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Our fight against flu
The Press | Saturday, 19 April 2008
A-tishoo: a good sneeze can splutter virus-laden mucus droplets over a three-metre radius.
With the threat of winter colds and flu looming, JOHN McCRONE looks at how our bodies deal with viruses, including the big one, bird flu.
Whatever happened to bird flu? Just a few years ago, its mutation into a human plague was said to be not just possible but inevitable.
Perhaps 100 million would die. The world economy would be crippled. Here in New Zealand the authorities were getting prepared, handing out "nanoparticle" face masks to health workers, stockpiling emergency vaccine, and figuring in which quiet field all the bodies were to be buried.
Now those pandemic-action plans must be gathering dust on top shelves, forgotten along with the family packs of Tamiflu, bought in a panic back in 2005 and probably fast approaching their expiry date in the back of a kitchen drawer.
In fact, bird flu remains just as big a threat as ever. Ministry of Health national pandemic planner Steve Brazier says every day could be the day the alarm goes out to shut down airports, isolate towns and cities, and put the hospitals and undertakers on standby.
"The risk is unchanged as far as we're concerned," Brazier says grimly.
A shiver went down the spine of the medical community just this month when it was confirmed a 52-year-old man from Jiangsu province in China had caught bird flu from his son -- a case of human-to-human transmission. Fortunately tests showed the virus had not yet mutated. It remained the hard-to-catch bird variety.
If alert levels are still the same, what has changed -- and indeed has been changing ever since the 2003 Sars (severe acute respiratory syndrome) crisis -- is that the science of colds and flus has been galloping ahead.
In the 1990s, cancer and other more serious ailments had been getting the big research dollars. However, one close shave with a dangerous respiratory virus was probably enough.
The thought of a third of the population laid up in bed for a few weeks and what it would do to businesses, infrastructure, all the workings of a modern economy, regardless of whether the ill survived or not -- well, it did not bear contemplation. A major scientific effort has been under way.
What has emerged is a fascinating tale of evolution in action. And it reveals exactly why bird flu has the authorities aquiver.
But first, some basics -- Christchurch virologist Dr Lance Jennings, an international influenza expert, explains -- a virus is a rogue scrap of genetic material, a strand of DNA or RNA, wrapped in a protective capsule. The capsule is made of proteins which will latch on to matching proteins on target cells.
Once docked in this way, a virus cracks open, releasing its genetic program. The program hijacks the cell's metabolism, forcing it to churn out replica viruses until it is exhausted. The cell then falls apart and releases thousands of fresh virus particles like spores.
Jennings says that to be successful, a virus has to strike a balance between infecting and killing its host. It is the same paradox as for any parasite. So while viruses might want to be virulent -- easily spread -- they do not want to be lethal. Given time, they will evolve to become relatively benign invaders. This is the story of the common cold.
The common cold is not a single disease, but rather a lifestyle enjoyed by a whole bunch of different well-adapted viruses.
There are about 200 cold viruses grouped into five broad families, with more variants being discovered all the time. What they share is that they have learnt how to colonise a prime bit of viral real estate -- our nasal cavities -- while doing us little actual damage.
About a quarter of the time, we will not even know we harbour an infection. There will be no clear symptoms. And where the virus does provoke a stronger immune-system reaction -- the familiar dripping, coughing, sneezing -- it is part of a cunning transmission mechanism.
Getting from host to host is a major problem for a virus. There has to be intimate contact involved. So being passed during sex is one option. The "enteric route" -- from hand to gut and back to hand again -- is an even more universal and effective option.
But nothing beats the nose and throat as infective sites, because a little congestion, a little inflammation and irritation, can really get a human hoicking and sneezing and smearing their sticky secretions about.
Coughs and sneezes are reflexes designed to clear our airways of dust and other physical obstructions. Yet just as cold viruses first hijack our nasal lining to reproduce themselves, so they then hijack our respiratory reflexes to ensure we pass them on down the line.
Jennings says a good sneeze can splutter virus-laden mucus droplets over a three-metre radius. After that, infection is almost guaranteed. Come into contact with a few drops of aerosoled snot and you have a 95 per cent chance of contracting a cold yourself.
This is why a key part of pandemic training involves simple habits of hygiene -- tricks like coughing into your sleeve, thoroughly drying your hands after washing and not rubbing your eyes. These small steps alone would drastically limit the spread of any new respiratory virus.
So the standard cold is a mild invader. The immune system copes with it pretty easily. Virus production reaches a peak at about three days, by which time the immune system has learnt to recognise the characteristic outer capsule proteins of the particular virus strain and the invasion is knocked on its head.
In young children, with less developed immune systems, virus production can go full steam for several weeks -- the reason why parents and grandparents of toddlers are never without a cold.
But generally speaking, while having a cold is no fun, it is also no great drama. One virus strain takes up residence and breeds fast for a few days before being booted onwards, leaving our nasal passages free for their next tenant.
The danger is always with some respiratory virus that is completely new to our immune system. If our immune system cannot recognise its outer proteins, the virus will replicate unchecked. Worse still, sensing something is wrong, but not knowing exactly what to attack, the immune system can start to thrash about, attacking everything.
This is when you get a runaway immune response known as a cytokine storm, says Jennings. There is massive inflammation. The respiratory system fills up with fluids and secondary bacterial infections can set in. Leaking blood vessels and cell walls allow the virus to start infecting organs of the body, like the heart and brain -- places where it would never normally be found. A person can die in a day.
Jennings says this situation is bad for both host and virus. A disease with extreme mortality will kill people faster than it can spread. The disease may erupt in a population and just as quickly make itself extinct.
But what generally happens with a new pandemic virus, especially respiratory diseases which are the really contagious ones, is there is a rapid evolution to some milder form. The disease tracks a fast-dropping curve of lethality. And it is just a simple game of numbers.
In the first wave of any break-out, a handful of viruses will turn out to be slightly less lethal than their fellows. This could be because they may not attack with quite the same vigour. They might not run down a cell's supplies so fast. Or they might be a little bit more recognisable to the immune system, offering just enough visibility for the brakes to be applied at the last minute.
Either way, all it takes is a slightly wimpier strain and more victims will survive to propagate this version of the virus. It is a particularly brutal example of natural selection. But in just a few weeks or months, a new pandemic virus can run its way down the slope of lethality to the point where it is a disease that only rarely kills.
After a few decades or centuries, it will probably join the long list of "common colds" -- the likely remnants of ancient epidemics.
Which brings us to the flu virus. All influenzas appear to be originally benign and well-adapted viruses in birds which have jumped the species gap to infect humans and animals. In birds, especially waterfowl like ducks, they are usually enteric viruses. Because ducks poop in the same water they dabble for food in, the gut route is as good a transmission path as the respiratory tract.
Humans suffer from two main kinds of flu bug. There is a legacy strain, Type B, which probably crossed over centuries ago. It still has that extra flu-like kick of aches and temperatures, but it is a noticeably milder infection.
Then there is Type A flu, or H1N1, the virus that sparked the Spanish flu pandemic of 1918. Spanish flu (which despite its name probably developed in Asia) was an example of a duck-gut virus that suddenly mutated to have the right proteins to latch on to the cells lining the human upper-respiratory system.
Recent scientific recreations of H1N1 suggest it could have grabbed the necessary equipment from other viral fragments floating around in human cells in a process known as reassortment. The right bits of some common-cold virus could have got tangled up with the right bits of a duck-flu virus to create a new Frankenstein's monster.
However it happened, H1N1 had hit the transmissibility jackpot. Spanish flu did indeed sweep the post-war world like wildfire. And being new to the human immune system, about 100 million died.
What was particularly tragic was the pandemic killed not just the very young and old -- those normally most vulnerable to infections -- but it was unusually severe on 20 to 40 year olds. Being fit and healthy was not a protection because a stronger immune system possibly just led to a stronger cytokine storm meltdown.
Jennings says there are other lessons we are learning from the re-examinations of the 1918 pandemic. The illness struck in three distinct waves, each spaced by a few months, like an earthquake and its aftershocks -- something we will have to prepare for with bird flu.
The value of staying isolated from the early stages of the disease has also become apparent. H1N1 hit Samoa early in its lifecycle, arriving on the island in October 1918, and killed 22% of those infected. It arrived in New Zealand just a month later and mortality was down to 2%. Australia's quarantine kept the disease out until January 1919 and the subsequent death rate was less than 1%.
Spanish flu ran down the lethality curve remarkably quickly. Jennings says this is why with pandemic planning now, every week the disease can be delayed is critical. Even travel between country towns will be restricted if it comes down to it.
The Spanish flu **** around for the next 40 years in its milder form, becoming just a nasty respiratory bug, until 1957 when there was another bird-flu crossover, H2N2 or the Asian flu (the H and N coding stand for the particular versions of the two proteins, hemagglutinin and neuraminidase, making up the outer shell of the virus).
This was a new mutant cocktail. But being only slightly different, humans had a little more immunity. It killed two million people rather than 100 million.
Another curious fact of pandemicology is that new viruses often make the old ones extinct. H2N2 replaced H1N1 as our Type A flu, possibly, says Jennings, because it simply had the vigour to out-compete it.
This happened yet again in 1968 with the Hong Kong flu or H3N2, which killed around one million people. Overnight, H2N2 disappeared and if you got Type A flu, it was some regional variant of H3N2.
Then in 1977, the old enemy, H1N1 made a surprise reappearance as Russian flu, or Red flu. Now there were three human flu viruses to contend with. Jennings says rumour has it the Soviets had been cultivating Spanish flu in their biological-warfare laboratories -- although luckily in its attenuated form -- and it had escaped.
Anyway, this is the reason why our annual winter-flu jabs have antigens to combat three flu strains.
It is uncovering the recent history of flu pandemics which is making medical researchers so nervous about the new "bird flu" -- or H5N1 avian influenza to give it its proper title.
H5N1 is another enteric virus. But even in birds it is a more deadly variant. It has become a particular problem in chicken and farmed ducks, where birds are often in cramped conditions and droppings spread the infection.
H5N1 already has a protein coat that can latch on to cells lining the lower-respiratory tract in humans -- the windpipe and lungs.
If it does, it is exceptionally lethal. Death rates as high as 80% are being recorded -- remembering Spanish flu in New Zealand had a mortality of just 2%. But fortunately it is hard to spread.
Humans can catch it from breathing in dust or splatter when working directly with infected poultry, however, it does not yet have the mutations needed to lodge in the upper-respiratory tract and so travel on coughs and sneezes.
Of course, says Jennings, once it is inside human cells, it could grab the necessary viral fragments to become a nasal disease. Every human case is another opportunity that increases the odds and so far there have been 380 cases around the world, with 240 deaths, more than half of which have been in Indonesia and Vietnam.
Even if it is not H5N1, some-day it could be another bird flu crossing over. It is a risk the planet needs to be taking more seriously, he says.
The public may have forgotten about the bird-flu threat but the vaccine researchers and pandemic planners still feel they are involved in a race against time.
The Press | Saturday, 19 April 2008
A-tishoo: a good sneeze can splutter virus-laden mucus droplets over a three-metre radius.With the threat of winter colds and flu looming, JOHN McCRONE looks at how our bodies deal with viruses, including the big one, bird flu.
Whatever happened to bird flu? Just a few years ago, its mutation into a human plague was said to be not just possible but inevitable.
Perhaps 100 million would die. The world economy would be crippled. Here in New Zealand the authorities were getting prepared, handing out "nanoparticle" face masks to health workers, stockpiling emergency vaccine, and figuring in which quiet field all the bodies were to be buried.
Now those pandemic-action plans must be gathering dust on top shelves, forgotten along with the family packs of Tamiflu, bought in a panic back in 2005 and probably fast approaching their expiry date in the back of a kitchen drawer.
In fact, bird flu remains just as big a threat as ever. Ministry of Health national pandemic planner Steve Brazier says every day could be the day the alarm goes out to shut down airports, isolate towns and cities, and put the hospitals and undertakers on standby.
"The risk is unchanged as far as we're concerned," Brazier says grimly.
A shiver went down the spine of the medical community just this month when it was confirmed a 52-year-old man from Jiangsu province in China had caught bird flu from his son -- a case of human-to-human transmission. Fortunately tests showed the virus had not yet mutated. It remained the hard-to-catch bird variety.
If alert levels are still the same, what has changed -- and indeed has been changing ever since the 2003 Sars (severe acute respiratory syndrome) crisis -- is that the science of colds and flus has been galloping ahead.
In the 1990s, cancer and other more serious ailments had been getting the big research dollars. However, one close shave with a dangerous respiratory virus was probably enough.
The thought of a third of the population laid up in bed for a few weeks and what it would do to businesses, infrastructure, all the workings of a modern economy, regardless of whether the ill survived or not -- well, it did not bear contemplation. A major scientific effort has been under way.
What has emerged is a fascinating tale of evolution in action. And it reveals exactly why bird flu has the authorities aquiver.
But first, some basics -- Christchurch virologist Dr Lance Jennings, an international influenza expert, explains -- a virus is a rogue scrap of genetic material, a strand of DNA or RNA, wrapped in a protective capsule. The capsule is made of proteins which will latch on to matching proteins on target cells.
Once docked in this way, a virus cracks open, releasing its genetic program. The program hijacks the cell's metabolism, forcing it to churn out replica viruses until it is exhausted. The cell then falls apart and releases thousands of fresh virus particles like spores.
Jennings says that to be successful, a virus has to strike a balance between infecting and killing its host. It is the same paradox as for any parasite. So while viruses might want to be virulent -- easily spread -- they do not want to be lethal. Given time, they will evolve to become relatively benign invaders. This is the story of the common cold.
The common cold is not a single disease, but rather a lifestyle enjoyed by a whole bunch of different well-adapted viruses.
There are about 200 cold viruses grouped into five broad families, with more variants being discovered all the time. What they share is that they have learnt how to colonise a prime bit of viral real estate -- our nasal cavities -- while doing us little actual damage.
About a quarter of the time, we will not even know we harbour an infection. There will be no clear symptoms. And where the virus does provoke a stronger immune-system reaction -- the familiar dripping, coughing, sneezing -- it is part of a cunning transmission mechanism.
Getting from host to host is a major problem for a virus. There has to be intimate contact involved. So being passed during sex is one option. The "enteric route" -- from hand to gut and back to hand again -- is an even more universal and effective option.
But nothing beats the nose and throat as infective sites, because a little congestion, a little inflammation and irritation, can really get a human hoicking and sneezing and smearing their sticky secretions about.
Coughs and sneezes are reflexes designed to clear our airways of dust and other physical obstructions. Yet just as cold viruses first hijack our nasal lining to reproduce themselves, so they then hijack our respiratory reflexes to ensure we pass them on down the line.
Jennings says a good sneeze can splutter virus-laden mucus droplets over a three-metre radius. After that, infection is almost guaranteed. Come into contact with a few drops of aerosoled snot and you have a 95 per cent chance of contracting a cold yourself.
This is why a key part of pandemic training involves simple habits of hygiene -- tricks like coughing into your sleeve, thoroughly drying your hands after washing and not rubbing your eyes. These small steps alone would drastically limit the spread of any new respiratory virus.
So the standard cold is a mild invader. The immune system copes with it pretty easily. Virus production reaches a peak at about three days, by which time the immune system has learnt to recognise the characteristic outer capsule proteins of the particular virus strain and the invasion is knocked on its head.
In young children, with less developed immune systems, virus production can go full steam for several weeks -- the reason why parents and grandparents of toddlers are never without a cold.
But generally speaking, while having a cold is no fun, it is also no great drama. One virus strain takes up residence and breeds fast for a few days before being booted onwards, leaving our nasal passages free for their next tenant.
The danger is always with some respiratory virus that is completely new to our immune system. If our immune system cannot recognise its outer proteins, the virus will replicate unchecked. Worse still, sensing something is wrong, but not knowing exactly what to attack, the immune system can start to thrash about, attacking everything.
This is when you get a runaway immune response known as a cytokine storm, says Jennings. There is massive inflammation. The respiratory system fills up with fluids and secondary bacterial infections can set in. Leaking blood vessels and cell walls allow the virus to start infecting organs of the body, like the heart and brain -- places where it would never normally be found. A person can die in a day.
Jennings says this situation is bad for both host and virus. A disease with extreme mortality will kill people faster than it can spread. The disease may erupt in a population and just as quickly make itself extinct.
But what generally happens with a new pandemic virus, especially respiratory diseases which are the really contagious ones, is there is a rapid evolution to some milder form. The disease tracks a fast-dropping curve of lethality. And it is just a simple game of numbers.
In the first wave of any break-out, a handful of viruses will turn out to be slightly less lethal than their fellows. This could be because they may not attack with quite the same vigour. They might not run down a cell's supplies so fast. Or they might be a little bit more recognisable to the immune system, offering just enough visibility for the brakes to be applied at the last minute.
Either way, all it takes is a slightly wimpier strain and more victims will survive to propagate this version of the virus. It is a particularly brutal example of natural selection. But in just a few weeks or months, a new pandemic virus can run its way down the slope of lethality to the point where it is a disease that only rarely kills.
After a few decades or centuries, it will probably join the long list of "common colds" -- the likely remnants of ancient epidemics.
Which brings us to the flu virus. All influenzas appear to be originally benign and well-adapted viruses in birds which have jumped the species gap to infect humans and animals. In birds, especially waterfowl like ducks, they are usually enteric viruses. Because ducks poop in the same water they dabble for food in, the gut route is as good a transmission path as the respiratory tract.
Humans suffer from two main kinds of flu bug. There is a legacy strain, Type B, which probably crossed over centuries ago. It still has that extra flu-like kick of aches and temperatures, but it is a noticeably milder infection.
Then there is Type A flu, or H1N1, the virus that sparked the Spanish flu pandemic of 1918. Spanish flu (which despite its name probably developed in Asia) was an example of a duck-gut virus that suddenly mutated to have the right proteins to latch on to the cells lining the human upper-respiratory system.
Recent scientific recreations of H1N1 suggest it could have grabbed the necessary equipment from other viral fragments floating around in human cells in a process known as reassortment. The right bits of some common-cold virus could have got tangled up with the right bits of a duck-flu virus to create a new Frankenstein's monster.
However it happened, H1N1 had hit the transmissibility jackpot. Spanish flu did indeed sweep the post-war world like wildfire. And being new to the human immune system, about 100 million died.
What was particularly tragic was the pandemic killed not just the very young and old -- those normally most vulnerable to infections -- but it was unusually severe on 20 to 40 year olds. Being fit and healthy was not a protection because a stronger immune system possibly just led to a stronger cytokine storm meltdown.
Jennings says there are other lessons we are learning from the re-examinations of the 1918 pandemic. The illness struck in three distinct waves, each spaced by a few months, like an earthquake and its aftershocks -- something we will have to prepare for with bird flu.
The value of staying isolated from the early stages of the disease has also become apparent. H1N1 hit Samoa early in its lifecycle, arriving on the island in October 1918, and killed 22% of those infected. It arrived in New Zealand just a month later and mortality was down to 2%. Australia's quarantine kept the disease out until January 1919 and the subsequent death rate was less than 1%.
Spanish flu ran down the lethality curve remarkably quickly. Jennings says this is why with pandemic planning now, every week the disease can be delayed is critical. Even travel between country towns will be restricted if it comes down to it.
The Spanish flu **** around for the next 40 years in its milder form, becoming just a nasty respiratory bug, until 1957 when there was another bird-flu crossover, H2N2 or the Asian flu (the H and N coding stand for the particular versions of the two proteins, hemagglutinin and neuraminidase, making up the outer shell of the virus).
This was a new mutant cocktail. But being only slightly different, humans had a little more immunity. It killed two million people rather than 100 million.
Another curious fact of pandemicology is that new viruses often make the old ones extinct. H2N2 replaced H1N1 as our Type A flu, possibly, says Jennings, because it simply had the vigour to out-compete it.
This happened yet again in 1968 with the Hong Kong flu or H3N2, which killed around one million people. Overnight, H2N2 disappeared and if you got Type A flu, it was some regional variant of H3N2.
Then in 1977, the old enemy, H1N1 made a surprise reappearance as Russian flu, or Red flu. Now there were three human flu viruses to contend with. Jennings says rumour has it the Soviets had been cultivating Spanish flu in their biological-warfare laboratories -- although luckily in its attenuated form -- and it had escaped.
Anyway, this is the reason why our annual winter-flu jabs have antigens to combat three flu strains.
It is uncovering the recent history of flu pandemics which is making medical researchers so nervous about the new "bird flu" -- or H5N1 avian influenza to give it its proper title.
H5N1 is another enteric virus. But even in birds it is a more deadly variant. It has become a particular problem in chicken and farmed ducks, where birds are often in cramped conditions and droppings spread the infection.
H5N1 already has a protein coat that can latch on to cells lining the lower-respiratory tract in humans -- the windpipe and lungs.
If it does, it is exceptionally lethal. Death rates as high as 80% are being recorded -- remembering Spanish flu in New Zealand had a mortality of just 2%. But fortunately it is hard to spread.
Humans can catch it from breathing in dust or splatter when working directly with infected poultry, however, it does not yet have the mutations needed to lodge in the upper-respiratory tract and so travel on coughs and sneezes.
Of course, says Jennings, once it is inside human cells, it could grab the necessary viral fragments to become a nasal disease. Every human case is another opportunity that increases the odds and so far there have been 380 cases around the world, with 240 deaths, more than half of which have been in Indonesia and Vietnam.
Even if it is not H5N1, some-day it could be another bird flu crossing over. It is a risk the planet needs to be taking more seriously, he says.
The public may have forgotten about the bird-flu threat but the vaccine researchers and pandemic planners still feel they are involved in a race against time.
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