What will not help is expecting the next pandemic to be like the last ones. Most predictions are simply the toll of one of the past three pandemics, scaled up to the current world population. These numbers are meaningless: the next pandemic will involve a different virus in a very different world from 1918 or 1968.
Here's another calculation that's just as valid: if H5N1 went pandemic with its current virulence and a third of the world got sick, as in 1918, roughly 10 per cent of all people would die. The truth is, we have no idea what the death rate would be, but that last calculation really worries some scientists.
Can't we just develop a vaccine?
The snag is that until the next flu pandemic begins, we won't know exactly what form the virus will take. So we can't produce a perfect vaccine in advance. Yet waiting for the pandemic to begin before starting to make any vaccine at all means the vaccine will arrive too late for most.
What we could do, though, is vaccinate people against the existing strain of H5N1. As long as the pandemic virus is not too different, this should provide partial immunity; it might not stop you getting sick but it could stop you dying.
By June 2004, scientists had created a vaccine virus bearing the surface proteins of the H5N1 then in Vietnam. But it must be tested in people to make sure it is safe and elicits a sufficient immune response. Drug companies were given the money to organise trials for an H5N1 vaccine only in mid-2005.
Then the first trials wasted time testing formulations that require large doses of viral protein. Even if all the world's flu vaccine factories switched to making such vaccines for H5N1, they could make only a few hundred million doses in a year - which won't go far in a world of 6.4 billion people.
Add an immune stimulant called an adjuvant, and much smaller doses of viral protein may suffice: 10 times as many people could be vaccinated. Tests on these low-dose formulations are now getting under way. Yet even with a low-dose formulation, it will still take months to make enough vaccine for the world after a pandemic starts, by which time the first wave could be over.
So a pre-pandemic vaccine makes sense. Yet most governments are not enthusiastic about it, and companies, of course, won't make an H5N1 vaccine unless governments pay them to do so. One reason for this lack of enthusiasm is that there's no ironclad guarantee that the next pandemic will even be H5N1. Other bird flu viruses may yet surprise us. As the Dutch discovered during a massive poultry outbreak in 2003, H7 can make people ill, occasionally kill and even spread a little between people. H9 is even better at infecting us: a third of the people in the southern Chinese city of Shantou have antibodies to it.
And let's say we do carry out widespread pre-pandemic vaccination against H5N1, but there's no pandemic and a few people suffer serious side effects. Flu vaccine is usually pretty safe, but there will always be the odd adverse event. Governments fear there would be hell to pay, and not without reason.
?A pre-pandemic vaccine might make the difference between life and death. Governments, however, are not enthusiastic about the idea?
In 1976, amid fears of an incipient flu pandemic, the US vaccinated thousands against one flu strain. The pandemic never materialised, but there was a flood of lawsuits from people who suffered side effects (due to problems unique to that vaccine). The debacle may even have contributed to Gerald Ford losing the 1976 presidential election. This liability issue could be avoided by stockpiling an H5N1 vaccine now and giving it to people only if a pandemic starts, but there are no plans to do this.
Another problem with the pre-pandemic vaccine is the limited capacity of the world's flu vaccine factories: to make an H5N1 vaccine now, they would have to stop making normal flu vaccine for months or years.
What about flu drugs, then?
There are two classes of antivirals for flu: adamantanes, of which two are sold, and neuraminidase inhibitors, of which there are also two. There are more in both classes that are not marketed, as the low demand for flu treatment makes such drugs unprofitable.
The H5N1 in east Asia is already resistant to adamantanes, apparently because Chinese farmers used these drugs in chicken feed. However, the virus that reached Europe and might reach Africa has swapped some genes with a non-resistant strain and is susceptible to the drugs. So a pandemic strain might be susceptible, too, at least at first.
The neuraminidase inhibitors, Tamiflu (oseltamivir) and Relenza (zanamivir), are a better bet. Few Asian victims have been saved by Tamiflu, but that may be because treatment started late. With ordinary flu, you have to take it no more than two days after the start of symptoms to make a difference. With H5N1, you may need it even earlier. Experiments in mice also suggest that larger doses than usual will be required. Some Tamiflu-resistant H5N1 has turned up in infected people in Asia, but the mutation that gives the virus resistance also makes it poor at spreading, so resistance should be rare.
The patent-holder, Swiss company Roche, is scaling up production, and other companies in Vietnam, Taiwan and India will soon start making it as well. But it will still be many years before the world has enough to meet the likely demand in a pandemic.
From issue 2533 of New Scientist magazine, 07 January 2006, page i
Think again Common misconceptions
A regular flu shot will help protect you from bird flu
No, it won't - it will help protect you from regular flu. If bird flu turns into a human pandemic then you'll need pandemic vaccine.
However, ordinary flu vaccination is a good idea for people closely exposed to birds with flu. By preventing people being infected by human and bird viruses at the same time, it could stop the viruses swapping genes to form a pandemic strain.
This is all just a load of scaremongering, like SARS and AIDS, and they didn't turn out to be nearly as bad as we were told they would be
That SARS didn't become any worse was largely due to the prompt, massive international response to limit it, after what some now call scaremongering. And to a bit of luck: SARS didn't become infectious until after an infected person developed symptoms, so we could tell who to quarantine. Flu, by contrast, can be infectious for a day before symptoms develop.
As for AIDS, 40 million people worldwide are now HIV-positive. If that isn't a disaster, what is?
More people should get ordinary flu vaccinations, because with more of a market for that vaccine, companies will have an incentive to build more vaccine plants
This idea is touted by a lot of experts, but it is a bit like saying, "If people ate more, farmers would have an incentive to grow more food and there would be no more starvation."
Certainly, more people who can afford it should get regular flu shots, and manufacturers could perhaps then build a few more, and more modern, vaccine factories. But most people in the world cannot afford flu vaccination. There is not enough of a market for ordinary flu vaccine to support the vaccine plants needed to supply pandemic vaccine to the entire world, whether or not this suits free-market ideology.
Why are we stockpiling Tamiflu? It doesn't stop flu, it only shortens its duration and it makes kids crazy
The visible effect of Tamiflu on ordinary flu is to shorten the duration of symptoms. This has led to the notion that it is merely a symptomatic treatment, like using aspirin to reduce fever.
No, it does slow viral replication, giving the immune system more time to kick in. That makes flu symptoms less severe, which could make the difference between life and death in a pandemic.
It's true that two teenagers in Japan attempted suicide on Tamiflu, and 10 others went into a coma and died. But flu sometimes affects the brain, causing strange behaviour. Since Tamiflu is now routinely given to children with flu in Japan, it is not surprising neurological effects are seen in a few of those taking the drug.
But a causal link is improbable. What is worrying is that Tamiflu did not prevent theneurological complications.
Pandemics start when bird and human flu viruses recombine in pigs
That has long been a popular idea. Flu viruses bind to a sugar called sialic acid on the surface of cells. It was thought that birds have one type, humans have another and pigs have both, meaning pigs can be infected by both bird and human flu viruses. This could allow the viruses to swap genes to create a hybrid pandemic strain.
It's a neat theory, but the hybrid viruses that caused the 1957 and 1968 pandemics did not form in pigs. That does not mean it cannot happen in the future. But it's unlikely with H5N1, as it does not spread from pig to pig.
Fit young adults have the most to worry about, because they have the strongest immunity and what kills you is your immune system over-reacting
This idea appears to have emerged from the fact that older people were less likely to die in the 1918 pandemic than those aged between 20 and 40, plus the fact that immune over-reaction is often how flu kills. One, however, does not lead to another.
Older people probably had some immunity against the 1918 flu because a similar virus circulated for a while during the late 19th century. Younger people were more vulnerable. This was a particular circumstance of 1918, not a characteristic of flu pandemics in general.
And older immune systems are more likely to go haywire. Saying there is "stronger" immunity in younger adults partly means that their systems are more resistant to such runaway reactions.
This is the 21st century, not the dark ages. We can't die of massive plagues any more
Like it or not, we are biological creatures. Plagues can happen. And in the age of mass air travel, we are in some ways more vulnerable than ever.
With flu, we do at least have the know-how to defeat any future pandemic. But even though leaders know death and misery anywhere will have global consequences, we don't have the capacity to produce antivirals or vaccine fast enough to protect everyone. We have 21st-century technology. But when it comes to getting it to people, we are still in the dark ages.
How to protect yourself and your family
PREPARE IN ADVANCE:
The antiviral question
We're not going to tell you not to get antiviral drugs such as Tamiflu or Relenza - we know of too many flu experts who have their own stash.
But governments are against private stockpiles, and you can see their point. If individuals buy up all the available supplies, health authorities might not have enough for the most seriously ill in the event of a pandemic. And if you panic and pop the pills when you are not sick, they will be wasted.
On the other hand, the distribution of official stocks could be a problem. It might be too late for the drug to work by the time you get it. You might have to wait in a huge queue of infected people or try to penetrate an angry mob. And you could be mugged on the way out of a dispensary by people desperate for the drug.
If you do decide to get antivirals, beware fakes. Don't order drugs on the internet unless it is from a reputable pharmacy in a well-regulated country. You will need two courses per person, as standard doses might not be enough. And don't be taken in by any of the companies peddling quack remedies.
Ask your doctor for a pneumococcus vaccination
This vaccine protects you from a kind of bacterium that can cause pneumonia when it infects lungs damaged by the flu virus. The protection lasts for five years.
You could also stock up on antibiotics for treating other kinds of bacterial pneumonia. Half the victims of 1918 died of such secondary infections. Ask your doctor which antibiotics work against the most common infections in your area.
Consider statins
Yes, we know, these drugs are for lowering your cholesterol. But there is very preliminary evidence that they might protect against the general inflammatory reaction caused by flu, which can trigger heart attacks or strokes. A Dutch study of several thousand people aged 60 or more found there was no surge in deaths during the flu season among those on statins.
Become indispensable
Some countries are creating lists of "priority" people who will be the first to get drugs, or a vaccine if one is available. Now might be a good time to realise those childhood dreams of becoming a nurse, a firefighter or head of state.
Stock up emergency supplies
If the pandemic is far worse than feared, or if you plan to isolate yourself during a pandemic (see right), you will need emergency supplies of food, water and fuel. Each person needs 2 to 3 litres of water a day just for drinking, more for keeping clean.
Companies should prepare for many workers being absent and, where possible, set up systems that allow people to work from home.
A healthy lifestyle will increase your chances of surviving pandemic flu. Eat plenty of fruit and vegetables, exercise and get enough sleep.
Get rich quick
The wealthy will fare better in a pandemic than the poor for many reasons: they are generally healthier and less likely to succumb to a virus, and they can afford to take measures to protect themselves and to pay for medical care. Far more poor people died in 1918, many for lack of simple nursing care. Needless to say, poor countries are definitely not the place to be.
IF A FLU PANDEMIC STARTS:
Wash your hands - often
Flu can be airborne, but it is mainly spread by touch. Someone sneezes on their hand and then touches a railing or an elevator button. Touch it after them and then touch your mouth, nose or eyes, and you could be infected by the virus.
We all touch our faces far more frequently than we think we do: just try not doing it. And the H5N1 in Asia can lurk for up to six days on surfaces, longer than most flu viruses.
So don't kiss or shake hands. If you have to touch public surfaces, wash thoroughly afterwards. Use a nail brush and carry little bottles of alcohol-based cleaning gel for when you don't have soap and water. You could use a clean tissue to touch things, or wear latex gloves, but discard them before touching your face. And if you do cough and sneeze, do it into a tissue, and dispose of it carefully to avoid infecting others.
Masks will do little to protect you from inhaling any airborne viruses unless they fit snugly and meet US standard N-95 or the equivalent - and such masks make it very hard to breathe. However, any mask will at least help remind you not to touch your mouth, nose and eyes.
Avoid people if you can
People carry pandemic flu. Staying away from other people will reduce your chances of getting it. Most countries' pandemic plans call for "social distancing", such as cancelling big public events, but this will make little difference if people still travel on buses, trains or aeroplanes, and go to shops and offices.
The most effective way to avoid infection would be to isolate yourself and your family at home with a lot of books and canned food, assuming you've stocked up in advance. If not, get groceries delivered if possible. In 1918, some institutions in the US successfully protected themselves in this way.
Isolating young children is particularly important, as they are not only more likely to get infected, thanks to their unhygienic habits, but also more vulnerable when they do fall ill.
The trouble with isolating yourself is that you could be in for a long wait. With 1918's flu, the first wave in spring lasted three months and was followed by a far more deadly wave in the autumn and another wave in early 1919. So if you have do go out, take precautions such as leaving your shoes and outer clothes at the door when you return, and washing your hands.
And as with antivirals, what's best for individuals could be bad for society. If too many workers stay at home, essential services such as water and electricity could be disrupted. In fact, fear of a pandemic might be worse than the virus itself, both for its effects on the economy and for the social breakdown that could result - children orphaned by flu in 1918 starved when people refused to care for them. Don't make things worse by taking extreme measures if a pandemic virus turns out to be only slightly worse than normal flu.
But there is no doubt that if you think you might be infected, you should go to bed and stay there. Don't risk infecting others. Remain in bed for a week or two after recovery to avoid post-flu complications.
Don't flee the city
Unless you are lucky enough to have an isolated, self-sufficient country house, fleeing the city will not help. A mass movement of people will carry the virus with it, and you will be far worse off if you end up in a crowded shelter.
In any case, even remote places are unlikely to escape. Studies suggest that 98 per cent of people alive in 1918 were exposed to the pandemic virus. A few small islands managed to keep the virus out by shutting their borders, but hardly anywhere else avoided infection.
The high-risk strategy
Trying to avoid infection makes sense if you assume the pandemic will be over in a month or two, or that a vaccine will soon become available, so you'll be safe when you emerge. But the virus could circulate for many months, and the second or third waves might be worse than the first, as happened in 1918.
An alternative strategy is to get infected early on, before the healthcare system is overwhelmed and antivirals run out. If you survive, you'll be immune. But you'll be gambling with your life.
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