TORONTO — Ominous changes in the behaviour and the makeup of the H5N1 avian influenza virus in northern Vietnam has the flu world worried the virus may be getting better at infecting humans.

In recent months the virus has sparked increasing numbers of small clusters of cases, suggesting more frequent occurrences of limited person-to-person spread. As well, it appears not to be killing as many of its human hosts - a biological change that cannot be assumed to be an entirely positive sign.

"Both of those observations, if they're true, might indicate that the virus is evolving to be a more efficient human pathogen. A more effective human pathogen," says Dr. Scott Dowell, the senior official in Southeast Asia for the U.S. Centers for Disease Control.

"We've been following that very, very closely and continue to be quite concerned that that may be the case . . . . (But) there is frank scientific uncertainty about what it really means."

Dowell is director of the CDC's international emerging infections program based in Thailand.

He has been heavily involved in tracking the progress of the avian flu virus since December 2003, when outbreaks ignited in poultry flocks throughout the region and started jumping with disturbing frequency into humans.

Vietnam, Thailand and Cambodia have reported 88 human cases of H5N1 infection to the World Health Organization since then. Of those, 51 people died.

Dowell, a man who measures his words with care, admits he is more concerned about the threat posed by H5N1 now than he was six months or a year ago.

The apparent changes to the pattern of human infections and an observed change in the molecular makeup of the few virus samples that have emerged from Vietnam this year account for his rising concern.

"The little (molecular) information that we have - and it's from a handful of isolates that have come out of Vietnam - is also concerning," Dowell said in an interview from Bangkok.

"What I'm hearing is concern that's paralleling the concern about the change in (disease) epidemiology."

While the level of unease is mounting, flu watchers know they understand so little about how pandemic strains evolve that they are incapable of judging whether these changes indicate H5N1 is making the final push toward pandemic strain status, or is setting off down a viral detour.

"That's the problem. You can sort of see it happening, but our predictive power is so crappy that even when you see it happening you don't know what the next step is, unfortunately," says Dr. Earl Brown, a virologist at the University of Ottawa who specializes in influenza evolution.

"They're real changes of biology but it's the relevance that I can't really give you any inkling of, really. Other than generalities: Keep this virus out of people"

Brown admits his interest was piqued when he heard reports that the fatality rate in Vietnam was dropping.

That type of the observation may only mean that Vietnam has gotten better at finding less severe H5N1 cases that previously flew under the radar. Or it could signify that the avian virus has undergone a real change that has put it on a path to becoming a human one.

"If the mortality is going down, that's a change. And if there's more . . . contacts getting infected, that's a change," Brown says.

"Is it the beginning of a trend? That's a question without an answer. Is it good? Well, it's not good per se, but it's not bad per se. You don't know where it's going to go."

Virology doctrine suggests that in order to become an effective and transmissible human pathogen, H5N1 would have to trade in some of its virulence cards. Highly virulent viruses don't spread very well. Dead hosts are dead ends.

That tradeoff could occur through reassortment - a process in which an avian virus and either a human or a swine flu virus swap genetic material. But it could also occur through a series of small evolutionary steps, each of which makes the virus better equipped to survive in people.

"You get one good mutation which then sweeps through the population because all the viruses with that mutation grow better," Brown explains.

"And then you can get another mutation on top of that and maybe another gene which gives you a leg up and that sweeps through the population. And then those become the dominant viruses."

That may be the process that is occurring now.

But the head of the WHO's global influenza program says there is simply too little information coming out of Vietnam to accurately assess what is going on with H5N1.

"We do perhaps see changes in age groups. We see perhaps changes in clusters. But what that means is absolutely unclear without having any more complex information," Dr. Klaus Stohr says from Geneva.

To know whether a new, more transmissible strain is emerging, researchers would have to be able to match isolates to case information - to see, for instance, if cases infected with viruses that had a specific mutation were more likely to happen in clusters. But that level of detail has not been emerging from Vietnam, Stohr says.

"There are too few viruses. No link between clinical data, disease outcome data and the genetic changes. And therefore drawing any conclusion on that very incomplete information is absolutely (impossible)."