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WHO Now Says Indonesia Bird Flu Cluster that Killed Seven Humans Had 21 Genetic Mutations

The World Health Organization wants the government of Indonesia to release a WHO-compiled report on a large cluster of human H5N1 avian flu cases, but it's worried about pressing the issue too hard, a top official of the Geneva-based agency said Thursday.

Dr. Paul Gully said the WHO is walking a fine line, aware that pushing too aggressively to get Jakarta to release the report or to share the genetic blueprints of viruses recovered from flu cases in the cluster may generate less co-operation, not more.

So despite the fact that Indonesian officials said weeks ago they would be willing to release sequence data of viruses from the Sumatra cluster to the broader scientific community, the WHO has not yet requested that the country do so.

"We have not asked them. . . . We would prefer to wait for the response of the country,'' said Gully, who was seconded to the WHO earlier this year from the Public Health Agency of Canada. Gully is senior adviser to Dr. Margaret Chan, the WHO's assistant director general and head of pandemic influenza efforts.

"We feel that asking them may not produce the results that we want. In other words, if Indonesia feels they're being pressured to release this, then they may decide -- and they have every right to do so -- not to release the information.''

Gully suggested other governments might hold more sway on the issue than WHO, which has no authority over its member countries.

"If other countries pressured Indonesia to release it, then that might help us,'' he said.

Gully's comments followed publication Thursday by the journal Nature of a portion of that as-yet unreleased report. It was prepared for a special meeting that drew some of the world's top minds on avian flu to Jakarta in late June to assess Indonesia's widespread and worrying avian flu problem and make recommendations on how it could be brought under control.

The meeting concluded that human-to-human-to-human spread of the virus had likely occurred in a large cluster of cases in Sumatra in May, but that transmission had ended with the death of a man on May 22.

The H5N1 virus is believed to be endemic in the world's fourth most populous country. Since July of last year, 52 Indonesians have been confirmed as being infected with the virus. Forty of those people have died, leaving Indonesia poised to soon overtake Vietnam as the country which has paid the highest price, in human lives, because of the virus.

Vietnam has recorded 93 cases and 42 deaths since late 2003. But the country, which has worked hard to eradicate the virus in poultry flocks, hasn't had a human case since last November.

The Nature news article said analysis of viruses recovered from members of a large family cluster of cases in the North Sumatran village of Kara showed multiple and apparently accelerating genetic changes as the virus moved through three generations of people. Viruses from each person, when compared to viruses from the rest of the cluster, showed one, two or four mutations.

But virus recovered from the last case in the cluster -- a man who is believed to the only person infected in the third generation of cases within this group -- had accumulated 21 mutations, according to the report, prepared by Dr. Malik Peiris. Peiris heads a laboratory at the University of Hong Kong which serves as the WHO collaborating laboratory for Southeast Asia.

At the time of the closed-door meeting, WHO officials downplayed the virologic findings to the media, speaking of a single mutation that was seen in viruses that developed in one of the second generation of cases, a 10-year-old boy, and which was passed to his father, the last victim.

The significance of the mutations -- and of the number accumulated -- is unclear. But the revelation that there were more mutations than have previously been reported renewed calls Thursday for the WHO to throw open a password-protected database of sequence data on a large collection of viruses from human H5N1 cases. Only scientists from select international laboratories have access to the database.

"This flu cluster raises important questions about human-to-human transmission,'' said Steven Salzberg, director of the Center for Bioinformatics at the University of Maryland and a harsh critic of the closed-access database.

"The expertise required to understand the flu is scattered around the world, and only by sharing the data can we draw upon that expertise.''

Gully said expert analysis of the viral sequences and more importantly information on the way the virus spread-- and died out -- leave the WHO confident the mutations seen in the Sumatran cluster did not increase the virus's transmissibility.

"It is the opinion of the people here and the people who have seen that information in the WHO collaborating network that these are not significant mutations,'' Gully said from Geneva.

An expert in the molecular genetics of influenza viruses agreed that for the most part, the number of mutations is in the range of what one would expect to see with an ever-changing RNA virus like flu.

"So when you see one mutation, one mutation, two mutations, that's probably normal,'' said Adolfo Garcia-Sastre, a microbiologist at Mt. Sinai School of Medicine in New York. Garcia-Sastre was not involved in the meeting in Jakarta.

He suggested 21 mutations would be more than one would expect to evolve by chance, but said without any information on where the mutations were on the virus, it would be impossible to guess at the significance of the number or the mutations themselves.

"Even if this virus was somehow more adapted to humans, this genetic lineage died when the transmission cycle was stopped,'' he said.

The cluster was the largest recorded to date, involving seven confirmed and one suspect case in a family, all blood relatives. It is believed the suspect case, who was never tested, passed the virus to six members of her family before she died in early May. Her 10-year-old nephew was among that second generation of cases; he is believed to have infected his father, who nursed the boy before his death. Only one member of the cluster survived.

Since the H5N1 virus re-emerged in Southeast Asia in late 2003, there have been 229 confirmed cases and 131 deaths.