For nearly four months, the spread of bird flu in the nation’s dairy cattle has stoked fears that, if left unchecked, the virus could eventually unleash a pandemic.

The recent cluster of human cases connected to poultry farms in Colorado only underscores that the threat remains real.

Genetic sequencing of the virus collected from the sickened poultry workers closely resembles what’s circulating in dairy herds, suggesting that cattle somehow introduced the virus into the poultry flock.

At one massive poultry facility, workers culled the birds under particularly dangerous circumstances.

As health officials describe it, they struggled to properly wear protective equipment over their mouth, nose and eyes as they handled thousands of sick birds in a sweltering barn, with industrial fans blowing feathers and other potentially virus-laden material into the air.

Given these conditions, it’s far from surprising that people would catch the virus themselves, says Jennifer Nuzzo, an epidemiologist at Brown University.

“It’s gambling with people’s lives,” she says. “There’s no other way to describe it.”

State and federal health officials are still investigating the scope of the outbreak, although so far all of those who’ve tested positive have only had mild, flu-like symptoms.

Nuzzo says the spillover at the poultry farms drives home the risks of having a viral reservoir in dairy herds that offers the virus ample opportunities to jump between species and potentially adapt to mammals.

“Every time you give an avian virus a chance to infect a human, it’s like buying a ticket for a lottery you don't want to win,” says Troy Sutton, a virologist at Penn State University who studies transmission of bird flu.

Based on the newest research, here’s what scientists are learning — and concerned about — as they study the virus.

Certain mutations could make the virus more dangerous

Luckily, there’s no indication that we have drawn the dreaded “winning ticket.” At least not yet.

The virus working its way through dairy cattle is still fundamentally well-suited to infect birds, not people; however, there are clearly some mutations helping it maintain a foothold in mammals, says Thomas Peacock, a virologist at the Pirbright Institute in the U.K. who studies avian influenza.

“I wouldn't be surprised if it's quite a lot more infectious at the same doses, than a purely avian virus that would have been seen last year in poultry,” says Peacock, adding that this may give it a leg up when it comes to infecting humans, too.

Scientists are still trying to get a better sense of what exactly these changes in the dairy cattle version of H5N1 are doing, but he says there are certainly some mutations that are already enhancing its ability to replicate in mammalian cells.

Of most concern would be the virus evolving to get better at using the type of receptors found in the upper respiratory tract of humans. Such a change could let bird flu spread easily via the airborne route between people similar to the seasonal influenza viruses that typically infect humans.

Peacock and other scientists are closely watching for changes in hemagglutinin proteins on the surface of the virus which would be ground zero for this development.

New study suggest virus may be better at infecting mammals than other types of bird flu

There are still many outstanding questions about how exactly humans are catching the virus.

One possibility, raised by federal health officials, is that a splash of milk, say, in the eyes or elsewhere could explain some of the infections in dairy workers, particularly those whose only symptoms were conjunctivitis. There’s also speculation that aerosolized milk could be another source of infection.

While the virus still doesn’t do well in the upper respiratory tract of humans, Peacock says, evidently there's a degree of replication because nasal swabs are testing positive for low amounts of viral genetic material, at least in some of the human infections.

Research on avian influenza predating the dairy cattle outbreak has shown that, with only a few mutations artificially inserted, airborne transmission can take place between ferrets, which are used as a model of human infection.

Since the dairy cattle outbreak began, scientists have begun to analyze how this version of the virus spreads, in hopes of understanding the threat it poses to humans.

The latest research, which comes from a team at the University of Wisconsin-Madison, shows the virus can be transmitted by respiratory droplets in ferrets, but inefficiently.

Amie Eisfeld, an author of the study, says their lab has not seen this kind of transmission event with any other version of highly pathogenic avian influenza that they’ve isolated from the natural world and tested in ferrets.

“There are features present in this virus that are concerning,” says Eisfeld, a researcher at the University of Wisconsin-Madison. “It’s important to be monitoring what is happening here, and to limit infections in cows and exposure in humans.”

In the experiment, only one of the four exposed ferrets caught bird flu from respiratory droplets. That animal didn't have any virus in the nasal swabs, but there were antibodies in the blood showing it had been exposed.

Sutton notes that just because a ferret in the lab caught the virus in this way doesn't necessarily mean humans will.

In another troubling finding from the study, the team discovered that the virus can bind to the type of receptors found in the upper respiratory tract of humans, suggesting it does possess “features that may facilitate infection and transmission in mammals,” the authors write.

To figure this out, Eisfeld says they artificially generated these receptors and attached them to a piece of plastic and then added the virus to see if it would stick.

Because this wasn’t done in actual people, she says the results need to be interpreted with caution: “I wouldn’t want to sound the alarm bells and [suggest] this is transmissible between humans.”

Peacock, who was not involved in the work, says the results do suggest this virus is “more infectious” in mammals than previous avian viruses. And while it doesn’t appear to be spreading between humans yet, he worries that could change. “It’s an influenza virus, if there's pressure for it to do something, it will learn to do it.”

While this kind of finding is unnerving, Troy Sutton says it needs to be put in context -- lab experiments are essentially creating a “pro-infection environment” that may not reflect what happens outside of the lab.

“This isn't exactly what a human nose is like out in the real world,” he says. “There’s snot and bacteria and there's all these other things that get in the way.”

The virus may be able to spread among cattle through respiratory transmission

It’s well-established that infected cattle are shedding high levels of virus in the milk for days or even weeks, before eventually recovering.

This has supported the hypothesis that the virus is primarily spreading from cow-to-cow during the milking process and through other shared equipment in the dairy barns rather than via the respiratory route.

However, some research hints that respiratory transmission can’t be ruled out.

In one recent study, a small number of non-lactating cows were purposefully infected with aerosols containing bird flu, which was collected from cow milk. Only one of the four animals consistently had viral genetic material in nasal swabs, whereas the rest only had positive results some days. Autopsies showed evidence of viral replication in their lungs, although none of the cattle had serious symptoms.

In contrast, the lactating cattle that were deliberately infected on their teats quickly showed signs of disease and increasing viral loads.

Taken together, those findings bolster the hypothesis that contact with infected milk is a key source of infection, but they also suggest the respiratory route may still have a role to play, says Dr. Amy Baker, the lead author of the pre-print study and a research veterinary medical officer at the National Animal Disease Center in Ames, Iowa. 

“This doesn't really tell us whether or not this is a main way that it's transmitting in these dairy farms, but it points to the fact that we need to at least keep an open mind that respiratory infection and transmission could occur,” she says.

The risks of a hands-off approach to stopping the outbreak

To be clear: There’s no evidence yet that humans who’ve caught the virus have spread it to others, which is why the CDC still deems the risk to the general public low. What’s more, a recent study of Michigan dairy workers at two farms with outbreaks analyzed blood samples and found no antibodies suggesting past infections that went undetected.

The human infections that have cropped up all seem to have occurred in “heavily virus contaminated, high virus dose environments,” which is reassuring because it means that steps can be taken to minimize the spread, says Sutton.

“If you started to see people getting infected, with low-virus doses, that would be alarming,” he says.

Federal health officials maintain it’s still possible to quash the outbreak in dairy cattle.

Nuzzo is skeptical. She’s yet to see a clearly articulated, viable strategy for ending the spread. New cases are still popping up in dairy herds every week.

As a scientist tracking the situation from outside the U.S., Peacock struggles to make sense of how the government hasn’t curtailed the spread of a virus that has true pandemic potential, even after months of mobilizing a response.

“My feeling is that if there were even just moderate efforts to stop this, it would have been stopped already,” he says.

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