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Influenza A virus subtype H5N1

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Influenza A virus subtype H5N1, also known as A(H5N1) or H5N1, is a subtype of the Influenza A virus that is capable of causing illness in many species, including humans.[1] An avian-adapted, highly pathogenic strain of H5N1 (called HPAI A(H5N1), for "highly pathogenic avian influenza virus of type A of subtype H5N1") is the causative agent of H5N1 flu, commonly known as "avian influenza" or simply "bird flu", and is endemic in many bird populations, especially in Southeast Asia.

An Asian lineage strain of HPAI A(H5N1) is spreading globally. It is epizootic (an epidemic in nonhumans) and panzootic (a disease 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 other birds in an attempt to control its spread. Most references in the media to "bird flu" and most references to H5N1 are about this specific strain.[2]

HPAI A(H5N1) is an avian disease and there is no evidence suggesting either efficient human-to-human transmission of HPAI A(H5N1) or of airborne transmission of HPAI A(H5N1) to humans. Those infected with H5N1 have had, in almost all cases, extensive physical contact with infected birds. However, H5N1 has the potential to mutate or reassort into a strain capable of efficient human-to-human transmission. Due to the high lethality and virulence of human HPAI A(H5N1) infection to date, its endemic presence, its large and increasing biological host reservoir, and its significant ongoing mutations, the H5N1 virus is today the world's major current pandemic threat, and billions of dollars are being raised and spent researching H5N1 and preparing for a potential influenza pandemic.[3]

In 2003, world-renowned virologist Robert 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 calling for adequate resources to fight what he saw as a major world threat to possibly billions of lives. [4] 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.[5] 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 a pandemic flu virus, and many of those key events have occurred more rapidly than expected.

Genetics

Template:Mainarticles 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 current highly pathogenic strain of H5N1. The dominant strain of HPAI A(H5N1) in 2004 evolved from 1999 to 2002 creating the Z genotype.[6] It has also been called "Asian lineage HPAI A(H5N1)".

Terminology

Influenza A virus, the virus that causes Avian flu. Transmission electron micrograph of negatively stained virus particles in late passage. (Source: Dr. Erskine Palmer, Centers for Disease Control and Prevention Public Health Image Library)

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

  • A stands for the species of influenza (A, B or C).
  • chicken is the species the isolate was found in
  • Nakorn-Patom/Thailand is the place this specific virus was isolated
  • CU-K2/04 is the identifier distinguishing it from other isolates at the place of the specimen it was isolated from with 04 representing the year 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: 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)).[7]

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 current strain of H5N1 responsible for the deaths of birds across the world is an HPAI strain; all other current 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 non-poultry birds. This current deadly strain of H5N1 is unusual in being deadly to so many species.

Genetic structure and related subtypes

H5N1 is a subtype of the species Influenza A virus of the Influenzavirus A genus of the Orthomyxoviridae family. It is a virus, a type of microscopic intracellular parasite that infects cells in biological organisms. 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, M and NS.

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.[8]

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 "Spanish Flu" and currently causes seasonal human flu
  • H2N2, which caused "Asian Flu"
  • H3N2, which caused "Hong Kong Flu" and currently causes seasonal human flu
  • H5N1, the world's major current pandemic threat
  • H7N7, which has unusual zoonotic potential and killed one person
  • H1N2, which is currently 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

Properties of H5N1

Template:Mainarticles

Infectivity

Highly pathogenic H5N1
Highly pathogenic H5N1
Highly pathogenic H5N1
 →  Countries with poultry or wild birds killed by H5N1.
 →  Countries with humans, poultry and wild birds killed by H5N1.

H5N1 is easily transmissible between birds facilitating a potential global spread of H5N1. While H5N1 undergoes specific mutations and reassorting creating variations which infect species not previously known to carry the virus, not all of these variant forms can infect humans. H5N1, as an avian virus preferentially bind to what are known as α2,3 galactose receptors, which populate the avian respiratory tract from the nose to the lungs. These receptors 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.[9][10][11]

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 themselves becoming sick.[12][13] 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.[14]

Virulence

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 currently belonging to genotype Z of avian influenza virus H5N1, now the dominant genotype.[15][16] 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 apperaring 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.[17] 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.[18][15][16] 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 are occurring within this genotype that are increasing their pathogenicity.[19] 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

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 ( 32.0 °F) (over one month at freezing temperature) or 6 days at 37 °C ( 98.6 °F) (one week at human body temperature) so at ordinary temperatures it lasts in the environment for weeks. In arctic temperatures, it doesn't 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 that H5N1 is far more dangerous than previously believed. Waterfowl were revealed to be directly spreading the highly pathogenic strain of H5N1 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".[20]

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".[21]

High mutation rate

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The segmentation of the influenza genome facilitates genetic recombination by segment reassortment in hosts who are infected with two different influenza viruses at the same time.[15][16] H5N1 viruses can reassort genes with other strains that co-infect a host organism, such as a pig, bird, or human, and mutate into a form that can pass easily among humans. This is one of many possible paths to a pandemic.

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.[22] 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.

H3N2 ("swine flu") 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 flu 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".[6]

Humans and H5N1

The early infections of humans by H5N1 coincided with an epizootic (an epidemic in nonhumans) of H5N1 influenza in Hong Kong's poultry population. 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.


Confirmed human cases and mortality rate of avian influenza (H5N1) 2003–2024
Country
 Australia
 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 2024 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
cases
deaths
CFR
1 0 0% 1 0 0%
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% 6 4 66.7% 5 1 20.0% 67 42 62.7%
1 1 100% 1 1 100%
1[23] 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% 1 0 0% 55 32 58.2%
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% 4 0 0% 5 0 0%
1 0 0% 3 0 0% 4 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% 1 1 100% 129 65 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% 12 4 33.3% 10 2 20.0% 892 463 51.9%


Symptoms in humans

Avian influenza HA bind alpha 2-3 sialic acid receptors while human influenza HA bind alpha 2-6 sialic acid receptors. Usually other differences also exist. There is as yet no human form of H5N1, so all humans who have caught it so far have caught avian H5N1.

Humans who catch a humanized Influenza A virus (in other words a human flu virus of type A) usually have symptoms that include fever, cough, sore throat, muscle aches, conjunctivitis and, in severe cases, severe breathing problems and pneumonia that may be fatal. The severity of the infection will depend to a large part on the state of the infected person's immune system and if the victim has been exposed to the strain before, and is therefore partially immune. No one knows if these or other symptoms will be the symptoms of a humanized H5N1 flu.

Highly pathogenic H5N1 avian flu in a human is far worse, killing 50% of humans that catch it. In one case, a boy with H5N1 experienced diarrhea followed rapidly by a coma without developing respiratory or flu-like symptoms.[24] 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 (TNFα), a protein that is 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.[4] 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 type flu virus induces higher levels of cytokines than the more common flu virus types such as H1N1.[25]

Treatment and prevention for humans

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 be seen as making preparations for a possible H5N1 pandemic.[26] On April 20, 2006, Roche AG announced that a stockpile of three million treatment courses of Tamiflu is 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 that lack the ability to purchase large quantities of the drug.[27]

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".[28]

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. Dr. Daniel 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".[29] 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.[30][31][32] 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.

Preparations for 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".[33]

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".[33]

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.[34]

Impact on human society

There has been a huge impact of H5N1 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 U.S. dollars are being raised and spent to research H5N1 and prepare for a potential avian flu pandemic. Over ten billion dollars have been lost and over two hundred million birds have been killed to try to contain H5N1.

This, like everything else, is subject to political spin; wherein every interest group picks and chooses among the facts to support their favorite cause resulting in a distortion of the overall picture, the motivations of the people involved and the believability of the predictions.

People have reacted by buying less chicken causing poultry sales and prices to fall. Many individuals have stockpiled supplies for a possible flu pandemic.

See also

Notes and references

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  2. ^ a b Li KS, Guan Y, Wang J, Smith GJ, Xu KM, Duan L, Rahardjo AP, Puthavathana P, Buranathai C, Nguyen TD, Estoepangestie AT, Chaisingh A, Auewarakul P, Long HT, Hanh NT, Webby RJ, Poon LL, Chen H, Shortridge KF, Yuen KY, Webster RG, Peiris JS. (2004). "Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia". Nature. 430 (6996): 209–213. PMID 15241415doi:10.1038/nature02746.{{cite journal}}: CS1 maint: multiple names: authors list (link)
    This was reprinted in 2005:
    Li KS, Guan Y, Wang J, Smith GJ, Xu KM, Duan L, Rahardjo AP, Puthavathana P, Buranathai C, Nguyen TD, Estoepangestie AT, Chaisingh A, Auewarakul P, Long HT, Hanh NT, Webby RJ, Poon LL, Chen H, Shortridge KF, Yuen KY, Webster RG, Peiris JS. (2005). "Today's Pandemic Threat: Genesis of a Highly Pathogenic and Potentially Pandemic H5N1 Influenza Virus in Eastern Asia,". In Forum on Microbial Threats Board on Global Health: Knobler SL, Mack A, Mahmoud A, Lemon SM. (ed.) (ed.). The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005). Washington DC: The National Academies Press. pp. 116–130. {{cite book}}: |editor= has generic name (help); External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help)CS1 maint: multiple names: authors list (link)
  3. ^ Rosenthal, E. and Bradsher, K. (2006-03-16). "Is Business Ready for a Flu Pandemic?". The New York Times. Retrieved 2006-04-17. {{cite news}}: Check date values in: |date= (help)CS1 maint: multiple names: authors list (link)
  4. ^ a b Webster, R. G. and Walker, E. J. (2003). "The world is teetering on the edge of a pandemic that could kill a large fraction of the human population". American Scientist. 91 (2): 122. doi:10.1511/2003.2.122.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "webster" was defined multiple times with different content (see the help page).
  5. ^ United Nations (2005-09-29). "Press Conference by UN System Senior Coordinator for Avian, Human Influenza". UN News and Media Division, Department of Public Information, New York. Retrieved 2006-04-17. {{cite news}}: Check date values in: |date= (help)
  6. ^ a b Harder, T. C. and Werner, O. (2006). "Avian Influenza". In Kamps, B. S., Hoffman, C. and Preiser, W. (ed.) (ed.). Influenza Report 2006. Paris, France: Flying Publisher. ISBN 392477451X. {{cite book}}: |access-date= requires |url= (help); |editor= has generic name (help); External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help)CS1 maint: multiple names: authors list (link)
    This e-book is under constant revision and is an excellent guide to Avian Influenza
  7. ^ Payungporn S, Chutinimitkul S, Chaisingh A, Damrongwantanapokin S, Nuansrichay B, Pinyochon W, Amonsin A, Donis RO, Theamboonlers A, Poovorawan T. (2006). "Discrimination between Highly Pathogenic and Low Pathogenic H5 Avian Influenza A Viruses". Emerging Infectious Diseases. 12 (4).{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Couch, R. (1996). "Chapter 58. Orthomyxoviruses Multiplication". In Baron, S. (ed.) (ed.). Medical Microbiology. Galveston, Texas: The University of Texas Medical Branch at Galveston. ISBN 0963117211. {{cite book}}: |editor= has generic name (help); External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help)
  9. ^ Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. (2006). "Avian flu: influenza virus receptors in the human airway". Nature. 440 (7083): 435–436. {{cite journal}}: Text "PMID 16554799" ignored (help); Text "doi:10.1126/science.1125548" ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, Osterhaus AD, Kuiken T. (2006). "H5N1 Virus Attachment to Lower Respiratory Tract". Science (Epub ahead of print). {{cite journal}}: Text "PMID 16556800" ignored (help); Text "doi:10.1126/science.1125548" ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Forbes.com (2006-03-22). "Studies Spot Obstacle to Human Transmission of Bird Flu". Retrieved 2006-04-18. {{cite web}}: Check date values in: |year= (help)
  12. ^ Food and Agricultural Organization of the United Nations (2005). "Wild birds and Avian Influenza". Retrieved 2006-04-18.
  13. ^ Brstilo M. (2006-01-19). "Highly Pathogenic Avian Influenza in Croatia Follow-up report No. 4". Retrieved 2006-04-18. {{cite web}}: Check date values in: |year= (help)
  14. ^ European Food Safety Authority (2006-04-04). "Scientific Statement on Migratory birds and their possible role in the spread of highly pathogenic avian influenza" (PDF format). Retrieved 2006-04-18. {{cite web}}: Check date values in: |year= (help)
  15. ^ a b c The World Health Organization Global Influenza Program Surveillance Network. (2005). "Evolution of H5N1 avian influenza viruses in Asia". Emerging Infectious Diseases. 11 (10).
    Figure 1 shows a diagramatic representation of the genetic relatedness of Asian H5N1 hemagglutinin genes from various isolates of the virus
  16. ^ a b c Kou Z, Lei FM, Yu J, Fan ZJ, Yin ZH, Jia CX, Xiong KJ, Sun YH, Zhang XW, Wu XM, Gao XB, Li TX. (2005). "New genotype of avian influenza H5N1 viruses isolated from tree sparrows in China". J. Virol. 79 (24): 15460–15466. {{cite journal}}: Text "PMID 16306617" ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Sturm-Ramirez KM, Ellis T, Bousfield B, Bissett L, Dyrting K, Rehg JE, Poon L, Guan Y, Peiris M, Webster RG. (2004). "Reemerging H5N1 influenza viruses in Hong Kong in 2002 are highly pathogenic to ducks". J. Virol. 78 (9): 4892–4901. {{cite journal}}: Text "PMID 15078970" ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ World Health Organization (2005-10-28). "H5N1 avian influenza: timeline" (PDF format). Retrieved 2006-04-18. {{cite web}}: Check date values in: |year= (help)
  19. ^ Chen H, Deng G, Li Z, Tian G, Li Y, Jiao P, Zhang L, Liu Z, Webster RG, Yu K. (2004). "The evolution of H5N1 influenza viruses in ducks in southern China". Proc. Natl. Acad. Sci. U. S. A. 101 (28): 10452–10457. PMID 15235128.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  27. ^ Associated Press, "Tamiflu is Set Aside for WHO," The Wall Street Journal, April 20, 2006, page D6.
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  29. ^ Schultz, J. (2005-11-28). "Bird flu vaccine won't precede pandemic". United Press International. Retrieved 2006-04-18. {{cite news}}: Check date values in: |date= (help)
  30. ^ Enserick, M. (2005-08-12). "Avian Influenza:'Pandemic Vaccine' Appears to Protect Only at High Doses". Science. doi:10.1511/2003.2.122. Retrieved 2006-04-18. {{cite news}}: Check date values in: |date= (help)
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  34. ^ United States Department of Health and Human Services (2002). "Pandemicflu.gov Monitoring outbreaks". Retrieved 2006-04-18.

Further reading

Official - international
Official - United States
  • PandemicFlu.Gov U.S. Government's avian flu information site
  • USAID U.S. Agency for International Development - Avian Influenza Response
  • CDC Centers for Disease Control - responsible agency for avian influenza in humans in US - Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus
  • USGS - NWHC National Wildlife Health Center - responsible agency for avian influenza in animals in US
  • HHS U.S. Department of Health & Human Services - Pandemic Influenza Plan
Official - United Kingdom
Technical

Please see H5N1 genetic structure.

News and General information

Please see Global spread of H5N1.