Bird flu keeps rewriting the textbooks. It’s why scientists are unsettled by the U.S. dairy cattle outbreak

Twenty-seven years ago today, a 3-year-old boy in Hong Kong developed a sore throat, spiked a fever, and started to cough. Six days later, he was hospitalized; six days after that, he died of acute respiratory distress caused by viral pneumonia. Testing showed the toddler, who’d had contact with sick chickens before becoming ill, had been infected with H5N1 bird flu.

His death was the first attributed to a bird flu virus, and since then, dozens more young children across a number of countries have died from this virus, H5N1. In fact, in the weeks that followed the boy’s death, 17 other children in Hong Kong contracted the virus and five more died. It was a tragedy — and a profound shock for the scientists who studied influenza.

Until 1997, it was thought avian flu viruses didn’t infect people very often, and when they did, at most they caused exceedingly mild disease. That was what was seen when scientists experimentally infected human volunteers with three different bird flu viruses — not H5N1 — about 35 years ago.

The Hong Kong outbreak was the first time the H5N1 virus pulled off the unexpected, rewriting the textbooks that sometimes over-confidently stated what the myriad versions of influenza A viruses found in wild birds and other species could and could not do. But it wouldn’t be the last time. In the nearly three decades since, flu scientists have tracked this virus with both vigilance and dread, watching it defy dogma again and again, learning through hard experience that it is a foe not to be underestimated.

Most scientists that STAT has spoken to since the H5N1 outbreak in cattle in the United States was confirmed are unsettled by the notion that the virus is spreading in mammals with which humans have close contact. “That’s a different ball game altogether,” said Malik Peiris, chair of virology at the University of Hong Kong’s School of Public Health. “That hadn’t happened in Asia all this time.”

Nancy Cox, who for years headed the influenza division at the Centers for Disease Control and Prevention, said this particular lineage of H5N1, a descendent of a virus first spotted in a goose in China’s Guangdong province in 1996, is unlike any other family of flu viruses she recalls.

“It seems that these viruses must have some kind of ‘special sauce’ that has allowed them to find ways to persistently spread, evolve, and cause what appear to be increasingly serious problems in both wildlife and domesticated animals,” Cox, who is now retired, told STAT in an email. “There is an element of unexpected robustness and malleability that has surprised even seasoned influenza watchers.”

One such observer is Peiris, who has been closely tracking H5N1 since its first known foray into people. A few years later, in December 2002, he was planning to travel home to Sri Lanka for Christmas, as he did every year. Then wild water birds — ducks, egrets, herons, and the like — started dying in two waterfowl reserves in the city. The cause: H5N1.

That too was startling. Wild birds had only been seen to be seriously sickened by bird flu viruses once before, in 1961. And ducks, the natural hosts of bird flu viruses, were thought to be more or less impervious to disease caused by them, said Thijs Kuiken, a pathologist in the department of viroscience at Erasmus Medical Center in Rotterdam, the Netherlands.

Flu viruses don’t attack the respiratory tracts of ducks and other wild water birds, as they do in people. In these birds, the viruses infect cells in the gut, passing through them before being excreted in their droppings. The birds don’t get visibly ill, the textbooks said. Until they did.

“All these species, they were falling over dead,” Peiris said in a recent interview. “I missed Christmas. … I stayed in Hong Kong and was swabbing birds.”

Necropsies — the name for an animal autopsy — showed a surprising pattern of disseminated disease atypical of previous observations of bird flu, and dramatically different from what is seen in human flu infection. This unusual finding of H5N1’s ability to spread outside the lungs, to organs like the liver and the brain, has been seen again and again over the intervening years — in laboratory studies of Kuiken conducted in cats and necropsies of foxes, skunks, mink, and other mammals found to have died of H5N1 infection. It was also reported in a human case, a boy from Vietnam who died in 2004.

In the spring of 2005, the phenomenon Peiris helped to record in the parks of Hong Kong happened on a much larger scale in a migratory bird reserve in Western China known as Qinghai Lake. Between April and June of that year, there was a large-scale die-off of wild birds there, again traced to H5N1.

A little avian flu background is helpful here. Two groups of bird flu viruses — those bearing H5 or H7 hemagglutinin proteins on their exteriors — can transition from being of low pathogenicity to being highly pathogenic when the viruses spread in domestic poultry. (The term highly pathogenic avian influenza, HPAI, refers to how the virus behaves in poultry.) Seeing highly pathogenic, or high-path, viruses move back into wild birds in a big way raised serious concerns that wild birds could transmit the virus further and faster than was already occurring via the movement of infected poultry across Southeast Asia.

“We published on it and we warned — because this is a migrating center — that this could be spreading far and wide,” Peiris said. Some scientists took a more sanguine view, spouting an aphorism that was heard often in 2005: Dead birds don’t fly. Apparently infected birds do, however. “Really, within a year it was in India and Egypt and Africa and Central Asia,” Peiris said.

In the nearly two decades since the Qinghai Lake incident, H5N1 viruses have made their way around the globe, even to perhaps the most unlikely spot of all, Antarctica, infecting penguins and other wild birds there. Only Australia and New Zealand have yet to find H5N1 at this point.

Another area in which H5 has rewritten the textbooks relates to what Cox referred to, the virus’ astonishing persistence. The former CDC flu director went back through influenza literature — back to reports of “fowl plague,” as avian flu outbreaks in poultry used to be called in the 1800s and early 1900s, before influenza viruses were first identified — to see how long outbreaks lasted.

Once high-path viruses emerged in poultry, the outbreaks they triggered tended to burn themselves out within a few years, especially when infected birds were culled to try to stop spread. But since reemerging in Hong Kong in late 2002, H5N1 has never really gone away. At some points it has been more headline grabbing than others — with the recent discovery that it can infect cows, for instance. (“Who would have thought cows would get infected? And in this way?” Peiris exclaimed.) But it has never disappeared.

“I’m not aware of another … avian flu virus that’s been circulating at this global scale for this long,” said Jeremy Farrar, the World Health Organization’s chief scientist. “That’s unprecedented.”

Cox agreed. “While it wasn’t exactly scientific dogma that [high-path] avian viruses would eventually burn themselves out or fade away, it was clear from the history of past outbreaks that this is what happened for the majority of our well-documented outbreaks,” she said.

Initially H5N1 was a problem in Southeast and then South Asia, later moving into the Nile River Delta of Egypt and Turkey, then into Europe. But for more than a decade, this highly problematic virus was not found in the Americas, which seemed to support another piece of flu dogma: Flu viruses found in birds that traveled in the migratory flyways that spanned Eurasia did not make their way to the flyways of the Americas. The oft-repeated claim was that the routes flown by migratory birds would keep H5 from crossing to the New World.

“Pretty sure I might have said something similar,” admitted Richard Webby, director of the WHO Collaborating Center for Studies on the Ecology of Influenza in Animals, at St. Jude Children’s Hospital in Memphis, Tenn.

And then, that “never the twain shall meet” situation turned out to be wishful thinking. In late 2014 and early 2015, H5N2 and H5N8 viruses — equally dangerous half siblings of H5N1 from Asia, bearing the same H5 hemagglutinin — were found in poultry operations in multiple U.S. states. And then in late 2021, H5N1 itself was found in poultry and wild birds in Newfoundland, Canada’s easternmost province. So much for the non-intersection of the flyways.

“By and large, that’s true — the gene pools in migratory birds are distinct,” Peiris said. “But looking back, there were some clues of the mixture of viruses at the individual gene level, that reassortment was occasionally taking place.” (Reassortment is a process by which different flu viruses swap genes within a host, creating hybrids, like H5N2 or H5N8.)

From eastern Canada, H5N1 has worked its way through the Americas, infecting two men in the United States, a young girl in Ecuador and a man in Chile in the past couple of years. It has also ignited large poultry outbreaks, and infected and killed an astonishing array of mammals — seals and sea lions, various types of bears, coyotes, bobcats, mountain lions, raccoons, and otters among them.

Some of these species have previously been seen to be susceptible to influenza, such as seals. But the scale of the toll the virus is taking on wildlife is unlike anything previously attributed to an influenza virus.

It’s believed H5N1 may be spreading mammal to mammal in some of the marine species, though this is hard to prove, Kuiken said. It’s clear that it is moving cow-to-cow in the U.S. dairy cattle outbreak — likely with human help. The dairy cow outbreak has uncovered a fact that had been seen before but not widely noted — mammary glands are susceptible to flu viruses. The previous such observation occurred in relation to the 2009 H1N1 flu pandemic, when some infected women complained of mastitis. Canadian scientists infected ferret pups with H1N1 and allowed them to nurse; their mothers developed infection in their mammary glands.

It is not knowable whether H5N1 will ever acquire the capacity to easily infect people and spread person-to-person — in other words, trigger a pandemic. But ongoing transmission in a mammalian species gives the virus a chance to adapt to hosts that are far closer, genetically, to humans than are ducks or chickens. No one who has watched this virus thinks letting H5 get seeded into cow populations is a good idea.

Adding to the complexity of this situation is that unlike its behavior in other species it infects, H5N1 isn’t making cows seriously ill. It makes the virus harder to track, and gives farmers less impetus to cooperate with authorities trying to determine how far the virus has spread.

“The latest curveball with [high-path] H5 infection in dairy cattle is very concerning because there is little incentive to test dairy cows or their human contacts,” Cox said. “One can see so many potential problems on dairy farms. There are the asymptomatic infections in cows and perhaps people. There are the cows, the dogs, and the cats, and the other farm animals including perhaps pigs, the farm workers, and the family members and so on. It is going to be very challenging to get a clear picture of what is actually happening in anything like real time.”

In the nearly three decades of human interaction with H5N1, the virus has taught us a lot about influenza viruses, consigning many things that were previously considered flu facts to the scientific trash bin. Kuiken said in the early 2000s he would give talks about H5N1 with the title “Breaking Rules.” He eventually stopped, he said, “because this lineage broke so many.”

All those information resets should have taught us an important and overarching lesson, flu experts say. We should never assume we know everything this virus can do.

“We absolutely should be hoping for the best, but planning for the possibility that this is going to be able to transmit human to human, and has the potential of becoming a pandemic virus,” said Michael Worobey, an evolutionary virologist at the University of Arizona who has been working with an international team of scientists to try to figure out when the cow outbreak started. “It’s much too early to sit back and say, ‘Well, it hasn’t happened yet, so it’s not going to happen.’”