Virus World

Federal public health officials are turning to wastewater surveillance to help fill in the gaps in efforts to track H5N1 bird flu outbreaks in dairy cows. R eluctance among dairy farmers to report H5N1 bird flu outbreaks within their herds or allow testing of their workers has made it difficult to keep up with the virus’s rapid spread, prompting federal public health officials to look to wastewater to help fill in the gaps. On Tuesday, the Centers for Disease Control and Prevention is expected to unveil a public dashboard tracking influenza A viruses in sewage that the agency has been collecting from 600 wastewater treatment sites around the country since last fall. The testing is not H5N1-specific; H5N1 belongs to the large influenza A family of viruses, as do two of the viruses that regularly sicken people during flu season. But flu viruses that cause human disease circulate at very low levels during the summer months. So the presence of high levels of influenza A in wastewater from now through the end of the summer could be a reliable indicator that something unusual is going on in a particular area.

Wastewater monitoring, at least at this stage, cannot discern the sources — be they from dairy cattle, run-off from dairy processors, or human infections — of any viral genetic fragments found in sewage, although the agency is working on having more capability to do so in the future. CDC wastewater team lead Amy Kirby told STAT that starting around late March or early April, some wastewater collection sites started to notice unusual increases in influenza A virus in their samplings. Those readings stood out because by the last week of March, data the CDC tracks on the percentage of people seeking medical care for influenza-like illnesses suggested that the 2023-2024 flu season was effectively over. The increases were very site-specific, she said, and were not reflected in other areas. In fact, she called it “a very limited phenomenon. … The vast majority of our sites are not seeing this.” To date there has been little information in the public sphere about where infected cattle herds have been located. When the U.S. Department of Agriculture announces positive test results, it merely names the state in which the herd was located when the testing took place. Last week, the USDA reported that six additional herds — in Michigan, Idaho, and Colorado — had tested positive for H5N1, bringing the total to 42....

The avian influenza virus that has been infecting dairy cows and spreading alarm in the United States was expected to reach Germany this week. But that’s actually good news. A shipment of samples of the H5N1 virus from Cornell University virologist Diego Diel is destined for the Federal Research Institute for Animal Health in Riems, which has one of the rare high-security labs worldwide that are equipped to handle such dangerous pathogens in cattle and other large animals. There, veterinarian Martin Beer will use the samples to infect dairy cows, in search of a fuller picture of the threat the virus poses, to both cattle and people, than researchers have been able to glean from spotty data collected in the field. Six weeks into the outbreak that has spread to farms in nine U.S. states, the flow of data from those locations remains limited as public health officials sort out authorities and some farms resist oversight. “It’s incredibly difficult to get the right sample sets off the infected farms,” says Richard Webby, an avian influenza researcher at St. Jude Children’s Research Hospital. “It’s clearly a barrier to understanding what’s going on. … That’s why these experimental infections of cows are really going to be super informative.”

Highly pathogenic avian influenza (HPAI) viruses cross species barriers and have the potential to cause pandemics. In North America, HPAI A(H5N1) viruses related to the goose/Guangdong 2.3.4.4b hemagglutinin phylogenetic clade have infected wild birds, poultry, and mammals. Our genomic analysis and epidemiological investigation showed that a reassortment event in wild bird populations preceded a single wild bird-to-cattle transmission episode. The movement of asymptomatic cattle has likely played a role in the spread of HPAI within the United States dairy herd. Some molecular markers in virus populations were detected at low frequency that may lead to changes in transmission efficiency and phenotype after evolution in dairy cattle. Continued transmission of H5N1 HPAI within dairy cattle increases the risk for infection and subsequent spread of the virus to human populations.

Preprint in bioRxiv (May 01, 2024):

https://doi.org/10.1101/2024.05.01.591751 

The bird flu virus spreading through dairy cattle in the United States may be expanding its reach via milking equipment, the people doing the milking, or both, U.S. Department of Agriculture (USDA) representatives reported today at an international, virtual meeting held to update the situation. The avian virus may not be spreading directly from cows breathing on cows, as some researchers have speculated, according to USDA scientists who took part in the meeting, organized jointly by the World Organisation for Animal Health and the United Nations’s Food and Agricultural Organization. “We haven’t seen any true indication that the cows are actively shedding virus and exposing it directly to other animals,” said USDA’s Mark Lyons, who directs ruminant health for the agency and presented some of its data. The finding might also point to ways to protect humans. So far one worker at a dairy farm with infected cattle was found to have the virus, but no other human cases have been confirmed.

USDA researchers tested milk, nasal swabs, and blood from cows at affected dairies and only found clear signals of the virus in the milk. “Right now, we don’t have evidence that the virus is actively replicating within the body of the cow other than the udder,” Suelee Robbe Austerman of USDA’s National Veterinary Services Laboratory told the gathering. The virus might be transmitted from cow to cow in milk droplets on dairy workers’ clothing or gloves, or in the suction cups attached to the udders for milking, Lyons said. (In a 30 March interview with Sciencenone, Thijs Kuiken, a leading avian influenza researcher at Erasmus Medical Center, had suggested the milking machines might be responsible because the components may not always be disinfected between cows.)

The influenza virus causing the outbreak, an H5N1 subtype that is known as clade 2.3.4.4b, has devastated wild birds and poultry around the world for more than 2 years, and researchers at first thought migratory birds were responsible for spreading it to all of the affected dairy farms. But USDA scientists now think the movement of cattle, which are frequently transported from the southern parts of the country to the Midwest and north in the spring, may also have played an important role. And they floated the possibility, without naming specific herds or locations, that all affected cows may trace back to a single farm. Since first revealing the infection of dairy cows with this bird flu virus on 25 March, USDA has confirmed it has spread to cattle in six states. And the agency has used the virus’ genetics to track its movements. The virus found on U.S. farms has a specific genetic signature, which led USDA to name it 3.13. “It’s not a common [strain], but it’s very much a descendant of the viruses that have been dominating the flyways in the Pacific and the central flyways in the United States,” Robbe Austerman said.

The USDA scientists reported that the agency’s analysis of the different viruses from the cows indicates they likely came from one source. Cows from infected farms in Texas appear to have moved the virus to farms in Idaho, Michigan, and Ohio. “The cow viruses so far have all been similar enough that it would be consistent with a single spillover event or a couple of very closely related spillover events,” Robbe Austerman said. “So far we don’t have any evidence that this is being introduced multiple times into the cows.” The virus in cows could spread to poultry, which has that industry on edge. USDA tightly regulates avian influenza virus strains that are deadly to poultry, requiring culling of entire flocks if one bird tests positive for this H5N1 or one of its relatives; to date, commercial and backyard poultry farms have had to cull 85 million birds because of this virus. But USDA is not calling for any such drastic measures with cow herds. In response to questions from Sciencenone, Ashley Peterson, who handles regulatory affairs for the National Chicken Council, said “out of an abundance of caution, we believe it is prudent to restrict the movement of cows from positive herds.” Although some researchers agree USDA should stop the transport of dairy cows, the agency has so far declined to take that disruptive action. “We heavily rely on the producers who have been isolating the animals within the dairy herds,” Lyons said. USDA also says it has no evidence of beef cattle becoming infected. USDA and the Food and Drug Administration have stressed that pasteurization kills viruses, so there is “no concern” about the safety of commercial milk. They do recommend people not consume raw milk or products made from it.

Sources tell Science none some dairy farms that were later shown to be infected first noticed dead cats as early as mid-February. The animals, which often drink spilled milk on farms, “were the canary in the mine,” one said. The cows’ milk was also unusually thick. Those signs, coupled with the discovery of dead birds on the farms, led to the testing of cow milk for the bird flu virus and the 25 March USDA announcement. Oddly, the dead birds on infected farms were not waterfowl, the migratory birds that typically spread the avian flu viruses to poultry, but “peridomestic” species such as grackles, blackbirds, and pigeons. One farm had the virus detected in poultry before it was found in its cows, and although Robbe Austerman said she hesitated to call it the “ancestral strain,” she noted that “all of the detection so far in cattle are clustered around that.” Further studies should clarify how the virus wound up in cows, which sometimes become infected with flu viruses but have never before been shown to have one that causes high mortality in birds. One possibility is that birds infected cows by shedding their droppings in the cows’ feed or water. But bird flu viruses in the past have also spread for many kilometers in the wind, moving from one poultry farm to another. So the current H5N1 strain could have moved from waterfowl to poultry to cattle—or directly from poultry to cattle and then even to the peridomestic birds. “This could be a multifactorial presentation that we’re seeing,” Lyons said. “Lots of questions still to be answered.”

The Idaho State Department of Agriculture announced that HPAI, known as highly pathogenic avian influenza, or bird flu, has been found in dairy cattle in Idaho.  This now brings the number of affected states to four, adding more evidence the virus may be spreading cow to cow. The cows were recently brought into the Cassia County dairy from another state that had found HPAI in dairy cattle, according to the ISDA. The USDA Animal and Plant Health Inspection Service (APHIS) announced that an investigation into mysterious illnesses in dairy cows in three states—Kansas, New Mexico, and Texas—was due to HPAI and that wild birds are the source of the virus.

Symptoms of HPAI in cattle include: 

• Drop in milk production 
• Loss of appetite 
• Changes in manure consistency 
• Thickened or colostrum-like milk 
• Low-grade fever 

At this stage, there is no concern about the safety of the commercial milk supply or that this circumstance poses a risk to consumer health. The pasteurization process of heating milk to a high temperature ensures milk and dairy products can be consumed safely. 

The ISDA encourages all dairy producers to closely monitor their herd and contact their local veterinarian immediately if cattle appear to show symptoms. HPAI is a mandatory reportable disease, and any Idaho veterinarians who suspect cases of HPAI in livestock should immediately report it to ISDA at 208-332-8540 or complete the HPAI Livestock Screen at agri.idaho.gov/main/animals/hpai/.  

APHIS (USDA) update on the dairy cattle bird flu outbreaks (March 29, 2024):

https://www.aphis.usda.gov/news/agency-announcements/usda-fda-cdc-share-update-hpai-detections-dairy-cattle 

Avian influenza (serotype H5N1) is a highly pathogenic virus that emerged in domestic waterfowl in 1996. Over the past decade, zoonotic transmission to mammals, including humans, has been reported. Although human to human transmission is rare, infection has been fatal in nearly half of patients who have contracted the virus in past outbreaks. The increasing presence of the virus in domesticated animals raises substantial concerns that viral adaptation to immunologically naive humans may result in the next flu pandemic. Wastewater-based epidemiology (WBE) to track viruses was historically used to track polio and has recently been implemented for SARS-CoV2 monitoring during the COVID-19 pandemic.

Here, using an agnostic, hybrid-capture sequencing approach, we report the detection of H5N1 in wastewater in nine Texas cities, with a total catchment area population in the millions, over a two-month period from March 4th to April 25th, 2024. Sequencing reads uniquely aligning to H5N1 covered all eight genome segments, with best alignments to clade 2.3.4.4b. Notably, 19 of 23 monitored sites had at least one detection event, and the H5N1 serotype became dominant over seasonal influenza over time. A variant analysis suggests avian or bovine origin but other potential sources, especially humans, could not be excluded. We report the value of wastewater sequencing to track avian influenza.

Preprint in medRxiv ( May 10, 2024):

https://www.medrxiv.org/content/10.1101/2024.05.10.24307179v1.full.pdf 

An outbreak of H5N1 highly pathogenic influenza A virus (HPIAV) has been detected in dairy cows in the United States. Influenza A virus (IAV) is a negative-sense, single-stranded, RNA virus that has not previously been associated with widespread infection in cattle. As such, cattle are an extremely under-studied domestic IAV host species. IAV receptors on host cells are sialic acids (SAs) that are bound to galactose in either an α2,3 or α2,6 linkage. Human IAVs preferentially bind SA-α2,6 (human receptor), whereas avian IAVs have a preference for α2,3 (avian receptor). The avian receptor can further be divided into two receptors: IAVs isolated from chickens generally bind more tightly to SA-α2,3-Gal-β1,4 (chicken receptor), whereas IAVs isolated from duck to SA-α2,3-Gal-β1,3 (duck receptor).

We found all receptors were expressed, to a different degree, in the mammary gland, respiratory tract, and cerebrum of beef and/or dairy cattle. The duck and human IAV receptors were widely expressed in the bovine mammary gland, whereas the chicken receptor dominated the respiratory tract. In general, only a low expression of IAV receptors was observed in the neurons of the cerebrum. These results provide a mechanistic rationale for the high levels of H5N1 virus reported in infected bovine milk and show cattle have the potential to act as a mixing vessel for novel IAV generation.

Preprint in bioRxiv (May 3, 2024):

https://doi.org/10.1101/2024.05.03.592326 

We report highly pathogenic avian influenza A(H5N1) virus in dairy cattle and cats in Kansas and Texas, United States, which reflects the continued spread of clade 2.3.4.4b viruses that entered the country in late 2021. Infected cattle experienced nonspecific illness, reduced feed intake and rumination, and an abrupt drop in milk production, but fatal systemic influenza infection developed in domestic cats fed raw (unpasteurized) colostrum and milk from affected cows. Cow-to-cow transmission appears to have occurred because infections were observed in cattle on Michigan, Idaho, and Ohio farms where avian influenza virus–infected cows were transported. Although the US Food and Drug Administration has indicated the commercial milk supply remains safe, the detection of influenza virus in unpasteurized bovine milk is a concern because of potential cross-species transmission. Continued surveillance of highly pathogenic avian influenza viruses in domestic production animals is needed to prevent cross-species and mammal-to-mammal transmission.

Published in Emerging Infectious Diseases (April 20, 2024)

https://doi.org/10.3201/eid3007.240508 

Health Alert: First Case of Novel Influenza A (H5N1) in Texas, March 2024 Health Alert April 1, 2024 Summary The Texas Department of State Health Services (DSHS) is reporting the first human case of novel avian influenza A(H5N1) in Texas. The patient became ill following contact with dairy cows presumed to be infected with avian influenza. The patient’s primary symptom was conjunctivitis. This is the second case of avian influenza A(H5N1) identified in a person in the United States and is believed to be associated with the recent detections of avian influenza A(H5N1) in dairy cows announced by the Texas Animal Health Commission. DSHS along with local, regional, state, and federal partners, is investigating this ongoing situation. Avian influenza A(H5N1) viruses have only rarely been transmitted from person to person. As such, the risk to the general public is believed to be low; however, people with close contact with affected animals suspected of having avian influenza A(H5N1) have a higher risk of infection.

DSHS is issuing this health alert to provide awareness to healthcare providers and ask them to be vigilant for people with signs and symptoms of avian influenza A(H5N1). Suspicion for avian influenza A(H5N1) should be heightened for people who have had contact with animals suspected of having avian influenza A(H5N1)...

U.S. regulators confirmed that sick cattle in Texas, Kansas and possibly in New Mexico contracted avian influenza. They stressed that the nation’s milk supply is safe. A highly fatal form of avian influenza, or bird flu, has been confirmed in U.S. cattle in Texas and Kansas, the Department of Agriculture announced on Monday. It is the first time that cows infected with the virus have been identified. The cows appear to have been infected by wild birds, and dead birds were reported on some farms, the agency said. The results were announced after multiple federal and state agencies began investigating reports of sick cows in Texas, Kansas and New Mexico. In several cases, the virus was detected in unpasteurized samples of milk collected from sick cows. Pasteurization should inactivate the flu virus, experts said, and officials stressed that the milk supply was safe.

“At this stage, there is no concern about the safety of the commercial milk supply or that this circumstance poses a risk to consumer health,” the agency said in a statement. Outside experts agreed. “It has only been found in milk that is grossly abnormal,” said Dr. Jim Lowe, a veterinarian and influenza researcher at the College of Veterinary Medicine at the University of Illinois at Urbana-Champaign. In those cases, the milk was described as thick and syrupy, he said, and was discarded. The agency said that dairies are required to divert or destroy milk from sick animals....

USDA report (March 25, 2024):

https://www.aphis.usda.gov/aphis/newsroom/news/sa_by_date/sa-2024/hpai-cattle