03/18/2010 05:12 am ET Updated Nov 17, 2011

Swine Flu Scare: A Trial Run for Something Far Worse?

Could the swine flu scare be a trial run for something far worse? Swine flu has given many a fright with parents lining up for hours to get their children vaccinated and hospital ICUs in some cities overflowing with patients. And the top pandemic flu expert at the World Health Organization, a veteran American flu hunter named Keiji Fukuda, has warned in recent weeks that the global epidemic isn't over yet. Still, for other people, swine flu has been an anticlimax, little more than a yawn.

Either way, swine flu is certain not to be the final chapter in the influenza saga. Here are five potential twists in the pandemic plot that flu specialists are watching for anxiously. Any one of these could spell a new, far more ruthless wave of disease.

1. The virus shifts its target.

Swine flu has so far proven no worse than regular seasonal flu for most people. But in a series of cases scattered across four continents, disease specialists have noticed that the virus has mutated, allowing it to strike deep inside the human lungs and cause illness that's far more severe, at times life-threatening.

Among viruses, influenza is exceptional because of its rare talent for mutating. So scientists are always on the lookout for ominous changes. Doctors in Norway sparked a fresh round of global anxiety this fall when they reported they'd detected a mutation in three hospital patients that had allowed swine flu to extend its range from the usual targets of the nose and throat and penetrate the lower airway. Similar mutations have been detected in at least six other countries, including the United States.

This lethal change has yet to become prevalent but if it does, the death toll could soar. After all, the lungs were the primary target for the Spanish flu of 1918, which killed more than 50 million people worldwide.

2. The virus steels itself against treatment.

The drug of choice for treating serious swine flu cases is Tamiflu. Yet in scores of cases this fall, scientists discovered that the virus had become resistant to this drug. Public health officials have been watching nervously for this development because resistance to Tamiflu is already widespread with seasonal flu.

Their fears were confirmed when doctors in Wales reported that five swine flu patients were infected with a resistant strain and that it had apparently spread from one person to another. More instances of Tamiflu resistance have surfaced in the United States, including in North Carolina, Maryland, Virginia and Washington state.

So far, Tamiflu resistance seems to be concentrated among patients with severely compromised immune systems. For instance, they had cancer, were undergoing chemotherapy or were receiving treatment after an organ transplant. Today, there are many more people with weakened immune systems - largely because of the prevalence of HIV infections - than during any previous flu pandemic, raising the urgent question: Will this be the recipe for a widespread, drug-resistant strain?

3. A killer emerges from Asia.

Swine flu is rarely lethal, but the virus called bird flu kills more than half of those known to catch it. And while the media has been focused on swine flu, bird flu has continued to circulate silently in East Asia and beyond.

Ever since bird flu stunned flu specialists by first jumping to people in Hong Kong more than a dozen years ago, it has relentlessly spread from country to country, thwarting the efforts of public health officials to root it out. Time after time, government officials have claimed to have the virus cornered only to see it break loose again. The longer scientists study this strain, the more similarities they've identified between bird flu and the devastating flu of 1918. One of America's most prominent public health experts has called bird flu the "kissing cousin" of Spanish flu.

The good news: bird flu has yet to figure out how to spread easily among people. But in at least six countries, it has already shown it can pass from one person to a second. With a few genetic tweaks to make it more contagious, tens of millions could die.

4. A sinister tryst breeds a new strain.

For flu specialists tracking swine flu, the nightmare is that it encounters bird flu and they combine, swapping genetic material. The result could be a hybrid strain that is as deadly as bird flu, with its 60 percent mortality rate, and as easy to catch as swine flu.

Influenza viruses are remarkable not just because of their facility at mutating. Unlike most viruses, one flu strain can actually trade attributes with another flu strain if they both infect the same human, or even pig, cell.

WHO's top official, Margaret Chan, urged the world's senior health experts this spring to keep their eyes out for just this development. Since then, flu hunters have watched closely as swine flu spread to countries like Vietnam and Egypt, places where bird flu is deeply entrenched and still killing people. While there's no evidence so far of what's called reassortment, WHO's director for East Asia repeated the warning in November. So did one of China's most prominent virologists, Zhong Nanshan, who helped blow the whistle on his government's cover up of SARS seven years ago. Noting that bird flu has been circulating there for a long time, he warned that that swine flu might hold the key to unlocking its horrors.

5. Novel threats spread beneath the radar.

As if H5N1 bird flu wasn't enough to fret about, there are other avian flu strains out there, and they may actually have an edge in the pandemic sweepstakes. They have names like H9N2 and H7. (The H's and N's refer to different types of proteins on the surface of a flu virus and are used to identify specific strains.) As with H5N1 bird flu, the vast majority of people on Earth have no immunity against them.

One of these little-noticed strains, H9N2, has already proven it can infect people, including several in China and Hong Kong. Some scientists believe that human cases are more common than most experts acknowledge and that the virus has already shown it can spread from one person to another. Like its better-known cousin, it has quietly spread across the birds of Asia and the Middle East on to Europe and Africa. Meantime, a separate family of flu strains, the H7s, has been circulating both in North America and Europe.

While these lesser-known viruses aren't as lethal as H5N1 bird flu, they've already demonstrated they're better at infecting humans. And if they start to get around, they could provoke a global outbreak that makes us nostalgic for the Pandemic of '09.