Arizona: Maricopa County Health Dept. Statement On H5 At Local Zoo

Maricopa County, AZ Credit Wikipedia

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A little over 3 weeks ago Arizona reported their Their 1st H5N1 Outbreak In Commercial Poultry flock in Pinal County, south of Phoenix.   Last week, we learned of 2 Human H5 Infections (based on local testing), among poultry workers.

Today the Maricopa County Health Department has announced an outbreak among (unspecified) zoo animals at the Wildlife World Zoo, Aquarium and Safari Park located in Litchfield, which is west of Phoenix. 

The official announcement from the Maricopa County Health Department follows:

Public Health

Posted on: December 11, 2024

Animals Identified with Avian Flu in Maricopa County

Maricopa County Department of Public Health (MCDPH) is working closely with state and federal partners to respond to detection of avian influenza in a small number of animals that are part of a zoo collection in Litchfield Park. Overall risk to the public and zoo visitors remains low. 

The Wildlife World Zoo identified ill animals and brought them into the Arizona Department of Agriculture to conduct testing. Test results indicated that these animals were likely ill from H5N1 avian flu, which was first seen in wild birds in the United States in 2015. MCDPH is working with the zoo to identify and contact staff and volunteers who are considered to be at higher risk from close, prolonged contact with the infected animals.

 “People who have job-related exposures to infected animals, especially close prolonged exposure, are at higher risk of infection,” said Dr. Nick Staab, assistant medical director at MCDPH. “Public health’s recommendations are intended to reduce the risk to those who have had direct contact with infected animals and to prevent further exposure,” added Dr. Staab.

In addition to MCDPH providing monitoring and post-exposure prophylaxis (i.e., steps to prevent illness once exposed) to staff and volunteers with close contact to sick animals, Wildlife World Zoo has also put guest activities with direct animal contact on hold temporarily. The zoo is implementing other increased health and safety precautions to protect animals, staff and guests, until animal health improves.

Upon detection of the virus, the zoo started implementing the following measures:

1. Isolation and Quarantine
   1. Immediate isolation of infected or exposed animals to prevent further spread.
   2. Quarantine of potentially-exposed animals, especially other avian species.
2. Enhanced Biosecurity
   1. Restricting access to affected areas, allowing only essential personnel in protective gear (e.g., masks, gloves, coveralls, and boot covers).
   2. Disinfecting enclosures, tools, and equipment used in affected areas.
   3. Implementing footbaths or mats with disinfectant at entry points to enclosures.
3. Monitoring and Testing
   1. Conducting health checks on all birds and other susceptible species.
   2. Testing birds for signs of illness or viral presence, both within and beyond the affected enclosure.
   3. Monitoring zookeepers and staff who have had close contact with infected animals for symptoms.

 "While we are deeply saddened to report the loss of a few cherished animals, we are grateful that the impact was limited thanks to our swift response, robust biosecurity protocols, and the invaluable support of Maricopa County Department of Public Health and state and federal agencies,” said Kristy Hayden, president of Wildlife World Zoo. “Our team worked diligently to contain the situation, and we remain committed to the health and safety of our animals, staff, and visitors."

Avian influenza H5 is a novel influenza A virus that primarily affects birds. It has previously been detected in Arizona, including a commercial poultry farm in Pinal County and a backyard flock in Maricopa County. 

Although human infections with H5 are rare, most human infections have occurred after unprotected exposure to sick or dead infected animals or their environment. H5 infection in people can range from mild (upper respiratory symptoms, conjunctivitis/pink eye) to severe (pneumonia, multi-organ failure, and death). There is currently no evidence of human-to-human transmission of H5, and the overall risk to the general public remains low. 

 To reduce the risk of infection, people should not consume unpasteurized (raw) dairy products and should avoid unprotected contact with sick or dead animals and their droppings or bedding. Anyone who suspects poultry to have bird flu should call the USDA’s sick bird hotline at 866-536-7593.

 MCDPH recommends general precautions to prevent the spread of flu and other respiratory viruses that commonly spread at this time of year. People can reduce their risk of illness with basic steps: 

• Practice good hand hygiene, which includes hand washing and using hand sanitizer when soap and water are not available. 
• Get your seasonal flu and COVID-19 vaccines. 
• Seasonal flu vaccination will not prevent infection with bird flu viruses but can reduce the risk of getting sick with human influenza viruses and thus the risk for seasonal and bird flu co-infection.

• Seasonal flu and COVID-19 vaccines are safe and effective at reducing severity of symptoms, and they also reduce the likelihood of getting infected with flu or COVID-19. 

• Talk with your healthcare provider about other vaccines that are recommended for certain groups, such as the RSV vaccine and pneumococcal vaccine. 
• Stay home and away from others if you are sick. 
• If symptoms worsen or you are at higher risk of severe illness, contact your medical provider. Consider wearing a mask if you seek healthcare for your symptoms. 

“We are in the middle of flu season, with other viruses like COVID-19 circulating as well, so people should stay watchful, especially with the holidays upon us,” added Dr. Staab. It takes about two weeks for your body to build immunity from a flu shot, so now is a good time to get one ahead of holiday and other social gatherings. 

 

Hawaii Dept. of Health: H5 Detected in Wastewater in Hilo

Hawaii lies beneath the West Pacific Flyway 

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Four weeks ago the Hawaii Dept. of Health released a Statement on Detection of H5 Influenza In Wastewater on the island of Oʻahu, followed by at least two outbreaks in captive and/or wild birds the following week.

The assumption is the virus arrived via the West Pacific Flyway. 

Overnight the Hawaii DOH announced a second detection - this time on the `big island' of Hawaiʻi - at the Hilo wastewater treatment plant. These two detections are roughly 200 miles apart (as the virus flies), which may suggest more than one introduction.

The DOH statement follows:

H5 AVIAN FLU DETECTED AT WASTEWATER SAMPLING SITE IN HILO

Posted on Dec 10, 2024 in Newsroom

HONOLULU — The Hawai‘i Department of Health (DOH) State Laboratories Division has detected H5 avian influenza (bird flu) in a wastewater sample collected on Dec. 2 at the Hilo Wastewater Treatment Plant on Hawaiʻi Island.

This is the first detection of bird flu on a neighbor island and indicates an H5 type of bird flu virus was present. Wastewater testing cannot determine if the detection is specifically the Highly Pathogenic Avian Influenza (HPAI) H5N1 subtype of bird flu virus which was recently found on Oʻahu. 

The presence of the H5N1 virus in Hawaiʻi was first confirmed in November 2024 in a backyard flock of birds in Central Oʻahu. That virus strain was a different genotype of the virus that has infected birds and dairy cows on the U.S. mainland.

While the risk to the public remains low, HPAI can cause severe illness with a high mortality rate among certain bird populations such as poultry. Commercial poultry producers and residents with backyard flocks are strongly advised to increase biosecurity measures to reduce the likelihood of infection. HPAI can also infect dairy cows. While pasteurized milk is safe, raw milk should be avoided.

To report multiple or unusual illnesses in poultry, livestock, or other wild birds or animals, contact HDOA Animal Industry Division at 808-483-7102, Monday to Friday from 7:45 a.m. to 4:30 p.m., or 808-837-8092 during non-business hours and holidays.

Residents who believe they may have been exposed to sick birds or other wildlife should contact the Disease Outbreak Control Division Disease Reporting Line at 808-586-4586 for additional guidance.

Resources on avian influenza:

• HDOA, Animal Disease Control: https://hdoa.hawaii.gov/ai/ldc/avian-influenza-information/
• HDOA, Avian Influenza – Biosecurity in The Context of Animal Agriculture: https://hdoa.hawaii.gov/ai/ldc/adconcerns/aiinfo/biosec/
• DOH avian influenza information: https://health.hawaii.gov/docd/disease_listing/avian-influenza/
• Centers for Disease Control and Prevention: https://www.cdc.gov/bird-flu/index.html
• U.S. Department of Agriculture: https://www.aphis.usda.gov/livestock-poultry-disease/avian/avian-influenza

EID Journal: Replication Restriction of Influenza A(H5N1) Clade 2.3.4.4b Viruses by Human Immune Factor, 2023–2024

Flu Virus binding to Receptor Cells – Credit CDC

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Over the past 2 decades we've discussed a number of potential `species barriers' that might prevent avian H5 or H7 viruses from ever sparking a pandemic.  As far as we can go back in time (about 130 years), all of the known human influenza pandemics have been from an H1, H2, or H3 virus. 

What subtypes of influenza that may have circulated in humans before that is unknown.  

There are at least three major barriers to avian flu becoming a `humanized' virus.

• First, avian flu viruses bind preferentially to alpha 2,3 receptor cells found in the gastrointestinal tract of birds, while `humanized’ flu viruses - like H3N2 and H1N1 - have an affinity for the alpha 2,6 receptor cells most commonly found in the human respiratory system.

• Second, birds run `hotter' than mammals, meaning an avian flu virus must adapt to replicate at the lower temperatures found in the human respiratory tract. 

• Third, the virus must get around the interferon-induced host restriction factor MxA, which is a protein that provides protection against a broad range of viruses, including some avian influenza viruses.

We've seen mutations (see here, here, and here) that allow avian influenza viruses to switch  binding to mammalian receptor cells, and mutations (notably PB2 E627K) which allow the virus to replicate at lower temperatures.

We've even seen reports of some avian-like viruses that are able to skirt around the MxA antiviral barrier (see Recent Papers On The Zoonotic Potential of Bat-borne H9N2). 

But so far, HPAI H5 hasn't managed to pull off the hat-trick; All three at once.  

And to be fair, even if that did happen, there may be some other inhibiting factor that could prevent efficient spread in humans.  We won't really know if an H5Nx pandemic is possible until it happens. 

All of which brings us to an EID Journal research letter which finds - while the current H5N1 clade 2.3.4.4b continues to be suppressed by MxA - there are at least a couple of ways that the H5N1 virus could get around this `species barrier'. 

• First, they have already observed that some H5 isolates have shown signs of partial adaptation, via mutations in the PB2 (E627K and M631L), which have weakened the antiviral impact of MxA.  

• And second, they warn that an H5 reassortment with a seasonal flu virus (like H1N1 or H3N2) could provide H5N1 with the keys to human adaptation. 

The takeaway is that the protection offered by the MxA protein is not absolute, and given the rapid spread and evolution of H5 viruses, MxA escape variants could emerge. 

This is admittedly a highly technical review, and I've only covered a few of the highlights, and have only posted some excerpts. Follow the link to read it in its entirety.

Research Letter

Replication Restriction of Influenza A(H5N1) Clade 2.3.4.4b Viruses by Human Immune Factor, 2023–2024

Jakob Ankerhold1, Susanne Kessler1, Martin Beer, Martin Schwemmle, and Kevin Ciminski

Abstract

We show that human myxovirus resistance protein 1 (MxA) suppresses replication of highly pathogenic avian influenza A(H5N1) viruses isolated from mammals in vitro and in MxA-transgenic mice. However, H5N1 can evade MxA restriction through replacement of individual viral polymerase complex components from a human-adapted MxA-resistant strain in vitro.

Since 2022, clade 2.3.4.4b highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype have caused an increasing number of outbreaks in mammals worldwide (1). Since spring 2024, outbreaks of H5N1 clade 2.3.4.4b viruses have occurred in dairy cows in the United States, leading to the transmission of the virus to dairy farm workers, likely through close contact with infected cows or milk (2,3). Those events have raised concerns that H5N1 clade 2.3.4.4b viruses may further adapt to humans.

Indeed, some current mammal H5N1 clade 2.3.4.4b isolates already carry adaptive mutations associated with enhanced binding to mammalian entry receptors, increased viral polymerase activity in mammalian cells, or escape from the recently identified BTN3A3 restriction factor (1,2,4). However, for sustained human-to-human transmission, HPAI H5N1 must overcome additional host barriers, including human myxovirus resistance protein 1 (MxA).

MxA is an interferon-induced innate immune protein that suppresses replication of zoonotic influenza A viruses (IAVs) (5,6). Previous studies have demonstrated that human-adapted IAVs, such as the pandemic H1N1 virus A/Hamburg/4/2009 (pH1N1), evade MxA restriction through adaptive amino acids in the viral nucleoprotein (NP) (7). In contrast, MxA escape-mediating amino acids are absent in avian IAVs, such as the human HPAI H5N1 isolate A/Thailand/1(KAN-1)/2004 and the current mamma H5N1 clade 2.3.4.4b isolates (Appendix Figure). We used a risk assessment approach to investigate whether human MxA restricts zoonotic infections with mammalian H5N1 clade 2.3.4.4b isolates.

(SNIP)

Our data show that human MxA restricts current mammalian H5N1 clade 2.3.4.4b isolates. However, because this MxA-mediated restriction was less pronounced in hMxAtg/tg mice, we speculate that adaptations in the viral polymerase, including PB2E627K and PB2M631L within the PB2 627 domain, have enabled the viruses to partially outpace MxA-mediated restriction (10).

Given the ongoing circulation of bovine H5N1 in dairy cattle expressing antivirally active Mx1, increased surveillance could identify the potential emergence of MxA escape variants and provide early warning for possible future human-to-human transmission of these viruses.

Mr. Ankerhold is an MD/PhD student at the Institute of Virology at the Medical Center of the University of Freiburg, Germany. His research interests include zoonotic viruses and molecular host determinants.

California: Marin County HHS Investigating A Suspected Avian Flu Patient Who Consumed Raw Milk

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On Sunday I carried a brief mention that the Marin County Health Dept. was investigating a second Bay Area child with suspected H5 infection, and at that time there was no known risk exposure.  According to both the California and CDC case lists, this case remains unconfirmed. 

At the same time, we've seen several recalls of raw milk in California after evidence of H5N1 contamination surfaced (see here, here, and here). 

Late yesterday the Marin county HHS announced that they were investigating a suspected avian flu infection in a sick child (who tested positive for influenza A), who also reportedly consumed raw milk.

Lacking a positive H5 test (which - depending on the timing, and viral load - can be difficult to obtain) this is something less than a slam dunk. But it does raise concerns.

The `raw milk' movement in the United States continues to grow, despite ample evidence of its dangers. A 2022 study published in the Journal of Food Protection reported that:

Results show that 4.4% of U.S. adults reported consuming raw milk at least once in the past year, with 1.6% reporting frequent consumption of raw milk (once per month or more often) and 1.0% reporting consumption once per week or more often. 

Which suggests that several million people in the United States regularly consume raw milk, a practice that becomes increasingly problematic with avian flu detected in dairy herds in at least 16 states. 

We may never know if this child actually had H5 influenza (although serological tests might yield further evidence), but there is apparently enough of an index of suspicion to warrant the following warning:

Health Officials Warn Against Consuming Raw Milk

Flu A detected in child who became sick after drinking raw milk. No person-to-person spread of the virus has been detected or is suspected; Risk to public remains low.

December 10, 2024
News Release
Health and Human Services

Body of News Release

San Rafael, CA – Marin County Public Health (MCPH) strong advises people not to consume any raw milk products. MCPH is reporting a suspected case of bird flu in a child who experienced fever and vomiting after drinking raw milk. The child has recovered, and no other family members became sick, indicating no person-to person transmission.

MCPH is actively investigating this possible case of bird flu linked to raw milk consumption with the California Department of Public Health (CDPH) and the federal Centers for Disease Control and Prevention (CDC).

On December 6, CDPH issued an alert[External] to health care providers to evaluate and test for human avian flu (H5N1) in people who develop flu-like symptoms after consuming raw milk. Due to widespread transmission of bird flu among wild birds, significant outbreaks among dairy cows, and sporadic human cases.

“Bird flu infections in humans are uncommon but there are ongoing outbreaks in dairy cattle and poultry farms in the United States,” said Dr. Lisa Santora, Marin County’s Public Health Officer, “The risk to the public remains low, as bird flu spread from person to person is rare.”

There have been 32 confirmed cases of bird flu reported in California this year. Most bird flu detections in the U.S. have been in poultry and dairy workers who were exposed to sick animals, but sporadic cases are expected.

Human, animal, and environmental health are connected. This possible case of bird flu linked to raw milk consumption highlights the importance of understanding how diseases can spread from animals to humans, especially through food. Raw milk, which hasn't been pasteurized poses a risk of spreading diseases, including influenza. Exposure to food-borne bacteria and viruses can make anyone sick, but they are especially dangerous for people with weak immune systems, as well as children, older adults, and pregnant women.

Health care providers should ​​​consider avian influenza A (H5N1) in persons with fever, gastrointestinal, respiratory symptoms and/or conjunctivitis with recent consumption of raw milk products or exposure to animals suspected or confirmed to have avian influenza. They should contact MCPH immediately for technical assistance on collecting respiratory specimens (nasopharyngeal and oropharyngeal swabs) for testing.

“We thank the teams at Napa-Solano-Yolo-Marin County Public Health Laboratory, CDPH and CDC for their prompt response, support and guidance,” Santora said.For the latest information on the county’s bird flu response, visit MCPH’s Bird Flu (H5N1) page.

 
For the latest information on the state’s bird flu response, visit CDPH’s Current Bird Flu Situation[External].
For the latest information on the national bird flu response, visit CDC's Bird Flu Response Update[External].

Emerg. Microbes & Inf.: Marked Neurotropism and Potential Adaptation of H5N1 Clade 2.3.4.4.b Virus in Naturally Infected Domestic Cats

Cats As Potential Vectors/Mixing Vessels for Novel Flu

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With highly mutable influenza viruses the only constant is change, and HPAI H5 is no exception.  

Over the past two decades we've watched as it has repeatedly reinvented itself, generating numerous subtypes (H5N1, H5N2, H5N5, H5N6, H5N8, etc.), dozens of subclades (2.2, 2.3.2.1a, 2.3.4.4b, etc.) and literally hundreds of genotypes (B3.13, D1.1, D1.2, etc.).

Most of these variants have fallen by the wayside, unable to compete with more `biologically fit' versions of the virus. But this winnowing process has also led to a far-more-capable group of viruses circulating today than 10 or 15 years ago. 

Starting in 2020 we began to see a new subclade (2.3.4.4b) begin to spread globally, carried by a wider range of avian hosts (see DEFRA: The Unprecedented `Order Shift' In Wild Bird H5N1 Positives In Europe & The UK).

While we'd seen sporadic spillover of HPAI to non-human mammals (primarily cats), starting in 2021 we began to see reports of numerous spillovers into a much wider range of mammals (see chart below).

Credit ECDC/EFSA

Also of concern, in many cases these mammalian infections presented with severe neurological manifestations, to the point that many H5 infected animals were initially suspected to be rabid (see CDC EID Journal: Encephalitis and Death in Wild Mammals at An Animal Rehab Center From HPAI H5N8 - UK).

Over the past 9 months we've seen yet another seismic shift, with livestock (dairy cows, goats, alpacas, pigs, and even horses) - previously assumed immune - now susceptible to infection. 

And since March of this year, we've seen an unprecedented surge in (mostly mild) human infections with the H5N1 virus in the United States.  While the CDC only lists 58 confirmed cases, the real number (based on serological tests and anecdotal reports) suggests a much higher number. 

This continued evolution, increased host range, and extrapulmonary spread in mammalian hosts is a genuine concern, as we really don't know what this H5 virus will do next. 

All of which brings us to a new research article, published yesterday in Emerging Microbes & Infections, that looks at a spillover of HPAI H5N1 earlier this year to a house full of domestic cats, all of which died, many with severe neurological symptoms. 

The authors also document a number of potentially significant mutations in these cats, along with demonstrating their ability to serve as a potential `mixing vessel' for influenza. 

This is a lengthy and highly detailed report, and it really deserves to be read in its entirety.  I've posted the link, and some extended excerpts below.  I'll have a postscript after the break. 

Research Article
Marked Neurotropism and Potential Adaptation of H5N1 Clade 2.3.4.4.b Virus in Naturally Infected Domestic Cats

Shubhada K. Chothe, Surabhi Srinivas, Sougat Misra, Noel Chandan Nallipogu, Elizabeth Gilbride, Lindsey LaBella, Swastidipa Mukherjee, Christian H Gauthier, Heidi L. Pecoraro, Brett T. Webb, James M. Pipas, Santhamani Ramasamy & Suresh V. Kuchipudi 
Article: 2440498 | Accepted author version posted online: 09 Dec 2024
Cite this article
https://doi.org/10.1080/22221751.2024.2440498

Abstract:

In April 2024, ten cats died in a rural South Dakota (SD) residence, showing respiratory and neurological symptoms. Necropsy and laboratory testing of two cats confirmed H5N1 clade 2.3.4.4b infection. The viral genome sequences are closely related to recent SD cattle H5N1 sequences.

Cat H5N1 genomes had unique mutations, including T143A in haemagglutinin, known to affect infectivity and immune evasion, and two novel mutations in PA protein (F314L, L342Q) that may affect polymerase activity and virulence, suggesting potential virus adaptation. Dead cats showed systemic infection with lesions and viral antigens in multiple organs. Higher viral RNA and antigen in the brain indicated pronounced neurotropism. 

Lectin-histochemistry revealed widespread co-expression of sialic acid α-2,6 and α-2,3 receptors, suggesting cats could serve as mixing vessels for reassortment of avian and mammalian influenza viruses. No differences in clade 2.2 or 2.3.4.4b H5 pseudoviruses binding to cat lung/brain tissues indicated the neurotropism is unlikely mediated by receptor binding affinity.

         (SNIP)

Discussion

Increasing evidence suggests recent shifts in the patterns of mammalian infections with the HPAI H5N1 viruses worldwide, indicating ongoing adaptation to infect mammalian hosts [42] In addition, the host range of the HPAIV H5N1 virus has been expanding, with clade 2.3.4.4b spillovers now detected in various mammalian species. These include both domestic and wild carnivores, such as domestic cats [43], red foxes [44], multiple bear species [45], and seals [10] among others. This growing list of susceptible mammalian hosts highlights the virus's ability to cross species barriers, raising concerns about its potential impact on wildlife and domestic animal populations.

In this study, we report a natural H5N1 clade 2.3.4.4b virus infection resulting in the deaths of ten cats in rural South Dakota. The exact source of infection remains unclear; however, phylogenetic analysis of H5N1 sequences from two of the cats reveals a close genetic relationship to clade 2.3.4.4b strains previously detected in local cattle, suggesting a possible link. Additionally, the presence of bird feathers near the deceased cats indicates the likelihood that infection may have occurred through the consumption of virus-infected birds. However, because the disease typically requires several days to manifest post-ingestion, the exact timing of exposure is unclear. This evidence points toward a plausible cattle-to-bird-to-cat transmission pathway, supported by recent studies that identified H5N1 sequences across multiple species on affected farms, including dairy cows, wild birds, domestic cats, and raccoons [46].

Our study provides a significant new insight into the neurotropism of the H5N1 clade 2.3.4.4b virus in naturally infected domestic cats. There is a notable shift in the neurotropism of HPAI H5N1 viruses, particularly with the emergence of clade 2.3.4.4b in cats and wild carnivores like foxes. For example, in cats, experimental infection with the H5N1 Vietnam isolate (clade 2.2 - A/Vietnam/1194/04) showed primarily respiratory disease, with only one of three infected cats succumbing and no neurological symptoms[20]. Similarly, a natural H5N1 infection in Germany (A/swan/Germany/R65/06) in domestic cats displayed higher viral loads in the lungs than in the brain, with infection linked mainly to broncho-interstitial pneumonia [21]. Furthermore, studies on red foxes fed bird carcasses infected with clade 2.2 H5N1 also demonstrated limited clinical impact, with the foxes excreting the virus without developing severe disease. In contrast, recent H5N1 clade 2.3.4.4b infection in two cats from Texas [47] resulted in neurological signs and 50% mortality, likely due to ingestion of unpasteurized milk from infected cattle. Further, recent reports from Europe and the United States involving infection of red foxes with H5N1 clade 2.3.4.4b have shown a marked shift toward neurotropism [44]. These cases have documented viral adaptations that facilitate central nervous system involvement, with some infections exhibiting viral mutations indicative of enhanced neurotropism [46].

We identified several key mutations in the H5N1 sequence from infected cats that may suggest adaptation to cats. We observed a threonine-to-alanine mutation at residue 143 in HA (T143A). In A/Netherlands/219/2003 HA, this threonine (T143) forms a glycosylation motif (N-X-T/S) involving asparagine 141 (N141) around the receptor binding site (RBS), which is known to increase virus infectivity and resistance to neutralizing antibodies [48]. While the potential implications of the T143A mutation in clade 2.3.4.4.b are unclear, it could represent an adaptation mutation in cats that warrants further investigation. Notably, residue 143 in HA has been identified as a major mutation site in the RBS of H5 that contributes to viral escape from neutralizing antibodies among the different subclades, including 2.3.4.4b [49].

The N71S mutation in NA has not been previously reported in H5N1. While this mutation may not likely alter substrate specificity directly, it could potentially reduce efficiency on some substrates because phosphorylation or glycosylation of the serine residue might make the stalk of NA more rigid [50, 51]. The PA mutations (F314L and L342Q) are novel, and their functional implications are unknown. However, it is important to note that mutations in residues adjacent to these positions (343 and 347) in avian H5N1 influenza viruses have been shown to affect polymerase activity and virulence in mice [52]. Therefore, further investigation of these two PA mutations is critical to better understand their impact on the virus's polymerase activity and mammalian pathogenicity.

(SNIP)

In many rural households, as was the case with the infected cats in rural South Dakota reported in this study, cats are often housed outdoors, used for pest control, and considered family pets. This unique role exposes them to diverse environments and interactions, including terrestrial, aquatic, wild birds, and other livestock animals and humans. This exposure puts cats at a higher risk of encountering a broad spectrum of avian and mammalian influenza viruses. Notably, a recent study found that stray cats in the Netherlands were frequently exposed to HPAI H5, with a seropositivity rate of 11.8% among clinically healthy individuals [57]. The presence of asymptomatic infections in cats with H5N1 is a significant threat as these cats could serve as silent carriers, transmitting the virus to humans without showing any clinical signs of illness.

The continued exposure, viral circulation, and adaptation of the H5N1 virus in cats raise significant concerns for transmission and public health. Cats, common companion animals that frequently interact with humans and other species, could serve as a bridge for cross-species transmission of H5N1 viruses. Infected cats develop systemic infections and shed the virus through both respiratory and digestive tracts [58], potentially creating multiple routes of exposure to humans. Furthermore, the ability of the virus to persist and adapt in mammalian hosts heightens the risk of evolving into strains with increased transmissibility, posing an emerging zoonotic threat with profound public health implications. As H5N1 viruses continue to infect a wide range of avian and mammalian hosts, including an increasing number of human cases, there is an urgent need for coordinated One Health surveillance to monitor the spread of H5N1 among domestic and wild birds, animals, and humans.

          (Continue . . . )

While far from complete, the USDA lists > 2 dozen wildlife species of mammals affected by H5N1, including:

The state of South Dakota has reported 9 cats infected (see below), but this list only includes 2 of the 10 cats mentioned in this report.  Most infected cats - like many other peridomestic species - are unlikely to be discovered or tested for the virus. 

Making the 53 domestic cats confirmed infected with H5 by the USDA undoubtedly just the tip of the iceberg. 

While the CDC continues to rank the risk to general public from avian flu as low, they do provide very specific guidance to pet owners on how to limit their risk of infection from the virus (see What Causes Bird Flu in Pets and Other Animals). 

And given the amount of HPAI virus being reported in wild birds, poultry, and livestock around the country, it is advice well worth heeding. 

EID Journal: Influenza A(H5N1) Virus Clade 2.3.2.1a in Traveler Returning to Australia from India, 2024

Two Reasons Why H5N1 clade 2.3.4.4b isn't the only game in town
 

#18,474

Although the 60+ H5N1 cases reported in the United States in 2024 have all been mild, in many other parts of the world different incarnations (subtypes, clades, or genotypes) of the HPAI H5 virus have not been so benign.

• In Cambodia, we've seen 18 human H5N1 infections (clade 2.3.2.1c) reported since early 2023, with nearly a 40% fatality rate. And as we've seen previously with other incarnations of HPAI H5N1, Children and adolescents have been the hardest hit.

• While in China, more than 90 clade 2.3.4.4 H5N6 infections have been reported over the past decade (likely an undercount) with a greater than 50% fatality rate.

Although the reasons aren't fully understood, there can be huge differences in the virulence of closely related H5 viruses. In British Columbia, a teenager remains in critical condition after more than a month following infection with an H5N1 D1.1 genotype, similar to that which mildly infected > a dozen poultry workers in Washington State. 

There may also be host differences at work; age, vaccination and previous influenza exposures, preexisting conditions, etc. 

As a segmented virus with 8 largely interchangeable parts, the flu virus is like a viral LEGO (TM) set which allows for the creation of new subtypes - and within each subtype - variants called genotypes.  There are already well over 100 H5N1 genotypes circulating in North America. 

The waxing and waning of H5 outbreaks in places like Indonesia, Vietnam, Egypt - and even globally - over the years is largely due to the virus's continual genetic reorganization.  Some of these generated variants are simply more transmissible, or more virulent, than others. 

Last April,  in - FAO Statement On Reassortment Between H5N1 Clade 2.3.4.4b & Clade 2.3.2.1c Viruses In Mekong Delta Region - we learned that a new genotype - made up of an older clade (2.3.2.1c) and the newer 2.3.4.4b clade of H5N1 - had emerged in Southeast Asia.

After a lull of nearly a decade, this `new' genotype appears to have sparked a resurgence of H5N1 in Southeast Asia, with reports coming from both Cambodia and Vietnam. 

Last May Australia reported their first H5N1 case (see Australia: Victoria Reports Imported H5N1 Case (ex India)) in a 2 year-old child who recently traveled from India. The virus was originally identified as an older H5N1 clade 2.3.2.1a virus, which is known to circulate in poultry in Bangladesh and India. 

Last week the CDC's EID Journal published a dispatch which reveals this older clade was actually - much like the example above from Cambodia -  a new genotype, with contributions from newer clade 2.3.4.4b viruses.

Since new genotypes can abruptly alter the behavior of a virus, they are important to monitor and analyse. 

I've only reproduced the abstract and excepts from the discussion below, so follow the link to read this dispatch in its entirety.  I'll have a brief postscript after the break. 

Dispatch

Influenza A(H5N1) Virus Clade 2.3.2.1a in Traveler Returning to Australia from India, 2024

Yi-Mo Deng1, Michelle Wille1, Clyde Dapat, Ruopeng Xie, Olivia Lay, Heidi Peck, Andrew J. Daley, Vijaykrishna Dhanasakeran, and Ian G. Barr 

Abstract

We report highly pathogenic avian influenza A(H5N1) virus clade 2.3.2.1a in a child traveler returning to Australia from India. The virus was a previously unreported reassortant consisting of clade 2.3.2.1a, 2.3.4.4b, and wild bird low pathogenicity avian influenza gene segments. These findings highlight surveillance gaps in South Asia.

The global panzootic of highly pathogenic avian influenza (HPAI) A(H5N1) clade 2.3.4.4b is affecting wild and domestic birds and mammals worldwide (1). This viral clade emerged after decades of evolution of goose/Guangdong (gs/Gd) lineage HPAI H5N1 viruses, first detected in geese in China in 1996 (2). Although clade 2.3.4.4b is globally dominant, a diversity of HPAI H5N1 clades are present in poultry in Asia today. Since 2005, >900 zoonotic infections have been recorded, primarily caused by contact with infected poultry (3); no evidence exists of human-to-human transmission. Reflecting the diversity of gs/Gd clades in Asia, human infections in Asia have been caused by a variety of clades. For example, Cambodia recorded 11 human infections caused by HPAI H5N1 clade 2.3.2.1c in the past 2 years, and China recorded 91 human infections caused by HPAI H5N6 and 2 cases caused by clade 2.3.4.4b H5N1 since 2014, many of them fatal.

Clade 2.3.2.1a continues to be detected in South Asia, particularly in India and Bangladesh. However, human infections have been rare; to our knowledge, only 2 cases have been reported (4,5). In recent years, several poultry outbreaks of H5N1 have occurred in India (6), raising concerns about the spread and evolution of clade 2.3.2.1a HPAI H5N1 viruses. We describe HPAI H5N1 clade 2.3.2.1a infection in a traveler returning to Australia from India.

The Study

A previously healthy 2.5-year-old girl returned to Melbourne, Victoria, Australia, after visiting Kolkata, India, during February 12–29, 2024. The child became ill in India; her family sought medical care on February 28. After returning to Australia, she was hospitalized on March 2, then transferred with severe influenza on March 4 and admitted to intensive care with respiratory failure requiring mechanical ventilation. Influenza A virus was detected by PCR, but no subtyping was performed. A 5-day course of oseltamivir was administered beginning on day 3 after admission; she recovered fully and was discharged after 2.5 weeks. No clinical illness was apparent in other family members, and no samples were taken or tested (7,8).

(SNIP)

Conclusions

This report of a human HPAI H5N1 case in a traveler returning from India highlights several issues.

First, clinicians should be vigilant for serious influenza A cases in returned travelers from regions with circulating avian influenza viruses; subtyping is essential for such cases of influenza A to eliminate nonseasonal influenza infections. This step is crucial for early antiviral treatment, especially for the H5N1 and H5N6 viruses currently circulating in South/Southeast Asia, which can be serious or even fatal.

Second, although global attention is focused on the panzootic clade 2.3.4.4b viruses, a relatively small number of human infections (<100) have been recorded, and few have been serious. This contrasts with ≈100 human cases of clade 2.3.4.4 H5N6 viruses in China and clade 2.3.2.1c H5N1 in Cambodia, which caused many deaths.

Third, this case highlights the lack of H5N1 data from India. Clade 2.3.2.1a human infections in India and Nepal coincided with circulation in poultry and wild birds in Bangladesh (12). The fatal case in New Delhi in 2021, involving an 11-year-old boy who had contact with poultry (although no infected birds were reported) (4), is consistent with the genome reported here and genetically similar to H5N1 viruses present in Bangladesh. However, the patient in this study had no confirmed contact with poultry or raw poultry products; hence, the mode and route of infection cannot be determined. However, H5N1 was reported in 2023 and 2024 in Ranchi, India, 400 km from Kolkata (13,14). Since 2020, only 2 H5N1 sequences from India have been reported, compared with 314 H5N1 sequences from Bangladesh (197 in clade 2.3.2.1a) (Figure 2). Furthermore, the most recent common ancestor to A/Victoria/149/2024(H5N1) occurred almost 4 years before, highlighting the need for more sequence data from this region (Appendix Figure 2).

The complex reassortment origins of A/Victoria/149/2024(H5N1) show that clade 2.3.4.4.b viruses disseminated globally through wild birds might be transforming the genetic structure of other H5N1 clades endemic in poultry. Although HPAI H5N1 clade 2.3.4.4b viruses continue to be the focus of global attention, persistent HPAI H5Nx infections in Asia should not be overlooked.

Dr. Deng heads the Genetic Analysis Unit at the WHO Collaborating Centre for Reference and Research on Influenza in Australia. Her research interests encompass the genomics and evolution of human and animal influenza viruses. Dr. Wille is a senior research fellow at the Centre for Pathogen Genomics. Her primary research interest is the ecology and evolution of avian influenza viruses, in addition to other viruses found in wild birds, and more recently, entire virus communities revealed through metagenomics.

Although the history of H5Nx over the past 2+ decades has been one of sharp advances, followed by slow retreats, the HPAI H5 virus has continued to consistently gain ground over time, as well as expand its diversity. 

• Between 1997 and 2004, H5N1 was strictly a Southeast Asia problem.  
• Between 2004 and 2012 it had expanded its range to Europe, Africa, and the Middle East
• In 2014 it diversified into H5N6 in China and as H5N8 in South Korea
• In 2014, as H5N8, it made it to North America for the first time, then vanished 
• In 2016, H5N8 made it to Europe, and in 2017 it make its way into the Southern Hemisphere
• And since 2021, as H5N1 it has conquered North and South America, and made inroads into Antarctica

Where H5Nx goes from here is anyone's guess.  While some genotypes or subtypes may lose virulence, others may gain it.  Some variants will thrive, while others will fall by the wayside.  The virus we see tomorrow may look quite different from the virus we see today.

The only thing we can say with any certainty is the virus continues to evolve, and that its current trajectory is still on the upswing.  

We ignore it at our own considerable risk.