The world is one step closer to a devastating killer flu pandemic, World Health Organization (WHO) experts suspect.

Two developments in northern Vietnam spur the renewed concern:

—Deadly bird flu infections are being seen in larger clusters of people — with a much wider age range — than ever before.

—The virus is changing in ways that suggest it may be adapting to humans.

—Also of concern is the revelation that one virus isolate was partially resistant to TamiFlu, the only effective treatment for human infection with type H5N1 bird flu.

Because of these developments, the WHO urgently convened a panel of experts that met earlier this month in Manila, Philippines. The panel's report, written on May 11, was released yesterday.

"All countries, both those affected and unaffected by avian H5N1 ... should move ahead as quickly as possible and develop or finalize practical operational pandemic preparedness plans," the panel advised.

Another Tick of the Pandemic Clock

The WHO lists six stages leading from the detection of a new flu virus in animals to a global human flu pandemic. So far, the H5N1 bird flu has been at stage 4: small, highly localized clusters of human infections. At this stage, the virus cannot spread easily from person to person.

The new evidence suggests — but does not yet prove — that bird flu may be moving to stage 5. That would mean the virus is becoming increasingly better at person-to-person spread. When stage 6 is reached, there will be rapid human-to-human flu spread and pandemic flu.

It's only a matter of time, says virologist Klaus Stöhr, PhD, DVM, project leader for the WHO Global Influenza Program.

"We are in a situation where we simply have to deal with uncertainties on when this will happen — not whether this will happen or not," Stöhr said yesterday in a news conference. "We believe a pandemic will happen, but we don't know when and also [we don't know] the severity of the event."

The last flu pandemic was in 1968. That means that this is the first time the world has had the tools in place to track a flu pandemic as it develops. Guénaël Rodier, MD, MSc, director of the WHO Department of Communicable Disease Surveillance and Response, says it's becoming clear that there are many small steps — rather than alarming leaps — that lead to a flu pandemic.

"There is no evidence of a big crisis," Rodier said at the news conference. "But there are enough elements to say there may be something going on. ... We have enough data to be concerned. At the same time we don't have enough data to be sure."

"In the last 18 months, we have seen an incremental increase in our concern," Stöhr said. "We do not know if a pandemic can occur next week or next year."

Killer Flu Pandemic: What Could Happen?

The H5N1 bird flu virus could, theoretically, become a pandemic flu virus overnight. That could happen if a person or animal were infected with a human flu virus and the bird flu virus at the same time. In that case, the viruses could "reassort" — that is, swap genes.

On the other hand, what seems to be happening is that the H5N1 virus is only gradually learning how to pass more easily from human to human. That, Stöhr says, is giving us time to prepare. But when the virus does learn this trick, it's going to be hard to stop.

This last happened in 1968, when a new human flu virus appeared in Asia. It took six to nine months to reach the U.S. Today, it would probably take only three months.

Right now, the world has only 2 million doses of a new vaccine against H5N1 bird flu — all in the U.S. Safety tests aren't yet complete. And it's not even clear whether the vaccine will really work against the strain of flu that eventually emerges.

Although the bird flu virus is extremely deadly to humans, it's likely that it would become less virulent if it adapted for human-to-human spread. But it could easily be as deadly as the worst flu virus yet: the pandemic flu of 1918 that killed 50 million people worldwide — half of them young, healthy adults.

So what might happen? Michael T. Osterholm, PhD, MPH, is director of the Center for Infectious Disease Research at the University of Minnesota. He sketched out a likely scenario in the May 5 issue of The New England Journal of Medicine.

Osterholm notes that with current technology, it would take at least six months to start producing a vaccine — and two doses would be needed for protection. And as Stöhr notes, the virus would reach the U.S. within three months.

If the bird flu started a pandemic now, Osterholm wrote:

"We would be facing a 1918-like scenario. ... We would have no surge capacity for health care, food supplies, and many other products and services. ... We have no detailed plans for staffing the temporary hospitals that would have to be set up in high-school gymnasiums and community centers — and that might need to remain in operation for one to two years. ... We have no way of urgently increasing production of critical items such as antiviral drugs, masks for respiratory protection, or antibiotics for the treatment of secondary bacterial infections. ... Nor do we have detailed plans for handling the massive number of dead bodies that would soon exceed our ability to cope with them."

The WHO expert panel underscores this concern. They note that the H5N1 virus already has resulted in the death — or culling — of 100 million chickens and ducks. To date there have been 97 confirmed human cases and 53 deaths in Vietnam, Thailand, and Cambodia. Many more cases undoubtedly have gone unreported.

"H5N1 viruses have the potential to cause far greater harm if they evolve and gain the ability to easily infect and transmit among people," the panel's report notes. "An H5N1 virus with this ability could lead to a global pandemic and many millions of deaths worldwide."

Action Needed

The WHO panel recommends rapid action, including:

—Improving cooperation and information sharing among all human and animal health agencies.

—Improved surveillance of all clusters of human infections.

—Regular meetings of a WHO task force.

—An international stockpile of antiviral drugs.

—Nations should rehearse their rapid response plans to contain early flu outbreaks.

—WHO should explore ways to make human H5N1 vaccine available to affected Asian countries before the start of a pandemic.

Osterholm calls for a huge U.S. effort.

"Planning for a pandemic must be on the agenda of every public health agency, school board, manufacturing plant, investment firm, mortuary, state legislature, and food distributor," he writes.

If a pandemic were 10 years off, Osterholm says a "worldwide influenza Manhattan Project" to develop and distribute a vaccine "just might make a real difference."

By Daniel J. DeNoon, reviewed by Charlotte E. Grayson, MD

SOURCES: WHO Inter-country Consultation: Influenza A/H5N1 in Humans in Asia, Manila, May 6-7, 2005. News conference transcript, Klaus Stöhr, PhD, DVM, project leader, Global Influenza Program; and Guénaël Rodier, MD, MSc, director, Department of Communicable Disease Surveillance and Response, WHO, Geneva.