# data[].attributes.body
This webpage from the CDC provides a multitude of resources regarding the bird flu, including information on the current risk of the disease as well as signs of contamination in humans.

# data[].attributes.attachment_link.provider_name
Centers for Disease Control and Prevention

# data[].attributes.attachment_link.readable_text
Avian influenza or bird flu refers to the disease caused by infection with avian (bird) influenza (flu) Type A viruses. These viruses naturally spread among wild aquatic birds worldwide and can infect domestic poultry and other bird and animal species. Bird flu viruses do not normally infect humans. However, sporadic human infections with bird flu viruses have occurred. The links below offer more information about bird flu.

# data[].attributes.attachment_link.description
Avian influenza refers to the disease caused by infection with avian (bird) influenza (flu) Type A viruses.

# data[].attributes.headline
Bird flu declared animal health emergency

# data[].attributes.subject
Bird flu declared animal health emergency

# data[].attributes.body
This past May, following serious outbreaks, Brazil declared the bird flu as an animal health emergency. This emergency is in effective through December of this year. While primarily a precautionary measure, the Brazilian government transitioned into this state of emergency to best ensure that the bird flu is contained and has limited reach in terms of human contamination.

# data[].attributes.attachment_link.title
Bird flu: Brazil declares animal health emergency after several cases found

# data[].attributes.attachment_link.description
The country is the world's largest exporter of chicken meat, and wants to stop the virus spreading.

# data[].attributes.headline
Brazilian article about declaration of emergency

# data[].attributes.subject
Brazilian article about declaration of emergency

# data[].attributes.body
This article from Brazilian news outlet "Correio de Povo" discusses the declaration of animal emergency in regards to the bird flu.

# data[].attributes.attachment_link.readable_text
O Rio Grande do Sul deve decretar em breve o estado de emergência zoossanitária recomendado pelo Ministério da Agricultura e Pecuária (Mapa) para todas as unidades da federação como medida de prevenção e enfrentamento da influenza aviária. Segundo a assessoria de imprensa da Secretaria da Agricultura, Pecuária, Produção Sustentável e Irrigação (Seapi), a decisão foi consolidada no final da tarde de quarta-feira e não foi comunicada no site da pasta porque o documento ainda aguarda análise e assinatura do governador Eduardo Leite.

O estado de emergência zoossanitária foi adotado nacionalmente pelo Mapa no final de maio. Há cerca de uma semana, o titular da pasta, Carlos Fávaro, fez a recomendação de que a medida fosse decretada individualmente para cada estado, como forma de facilitar o acesso a recursos governamentais para ações de controle da doença.

# data[].attributes.attachment_link.title
Rio Grande do Sul vai adotar estado de emergência zoossanitária para enfrentamento da gripe aviária

# data[].attributes.attachment_link.description
De acordo com a Secretaria da Agricultura do Estado, decreto com a medida recomendada pelo Ministério da Agricultura aguarda apenas a análise e assinatura do governador Eduardo Leite

# data[].attributes.headline
Bird flu cases confirmed in main-poultry producing state

# data[].attributes.subject
Bird flu cases confirmed in main-poultry producing state

# data[].attributes.body
This article discusses the recent presence of bird flu cases amongst wildlife in a region that produces approximately 35% of the nation's poultry. Because of the presence of the bird flu in this area, a greater risk of human contamination is posed.

# data[].attributes.attachment_link.readable_text
A wild bird confirmed to be infected with avian influenza at Rio Grande do Sul. Photo: Rio Grande do Sul state

According to Brazil's Official Veterinary Service, 2 new outbreaks have been confirmed in the country, this time in the state of Paraná, a state that accounts for 35% of Brazil's poultry production.

The Brazilian Ministry of Agriculture, Livestock, and Supply updated the number of cases of highly pathogenic avian influenza (HPAI) in wild birds to 48 in the country. The first case of avian flu in Brazil was registered on 15 May.

The discovery of the disease in wild birds in Paraná - one was in the city of Pontal do Paraná and the other in Antonina municipality - highlights another warning sign as the state is the country's largest producer and exporter of chicken meat. In 2022, the state accounted for 35.54% of Brazilian production, according to data from ABPA (Brazilian Association of Animal Protein).

So far, only wild birds have been affected, and no cases of the disease have been registered in poultry from commercial production farms or in subsistence farming, according to the Ministry.

For the latest news and updates on avian influenza around the world, click here ...

On 22 May, the Ministry of Agriculture declared a zoosanitary emergency and measures to prevent the disease from reaching commercial herds were reinforced.

On 7 June, the Federal Government published a provisional measure opening an extraordinary credit of R$200 million for actions to be taken by the ministry to combat highly pathogenic avian influenza (H5N1).

As there are no cases in commercial herds, Brazil remains free of avian influenza before the World Organization for Animal Health (WHOA), and there are no restrictions on Brazilian chicken meat.

ALSO READ: Brazil confirms first cases of avian influenza

Poultry exports rising

Brazilian chicken exports are still on the rise. In the accumulated result for the year (January to May), sector sales reached a total volume of 2,183 million tonnes, an amount 9.7% higher than that recorded in the first 5 months of 2022 (1,990 million tonnes).

In revenue, accumulated shipments reached US$4.281 billion, a figure 13.4% higher than that between January and May 2022 (US$3,776 billion).

# data[].attributes.attachment_link.title
Brazil confirms bird flu in main poultry-producing state - Poultry World

# data[].attributes.attachment_link.description
According to Brazil's Official Veterinary Service, 2 new outbreaks have been confirmed in the country, this time in the state of Paraná, a state that

# data[].attributes.headline
Brazil's animal health emergency...and its potential for a human health epidemic

# data[].attributes.subject
Brazil's animal health emergency...and its potential for a human health epidemic

# data[].attributes.body
This video is focused on Brazil's declaration of an animal health emergency for the bird flu this past May. It also discusses the potential that these large outbreaks in Brazil create for a human health disaster.

# data[].attributes.attachment_link.title
Brazil Imposes Animal Health Emergency Amid Widespread Bird Flu Outbreak

# data[].attributes.headline
World Health Organization findings on the threat of the bird flu to human population

# data[].attributes.subject
World Health Organization findings on the threat of the bird flu to human population

# data[].attributes.body
This article from the World Health Organization discusses why the bird flu poses such a threat to the human population, despite being a mostly animal-centric issue. The research in this article is very informative and educational on this topic.

# data[].attributes.attachment_link.readable_text
The current outbreaks of avian influenza (also called "bird flu") have caused devastation in animal populations, including poultry, wild birds, and some mammals, and harmed farmers' livelihoods and the food trade. Although largely affecting animals, these outbreaks pose ongoing risks to humans.

The Food and Agriculture Organization of the United Nations (FAO), the World Health Organization (WHO), and the World Organisation for Animal Health (WOAH) are urging countries to work together across sectors to save as many animals as possible and to protect people.

Avian influenza viruses normally spread among birds, but the increasing number of H5N1 avian influenza detections among mammals-which are biologically closer to humans than birds are-raises concern that the virus might adapt to infect humans more easily. In addition, some mammals may act as mixing vessels for influenza viruses, leading to the emergence of new viruses that could be more harmful to animals and humans.

The goose/Guangdong-lineage of H5N1 avian influenza viruses first emerged in 1996 and have been causing outbreaks in birds since then. Since 2020, a variant of these viruses belonging to the H5 clade 2.3.4.4b has led to an unprecedented number of deaths in wild birds and poultry in many countries in Africa, Asia and Europe. In 2021, the virus spread to North America, and in 2022, to Central and South America.

In 2022, 67 countries in five continents reported H5N1 high pathogenicity avian influenza outbreaks in poultry and wild birds to WOAH, with more than 131 million domestic poultry lost due to death or culling in affected farms and villages. In 2023, another 14 countries reported outbreaks, mainly in the Americas, as the disease continues to spread. Several mass death events have been reported in wild birds, caused by influenza A(H5N1) clade 2.3.4.4b viruses.
Monitoring the recent surge in outbreaks among mammals
Recently, there have been increasing reports of deadly outbreaks among mammals also caused by influenza A(H5)-including influenza A(H5N1)-viruses. 10 countries across three continents have reported outbreaks in mammals to WOAH since 2022. There are likely to be more countries where outbreaks have not yet been detected or reported. Both land and sea mammals have been affected, including outbreaks in farmed mink in Spain, seals in the United States of America, and sea lions in Peru and Chile, with at least 26 species known to have been affected. H5N1 viruses have also been detected in domestic animals such as cats and dogs in several countries, with recent detections of H5N1 in cats announced by authorities in Poland.

"There is a recent paradigm change in the ecology and epidemiology of avian influenza which has heightened global concern as the disease spread to new geographical regions and caused unusual wild bird die-offs, and alarming rise in mammalian cases," said Dr Gregorio Torres, Head of the Science Department at WOAH.
Assessing the risk to humans
Sporadic influenza A(H5N1) clade 2.3.4.4b virus detections in humans have also been reported, but remain very rare, with 8 cases reported since December 2021. Infections in humans can cause severe disease with a high mortality rate. The human cases detected thus far are mostly linked to close contact with infected birds and contaminated environments.

"With the information available so far, the virus does not appear to be able to transmit from one person to another easily, but vigilance is needed to identify any evolution in the virus that can change that," said Dr Sylvie Briand, Director of Epidemic and Pandemic Preparedness and Prevention, WHO. "WHO is working closely with FAO and WOAH, and laboratory networks to monitor the evolution of these viruses, looking for signals of any change that could be more dangerous to humans. We encourage all countries to increase their ability to monitor these viruses and to detect any human cases. This is especially important as the virus is now affecting countries with limited prior experience in avian flu surveillance."

Studies are underway to identify any changes in the virus that may help the virus to spread more easily among mammals, including humans.

"The epidemiology of H5N1 continues to rapidly evolve," said Keith Sumption, Chief Veterinary Officer, FAO. "FAO brings attention to the need for vigilance and timely sharing of genetic sequences to monitor the molecular epidemiology for risk assessment and better disease control."
Curbing the spread of avian influenza
Given the unprecedented spread of the A(H5N1) avian influenza virus among birds and mammals, and the potential risk to human health, the tripartite partners-FAO, WHO and WOAH-urge countries to take the following actions:

Prevent avian influenza at its source, mainly through enhanced biosecurity measures in farms and in poultry value chains, and apply good hygiene practices. WOAH members, in consultation with the poultry sector, may consider the vaccination of poultry as a complementary disease control tool based on sound surveillance and taking into account local factors such as circulating virus strains, risk assessment and vaccination implementation conditions.

Rapidly detect, report and respond to animal outbreaks as the first line of defence. When an infection is detected in animals, countries are encouraged to implement control strategies as described in WOAH standards.

Strengthen influenza surveillance in animals and humans. To allow for early response, risk-based surveillance in animals should be enhanced before and during high-risk periods. Animal cases of avian influenza should be reported to WOAH in a timely manner. Genetic sequencing should be conducted periodically to detect any changes in the viruses already present in the area or the introduction of new viruses. In humans, the following should be prioritized: (i) surveillance for severe acute respiratory infections and influenza-like illnesses, (ii) careful review of any unusual epidemiological patterns, (iii) reporting of human infections under the International Health Regulations, and (iv) sharing of influenza viruses with WHO Global Influenza Surveillance and Response System (GISRS) Collaborating Centres for Reference and Research on Influenza.

Conduct epidemiological and virological investigations around animal outbreaks and human infections. Surveillance should be enhanced to rapidly detect and investigate further suspected animal and human cases.

Share the genetic sequence data of viruses from humans, animals or their environments in publicly accessible databases rapidly, even before peer-reviewed publication.

Encourage collaboration between the animal and human health sectors, especially in the areas of information sharing, joint risk assessment and response.

Communicate the risk. Alert and train healthcare workers and occupationally-exposed persons on ways to protect themselves. The general public as well as animal workers should be advised to avoid contact with sick and dead animals, and to report these to animal health authorities. They should also be advised to seek medical care if unwell and to report any exposure to animals to their healthcare provider.

Ensure influenza pandemic preparedness at all levels.

FAO, WHO and WOAH have been convening experts to review the situation, monitoring the rapidly evolving nature of the virus, and updating recommendations for curbing its spread, in addition to working with countries in preparedness and response, and facilitating collaboration across countries and sectors. The spread of the virus to five continents speaks to the need for global cooperation and alertness to protect animals, people and economies.
Notes to editors

Species of mammals known to be infected with A(H5N1) clade 2.3.4.4b viruses to date: ferret, mink, European otter, North American river otter, marine otter, European badger, skunk, Virginia opossum, Amur leopard, Amur tiger, mountain lion, fisher, European polecat, lynx, bobcat, domestic cat, red fox, coyote, racoon, racoon dog, South American bush dog, American black bear, brown Bear, grizzly bear, Kodiak bear, domestic pig (serology only), grey seal, harbour seal, fur seal, sea lion, porpoise, bottlenose dolphin, short-beaked common dolphin, white sided dolphin, dogs, Japanese raccoon dogs, Beech marten, Caspian seals, Asiatic black bear, Chilean dolphin, Burmeister's porpoise. More studies are needed to understand baseline levels of infection in wild mammals.

Current virological assessment/summary

Markers for mammalian adaptation:

The molecular marker 627K, or its equivalents such as 701N, in the PB2 gene have been detected in some but not all sequences of viruses obtained from mammalian infections. It has been detected in very few sporadic wild bird and poultry cases. These markers are known to increase viral replication in mammalian cells.

None of the viruses from infected mammals, including humans, have changes indicating increased specificity of binding to human-like receptors.

In studies on viruses from wild birds and poultry, there is no indication that the viruses have changed their preference for binding to avian-like receptors. However, some genetic mutations are present which have been demonstrated to increase the ability to bind to human-like receptors.

The virus isolated from the infected minks has a genetic mutation that might make the virus replicate better in mammal cells. The viruses from mink, and some viruses from birds, had additional mutations more commonly seen in human viruses.

Antiviral susceptibility:

Virus sequences from human cases, where available, did not show markers for resistance to neuraminidase inhibitors (such as oseltamivir) or endonuclease inhibitors (such as baloxavir).

Sequences analyzed from circulating viruses in animal species contained only sporadic mutations which are associated with resistance to antivirals.

Based on the available information human population immunity against the influenza A(H5) clade 2.3.4.4b virus haemagglutinin is expected to be minimal.

Further resources

WHO assessment of risk associated with recent influenza A(H5N1) clade 2.3.4.4b viruses, 21 December 2022

OFFLU meeting to discuss avian influenza events in mammals, 2 March 2023

FAO Global consultation on Highly Pathogenic Avian Influenza, 2-5 May 2023

WOAH Animal Health Forum on avian influenza, 22-23 May 2023

WHOFactsheet on avian and other zoonotic influenz a, WHO Q&A on avian influenza

WOAH Infographic on the new dynamics of avian influenza

EFSA (European Food Safety Authority), ECDC (European Centre for Disease Prevention and Control), EURL (European Reference Laboratory for Avian Influenza), Adlhoch, C, Fusaro, A, Gonzales, JL, Kuiken, T, Marangon, S, Stahl, K, Niqueux, É, Staubach, C, Terregino, C, Mirinaviciute, G, Aznar, I, Broglia, A and Baldinelli, F, 2023. Scientific report: Avian influenza overview December 2022-March 2023. EFSA Journal 2023; 21( 3):7917, 43 pp. https://doi.org/10.2903/j.efsa.2023.7917

https://www.efsa.europa.eu/en/efsajournal/pub/8039

Agüero Montserrat, Monne Isabella, Sánchez Azucena, Zecchin Bianca, Fusaro Alice, Ruano María José, del Valle Arrojo Manuel, Fernández-Antonio Ricardo, Souto Antonio Manuel, Tordable Pedro, Cañás Julio, Bonfante Francesco, Giussani Edoardo, Terregino Calogero, Orejas Jesús Javier. Highly pathogenic avian influenza A(H5N1) virus infection in farmed minks, Spain, October 2022. Euro Surveill. 2023;28(3):pii=2300001. https://doi.org/10.2807/1560-7917.ES.2023.28.3.2300001

De Vries E, de Haan CA. Letter to the editor: Highly pathogenic influenza A(H5N1) viruses in farmed mink outbreak contain a disrupted second sialic acid binding site in neuraminidase, similar to human influenza A viruses. Euro Surveill. 2023 Feb;28(7):2300085. https://doi.org/10.2807/1560-7917.es.2023.28.7.2300085

# data[].attributes.attachment_link.title
Ongoing avian influenza outbreaks in animals pose risk to humans

# data[].attributes.attachment_link.description
The current outbreaks of avian influenza (also called "bird flu") have caused devastation in animal populations, including poultry, wild birds, and some mammals, and harmed farmers' livelihoods and the food trade. Although largely affecting animals, these outbreaks pose ongoing risks to humans.

# data[].attributes.body
This video discusses the devastating impacts that the bird flu has had to nations worldwide, both economically and in terms of public health. It also discusses the concern and possibility for human-to-human transmission if the virus were to mutate, which is why there is such urgency among scientists and epidemiologists to try to best control bird flu outbreaks.

# data[].attributes.attachment_link.title
Bird Flu Surge Has Scientists Seeking Clues to Prevent Next Pandemic

# data[].attributes.headline
Why it is important to control the bird flu

# data[].attributes.subject
Why it is important to control the bird flu

# data[].attributes.body
This peer reviewed piece tackles this subject by emphasizing the importance of assessing the current risk of the bird flu and urgently seeking to control it.

# data[].attributes.attachment_link.readable_text
Nature Reviews Immunology 23, 267-268 (2023) Cite this article

6782 Accesses

4 Citations

135 Altmetric

Metrics

H5N1 avian influenza viruses of the A/goose/Guangdong/1/96 lineage have been circulating in wild birds for many years, have inflicted significant economic losses on the poultry industry and have caused zoonotic infections since 1997. However, the recent spread of avian H5N1 virus to the Americas and its detection in mammals have raised concerns about its pandemic potential.

Avian influenza viruses are typically relatively harmless for humans. Even in birds, infections are often mild or asymptomatic. However, these viruses can become of greater concern under certain circumstances. One problematic scenario is when avian influenza viruses become highly pathogenic for poultry. This typically happens when the haemagglutinin (HA), one of the two proteins on the surface of the virus (with neuraminidase (NA) being the second protein), acquires a polybasic cleavage site. This allows the HA to be activated not just by select proteases, which restricts the virus to certain tissues, but by furin-like proteases found in most tissues, allowing wider dissemination of the virus throughout the host. This polybasic cleavage site is the same element that is found in some coronaviruses, including SARS-CoV-2 and some human seasonal coronaviruses. Acquisition of a polybasic cleavage site can happen spontaneously, often when an avian influenza virus enters a poultry farm and replicates extensively in large concentrations of susceptible animals. Extensive replication increases the chance of insertions occurring in the viral genome, which can lead to the emergence of a polybasic cleavage site. In some cases, the source material of the insertion seems to be fragments of chicken ribosomal RNA1. This acquisition of a polybasic cleavage site by avian influenza viruses has been well documented in poultry farms across the United States; for example, it has occurred twice in the past few years, with an H7N8 virus in Indiana in 2016 (ref. 2) and with an H7N9 virus in Tennessee in 2017 (ref. 3). It has also been documented for H5 subtype HA. Avian H5 and H7 subtype influenza viruses with polybasic cleavage sites cause severe disease in poultry, result in economic losses including increased poultry and egg prices, and endanger wild birds. These viruses can also cause severe disease in humans if large amounts are inhaled deep into the lungs. When that occurs, the fatality rates can be high. However, these avian influenza viruses are not efficient in infecting humans or other mammals, do not replicate well in the human upper respiratory tract and, therefore, usually do not spread from human to human. Typically, they are problematic for individuals in direct contact with infected birds but they are unlikely to cause larger human outbreaks.

However, there are two other concerning scenarios for avian influenza viruses that can occur even in the absence of acquisition of a polybasic cleavage site. One, an avian influenza virus may infect a person who is at the same time infected with a human influenza virus. In that case, the two viruses may infect the same cell and re-assort their genomic segments, which could result in a virus that replicates well in human cells but has HA and NA glycoproteins to which humans are naive. Similar mixing can happen in other mammals including domestic pigs. This mechanism was likely involved in the emergence of at least three, if not all, of the four historic influenza pandemics. Two, an avian influenza virus may grow in a mammal and start to mutate in a way that would allow it to spread efficiently from mammal to mammal (and potentially to humans). A recent example is an outbreak of H10N7 infections in seals in Northern Europe, in which the virus mutated to become mammalian transmissible4. This virus did not have a polybasic cleavage site but still led to mass mortality among seals.

All of the current highly pathogenic avian H5N1 viruses that are endemic in many parts of the world trace back to A/goose/Guangdong/1/96 (ref. 5). This virus lineage caused its first zoonotic outbreak in 1997 in Hong Kong. After a short break, zoonotic infections were recorded again in 2003 through to present day, with the virus spreading across Eurasia and Africa in wild birds. According to the World Health Organization, 868 human cases of H5N1 infection with 457 fatalities were recorded between January 2003 and 23 January 2023 (ref. 6), with most of the cases occurring before 2016. This suggests a very high case fatality rate of 53%. However, many cases of asymptomatic or abortive infection may not have been recorded in areas where there is increased human contact with the virus7.

The H5 viruses have diversified into different genetic clades. Clade 2.3.4.4 viruses emerged in China around 2010-2011 and showed a propensity to re-assort with other avian influenza viruses, acquiring NAs other than N1 in the process. These viruses, often H5N2, H5N6 and H5N8, are summarized under the term H5NX. H5NX viruses were introduced in North America through migrating birds in late 2014, causing economic issues in the poultry industry, but they had apparently mostly disappeared from the wild bird population by the end of 2015. A subclade of clade 2.3.4.4, namely 2.3.4.4b, now having an N1 NA again, started to spread extensively across Eurasia and Africa in 2020. Clade 2.3.4.4b viruses were then detected in North America early in 2022, where they arrived via migratory birds from Europe8; they have now spread across the Americas. Similar to the situation in Eurasia and Africa, the clade 2.3.4.4b H5N1 virus is causing much damage to the poultry industry in North America and has devastated wild bird populations. The virus has also infected many mammals that may feed on carcasses of dead birds, including foxes, raccoons and bears. These infections in mammals have caused severe disease, including neurological symptoms and often death. Most have been 'dead end' infections, meaning that the virus spread from birds to mammals but did not spread among mammals. Very few human cases have been reported, and only after close contact with infected birds. All but one of those cases presented with very mild disease. The exception was a young girl in Ecuador who seemed to have acquired the infection after interaction with infected chickens and who had to be hospitalized. Note that the lethal case of H5N1 infection that was recently reported in Cambodia was caused by a different virus from clade 2.3.2.1c (ref. 9). No human-to-human transmission has been recorded. Although these findings suggest that we need to keep an eye on H5N1, none of these events is immediately concerning in terms of pandemic potential and public health.

However, recently reported events increase the concerns. According to a scientific report published in January 2023, mink in a fur farm in Spain started to die in October 2022 from H5N1 infection, and it seems that the virus may have acquired the ability to spread between these animals, which suggests that it has acquired mutations that facilitate transmission among mammals10. In addition, transmission among marine mammals is suspected in outbreaks in the Caspian Sea and along the Pacific coast of South America. If confirmed, this is concerning as the propensity to transmit among mammals is not typically seen with H5N1 viruses and it suggests that the 2.3.4.4b clade of H5N1 could perhaps also acquire the ability to transmit among humans.

Importantly, this is not a reason for panic. We have several antivirals such as neuraminidase inhibitors and cap-snatching inhibitors that efficiently target influenza viruses including H5N1. Also, there is likely at least partial immunity in the adult population to the N1 NA component of the virus as humans have been repeatedly exposed to the 2009 pandemic H1N1 virus through infection and vaccination. In addition, the virus strain that was able to spread among mink was likely eradicated when these animals were culled in November 2022. Nevertheless, we need to increase our awareness and preparedness. Physicians should be informed to be vigilant about non-seasonal influenza virus infections and a specific vaccine for clade 2.3.4.4b H5N1 should be produced and stockpiled, which is routine for avian influenza viruses with pandemic potential. In addition, the public needs to be aware of H5N1 and should not touch dead, sick or strangely behaving birds or mammals if they are not trained and equipped to handle these animals safely. It would also be advisable to keep pets, such as dogs, away from potentially infected animals. Importantly, this includes urban areas, which often have dense wild bird populations in parks and green spaces.

We also need to think about safe farming practices. As the case of the mink farm shows (as well as the examples from poultry farms in Indiana and Tennessee), influenza virus outbreaks in farms with large numbers of susceptible animals can lead to the emergence of novel and potentially dangerous viral strains that may have pandemic potential. There has recently been a lot of debate about revising regulations for experiments with viruses in laboratories, and this discussion is good to have. However, we should not forget that 'Mother Nature' is the biggest bioterrorist and that unsafe farming practices assist her in creating potentially dangerous viruses. Perhaps, while debating laboratory safety, we may also want to discuss the role of unsafe farming in the emergence of concerning pathogens such as mammalian transmissible avian influenza virus or antibiotic-resistant bacteria.

References

1. Maurer-Stroh, S., Lee, R. T., Gunalan, V. & Eisenhaber, F. The highly pathogenic H7N3 avian influenza strain from July 2012 in Mexico acquired an extended cleavage site through recombination with host 28S rRNA. Virol. J. 10, 139 (2013).

Article CAS PubMed PubMed Central Google Scholar

2. Herfst, S. et al. Hemagglutinin traits determine transmission of avian A/H10N7 influenza virus between mammals. Cell Host Microbe 28, 602-613 (2020).

Article CAS PubMed PubMed Central Google Scholar

3. World Health Organization. Avian influenza weekly update number 884. https://www.who.int/docs/default-source/wpro---documents/emergency/surveillance/avian-influenza/ai_20230224.pdf?sfvrsn=5f006f99_111 (2023).

4. Wang, T. T., Parides, M. K. & Palese, P. Seroevidence for H5N1 influenza infections in humans: meta-analysis. Science 335, 1463 (2012).

Article CAS PubMed PubMed Central Google Scholar

5. Centers for Disease Control and Prevention. Update on H5N1 bird flu in Cambodia. https://www.cdc.gov/flu/avianflu/spotlights/2022-2023/avian-flu-cambodia.htm (2023).

Download references

Acknowledgements

The Krammer laboratory receives support for work in the immunology, virology, therapeutics and vaccine space from NIAID Centers of Excellence for Influenza Research and Response (CEIRR, 75N93021C00014) and Collaborative Influenza Vaccine Innovation Centers (CIVICs, 75N93019C00051) contracts, as well as NIAID grants and contracts U19 AI168631, R01 AI154470, U19 AI162130, R01 AI137146, U01 AI144616, HHSN272201800048C and U19 AI118610. Additional support comes from FluLab and the Bill and Melinda Gates Foundation. Finally, the laboratory is also supported by NCI U54 CA260560 and by the Serological Sciences Network (SeroNet) in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024, Task Order No. 75N91021F00001. The Schultz-Cherry laboratory receives support from NIAID Centers of Excellence for Influenza Research and Response (CEIRR, 75N93021C00016 and 75N93021C00018) and Collaborative Influenza Vaccine Innovation Centers (CIVICs, 75N93019C00052) contracts, as well as NIAID grant 5R01AI140766-04. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

Author information

Authors and Affiliations

1. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Florian Krammer

2. Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA

Florian Krammer

3. Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Florian Krammer

4. Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA

Stacey Schultz-Cherry

Corresponding authors

Correspondence to Florian Krammer or Stacey Schultz-Cherry.

Ethics declarations

Competing interests

F.K. has been consulting for Curevac, Seqirus and Merck and is currently consulting for Pfizer, Third Rock Ventures, Avimex and GSK. He is named on several patents regarding influenza virus and SARS-CoV-2 vaccines, influenza virus therapeutics and SARS-CoV-2 serological tests. Some of these technologies have been licensed to commercial entities and F.K. is receiving royalties from these entities. F.K. is also an advisory board member of Castlevax, a spin-off company formed by the Icahn School of Medicine at Mount Sinai to develop SARS-CoV-2 vaccines. The Krammer laboratory has received funding for research projects from Pfizer, GSK and Dynavax and three of F.K.'s mentees have recently joined Moderna. S.S.-C. declares no competing interests.

About this article

Cite this article

Krammer, F., Schultz-Cherry, S. We need to keep an eye on avian influenza. Nat Rev Immunol 23, 267-268 (2023). https://doi.org/10.1038/s41577-023-00868-8
Download citation

Share this article

Anyone you share the following link with will be able to read this content:

Get shareable link

Provided by the Springer Nature SharedIt content-sharing initiative

# data[].attributes.attachment_link.title
We need to keep an eye on avian influenza - Nature Reviews Immunology

# data[].attributes.attachment_link.description
Recent evidence of transmission of avian H5N1 viruses among mammals raises concerns about their pandemic potential. We need to increase our awareness and preparedness, and should also be thinking about safe farming practices to prevent the emergence of concerning pathogens in the future.

# data[].attributes.headline
Pathology and biology of bird flu infection in humans

# data[].attributes.subject
Pathology and biology of bird flu infection in humans

# data[].attributes.body
This pieces discusses the implications of the bird flu infection on humans in a highly scientific way. This research is incredibly valuable in understanding how the bird flu is transmitted as well as its potential for mutation and human infection.

# data[].attributes.attachment_link.readable_text
H5N1 avian influenza is a highly fatal infectious disease that could cause a potentially devastating pandemic if the H5N1 virus mutates into a form that spreads efficiently among humans. Recent findings have led to a basic understanding of cell and organ histopathology caused by the H5N1 virus. Here we review the pathology of H5N1 avian influenza reported in postmortem and clinical studies and discuss the key pathogenetic mechanisms. Specifically, the virus infects isolated pulmonary epithelial cells and causes diffuse alveolar damage and hemorrhage in the lungs of infected patients. In addition, the virus may infect other organs, including the trachea, the intestines, and the brain, and it may penetrate the placental barrier and infect the fetus. Dysregulation of cytokines and chemokines is likely to be one of the key mechanisms in the pathogenesis of H5N1 influenza. We also review the various molecular determinants of increased pathogenicity that have been identified in recent years and the role of avian and human influenza virus receptors in relation to the transmissibility of the H5N1 virus. A comprehensive appreciation of H5N1 influenza pathogenetic mechanisms should aid in the design of effective strategies for prevention, diagnosis, and treatment of this emerging disease.

H5N1 avian influenza was initially confined to poultry, but in recent years it has emerged as a highly fatal infectious disease in the human population. In 1997, the avian influenza A virus subtype H5N1 crossed the avian-human species barrier for the first time. 1 Eighteen individuals were infected, six of whom died. 2 In January 2003, avian influenza re-emerged among humans in Hong Kong, 3 and since 2004 numerous human infections have also occurred in other Asian and non-Asian countries. To date, the World Health Organization has reported 348 laboratory-confirmed cases, 216 of which were fatal, resulting in a fatality rate of ∼60% (World Health Organization: http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_01_03/en/index.html; accessed January 2008). Human infections mainly resulted from poultry-to-human transmission. Recently, however, there have been reports of human-to-human transmission, 4, 5 increasing fears of a human pandemic.

H5N1 influenza is still a relatively novel disease with poorly understood pathology and pathogenesis. During the period from the first known outbreak nearly a decade ago until the present, only a limited number of reports describing pathological findings in human H5N1 cases has been published. Nevertheless, recent studies combined with early findings have gradually resulted in a better understanding of the cell and organ pathology caused by the H5N1 virus, as well as the viral tissue tropism. These findings together with animal and in vitro experiments have also contributed to a basic understanding of the pathogenesis of this disease. On the molecular level, several viral genes and gene products have been identified that may be responsible for the high pathogenicity of H5N1 influenza viruses. Herein, we describe the pathology of H5N1 avian influenza by reviewing the major pathological findings reported in hitherto published postmortem studies of human H5N1 cases as well as some key findings of animal studies. In addition, the major pathogenetic mechanisms and etiological factors of H5N1 influenza are discussed. The various molecular determinants of increased pathogenicity of H5N1 avian influenza viruses that have been identified in recent years are also presented. Finally, we have taken a closer look at the role of avian and human influenza virus receptors in relation to the transmissibility of the H5N1 virus.

Pathology

Virus Distribution

A number of studies have been performed applying immunohistochemistry (IHC) with monoclonal antibodies to hemagglutinin (HA) and nucleocapsid protein (NP) and/or in situ hybridization with sense and anti-sense probes to HA and NP to detect viral antigens and genomic sequences in various organs of H5N1 cases. 3, 4, 6, 7, 8, 9 In addition, RT-PCR, strand-specific RT-PCR, and nucleic acid sequence-based amplification H5 detection assays have been performed to investigate virus tissue tropism. 3, 6, 7, 8, 9 According to early studies H5N1 infection appeared to be confined to the lungs. 3, 6 However, the findings of recent studies indicate that the virus disseminates beyond the respiratory tract. 7, 8, 9 The main findings of these studies are summarized below.

The Respiratory Tract

Viral antigens and genomic sequences have been found in epithelial cells of the trachea 8(Figure 1B) and alveoli (Figure 1C) . 3, 4, 7, 8, 9 Tracheal epithelial cells were identified as both ciliated and nonciliated cells by double labeling with antibodies to tubulin. 7 The alveolar cells were identified as type II pneumocytes by double labeling with antibodies to surfactant protein (Figure 1D) . 7, 8 RT-PCR and nucleic acid sequence-based amplification-based H5 detection assays have detected viral RNA in both the trachea 7, 9 and lungs. 7, 8, 9 Positive-stranded RNA has been detected in lung 7, 8, 9 and trachea 7, 9 tissue samples. Because the H5N1 virus is a negative-stranded RNA virus, presence of positive-stranded RNA (mRNA and complement RNA, both necessary for viral replication) in a specific tissue suggests active viral replication at that site.

Brain

Viral sequences (Figure 1E) and antigens have been found in neurons of the brain 7 and H5N1 virus has been isolated from cerebrospinal fluid. 15 RT-PCR has detected both negative- and positive-stranded RNA in the brain. Dissemination to the central nervous system may be blood-borne or may alternatively occur via the afferent fibers of the olfactory, vagal, trigeminal, and sympathetic nerves after replication in the lungs, as has been observed in a mouse model. 16

Intestines

Viral genomic sequences have been detected in epithelial cells of the intestines by in situ hybridization. 7 RT-PCR has detected both negative- and positive-stranded RNA in the intestines. 7, 8 These findings are consistent with reports of viral shedding in stool samples, as detected by RT-PCR and viral isolation, 15, 17 and with frequently observed clinical symptoms related to the gastrointestinal tract. 2, 18, 19 Because avian influenza viruses maintain sialidase activities, despite the low pH conditions in the upper gastrointestinal tract, infection of the intestines may be the result of ingestion of infected secretions. 20 In contrast to viral sequences, viral antigens have not been detected in the intestines. 7, 8 The reason for this is at present undetermined.

Other Organs

In situ hybridization and IHC are both negative for the heart, spleen, kidneys, and liver. In contrast, RT-PCR and nucleic acid sequence-based amplification-based H5 detection assay are positive for these organs. 7 The discrepancies between the in situ hybridization/IHC and RT-PCR results may be explained by either false-negative results of the in situ hybridization and IHC assays attributable to limitations in sensitivity or false-positive RT-PCR results attributable to viremia in blood perfusing the organs without actual viral replication in the tissues. 21

Placenta and Fetus

In the placenta of a female infected with H5N1 influenza virus, viral antigens and sequences have been found in Hofbauer cells (fetal macrophages) (Figure 1F) and cytotrophoblasts, but not in syncytiotrophoblasts. 7 RT-PCR results have indicated viral replication in the placenta. 7 In addition, in situ hybridization, IHC (Figure 1G) , and real-time RT-PCR confirmed infection of the fetus, demonstrating that the virus is vertically transmissible from mother to fetus. 7 Transplacental transmission of the virus may occur through mechanisms similar to those for transmission of the cytomegalovirus, a virus that is also known to infect mainly cytotrophoblasts and Hofbauer cells. 22 Transmission may take place via transcytosis across syncytiotrophoblasts to cytotrophoblasts in chorionic villi. 22 Alternatively, the virus may infect invasive cytotrophoblasts within the uterine wall after contact with maternal blood. These infected cells would subsequently transmit the virus via the cell columns to the anchoring chorionic villi. 22 The virus may then be transmitted to Hofbauer cells, which would enter the fetal circulation and carry the virus to the fetus.

Immune Cells and Blood

Viral sequences and antigens have been detected in lymphocytes in lymph node tissue, as well as in Hofbauer cells (macrophages of the placenta), Kupffer cells (macrophages of the liver), and mononuclear cells in the intestinal mucosa. 7 These findings are consistent with in vitro experiments demonstrating infection of macrophages by the H5N1 influenza virus 23, 24, 25 and with ex vivo experiments showing H5N1 virus attachment to and infection of alveolar macrophages in human lung tissue. 26, 27 Viral RNA has been detected in blood samples of several H5N1 cases, all of them fatal. 17 Viremia may occur in the course of the disease, as evidenced by virus isolation from serum and plasma samples of two fatal cases. 15, 28 Accordingly, extra-pulmonary dissemination may be the result of viremia or of infected immune cells transporting the virus to other organs.

Implications on Pathology

H5N1 influenza appears to be a systemic infection in both human and animal cases. In humans the trachea, brain, and intestines may be infected in addition to the lungs. It appears that the virus may also spread to other organs, such as the kidneys and liver, as has also been demonstrated in animals. To gain a better understanding of viral distribution in humans, additional autopsy studies with molecular methods will be necessary. In view of adequate treatment of patients with avian influenza, it is important to realize that the disease affects multiple organs. Therapeutic regimes should therefore not only comprise optimal respiratory care but should also pay attention to adequate supportive care of other organs involved. Multiple-organ infection and vertical transmission of H5N1 have public health implications. The fact that the virus has been isolated from serum and feces makes it possible that infection can be transmitted through gastrointestinal contamination or infected blood. Needless to say that extreme care should be taken when handling body fluids from H5N1 cases. The finding that the virus is transmissible from mother to fetus is alarming and might reflect enhanced pathogenicity of the H5N1 virus. Care should be taken when handling delivery or abortion from H5N1-infected mothers.

Pathogenesis

Various factors are thought to be involved in the pathogenesis of H5N1 influenza (Figure 2) , and a combination of these factors most likely determines the extent of tissue injury and disease outcome. The role of dysregulation of cytokines and chemokines has been studied extensively and may be one of the key mechanisms in the pathogenesis of H5N1 influenza, in addition to injury resulting from viral replication. Other factors, such as up-regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and reduced cytotoxicity of CD8⁺ lymphocytes are also believed to be involved in the pathogenesis, although their exact roles are less clear at present. We discuss these factors and related mechanisms below.

Up-Regulation of TRAIL and Apoptosis

Up-regulation of functional TRAIL in macrophages infected with the H5N1 virus may be another important factor in the pathogenesis of H5N1 influenza virus infection. 54 TRAIL is one of the many death receptor ligands that trigger apoptosis of cells by binding to death receptor ligand receptors expressed on target cells. Zhou and colleagues 54 have demonstrated significantly higher expression of TNF-α and TRAIL in macrophages infected with H5N1 virus in vitro than in macrophages infected with human H1N1 influenza virus. In addition, T lymphocytes co-cultured with macrophages infected with H5N1 virus show increased induction of apoptosis compared to T lymphocytes co-cultured with macrophages infected with other influenza viruses. Enhanced sensitization of virus-infected T lymphocytes to death receptor ligand-induced apoptosis has also been demonstrated. 54 Both sensitization and up-regulation of TRAIL may partially account for the lymphopenia and lung injury frequently observed in H5N1 patients. 54 In addition, a delayed onset of apoptosis has been demonstrated in vitro in H5N1-infected macrophages compared with H1N1-infected macrophages. 25 Prolonged survival of infected macrophages may further enhance the induction of apoptosis in T lymphocytes. 25 It may also augment immune-mediated pathology because macrophages secrete cytokines and chemokines for a longer period of time. In human autopsies apoptosis has been detected in both alveolar epithelial cells and leukocytes in the lungs, as well as in spleen and intestinal tissues. 9 Apoptosis may, therefore, be one of the pathogenetic mechanisms contributing to injury in the lungs and other organs. Apoptosis may occur as a result of direct viral replication or up-regulation of cytokines and chemokines. 9

Reduced Cytotoxicity of CD8⁺ Lymphocytes

As opposed to H1N1 and H3N2 viruses, the HAs of H5N1 viruses suppress perforin expression in cytotoxic T lymphocytes according to in vitro experiments. 55 It has been suggested that this may result in impaired cytotoxic activity causing failure of clearance of H5N1 virus or HA (H5) protein-bearing cells, including antigen-presenting cells. Excessive production of interferon-γ caused by sustained antigenic stimulation of cytotoxic T lymphocytes may subsequently lead to up-regulation of proinflammatory cytokines in macrophages. 55

Implications on Pathogenesis

H5N1 viral replication appears to be prolonged with high levels of viral RNA, and the virus may disseminate to extra-pulmonary organs. Timely suppression of viral replication is the mainstay of therapy in H5N1 infection. Oseltamivir, a neuraminidase inhibitor is the principal antiviral agent of choice because many H5N1 isolates are resistant to amantadines (World Health Organization: Clinical management of human infection with avian influenza A (H5N1) virus. http://www.who.int/csr/disease/avian_influenza/guidelines/clinicalmanagement07.pdf; accessed January 2008). Given the potential role of up-regulation of cytokines and chemokines in the pathogenesis of H5N1 infection, it has been suggested that suppression of the exaggerated host immune response may also be a beneficial therapeutic strategy. Unfortunately, the data on treatment with corticosteroids, albeit limited, have thus far not shown any obvious clinical benefit in treatment of human H5N1 infection. 41 Similarly, corticosteroids have failed to show any clear benefits in the treatment of other viral respiratory infections, including SARS. 56 Further, no human trial with specific cytokine blockers for treatment of H5N1 influenza has been published to date. As to the use of cytokine blockers in animal experiments, only one study has been published describing reduced illness severity in human influenza virus-infected mice treated with anti-TNF antibodies. 57 Altogether, there is insufficient data supporting the use of immunomodulating agents in the treatment of H5N1 influenza. There is an obvious need for more studies into pathogenetic factors as well as therapeutic intervention strategies including immunotherapy.

Viral Genes and Gene Products Involved in the Pathogenesis of H5N1 Influenza

Influenza viruses belong to the family of Orthomyxoviridae. There are three types of influenza viruses: type A, type B, and type C. Avian influenza viruses are all classified as type A influenza viruses. 58 Influenza viruses can be subtyped based on the antigenicity of their two surface glycoproteins, HA and neuraminidase (NA). 58, 59 Sixteen HA and nine NA subtypes have thus far been identified. 59, 60 The influenza A virus genome consists of eight gene segments encoding 11 viral proteins (gene products) including HA, NA, polymerase proteins (PB1, PB2, PA, and PB1-F2), NP, nonstructural proteins (NS1 and NS2), and M1 and M2 proteins (Figure 2) . 61, 62 These genes and/or gene products have various basic functions ranging from viral RNA synthesis to receptor binding (Table 2) . 58, 59 Several of these genes and/or gene products have additional functions that may contribute to the pathogenesis of H5N1 influenza and enhance pathogenicity of H5N1 influenza viruses. Both the basic functions of influenza A viral proteins and the specific functions accounting for increased pathogenicity are summarized in Table 2 and discussed in the following sections. Figure 2 contains a schematic presentation of the viral genes and gene products that may be involved in the key pathogenetic mechanisms of H5N1 influenza.

Table 2

RNA segment

Viral gene product

Basic functions

H5N1 viral proteins contributing to pathogenicity

4

HA

Receptor binding site, membrane fusion, main target for neutralizing antibodies

Multiple residues at cleavage site increase virulence (64,66), H5 suppresses perforin expression in cytotoxic T cells (Vn/1203/04)*(54)

6

NA

Cleavage of progeny virions from host cell receptors, minor target for neutralizing antibodies

Histidine to tyrosine substitution at position 274 confers resistance to oseltamivir (78,79)

8

NS

NS1 participates in processing of mRNA, NS1 antagonizes host innate and adaptive immune response, NS2 controls export of RNP from nucleus

Glutamic acid at position 92 of NS1 confers resistance to TNF-α and interferons (Hk/156/97, Hk/483/97, Hk/486/97)* (88), Glu-Pro-Glu-Val (EPEV) and Glu-Ser-Glu-Val (ESEV) motifs at the C-terminus of NS1 may disrupt important cell signaling pathways (85), NS gene contributes to dysregulation of cytokines and chemokines (Hk/156/97)* (24,47)

7

M1

Virus assembly, major component of virion

M2

H⁺ channel controls pH during virus uncoating and HA synthesis

Serine to asparagine substitution at position 31 confers resistance to amantadine (67,69)

1, 2, 3

PB1, PB2, PA, PB1-F2, NP

The polymerases (PB1, PB2, and PA) and NP form the ribonucleoprotein complex that plays a role in RNA replication and transcription. PB1-F2 induces apoptosis

Lysine at position 627 of PB2 enhances pathogenicity and promotes replication in cells of the upper respiratory tract, at lower temperatures (Hk/483/97, Vn1203/04)* (66,83). The PB1-F2 gene is under strong positive selection pressure in avian influenza isolates (85). Serine at position 66 of PB2-F1 increases virulence (various highly virulent Hk/97 viruses)* (46)

Nonstructural Proteins

The NS proteins (NS1 and NS2) are viral proteins that play a significant role in viral replication. 58 The NS1 protein is crucial for evading the innate immune response of the host by inhibiting the antiviral response mediated by type I interferons. 87 The NS gene of certain H5N1 viruses may play an additional role in the pathogenesis of H5N1 influenza because it may confer resistance to the antiviral effects of TNF-α and interferons. In vitro experiments have shown that the replication of H5N1/97 viruses in porcine lung epithelial cells was not inhibited by pretreatment with either interferons or TNF-α. 88 The presence of glutamic acid at position 92 of NS1 appeared to be a prerequisite for the resistance to antiviral cytokines. 88 This in vitro resistance is supported by results of in vivo animal experiments in which pigs infected with a reassortant influenza virus (H1N1) bearing the NS gene of the H5N1/97 virus display a more severe disease compared to pigs inoculated with the parental H1N1 virus. 72 Recent human and avian isolates, however, lack glutamic acid at position 92 of the NS1 protein. 17, 45, 68, 82

The NS gene of H5N1 viruses may also account for up-regulation of cytokines and chemokines. High concentrations of proinflammatory cytokines and low concentrations of an anti-inflammatory cytokine (interleukin-10) have been detected in lung homogenates of mice infected with a reassortant influenza virus encoding the NS gene of the H5N1/97 virus. Similar cytokine imbalances have not been found in mice inoculated with a reassortant influenza virus encoding the NS gene of the low pathogenic H5N1/2001 virus or an NS gene encoding a glutamic acid to asparagine substitution at position 92 of NS1. 47 Furthermore, TNF-α concentrations in the supernatants from macrophages infected with recombinant viruses encoding the NS gene of the H5N1/97 are significantly higher than in those from macrophages infected with recombinant viruses containing the NS gene of nonrelated influenza viruses. 24 It has been argued that both increased resistance to antiviral effects of cytokines and up-regulation of cytokine production may act synergistically to induce pulmonary injury. 24

Two PDZ ligand (PL) sequence motifs in the NS1 gene of H5N1 viruses have recently been identified as potential co-determinants of virulence. Viruses isolated during the 1997 outbreak contain a Glu-Pro-Glu-Val (EPEV) motif at the carboxyl terminus of NS1, and 2003 to 2004 isolates contain a Glu-Ser-Glu-Val (ESEV) motif. These avian PLs bind in vitro to the PDZ domains of several human proteins that are crucial for cell signaling. 85 Infection of human cells by viruses with avian PL motifs may therefore disrupt several PDZ-domain protein-mediated pathways, thus contributing to pathogenicity of H5N1 viruses. 85 However, recently isolated, highly pathogenic viruses lack these motifs. The presence of EPEV or ESEV motifs at the carboxyl terminals of NS1 proteins thus appears not to be a prerequisite for virulence of H5N1 viruses. 89

M1 and M2 Proteins

The M gene encodes two proteins: M1 (matrix protein) and M2. The matrix protein lies underneath the viral envelope and plays a significant role in virus assembly. 65 M2 is a small protein embedded in the viral envelope that functions as a H⁺ ion channel, thus controlling the pH in the Golgi complex during HA synthesis and virion disassembly. 62 In a study of Thai and Indonesian isolates, the gene encoding the M2 protein was found to be one of the two gene segments (in addition to PB1-F2) under positive selection, indicating a possible role for M2 in the adaptation of the virus to a new host. 69 Most viruses isolated from humans and/or birds in countries on the Indo-China peninsula (the so-called "clade 1 viruses") contain a serine to asparagine substitution at residue 31 of the M2 protein, which is associated with resistance to amantadines. 67, 69 In contrast, only few viruses isolated from humans and/or birds in China, Indonesia, Japan, and South Korea (the so-called "clade 2 viruses") possess such a substitution. 7, 77, 80, 90

Implications for Viral Genes and Gene Products

Since the first avian influenza outbreak in 1997 several amino acid substitutions including the glutamic acid to lysine substitution at position 627 of PB2 and glutamic acid at position 92 of NS1 have been indicated as major contributors to virulence. In view of the observations that recent H5N1 viruses, including the ones isolated from fatal cases, lack these substitutions and that recent isolates have been found to posses other mutations, it becomes increasingly apparent that virulence cannot be attributed to a single gene or amino acid substitution. In fact virulence appears to be a polygenic trait with several genes co-operating together. The precise role of the recently discovered PB1-F2 protein in the pathogenesis of H5N1 influenza requires further exploration. Future studies will most likely identify other molecular determinants of pathogenicity.

Receptor Specificity and Transmissibility of the H5N1 Virus

Receptor Switch and Human-to-Human Transmission

Most avian and human H5N1 isolates only bind to avian influenza virus receptors. 67, 70, 71 Only a limited number of H5N1 human isolates have been identified that are capable of binding to human influenza virus receptors in vitro. 35, 71, 96, 97 It is thought that for efficient human-to-human transmission the HA protein of influenza viruses should preferentially recognize human influenza virus receptors. 96, 107, 108 Previous studies with H1, H2, and H3 serotypes have demonstrated that minor mutations in the HA gene may cause receptor specificity to switch from recognizing avian influenza virus receptors to recognizing human influenza virus receptors. 94, 95, 109, 110 Similar mutations have been introduced on the framework of an A/Vietnam/2004 H5N1 virus. 108 Mutations enabling H1 serotypes to recognize human receptors applied to H5N1 virus affect its affinity for avian receptors but do not result in human receptor specificity. In contrast, mutations enabling H2 and H3 receptors to recognize human receptors applied to H5N1 virus resulted in significant binding of the mutant virus to a natural, branched α-2,6-linked biantennary N-linked glycan and in a reduced binding to α-2,3-linked SA receptors. Viruses with these properties would be able to evade the virus-neutralizing effects of mucins containing α-2,3-linked SAs and bind more avidly to lung epithelial cells expressing α-2,6-linked biantennary N-linked glycans. 108 Yamada and colleagues 107 have recently provided further insight in possible mutations affecting the ability of the H5N1 virus to bind to human receptors. By performing reverse genetics studies and crystal structure determination, they have identified two mutations at position 182 and 192 of HA that enhance binding of H5N1 viruses to human influenza virus receptors. Despite the capability of a number of human H5N1 isolates to bind to human influenza virus receptors in vitro, 35, 71, 96, 107 these isolates do not spread efficiently from human-to-human in vivo. Animal experiments with reassortant viruses have also shown that the mere acquisition of human influenza surface proteins does not necessarily confer transmissibility of H5N1 virus. 111 Inoculation with a reassortant virus containing genes for internal proteins of H5N1 A/Hk/486 and for surface proteins of human H3N2 A/vic/75 did not result in efficient transmission among ferrets in a respiratory droplet experimental design, even though viral replication was not compromised. 101 In addition, four H5N1 human isolates (A/Vn/1203/04, A/Vn/JP36-2/05, A/Hk/213/03, and A/Turkey/65-596/06), including isolates capable of binding to human influenza virus receptors (A/Hk/213/03 and A/Turkey/65-596/06), have been studied in a direct contact model of ferrets. 35 No transmission of either H5N1 A/Vn/1203/04 or A/Turkey/65-596/06 virus was detected. Although transmission of both H5N1 A/Hk/213/03 and A/Vn/JP36-2/05 viruses occurred, it appeared to be far from efficient. No secondary transmission from an infected contact ferret to a naïve contact ferret was demonstrated. On the basis hereof it appears that increased binding affinity for human influenza receptors alone is not sufficient for efficient transmission. Additional molecular determinants seem to be required. It has been suggested that certain biological properties such as the capacity to induce virus excretion from the upper respiratory tract (coughing and sneezing) may enhance efficient transmission. 111 As mentioned above, the presence of lysine at position 627 is a molecular determinant associated with such a capacity and may, therefore, contribute to efficient spread among humans. However, it seems likely that various additional amino acid changes are required to give avian influenza viruses the capacity to spread among humans. 83 In fact for the 1918 H1N1 influenza virus, a human influenza virus that is supposed to be derived solely from an avian source, various amino acid changes differentiate the human isolate from its avian consensus sequences. 84, 112

Implications on Receptors

The widespread distribution of avian influenza virus receptors in various organs may explain the multiple organ involvement seen in H5N1-infected humans. However, there are a number of discrepancies between the cell types expressing avian influenza receptors and the cell types found to be infected by the H5N1 virus. Despite the relative lack of avian influenza virus receptors, viral replication has been demonstrated in the upper respiratory tract. Therefore, further research is needed to investigate the possible role of other receptors or mechanisms involved in the interaction between the virus and its target cells. The identification of other receptors could help the design of effective drugs treating H5N1 infection or preventing transmission. Recent studies have shown that not only the acquisition of the capacity to bind to human influenza virus receptors but also other genetic changes may be necessary for efficient transmission among humans. Continuous surveillance of the circulating H5N1 strains is of key importance as the emergence of amino acid substitutions similar to those demonstrated for the 1918 H1N1 virus might indicate that the virus could acquire pandemic potential in the near future.

Final Remarks

Since 1997 several studies have contributed to fundamental insights into the pathology and pathogenesis of human H5N1 influenza. Aside from the respiratory tract, other organs such as the intestines, the brain, and the placenta appear to be infection targets of the virus. The H5N1 virus is also capable of transplacental transmission to the fetus. Dysfunction of the immune system may be a key pathogenetic mechanism. At the molecular level, several viral genes and mutations in gene products have been suggested to be involved in increased virulence of H5N1 viruses. At the same time, however, it becomes increasingly apparent that what is known today about the virus and its pathogenicity is only the tip of the iceberg and that there are likely several additional pathogenetic mechanisms and molecular determinants of pathogenicity in H5N1 influenza yet to be identified. In light of the subsisting threat of a potentially devastating influenza pandemic, further investigations in these respects are urgently required.

Acknowledgments

We thank Juxiang Ye, Lu Yao, and Ruishu Deng for composing the pictures.

Footnotes

Address reprint requests to Jiang Gu, M.D., Ph.D., Department of Pathology, School of Basic Medical Sciences, Infectious Disease Center, Peking (Beijing) University, 38 Xueyuan Rd., Beijing, China 100083. E-mail: nc.ude.umjb@uggnaij.

Supported in part by the LiFu Educational Foundation; and the Prins Bernhard Cultuurfonds (Wassink-Hesp Fonds and Kuitse Fonds), the Netherlands (to C.K.).

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

# data[].attributes.attachment_link.title
Pathology, Molecular Biology, and Pathogenesis of Avian Influenza A (H5N1) Infection in Humans

# data[].attributes.attachment_link.description
H5N1 avian influenza is a highly fatal infectious disease that could cause a potentially devastating pandemic if the H5N1 virus mutates into a form that spreads efficiently among humans. Recent findings have led to a basic understanding of cell and organ histopathology caused by the H5N1 virus.

# data[].attributes.headline
Brazil's suspected cases of the bird flu in humans

# data[].attributes.subject
Brazil's suspected cases of the bird flu in humans

# data[].attributes.body
This translated article from Brazilian news outlet "Folha de S.Paulo" focuses on four different suspected cases of the bird flu in humans that were identified shortly after the Brazilian government declared the bird flu outbreaks to be an animal health emergency. However, the tests conducted to determine whether this flu has spread to humans highlight why this topic is such a pressing global health issue, as transmission to humans is greatly dangerous and requires quick action to combat deeply negative impacts on the human population.

# data[].attributes.attachment_link.readable_text
The Ministry of Health informed this Tuesday (23) that four residents of Espírito Santo are still under suspicion of being contaminated with the avian flu virus (H5N1). The blood samples collected from these people are being analyzed by Fiocruz (Oswaldo Cruz Foundation).

On the other hand, all the other 38 tests carried out (34 in Espírito Santo and four in Rio de Janeiro) in people who had contact with sick birds were negative.

On the night of this Monday (22), Mapa (Ministry of Agriculture and Livestock) published an ordinance in the Federal Official Gazette declaring a state of zoosanitary emergency throughout the country, which must remain in force for a period of 180 days and may be extended for a period undetermined. The purpose of this decree is to prevent the disease from reaching subsistence and commercial poultry production, in addition to preserving fauna and human health.

Mapa will continue to alert the population not to collect sick or dead birds and call the veterinary service in their city if they find any in these conditions.
Translated by Cassy Dias Read the article in the original language

# data[].attributes.attachment_link.title
Brazil Has 4 Suspected Cases of Avian Flu in Humans

# data[].attributes.attachment_link.description
Ministry of Health says samples from 38 people came out negative

# data[].attributes.body
Avian Influenza (bird flu) has long been a problem in many nations throughout the world, though the most recent outbreaks have occurred primarily in Brazil. While the bird flu is found and spread among birds, this illness poses a threat to humans who come into contact with contaminated birds. As this article from the CDC describes, human exposure to contaminated animals can lead to severe illness and even death. As such, it is important to ensure that this illness is contained, especially amidst the current outbreaks in Brazil.

# data[].attributes.attachment_link.readable_text
This page provides information about avian influenza for employers and workers. Visit the CDC Avian Influenza webpage for current situation information.

Avian influenza (or bird flu) is a disease of birds caused by infection with avian influenza A viruses. Infected birds shed bird flu virus in their saliva, mucous, and feces. People rarely get bird flu; however, human infections with bird flu viruses can happen if enough virus is inhaled or gets into a person's mouth, eyes, or nose. Bird flu infections happen most often after someone has close, prolonged and unprotected (no gloves or other personal protective equipment) contact with infected birds and then touches their mouth, eyes, or nose.

Domestic poultry may be infected with highly pathogenic avian influenza (HPAI) A viruses or low pathogenic avian influenza (LPAI) A viruses:

The highly pathogenic viruses spread quickly and may kill nearly an entire poultry flock within 48 hours.

The low pathogenic viruses may not cause symptoms or may cause only mild symptoms such as ruffled feathers or a drop in egg production.

The classification of low pathogenic or highly pathogenic avian influenza A virus refers to the ability of the virus to cause disease in chickens in the laboratory, not in humans. Human infection with low pathogenic and highly pathogenic avian influenza A viruses have resulted in a range of symptoms from mild to severe.

Avian influenza A viruses are a public and occupational health concern for several reasons, including:

Some of these viruses have passed sporadically from poultry to humans and caused serious illness and death.

They may change into a form that is highly infectious in humans and spreads easily from person to person.

As these viruses threaten domestic poultry throughout the world, they are also a risk to workers worldwide who have contact with poultry.

Avian influenza A viruses occur naturally among wild aquatic birds worldwide. Avian influenza viruses have also infected other animals, including ducks, chickens, turkeys, pigs, whales, horses, seals, dogs, and cats. Influenza A viruses that infect one animal species may sometimes cross over and cause illness in another species, including people.

For more information: CDC Transmission of Avian Influenza A Viruses Between Animals and People.

Avian influenza A viruses usually do not infect humans; however, sporadic cases have been reported. The disease can be transmitted to unprotected workers who have contact with infected wild birds, poultry, or contaminated materials or surfaces.

Examples of poultry workers and other workers at risk include the following:

Broiler breeder farms, hatcheries, grow-out farms, and processing plant workers

Layer farm workers

Turkey farm workers

Disease control and eradication workers (including Federal, contract, and company workers)

Live-bird market workers

Wildlife biologists who handle birds

Animal welfare and rescue workers who handle infected animals

Animal control workers who handle infected animals

The signs and symptoms of bird flu virus infections in humans range from no symptoms or mild illness such as eye redness or mild flu-like upper respiratory symptoms to severe illness such as pneumonia requiring hospitalization.

Other symptoms may include:

fever or feeling feverish

cough

sore throat

runny or stuff nose

muscle or body aches

headaches

fatigue

shortness of breath or difficulty breathing.

Less common signs and symptoms include diarrhea, nausea, vomiting, or seizures.

Avian influenza A viruses are routinely detected in wild birds. Around the world and in North America, avian influenza A outbreaks occur in poultry from time to time. Outbreaks of some avian influenza A viruses in poultry have been associated with illness and death in humans in Asia, Africa, Europe, the Pacific, and the Near East. While very rare, some avian influenza A viruses have caused illness in humans in North America.

For more information: CDC avian influenza current situation information.

Responders to an avian influenza outbreak may be at risk of exposure to additional hazards including:

Depopulation and disposal processes may have hazards associated with them such as carbon dioxide exposure, heat exposure, and slips on wet surfaces if proper procedures are not followed.

# data[].attributes.attachment_link.description
Avian influenza (or bird flu) is a disease of birds caused by infection with avian influenza A viruses. These viruses are excreted in the droppings, saliva, and nasal secretions of infected birds. Avian influenza A viruses usually do not infect humans; however, sporadic cases have been reported

# data[].attributes.headline
Research on highly pathogenic bird flu viruses

# data[].attributes.subject
Research on highly pathogenic bird flu viruses

# data[].attributes.body
This technical piece compiles research internationally about the presence of the bird flu and its recent rise, which is particularly relevant in the context of the conversation about Brazil's bird flu outbreaks.

# data[].attributes.attachment_link.provider_name
Centers for Disease Control and Prevention

# data[].attributes.attachment_link.readable_text
This report provides an update to the original report posted on March 17, 2023, to include information on additional sporadic human cases and activity in wild birds, poultry and other animals. The overall risk to human health associated with the ongoing outbreaks of highly pathogenic A(H5N1) viruses in wild birds and poultry has not changed and remains low at this time.

Executive summary
Despite the panzootic nature of highly pathogenic avian influenza (HPAI) A(H5N1) viruses in wild birds and poultry, only a small number of sporadic human cases of A(H5N1) have been identified since 2022. Nearly allreported human cases since 2022 were associated with recent poultry exposures, and no cases of mammal-to-human or human-to-human transmission of HPAI A(H5N1) virus have been identified. In a few cases, the source of exposure to HPAI A(H5N1) virus was unknown. To date, HPAI A(H5N1) viruses currently circulating in birds and poultry, with spillover to mammals, and those that have caused human infections do not have the ability to easily bind to receptors that predominate in the human upper respiratory tract. Therefore, the current risk to the public from HPAI A(H5N1) viruses remains low. However, because of the wide global prevalence of HPAI A(H5N1) viruses in wild birds and poultry outbreaks, continued sporadic human infections are anticipated. While U.S. flock outbreaks have declined substantially during spring and summer months, the ongoing global circulation of HPAI A(H5N1) viruses in wild birds, their ability to spread along migratory flyways and rapidly evolve warrants comprehensive surveillance of these viruses in wild birds, poultry, mammals, and people worldwide, and frequent reassessments are critical to determine the public health risk, along with ongoing preparedness efforts.

CDC is actively working on the domestic situation with current clade 2.3.4.4b HPAI A(H5N1) viruses associated with infections in wild birds and poultry outbreaks, including conducting surveillance among people with relevant exposures and preparing for the possibility that these HPAI A(H5N1) viruses gain the ability for increased transmissibility to people.

CDC, along with state and local public health partners, continues to actively monitor people in the United States who have been exposed to infected birds and poultry for 10 days after exposure. To date, more than 6,500 people in 52 jurisdictions have been monitored since 2022, and only one human case has been identified.

An H5 candidate vaccine virus (CVV) produced by CDC that is expected to provide good protection against current clade 2.3.4.4b HPAI A(H5N1) viruses in birds and mammals is available and has been shared with vaccine manufacturers.

Because influenza viruses are constantly changing, CDC performs ongoing analyses of HPAI A(H5N1) viruses to identify changes that might allow for spread more easily to and between people, cause serious illness in people, reduce susceptibility to antivirals, affect the sensitivity of diagnostic assays, or reduce neutralization of the virus by vaccine induced antibodies. To date, few changes in HPAI A(H5N1) viruses of public health concern have been identified and such changes have differed between various HPAI A(H5N1) viruses circulating in wild birds and poultry worldwide or that have sporadically infected humans. No changes in current clade 2.3.4.4b HPAI A(H5N1) viruses in wild birds, poultry, mammals, or human cases have been identified that would suggest increased transmissibility to humans.

Currently, HPAI A(H5N1) viruses circulating in birds are believed to pose a low risk to the health of the general public in the United States; however, people who have job-related or recreational exposures to infected birds may be at higher risk of infection and should take appropriate precautions outlined in CDC guidance.

Comprehensive surveillance and readiness efforts are ongoing, and CDC continually takes preparedness measures to be ready in case the risk to people from HPAI A(H5N1) or other novel influenza A viruses changes.

HPAI A(H5N1) viruses in wild birds and poultry

Since 2005, HPAI A(H5N1) viruses have undergone extensive genetic diversification including the formation of hundreds of genotypes following reassortment with other avian influenza A viruses. Clade 2.3.4.4b HPAI A(H5N1) viruses emerged in 2020 and were introduced into North America in late 2021 [ 1,2] and have spread to Central and South America, resulting in wild bird and poultry outbreaks in many countries [ 3- 5].

Globally, this 2.3.4.4b clade of HPAI A(H5N1) viruses has become widespread causing record numbers of bird outbreaks in wild, backyard, village, and farm birds. Over 15,600 animal outbreaks of HPAI A(H5N1) viruses were reported by 77 member states to the World Organisation for Animal Health since January 2022.

In the United States, USDA APHIS monitors for avian influenza viruses in wild, commercial, and backyard birds. From January 2022 to June 27, 2023, APHIS reported HPAI A(H5)/A(H5N1) virus detections in more than 7,000 wild birds in 50 states or territories and more than 800 commercial and backyard flocks in 47 states or territories. HPAI A(H5)/A(H5N1) viruses have not been detected in U.S. commercial or backyard flocks since April 19, 2023 and May 18, 2023, respectively, representing a decline when compared with the same time period in 2022.

HPAI A(H5N1) virus infections among mammals

Sporadic HPAI A(H5N1) virus infections of mammals have been reported since 2003 during HPAI A(H5N1) virus outbreaks in poultry or wild birds [ 6- 8]. HPAI A(H5) viruses are known to occasionally infect mammals that eat (presumably infected) birds or poultry and mammals that are exposed to environments with a high concentration of virus.

In the United States, from May 2022 to June 27, 2023, USDA APHIS reported HPAI A(H5N1) virus detections in 196 mammals of different species in 26 states or territories. Globally, sporadic HPAI A(H5N1) virus infections have been reported in multiple mammalian species in many countries; for example, in farmed mink in Spain, harbor and gray seals in the United States, sea lions in Peru and Chile, a cat in France and other countries, and foxes in North America and Europe [ 9]. The reports of HPAI A(H5N1) virus infections in mammals are not surprising given the widespread outbreaks of HPAI A(H5N1) virus infections in wild birds.

Genetic data have revealed that when some mammals are infected with HPAI A(H5N1) virus, the virus may undergo intra-host evolution resulting in genetic changes that allow the virus to replicate more efficiently in the lower respiratory tract [ 10-12].

Although these genetic changes may impact mammalian disease outcome, they have not been associated with changes to receptor binding specificity or enhanced transmissibility of the virus to humans. HPAI A(H5N1) viruses do not currently have an ability to easily infect and bind to α2,6-linked sialic acid receptors that are predominant in the human upper respiratory tract [ 2], which would be needed to increase the risk of transmission to people [ 13, 14].

Human cases of A(H5N1)

While HPAI A(H5N1) viruses are currently circulating widely in wild birds and poultry in many geographic regions, relatively few human cases of A(H5N1) have been reported in recent years [ Figure 1]. From January 2022 to June 29, 2023, thirteen sporadic human cases of A(H5N1) were reported from eight countries, including six cases of severe disease and two deaths, two cases of mild illness, and five asymptomatic cases [ Table 1].

One human case of A(H5N1) was reported in the United States in April 2022. The individual reported fatigue without other symptoms and a low level of A(H5N1) viral RNA was detected in a single upper respiratory tract specimen. It is possible that detection of A(H5N1) viral RNA resulted from deposition of non-infectious viral material in the upper respiratory tract of the individual and did not represent true infection, similar to the environmental contamination attributed to two asymptomatic cases in poultry workers reported in Spain [15] and may also explain the detection of A(H5N1) viral RNA in other asymptomatic poultry workers in the U.K. [ 16].

Nearly all human cases of A(H5N1) reported since 2022 had recent exposure to sick or dead poultry, and no cases of human-to-human HPAI A(H5N1) virus transmission were identified. Six cases (3 children, 3 adults) had severe disease, and two died. Ten cases were associated with clade 2.3.4.4b HPAI A(H5N1) viruses, the HA clade in one case in Vietnam could not be determined, and two cases in Cambodia were associated with clade 2.3.2.1c HPAI A(H5N1) viruses; none of the HPAI A(H5N1) virus genetic sequences contained any known markers of reduced susceptibility to currently recommended FDA-approved influenza antiviral medications.

Table 1. Reported A(H5N1) human cases, January 2022 to June 29, 2023

*More details on the Chile case-patient and virus characteristics are available at: /flu/avianflu/spotlights/2022-2023/chile-first-case-h5n1-addendum.htm

Since 1997, a total of 896 sporadic human A(H5N1) cases have been reported from 22 countries [ Figure 1], caused by different HPAI A(H5N1) virus clades [ 17], with a cumulative case fatality proportion of greater than 50%. The annual incidence of human A(H5N1) cases was highest in 2015 (145 cases, 4 countries) primarily due to a large epidemic in Egypt with 136 cases, followed by 2006 (115 cases, 9 countries) [ Figure 1].

Nearly all reported human A(H5N1) cases had poultry exposures, such as to sick or dead poultry or visiting live poultry markets. Rare instances of limited, non-sustained human-to-human HPAI A(H5N1) influenza virus transmission likely occurred in a small number of family members following prolonged, close unprotected exposure with a symptomatic case-patient during 2004-2007 in multiple countries [ 18-21].

Active monitoring of persons exposed to HPAI A(H5N1) virus in the United States

Although few human cases have occurred recently, given widespread infection among poultry and wild birds, people who have job-related or recreational exposures to infected birds or sick or dead mammals might be at higher risk of infection.

CDC, in collaboration with state, territorial, and local public health partners, actively monitors people exposed (e.g., flock owners, farm workers, and cullers) to commercial poultry, backyard flocks, wild birds, and the environments of birds infected with HPAI A(H5N1) virus for 10 days after their last exposure [ 22]. As of June 29, 2023:

Total monitored: more than 6,500 people in 52 jurisdictions since February 2022

Total illnesses with influenza testing reported among monitored persons: more than 160 people

Number positive for influenza A(H5N1) virus: 1

Of the approximately 160 people showing symptoms who were tested for novel influenza A and seasonal flu viruses along with other respiratory viruses, HPAI A(H5N1) virus genetic material was detected in a respiratory specimen from one person in Colorado who experienced fatigue without any other symptoms while participating in poultry culling activities. [See above section on " Human cases of A(H5N1)."]

U.S. influenza surveillance for human infections with novel influenza A viruses, including HPAI A(H5N1) virus

Human infection with a novel influenza A virus, including HPAI A(H5N1) virus, is a nationally notifiable condition (case definition: Novel Influenza A Virus Infections 2014 Case Definition | CDC)

Influenza testing is widely available in clinical laboratories and health care facilities. Assays in these settings would detect A(H5N1) virus infections as influenza A positive, and a subset of assays would be able to also determine that they are not influenza A virus subtypes (H1 or H3) that commonly circulate among humans. Specimens from persons possibly exposed to H5N1 virus or that test positive for an influenza A virus but negative for A(H1) and A(H3) subtypes should be forwarded to the appropriate state or local public health laboratory for further testing. Very few specimens have been submitted to CDC for H5 testing since January 2022.

Seasonal influenza virus detection assays that can also detect novel influenza A viruses are used in 128 public health laboratories in all 50 U.S states.

Specific diagnostic assays to detect current A(H5) viruses are available at 99 public health laboratories in all 50 states.

Per long-standing protocols, upon detection of a virus that tests positive for influenza A but is negative for human H1 or H3 genes the public health laboratory will rapidly contact CDC and ship the specimen to CDC. Specimens that are influenza A positive but negative for human H1 or H3 genes may also be tested for H5 by state public health laboratories and are rapidly sent to CDC for a diagnostic result. An investigation of the case will be initiated, and a case report form submitted to CDC through the novel influenza A reporting module.

CDC and U.S. Government Preparedness Activities

Limitations of the Report

This report is subject to the following limitations. First, the number of human infections with currently circulating clade 2.3.4.4b HPAI A(H5N1) viruses is small. Conclusions regarding virus characterization analyses, transmissibility from animals to people, transmissibility among people, and clinical spectrum of illness in people should be interpreted in light of this small number. Second, detailed exposure information was not available for all persons actively monitored for illness after exposure to HPAI A(H5N1) virus-infected birds and poultry in the United States. Thus, we were not able to assess the impact of exposure variables such as duration of exposure, nature of exposure (e.g., direct vs. indirect contact), and use of personal protective equipment on infection risk.

Conclusions

To date, CDC analyses of clade 2.3.4.4b HPAI A(H5N1) viruses detected in wild birds, poultry, and sporadically in mammals since late 2021 indicate that these viruses all have a high degree of genetic identity with each other, and no significant mammalian adaptive substitutions, insertions or deletions have been identified, particularly in the HA gene, which is important for zoonotic and subsequent human-to-human transmission.

Considering the high prevalence of HPAI A(H5N1) viruses detected in wild birds, and poultry worldwide, spill over into mammals (particularly carnivores that may feed on infected avian species), additional sporadic zoonotic infections among people with exposures to sick or dead poultry or wild birds are anticipated.

HA clade 2.3.4.4b A(H5N1) viruses currently circulating in wild birds and poultry worldwide lack the ability to preferentially bind to the types of sialic acid receptors that are predominant in the upper respiratory tract of humans and therefore do not currently have the ability to easily infect or transmit among people.

Despite extensive worldwide spread of influenza A(H5N1) viruses in wild birds and poultry in recent years, only a small number of sporadic human infections with 2.3.4.4b or clade 2.3.2.1c H5N1 viruses have been reported since 2022; nearly all cases had recent exposure to poultry and no cases of human-to-human influenza A(H5N1) virus transmission were identified.

While CDC's assessment is that the overall threat of HA clade 2.3.4.4b A(H5N1) viruses to public health is currently low, the widespread geographic prevalence of infected birds and poultry worldwide raises the potential for exposures of humans and other mammals that could result in viral evolution or reassortment events which might change the current risk assessment. Although virus detections in commercial poultry and backyard flocks in the U.S. declined substantially in recent months, the situation could change at any time. Vigilance and ongoing surveillance of HPAI A(H5N1) viruses circulating in wild birds, poultry, and in sporadic infections of mammals and people worldwide is critical to monitor the public health risk and to detect genetic changes (particularly in the HA gene) that would change CDC's risk assessment.

References

1. Bevins SN, Shriner SA, Cumbee JC Jr, Dilione KE, Douglass KE, Ellis JW et al. Intercontinental Movement of Highly Pathogenic Avian Influenza A(H5N1) Clade 2.3.4.4 Virus to the United States, 2021. Emerg Infect Dis. 2022 May;28(5):1006-1011. doi: 10.3201/eid2805.220318.

2. Kandeil A, Patton C, Jones JC, Jeevan T, Harrington WN, Trifkovic S et al. Rapid evolution of A(H5N1) influenza viruses after intercontinental spread to North America. Nat Commun. 2023 May 29;14(1):3082. doi: 10.1038/s41467-023-38415-7.

3. World Health Organization. Antigenic and genetic characteristics of zoonotic influenza A viruses and development of candidate vaccine viruses for pandemic preparedness. February 2023. https://cdn.who.int/media/docs/default-source/influenza/who-influenza-recommendations/vcm-northern-hemisphere-recommendation-2023-2024/20230224_zoonotic_recommendations.pdf?sfvrsn=38c739fa_4 [1.13 MB, 12 pages]

4. European Food Safety Authority, European Centre for Disease Prevention and Control, European Union Reference Laboratory for Avian Influenza. Avian influenza overview March - April 2023. EFSA J 2023 Jun 7;21(6):e08039. doi: 10.2903/j.efsa.2023.8039.

5. Food and Agriculture Organization of the United Nations. Global Avian Influenza Viruses with Zoonotic Potential situation update, 22 June 2023. https://www.fao.org/animal-health/situation-updates/global-aiv-with-zoonotic-potential

6. Keawcharoen J, Oraveerakul K, Kuiken T, Fouchier RAM, Amonsin A, Payungporn S et al. Avian influenza H5N1 in tigers and leopards. Emerg Infect Dis. 2004 Dec;10(12):2189-91. doi: 10.3201/eid1012.040759.

7. Songserm T, Amonsin A, Jam-on R, Sae-Heng N, Pariyothorn N, Payungporn S et al. Fatal avian influenza A H5N1 in a dog. Emerg Infect Dis. 2006 Nov;12(11):1744-7. doi: 10.3201/eid1211.060542.

8. Songserm T, Amonsin A, Jam-on R, Sae-Heng N, Meemak N, Pariyothorn N et al. Avian influenza H5N1 in naturally infected domestic cat. Emerg Infect Dis. 2006 Apr;12(4):681-3. doi: 10.3201/eid1204.051396.

9. Pan American Health Organization. Epidemiological Update Outbreaks of avian influenza caused by influenza A(H5N1) in the Region of the Americas, 17 May 2023. epiupdate-avianflu-may-2023-v2.pdf.

10. Gabriel G, Czudai-Matwich V, Klenk HD. Adaptive mutations in the H5N1 polymerase complex. Virus Res. 2013 Dec 5;178(1):53-62. doi: 10.1016/j.virusres.2013.05.010.

11. Bogs J, Kalthoff D, Veits J, Pavlova S, Schwemmle M, Mänz B et al. Reversion of PB2-627E to -627K during replication of an H5N1 Clade 2.2 virus in mammalian hosts depends on the origin of the nucleoprotein. J Virol. 2011 Oct;85(20):10691-8. doi: 10.1128/JVI.00786-11.

12. Agüero M, Monne I, Sánchez A, Zecchin B, Fusaro A, Ruano MJ et al. Highly pathogenic avian influenza A(H5N1) virus infection in farmed minks, Spain, October 2022. Euro Surveill. 2023 Jan;28(3):2300001. doi: 10.2807/1560-7917.ES.2023.28.3.2300001.

13. van Riel D, den Bakker MA, Leijten LM, Chutinimitkul S, Munster VJ, de Wit E et al. Seasonal and pandemic human influenza viruses attach better to human upper respiratory tract epithelium than avian influenza viruses. Am J Pathol. 2010 Apr;176(4):1614-8. doi: 10.2353/ajpath.2010.090949.

14. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: influenza virus receptors in the human airway. Nature. 2006 Mar 23;440(7083):435-6. doi: 10.1038/440435a.

15. Aznar E, Casas I, González Praetorius A, Ruano Ramos MJ, Pozo F, Sierra Moros MJ et al.Influenza A(H5N1) detection in two asymptomatic poultry farm workers in Spain, September to October 2022: suspected environmental contamination. Euro Surveill. 2023 Feb;28(8):2300107. doi: 10.2807/1560-7917.ES.2023.28.8.2300107. https://pubmed.ncbi.nlm.nih.gov/36820643/

16. World Health Organization. Avian Influenza A(H5N1) - United Kingdom of Great Britain and Northern Ireland. 30 May 2023. Accessed at: https://www.who.int/emergencies/disease-outbreak-news/item/2023-DON468

17. Lai S, Qin Y, Cowling BJ, Ren X, Wardrop NA, Gilbert M et al. Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997-2015: a systematic review of individual case data. Lancet Infect Dis. 2016 Jul;16(7):e108-e118. doi: 10.1016/S1473-3099(16)00153-5.

18. Ungchusak K, Auewarakul P, Dowell SF, Kitphati R, Auwanit W, Puthavathana P et al. Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med. 2005 Jan 27;352(4):333-40. doi: 10.1056/NEJMoa044021.

19. Wang H, Feng Z, Shu Y, Yu H, Zhou L, Zu R et al. Probable limited person-to-person transmission of highly pathogenic avian influenza A (H5N1) virus in China. Lancet. 2008 Apr 26;371(9622):1427-34. doi: 10.1016/S0140-6736(08)60493-6.

20. WHO Disease Outbreak News. 2006 - Indonesia. 31 May 2006. Accessed at: https://www.who.int/emergencies/disease-outbreak-news/item/2006_05_31-en

21. World Health Organization. Human cases of avian influenza A (H5N1) in North-West Frontier Province, Pakistan, October-November 2007. Wkly Epidemiol Rec. 2008 Oct 3;83(40):359-64. Accessed at: https://reliefweb.int/report/guinea/weekly-epidemiological-record-wer-3-october-2008-vol-83-no-40-pp-357-364-enfr

22. Kniss K, Sumner KM, Tastad KJ, Lewis NM, Jansen L, Julian D et al. Risk for Infection in Humans after Exposure to Birds Infected with Highly Pathogenic Avian Influenza A(H5N1) Virus, United States, 2022. Emerg Infect Dis. 2023 Jun;29(6):1215-1219. doi: 3201/eid2906.230103.

References to non-CDC sites are provided as a service and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of pages found at these sites. URL addresses listed were current as of the date of publication.

# data[].attributes.attachment_link.title
Technical Report: Highly Pathogenic Avian Influenza A(H5N1) Viruses

# data[].attributes.attachment_link.description
This report provides a review of current outbreaks of influenza A(H5N1) viruses in animals and a discussion of risk for public health.

# data[].attributes.body
This podcast discusses the level of concern that scientists believe we should have in regards to the bird flu.

# data[].attributes.attachment_link.title
Bird Flu: How Concerned Should We Be? | Podcast

# data[].attributes.attachment_link.description
We have been monitoring the virus and outbreaks in birds, mammals as well as sporadic human cases around the world.

# data[].attributes.body
This CDC webpage provides frequently updated statistics and measures on the spread of bird flu throughout the world.

# data[].attributes.attachment_link.provider_name
Centers for Disease Control and Prevention

# data[].attributes.attachment_link.title
Avian Influenza Current Situation Summary

# data[].attributes.attachment_link.description
Learn more about the latest avian influenza situation in the United States and globally.