``It's going to happen,'' said Dr. Greg Poland of the Mayo
Clinic. ``For the American public in particular, I think it will be
horrific.''

Many Americans haven't experienced the overwhelming crush of
patients at hospitals and doctors' offices and the widespread fear
a flu pandemic could bring. And by historical pattern, Poland said
it's about time for the next one.

There have been three in the past 100 years, igniting in 1918,
1957 and 1968. There's no way to predict when the next one will
appear, but the pattern does give experts pause.

It's all up to a virus that is variable and fickle, constantly
changing its genetic makeup, and the time when it hits upon a
combination that lets it take off worldwide is a ``roll of the
genetic dice,'' said Dr. William Schaffner of Vanderbilt
University.

So the lack of a pandemic in the past 35 years basically means
``the genetic dice haven't been rolled that way,'' Schaffner said.
``While we're grateful for that, it makes us nervous.''

There's plenty to be nervous about. It's estimated that in the
industrialized nations alone, the next pandemic is likely to send 1
million to 2.3 million people to the hospital and kill 280,000 to
650,000, according to the World Health Organization. Its impact
will probably be greatest in developing countries.

As a practical matter, flu shots probably could not be counted
on to prevent a pandemic. For one thing, pandemic virus strains
emerge unexpectedly, and there would probably not be enough time to
recognize the threat and then provide vaccines that target them,
Schaffner said. What's more, many countries outside the United
States wouldn't have the means to give enough flu shots to stop the
spread, Poland said.

Dr. Robert Couch of the Baylor College of Medicine noted that
health authorities are making major efforts to prepare for
controlling a pandemic, including putting an emphasis on developing
and manufacturing vaccines faster and in greater quantities.

The pandemic of 1918-19, known as the Spanish flu, sickened an
estimated 20 percent to 40 percent of the worldwide population,
with a death toll believed to exceed 20 million. In the United
States alone, some 500,000 people died. An ordinary flu epidemic
kills an average of 36,000 Americans.

The next pandemic, the Asian flu of 1957-58, killed about 70,000
in the United States. The 1968-69 Hong Kong flu led to about 34,000
deaths in the United States. Scientists suggest several reasons why
this rate was lower than in previous pandemics, including that the
illness did not gain momentum until near the school holidays in
December, when children were home rather than infecting each other
at school.

New strains of the flu virus, and so potential pandemics, get
their start in rural Asia, where the various strains that infect
chickens and other birds, pigs and humans can mingle. That gives
them a chance to swap genetic information as well as mutate on
their own.

The potential spark for a pandemic occurs when that environment
produces a new virus that infects people and bears surface proteins
that people's bodies have never seen before. That means people have
no natural defense against it.

In contrast, ordinary outbreaks like this year's come from a
virus that has changed only slightly from previous ones, so that
the population it enters still has some natural immunity from
encounters with the previous germs.

But the genetic shift alone is not enough to launch a pandemic.
In addition, the new virus must acquire the ability to pass easily
from person to person, either by random genetic change or by
picking up genetic material from a previous human flu virus.

The world has had some close calls in the past few years, says
Richard Webby of St. Jude's Children's Research Hospital in
Memphis. In 1997, a bird flu in Hong Kong jumped to people, killing
six. But the virus never developed the ability to pass easily from
person to person, Webby said. Hong Kong authorities slaughtered 1.4
million chickens to end the threat.

Just this year, authorities became alarmed when a father and son
in Hong Kong were hospitalized because of a bird flu virus, and
when flu virus infected some workers in the Netherlands who had
slaughtered infected chickens. The Netherlands outbreak was
contained by anti-flu drugs and fast vaccination, and slaughter of
the poultry, Webby said.

Scientists have been noticing a lot of flu virus in chickens and
pigs globally, and a lot of variety in the strains, which is
worrisome, Webby said. It's impractical to develop vaccines against
all the animal strains in case they jump to humans, and there's no
reliable way to identify the most hazardous ones, he said.

When the next pandemic shows up, experts say, it will find a
population with many more vulnerable people like the elderly,
infirm and those with weakened natural defenses than were living 35
years ago. It will also find a trimmed-down hospital system with
fewer beds to handle a surge of patients. And while today's
anti-flu drugs will probably attack the new strain, that's not yet
clear. Supplies of the drugs and vaccines would be strained.

But still, with the improvements in health care since the last
pandemic, might the next one be less serious?

``I want to believe that,'' Poland said, ``but we won't know
until it happens.''

On the Net:

Pandemic information: www.cdc.gov/od/nvpo/pandemics

www.who.int/csr/disease/influenza/pandemic/en/