Public enemy

Every century a few viruses become so powerful they destroy societies, wreck economies and claim millions of lives. Adam Luck investigates the deadliest of diseases and a potential pandemic of our time - avian flu

Vision blurred and heart pounding, Nguyen Thanh Hung struggled for breath as he endured three days of white-hot fever. Plagued by excruciating pains in his rigid legs and arms, the 42-year-old Vietnamese cement salesman knew he was staring death in the face.

His brother Viet had died just days before, on January 9 last year, two weeks after being admitted to the Institute of Tropical Diseases in Hanoi with tests revealing that he had fallen victim to the H5N1 avian influenza type A virus, also known as "bird flu". Just a day later Hung had begun exhibiting the same symptoms and was swiftly confined to an isolation ward where doctors began pumping him full of antibiotics and the anti-viral drug Tamiflu.

The rapid spread of the virus showed up on X-rays with the chalky white imprint on his lungs spreading from an area the size of two fingers one day to the size of a hand the next. His lungs were closing down. Nguyen Thanh Hung says: "I felt like my head was pressured by a vice and breaking into pieces. I told myself to be alert and not fall into my brother's condition.

I thought that if I went to sleep, I could go into a coma."

Miraculously, he not only survived H5N1, but showed no signs of lasting damage to his lungs or body when he was released from hospital on January 28, after repeatedly testing negative for the virus. Nguyen Thanh Hung is one of the few people to have contracted H5N1 and survived to tell the tale. The source of his infection was thought to be the traditional family meal of tiet canh, which consists of chopped, congealed raw duck blood and herbs. However, doctors are examining a more sinister explanation - that he contracted the flu from his brother. This would mean human-to-human transmission - the doomsday scenario that would bring mankind one step closer to a global pandemic. And, paradoxically, Nguyen Thanh Hung's survival is not necessarily good news for mankind. Only when a disease becomes less lethal can it spread with ease. This is because if the virus is too lethal it will kill the host and, therefore, won't be able to spread among the general population.

A pandemic is a new infectious disease that spreads over a wide geographical area, with the proven ability to destroy empires, wreck economies, paralyse societies and kill tens of millions of people in a matter of months. The origins of pandemics are believed to rest in the domestication of animals, which occurred in pre-history when man moved from a largely nomadic life to one based on agriculture and the domestication of animals. With these animals came their diseases - both influenza and tuberculosis - and it was not long before these viruses were able to leap to humans.

The first recorded pandemic occurred during the Peloponnesian War in 430 bc, when an unknown disease killed a quarter of the population of Athens over a four-year period. The Greek historian Thucydides survived to tell the tale: "People in good health were all of a sudden attacked by violent heats in the head, and inflammation in the eyes; the inward parts, such as the tongue or throat, becoming bloody and emitting an unnatural and fetid breath." This was followed by sneezing, coughing, diarrhoea, vomiting, skin covered in ulcers, dehydration and almost always death; scientists have speculated that this was smallpox.

The Black Death of the 1300s - so-called because it caused a blackening of the skin - was a bubonic plague which arrived from Asia and killed a quarter of Europe's population between 1347 and 1350.

Mankind has endured an average of three pandemics each century since the 1500s, and the 20th century was no exception to this pattern. The most frightening example was the Spanish flu of 1918. The first recorded outbreak came in March, that year, when an army cook became ill at Fort Riley in Kansas and within days hundreds more had taken ill. In a world exhausted by war, this went unheeded, and only as summer ended did the spread begin in earnest. The flu is estimated to have killed 25 million people in six months and infected at least a quarter of the world's population. Initially, doctors thought it was an airborne version of bubonic plague, because those infected died so quickly. Then, virtually overnight, it disappeared, after killing 40 million people.

Spanish flu would have remained little more than an historical footnote were it not for the fact that disturbing new research shows its relevance to H5N1. A team at the US Armed Forces Institute of Pathology was able to piece together the genetic sequence of the 1918 virus from the remains of pandemic victims. This data was used to recreate the virus in mice at the US Centers for Disease Control and Prevention. They discovered that the virus's genetic code revealed mutations in genes that control its ability to replicate in host cells and, alarmingly, that they mirrored those viruses found only in birds, such as H5N1.

Like the Spanish flu virus, H5N1 has the ability to leap across the species barrier and kill people directly. And, instead of killing infants, the elderly and the sick - as with most types of flu we see each winter - Spanish flu killed those in the prime of their life. It attacked deep within the lung, destroying tissue and provoking a huge immune response, which led to the victims drowning in their own blood. And although the exact mechanism through which H5N1 spreads and kills its hosts is unclear, it appears likely that it, too, provokes a huge immune system response. As well as destroying the lungs of the victim, H5N1 induces pneumonia and ultimately leads to multi-organ failure among the young and healthy.

So far, the H5N1 strain shows only some characteristics of Spanish flu, but one common feature is an ability to mutate repeatedly.

The race to prevent a catastrophe

Since the latest outbreak of avian flu in South Korea in late 2003, it has killed 70 people out of the 137 human cases reported to the World Health Organization (as of December 9, 2005). Thailand, Indonesia and Vietnam are the worst affected. Fifteen countries have been affected across Asia and Europe and an estimated 150 million birds have died from infection or been culled in a vain attempt to stop it spreading. Aside from the virus itself, a mix of social, political, economic and cultural factors all suggest that the spread of H5N1 is unlikely to be contained.

In October, David Nabarro, the UN's new co-ordinator for avian and human influenza, predicted that up to 150 million could die and that mankind was in a race against time to limit the loss of life. A more upbeat note is sounded by Margaret Chan, WHO's assistant director general in communicable diseases: "In history, no human intervention has managed to stop a pandemic once it starts. For the first time we are seeing a pandemic unfolding before our eyes. There is a chance that we could smother the spark of a fire before it catches on. It will depend then on spotting an outbreak of human transmission quickly and acting quickly."

Chan speaks from personal experience, because she was the health secretary in Hong Kong, which is where both avian flu and Severe Acute Respiratory Syndrome came to world attention.

Sars emerged in late 2002, in Guangdong - the mainland Chinese province that borders the former British colony - when a single carrier visiting Hong Kong is believed to have been the source for a worldwide spread of the virus, which eventually infected 8,437 and killed 813. The virus is now thought to have originated in bats, before infecting civet cats and eventually humans.

Avian flu first emerged in the territory in 1997, just after it had been returned to Chinese rule. It infected 18 people, killed six of them, and was only stopped when officials ordered the cull of the territory's entire 1.5 million birds. Virologist Malik Peiris, a member of the microbiology team at the University of Hong Kong, which helped identify H5N1 eight years ago, says: "All of us were extremely concerned then, because this was the first time that we had seen a purely avian virus jump to humans. We were concerned that there could be a pandemic, but from that time there has not been a single case in Hong Kong."

With its developed infrastructure, however, Hong Kong is the exception.

Avian flu was first identified in 1996, across the then border in Guangdong. Both the 1957 Asian flu and the Hong Kong flu of 1968, which each claimed around 4 million lives, are thought to have come from the same region. Experts believe the origins lie in China's farms where animals and humans live in close proximity and are exposed to each other's viruses.

Genetic scientist Antoine Danchin, a professor at the Pasteur Institute in Paris, says: "Flu is a normal disease of ducks and geese. In China, you have ducks, geese and pigs together on small farms. Usually, the disease goes from ducks to pigs and then humans."

Infected birds pass on H5N1 through their saliva, nasal secretions and faeces. Other birds may become infected through direct contact with these secretions or with contaminated surfaces. However, while H5N1 is fatal to most poultry, it is relatively benign for most wild birds. Scientists believe that wild migrating birds are responsible for the spread of avian flu.

The Chinese Government is optimistic about its ability to tackle avian flu, but this is where politics kick in. Despite evidence that China has been the source of repeated outbreaks of H5N1, the country remains wedded to secrecy. For example, it seems scarcely credible that China has just uncovered its first possible cases of human H5N1 infection since the virus was identified. When the Sars virus emerged in Hong Kong in 2003, China was transparently the source of the disease, yet the Communist government denied it.

China insists it has learned its lesson and that it has embraced a new spirit of transparency. Yet only this July, microbiology professor Guan Yi, a close colleague of Peiris's, was "leaned on" by Chinese officials after he released information about H5N1 spreading through wild birds in China.

Such is the fear that the authorities cause among academics that Peiris declined to discuss China for this article, and the once outspoken Guan Yi is now rarely heard publicly. When you consider that the world may have only 20 days in which to prepare and distribute vaccines, once a pandemic has been identified, such intimidation does not inspire confidence.

For all developing countries, however, the stakes are particularly high, with farmers relying on poultry to survive. A pandemic will paralyse economies and may start a global recession. The Asian Development Bank predicts up to a US$2.5 trillion contraction in trade, while the World Bank goes for a more conservative US$800 billion.

The challenges of preventing a pandemic

The world economy's best line of defence appears to be combination of anti-viral medicine and vaccines. Antoine Danchin says: "There are six billion people, so we need to make vaccine doses in huge amounts and this presents political and economic problems. There is simply not enough profit in vaccines, because it is so efficient. One dose lasts for years - where is the money in that?"

Peiris also blames litigious patients for the declining numbers of companies manufacturing vaccines. "One bad side effect in a million doses is enough to cause havoc in terms of legal action. But there is also the lobby in so-called educated cultures 'knocking' vaccines such as MMR, and in retrospect this is false. For these reasons vaccines are in retreat."

There is another problem: we don't know which virus will provoke the pandemic, and there is no guarantee it will be H5N1. Any H5N1 vaccines produced using the current strains of the virus may prove largely useless against a new strain of H5N1 or even another virus altogether when it starts infecting people in huge numbers. And once the virus is identified it may take weeks before the first vaccine rolls off the production lines.

The British government has been complimented by the WHO for its pandemic plan of action. It is relying on 14.6 million courses of the anti-viral drug Tamiflu to hold the line in the first few weeks, and contracts are currently out to tender to produce 120 million vaccine doses - enough for every person in the UK to have the two doses which are considered adequate to provide immunity. If the vaccine is administered within 48 hours of the onset of symptoms, it is expected to lessen the severity of the symptoms - it is not a cure - but doubts are now growing as to Tamiflu's continuing effectiveness.

Anne Moscona, a professor at Cornell University in New York, says Tamiflu-resistant H5N1 "is now a reality", and calls for efforts to prevent individuals stockpiling the drug, whose misuse - by taking too low a dose - will breed resistance. Other doctors are calling for other antiviral drugs to be deployed alongside Tamiflu. That would seem a wise strategy.

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