Influenza A virus subtype H5N1


Influenza A virus subtype H5N1

Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species.

cite web
author=International Committee on Taxonomy of Viruses | publisher= | year=2002 | url=http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/46010000.htm | title=46.0.1. Influenzavirus A | accessdate=2006-04-17

] A bird-adapted 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 "bird flu". It is enzootic 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. Most references to "bird flu" and H5N1 in the popular media refer to this strain.

cite journal
author=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. | title=Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia | journal=Nature | year=2004 | pages=209–213 | volume=430 | issue=6996 | pmid=15241415DOI|10.1038/nature02746
doi=10.1038/nature02746
This was reprinted in 2005:

cite book
author =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.
year = 2005
title = The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005)
chapter = Today's Pandemic Threat: Genesis of a Highly Pathogenic and Potentially Pandemic H5N1 Influenza Virus in Eastern Asia,
chapterurl = http://darwin.nap.edu/books/0309095042/html/116.html
editor = Forum on Microbial Threats Board on Global Health: Knobler SL, Mack A, Mahmoud A, Lemon SM. (ed.)
pages = 116–130
publisher = The National Academies Press
location = Washington DC

]

As of the July 25, 2008 FAO Avian Influenza Disease Emergency Situation Update, H5N1 pathogenicity is continuing to gradually rise in wild birds in endemic areas but the avian influenza disease situation in farmed birds is being held in check by vaccination. 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 can be said to haveimproved markedly in the first half of 2008 [but] cases of HPAI are still underestimated and underreported in many countries because of limitations in country disease surveillance systems". [ [http://www.fao.org/docs/eims/upload//246457/aj097e00.pdf July 25, 2008 FAO Avian Influenza Disease Emergency Situation Update] ]

Overview

HPAI A(H5N1) is an avian disease. There is some evidence of limited human-to-human transmission of the virus. [cite journal |author=Ungchusak K, Auewarakul P, Dowell SF, "et al" |title=Probable person-to-person transmission of avian influenza A (H5N1) |journal=N Engl J Med |volume=352 |issue=4 |pages=333–40 |year=2005 |month=January |pmid=15668219 |doi=10.1056/NEJMoa044021 |url=] A risk factor for contracting the virus is handling of infected poultry, but transmission of the virus from infected birds to humans is inefficient. [cite journal |author=Ortiz JR, Katz MA, Mahmoud MN, "et al" |title=Lack of evidence of avian-to-human transmission of avian influenza A (H5N1) virus among poultry workers, Kano, Nigeria, 2006 |journal=J Infect Dis |volume=196 |issue=11 |pages=1685–91 |year=2007 |month=December |pmid=18008254 |doi=10.1086/522158 |url=] Still, around 60% of humans known to have been infected with the current 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, 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". He called for adequate resources to fight what he sees as a major world threat to possibly billions of lives.

cite journal
author=Webster, R. G. and Walker, E. J. | title=The world is teetering on the edge of a pandemic that could kill a large fraction of the human population | journal=American Scientist | year=2003 | pages=122 | volume=91 | issue=2 |url=http://www.americanscientist.org/template/AssetDetail/assetid/17221?fulltext=true | doi=10.1511/2003.2.122

] 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.

cite news
author=United Nations
url=http://www.un.org/News/briefings/docs/2005/050929_Nabarro.doc.htm
title=Press Conference by UN System Senior Coordinator for Avian, Human Influenza
publisher=UN News and Media Division, Department of Public Information, New York
date=2005-09-29
accessdate=2006-04-17
] 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.

Due to the high lethality and virulence of HPAI A(H5N1), its endemic presence, its increasingly large host reservoir, and its significant ongoing mutations, the H5N1 virus is the world's largest current pandemic threat, and billions of dollars are being spent researching H5N1 and preparing for a potential influenza pandemic.

cite news
author=Rosenthal, E. and Bradsher, K.
url=http://www.nytimes.com/2006/03/16/business/16bird.html?_r=1&oref=slogin
title=Is Business Ready for a Flu Pandemic?
publisher=The New York Times
date=2006-03-16
accessdate=2006-04-17
] At least 12 companies and 17 governments are developing pre-pandemic 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. [ [http://www.scidev.net/gateways/index.cfm?fuseaction=readitem&rgwid=2&item=Features&itemid=515&language=1 Science and Development Network] article "Pandemic flu: fighting an enemy that is yet to exist" published May 3, 2006.]

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. [ cite journal
url=http://content.nejm.org/cgi/content/full/355/21/2174
title=H5N1 Influenza — Continuing Evolution and Spread
author= Robert G. Webster, Ph.D., and Elena A. Govorkova, M.D., Ph.D.
journal=NEJM
volume=355
pages=2174–2177
date=November 23, 2006
issue=21
doi=10.1056/NEJMp068205
pmid=17124014
] Influenza pandemics from its genetic offspring may include influenza A virus subtypes other than H5N1. [ [http://www.cdc.gov/ncidod/EID/vol12no01/05-0979.htm CDC] ARTICLE "1918 Influenza: the Mother of All Pandemics" by Jeffery K. Taubenberger published January 2006] 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, [http://www.informaworld.com/smpp/1150732152-62988796/content~content=a768149644~db=all~order=page Informaworld] article "Why is the world so poorly prepared for a pandemic of hypervirulent avian influenza?" published December 2006] 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. [ cite web | url=http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/feb0107pandemic.html|accessdate=2007-02-03|date=February 1, 2007|last=Roos|first=Robert|coauthors=Lisa Schnirring|title=HHS ties pandemic mitigation advice to severity|publisher=University of Minnesota Center for Infectious Disease Research and Policy (CIDRAP)]

Genetics

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.

cite book
author =Harder, T. C. and Werner, O.
year = 2006
title = Influenza Report 2006
chapter = Avian Influenza
chapterurl = http://www.influenzareport.com/ir/ai.htm
editor = Kamps, B. S., Hoffman, C. and Preiser, W. (ed.)
edition =
pages =
publisher = Flying Publisher
location = Paris, France
id = ISBN 3-924774-51-X
accessdate=2006-04-18

] 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: [http://content.nejm.org/content/vol355/issue21/images/large/03f1.jpeg Map]
* Subclade 1, Indonesia
* Subclade 2, Europe, Middle East, and Africa (called EMA)
* Subclade 3, China" [ cite journal
url=http://content.nejm.org/cgi/content/full/355/21/2174
title=H5N1 Influenza — Continuing Evolution and Spread
author= Robert G. Webster, Ph.D., and Elena A. Govorkova, M.D., Ph.D.
journal=NEJM
volume=355
pages=2174–2177
date=November 23, 2006
issue=21
doi=10.1056/NEJMp068205
pmid=17124014
] [ cite web
url=http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/aug1806vaccines.html
publisher=CIDRAP
title=WHO changes H5N1 strains for pandemic vaccines, raising concern over virus evolution
date=August 18, 2006
] [cite web
url=http://www.who.int/csr/disease/avian_influenza/guidelines/recommendationvaccine.pdf
publisher=WHO
title=Antigenic and genetic characteristics of H5N1 viruses and candidate H5N1 vaccine viruses developed for potential use as pre-pandemic vaccines
date=August 18, 2006
]

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." [ [http://www.cdc.gov/eid/content/13/5/713.htm CDC] article "Genome Analysis Linking Recent European and African Influenza (H5N1) Viruses" EID Journal Home > Volume 13, Number 5–May 2007 Volume 13, Number 5–May 2007]

Terminology

H5N1 isolates are identified like 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 identifies it from other influenza viruses isolated at the same place
*04 represents 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)).

cite journal
author=Payungporn S, Chutinimitkul S, Chaisingh A, Damrongwantanapokin S, Nuansrichay B, Pinyochon W, Amonsin A, Donis RO, Theamboonlers A, Poovorawan T. | title=Discrimination between Highly Pathogenic and Low Pathogenic H5 Avian Influenza A Viruses | journal=Emerging Infectious Diseases | year=2006 | volume=12 | issue=4 | url=http://www.cdc.gov/ncidod/EID/vol12no04/05-1427.htm

]

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, including some, like domestic cats, never previously susceptible to any influenza virus.

Genetic structure and related subtypes

H5N1 is a subtype of the species "Influenza A virus" of the "Influenzavirus A" genus of the "Orthomyxoviridae" family. 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.

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.

cite book
author =Couch, R.
year = 1996
title = Medical Microbiology
chapter =Chapter 58. Orthomyxoviruses Multiplication
chapterurl = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.3069
editor = Baron, S. (ed.)
edition =
pages =
publisher = The University of Texas Medical Branch at Galveston
location = Galveston, Texas
id = ISBN 0-9631172-1-1

] 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

Low pathogenic H5N1

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.

* 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.

"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." [cite news
url=http://www.usda.gov/wps/portal/!ut/p/_s.7_0_A/7_0_1OB?contentidonly=true&contentid=2006/08/0296.xml
publisher=USDA
title=AVIAN INFLUENZA Low Pathogenic H5N1 vs. Highly Pathogenic H5N1 - Latest UPDATE
date=August 17, 2006
]

Properties of H5N1

Infectivity

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.

cite journal
author=Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. | title=Avian flu: influenza virus receptors in the human airway | journal=Nature | year=2006 | pages=435–436 | volume=440 | issue=7083 | pmid=16554799 | doi=10.1126/science.1125548

]

cite journal
author=van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, Osterhaus AD, Kuiken T. | title=H5N1 Virus Attachment to Lower Respiratory Tract | journal=Science | year=2006

pages=399| volume= 312| issue=Epub ahead of print | pmid=16556800 | doi=10.1126/science.1125548]

cite web
author=Forbes.com | year=2006-03-22 | url=http://www.forbes.com/lifestyle/health/feeds/hscout/2006/03/22/hscout531699.html | title=Studies Spot Obstacle to Human Transmission of Bird Flu | accessdate=2006-04-18

]

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.

cite web
author=Food and Agricultural Organization of the United Nations | year=2005 | url=http://www.fao.org/ag/againfo/subjects/en/health/diseases-cards/avian_HPAIrisk.html | title=Wild birds and Avian Influenza | accessdate=2006-04-18

]

cite web
author=Brstilo M. | year=2006-01-19 | url=http://www.oie.int/eng/info/hebdo/AIS_35.HTM#Sec14 | title=Highly Pathogenic Avian Influenza in Croatia Follow-up report No. 4 | accessdate=2006-04-18

] 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.

cite web
author=European Food Safety Authority | year=2006-04-04 | url=http://www.efsa.eu.int/science/ahaw/ahaw_opinions/1438/ahaw_ai_statement_19th_plenmeet1.pdf | title=Scientific Statement on Migratory birds and their possible role in the spread of highly pathogenic avian influenza|format=PDF format | accessdate=2006-04-18

]

According to a report by the World Health Organization, H5N1 may be spread indirectly. The report stated that the virus may sometimes stick to surfaces or get kicked up in fertilizer dust to infect people. [cite web
title =Bird flu may be spread indirectly, WHO says
work =Reuters
publisher =Yahoo! News
date =2008-01-17
url =http://news.yahoo.com/s/nm/20080117/hl_nm/birdflu_origin_dc
accessdate =2008-01-17
]

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.

cite journal
author=The World Health Organization Global Influenza Program Surveillance Network. | title=Evolution of H5N1 avian influenza viruses in Asia | journal=Emerging Infectious Diseases | year=2005 | volume=11 | issue=10 | url=http://www.cdc.gov/ncidod/EID/vol11no10/05-0644.htm

"Figure 1 shows a diagramatic representation of the genetic relatedness of Asian H5N1 hemagglutinin genes from various isolates of the virus"]

cite journal
author=Kou Z, Lei FM, Yu J, Fan ZJ, Yin ZH, Jia CX, Xiong KJ, Sun YH, Zhang XW, Wu XM, Gao XB, Li TX. | title=New genotype of avian influenza H5N1 viruses isolated from tree sparrows in China | journal=J. Virol. | year=2005 | pages=15460–15466 | volume=79 | issue=24 | pmid=16306617

doi=10.1128/JVI.79.24.15460-15466.2005] 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.

cite journal
author=Sturm-Ramirez KM, Ellis T, Bousfield B, Bissett L, Dyrting K, Rehg JE, Poon L, Guan Y, Peiris M, Webster RG. | title=Reemerging H5N1 influenza viruses in Hong Kong in 2002 are highly pathogenic to ducks | journal=J. Virol. | year=2004 | pages=4892–4901 | volume=78 | issue=9 | pmid=15078970

doi=10.1128/JVI.78.9.4892-4901.2004] Genotype Z emerged in 2002 through reassortment from earlier highly pathogenic genotypes of H5N1 that first infected birds in China in 1996, and first infected humans in Hong Kong in 1997.

cite web
author=World Health Organization | year=2005-10-28 | url=http://www.who.int/csr/disease/avian_influenza/Timeline_28_10a.pdf | title=H5N1 avian influenza: timeline |format=PDF format | accessdate=2006-04-18

] 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.

cite journal
author=Chen H, Deng G, Li Z, Tian G, Li Y, Jiao P, Zhang L, Liu Z, Webster RG, Yu K. | title=The evolution of H5N1 influenza viruses in ducks in southern China | journal=Proc. Natl. Acad. Sci. U. S. A. | year=2004 | pages=10452–10457 | volume=101 | issue=28 | pmid=15235128

doi=10.1073/pnas.0403212101] 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 was 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."

cite journal
author=Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, Lochindarat S, Nguyen TK, Nguyen TH, Tran TH, Nicoll A, Touch S, Yuen KY; Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. | title=Avian influenza A (H5N1) infection in humans | journal=N. Engl. J. Med. | year=2005 | pages=1374–1385 | volume=353 | issue=13 | pmid=16192482 | doi=10.1056/NEJMra052211

]

"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".

cite news
author=Rosenthal, E.
url=http://www.nytimes.com/2006/04/15/world/europe/15bird.html?_r=1&th&emc=th&oref=slogin
title=Bird Flu Virus May Be Spread by Smuggling
publisher=The New York Times
date=2006-04-15
accessdate=2006-04-18
]

The H5N1 bird flu virus can also pass through a pregnant woman's placenta to infect the fetus, researchers reported on Thursday 27 September 2007.They also found evidence of what doctors had long suspected -- that the virus not only affects the lungs, but also passes throughout the body into the gastrointestinal tract, the brain, liver, and blood cells. [ [http://www.pandemic.org.au/alertDetail.php?id=000100 Pandemic.org.au, H5N1 Transmission Update] ]

High mutation rate

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 influenza viruses at the same time. A previously uncontagious strain may then be able to pass between humans, one of several 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.

cite journal
author=Gambaryan A, Tuzikov A, Pazynina G, Bovin N, Balish A, Klimov A. | title=Fatal Evolution of the receptor binding phenotype of influenza A (H5) viruses | journal=Virology | year=2006 | pages=432–438 | volume=344 | issue=2 | pmid=16226289

doi=10.1016/j.virol.2005.08.035] 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 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".

cite book
author =Harder, T. C. and Werner, O.
year = 2006
title = Influenza Report 2006
chapter = Avian Influenza
chapterurl = http://www.influenzareport.com/ir/ai.htm
editor = Kamps, B. S., Hoffman, C. and Preiser, W. (ed.)
edition =
pages =
publisher = Flying Publisher
location = Paris, France
id = ISBN 3-924774-51-X
accessdate=2006-04-18

"This e-book is under constant revision and is an excellent guide to Avian Influenza"]

Humans and 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. 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.

ymptoms in humans

Avian influenza hemagglutinin bind alpha 2-3 sialic acid receptors while human influenza hemagglutinin 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.

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. The severity of the infection depends to a large part on the state of the infected person's immune system and whether the victim has 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 reported mortality rate of highly pathogenic H5N1 avian influenza in a human is high; WHO data indicates that 60% of cases classified as H5N1 resulted in death. However, there is some evidence that the actual mortality rate of avian flu could be much lower, as there may be many people with a milder symptoms who do not seek treatment and are not counted.

cite journal
author= Leslie Taylor | title=Overestimating Avian Flu | journal=Seed Magazine | year=2006 | url=http://seedmagazine.com/news/2006/01/overestimating_avian_flu.php

]

cite journal
author= Anna Thorson, MD, PhD; Max Petzold, PhD; Nguyen Thi Kim Chuc, PhD; Karl Ekdahl, MD, PhD | title=Is Exposure to Sick or Dead Poultry Associated With Flulike Illness? | journal=Arch Intern Med | year=2006 | pages=119–123 | volume=166 | issue=1 | url=http://archinte.ama-assn.org/cgi/content/full/166/1/119 | doi=10.1001/archinte.166.1.119 | pmid=16401820

]

In one case, a boy with H5N1 experienced diarrhea followed rapidly by a coma without developing respiratory or flu-like symptoms.

cite journal
author=de Jong MD, Bach VC, Phan TQ, Vo MH, Tran TT, Nguyen BH, Beld M, Le TP, Truong HK, Nguyen VV, Tran TH, Do QH, Farrar J. | title=Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma | journal=N. Engl. J. Med. | year=2005 | pages=686–691 | volume=352 | issue=7 |url=http://content.nejm.org/cgi/content/short/352/7/686 | pmid=15716562 | doi=10.1056/NEJMoa044307

] 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 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.

cite journal
author=Webster, R. G. and Walker, E. J. | title=The world is teetering on the edge of a pandemic that could kill a large fraction of the human population | journal=American Scientist | year=2003 | pages=122 | volume=91 | issue=2 |url=http://www.americanscientist.org/template/AssetDetail/assetid/17221?fulltext=true | doi=10.1511/2003.2.122

] 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.

cite journal
author=Chan MC, Cheung CY, Chui WH, Tsao SW, Nicholls JM, Chan YO, Chan RW, Long HT, Poon LL, Guan Y, Peiris JS. | title=Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells | journal=Respir. Res. | year=2005 | pages=135 | volume=6 | pmid=16283933

doi=10.1186/1465-9921-6-135]

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. cite web
author=Medline Plus | publisher=NIH | year=2006-01-12 | url=http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500062.html | title=Oseltamivir (Systemic) | accessdate=2006-04-18
] 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 lack the ability to purchase large quantities of the drug. [ Associated Press, "Tamiflu is Set Aside for WHO," The Wall Street Journal, April 20, 2006, page D6.]

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".

cite news
author=Integrated Regional Information Networks
url=http://www.alertnet.org/thenews/newsdesk/IRIN/e83d17668fc60eb55518a76c1de858fd.htm
title=Middle East: Interview with WHO experts Hassan al-Bushra and John Jabbour
publisher=Alertnet Reuters foundation
date=2006-04-02
accessdate=2006-04-18
]

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".

cite news
author=Schultz, J.
url=http://www.upi.com/ConsumerHealthDaily/view.php?StoryID=20051128-054641-9412r
title=Bird flu vaccine won't precede pandemic
publisher=United Press International
date=2005-11-28
accessdate=2006-04-18
] 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.

cite news
author=Enserick, M.
url=http://www.sciencemag.org/cgi/content/full/309/5737/996b
title=Avian Influenza:'Pandemic Vaccine' Appears to Protect Only at High Doses
publisher=Science
date=2005-08-12
accessdate=2006-04-18
doi=10.1511/2003.2.122
]

cite news
author=Walker, K.
url=http://www.sciencedaily.com/upi/index.php?feed=Science&article=UPI-1-20060127-15211900-bc-us-fluwrap.xml
title= Two H5N1 human vaccine trials to begin
publisher=Science Daily
date=2006-01-27
accessdate=2006-04-18
]

cite journal
author=Gao W, Soloff AC, Lu X, Montecalvo A, Nguyen DC, Matsuoka Y, Robbins PD, Swayne DE, Donis RO, Katz JM, Barratt-Boyes SM, Gambotto A. | title=Protection of mice and poultry from lethal H5N1 avian influenza virus through adenovirus-based immunization | journal=J. Virol. | year=2006 | pages=1959 | volume=80 | issue=4 | pmid=16439551

doi=10.1128/JVI.80.4.1959-1964.2006] 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.

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".cite web
url=http://www.influenzareport.com/ir/drugs/zanami.htm
publisher=Influenza Report
title=Zanamivir
author=Bernd Sebastian Kamps and Christian Hoffmann
accessdate=2006-10-15
] 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 currently be manufactured in quantities that would be meaningful once efficient human transmission starts. [cite news
title=Oseltamivir-resistant H5N1 virus isolated from Vietnamese girl
publisher=CIDRAP
date=October 14, 2005
accessdate=2006-10-15
url=http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/oct1405resistance.html
]

In September, 2006, a WHO scientist announced that studies had confirmed cases of H5N1 strains resistant to Tamiflu and Amantadine. [cite news
title=U.N. Says Bird Flu Awareness Increases
url=http://www.npr.org/templates/story/story.php?storyId=6160868
publisher=NPR
date=October 12, 2006
accessdate=2006-10-15
]

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".

cite web
author=United States Agency for International Development | year=2006 | url=http://www.usaid.gov/our_work/global_health/home/News/news_items/ai_activities.html | title=Avian Influenza Response: Key Actions to Date | accessdate=2006-04-18

]

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".

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.

cite web
author=United States Department of Health and Human Services | publisher= | year=2002 | url=http://www.pandemicflu.gov/outbreaks/ | title=Pandemicflu.gov Monitoring outbreaks | accessdate=2006-04-18

]

Effect on human society

H5N1 has had a huge 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 U.S. dollars are being raised and spent to research H5N1 and prepare for a potential avian influenza pandemic. Over ten billion dollars have been spent and over two hundred million birds killed to try to contain H5N1. [ [http://www.nytimes.com/2006/03/16/business/16bird.html?_r=1&oref=slogin NYT] ] [ [http://usinfo.state.gov/gi/Archive/2005/Nov/01-432345.html State.gov] ] [ [http://www.ens-newswire.com/ens/jan2006/2006-01-18-02.asp Newswire] ] [ [http://msnbc.msn.com/id/12033509/ MSNBC] [http://www.usaid.gov/about_usaid/acvfa/intro_ai.pdf US AID] ] [ [http://www2.bmo.com/news/article/0,1257,contentCode-4922_divId-4_langId-1_navCode-112,00.html BMO Financial Group] ] [ [http://www.cfr.org/pub8198/laurie_garrett_anthony_s_fauci_michael_osterholm_rita_colwell/the_threat_of_global_pandemics.php Council on Foreign Relations] ] [ [http://today.reuters.co.uk/news/newsArticle.aspx?type=worldNews&storyID=2006-04-28T080147Z_01_HAN5054_RTRUKOC_0_UK-BIRDFLU-VIETNAM.xml Reuters] article "Vietnam to unveil advanced plan to fight bird flu" published on April 28, 2006] [ [http://www.alertnet.org/thenews/newsdesk/IRIN/a13fd43bc74b6209dc90f6d849ffa45b.htm Poultry sector suffers despite absence of bird flu] ]

People have reacted by buying less chicken causing poultry sales and prices to fall. [ [http://www.indiaenews.com/pakistan/20060507/6960.htm India eNews] article "Pakistani poultry industry demands 10-year tax holiday" published May 7, 2006 says "Pakistani poultry farmers have sought a 10-year tax exemption to support their dwindling business after the detection of the H5N1 strain of bird flu triggered a fall in demand and prices, a poultry trader said."] Many individuals have stockpiled supplies for a possible flu pandemic. One of the best known experts on H5N1, Dr. Robert Webster, told ABC News he had a three month supply of food and water in his house as he prepared for what he considered a reasonably likely occurrence of a major pandemic.

International health officials and other experts have pointed out that many unknown questions still hover around the disease [http://www.iisd.ca/ymb/ais/ymbvol123num1e.html International Institute for Sustainable Development (IISD)] "SCIENTIFIC SEMINAR ON AVIAN INFLUENZA, THE ENVIRONMENT AND MIGRATORY BIRDS ON 10-11 APRIL 2006" published 14 April 2006. ]

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 the potential of 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.cite news
author = Donald G. McNeil Jr.
title = The response to bird flu: Too much or not enough? UN expert stands by his dire warnings
url = http://www.iht.com/articles/2006/03/27/news/worrier.php?page=1
publisher = International Herald Tribune
date=March 28, 2006
]

ee also

*Antigenic shift
*Influenza research
*Fujian flu
*Global spread of H5N1
*H5N1 clinical trials
*ICEID
*National Influenza Centers
*Reporting disease cases
*Zoonosis

ources and notes

External links

;Official - international
*UN United Nations
**WHO World Health Organization
*** [http://www.who.int/csr/disease/avian_influenza/avianinfluenza_factsheetJan2006/en/index.html The United Nation's World Health Organization's Avian Flu Facts Sheet for 2006]
*** [http://www.who.int/csr/en/ Epidemic and Pandemic Alert and Response] Guide to WHO's H5N1 pages
*** [http://www.who.int/csr/disease/avian_influenza/en/ Avian Influenza Resources (updated)] - tracks human cases and deaths
*** [http://www.who.int/csr/disease/influenza/nationalpandemic/en/index.html National Influenza Pandemic Plans]
*** [http://www.who.int/csr/disease/influenza/collabcentres/en/ WHO Collaborating Centres and Reference Laboratories] Centers, names, locations, and phone numbers
** [http://www.fao.org/ag/avian.html FAO Avian Influenza portal] Information resources, animations, videos, photos
*** [http://www.fao.org/ag/againfo/programmes/en/empres/maps.html FAO] Food and Agriculture Organisation - Bi-weekly Avian Influenza Maps - tracks animal cases and deaths
*** [http://www.fao.org/ag/againfo/subjects/en/health/diseases-cards/avian.html FAO Bird Flu disease card]
*** [http://www.fao.org/ag/againfo/subjects/en/economics.html FAO Socio-Economic impact of AI] Projects, Information resources
*OIE World Organisation for Animal Health - tracks animal cases and deaths
** [http://www.oie.int/downld/AVIAN%20INFLUENZA/A_AI-Asia.htm Official outbreak reports by country]
** [http://www.oie.int/eng/info/hebdo/a_isum.htm Official outbreak reports by week]
** [http://www.oie.int/downld/AVIAN%20INFLUENZA/graph%20HPAI%2010112005.pdf Chart of outbreaks by country]

;Official - United States
* [http://www.pandemicflu.gov PandemicFlu.Gov] U.S. Government's avian flu information site
* [http://www.usaid.gov/our_work/global_health/home/News/news_items/avian_influenza.html USAID] U.S. Agency for International Development - Avian Influenza Response
* [http://www.cdc.gov/flu/avian/gen-info/facts.htm 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
* [http://www.nwhc.usgs.gov/disease_information/avian_influenza/ USGS - NWHC] National Wildlife Health Center - responsible agency for avian influenza in animals in US
* [http://www.hhs.gov/pandemicflu/plan/ HHS] U.S. Department of Health & Human Services - Pandemic Influenza Plan

; Official - European Union
*ECDC|avian_influenza/qa.aspx|Avian influenza - Q & A's

;Official - United Kingdom
* [http://news.bbc.co.uk/1/shared/bsp/hi/pdfs/23_02_06_defra_plan.pdf 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 (a government entity).
* [http://news.bbc.co.uk/1/shared/bsp/hi/pdfs/19_10_05_bird_flu.pdf UK Influenza Pandemic Contingency Plan] — NHS (a government entity). Contingency planning for an influenza pandemic. PDF hosted by BBC

;TechnicalExternal links dealing with technical aspects can be found here.

;News and General informationExternal links dealing with news and general information can be found here.

nds:A/H5N1


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