Studies Spot Obstacle to Human Transmission of Bird Flu

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Two new studies help explain why human-to-human transmission of the bird flu virus has so far not happened -- and might not happen in the future.

Both reports found the H5N1 virus prefers to settle in cells deep within the lungs, rather than in the upper respiratory tract, as happens with human flu strains.

That's important because "most of the coughing and sneezing that transmits flu is going to be from the upper respiratory tract, and not way down in the lower respiratory tract," explained Dr. Arnold S. Monto, a professor of epidemiology at the University of Michigan School of Public Health. "So, unless you have relatively close contact, you're not going to have much [bird flu ] virus get out."

The findings may also explain why bird flu has proven so lethal whenever it has managed to get a foothold in humans, the experts added.

Since 2003, the H5N1 virus has been found in Asia, Europe, Africa and the Middle East, and has led to the slaughter of tens of millions of domestic fowl. While infection has primarily been limited to birds, the virus has killed 103 people via bird-to-human transmission. Scientists worry, however, that the germ could mutate into a form that would make human-to-human transmission far easier, raising the specter of a pandemic that could kill millions of people.

One of two studies published this week that looked at that possibility was conducted by researchers working at the University of Wisconsin and the University of Tokyo. They reported their findings in the March 23 issue of Nature.

The team focused on two variants of a receptor molecule lying on the surface of cells that line the nasal/bronchial passages and the lungs. These receptors, called SAalpha2,3Gal and SAalpha2,6Gal (2,3 and 2,6, for short), are the biochemical "hook" flu viruses use to latch onto cells.

Scientists long ago determined that H5N1 strongly prefers the 2,3 form of the molecule. "What this paper was doing was identifying where the locus of these 2,3 receptors are in humans," Monto explained.

The Japanese-American team found that, as expected, H5N1 avian flu is drawn to the 2,3 receptors. Luckily for humans, they also found that 2,3 is most abundant on cells within the alveoli, the most remote, microscopic branches of the lungs' "respiratory tree."

H5N1 was much less likely to bind to cells in the upper respiratory tract.

In contrast, common human flu strains prefer to bind with the 2,6 receptor, which is found in plentiful numbers on upper respiratory tract cells. That makes sense, experts say, because every time humans cough or sneeze, droplets from this area are easily expelled into the air, making human-to-human transmission of ordinary seasonal flu possible.

H5N1 colonizes a much deeper, tough-to-access region of the lung -- making infection more difficult to spread and treat in humans, the researchers said.

The finding also helps explain another phenomenon: The fact that many people have tested positive for exposure to H5N1, but have never developed actual infection or illness.

"They didn't have bird flu, but they made antibodies to it," explained Dr. Marc Siegel, a clinical associate professor of medicine at New York University School of Medicine and author of Bird Flu: Everything You Need to Know About the Next Pandemic.

According to Siegel, it appears that these people may have encountered H5N1, but because the virus failed to reach the lower lung, it never gained a "foothold" for infection.

How, then, to explain the more than 200 documented human cases where people did develop full-blown bird flu?

"I've always assumed it's due to [the patient's] high viral load," Siegel said. In other words, these patients -- most of whom worked every day in close proximity to infected birds -- were so surrounded by H5N1 that it eventually managed to colonize the lower reaches of their lungs.

Once the virus does lodge and flourish in the lower lung, it can quickly prove deadly, Monto said. "It causes pneumonia, a whiting out of the lungs," he said. "In fact, a lower respiratory pathology fits very well with what we are finding" in human cases.

The Japanese/American findings were echoed in another paper, scheduled for release in the March 24 issue of Science but published early to coincide with the Nature study.

In that study, Dutch researchers at the University of Rotterdam again found that avian flu preferred receptors on cells deep in the lungs, and shunned binding with cells in the upper respiratory tract.

All of this means that human-to-human transmission of H5N1 is highly unlikely, at least for now, experts say. However, any mutation or series of mutations that caused H5N1 to switch its preference from the 2,3 receptor to the 2,6 receptor could change all that.

Could such genetic changes occur, as experts believe may have happened in the 1918 Spanish flu pandemic?

"That's the $64,000 question," Monto said. "We're all concerned about mutations or any re-assortment that might change the virus."

But Siegel believes the virus would have to undergo a number of complex genetic mutations to move up the respiratory tract. "And even if it does, that's still not an assumption that it's going to cause a severe pandemic," he said.

Still, he and other experts agree that as the virus circulates in millions of migrating birds, vigilance will be key.

"All of this argues for intensified surveillance and attempting to contain, if possible, the disease in poultry," Monto said.