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Genetic Analysis Reveals H5N1 Flu Virus Outbreak In Cows Likely Started Earlier Than Thought

The H5N1 bird flu outbreak in dairy cows in the United States has likely been going on for months longer than was previously realized, and has probably spread more widely across the country than the confirmed outbreaks would imply, according to an analysis of genetic sequences that were released Sunday by the U.S. Department of Agriculture.

The genetic data point to a single spillover event that probably occurred in late 2023, Michael Worobey, an evolutionary virologist at the University of Arizona, told STAT on Tuesday.

"The bad news is it looks like this is well entrenched and has been in cattle for a long time and … probably very, very, very widespread," said Worobey, who worked on the analysis with a number of scientists in the U.S. And Europe.

He suggested the outbreak needs to be taken more seriously than it has been until now, especially given the amount of exposure humans have with cattle. "We need to just study the hell out of it for starters … and see if we can close the gap on what is happening and what we know."

Though there were reports of a mysterious illness affecting dairy cows in Texas as early as February, the USDA first confirmed an outbreak of H5N1 in dairy cows in that state in late March. Since then, the number of confirmed outbreaks has climbed to 33 herds in eight states. One person — a farm worker who developed conjunctivitis — has been confirmed to have been infected.

The USDA has been unclear about whether these outbreaks are all linked — the result of the movement of cattle, farm equipment, or workers — or whether there have been multiple spillover events where infected wild birds have transmitted the virus to cows. Last week, it told STAT it could find links between the infected herds in Texas, Kansas, and New Mexico; it is also known that cows in the first infected Michigan herd detected had been brought in from Texas. But USDA hasn't been able to draw a line between those outbreaks and others in Idaho, Ohio, North Carolina, and South Dakota.

The genetic sequences cluster too closely for this to be anything other than a single spillover, Worobey said. "If it were jumping from bird to cattle over and over again … I wouldn't think you would just get this same very reduced genetic diversity where each of the internal segments are showing the same pattern."

The prospect of an outbreak that has been underway for months longer than had been previously known is not reassuring to those who follow the dangerous H5N1 virus.

"If that's true, it's been flying under the radar for a really embarrassingly, frustratingly long time," Worobey said. "And we have no idea how much it's spreading asymptomatically and how widespread it is. And we're trying to deal with something long after the horse has bolted."

Tom Peacock, an influenza virologist at the Pirbright Institute, a British organization that focuses on controlling viral illnesses in animals, concurred with Worobey's read of the data.

The USDA has previously reported that it believed that virus from an infected cattle herd had found its way into a nearby chicken operation in Michigan. The genetic sequences for cows, poultry, and other infected species that were released by the USDA suggest that hypothesis is correct, Peacock said. "If you look at all the cattle sequences together, they all cluster, as do the cats and the chickens and the grackles and stuff."

"The thing that doesn't fit that picture is the human case," he said.

The genetic sequence from the human case, which occurred on an unidentified farm in Texas, is sufficiently different from the cattle sequences that it can't be easily linked to them, he said. The differences suggest that the individual was either infected in a separate event — maybe not via a cow, but through contact with infected wild birds — or that there might have been another line of viruses in cattle early on and it has since died out.

"It's basically too distant a cousin to be connected directly to this outbreak, which either means it's a second spillover or there was an early bifurcation of the cattle sequences," Peacock said.

The 239 genetic sequences the USDA shared on Sunday did not include what's known as metadata — information on where the sample that generated the sequence was taken, what part of the body of the infected animal it was taken from, or when precisely the collection occurred. They simply state "USA" and "2024," which limits how well outside scientists can interpret what they are seeing.

Peacock said it would have been helpful to know whether any of the cattle sequences had been generated from samples taken on the farm where the infected worker was thought to have been exposed to the virus. But that information is not available.

Asked whether the analysis of the genetic data increases his sense of the risk H5N1 poses to humans, Worobey suggested he was uncomfortable with the knowledge that H5N1 seems to be spreading in mammals, calling that unprecedented.

Having the virus in a mammalian species with which people have frequent contact gives H5N1 more opportunities to acquire the mutations needed to be able to evolve to be able to infect people, or "more shots on goal," Worobey said. "That's bad."

Early Tests Of H5N1 Prevalence In Milk Suggest U.S. Bird Flu Outbreak In Cows Is Widespread

Andrew Bowman, a veterinary epidemiologist at Ohio State University, had a hunch. He had been struck by the huge amounts of H5N1 virus he'd seen in milk from cows infected with the bird flu and thought that at least some virus was getting off of farms and going downstream — onto store shelves.

He knew the Food and Drug Administration was working on its own national survey of the milk supply. But he was impatient. So he and a graduate student went on a road trip: They collected 150 commercial milk products from around the Midwest, representing dairy processing plants in 10 different states, including some where herds have tested positive for H5N1. Genetic testing found viral RNA in 58 samples, he told STAT.

The researchers expect additional lab studies currently underway to show that those samples don't contain live virus with the capability to cause human infections, meaning that the risk of pasteurized milk to consumer health is still very low. But the prevalence of viral genetic material in the products they sampled suggest that the H5N1 outbreak is likely far more widespread in dairy cows than official counts indicate. So far, the U.S. Department of Agriculture has reported 33 herds in eight states have tested positive for H5N1.

"The fact that you can go into a supermarket and 30% to 40% of those samples test positive, that suggests there's more of the virus around than is currently being recognized," said Richard Webby, an influenza virologist who has been analyzing the samples at St. Jude's Children's Research Hospital in Memphis, Tenn., where he heads the WHO Collaborating Center for Studies on the Ecology of Influenza in Animals.

Earlier this week, the FDA announced that its effort had found evidence of the H5N1 virus in samples of milk purchased from store shelves, but it provided no detailed results. On Thursday, during an online symposium hosted by the Association of State and Territorial Health Officials, the FDA disclosed a high-level readout from the agency's investigation. Results returned Thursday morning showed PCR-positive milk in 20% of samples, "maybe with some preponderance for areas with known herds," said Donald Prater, acting director of the FDA's Center for Food Safety and Applied Nutrition. He did not say how many samples the FDA had analyzed or from what geographic area.

The testing by PCR — polymerase chain reaction — turned up only genetic traces of the virus, not evidence that it's alive or infectious. The FDA has been adamant that H5N1, which is heat-sensitive, is very likely killed through the process of pasteurization.

The agency is still assessing those samples for viral viability by attempting to grow virus from milk found to contain RNA from H5N1. The FDA plans to release results of those studies in the coming days. On Wednesday, Jeanne Marrazzo, the new director of the National Institute of Allergy and Infectious Diseases, told reporters that a team of NIAID-funded researchers had early data to suggest that pasteurization does appear to be effective.

The team that produced that data — the St. Jude and OSU groups — told STAT that it has so far analyzed four samples of store-bought milk that had tested positive via PCR for H5N1 genetic material. "We've done the viral growth assays to see if we can recover any virus from them and we can't," Webby said.

Those four samples came from an initial collection of 22 commercial milk products purchased in the Columbus, Ohio, area. "It was basically just me hitting up the five grocery stores between campus and my house," said Bowman.

Further reading

PCR testing at OSU revealed three of those 22 products to be positive for viral RNA. Bowman sent them to Webby to inject into plates of mammalian cells and embryonated chicken eggs and look for any signs of active viral replication. In order to do that, Webby needed a negative control, so he went and bought milk at a store near his lab in Memphis. But PCR testing found H5N1 RNA in that sample too, making it useless as a negative control, but an additional data point showing a lack of live virus.

That sample is still in Webby's fridge at home. He used it to make dinner earlier this week. "I'm not concerned about it all," he said.

Although the risk of infection from dairy products is very low, the worry is that the wider H5N1 spreads in cows, the more opportunities the virus has to adapt to transmit efficiently in mammalian hosts. It also increase the chances H5N1 could get into pigs, where it could swap genes and form hybrids with other flu viruses. Viruses that mutate to be able to spread easily through one species of mammals could find it easier to infect people.

The St. Jude group is now repeating its analyses with the additional samples Bowman and his graduate student bought around the Midwest. Their early findings provide further evidence that H5N1 is spreading broadly among dairy cows in the U.S.

This week, researchers examining viral genome sequences released Sunday by the USDA found that the outbreak has likely been underway for months longer than previously known. "Both of these data — the milk data and the genetic data that shows this has been around since December of last year — suggests that the outbreak is probably much bigger than we know," said Angie Rasmussen, a virologist who studies emerging zoonotic pathogens at the Vaccine and Infectious Disease Organization at the University of Saskatchewan in Canada.

It may also signal that herds can be infectious with only mild symptoms or no symptoms at all, which would complicate the response and make containment much more difficult.

"This is telling us that we're probably already seeing that milk from asymptomatically infected cows does have some virus in there," said Andrew Pekosz, a molecular microbiologist who studies respiratory viruses at Johns Hopkins Bloomberg School of Public Health.

So far, there has been only one report of H5N1 infections in a cattle herd with no symptoms — in North Carolina. But USDA officials have not disclosed further details beyond the fact that milk from infected but asymptomatic cows seems unchanged.

In H5N1-infected cows, the first thing that tends to happen is their appetite disappears and their activity goes down. Then their milk production dries up. In some animals, the milk they do produce turns yellow and thick. "It's an odd thing that seems to be unique to this particular virus," said Keith Poulsen, director of the Wisconsin Veterinary Diagnostic Laboratory. And it's one of the chief red flags that dairy farmers are supposed to be on the lookout for when deciding whether to test their herds. If milk from asymptomatic or pre-symptomatic cows looks normal but can carry virus, it would obscure the need for testing.

To really understand the scale of spread as well as possible mechanisms of viral transmission, it's necessary to conduct widespread testing of animals with and without symptoms, said Jennifer Nuzzo, an epidemiologist and director of Brown University's Pandemic Center. "If we're only testing cows with outward symptoms, we're missing infections in those without."

Up until this week, USDA policy did not require testing of any animals, and only recommended it for dairy cows greater than 3 years of age that have been lactating for at least 150 days and are showing severe clinical symptoms like fever, lethargy, abnormal milk production, and loose stool.

On Wednesday, the agency issued a federal order requiring an animal to test negative for the virus before it can be transported across state lines. It also requires laboratories and state veterinarians to report to the USDA any animals that have tested positive for H5N1 or any other influenza A virus. But outside of interstate travel, testing remains voluntary and encouraged only for visibly ill animals.

Public health experts told STAT that such narrow testing criteria are likely distorting the true extent of the outbreak. "I have not seen evidence that makes me want to discard the fear that testing practices are absolutely shaping what we think we know about this virus," Nuzzo said. "We just don't have the right data right now to tell us what's going on."

The situation is reminiscent, she said, of the Covid-19 pandemic. In the early weeks of that outbreak, testing policies were narrow — limited to symptomatic individuals who had traveled to China. Meanwhile, the SARS-CoV-2 virus was spreading undetected throughout the U.S., as genomic analyses would later show. Later, when at-home tests became widely available, official counts became unreliable, leaving state and local health departments in the dark.

"At least with Covid, wastewater surveillance eventually kicked in to supplement our picture," Nuzzo said. "With H5N1, we don't have that."

On Wednesday, the Centers for Disease Control and Prevention said it is exploring wastewater testing for H5N1, but noted significant hurdles, including farms not being linked to municipal wastewater systems and the potential for infected wild birds to confound testing of water around farms.

Requiring dairy farms to regularly test all their animals, including asymptomatic ones, is not logistically feasible given the current capacity of state veterinary diagnostic laboratories, Poulsen said. He and other lab directors are already bracing for the massive ramp-up in testing they expect to begin when the USDA order goes into effect Monday. But he does think more has to be done at the federal level to encourage farmers to test their herds.

"At this point, farms just aren't volunteering samples because they don't have any incentives to raise their hand," Poulsen said. That information blackout makes it much more challenging for epidemiologists to trace the virus and understand how it's spreading, the exact mechanisms of which are still unclear.

"We need to do what we can now to understand it and contain it so it doesn't turn into a pathogen of pandemic potential," Poulsen said. "That is a real risk if we continue to ignore it."

With Bird Flu Found In Milk, What You Need To Know About Outbreak

Holstein heifers are loaded into trucks at a dairy in Oregon on Jan. 21, 2011. Dairy cattle moving between states must be tested for the bird flu virus, U.S. Agriculture officials said Wednesday, April 24, 2024, as they try to track and control the growing outbreak.Kobbi R. Blair

Federal food safety regulators believe that retail milk is still safe to consume, despite the fact that 1 in 5 samples tested nationwide by the U.S. Food and Drug Administration show traces of highly pathogenic avian influenza's viral fragments. Most of the positive results showed up in areas where an outbreak of bird flu has been found in dairy cattle herds.

The U.S. Department of Agriculture, the FDA and the Centers for Disease Control and Prevention are partnering with state agencies to investigate the outbreak, which has infected dairy cows in multiple states, according to an FDA advisory. The notice said that the viral infection in the cattle "is causing decreased lactation, low appetite and other symptoms in infected cattle."

After the milk sampling returned findings of viral fragments in so much of the milk supply, the USDA ordered all dairy cows be tested for bird flu before they can be transported between states. Any positive finding must be reported to federal health officials.

USDA and FDA food safety experts say that current information suggests the commercial supply is safe "because of these two reasons: 1) the pasteurization process and 2) the diversion or destruction of milk from sick cows."

Pasteurization, a heating process, is done to kill pathogens "to a level that does not pose a risk to consumer health." The process of pasteurizing milk is more than a century old. The regulators said while pasteurization "is likely to inactivate the virus," it's not expected to remove viral particles like those detected, so the finding in milk samples was not especially surprising.

The agencies said they're vetting their determination that pasteurized retail milk is safe by checking positive findings using another type of test called egg inoculation, which is deemed "a gold standard for determining viable virus."

In that test, samples of the milk that tested positive are injected into an egg to see if the virus replicates, as Nam Tran, senior director of clinical pathology at UC Davis Health, explained in a news release. UC Davis said the results from that test are more sensitive, but the test takes longer to complete, so results are pending.

The FDA said results from its various studies will be available in a few days to weeks.

History of the outbreak

By late this week, 33 herds in eight states tested positive for bird flu. The states were Idaho, Kansas, Michigan, New Mexico, North Carolina, South Dakota, Ohio and Texas.

There are many strains of avian influenza, but the one that's the focus of concern is a type A influenza designated H5N1 or A(H5N1). It's worrisome because while it doesn't easily spread to humans — in the U.S. There are just two known recent cases — globally more than half of the people who contracted the illness died, per the CDC. The U.S. Cases, one this year related to the cattle outbreak and another in 2022, have both produced just mild symptoms.

The virus does not transfer easily from person to person, according to health experts. CDC has reported, however, that while human infections are rare, they "have occurred sporadically worldwide. CDC has been monitoring for illness among people exposed to H5 virus-infected birds since outbreaks were first detected in U.S. Wild birds and poultry in late 2021. Human illnesses with H5N1 bird flu have ranged from mild (e.G., eye infection, upper respiratory symptoms) to severe illness (e.G., pneumonia) that have resulted in death in other countries."

Dr. Dean Blumberg, chief of pediatric infectious diseases at UC Davis Health, said human infections "can be effectively treated with the antiviral oseltamivir (Tamiflu)."

CDC notes that H5 bird flu is widespread among wild birds around the world, including in the U.S.

But health officials are concerned because viruses tend to mutate and a change that made it easier for the strain of influenza to infect humans could be dire. Bird flu has already been detected in a number of types of mammals — examples include mink, red foxes, bears, cows and mountain lions, among others — though primarily in small numbers.

Officials have warned against consuming raw dairy milk, since it's not known whether H5N1 can be transmitted that way. It is believed that some infected animals, including sea lions, contracted illness through consuming infected wild birds, for example.

Underestimating size of outbreak?

Experts believe the outbreak in cattle may have been underway longer than previously known, in part based on viral genome sequences the USDA released Sunday. As STAT News reported, "Both of these data — the milk data and the genetic data that shows this has been around since December of last year — suggests that the outbreak is probably much bigger than we know," said Angie Rasmussen, a virologist studying emerging zoonotic pathogens at the Vaccine and Infectious Disease Organization at the University of Saskatchewan in Canada.

"It may also signal that herds can be infectious with only mild symptoms or no symptoms at all, which would complicate the response and make containment much more difficult," per the article.

Some experts question if all the infected herds have been found. A veterinary epidemiologist at Ohio State University, Andrew Bowman, and one of his graduate students figured a complete accounting of the outbreak was unlikely, so they collected 150 commercial milk products around the Midwest and did their own testing.

They told STAT that the samples included milk products from processing plants in 10 different states and they found viral RNA from bird flu in well over a third of the samples.

Per STAT, "The researchers expect additional lab studies currently underway to show that those samples don't contain live virus with the capability to cause human infections, meaning that the risk of pasteurized milk to consumer health is still very low. But the prevalence of viral genetic material in the products they sampled suggests that the H5N1 outbreak is likely far more widespread in dairy cows than official counts indicate."

NBC News quoted a flu virologist at St. Jude Children's Research Hospital, Richard Webby, who noted that the number of milk samples that tested positive for viral fragments "does seem high if the number of infected farms is indeed only 30-odd. Clearly there are more infected animals out there than being reported."

Of the outbreak, "I think it's safe to say that it's longer and much more extensive that has been realized," Dr. Michael Mina, an epidemiologist and former professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, told reporters during a briefing midweek.

But again, health experts are not unduly worried about human health related to avian influenza in cattle at the moment.

"CDC has not identified any out-of-the-ordinary influenza-related emergency department visits, even when we compare areas where H5N1 has spread among cattle against areas where it has not," Dr. Nirav Shah, principal deputy director of the CDC, said during the media briefing.

Safety advice

As for staying safe, CDC recommends that people avoid entirely or use respiratory and eye protection around sick or dead birds and animals, domesticated or wild, as well as "animal feces, litter or materials contaminated by birds or other animals" that might have bird flu infection.

CDC also warns against preparing or eating uncooked or undercooked food or "related uncooked food products, such as unpasteurized (raw) milk or raw cheeses" from animals with suspected or confirmed bird flu.

For farmers or those with livestock or backyard flocks, the safety recommendations extend to surfaces and water that might be contaminated with animal excretion, as well.

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