Diligent detective work leads to discovery of HPAI in dairy cattle

It started with the cats, or the lack thereof.

Dr. Tim Dickerson, a large animal veterinarian in New Mexico, usually gets swarmed by barn cats when visiting one of his client’s dairy farms. But this time, they were nowhere to be found.

He mentioned this offhand when talking to a colleague, Dr. Barbara Petersen, another large animal veterinarian based in the Texas Panhandle. Around the same time, she was talking with a local veterinarian at the end of February, who asked if she had seen cows with diarrhea or pneumonia. She hadn’t. That is, not until a week later, when Dr. Petersen has an increase of sick cows in one of the herds she collaborates on with another veterinarian. Some of the cows had mastitis and their milk had the consistency of “colostrum and Elmer’s glue.”

What happened from there turned into the discovery of the first national outbreak of highly pathogenic avian influenza (HPAI) in dairy cattle. As of April 30, avian influenza virus type A (H5N1) has been confirmed in dairy cattle in nine states: 12 herds in Texas, eight in New Mexico, six in Michigan, four in Kansas, two in Idaho, and one each in Ohio, North Carolina, South Dakota, and Colorado.

The U.S. Department of Agriculture’s (USDA) Animal and Plant Health Inspection Service (APHIS) has since instituted a federal order requiring testing of lactating dairy cattle for HPAI prior to interstate movement and reporting of positive results for livestock. While the movement restriction initially applies to lactating dairy cows, this may be adjusted based on an evolving scientific understanding of the disease and risks.

In addition, four more sick cats have tested positive for H5N1, according to state and federal officials, raising the number of cat cases connected to the current dairy cow outbreak to seven.

Ruling out diagnoses

Initially, Dr. Petersen chalked up the illness in cattle to recent changes in feed. Perhaps it was feed toxicosis? The lactating cows were diverted to hospital pens and treated with fluid therapy. She sent off milk samples to Dr. Alexis Thompson, lead diagnostician at the Texas A&M University’s Veterinary Medical Diagnostic Lab (TVMDL)-Canyon. The bacterial culture results did not find any atypical pathogens.

A week later a third dairy herd in the area was showing similar signs—the cows were off their feed and milk production was down. The dairy owner also mentioned that half of his barn cats had died.

“I said, ‘You’ve got to be kidding me,” recalled Dr. Petersen, who had already collected dead birds for testing because HPAI had been diagnosed in some flocks in a county east of her. “I get what’s happening with the birds, but what the heck is happening with cows and cats?”

By this point, Dr. Fabio Texeira, a colleague of Dr. Petersen’s in New Mexico, and Dr. Nicholas Schneider, a fellow veterinarian in Colorado who also works in Texas, were all texting each other frequently, trying to figure out what to test for and what questions to ask. Dr. Kay Russo, a veterinarian colleague with practical experience in poultry and dairy cattle health, provided support to Dr. Petersen as well during this time on differential diagnoses that impact wild and domestic birds.

Various diagnostic laboratories, including Texas A&M and Iowa State University (ISU), had run hundreds of tests. They had considered everything from mycotoxins to infectious cattle diseases to metagenomic testing.

“I was thinking this was a feed issue initially. If this was an infectious disease, either it was going to be something completely novel or maybe a slight change in a virus that meant we could no longer detect it,” said Dr. Drew Magstadt, a pathologist at ISU’s Veterinary Diagnostic Laboratory. “An interesting part of this was the low numbers. Certainly, there was an increase in sick cattle, but not all or even a majority of them were getting sick which we might expect with a novel agent.”

By mid-March, bovine veterinarians from affected sites and veterinary diagnosticians were comparing notes on conference calls. They discussed what they were seeing and not seeing and tried to come up with a common set of factors at the dairies, followed by a testing plan. It became apparent that they were all seeing more dead wild birds on these dairies as well as neurologic disease in cats, with some going blind or ataxic. Several dairies reported cats missing.

Drs. Magstadt and Petersen, former classmates at Iowa State, were both on the calls. They talked further after one call. Dr. Petersen agreed to send him some samples from dead cats along with milk and blood from cows from affected dairies. She sent them, in part, to decrease the burden on the Texas laboratory but also to test a question she had.

“I think everyone thought I was nuts,” Dr. Petersen said. “I thought there was something, somehow. I don’t know how it was connected but I asked, ‘Can you investigate the cats for me?'”

She received a text from Dr. Magstadt the evening of March 21: “Do you have a sec? I need to talk to you about the samples you sent.”

‘Trust but verify’

Dr. Magstadt didn’t think the samples would test positive for HPAI but needed to rule it out. Yet the samples tested positive for influenza A—the cats’ brains and lungs, the milk, everything.

“There was a moment of disbelief. I asked, ‘Will you please rerun those in the morning?’ because they ran them as a pool, so both he and I wanted them run individually,” Dr. Petersen said. “He said, ‘If they’re positive, I have to send them to the (National Veterinary Services Laboratory).’”

The next day, Dr. Magstadt retested the milk samples along with milk samples that had just arrived from other dairies. He also wanted to make sure the results weren’t due to a reporting error or contamination issue. The Texas laboratory confirmed the results that day on milk samples.

“Truly, this came down to observations of field vets on sites. If that link doesn’t get made—cats with neurologic signs on multiple sites at the same time—there’s really no reason to start testing for influenza, much less in milk. Disease in cats due to HPAI has been well described, but detection of the virus in milk is really the novel part of all this,” Dr. Magstadt said. “If someone was doing genetic sequencing, they would have ultimately found (HPAI) but the targeted testing was because of observations and veterinarians collaborating and corresponding.”

Dr. Magstadt’s and the other diagnosticians’ training had also helped put the pieces together. His job largely involves case coordination and communication with people doing necropsy work in the field, mostly involving swine and cattle. He’s there to give answers from a diagnostic perspective.

“In situations like this, the big thing is trying to get accurate information. Trust but verify,” Dr. Magstadt said. “With clinical signs, what is and isn’t happening? What is the information regarding affected animals, especially when multiple sites are affected? What are they doing that put them at risk or differently from nearby places that are not affected?

“It’s getting interested parties together and asking a lot of questions. We maneuver our way toward a list of what’s most likely, and then start figuring out how we can confidently rule each of those possibilities in or out.”

Vigilance for small animal veterinarians

The HPAI spillover from wild birds to dairy cattle is a good reminder of just how much this virus can infect multiple mammals, Dr. Petersen said.

“Maybe in the future, in cases where we don’t know initially what’s going on, maybe we test for this virus sooner than we would have otherwise,” Dr. Magstadt said.

Dr. Petersen has been advocating for measures to help improve the epidemiological understanding of the virus. With all the uncertainty and challenges in communications from federal agencies, many dairy owners have been hesitant to have their veterinarians submit samples.

Dr. Petersen also has spoken to the USDA about better surveillance mechanisms, so that animals that have been or are affected aren’t introduced to a naïve herd. Recalling how important it was to link the dead and missing cats to some of the infected dairy herds, she’s concerned that all veterinarians—not just bovine or poultry practitioners—are aware of just how infectious and mutable this particular virus is.

The Centers for Disease Control and Prevention’s Influenza Division reported three new cases in cats on April 25 and state officials reported a fourth case on April 26.

Three of the new cases in cats were found at two dairy farms in Curry County, New Mexico, and all of them died, according to the state’s Agriculture Department. The fourth case was found at a dairy farm in Wood County, Ohio. The cats reportedly had neurologic signs and a rapid decline before dying.

“For small and mixed animal vets, if presented with a neurologic cat, it might have rabies. Or if it had matted eyes, it might have herpes or calicivirus,” but it could also be HPAI, she said. “I don’t want a colleague to get exposed by accident. It wouldn’t be on my radar as a small animal practitioner, so I want them to be aware of this. Ask if the cat has farm exposure or could have.”

Answering lingering questions

For diagnosticians, the work now turns to validating the tools they have to understand this disease. Specifically, validating serology testing for influenza A in cattle. They’re also trying to figure out what the best samples are. Milk is the choice for lactating cows, but that’s not possible for heifers, calves, and dry cows on these sites. Researchers are trying to find out if these animals are getting infected, too, and if so, are they seroconverting? They now have reason to believe cows that are asymptomatic could still shed virus in milk.

So far, they have determined there is a heavy load of the virus in raw milk and have identified lactating cattle as a subset population that is amplifying the virus in the environment.

From genetic analysis, Dr. Magstadt agrees with findings that the initial introduction of HPAI to cows came from wild birds but now there is lateral transmission between cows. How that is happening, exactly, is still not fully known.

Dr. Magstadt’s colleague at the laboratory, Dr. Eric Burrough, is looking further at the cats. He’s found at the microscopic level that their brains and eyes have certain lesions.

“We are trying hard to answer the many questions we still have as accurately as possible, so the people making decisions on animal movement and disease mitigation can make good recommendations from an animal-testing perspective,” Dr. Magstadt said.