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The Birds

An avian-human hybrid flu threatens to bear horrors of Hitchcockian proportions. Can history help us decifer the solution to the next conundrum in influenza evolution?

An avian-human hybrid flu threatens to bear horrors of Hitchcockian proportions.

Can history help us decifer the solution to the next conundrum in influenza evolution?

Hospital wards full. Mortuaries overflowing. Supposedly fit adults dropping dead in the street. A ban on public meetings and gatherings.

No, not some grim vision of a modern world assailed by bird flu, but 1918. This has already happened. While our current obsession with H5N1 avian flu may be justifiable, we have been there before; not once, but several times.

Flu was often called by its French name, la grippe, but the word `influenza' originates from the Italian for `influence', as the disease was originally believed to be influenced by the stars.

The term was first used in 1357, although outbreaks of flu-like epidemics were recorded earlier. In the past 200 years, there have been several recurrences with global significance. There were pandemics in 1830-33, and again in 1847. The Russian flu pandemic in 1889-1900 was estimated to have killed 250,000 in Europe alone. Sero-archaeologists think it was an H2 variant that circulated for many years only to be replaced after a decade by H3.


1918: Spanish Flu (H1N1)
No one knew what caused the Spanish flu pandemic, but the First World War, with the mass movement and concentration of soldiers, refugees and animals, meant that conditions were ripe for the all important mutation and species migration.

The first cases of H1N1 in Britain appeared in Glasgow, in May 1918, and as it spread it killed almost 250,000 people; more than 150,000 in England and Wales alone.

This flu was many times more deadly than normal flu which has a mortality of 0.1 per hundred. This flu had a mortality 25 times as great. As one fifth of the world's population contracted it, the number of deaths was staggering. Estimates vary wildly but, conservatively, it must have killed around 40 million people worldwide. This was a true pandemic.

Some authorities claim that 16 million were killed in India alone - and that the true number of total victims could have been as high as 100 million. What is beyond doubt, however, is that the Spanish flu killed more people than died on the battlefields of the First World War.

Some 20-40 per cent of the world's population became ill during the Spanish flu pandemic, and only one or two places avoided it entirely, such as Iceland, through the use of stringent travel restrictions. The 1918 flu pandemic killed more people in a year than the Black Death of the Middle Ages killed in a century.

What was also so terrifying about the 1918 pandemic was the suddenness of the illness. It could kill within hours. There are countless cases of people who awoke fine in the morning, fell ill after lunch and were dead by the next morning.

Ironically, this strain killed not only the very young and the very old, the traditional victims of any disease outbreak, but also the fit and young (half of the victims were aged between 20 and 40).

The mortality curve was, unusually, `W' shaped. The reason for this is believed to be that the flu triggered an over-reaction in the auto-immune system, a cytokine storm, which turned on healthy cells and destroyed them. Those with a healthy auto-immune system were, therefore, most at risk!


The Spanish lady
The effects were particularly gruesome. Victims bled from their noses, mouths and ears. They coughed up and vomited blood, before finally drowning in it; their lungs turned to a formless mush.

This flu was distinguished, too, by the appearance of its victims; a blue tinge to the lips and skin that darkened - a cyanosis caused by the inability of the lungs to extract enough oxygen for the body's needs.

Of course it had to have a name, but no one is really sure why it was called Spanish flu. One theory is that the King of Spain was one of those infected (and he survived). Another, more likely, theory is that, with most European countries locked in battle, military censorship meant that news of the disease affecting the troops was suppressed. Only neutral Spain went public right from the start - and ended up lending its name to the outbreak! In a macabre turn, the outbreak was also known as `The Spanish Lady'.

This flu outbreak seemed to run in two phases. In 1917 and into the spring of 1918, it was unpleasant but relatively mild. The incidence moved progressively around the world and then seemed to disappear; in the autumn of 1918, it reappeared suddenly in a new and deadly form.

The most surprising aspect was that even before international air travel, it erupted in places as far apart as Baltimore and Bombay almost simultaneously. The only positive note was that people who had been affected by the milder form in the Spring seemed to have immunity to the autumnal strain.

Yet, human influenza was not isolated for another 15 years. At the time it was thought that an organism called Pfeiffer's bacillus (later identified as Haemophilus influenzae) was responsible.

We only know about the 1918 virus now through tissue samples stored by the US Military at the Armed Forces Institute of Pathology, in Maryland, and others taken from bodies that had been preserved in permafrost.

Yet back then, as now, species transmission was involved. Throughout 1917, there were reports of horses falling ill and dying with bronchial-pneumonia conditions, especially on the European battlefields. Swine flu was also present in 1918 and research later showed that people born in the last years of the First World War had high levels of swine virus antibodies in their bloodstream.

It was thought, at one time, that the disease might have lain dormant in the pig population during the summer months only to re-enter the human chain again in the autumn; this is no longer believed to have been the case, however.

Some 40 years later, the 1957 Asian Flu (H2N2) circulated for approximately 11 years and, while it was a milder illness than the 1918 outbreak, it killed around two million people worldwide.


1968: Hong Kong Flu (H3N2)
This was the last true flu pandemic. Detected in the Far East in early 1968, it spread around the world over the subsequent two years, killing around one million people. Deaths were highest in the over `65s.

The haemagglutinin (`H' element) had changed from the 1957 virus but the neuraminidase (`N') had not. This meant that those who had lived through the outbreak a decade before had no automatic immunity.

1976: The Pandemic that never was
In February 1976, a fit young soldier at Fort Dix training camp in New Jersey fell ill and died a few hours later. There had been a mid flu-like illness running through the camp for several weeks, but it had not caused any fatalities.

When the causative organism from the dead soldier was identified, alarm bells rang. It was a swine flu virus - closely related to the one that was thought to be responsible for the1918 outbreak - and at least four other soldiers now had it. Whereas the 1918 outbreak had killed half a million Americans, the mortality was expected to be at least twice that.

The US government had difficult decisions to make. Do nothing? Start mass vaccination? Produce the vaccine and hold it ready, just in case? Each option carried a risk, but with another 500 recruits showing signs of infection the decision was made to start mass vaccination.

The only problem was that the vaccine producers were already manufacturing millions of doses to protect vulnerable patients against influenza A/Victoria, which was the expected strain for that year. This was stopped and production switched to a vaccine for the Fort Dix Swine Flu.

By mid-December 1976, some 40 million patients - a third of the adult population - had received swine flu shots, but stories had been circulating about an association between the vaccine and instances of Guillain-BarrÈ syndrome, a rare neurological and muscular condition.

The programme was halted on December 16. Ultimately, however, no causal relationship was shown to exist between the vaccine and the syndrome, and it was concluded that they were unlikely to be related; when n=40,000,000, you're likely to find all sorts of relationships!

More to the point, there was no flu pandemic either. Not even an epidemic. In fact, there were no cases of swine flu anywhere. If it had been swine flu that killed the young soldier, it certainly hadn't been capable of human-to-human transmission.

The aborted programme had cost $135m, and a wave of litigation followed. People who thought they had been affected by the unnecessary vaccination sued, and by May 1980 the compensation claims amounted to $3.5bn. A rather expensive exercise for a pandemic that never happened.


1997: Avian flu (H5n1)
Hong Kong, in 1997, was the last big flu outbreak and this was an avian flu strain (H5N1) - the one that threatens us currently.

Bird flu viruses are usually quite benign, even for birds, living quietly in birds' intestines. Occasionally they mutate and infect birds' lungs, which can kill them. Yet, it is hard for the virus to mutate, in one jump, into a type infectious in humans, and this is where the pigs come back into the picture.

Pigs can harbour both avian and human flu viruses. All it takes is for a pig to get both at the same time and the genes from the two types can mix and form a new hybrid: a bird virus that can infect humans. This would explain why people who had survived the 1918 pandemic had antibodies to swine flu.

Yet, this virus was different because it moved straight from chickens to humans without passing through a swine vector. Although human-to-human transmission did not occur, 18 people were hospitalised and six died. Prompt action by the authorities, which involved the slaughter of around 1.5 million chickens, meant that it did not go much further.

There was another Hong Kong avian flu outbreak in 1999, an H9N2 version that caused illness in a limited number of subjects, but which failed to develop further.

So what does the future hold? As the World Health Organisation (WHO) points out, an avian virus does not jump easily from birds to humans, nor spread readily and sustainably among the human population. However, we are warned, if H5N1 evolves into a form as contagious as normal flu, a pandemic could begin.

All countries will be affected. Though border controls might delay its appearance, previous pandemics encircled the globe in six to nine months - and that was mainly by ship, at a time with far less international travel.

The WHO states, grimly, that `given the speed and volume of international air travel today, the virus could spread more rapidly, possibly reaching all continents in less than three months'. Many people in the world would die.

As the philosopher George Santayana declared, those who do not learn from the mistakes of history are condemned to repeat them. The question for us is whether, despite our advances in viral identification and diagnosis, we are really any wiser than we were 90 years ago.

The Author
Phil Cox is creative director at LEC Advertising (

2nd September 2008


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