Commonground
Senior Moderator
[emphasis is mine]
Patrick C. Y. Woo 1,2
1 Doctoral Program in Translational Medicine and Department of Life Sciences, National Chung Hsing University,
Taichung 402, Taiwan; pcywoo@hku.hk; Tel.: +886-4-22840370 (ext. 19); Fax: +886-4-22860164
2 The iEGG and Animal Biotechnology Research Center, National Chung Hsing University, Taichung 402, Taiwan
How To Cite: Woo, P.C.Y. Emergence of Fatal Influenza A Virus H5N5 Infection in Human. eMicrobe 2026, 2(1), 2.
https://doi.org/10.53941/emicrobe.2026.100002.
In November 2025, a patient from the Grays Harbor County, Washington State, USA, died of influenza A
virus H5N5 infection (https://www.latimes.com/science/story/2025-11-21/washington-state-resident-dies-of-
new-h5n5-form-of-bird-flu; accessed on 4 December 2025). This was, in fact, the first known case as well as the
first fatal case of human H5N5 infection. The patient had a backyard flock consisting of mixed domestic poultry.
Influenza A viruses represent a vast and evolutionary dynamic group of pathogens capable of infecting a high
diversity of avian and mammalian hosts [1–3]. They have a segmented RNA genome composed of eight negative-
sense strands, enabling genetic reassortment when two different influenza viruses co-infect a host cell. This
reassortment capacity is a defining feature of influenza virus evolution. Influenza A viruses are classified into
different subtypes by two surface glycoproteins: hemagglutinin (H) and neuraminidase (N). Some of the subtypes
(e.g., H1N1, H3N2) have been well-known to be circulating in humans for a long time, others are restricted only
to birds; while a few of them were occasionally transmitted from birds to humans, sometimes causing devastating
outbreaks [4].
Among the different influenza A viruses, the H5 lineage, particularly influenza A virus H5N1, has attracted
considerable global attention due to its potential for high pathogenicity. Since the first reported outbreak of H5N1
infection in humans from Hong Kong in 1997, more than a thousand cases have been reported, mostly from patients
in Southeast Asia who have been linked to direct contact with infected poultry, sick or dead birds, or environments
contaminated by them [4]. H5N1 infection in humans was associated with a high case fatality rate of around 50%,
although this figure was influenced by limited surveillance and the likelihood that mild cases go undetected.
Sustained human-to-human transmission has not been established, although limited, non-sustained transmission
has been reported in rare family clusters. In addition to H5N1, H5N8 is another H5 influenza A virus that has been
confirmed to cause human infection. In 2021, a number of workers in a poultry farm in Russia had asymptomatic
H5N8 infections, without any evidence of human-to-human transmission [5]. The workers were exposed during a
large outbreak among egg-laying hens.
Influenza A virus H5N5 has appeared multiple times independently rather than descending from a single
lineage. Many strains emerged when an H5 lineage virus, such as clade 2.3.4, 2.3.4.4, or related subclades,
reassorted with viruses carrying the N5 segment [6]. Such reassortment events typically occur in wild waterfowl,
which act as natural reservoirs for nearly all known H and N subtypes. Particularly, the clade 2.3.4.4 H5 viruses,
which have demonstrated extraordinary reassortment diversity, have produced numerous combinations with
various neuraminidases, including N2, N6, N8, and N5 [7–9]. H5N5 sublineages have therefore appeared in
different geographical regions at different times, often sharing genetic backbones with better-known H5 strains
but differing in their neuraminidase segment and sometimes internal genes. Since the early 2010s, H5N5 has been
detected in Asia, Europe, the Middle East, and occasionally Africa, usually aligning with waterfowl migratory
routes. The distribution of H5N5 is sporadic, with periodic introductions rather than sustained global circulation.
Many detections have been associated with migratory bird populations, which can transport the virus across
continents. However, unlike some H5 subtypes (e.g., H5N1) that have become well-established in poultry, H5N5
has more often remained a spillover virus, appearing in wild birds or causing limited outbreaks in domestic flocks.
The natural hosts of H5N5 are wild aquatic birds. Similar to other influenza viruses in aquatic birds,
transmission occurs through the classical fecal-oral route associated with waterborne influenza ecology. In these
species, infection may be asymptomatic or mild, allowing the virus to spread silently across long distances.
Occasional spillover to domestic poultry can occur, particularly in areas where wild birds and domestic flocks
interact around shared water sources or open-air environments. The pathogenicity of H5N5 varies widely. Some
early H5N5 detections involved low-pathogenicity avian influenza strains, causing minimal diseases in birds.
However, many more recent strains have been classified as high-pathogenicity influenza strains, particularly those
emerging from clade 2.3.4.4 [6,9]. Some H5N5 strains have demonstrated the molecular hallmarks of high
pathogenicity in poultry, such as polybasic cleavage sites in the hemagglutinin protein, enabling systemic infection
in chickens and turkeys. Outbreaks in poultry can cause sudden death and a variety of other symptoms, depending
on the particular strain. Evidence of infections in mammals is limited but not absent. Like many avian influenza
viruses, H5N5 has occasionally been detected in scavenging or predatory mammals that consume infected birds.
However, these cases do not necessarily indicate sustained mammalian transmission; instead, they usually reflect
isolated spillovers facilitated by ingestion of contaminated animal.
Before the present incident, H5N5 was not considered a major zoonotic threat. Although several molecular
characteristics limit its capacity to infect humans, such as receptor-binding preferences that strongly favor avian-
type α2,3-linked sialic acid receptors, a recent study in fact described that a novel strain of highly pathogenic avian
influenza clade 2.3.4.4b in North America may carry a key mutation (PB2-E627K substitution) which facilitated
its adaptation in mammals [10]. The present alarming case of fatal human H5N5 infection implies that more active
surveillance of H5N5, which relies on close monitoring of wild birds, particularly waterfowls, as well as in poultry
farms, live markets, and other high-risk interfaces between wildlife and domestic animals and humans, is crucial [11].
In parallel with the emergence of fatal influenza A virus H5N5 infection in humans is the emergence of new
bioinformatics tools and artificial intelligence algorithms for tracking and predicting the evolution of influenza
viruses [12,13]. Such improvement of in silico technologies is of paramount importance in the prediction of
possible interspecies jumping, development of vaccines, and timely implementation of public health measures for
this centuries’ old infection that has been associated with countless epidemics and outbreaks in the history of
mankind [14].
Funding
This work was partly supported by the Feature Areas Research Center Program within the framework of the
Higher Education Sprout Project by the Ministry of Education (MOE-114-S-0023-A) in Taiwan.
Conflicts of Interest
The author declares no conflict of interest.
Use of AI and AI-Assisted Technologies
No AI tools were utilized for this paper.
References
continued: https://media.sciltp.com/articles/2512002453/2512002453.pdf
Patrick C. Y. Woo 1,2
1 Doctoral Program in Translational Medicine and Department of Life Sciences, National Chung Hsing University,
Taichung 402, Taiwan; pcywoo@hku.hk; Tel.: +886-4-22840370 (ext. 19); Fax: +886-4-22860164
2 The iEGG and Animal Biotechnology Research Center, National Chung Hsing University, Taichung 402, Taiwan
How To Cite: Woo, P.C.Y. Emergence of Fatal Influenza A Virus H5N5 Infection in Human. eMicrobe 2026, 2(1), 2.
https://doi.org/10.53941/emicrobe.2026.100002.
In November 2025, a patient from the Grays Harbor County, Washington State, USA, died of influenza A
virus H5N5 infection (https://www.latimes.com/science/story/2025-11-21/washington-state-resident-dies-of-
new-h5n5-form-of-bird-flu; accessed on 4 December 2025). This was, in fact, the first known case as well as the
first fatal case of human H5N5 infection. The patient had a backyard flock consisting of mixed domestic poultry.
Influenza A viruses represent a vast and evolutionary dynamic group of pathogens capable of infecting a high
diversity of avian and mammalian hosts [1–3]. They have a segmented RNA genome composed of eight negative-
sense strands, enabling genetic reassortment when two different influenza viruses co-infect a host cell. This
reassortment capacity is a defining feature of influenza virus evolution. Influenza A viruses are classified into
different subtypes by two surface glycoproteins: hemagglutinin (H) and neuraminidase (N). Some of the subtypes
(e.g., H1N1, H3N2) have been well-known to be circulating in humans for a long time, others are restricted only
to birds; while a few of them were occasionally transmitted from birds to humans, sometimes causing devastating
outbreaks [4].
Among the different influenza A viruses, the H5 lineage, particularly influenza A virus H5N1, has attracted
considerable global attention due to its potential for high pathogenicity. Since the first reported outbreak of H5N1
infection in humans from Hong Kong in 1997, more than a thousand cases have been reported, mostly from patients
in Southeast Asia who have been linked to direct contact with infected poultry, sick or dead birds, or environments
contaminated by them [4]. H5N1 infection in humans was associated with a high case fatality rate of around 50%,
although this figure was influenced by limited surveillance and the likelihood that mild cases go undetected.
Sustained human-to-human transmission has not been established, although limited, non-sustained transmission
has been reported in rare family clusters. In addition to H5N1, H5N8 is another H5 influenza A virus that has been
confirmed to cause human infection. In 2021, a number of workers in a poultry farm in Russia had asymptomatic
H5N8 infections, without any evidence of human-to-human transmission [5]. The workers were exposed during a
large outbreak among egg-laying hens.
Influenza A virus H5N5 has appeared multiple times independently rather than descending from a single
lineage. Many strains emerged when an H5 lineage virus, such as clade 2.3.4, 2.3.4.4, or related subclades,
reassorted with viruses carrying the N5 segment [6]. Such reassortment events typically occur in wild waterfowl,
which act as natural reservoirs for nearly all known H and N subtypes. Particularly, the clade 2.3.4.4 H5 viruses,
which have demonstrated extraordinary reassortment diversity, have produced numerous combinations with
various neuraminidases, including N2, N6, N8, and N5 [7–9]. H5N5 sublineages have therefore appeared in
different geographical regions at different times, often sharing genetic backbones with better-known H5 strains
but differing in their neuraminidase segment and sometimes internal genes. Since the early 2010s, H5N5 has been
detected in Asia, Europe, the Middle East, and occasionally Africa, usually aligning with waterfowl migratory
routes. The distribution of H5N5 is sporadic, with periodic introductions rather than sustained global circulation.
Many detections have been associated with migratory bird populations, which can transport the virus across
continents. However, unlike some H5 subtypes (e.g., H5N1) that have become well-established in poultry, H5N5
has more often remained a spillover virus, appearing in wild birds or causing limited outbreaks in domestic flocks.
The natural hosts of H5N5 are wild aquatic birds. Similar to other influenza viruses in aquatic birds,
transmission occurs through the classical fecal-oral route associated with waterborne influenza ecology. In these
species, infection may be asymptomatic or mild, allowing the virus to spread silently across long distances.
Occasional spillover to domestic poultry can occur, particularly in areas where wild birds and domestic flocks
interact around shared water sources or open-air environments. The pathogenicity of H5N5 varies widely. Some
early H5N5 detections involved low-pathogenicity avian influenza strains, causing minimal diseases in birds.
However, many more recent strains have been classified as high-pathogenicity influenza strains, particularly those
emerging from clade 2.3.4.4 [6,9]. Some H5N5 strains have demonstrated the molecular hallmarks of high
pathogenicity in poultry, such as polybasic cleavage sites in the hemagglutinin protein, enabling systemic infection
in chickens and turkeys. Outbreaks in poultry can cause sudden death and a variety of other symptoms, depending
on the particular strain. Evidence of infections in mammals is limited but not absent. Like many avian influenza
viruses, H5N5 has occasionally been detected in scavenging or predatory mammals that consume infected birds.
However, these cases do not necessarily indicate sustained mammalian transmission; instead, they usually reflect
isolated spillovers facilitated by ingestion of contaminated animal.
Before the present incident, H5N5 was not considered a major zoonotic threat. Although several molecular
characteristics limit its capacity to infect humans, such as receptor-binding preferences that strongly favor avian-
type α2,3-linked sialic acid receptors, a recent study in fact described that a novel strain of highly pathogenic avian
influenza clade 2.3.4.4b in North America may carry a key mutation (PB2-E627K substitution) which facilitated
its adaptation in mammals [10]. The present alarming case of fatal human H5N5 infection implies that more active
surveillance of H5N5, which relies on close monitoring of wild birds, particularly waterfowls, as well as in poultry
farms, live markets, and other high-risk interfaces between wildlife and domestic animals and humans, is crucial [11].
In parallel with the emergence of fatal influenza A virus H5N5 infection in humans is the emergence of new
bioinformatics tools and artificial intelligence algorithms for tracking and predicting the evolution of influenza
viruses [12,13]. Such improvement of in silico technologies is of paramount importance in the prediction of
possible interspecies jumping, development of vaccines, and timely implementation of public health measures for
this centuries’ old infection that has been associated with countless epidemics and outbreaks in the history of
mankind [14].
Funding
This work was partly supported by the Feature Areas Research Center Program within the framework of the
Higher Education Sprout Project by the Ministry of Education (MOE-114-S-0023-A) in Taiwan.
Conflicts of Interest
The author declares no conflict of interest.
Use of AI and AI-Assisted Technologies
No AI tools were utilized for this paper.
References
continued: https://media.sciltp.com/articles/2512002453/2512002453.pdf