The cases raise the frightening possibility that there have been far
more human infections with H5N1 than thought, because many cases have been
overlooked by doctors watching for the fever and cough of typical flu.

More human infections mean that H5N1 has had even more chances to adapt
itself to humans. And if the virus often starts as gastrointestinal
disease it will be very hard to detect against a high background incidence of
such disorders in the region.

A four-year-old boy was taken to hospital in Ho Chi Minh City in
February 2004 with severe diarrhoea and increasing drowsiness. He slipped into a
coma and died. His nine-year-old sister had died with similar symptoms two
weeks before. The boy had some symptoms of chest infection just before he
died, but neither were suspected of having flu.

Samples from the boy's blood, throat, spinal fluid and faeces were sent
to Oxford University, UK, as part of a project to find out which pathogens
most frequently cause acute encephalitis, or brain inflammation, in Vietnam.
After tests for all the suspected viruses came up negative, wider viral
screening revealed H5N1 in all the samples.

Swimming with ducks
There were no samples from the girl, but because her symptoms were so
similar the authors suspect she died of the same infection. She also
swam frequently in a canal used by domestic ducks, which can harbour the
H5N1 infection.

"These cases have important clinical, scientific and public health
implications," the scientists write in the New England Journal of
Medicine Severe gastrointestinal infections and encephalitis are common in
children in the region, they note, both alone and together, making unusual
clusters due to H5N1 hard to spot. Moreover, neither child started out with the
high fever that had been considered a hallmark of the flu.

The hitherto unsuspected presence of the virus in faeces could pose a
problem in regions with poor sanitation if H5N1 ever acquires the
ability to readily infect humans.

Antibody search
And there is evidence the virus might have caused more cases like that
of the Vietnamese siblings. In Thailand in 2004, doctors reported a
39-year-old woman who went to hospital with nausea and diarrhoea. But since she
then developed pneumonia and respiratory failure - and had also been exposed
to sick poultry - she was tested for H5N1, and the infection was
confirmed. The woman subsequently died.

The World Health Organization is now analysing blood from people in
areas affected by H5N1, to see how many carry antibodies to the virus -
indicating they had survived infection by it - and hence how many unsuspected
infections there may have been.

Studies are also underway in macaque monkeys at Erasmus University in
Rotterdam, the Netherlands, to see what spectrum of disease symptoms
H5N1 can produce in primates, says Albert Osterhaus, who is running the
studies.

"Flu viruses infect the brain in some mice, and in ferrets," says
Osterhaus. There was also a suspicion that the virus affected people's brains
during the great 1918 flu pandemic, and might have led to the widespread
"sleeping sickness" afterwards, he says, but this has never been proven.

Journal reference: New England Journal of Medicine (vol 352 p 686)