The victims of the deadliest flu pandemic in history were killed when their bodies unleashed an uncontrolled immune reaction as a protective mechanism, say scientists. Patients' lungs rapidly became inflamed and filled with blood and other fluids which eventually drowned them.

The discovery could help emergency authorities prepare for flu pandemics caused by the H5N1 avian flu virus, which appears to kill in a similar way. It may also give scientists ideas for making flu vaccines.

In 1918 a strain of influenza ravaged populations around the world, killing an estimated 50 million people before it eventually died out. In a bid to understand why this strain, called the Spanish flu, was so dangerous, American scientists re-constructed the virus in 2005.

In the latest experiment scientists used the re-constructed virus to infect macaque monkeys. They found that the over-reaction of the immune system destroyed the monkeys' lungs within a week.

There are strong parallels between this reaction and the one that almost killed six volunteers who were given the experimental antibody drug TGN1412 at London's Northwick Park hospital in March last year. Both the virus and the drug caused a surge of cytokines, the molecules in the blood that activate immune cells. When this "cytokine storm" occurs in the lungs, body fluids and immune cells can accumulate and block the airways, quickly leading to death.

"Essentially, people are drowned by themselves," said Yoshihiro Kawaoka, a virologist at the University of Wisconsin and a co-author of the study published today in Nature.
In the trials seven macaques were infected with the reconstructed 1918 virus. The experiment was supposed to last 21 days but after eight days the monkeys were so sick with fever, pain and breathing difficulties the researchers, following laboratory guidelines, killed the animals.

Scientists believe the 1918 virus had the same effect on humans. "There was some surprise that it was that nasty. It was the robustness of the immune system that helped victimise them," said Michael Katze, a microbiologist at the University of Washington in Seattle, who took part in the research. "That breaks the paradigm as always thinking of the host response as protective."

It might also explain why the 1918 flu virus killed so many healthy adults in their 20s and 30s; conventional influenza preys mostly on babies, the elderly or sick.

Darwyn Kobasa, of the Public Health Agency of Canada in Winnipeg, said the experiment was highly topical for researchers preparing for a possible flu pandemic from the avian H5N1 virus. "This can also cause very serious disease and it appears to do this in a way that appears quite similar to the 1918 virus. Although no one can predict if the H5 virus will cause a pandemic, the threat posed by the virus is significant."
Professor Kawaoka said that no flu virus other than the 1918 strain had been found to be deadly to monkeys. The speed that it spread and the overwhelming immune system response was only similar to those for the H5N1 avian flu. The only thing preventing a human flu outbreak from H5N1 was that the virus would need to mutate or combine with another strain. The 161 people killed by H5N1 since 2003 had had direct contact with infected birds.

"A greater understanding of the viruses that caused past pandemics will help us predict what to expect to reduce the impact of a new pandemic," said Professor Kobasa.
Professor Katze said: "Our analysis revealed potential mechanisms of virulence, which we hope will help us develop novel anti-viral strategies to both outwit the virus and moderate the host immune response. It's best to be prepared for a pathogenic virus by studying a pathogenic virus." He added that if a new virus were to cause a similar immune response to the 1918 flu authorities could prepare frontline staff in hospitals by treating them with a combination of anti-viral drugs, such as Tamiflu, and medicines to control inflammation.