A(H5N1) Avian Influenza Virus: A New Pandemic Threat on the Horizon?

Despite its zoonotic potential, the highly pathogenic avian influenza (HPAI) A(H5N1) virus is far from being easily transmissible between people. However, the rapidly expanding range of susceptible bird and mammalian species alongside the increasing viral spread among USA cattle, are of concern.
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The remarkable neurotropism and neuropathogenicity exhibited by the highly pathogenic avian influenza (HPAI) virus A(H5N1) in several bird and mammalian hosts - with special reference to the viral clade - are a matter of concern, together with the largely and rapidly expanding number of virus-susceptible animals, including several species phylogenetically distant from each other (1-6). Additional worrysome issues are represented by the transmission of A(H5N1) virus from wild birds to cattle, with cows from 9 States in USA having tested positive to laboratory investigations (7). Noteworthy, while most infected bovines tend to develop mild clinical signs - with the subsequent risk of getting A(H5N1) avian influenza virus frequently undetected in cattle - consistent amounts of viral infectivity may be also found in raw, unpasteurized cow milk (8). In this respect, a surprisingly high expression of both the avian - sialic acid (SA) alfa-2-3-galactose (gal) - and the human - SA-alfa-2-6-gal - influenza virus receptors has been recently reported within the mammary gland tissue (but not in the upper airways and in the brain) from cattle (9), thus "candidating" the bovine species as a new "mixing vessel" potentially allowing the genetic reassortment/recombination between influenza viruses originating from different animal sources, as it "historically" happens in pigs with avian and human viruses (9). Although there is a paucity of studies aimed at defining how A(H5N1) avian influenza moves between cattle and people, one dairy worker in Texas - where the first case of this viral infection in cows was ascertained in March 2024 - developed a bilateral, virus-induced conjunctivitis (10), followed by a similar ocular disease case ascertained thereafter in another farm worker from Michigan (https://www.nytimes.com/2024/05/22/health/h5n1-bird-flu-dairy.html)

Noteworthy, despite the almost 900 human cases of A(H5N1) viral disease which have been reported from 2003 until now by the World Health Organization (WHO) - 52% of which being characterized by a lethal outcome - an efficient and sustained interhuman infection transmission's chain of such viral pathogen has never been documented, thus far. Nevertheless, based upon the high propensity of influenza viruses to undergo mutations in their genomic make-up through the well-known mechanisms of genetic reassortment/recombination, coupled with the rapidly and consistently expanding viral host range, the possibility the A(H5N1) virus will become easily transmissible between people, thereby acquiring a "pandemic behaviour", appears to be more than plausible (1).

Consequently, an "ad hoc" robust and multidisciplinary "preparedness and readiness effort", strongly relying on the lessons learned from the COVID-19 pandemic and accompanied by a close intersectorial collaboration between human and veterinary medicine, is urgently needed in order to properly counteract this alarming scenario, within a sound One Health perspective's framework.


1) Di Guardo, G., Roperto S. (2024). A(H5N1) avian influenza: A new pandemic? Vet. Rec. 194, in press.

2) Ariyama, N., et al. (2023). Highly Pathogenic Avian Influenza A(H5N1) Clade Virus in Wild Birds, Chile. Emerg. Infect Dis. 29:1842-1845. doi: 10.3201/eid2909.230067.

3) Puryear, W., et al. (2023). Highly Pathogenic Avian Influenza A(H5N1) Virus Outbreak in New England Seals, United States. Emerg. Infect. Dis. 29:786-791. doi: 10.3201/eid2904.221538.

4) Gamarra-Toledo, V., et al. (2023). Mass Mortality of Sea Lions Caused by Highly Pathogenic Avian Influenza A(H5N1) Virus. Emerg. Infect. Dis. 29:2553-2556. doi: 10.3201/eid2912.230192.

5) Thorsson, E., et al. (2023). Highly Pathogenic Avian Influenza A(H5N1) Virus in a Harbor Porpoise, Sweden. Emerg. Infect. Dis. 29:852-855. doi: 10.3201/eid2904.221426.

6) Murawski, A., et al. (2024). Highly pathogenic avian influenza A(H5N1) virus in a common bottlenose dolphin (Tursiops truncatus) in Florida. Commun. Biol. 7:476. doi: 10.1038/s42003-024-06.

7) Reardon, S. (2024). Bird flu in US cows: Where will it end? Nature https://www.nature.com/articles/d41586-024-01333-9.

8) Gerhard, D. (2024). Deciphering the unusual pattern of bird flu symptoms in cows. The Scientist Magazine. https://www.the-scientist.com/deciphering-the-unusual-pattern-of-bird-fl....

9) Kristensen, C., et al. (2024). The avian and human influenza A virus receptors sialic acid (SA)-α2,3 and SA-α2,6 are widely expressed in the bovine mammary gland. bioRxiv 2024. 05.03.592326.

10) Uyeki, T.M., et al. (2024). Highly pathogenic avian influenza A(H5N1) virus infection in a dairy farm worker. N. Engl. J. Med. doi: 10.1056/NEJMc2405371.

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