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Influenza A virus subtype H5N1

October 21, 2023

Influenza A virus subtype H5N1 (A/H5N1) is a subtype of the influenza A virus which can cause illness in humans and many other species.[1] A bird-adapted strain of H5N1, called HPAI A(H5N1) for highly pathogenic avian influenza virus of type A of subtype H5N1, is the highly pathogenic causative agent of H5N1 flu, commonly known as avian influenza ("bird flu"). It is enzootic (maintained in the population) in many bird populations, especially in Southeast Asia. One strain of HPAI A(H5N1) is spreading globally after first appearing in Asia. It is epizootic (an epidemic in nonhumans) and panzootic (affecting animals of many species, especially over a wide area), killing tens of millions of birds and spurring the culling of hundreds of millions of others to stem its spread. Many references to "bird flu" and H5N1 in the popular media refer to this strain.[2]

Influenza A virus subtype H5N1
Colorized transmission electron micrograph of Avian influenza A H5N1 viruses (seen in gold) grown in MDCK cells (seen in green).
Virus classification
(unranked): Virus
Realm: Riboviria
Kingdom: Orthornavirae
Phylum: Negarnaviricota
Class: Insthoviricetes
Order: Articulavirales
Family: Orthomyxoviridae
Genus: Alphainfluenzavirus
Species:
Influenza A virus
Serotype:
Influenza A virus subtype H5N1
Notable strains

According to the World Health Organization (WHO) and the United Nations Food and Agriculture Organization, H5N1 pathogenicity is gradually continuing to rise in endemic areas, but the avian influenza disease situation in farmed birds is being held in check by vaccination, and there is "no evidence of sustained human-to-human transmission" of the virus.[3] Eleven outbreaks of H5N1 were reported worldwide in June 2008, in five countries (China, Egypt, Indonesia, Pakistan and Vietnam) compared to 65 outbreaks in June 2006, and 55 in June 2007. The global HPAI situation significantly improved in the first half of 2008, but the FAO reports that imperfect disease surveillance systems mean that occurrence of the virus remains underestimated and underreported.[4] As of May 2020, the WHO reported a total of 861 confirmed human cases which resulted in the deaths of 455 people since 2003.[5]

Several H5N1 vaccines have been developed and approved, and stockpiled by a number of countries, including the United States (in its National Stockpile),[6][7] Britain, France, Canada, and Australia, for use in an emergency.[8]

Overview Edit

HPAI A(H5N1) is considered an avian disease, although there is some evidence of limited human-to-human transmission of the virus.[9] A risk factor for contracting the virus is handling of infected poultry, but transmission of the virus from infected birds to humans has been characterized as inefficient.[10] Still, around 60% of humans known to have been infected with the Asian strain of HPAI A(H5N1) have died from it, and H5N1 may mutate or reassort into a strain capable of efficient human-to-human transmission. In 2003, virologist Robert G. Webster published an article titled "The world is teetering on the edge of a pandemic that could kill a large fraction of the human population" in American Scientist. He called for adequate resources to fight what he sees as a major world threat to possibly billions of lives.[11] On September 29, 2005, David Nabarro, the newly appointed Senior United Nations System Coordinator for Avian and Human Influenza, warned the world that an outbreak of avian influenza could kill anywhere between 5 million and 150 million people.[12] Experts have identified key events (creating new clades, infecting new species, spreading to new areas) marking the progression of an avian flu virus towards becoming pandemic, and many of those key events have occurred more rapidly than expected.[citation needed]

Due to the high lethality and virulence of HPAI A(H5N1), its endemic presence, its increasingly large host reservoir, and its significant ongoing mutations, in 2006, the H5N1 virus has been regarded to be the world's largest pandemic threat, and billions of dollars are being spent researching H5N1 and preparing for a potential influenza pandemic.[13] At least 12 companies and 17 governments are developing prepandemic influenza vaccines in 28 different clinical trials that, if successful, could turn a deadly pandemic infection into a nondeadly one. Full-scale production of a vaccine that could prevent any illness at all from the strain would require at least three months after the virus's emergence to begin, but it is hoped that vaccine production could increase until one billion doses were produced by one year after the initial identification of the virus.[14]

H5N1 may cause more than one influenza pandemic, as it is expected to continue mutating in birds regardless of whether humans develop herd immunity to a future pandemic strain.[15] Influenza pandemics from its genetic offspring may include influenza A virus subtypes other than H5N1.[16] While genetic analysis of the H5N1 virus shows that influenza pandemics from its genetic offspring can easily be far more lethal than the Spanish flu pandemic,[17] planning for a future influenza pandemic is based on what can be done and there is no higher Pandemic Severity Index level than a Category 5 pandemic which, roughly speaking, is any pandemic as bad as the Spanish flu or worse; and for which all intervention measures are to be used.[18]

Signs and symptoms Edit

Further information: Influenza
 
The different sites of infection (shown in red) of seasonal H1N1 versus avian H5N1 influences their lethality and ability to spread.[19]

In general, humans who catch a humanized influenza A virus (a human flu virus of type A) usually have symptoms that include fever, cough, sore throat, muscle aches, conjunctivitis, and, in severe cases, breathing problems and pneumonia that may be fatal.[20] The severity of the infection depends in large part on the state of the infected persons' immune systems and whether they had been exposed to the strain before (in which case they would be partially immune). No one knows if these or other symptoms will be the symptoms of a humanized H5N1 flu.

The avian influenza hemagglutinin binds alpha 2-3 sialic acid receptors, while human influenza hemagglutinins bind alpha 2-6 sialic acid receptors.[21] This means when the H5N1 strain infects humans, it will replicate in the lower respiratory tract, and consequently will cause viral pneumonia.[22] There is as yet no human form of H5N1, so all humans who have caught it so far have caught avian H5N1.

The reported mortality rate of highly pathogenic H5N1 avian influenza in a human is high; WHO data indicate 60% of cases classified as H5N1 resulted in death. However, there is some evidence the actual mortality rate of avian flu could be much lower, as there may be many people with milder symptoms who do not seek treatment and are not counted.[23][24]

In one case, a boy with H5N1 experienced diarrhea followed rapidly by a coma without developing respiratory or flu-like symptoms.[25] There have been studies of the levels of cytokines in humans infected by the H5N1 flu virus. Of particular concern is elevated levels of tumor necrosis factor-alpha, a protein associated with tissue destruction at sites of infection and increased production of other cytokines. Flu virus-induced increases in the level of cytokines is also associated with flu symptoms, including fever, chills, vomiting and headache. Tissue damage associated with pathogenic flu virus infection can ultimately result in death.[11] The inflammatory cascade triggered by H5N1 has been called a 'cytokine storm' by some, because of what seems to be a positive feedback process of damage to the body resulting from immune system stimulation. H5N1 induces higher levels of cytokines than the more common flu virus types.[26]

In birds Edit

Clinical signs of H5N1 in birds range from mild—decrease in egg production, nasal discharge, coughing and sneezing—to severe, including loss of coordination, energy, and appetite; soft-shelled or misshapen eggs; purple discoloration of the wattles, head, eyelids, combs, and hocks; and diarrhea. Sometimes the first noticeable sign is sudden death.[20]

Genetics Edit

 
The H in H5N1 stands for "hemagglutinin", as depicted in this molecular model
Further information: Influenzavirus A and H5N1 genetic structure

The first known strain of HPAI A(H5N1) (called A/chicken/Scotland/59) killed two flocks of chickens in Scotland in 1959, but that strain was very different from the highly pathogenic strain of H5N1. The dominant strain of HPAI A(H5N1) in 2004 evolved from 1999 to 2002 creating the Z genotype.[27] It has also been called "Asian lineage HPAI A(H5N1)".

Asian lineage HPAI A(H5N1) is divided into two antigenic clades. "Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections:

  • Subclade 1, Indonesia
  • Subclade 2, Europe, Middle East, and Africa (called EMA)
  • Subclade 3, China[15][28][29]

A 2007 study focused on the EMA subclade has shed further light on the EMA mutations. "The 36 new isolates reported here greatly expand the amount of whole-genome sequence data available from recent avian influenza (H5N1) isolates. Before our project, GenBank contained only 5 other complete genomes from Europe for the 2004–2006 period, and it contained no whole genomes from the Middle East or northern Africa. Our analysis showed several new findings. First, all European, Middle Eastern, and African samples fall into a clade that is distinct from other contemporary Asian clades, all of which share common ancestry with the original 1997 Hong Kong strain. Phylogenetic trees built on each of the 8 segments show a consistent picture of 3 lineages, as illustrated by the HA tree shown in Figure 1. Two of the clades contain exclusively Vietnamese isolates; the smaller of these, with 5 isolates, we label V1; the larger clade, with 9 isolates, is V2. The remaining 22 isolates all fall into a third, clearly distinct clade, labeled EMA, which comprises samples from Europe, the Middle East, and Africa. Trees for the other 7 segments display a similar topology, with clades V1, V2, and EMA clearly separated in each case. Analyses of all available complete influenza (H5N1) genomes and of 589 HA sequences placed the EMA clade as distinct from the major clades circulating in People's Republic of China, Indonesia, and Southeast Asia."[30]

Terminology Edit

H5N1 isolates are identified like this actual HPAI A(H5N1) example, A/chicken/Nakorn-Patom/Thailand/CU-K2/04(H5N1):

  • A stands for the genus of influenza (A, B or C).
  • chicken is the animal species the isolate was found in (note: human isolates lack this component term and are thus identified as human isolates by default)
  • Nakorn-Patom/Thailand is the place this specific virus was isolated
  • CU-K2 is the laboratory reference number that identifies it from other influenza viruses isolated at the same place and year
  • 04 represents the year of isolation 2004
  • H5 stands for the fifth of several known types of the protein hemagglutinin.
  • N1 stands for the first of several known types of the protein neuraminidase.

Other examples include: A/duck/Hong Kong/308/78(H5N3), A/avian/NY/01(H5N2), A/chicken/Mexico/31381-3/94(H5N2), and A/shoveler/Egypt/03(H5N2).[31]

As with other avian flu viruses, H5N1 has strains called "highly pathogenic" (HP) and "low-pathogenic" (LP). Avian influenza viruses that cause HPAI are highly virulent, and mortality rates in infected flocks often approach 100%. LPAI viruses have negligible virulence, but these viruses can serve as progenitors to HPAI viruses. The strain of H5N1 responsible for the deaths of birds across the world is an HPAI strain; all other strains of H5N1, including a North American strain that causes no disease at all in any species, are LPAI strains. All HPAI strains identified to date have involved H5 and H7 subtypes. The distinction concerns pathogenicity in poultry, not humans. Normally, a highly pathogenic avian virus is not highly pathogenic to either humans or nonpoultry birds. This deadly strain of H5N1 is unusual in being deadly to so many species, including some, like domestic cats, never previously susceptible to any influenza virus.[32]

Genetic structure and related subtypes Edit

 
The N in H5N1 stands for "Neuraminidase", the protein depicted in this ribbon diagram

H5N1 is a subtype of the species Influenza A virus of the genus Alphainfluenzavirus of the family Orthomyxoviridae. Like all other influenza A subtypes, the H5N1 subtype is an RNA virus. It has a segmented genome of eight negative sense, single-strands of RNA, abbreviated as PB2, PB1, PA, HA, NP, NA, MP and NS.[citation needed]

HA codes for hemagglutinin, an antigenic glycoprotein found on the surface of the influenza viruses and is responsible for binding the virus to the cell that is being infected. NA codes for neuraminidase, an antigenic glycosylated enzyme found on the surface of the influenza viruses. It facilitates the release of progeny viruses from infected cells.[33] The hemagglutinin (HA) and neuraminidase (NA) RNA strands specify the structure of proteins that are most medically relevant as targets for antiviral drugs and antibodies. HA and NA are also used as the basis for the naming of the different subtypes of influenza A viruses. This is where the H and N come from in H5N1.

Influenza A viruses are significant for their potential for disease and death in humans and other animals. Influenza A virus subtypes that have been confirmed in humans, in order of the number of known human pandemic deaths that they have caused, include:

  • H1N1, which caused the 1918 flu pandemic ("Spanish flu") and the 2009 flu pandemic ("swine flu"), and is causing seasonal human flu
  • H2N2, which caused "Asian flu"
  • H3N2, which caused "Hong Kong flu" and causes seasonal human flu
  • H5N1 ("bird flu"), which is noted for having a strain (Asian-lineage HPAI H5N1) that has killed over half the humans known to have been infected by it, infecting and killing species that were never known to suffer from influenza viruses before (e.g. cats), unstoppable even by culling all involved poultry – due, some think, to it being endemic in wild birds
  • H7N7, which has unusual zoonotic potential and killed one person
  • H1N2, which is endemic in humans and pigs and causes seasonal human flu
  • H9N2, which has infected three people
  • H7N2, which has infected two people
  • H7N3, which has infected two people
  • H10N7, which has infected two people
  • H7N9, which as of February 2014 has infected 309 people and led to 70 deaths

Low pathogenic H5N1 Edit

Low pathogenic avian influenza H5N1 (LPAI H5N1), also called "North American" H5N1, commonly occurs in wild birds. In most cases, it causes minor sickness or no noticeable signs of disease in birds. It is not known to affect humans at all. The only concern about it is that it is possible for it to be transmitted to poultry and in poultry mutate into a highly pathogenic strain.

  • 1966 – LPAI H5N1 A/Turkey/Ontario/6613/1966(H5N1) was detected in a flock of infected turkeys in Ontario, Canada.[34][35]
  • 1975 – LPAI H5N1 was detected in a wild mallard duck and a wild blue goose in Wisconsin.
  • 1981 and 1985 – LPAI H5N1 was detected in ducks by the University of Minnesota conducting a sampling procedure in which sentinel ducks were monitored in cages placed in the wild for a short period of time.
  • 1983 – LPAI H5N1 was detected in ring-billed gulls in Pennsylvania.
  • 1986 – LPAI H5N1 was detected in a wild mallard duck in Ohio.
  • 2005 – LPAI H5N1 was detected in ducks in Manitoba, Canada.
  • 2008 – LPAI H5N1 was detected in ducks in New Zealand.
  • 2009 – LPAI H5N1 was detected in commercial poultry in British Columbia.[36]

"In the past, there was no requirement for reporting or tracking LPAI H5 or H7 detections in wild birds so states and universities tested wild bird samples independently of USDA. Because of this, the above list of previous detections might not be all inclusive of past LPAI H5N1 detections. However, the World Organization for Animal Health (OIE) recently changed its requirement of reporting detections of avian influenza. Effective in 2006, all confirmed LPAI H5 and H7 AI subtypes must be reported to the OIE because of their potential to mutate into highly pathogenic strains. Therefore, USDA now tracks these detections in wild birds, backyard flocks, commercial flocks and live bird markets."[37]

High mutation rate Edit

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The segmentation of its genome facilitates genetic recombination by segment reassortment in hosts infected with two different strains of influenza viruses at the same time.[38][39] A previously uncontagious strain may then be able to pass between humans, one of several possible paths to a pandemic.[citation needed]

The ability of various influenza strains to show species-selectivity is largely due to variation in the hemagglutinin genes. Genetic mutations in the hemagglutinin gene that cause single amino acid substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors on the surface of host cells. Such mutations in avian H5N1 viruses can change virus strains from being inefficient at infecting human cells to being as efficient in causing human infections as more common human influenza virus types.[40] This doesn't mean that one amino acid substitution can cause a pandemic, but it does mean that one amino acid substitution can cause an avian flu virus that is not pathogenic in humans to become pathogenic in humans.[citation needed]

Influenza A virus subtype H3N2 is endemic in pigs in China, and has been detected in pigs in Vietnam, increasing fears of the emergence of new variant strains. The dominant strain of annual flu virus in January 2006 was H3N2, which is now resistant to the standard antiviral drugs amantadine and rimantadine. The possibility of H5N1 and H3N2 exchanging genes through reassortment is a major concern. If a reassortment in H5N1 occurs, it might remain an H5N1 subtype, or it could shift subtypes, as H2N2 did when it evolved into the Hong Kong Flu strain of H3N2.

Both the H2N2 and H3N2 pandemic strains contained avian influenza virus RNA segments. "While the pandemic human influenza viruses of 1957 (H2N2) and 1968 (H3N2) clearly arose through reassortment between human and avian viruses, the influenza virus causing the 'Spanish flu' in 1918 appears to be entirely derived from an avian source".[41]

Prevention Edit

See also: Yarding

Vaccine Edit

There are several H5N1 vaccines for several of the avian H5N1 varieties, but the continual mutation of H5N1 renders them of limited use to date: while vaccines can sometimes provide cross-protection against related flu strains, the best protection would be from a vaccine specifically produced for any future pandemic flu virus strain. Daniel R. Lucey, co-director of the Biohazardous Threats and Emerging Diseases graduate program at Georgetown University has made this point, "There is no H5N1 pandemic so there can be no pandemic vaccine".[42] However, "pre-pandemic vaccines" have been created; are being refined and tested; and do have some promise both in furthering research and preparedness for the next pandemic.[43][44][45] Vaccine manufacturing companies are being encouraged to increase capacity so that if a pandemic vaccine is needed, facilities will be available for rapid production of large amounts of a vaccine specific to a new pandemic strain.

Public health Edit

Further information: Influenza pandemic

"The United States is collaborating closely with eight international organizations, including the World Health Organization (WHO), the Food and Agriculture Organization of the United Nations (FAO), the World Organization for Animal Health (OIE), and 88 foreign governments to address the situation through planning, greater monitoring, and full transparency in reporting and investigating avian influenza occurrences. The United States and these international partners have led global efforts to encourage countries to heighten surveillance for outbreaks in poultry and significant numbers of deaths in migratory birds and to rapidly introduce containment measures. The U.S. Agency for International Development (USAID) and the U.S. Department of State, the U.S. Department of Health and Human Services (HHS), and Agriculture (USDA) are coordinating future international response measures on behalf of the White House with departments and agencies across the federal government".[46]

Together steps are being taken to "minimize the risk of further spread in animal populations", "reduce the risk of human infections", and "further support pandemic planning and preparedness".[46]

Ongoing detailed mutually coordinated onsite surveillance and analysis of human and animal H5N1 avian flu outbreaks are being conducted and reported by the USGS National Wildlife Health Center, the Centers for Disease Control and Prevention, the World Health Organization, the European Commission, and others.[47]

Treatment Edit

Further information: Flu research

There is no highly effective treatment for H5N1 flu, but oseltamivir (commercially marketed by Roche as Tamiflu) can sometimes inhibit the influenza virus from spreading inside the user's body. This drug has become a focus for some governments and organizations trying to prepare for a possible H5N1 pandemic.[48] On April 20, 2006, Roche AG announced that a stockpile of three million treatment courses of Tamiflu are waiting at the disposal of the World Health Organization to be used in case of a flu pandemic; separately Roche donated two million courses to the WHO for use in developing nations that may be affected by such a pandemic but lack the ability to purchase large quantities of the drug.[49]

However, WHO expert Hassan al-Bushra has said:

"Even now, we remain unsure about Tamiflu's real effectiveness. As for a vaccine, work cannot start on it until the emergence of a new virus, and we predict it would take six to nine months to develop it. For the moment, we cannot by any means count on a potential vaccine to prevent the spread of a contagious influenza virus, whose various precedents in the past 90 years have been highly pathogenic".[50]

Animal and lab studies suggest that Relenza (zanamivir), which is in the same class of drugs as Tamiflu, may also be effective against H5N1. In a study performed on mice in 2000, "zanamivir was shown to be efficacious in treating avian influenza viruses H9N2, H6N1, and H5N1 transmissible to mammals".[51] In addition, mice studies suggest the combination of zanamivir, celecoxib and mesalazine looks promising producing a 50% survival rate compared to no survival in the placebo arm.[52] While no one knows if zanamivir will be useful or not on a yet to exist pandemic strain of H5N1, it might be useful to stockpile zanamivir as well as oseltamivir in the event of an H5N1 influenza pandemic. Neither oseltamivir nor zanamivir can be manufactured in quantities that would be meaningful once efficient human transmission starts.[53] In September, 2006, a WHO scientist announced that studies had confirmed cases of H5N1 strains resistant to Tamiflu and Amantadine.[54] Tamiflu-resistant strains have also appeared in the EU, which remain sensitive to Relenza.[55][56]

Epidemiology Edit

Further information: Transmission and infection of H5N1 and Global spread of H5N1

The earliest infections of humans by H5N1 coincided with an epizootic (an epidemic in nonhumans) of H5N1 influenza in Hong Kong's poultry population in 1997. This panzootic (a disease affecting animals of many species, especially over a wide area) outbreak was stopped by the killing of the entire domestic poultry population within the territory. However, the disease has continued to spread; outbreaks were reported in Asia again in 2003. On December 21, 2009, the WHO announced a total of 447 cases which resulted in the deaths of 263.[20][57]

Contagiousness Edit

 
Highly pathogenic H5N1
  Countries with humans, poultry and wild birds killed by H5N1
  Countries with poultry or wild birds killed by H5N1 and has reported human cases of H5N1
  Countries with poultry or wild birds killed by H5N1

H5N1 is easily transmissible between birds, facilitating a potential global spread of H5N1. While H5N1 undergoes mutation and reassortment, creating variations which can infect species not previously known to carry the virus, not all of these variant forms can infect humans. H5N1 as an avian virus preferentially binds to a type of galactose receptors that populate the avian respiratory tract from the nose to the lungs and are virtually absent in humans, occurring only in and around the alveoli, structures deep in the lungs where oxygen is passed to the blood. Therefore, the virus is not easily expelled by coughing and sneezing, the usual route of transmission.[21][22][58]

H5N1 is mainly spread by domestic poultry, both through the movements of infected birds and poultry products and through the use of infected poultry manure as fertilizer or feed. Humans with H5N1 have typically caught it from chickens, which were in turn infected by other poultry or waterfowl. Migrating waterfowl (wild ducks, geese and swans) carry H5N1, often without becoming sick.[59][60] Many species of birds and mammals can be infected with HPAI A(H5N1), but the role of animals other than poultry and waterfowl as disease-spreading hosts is unknown.[61]

According to a report by the World Health Organization, H5N1 may be spread indirectly. The report stated the virus may sometimes stick to surfaces or get kicked up in fertilizer dust to infect people.[62]

Virulence Edit

H5N1 has mutated into a variety of strains with differing pathogenic profiles, some pathogenic to one species but not others, some pathogenic to multiple species. Each specific known genetic variation is traceable to a virus isolate of a specific case of infection. Through antigenic drift, H5N1 has mutated into dozens of highly pathogenic varieties divided into genetic clades which are known from specific isolates, but all belong to genotype Z of avian influenza virus H5N1, now the dominant genotype.[39][38] H5N1 isolates found in Hong Kong in 1997 and 2001 were not consistently transmitted efficiently among birds and did not cause significant disease in these animals. In 2002, new isolates of H5N1 were appearing within the bird population of Hong Kong. These new isolates caused acute disease, including severe neurological dysfunction and death in ducks. This was the first reported case of lethal influenza virus infection in wild aquatic birds since 1961.[63]

Genotype Z emerged in 2002 through reassortment from earlier highly pathogenic genotypes of H5N1[2] that first infected birds in China in 1996, and first infected humans in Hong Kong in 1997.[38][39][64] Genotype Z is endemic in birds in Southeast Asia, has created at least two clades that can infect humans, and is spreading across the globe in bird populations. Mutations occurring within this genotype are increasing their pathogenicity.[65] Birds are also able to shed the virus for longer periods of time before their death, increasing the transmissibility of the virus.

Transmission and host range Edit

 
Transmission electron micrograph (TEM) of negatively stained Influenza A virus particles (small and white) attached to host cells (large and irregular) (late passage). (Source: Dr. Erskine Palmer, Centers for Disease Control and Prevention Public Health Image Library)

Infected birds transmit H5N1 through their saliva, nasal secretions, feces and blood. Other animals may become infected with the virus through direct contact with these bodily fluids or through contact with surfaces contaminated with them. H5N1 remains infectious after over 30 days at 0 °C (32 °F) (over one month at freezing temperature) or 6 days at 37 °C (99 °F) (one week at human body temperature); at ordinary temperatures it lasts in the environment for weeks. In Arctic temperatures, it does not degrade at all.

Because migratory birds are among the carriers of the highly pathogenic H5N1 virus, it is spreading to all parts of the world. H5N1 is different from all previously known highly pathogenic avian flu viruses in its ability to be spread by animals other than poultry.

In October 2004, researchers discovered H5N1 is far more dangerous than was previously believed. Waterfowl were revealed to be directly spreading this highly pathogenic strain to chickens, crows, pigeons, and other birds, and the virus was increasing its ability to infect mammals, as well. From this point on, avian flu experts increasingly referred to containment as a strategy that can delay, but not ultimately prevent, a future avian flu pandemic.

"Since 1997, studies of influenza A (H5N1) indicate that these viruses continue to evolve, with changes in antigenicity and internal gene constellations; an expanded host range in avian species and the ability to infect felids; enhanced pathogenicity in experimentally infected mice and ferrets, in which they cause systemic infections; and increased environmental stability."[66]

The New York Times, in an article on transmission of H5N1 through smuggled birds, reports Wade Hagemeijer of Wetlands International stating, "We believe it is spread by both bird migration and trade, but that trade, particularly illegal trade, is more important".[67]

On September 29, 2007, researchers reported the H5N1 bird flu virus can also pass through a pregnant woman's placenta to infect the fetus. They also found evidence of what doctors had long suspected—the virus not only affects the lungs, but also passes throughout the body into the gastrointestinal tract, the brain, liver, and blood cells.[68]


Confirmed human cases and mortality rate of avian influenza (H5N1) – 2003–2023
Country
  Azerbaijan
  Bangladesh
  Cambodia
  Canada
  Chile
  China
  Djibouti
  Ecuador
  Egypt
  India
  Indonesia
  Iraq
  Laos
  Myanmar
  Nepal
  Nigeria
  Pakistan
  Spain
  Thailand
  Turkey
  United Kingdom
  United States
  Vietnam
Total
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 Total
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
8 5 62.5% 8 5 62.5%
1 0 0% 2 0 0% 3 0 0% 1 1 100% 1 0 0% 8 1 12.5%
4 4 100% 2 2 100% 1 1 100% 1 0 0% 1 0 0% 1 1 100% 8 8 100% 3 3 100% 26 14 53.8% 9 4 44.4% 56 37 66.1%
1 1 100% 1 1 100%
1[69] 0 0% 1 0 0%
1 1 100% 8 5 62.5% 13 8 61.5% 5 3 60.0% 4 4 100% 7 4 57.1% 2 1 50.0% 1 1 100% 2 1 50.0% 2 2 100% 2 0 0% 6 1 16.7% 1 1 100% 54 32 59.3%
1 0 0% 1 0 0%
1 0 0% 1 0 0%
18 10 55.6% 25 9 36.0% 8 4 50.0% 39 4 10.3% 29 13 44.8% 39 15 38.5% 11 5 45.5% 4 3 75.0% 37 14 37.8% 136 39 28.7% 10 3 30.0% 3 1 33.3% 359 120 33.4%
1 1 100% 1 1 100%
20 13 65.0% 55 45 81.8% 42 37 88.1% 24 20 83.3% 21 19 90.5% 9 7 77.8% 12 10 83.3% 9 9 100% 3 3 100% 2 2 100% 2 2 100% 1 1 100% 200 168 84.0%
3 2 66.6% 3 2 66.6%
2 2 100% 1 0 0% 3 2 66.7%
1 0 0% 1 0 0%
1 1 100% 1 1 100%
1 1 100% 1 1 100%
3 1 33.3% 3 1 33.3%
2 0 0% 2 0 0%
17 12 70.6% 5 2 40.0% 3 3 100% 25 17 68.0%
12 4 33.3% 12 4 33.3%
1 0 0% 1 0 0%
1 0 0% 1 0 0%
3 3 100% 29 20 69.0% 61 19 31.1% 8 5 62.5% 6 5 83.3% 5 5 100% 7 2 28.6% 4 2 50.0% 2 1 50.0% 2 2 100% 1 0 0% 128 64 50.0%
4 4 100% 46 32 69.6% 98 43 43.9% 115 79 68.7% 88 59 67.0% 44 33 75.0% 73 32 43.8% 48 24 50.0% 62 34 54.8% 32 20 62.5% 39 25 64.1% 52 22 42.3% 145 42 29.0% 10 3 30.0% 4 2 50.0% 0 0 0% 1 1 100% 1 0 0% 2 1 50.0% 6 1 16.7% 1 0 0% 870 457 52.5%
Source: World Health Organization Human Animal Interface · edit this table


In May 2013, North Korea confirmed a H5N1 bird flu outbreak that forced authorities to kill over 160,000 ducks in Pyongyang.[70]

Regional and global outbreaks Edit

2021–2022 outbreaks in Europe/Atlantic flyway Edit

Over the winter of 2021 and 2022 avian flu spread among the population of barnacle geese on the Solway Firth, UK, with estimates of up to a third of the Svalbard population being lost;[71][72] pink-footed geese were also affected there and it seems carried the virus to new sites in northern Scotland. The disease was confirmed in sandwich terns in South Africa in April 2022.[73] In late spring 2022 avian flu outbreaks affected many species of wild bird in the United Kingdom, with heavy losses reported among seabirds returning to breed at colonies in the Northern Isles and Outer Hebrides,[74] including great skuas (bonxie) for which outbreaks had initially been reported in 2021[75] (Scotland hosts c. 60% of the world's breeding population) - the 2022 census on St Kilda showed a 64% decline on 2019 with 106 dead birds recorded so far (to 6 June),[76] gannets (1000+ birds reported dead at the Shetlands' Hermaness colony alone,[74] where there are around 26,000 breeding pairs), with many more gannets being reported dead at other colonies (Troup Head, Bass Rock, and St Kilda);[77] the range of species also seems to be expanding, with reports for many species of wildfowl, seabirds (auks, terns and gulls) and scavenging species (corvids and raptors).[78][79]

Elsewhere in Europe the virus killed hundreds (574+) of Dalmatian pelicans in Greece,[80][81] and in Israel around 6000 common cranes were found dead at Hula in December 2021.[82] A report by Scientific Task Force on Avian Influenza and Wild Birds on: "H5N1 Highly Pathogenic Avian Influenza in poultry and wild birds: Winter of 2021/2022 with focus on mass mortality of wild birds in UK and Israel" summarises the situation up to 24 January 2022 and mentions that "H5N8 HPAI is still responsible for poultry and wild bird cases mainly in Asia, H5N1 has now in effect replaced this subtype in Africa and Eurasia in both poultry and wild birds".[83]

2022–2023 global outbreaks Edit

Main article: 2020–2023 H5N1 outbreak
Americas Edit

Similar to 2021 reports, outbreaks were noted from gannet colonies in Canada, with thousands of birds dead in June 2022,[84] as well as common eiders and great black-backed gulls.[85] Prior to that there were reports of spread in wild birds in over 30 states in the US, including major mortalities in a double-crested cormorant colony in Barrington, Illinois,[86][87] the virus also spreading to scavengers including three bald eagles in Georgia.[88] Mass die-offs of both birds and mammals were noted in Peru during the 2022–2023 season.[89] In particular, the Peruvian government reported the deaths of approximately 63,000 birds as well as 716 sea lions, with the WHO noting that mammalian spillovers needed to be "monitored closely".[90][91] In the United States, the 2022–2023 avian outbreak was the worst since H5N1 was first detected.[90]

Ecuador entered into a three-month "animal-health emergency" on 29 November 2022, just days after its first case was reported, whereas Argentina and Uruguay both declared "national sanitary emergencies" on 15 February 2023, after their respective first cases were discovered.[92] On 22 May 2023, Brazil, as the world's largest exporter of chicken meat, declared a 180-day emergency following several cases detected in wild birds and created an emergency operations center to plan for and mitigate potential further spread of H5N1.[93]

Europe Edit

The 2022–2023 season was also the worst recorded outbreak in the United Kingdom, with the British government requiring a so-called "poultry lockdown" which required that farmers keep their birds indoors.[90] Meanwhile, an outbreak of H5N1 on a Spanish mink farm led researchers to believe that they had observed the first case of mammal-to-mammal transmission of H5N1.[94]

Mammalian infections Edit

Main article: List of mammals that can get H5N1

H5N1 transmission studies in ferrets (2011) Edit

Novel, contagious strains of H5N1 were created by Ron Fouchier of the Erasmus Medical Center in Rotterdam, the Netherlands, who first presented his work to the public at an influenza conference in Malta in September 2011. Three mutations were introduced into the H5N1 virus genome, and the virus was then passed from the noses of infected ferrets to the noses of uninfected ones, which was repeated 10 times.[95] After these 10 passages the H5N1 virus had acquired the ability of transmission between ferrets via aerosols or respiratory droplets.

After Fouchier offered an article describing this work to the leading academic journal Science, the US National Science Advisory Board for Biosecurity (NSABB) recommended against publication of the full details of the study, and the one submitted to Nature by Yoshihiro Kawaoka of the University of Wisconsin describing related work. However, after additional consultations at the World Health Organization and by the NSABB, the NSABB reversed its position and recommended publication of revised versions of the two papers.[96] However, then the Dutch government declared that this type of manuscripts required Fouchier to apply for an export permit in the light of EU directive 428/2009 on dual use goods.[note 1] After much controversy surrounding the publishing of his research, Fouchier complied (under formal protest) with Dutch government demands to obtain a special permit[97] for submitting his manuscript, and his research appeared in a special issue of the journal Science devoted to H5N1.[98][99][100] The papers by Fouchier and Kawaoka conclude that it is entirely possible that a natural chain of mutations could lead to an H5N1 virus acquiring the capability of airborne transmission between mammals, and that a H5N1 influenza pandemic would not be impossible.[101]

In May 2013, it was reported that scientists at the Harbin Veterinary Research Institute in Harbin, China, had created H5N1 strains which passed between guinea pigs.[102]

In response to Fouchier and Kawaoka's work, a number of scientists expressed concerns with the risks of creating novel potential pandemic pathogens, culminating in the formation of the Cambridge Working Group, a consensus statement calling for an assessment of the risks and benefits of such research.[103][104]

Mammal-to-mammal transmission (2022–2023) Edit

Although mammals, including humans, had become infected with H5N1 bird flu strains in the past, these cases had ostensibly been caused by direct exposure to infected birds, such as through consumption of birds by wildlife or exposure to infected poultry by farmers. In contrast, the October 2022 mammalian outbreak of H5N1 on a Spanish mink farm showed evidence of being the first recorded case of mammal-to-mammal transmission, with 4 percent of the farm's mink population dying from H5N1-related haemorrhagic pneumonia.[94][105] The mink respiratory tract is particularly well suited to act as a pathway of viral transmission into humans, which has concerned public health professionals due to the production of all but one approved human vaccine requiring the eggs of chickens, which H5N1 kills at a 90-100 percent fatality rate.[106] Infected mink in Spain were also found to have exhibited the "PB2" viral mutation found when H5N1 jumped into pigs over a decade prior, adding to fears that farms could be acting as incubators and/or reservoirs of the virus, similar to the role of minks in SARS-CoV-2.[94]

As of January 2023, fifteen species of wild and captive mammals had become infected with H5N1 throughout the United States.[107] A mass Caspian seal die-off in December 2022, with 700 infected seals found dead along the Caspian Sea coastline of Russia's Dagestan republic, worried researchers regarding the possibility that wild mammal-to-mammal spread had begun.[108]

Human infections Edit

As of May 2020, the WHO reported a total of 861 confirmed human cases which resulted in the deaths of 455 people since 2003.[5]

Human-to-human transmission Edit

Main article: 2020–2023 H5N1 outbreak
Cambodia (2023) Edit

Following the February 2023 H5N1 death of an 11-year-old girl from Cambodia's Prey Veng province, her father was confirmed positive for the virus and several close contacts also began showing signs of infection. On 24 February 2023, the WHO expressed concern that the virus had potentially begun to spread among humans and ordered the production of a new human vaccine for H5N1.[109] Following the confirmed infections, the WHO began working with the Cambodian government to determine whether both individuals had gotten the virus directly from infected poultry or if it had indeed been a case of human-to-human transmission.[110] Further sequencing determined that at least one of the two cases was from an older H5N1 clade, 2.3.2.1c, which had circulated as a common H5N1 strain in Cambodia for many years, rather than the more recent clade 2.3.4.4b, which had caused mass poultry deaths since 2020. This older clade had jumped to humans in the past yet hadn't previously resulted in any known human-to-human transmission.[111]

On March 1, 2023, as Taiwan raised its travel alert for Cambodia, the WHO and the U.S. CDC, in concert with Cambodian authorities, determined that both of the individuals had been infected through direct contact with poultry.[112][113]

Society and culture Edit

Main article: Social impact of H5N1

H5N1 has had a significant effect on human society, especially the financial, political, social, and personal responses to both actual and predicted deaths in birds, humans, and other animals. Billions of dollars are being raised and spent to research H5N1 and prepare for a potential avian influenza pandemic. Over $10 billion have been spent and over 200 million birds have been killed to try to contain H5N1.[13][114][115][116][117][118][119][120][121]

People have reacted by buying less chicken, causing poultry sales and prices to fall.[122] Many individuals have stockpiled supplies for a possible flu pandemic. International health officials and other experts have pointed out that many unknown questions still hover around the disease.[123]

Dr. David Nabarro, Chief Avian Flu Coordinator for the United Nations, and former Chief of Crisis Response for the World Health Organization has described himself as "quite scared" about H5N1's potential impact on humans. Nabarro has been accused of being alarmist before, and on his first day in his role for the United Nations, he proclaimed the avian flu could kill 150 million people. In an interview with the International Herald Tribune, Nabarro compares avian flu to AIDS in Africa, warning that underestimations led to inappropriate focus for research and intervention.[124]

In February 2020 an outbreak of H5N1 avian flu occurred in Shuangqing District of Shaoyang City, in the Hunan province. After poultry had become ill from the virus the city killed close to 18,000 chickens to prevent the spread of the illness. Hunan borders Hubei province where Wuhan is located, the epicenter of the coronavirus pandemic.[125]

See also Edit

Notes Edit

  1. ^ The World Intellectual Property Organization (WIPO) lists strategic goods with prohibited goods or goods that require a special permit for import and export without which the carrier faces pecuniary punishment or up to 5 years' imprisonment.

References Edit

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Sources Edit

  • Analysis of the efficacy of an adjuvant-based inactivated pandemic H5N1 influenza virus vaccine. https://link.springer.com/article/10.1007%2Fs00705-019-04147-7 Ainur NurpeisovaEmail authorMarkhabat KassenovNurkuisa RametovKaissar TabynovGourapura J. RenukaradhyaYevgeniy VolginAltynay SagymbayAmanzhol MakbuzAbylay SansyzbayBerik Khairullin

Research Institute for Biological Safety Problems (RIBSP), Zhambyl Region, Republic of Kazakhstan

External links Edit

 
Wikimedia Commons has media related to H5N1.
 
Wikinews has news related to:
Avian Flu
  • Influenza Research Database – Database of influenza genomic sequences and related information.
  • WHO World Health Organization
    • Guide to WHO's H5N1 pages
    • – tracks human cases and deaths
    • Centers, names, locations, and phone numbers
  • FAO Avian Influenza portal 2012-01-26 at the Wayback Machine Information resources, animations, videos, photos
    • FAO Food and Agriculture Organisation – Bi-weekly Avian Influenza Maps – tracks animal cases and deaths
    • FAO Bird Flu disease card
    • Projects, Information resources
  • OIE World Organisation for Animal Health – tracks animal cases and deaths
European Union
United Kingdom
  • Exotic Animal Disease Generic Contingency Plan – DEFRA generic contingency plan for controlling and eradicating an outbreak of an exotic animal disease. PDF hosted by BBC.
  • UK Influenza Pandemic Contingency Plan by the National Health Service – a government entity. PDF hosted by BBC
  • UK Department of Health 2009-07-09 at the Wayback Machine
United States
  • Center for Infectious Disease Research and Policy 2013-06-17 at the Wayback Machine Avian Influenza (Bird Flu): Implications for Human Disease – An overview of Avian Influenza
  • PandemicFlu.Gov U.S. Government's avian flu information site
  • U.S. Agency for International Development – Avian Influenza Response
  • CDC, Centers for Disease Control and Prevention – responsible agency for avian influenza in humans in US – Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus
  • National Wildlife Health Center – responsible agency for avian influenza in animals in US
  • A part of the National Biological Information Infrastructure and partner of the NWHC, this agency collects and distributes news and information about wildlife diseases such as avian influenza and coordinates collaborative information sharing efforts.
  • U.S. Department of Health & Human Services's Pandemic Influenza Plan

October 21, 2023
influenza, virus, subtype, h5n1, h5n1, subtype, influenza, virus, which, cause, illness, humans, many, other, species, bird, adapted, strain, h5n1, called, hpai, h5n1, highly, pathogenic, avian, influenza, virus, type, subtype, h5n1, highly, pathogenic, causat. Influenza A virus subtype H5N1 A H5N1 is a subtype of the influenza A virus which can cause illness in humans and many other species 1 A bird adapted strain of H5N1 called HPAI A H5N1 for highly pathogenic avian influenza virus of type A of subtype H5N1 is the highly pathogenic causative agent of H5N1 flu commonly known as avian influenza bird flu It is enzootic maintained in the population in many bird populations especially in Southeast Asia One strain of HPAI A H5N1 is spreading globally after first appearing in Asia It is epizootic an epidemic in nonhumans and panzootic affecting animals of many species especially over a wide area killing tens of millions of birds and spurring the culling of hundreds of millions of others to stem its spread Many references to bird flu and H5N1 in the popular media refer to this strain 2 Influenza A virus subtype H5N1Colorized transmission electron micrograph of Avian influenza A H5N1 viruses seen in gold grown in MDCK cells seen in green Virus classification unranked VirusRealm RiboviriaKingdom OrthornaviraePhylum NegarnaviricotaClass InsthoviricetesOrder ArticulaviralesFamily OrthomyxoviridaeGenus AlphainfluenzavirusSpecies Influenza A virusSerotype Influenza A virus subtype H5N1Notable strainsGoose Guangdong virus A Fujian H5N1 According to the World Health Organization WHO and the United Nations Food and Agriculture Organization H5N1 pathogenicity is gradually continuing to rise in endemic areas but the avian influenza disease situation in farmed birds is being held in check by vaccination and there is no evidence of sustained human to human transmission of the virus 3 Eleven outbreaks of H5N1 were reported worldwide in June 2008 in five countries China Egypt Indonesia Pakistan and Vietnam compared to 65 outbreaks in June 2006 and 55 in June 2007 The global HPAI situation significantly improved in the first half of 2008 but the FAO reports that imperfect disease surveillance systems mean that occurrence of the virus remains underestimated and underreported 4 As of May 2020 the WHO reported a total of 861 confirmed human cases which resulted in the deaths of 455 people since 2003 5 Several H5N1 vaccines have been developed and approved and stockpiled by a number of countries including the United States in its National Stockpile 6 7 Britain France Canada and Australia for use in an emergency 8 Contents 1 Overview 2 Signs and symptoms 2 1 In birds 3 Genetics 3 1 Terminology 3 2 Genetic structure and related subtypes 3 3 Low pathogenic H5N1 3 4 High mutation rate 4 Prevention 4 1 Vaccine 4 2 Public health 5 Treatment 6 Epidemiology 6 1 Contagiousness 6 2 Virulence 6 3 Transmission and host range 6 4 Regional and global outbreaks 6 4 1 2021 2022 outbreaks in Europe Atlantic flyway 6 4 2 2022 2023 global outbreaks 6 4 2 1 Americas 6 4 2 2 Europe 6 5 Mammalian infections 6 5 1 H5N1 transmission studies in ferrets 2011 6 5 2 Mammal to mammal transmission 2022 2023 6 6 Human infections 6 6 1 Human to human transmission 6 6 1 1 Cambodia 2023 7 Society and culture 8 See also 9 Notes 10 References 10 1 Citations 10 2 Sources 11 External linksOverview EditHPAI A H5N1 is considered an avian disease although there is some evidence of limited human to human transmission of the virus 9 A risk factor for contracting the virus is handling of infected poultry but transmission of the virus from infected birds to humans has been characterized as inefficient 10 Still around 60 of humans known to have been infected with the Asian strain of HPAI A H5N1 have died from it and H5N1 may mutate or reassort into a strain capable of efficient human to human transmission In 2003 virologist Robert G Webster published an article titled The world is teetering on the edge of a pandemic that could kill a large fraction of the human population in American Scientist He called for adequate resources to fight what he sees as a major world threat to possibly billions of lives 11 On September 29 2005 David Nabarro the newly appointed Senior United Nations System Coordinator for Avian and Human Influenza warned the world that an outbreak of avian influenza could kill anywhere between 5 million and 150 million people 12 Experts have identified key events creating new clades infecting new species spreading to new areas marking the progression of an avian flu virus towards becoming pandemic and many of those key events have occurred more rapidly than expected citation needed Due to the high lethality and virulence of HPAI A H5N1 its endemic presence its increasingly large host reservoir and its significant ongoing mutations in 2006 the H5N1 virus has been regarded to be the world s largest pandemic threat and billions of dollars are being spent researching H5N1 and preparing for a potential influenza pandemic 13 At least 12 companies and 17 governments are developing prepandemic influenza vaccines in 28 different clinical trials that if successful could turn a deadly pandemic infection into a nondeadly one Full scale production of a vaccine that could prevent any illness at all from the strain would require at least three months after the virus s emergence to begin but it is hoped that vaccine production could increase until one billion doses were produced by one year after the initial identification of the virus 14 H5N1 may cause more than one influenza pandemic as it is expected to continue mutating in birds regardless of whether humans develop herd immunity to a future pandemic strain 15 Influenza pandemics from its genetic offspring may include influenza A virus subtypes other than H5N1 16 While genetic analysis of the H5N1 virus shows that influenza pandemics from its genetic offspring can easily be far more lethal than the Spanish flu pandemic 17 planning for a future influenza pandemic is based on what can be done and there is no higher Pandemic Severity Index level than a Category 5 pandemic which roughly speaking is any pandemic as bad as the Spanish flu or worse and for which all intervention measures are to be used 18 Signs and symptoms EditFurther information Influenza nbsp The different sites of infection shown in red of seasonal H1N1 versus avian H5N1 influences their lethality and ability to spread 19 In general humans who catch a humanized influenza A virus a human flu virus of type A usually have symptoms that include fever cough sore throat muscle aches conjunctivitis and in severe cases breathing problems and pneumonia that may be fatal 20 The severity of the infection depends in large part on the state of the infected persons immune systems and whether they had been exposed to the strain before in which case they would be partially immune No one knows if these or other symptoms will be the symptoms of a humanized H5N1 flu The avian influenza hemagglutinin binds alpha 2 3 sialic acid receptors while human influenza hemagglutinins bind alpha 2 6 sialic acid receptors 21 This means when the H5N1 strain infects humans it will replicate in the lower respiratory tract and consequently will cause viral pneumonia 22 There is as yet no human form of H5N1 so all humans who have caught it so far have caught avian H5N1 The reported mortality rate of highly pathogenic H5N1 avian influenza in a human is high WHO data indicate 60 of cases classified as H5N1 resulted in death However there is some evidence the actual mortality rate of avian flu could be much lower as there may be many people with milder symptoms who do not seek treatment and are not counted 23 24 In one case a boy with H5N1 experienced diarrhea followed rapidly by a coma without developing respiratory or flu like symptoms 25 There have been studies of the levels of cytokines in humans infected by the H5N1 flu virus Of particular concern is elevated levels of tumor necrosis factor alpha a protein associated with tissue destruction at sites of infection and increased production of other cytokines Flu virus induced increases in the level of cytokines is also associated with flu symptoms including fever chills vomiting and headache Tissue damage associated with pathogenic flu virus infection can ultimately result in death 11 The inflammatory cascade triggered by H5N1 has been called a cytokine storm by some because of what seems to be a positive feedback process of damage to the body resulting from immune system stimulation H5N1 induces higher levels of cytokines than the more common flu virus types 26 In birds Edit Clinical signs of H5N1 in birds range from mild decrease in egg production nasal discharge coughing and sneezing to severe including loss of coordination energy and appetite soft shelled or misshapen eggs purple discoloration of the wattles head eyelids combs and hocks and diarrhea Sometimes the first noticeable sign is sudden death 20 Genetics Edit nbsp The H in H5N1 stands for hemagglutinin as depicted in this molecular modelFurther information Influenzavirus A and H5N1 genetic structure The first known strain of HPAI A H5N1 called A chicken Scotland 59 killed two flocks of chickens in Scotland in 1959 but that strain was very different from the highly pathogenic strain of H5N1 The dominant strain of HPAI A H5N1 in 2004 evolved from 1999 to 2002 creating the Z genotype 27 It has also been called Asian lineage HPAI A H5N1 Asian lineage HPAI A H5N1 is divided into two antigenic clades Clade 1 includes human and bird isolates from Vietnam Thailand and Cambodia and bird isolates from Laos and Malaysia Clade 2 viruses were first identified in bird isolates from China Indonesia Japan and South Korea before spreading westward to the Middle East Europe and Africa The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006 according to WHO Genetic analysis has identified six subclades of clade 2 three of which have a distinct geographic distribution and have been implicated in human infections Map Subclade 1 Indonesia Subclade 2 Europe Middle East and Africa called EMA Subclade 3 China 15 28 29 A 2007 study focused on the EMA subclade has shed further light on the EMA mutations The 36 new isolates reported here greatly expand the amount of whole genome sequence data available from recent avian influenza H5N1 isolates Before our project GenBank contained only 5 other complete genomes from Europe for the 2004 2006 period and it contained no whole genomes from the Middle East or northern Africa Our analysis showed several new findings First all European Middle Eastern and African samples fall into a clade that is distinct from other contemporary Asian clades all of which share common ancestry with the original 1997 Hong Kong strain Phylogenetic trees built on each of the 8 segments show a consistent picture of 3 lineages as illustrated by the HA tree shown in Figure 1 Two of the clades contain exclusively Vietnamese isolates the smaller of these with 5 isolates we label V1 the larger clade with 9 isolates is V2 The remaining 22 isolates all fall into a third clearly distinct clade labeled EMA which comprises samples from Europe the Middle East and Africa Trees for the other 7 segments display a similar topology with clades V1 V2 and EMA clearly separated in each case Analyses of all available complete influenza H5N1 genomes and of 589 HA sequences placed the EMA clade as distinct from the major clades circulating in People s Republic of China Indonesia and Southeast Asia 30 Terminology Edit H5N1 isolates are identified like this actual HPAI A H5N1 example A chicken Nakorn Patom Thailand CU K2 04 H5N1 A stands for the genus of influenza A B or C chicken is the animal species the isolate was found in note human isolates lack this component term and are thus identified as human isolates by default Nakorn Patom Thailand is the place this specific virus was isolated CU K2 is the laboratory reference number that identifies it from other influenza viruses isolated at the same place and year 04 represents the year of isolation 2004 H5 stands for the fifth of several known types of the protein hemagglutinin N1 stands for the first of several known types of the protein neuraminidase Other examples include A duck Hong Kong 308 78 H5N3 A avian NY 01 H5N2 A chicken Mexico 31381 3 94 H5N2 and A shoveler Egypt 03 H5N2 31 As with other avian flu viruses H5N1 has strains called highly pathogenic HP and low pathogenic LP Avian influenza viruses that cause HPAI are highly virulent and mortality rates in infected flocks often approach 100 LPAI viruses have negligible virulence but these viruses can serve as progenitors to HPAI viruses The strain of H5N1 responsible for the deaths of birds across the world is an HPAI strain all other strains of H5N1 including a North American strain that causes no disease at all in any species are LPAI strains All HPAI strains identified to date have involved H5 and H7 subtypes The distinction concerns pathogenicity in poultry not humans Normally a highly pathogenic avian virus is not highly pathogenic to either humans or nonpoultry birds This deadly strain of H5N1 is unusual in being deadly to so many species including some like domestic cats never previously susceptible to any influenza virus 32 Genetic structure and related subtypes Edit nbsp The N in H5N1 stands for Neuraminidase the protein depicted in this ribbon diagramH5N1 is a subtype of the species Influenza A virus of the genus Alphainfluenzavirus of the family Orthomyxoviridae Like all other influenza A subtypes the H5N1 subtype is an RNA virus It has a segmented genome of eight negative sense single strands of RNA abbreviated as PB2 PB1 PA HA NP NA MP and NS citation needed HA codes for hemagglutinin an antigenic glycoprotein found on the surface of the influenza viruses and is responsible for binding the virus to the cell that is being infected NA codes for neuraminidase an antigenic glycosylated enzyme found on the surface of the influenza viruses It facilitates the release of progeny viruses from infected cells 33 The hemagglutinin HA and neuraminidase NA RNA strands specify the structure of proteins that are most medically relevant as targets for antiviral drugs and antibodies HA and NA are also used as the basis for the naming of the different subtypes of influenza A viruses This is where the H and N come from in H5N1 Influenza A viruses are significant for their potential for disease and death in humans and other animals Influenza A virus subtypes that have been confirmed in humans in order of the number of known human pandemic deaths that they have caused include H1N1 which caused the 1918 flu pandemic Spanish flu and the 2009 flu pandemic swine flu and is causing seasonal human flu H2N2 which caused Asian flu H3N2 which caused Hong Kong flu and causes seasonal human flu H5N1 bird flu which is noted for having a strain Asian lineage HPAI H5N1 that has killed over half the humans known to have been infected by it infecting and killing species that were never known to suffer from influenza viruses before e g cats unstoppable even by culling all involved poultry due some think to it being endemic in wild birds H7N7 which has unusual zoonotic potential and killed one person H1N2 which is endemic in humans and pigs and causes seasonal human flu H9N2 which has infected three people H7N2 which has infected two people H7N3 which has infected two people H10N7 which has infected two people H7N9 which as of February 2014 has infected 309 people and led to 70 deathsLow pathogenic H5N1 Edit Low pathogenic avian influenza H5N1 LPAI H5N1 also called North American H5N1 commonly occurs in wild birds In most cases it causes minor sickness or no noticeable signs of disease in birds It is not known to affect humans at all The only concern about it is that it is possible for it to be transmitted to poultry and in poultry mutate into a highly pathogenic strain 1966 LPAI H5N1 A Turkey Ontario 6613 1966 H5N1 was detected in a flock of infected turkeys in Ontario Canada 34 35 1975 LPAI H5N1 was detected in a wild mallard duck and a wild blue goose in Wisconsin 1981 and 1985 LPAI H5N1 was detected in ducks by the University of Minnesota conducting a sampling procedure in which sentinel ducks were monitored in cages placed in the wild for a short period of time 1983 LPAI H5N1 was detected in ring billed gulls in Pennsylvania 1986 LPAI H5N1 was detected in a wild mallard duck in Ohio 2005 LPAI H5N1 was detected in ducks in Manitoba Canada 2008 LPAI H5N1 was detected in ducks in New Zealand 2009 LPAI H5N1 was detected in commercial poultry in British Columbia 36 In the past there was no requirement for reporting or tracking LPAI H5 or H7 detections in wild birds so states and universities tested wild bird samples independently of USDA Because of this the above list of previous detections might not be all inclusive of past LPAI H5N1 detections However the World Organization for Animal Health OIE recently changed its requirement of reporting detections of avian influenza Effective in 2006 all confirmed LPAI H5 and H7 AI subtypes must be reported to the OIE because of their potential to mutate into highly pathogenic strains Therefore USDA now tracks these detections in wild birds backyard flocks commercial flocks and live bird markets 37 High mutation rate Edit Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses The segmentation of its genome facilitates genetic recombination by segment reassortment in hosts infected with two different strains of influenza viruses at the same time 38 39 A previously uncontagious strain may then be able to pass between humans one of several possible paths to a pandemic citation needed The ability of various influenza strains to show species selectivity is largely due to variation in the hemagglutinin genes Genetic mutations in the hemagglutinin gene that cause single amino acid substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors on the surface of host cells Such mutations in avian H5N1 viruses can change virus strains from being inefficient at infecting human cells to being as efficient in causing human infections as more common human influenza virus types 40 This doesn t mean that one amino acid substitution can cause a pandemic but it does mean that one amino acid substitution can cause an avian flu virus that is not pathogenic in humans to become pathogenic in humans citation needed Influenza A virus subtype H3N2 is endemic in pigs in China and has been detected in pigs in Vietnam increasing fears of the emergence of new variant strains The dominant strain of annual flu virus in January 2006 was H3N2 which is now resistant to the standard antiviral drugs amantadine and rimantadine The possibility of H5N1 and H3N2 exchanging genes through reassortment is a major concern If a reassortment in H5N1 occurs it might remain an H5N1 subtype or it could shift subtypes as H2N2 did when it evolved into the Hong Kong Flu strain of H3N2 Both the H2N2 and H3N2 pandemic strains contained avian influenza virus RNA segments While the pandemic human influenza viruses of 1957 H2N2 and 1968 H3N2 clearly arose through reassortment between human and avian viruses the influenza virus causing the Spanish flu in 1918 appears to be entirely derived from an avian source 41 Prevention EditSee also Yarding Vaccine Edit There are several H5N1 vaccines for several of the avian H5N1 varieties but the continual mutation of H5N1 renders them of limited use to date while vaccines can sometimes provide cross protection against related flu strains the best protection would be from a vaccine specifically produced for any future pandemic flu virus strain Daniel R Lucey co director of the Biohazardous Threats and Emerging Diseases graduate program at Georgetown University has made this point There is no H5N1 pandemic so there can be no pandemic vaccine 42 However pre pandemic vaccines have been created are being refined and tested and do have some promise both in furthering research and preparedness for the next pandemic 43 44 45 Vaccine manufacturing companies are being encouraged to increase capacity so that if a pandemic vaccine is needed facilities will be available for rapid production of large amounts of a vaccine specific to a new pandemic strain Public health Edit Further information Influenza pandemic The United States is collaborating closely with eight international organizations including the World Health Organization WHO the Food and Agriculture Organization of the United Nations FAO the World Organization for Animal Health OIE and 88 foreign governments to address the situation through planning greater monitoring and full transparency in reporting and investigating avian influenza occurrences The United States and these international partners have led global efforts to encourage countries to heighten surveillance for outbreaks in poultry and significant numbers of deaths in migratory birds and to rapidly introduce containment measures The U S Agency for International Development USAID and the U S Department of State the U S Department of Health and Human Services HHS and Agriculture USDA are coordinating future international response measures on behalf of the White House with departments and agencies across the federal government 46 Together steps are being taken to minimize the risk of further spread in animal populations reduce the risk of human infections and further support pandemic planning and preparedness 46 Ongoing detailed mutually coordinated onsite surveillance and analysis of human and animal H5N1 avian flu outbreaks are being conducted and reported by the USGS National Wildlife Health Center the Centers for Disease Control and Prevention the World Health Organization the European Commission and others 47 Treatment EditFurther information Flu research There is no highly effective treatment for H5N1 flu but oseltamivir commercially marketed by Roche as Tamiflu can sometimes inhibit the influenza virus from spreading inside the user s body This drug has become a focus for some governments and organizations trying to prepare for a possible H5N1 pandemic 48 On April 20 2006 Roche AG announced that a stockpile of three million treatment courses of Tamiflu are waiting at the disposal of the World Health Organization to be used in case of a flu pandemic separately Roche donated two million courses to the WHO for use in developing nations that may be affected by such a pandemic but lack the ability to purchase large quantities of the drug 49 However WHO expert Hassan al Bushra has said Even now we remain unsure about Tamiflu s real effectiveness As for a vaccine work cannot start on it until the emergence of a new virus and we predict it would take six to nine months to develop it For the moment we cannot by any means count on a potential vaccine to prevent the spread of a contagious influenza virus whose various precedents in the past 90 years have been highly pathogenic 50 Animal and lab studies suggest that Relenza zanamivir which is in the same class of drugs as Tamiflu may also be effective against H5N1 In a study performed on mice in 2000 zanamivir was shown to be efficacious in treating avian influenza viruses H9N2 H6N1 and H5N1 transmissible to mammals 51 In addition mice studies suggest the combination of zanamivir celecoxib and mesalazine looks promising producing a 50 survival rate compared to no survival in the placebo arm 52 While no one knows if zanamivir will be useful or not on a yet to exist pandemic strain of H5N1 it might be useful to stockpile zanamivir as well as oseltamivir in the event of an H5N1 influenza pandemic Neither oseltamivir nor zanamivir can be manufactured in quantities that would be meaningful once efficient human transmission starts 53 In September 2006 a WHO scientist announced that studies had confirmed cases of H5N1 strains resistant to Tamiflu and Amantadine 54 Tamiflu resistant strains have also appeared in the EU which remain sensitive to Relenza 55 56 Epidemiology EditFurther information Transmission and infection of H5N1 and Global spread of H5N1 The earliest infections of humans by H5N1 coincided with an epizootic an epidemic in nonhumans of H5N1 influenza in Hong Kong s poultry population in 1997 This panzootic a disease affecting animals of many species especially over a wide area outbreak was stopped by the killing of the entire domestic poultry population within the territory However the disease has continued to spread outbreaks were reported in Asia again in 2003 On December 21 2009 the WHO announced a total of 447 cases which resulted in the deaths of 263 20 57 Contagiousness Edit nbsp Highly pathogenic H5N1 Countries with humans poultry and wild birds killed by H5N1 Countries with poultry or wild birds killed by H5N1 and has reported human cases of H5N1 Countries with poultry or wild birds killed by H5N1H5N1 is easily transmissible between birds facilitating a potential global spread of H5N1 While H5N1 undergoes mutation and reassortment creating variations which can infect species not previously known to carry the virus not all of these variant forms can infect humans H5N1 as an avian virus preferentially binds to a type of galactose receptors that populate the avian respiratory tract from the nose to the lungs and are virtually absent in humans occurring only in and around the alveoli structures deep in the lungs where oxygen is passed to the blood Therefore the virus is not easily expelled by coughing and sneezing the usual route of transmission 21 22 58 H5N1 is mainly spread by domestic poultry both through the movements of infected birds and poultry products and through the use of infected poultry manure as fertilizer or feed Humans with H5N1 have typically caught it from chickens which were in turn infected by other poultry or waterfowl Migrating waterfowl wild ducks geese and swans carry H5N1 often without becoming sick 59 60 Many species of birds and mammals can be infected with HPAI A H5N1 but the role of animals other than poultry and waterfowl as disease spreading hosts is unknown 61 According to a report by the World Health Organization H5N1 may be spread indirectly The report stated the virus may sometimes stick to surfaces or get kicked up in fertilizer dust to infect people 62 Virulence Edit H5N1 has mutated into a variety of strains with differing pathogenic profiles some pathogenic to one species but not others some pathogenic to multiple species Each specific known genetic variation is traceable to a virus isolate of a specific case of infection Through antigenic drift H5N1 has mutated into dozens of highly pathogenic varieties divided into genetic clades which are known from specific isolates but all belong to genotype Z of avian influenza virus H5N1 now the dominant genotype 39 38 H5N1 isolates found in Hong Kong in 1997 and 2001 were not consistently transmitted efficiently among birds and did not cause significant disease in these animals In 2002 new isolates of H5N1 were appearing within the bird population of Hong Kong These new isolates caused acute disease including severe neurological dysfunction and death in ducks This was the first reported case of lethal influenza virus infection in wild aquatic birds since 1961 63 Genotype Z emerged in 2002 through reassortment from earlier highly pathogenic genotypes of H5N1 2 that first infected birds in China in 1996 and first infected humans in Hong Kong in 1997 38 39 64 Genotype Z is endemic in birds in Southeast Asia has created at least two clades that can infect humans and is spreading across the globe in bird populations Mutations occurring within this genotype are increasing their pathogenicity 65 Birds are also able to shed the virus for longer periods of time before their death increasing the transmissibility of the virus Transmission and host range Edit nbsp Transmission electron micrograph TEM of negatively stained Influenza A virus particles small and white attached to host cells large and irregular late passage Source Dr Erskine Palmer Centers for Disease Control and Prevention Public Health Image Library Infected birds transmit H5N1 through their saliva nasal secretions feces and blood Other animals may become infected with the virus through direct contact with these bodily fluids or through contact with surfaces contaminated with them H5N1 remains infectious after over 30 days at 0 C 32 F over one month at freezing temperature or 6 days at 37 C 99 F one week at human body temperature at ordinary temperatures it lasts in the environment for weeks In Arctic temperatures it does not degrade at all Because migratory birds are among the carriers of the highly pathogenic H5N1 virus it is spreading to all parts of the world H5N1 is different from all previously known highly pathogenic avian flu viruses in its ability to be spread by animals other than poultry In October 2004 researchers discovered H5N1 is far more dangerous than was previously believed Waterfowl were revealed to be directly spreading this highly pathogenic strain to chickens crows pigeons and other birds and the virus was increasing its ability to infect mammals as well From this point on avian flu experts increasingly referred to containment as a strategy that can delay but not ultimately prevent a future avian flu pandemic Since 1997 studies of influenza A H5N1 indicate that these viruses continue to evolve with changes in antigenicity and internal gene constellations an expanded host range in avian species and the ability to infect felids enhanced pathogenicity in experimentally infected mice and ferrets in which they cause systemic infections and increased environmental stability 66 The New York Times in an article on transmission of H5N1 through smuggled birds reports Wade Hagemeijer of Wetlands International stating We believe it is spread by both bird migration and trade but that trade particularly illegal trade is more important 67 On September 29 2007 researchers reported the H5N1 bird flu virus can also pass through a pregnant woman s placenta to infect the fetus They also found evidence of what doctors had long suspected the virus not only affects the lungs but also passes throughout the body into the gastrointestinal tract the brain liver and blood cells 68 Confirmed human cases and mortality rate of avian influenza H5N1 2003 2023 Country nbsp Azerbaijan nbsp Bangladesh nbsp Cambodia nbsp Canada nbsp Chile nbsp China nbsp Djibouti nbsp Ecuador nbsp Egypt nbsp India nbsp Indonesia nbsp Iraq nbsp Laos nbsp Myanmar nbsp Nepal nbsp Nigeria nbsp Pakistan nbsp Spain nbsp Thailand nbsp Turkey nbsp United Kingdom nbsp United States nbsp VietnamTotal2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 Totalcases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR cases deaths CFR8 5 62 5 8 5 62 5 1 0 0 2 0 0 3 0 0 1 1 100 1 0 0 8 1 12 5 4 4 100 2 2 100 1 1 100 1 0 0 1 0 0 1 1 100 8 8 100 3 3 100 26 14 53 8 9 4 44 4 56 37 66 1 1 1 100 1 1 100 1 69 0 0 1 0 0 1 1 100 8 5 62 5 13 8 61 5 5 3 60 0 4 4 100 7 4 57 1 2 1 50 0 1 1 100 2 1 50 0 2 2 100 2 0 0 6 1 16 7 1 1 100 54 32 59 3 1 0 0 1 0 0 1 0 0 1 0 0 18 10 55 6 25 9 36 0 8 4 50 0 39 4 10 3 29 13 44 8 39 15 38 5 11 5 45 5 4 3 75 0 37 14 37 8 136 39 28 7 10 3 30 0 3 1 33 3 359 120 33 4 1 1 100 1 1 100 20 13 65 0 55 45 81 8 42 37 88 1 24 20 83 3 21 19 90 5 9 7 77 8 12 10 83 3 9 9 100 3 3 100 2 2 100 2 2 100 1 1 100 200 168 84 0 3 2 66 6 3 2 66 6 2 2 100 1 0 0 3 2 66 7 1 0 0 1 0 0 1 1 100 1 1 100 1 1 100 1 1 100 3 1 33 3 3 1 33 3 2 0 0 2 0 0 17 12 70 6 5 2 40 0 3 3 100 25 17 68 0 12 4 33 3 12 4 33 3 1 0 0 1 0 0 1 0 0 1 0 0 3 3 100 29 20 69 0 61 19 31 1 8 5 62 5 6 5 83 3 5 5 100 7 2 28 6 4 2 50 0 2 1 50 0 2 2 100 1 0 0 128 64 50 0 4 4 100 46 32 69 6 98 43 43 9 115 79 68 7 88 59 67 0 44 33 75 0 73 32 43 8 48 24 50 0 62 34 54 8 32 20 62 5 39 25 64 1 52 22 42 3 145 42 29 0 10 3 30 0 4 2 50 0 0 0 0 1 1 100 1 0 0 2 1 50 0 6 1 16 7 1 0 0 870 457 52 5 Source World Health Organization Human Animal Interface edit this table In May 2013 North Korea confirmed a H5N1 bird flu outbreak that forced authorities to kill over 160 000 ducks in Pyongyang 70 Regional and global outbreaks Edit 2021 2022 outbreaks in Europe Atlantic flyway Edit Over the winter of 2021 and 2022 avian flu spread among the population of barnacle geese on the Solway Firth UK with estimates of up to a third of the Svalbard population being lost 71 72 pink footed geese were also affected there and it seems carried the virus to new sites in northern Scotland The disease was confirmed in sandwich terns in South Africa in April 2022 73 In late spring 2022 avian flu outbreaks affected many species of wild bird in the United Kingdom with heavy losses reported among seabirds returning to breed at colonies in the Northern Isles and Outer Hebrides 74 including great skuas bonxie for which outbreaks had initially been reported in 2021 75 Scotland hosts c 60 of the world s breeding population the 2022 census on St Kilda showed a 64 decline on 2019 with 106 dead birds recorded so far to 6 June 76 gannets 1000 birds reported dead at the Shetlands Hermaness colony alone 74 where there are around 26 000 breeding pairs with many more gannets being reported dead at other colonies Troup Head Bass Rock and St Kilda 77 the range of species also seems to be expanding with reports for many species of wildfowl seabirds auks terns and gulls and scavenging species corvids and raptors 78 79 Elsewhere in Europe the virus killed hundreds 574 of Dalmatian pelicans in Greece 80 81 and in Israel around 6000 common cranes were found dead at Hula in December 2021 82 A report by Scientific Task Force on Avian Influenza and Wild Birds on H5N1 Highly Pathogenic Avian Influenza in poultry and wild birds Winter of 2021 2022 with focus on mass mortality of wild birds in UK and Israel summarises the situation up to 24 January 2022 and mentions that H5N8 HPAI is still responsible for poultry and wild bird cases mainly in Asia H5N1 has now in effect replaced this subtype in Africa and Eurasia in both poultry and wild birds 83 2022 2023 global outbreaks Edit Main article 2020 2023 H5N1 outbreak Americas Edit Similar to 2021 reports outbreaks were noted from gannet colonies in Canada with thousands of birds dead in June 2022 84 as well as common eiders and great black backed gulls 85 Prior to that there were reports of spread in wild birds in over 30 states in the US including major mortalities in a double crested cormorant colony in Barrington Illinois 86 87 the virus also spreading to scavengers including three bald eagles in Georgia 88 Mass die offs of both birds and mammals were noted in Peru during the 2022 2023 season 89 In particular the Peruvian government reported the deaths of approximately 63 000 birds as well as 716 sea lions with the WHO noting that mammalian spillovers needed to be monitored closely 90 91 In the United States the 2022 2023 avian outbreak was the worst since H5N1 was first detected 90 Ecuador entered into a three month animal health emergency on 29 November 2022 just days after its first case was reported whereas Argentina and Uruguay both declared national sanitary emergencies on 15 February 2023 after their respective first cases were discovered 92 On 22 May 2023 Brazil as the world s largest exporter of chicken meat declared a 180 day emergency following several cases detected in wild birds and created an emergency operations center to plan for and mitigate potential further spread of H5N1 93 Europe Edit The 2022 2023 season was also the worst recorded outbreak in the United Kingdom with the British government requiring a so called poultry lockdown which required that farmers keep their birds indoors 90 Meanwhile an outbreak of H5N1 on a Spanish mink farm led researchers to believe that they had observed the first case of mammal to mammal transmission of H5N1 94 Mammalian infections Edit Main article List of mammals that can get H5N1 H5N1 transmission studies in ferrets 2011 Edit Novel contagious strains of H5N1 were created by Ron Fouchier of the Erasmus Medical Center in Rotterdam the Netherlands who first presented his work to the public at an influenza conference in Malta in September 2011 Three mutations were introduced into the H5N1 virus genome and the virus was then passed from the noses of infected ferrets to the noses of uninfected ones which was repeated 10 times 95 After these 10 passages the H5N1 virus had acquired the ability of transmission between ferrets via aerosols or respiratory droplets After Fouchier offered an article describing this work to the leading academic journal Science the US National Science Advisory Board for Biosecurity NSABB recommended against publication of the full details of the study and the one submitted to Nature by Yoshihiro Kawaoka of the University of Wisconsin describing related work However after additional consultations at the World Health Organization and by the NSABB the NSABB reversed its position and recommended publication of revised versions of the two papers 96 However then the Dutch government declared that this type of manuscripts required Fouchier to apply for an export permit in the light of EU directive 428 2009 on dual use goods note 1 After much controversy surrounding the publishing of his research Fouchier complied under formal protest with Dutch government demands to obtain a special permit 97 for submitting his manuscript and his research appeared in a special issue of the journal Science devoted to H5N1 98 99 100 The papers by Fouchier and Kawaoka conclude that it is entirely possible that a natural chain of mutations could lead to an H5N1 virus acquiring the capability of airborne transmission between mammals and that a H5N1 influenza pandemic would not be impossible 101 In May 2013 it was reported that scientists at the Harbin Veterinary Research Institute in Harbin China had created H5N1 strains which passed between guinea pigs 102 In response to Fouchier and Kawaoka s work a number of scientists expressed concerns with the risks of creating novel potential pandemic pathogens culminating in the formation of the Cambridge Working Group a consensus statement calling for an assessment of the risks and benefits of such research 103 104 Mammal to mammal transmission 2022 2023 Edit Although mammals including humans had become infected with H5N1 bird flu strains in the past these cases had ostensibly been caused by direct exposure to infected birds such as through consumption of birds by wildlife or exposure to infected poultry by farmers In contrast the October 2022 mammalian outbreak of H5N1 on a Spanish mink farm showed evidence of being the first recorded case of mammal to mammal transmission with 4 percent of the farm s mink population dying from H5N1 related haemorrhagic pneumonia 94 105 The mink respiratory tract is particularly well suited to act as a pathway of viral transmission into humans which has concerned public health professionals due to the production of all but one approved human vaccine requiring the eggs of chickens which H5N1 kills at a 90 100 percent fatality rate 106 Infected mink in Spain were also found to have exhibited the PB2 viral mutation found when H5N1 jumped into pigs over a decade prior adding to fears that farms could be acting as incubators and or reservoirs of the virus similar to the role of minks in SARS CoV 2 94 As of January 2023 fifteen species of wild and captive mammals had become infected with H5N1 throughout the United States 107 A mass Caspian seal die off in December 2022 with 700 infected seals found dead along the Caspian Sea coastline of Russia s Dagestan republic worried researchers regarding the possibility that wild mammal to mammal spread had begun 108 Human infections Edit As of May 2020 the WHO reported a total of 861 confirmed human cases which resulted in the deaths of 455 people since 2003 5 Human to human transmission Edit Main article 2020 2023 H5N1 outbreak Cambodia 2023 Edit Following the February 2023 H5N1 death of an 11 year old girl from Cambodia s Prey Veng province her father was confirmed positive for the virus and several close contacts also began showing signs of infection On 24 February 2023 the WHO expressed concern that the virus had potentially begun to spread among humans and ordered the production of a new human vaccine for H5N1 109 Following the confirmed infections the WHO began working with the Cambodian government to determine whether both individuals had gotten the virus directly from infected poultry or if it had indeed been a case of human to human transmission 110 Further sequencing determined that at least one of the two cases was from an older H5N1 clade 2 3 2 1c which had circulated as a common H5N1 strain in Cambodia for many years rather than the more recent clade 2 3 4 4b which had caused mass poultry deaths since 2020 This older clade had jumped to humans in the past yet hadn t previously resulted in any known human to human transmission 111 On March 1 2023 as Taiwan raised its travel alert for Cambodia the WHO and the U S CDC in concert with Cambodian authorities determined that both of the individuals had been infected through direct contact with poultry 112 113 Society and culture EditMain article Social impact of H5N1 H5N1 has had a significant effect on human society especially the financial political social and personal responses to both actual and predicted deaths in birds humans and other animals Billions of dollars are being raised and spent to research H5N1 and prepare for a potential avian influenza pandemic Over 10 billion have been spent and over 200 million birds have been killed to try to contain H5N1 13 114 115 116 117 118 119 120 121 People have reacted by buying less chicken causing poultry sales and prices to fall 122 Many individuals have stockpiled supplies for a possible flu pandemic International health officials and other experts have pointed out that many unknown questions still hover around the disease 123 Dr David Nabarro Chief Avian Flu Coordinator for the United Nations and former Chief of Crisis Response for the World Health Organization has described himself as quite scared about H5N1 s potential impact on humans Nabarro has been accused of being alarmist before and on his first day in his role for the United Nations he proclaimed the avian flu could kill 150 million people In an interview with the International Herald Tribune Nabarro compares avian flu to AIDS in Africa warning that underestimations led to inappropriate focus for research and intervention 124 In February 2020 an outbreak of H5N1 avian flu occurred in Shuangqing District of Shaoyang City in the Hunan province After poultry had become ill from the virus the city killed close to 18 000 chickens to prevent the spread of the illness Hunan borders Hubei province where Wuhan is located the epicenter of the coronavirus pandemic 125 See also EditAntigenic shift Avian influenza virus Favipiravir Fujian flu H5N1 clinical trials H7N9 Influenza research Influenzavirus A International Conference on Emerging Infectious Diseases National Influenza Centers Swine influenza ZoonosisNotes Edit The World Intellectual Property Organization WIPO lists strategic goods with prohibited goods or goods that require a special permit for import and export without which the carrier faces pecuniary punishment or up to 5 years imprisonment References EditCitations Edit International Committee on Taxonomy of Viruses 2002 46 0 1 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