H5N1

From Biocrawler, the free encyclopedia.

H5N1 is an avian virus which is an influenza virus. It is a pandemic threat.

Contents

1 Nontechnical introduction 2 Technical introduction 3 Terminology 4 H5N1 virus structure 5 Transmission and infection 5.1 Prevention 5.2 Incubation 5.3 Symptoms 5.4 Treatment 6 Global spread 2004/2005 6.1 Human and bird cases 6.2 Pig cases 6.3 Tigers, leopards, domestic cats 6.4 Worst case scenario 7 Preparations for a potential epidemic 8 See also 9 References 10 External links and sources 10.1 Official 10.2 Technical 10.3 News 10.4 General information

Nontechnical introduction

H5N1 is sometimes called bird flu, or avian influenza. It is a viral disease that causes illness in many species including humans.

As of December 14, 2005, 138 cases of infections in humans, resulting in 71 deaths, have been confirmed worldwide. Not all cases of H5N1 infection are reported, so the percent of reported deaths per reported infection is known, but the similar number for unreported cases is unknown ^{[1] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_npr5056105)}. Thirteen countries across Asia and Europe have been affected. Tens of millions of birds died of H5N1 influenza and hundreds of millions of birds were culled to protect humans from H5N1^[2].

The worst case scenario for a H5N1 pandemic is somewhere around 150,000,000 human deaths directly due to H5N1 infection (or two to three percent of the world's human population). No one knows what the chances are for this worst case scenario.

Technical introduction

H5N1 is a type of avian influenza virus (bird flu virus) that has mutated^{[2] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_CDCWHO)} through antigenic drift into dozens of highly pathogenic varieties, but all currently belonging to genotype Z of avian influenza virus H5N1. Genotype Z emerged through reassortment in 2002 from earlier highly pathogenic genotypes of H5N1^{[3] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_workshop)} that first appeared in China in 1996 in birds and in Hong Kong in 1997 in humans^{[4] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_timeline)}. The "H5N1 viruses from human infections and the closely related avian viruses isolated in 2004 and 2005 belong to a single genotype, often referred to as genotype Z." ^[1]

This infection of humans 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. The name H5N1 refers to the subtypes of surface antigens present on the virus: hemagglutinin type 5 and neuraminidase type 1.

Genotype Z of avian influenza virus H5N1 is now the dominant genotype of H5N1. Genotype Z is endemic in birds in southeast Asia and represents a long term pandemic threat.

The species called the avian flu virus has a subtype called H5N1 which has a strain called highly pathogenic H5N1 which includes genotype or strain Z which has been divided into two genetic clades which are known from specific isolates. Among H5N1 viruses, only clade one infects humans.

Terminology

"Virus" refers to either the complete virus assemblage or when distinguishing between its parts it refers to the molecules (RNA in the case of H5N1) comprising the genome that is surrounded (encapsidated) by a protective coat of protein called a capsid which binds directly to the viral genome. This complex of protein and nucleic acid is called the nucleocapsid. The complete virus assemblage is referred to as a virion. In normal useage "H5N1 virus" refers to the H5N1 nucleocapsid which is the same as the H5N1 virion since the H5N1 lacks an envelope (a membranous lipid structure that surrounds the nucleocapsid).

Avian influenza is not a genus of Orthomyxoviridae. The term "avian influenza" denotes a disease not a virus. The orthomyxovirus family consists of 5 genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus, and Thogotovirus. Influenzavirus A is not the same as "avian influenza": the former is a genus of viruses, the latter is an illness.

In phylogenetics based taxonomy the "RNA viruses" includes the "negative-sense ssRNA viruses" which includes the Order "Mononegavirales" which includes the Family "Orthomyxoviridae" which contains five genera, classified by variations in nucleoprotein (NP and M) antigens. One of these is the Genus "Influenzavirus A" which consists of a single species (or "type species") called "Influenza A virus" (AI) and one of its subtypes is H5N1. H5N1 (like the other avian flu viruses) has strains called "highly pathogenic" (HP) and and "low-pathogenic" (LP). "Avian influenza viruses that cause HPAI are highly virulent, and mortality rates in infected flocks often approach 100%. LPAI viruses are generally of lower virulence, but these viruses can serve as progenitors to HPAI viruses. The current strain of H5N1 responsible for die-offs of domestic birds in Asia is an HPAI strain; other strains of H5N1 occurring elsewhere in the world are less virulent and, therefore, are classified as LPAI strains. All HPAI strains identified to date have involved H5 and H7 subtypes." The species called the avian flu virus has a subtype called H5N1 which has a strain called highly pathogenic H5N1 which includes genotype or strain Z which has been divided into two genetic clades which are known from specific isolates. Only clade one infects humans but all clade one are resistant to adamantanes. Each specific known genetic variation is known from a virus isolate of a specific case of infection. [5] (http://www.ncbi.nlm.nih.gov/ICTVdb/Ictv/fr-fst-g.htm#DNA) [6] (http://id_center.apic.org/cidrap/content/influenza/panflu/biofacts/panflu.html) [7] (http://www.cdc.gov/ncidod/EID/vol11no10/05-0644.htm)

H5N1 virus structure

See also Virus, Orthomyxoviridae, Influenza virus, Avian influenza virus

Virus

A virus is one type of microscopic parasite that infects cells in biological organisms.

Orthomyxoviridae

The Orthomyxoviridae are a family of RNA viruses which infect vertebrates. It includes those viruses which cause influenza. Viruses of this family contain 7 to 8 segments of linear negative-sense single stranded RNA.

Influenza virus

"Influenza virus" refers to a subset of Orthomyxoviridae that create influenza. This is not a phylogenetics based taxonomic category.

Avian influenza virus

Avian influenza (also known as bird flu, avian flu, influenzavirus A flu, type A flu, or genus A flu) is a flu due to a type of influenza virus that is hosted by birds, but may infect several species of mammals. The avian influenzavirus subtypes that have been confirmed in humans, ordered by the number of known human deaths, are: H1N1 caused Spanish flu, H2N2 caused Asian Flu, H3N2 caused Hong Kong Flu, H5N1, H7N7, H9N2, H7N2, H7N3.

Avian influenza viruses have 10 genes on eight separate RNA molecules (called: PB2, PB1, PA, HA, NP, NA, M, and NS). (Table of molecular weights, nucleotide lengths, molecules per virion here (http://sunzi.lib.hku.hk/hkuto/view/B30456721/ft.pdf) ) HA, NA, and M specify the structure of proteins that are most medically relevant as targets for antiviral drugs and antibodies. This 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^[1]. Avian influenza viruses compose the Influenzavirus A genus of the Orthomyxoviridae family and are negative sense, single-stranded, segmented RNA viruses.

"The influenza virus RNA polymerase is a multifunctional complex composed of the three viral proteins PB1, PB2 and PA, which, together with the viral nucleoprotein NP, form the minimum complement required for viral mRNA synthesis and replication." [8] (http://pubmedcentral.com/articlerender.fcgi?artid=99831)

• Surface antigen encoding gene segments (RNA molecule): (HA, NA)
  • HA codes for Hemagglutinin which is 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. Hemagglutinin forms spikes at the surface of flu viruses that function to attach viruses to cells. This attachment is required for efficient transfer of flu virus genes into cells, a process that can be blocked by antibodies that bind to the hemagglutinin proteins.
  • NA codes for Neuraminidase which is an antigenic glycoprotein enzyme found on the surface of the influenza viruses. It helps the release of progeny viruses from infected cells.
• Internal viral protein encoding gene segments (RNA molecule): (M, NP, NS, PA, PB1, PB2) [9] (http://www.nap.edu/books/0309095042/html/118.html)
  • M codes for the matrix proteins that along with the two surface proteins (hemagglutinin and neuraminidase) make up the capsid (protective coat) of the virus. It encodes by using different reading frames from the same RNA segment.
    • M1 is a protein that binds to the viral RNA.
    • M2 is a protein that uncoats the virus exposing its contents (the eight RNA segments) to the cytoplasm of the host cell. The M2 transmembrane protein is an ion channel required for efficient infection ^{[10] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_mechanisms)}. The amino acid substitution (Ser31Asn) in M2 some H5N1 genotypes is associated with amantadine resistance [11] (http://www.pnas.org/cgi/content/full/101/21/8156).
  • NP codes for nucleoprotein.
  • NS: NS codes for two nonstructural proteins (NS1 and NEP). "[T]he pathogenicity of influenza virus was related to the nonstructural (NS) gene of the H5N1/97 virus" [12] (http://jvi.asm.org/cgi/content/full/79/6/3692?view=long&pmid=15731263) [13] (http://id_center.apic.org/cidrap/content/influenza/panflu/biofacts/panflu.html)
    • NS1: Non-structural: nucleus; effects on cellular RNA transport, splicing, translation. Anti-interferon protein. NS1 described in detail here (http://www.pathobiologics.org/ivphc/ref/ns1_ref121904.html). The "NS1 of the highly pathogenic avian H5N1 viruses circulating in poultry and waterfowl in Southeast Asia might be responsible for an enhanced proinflammatory cytokine response (especially TNFa) induced by these viruses in human macrophages" [14] (http://www.cdc.gov/ncidod/EID/vol12no01/05-1186.htm).
    • NEP: The "nuclear export protein (NEP, formerly referred to as the NS2 protein) mediates the export of vRNPs" [15] (http://jvi.asm.org/cgi/content/abstract/75/16/7375).
  • PA codes for the PA protein which is a critical component of the viral polymerase.
  • PB1 codes for the PB1 protein and the PB1-F2 protein.
    • The PB1 protein is a critical component of the viral polymerase.
    • The PB1-F2 protein is encoded by an alternative open reading frame of the PB1 RNA segment and "interacts with 2 components of the mitochondrial permeability transition pore complex, ANT3 and VDCA1, [sensitizing] cells to apoptosis. [...] PB1-F2 likely contributes to viral pathogenicity and might have an important role in determining the severity of pandemic influenza." [16] (http://www.cdc.gov/ncidod/EID/vol12no01/05-1186.htm) This was discovered by Chen et. al. and reported in Nature here (http://www.nature.com/nm/journal/v7/n12/full/nm1201-1306.html) in 2001.
  • PB2 codes for the PB2 protein which is a critical component of the viral polymerase. 75% of H5N1 human virus isolates from Vietnam had a mutation consisting of Lysine at residue 627 in the PB2 protein; which is believed to cause high levels of virulence. [17] (http://www.nap.edu/books/0309095042/html/126.html) [18] (http://jvi.asm.org/cgi/content/full/79/6/3692?view=long&pmid=15731263)

The hemagglutinin, neuraminidase, and M2 proteins are essential viral proteins with functions that can be inhibited by antiviral drugs such as oseltamivir and rimantadine or bound by virus-inactivating antibodies produced by the immune system.

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The H5N1 virus has mutated into a variety of types with differing pathogenic profiles; some pathogentic to one species but not others, some pathogenic to multiple species^{[19] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_variants)}. 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^{[20] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_specificity)}. This doesn't mean one amino acid substitution can cause a pandemic but it does mean one amino acid substitution can cause an avian flu virus that is not pathogenic in humans to become pathogenic in humans.

In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute, Harbin, China and Professor Robert Webster of the St Jude Children's Research Hospital, Memphis, Tennessee, reported results of experiments in which mice had been exposed to 21 isolates of confirmed H5N1 strains obtained from ducks in China between 1999 and 2002. They found "a clear temporal pattern of progressively increasing pathogenicity"^{[21] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_ducks)}. Results reported by Dr. Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks.

Recent research of Taubenberger et al ^{[22] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_Taubenberger)} has shown that the 1918 virus, like H5N1, was also an avian influenza virus. Furthermore, Tumpey and colleagues ^{[23] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_Tumpey)} who reconstructed the H1N1 virus of 1918 came to the conclusion that it is was most notably the polymerase genes and the HA and NA genes that caused the extreme virulence of this virus. The sequences of the polymerase proteins (PA, PB1, and PB2) of the 1918 virus and subsequent human viruses differ by only 10 amino acids from the avian influenza viruses. Human forms of seven of the ten amino acids have already been identified in currently circulating H5N1. It is not unlikely that the other mutations eventually will surface and make the H5N1 virus capable of human-to-human transmission. Another important factor is the change of the HA protein to a binding preference for alpha 2,6 sialic acid (the major form in the human respiratory tract). In avian virus the HA protein preferentially binds to alpha 2,3 sialic acid, which is the major form in the avian enteric tract. It has been shown that only a single amino acid change can result in the change of this binding preference. Altogether, only a handful of mutations need to take place in order for H5N1 avian flu to become a pandemic virus like the one of 1918.

Transmission and infection

Infected birds pass on H5N1 through their saliva, nasal secretions, and feces. Other birds may pick up the virus through direct contact with these excretions or when they have contact with surfaces contaminated with this material. Because migratory birds are among the carriers of the H5N1 virus it may spread to all parts of the world. Past outbreaks of avian flu have often originated in crowded conditions in southeast and east Asia, where humans, pigs, and poultry live in close quarters. In these conditions a virus can mutate into a form that more easily infects humans.

The majority of H5N1 flu cases have been reported in southeast and east Asia. Once an outbreak is detected, local authorities often order a mass slaughter of birds or animals affected. If this is done promptly, an outbreak of avian flu may be prevented. However, the United Nations (UN) World Health Organization (WHO) has expressed concern that not all countries are reporting outbreaks as completely as they should. China, for example, is known to have officially denied past outbreaks of severe acute respiratory syndrome (SARS) and HIV.

H5N1 infections in humans are generally caused by bird to human transmission of the virus. A few isolated cases of suspected human to human transmission exist, but there is no proof either way in those cases.

Prevention

The current method of prevention in animal populations is to destroy infected animals, as well as animals suspected of being infected. In southeast Asia, millions of domestic birds have been slaughtered to prevent the spread of the virus.

The probability of a "humanized" form of H5N1 emerging through genetic recombination in the body of a human co-infected with H5N1 and another influenza virus type could be reduced by influenza vaccination of those at risk for infection by H5N1. It is not clear at this point whether vaccine production and immunization could be stepped up sufficiently to meet this demand.

If an outbreak of pandemic flu does occur, its spread might be slowed by increasing hygiene in aircraft, and by examining airline cabin air filters for presence of H5N1 virus.

The American Centers for Disease Control and Prevention advises travelers to areas of Asia where outbreaks of H5N1 have occurred to avoid poultry farms and animals in live food markets^{[24] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_CDCtravel)}. Travelers should also avoid surfaces that appear to be contaminated by feces from any kind of animal, especially poultry.

There are several H5N1 vaccines for several of the avian H5N1 varieties. H5N1 continually mutates rendering them, so far for humans, of little use. While there can be some 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."^{[25] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_Schultz)} 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^{[26] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_Enserink)}. 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.

It is not likely that use of antiviral drugs could prevent the evolution of a pandemic flu virus ^{[27] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_tamifluNIH)}.

Incubation

The incubation period of avian influenza A (H5N1) is 2 to 17 days^{[28] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_NEJM29September2005)}.

Symptoms

Since H5N1 is an influenza virus, symptoms similar to those of the common flu, such as fever, cough, sore throat, and sore muscles, can develop in infected humans. However, in more severe cases, pneumonia and respiratory failure can develop and eventually cause death. Patients with H5N1 avian influenza have rarely had conjunctivitis^[9], unlike human cases of infection by the H7 virus. Severe infection from H5N1 caused multiple lung infections (including pus, fever, cough), lung scar tissue, fluid in the space surrounding the lungs, enlarged lymph nodes and cavities forming in the lung tissue.

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^{[29] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_cytokine1)}. 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^{[30] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_cytokine2)}.

Treatment

Neuraminidase inhibitors are a class of drugs that includes zanamivir and oseltamivir, the latter being licensed for prophylaxis treatment in the United Kingdom. Oseltamivir inhibits the influenza virus from spreading inside the user's body ^[8]. It is marketed by Roche as Tamiflu. This drug has become a focus for some governments and organizations trying to be seen as making preparations for a possible H5N1 pandemic. In August 2005, Roche agreed to donate three million courses of Tamiflu to the World Health Organization, to be deployed by the WHO to contain a pandemic in its region of origin. Although Tamiflu is patented, international law gives governments wide freedom to issue compulsory licenses for life-saving drugs.

A second class of drugs, which include amantadine and rimantadine, target the M2 protein. Unlike zanamivir and oseltamivir, these drugs are inexpensive and widely available and the WHO had initially planned to use them in efforts to combat a H5N1 pandemic. However, the potential of these drugs was considerably lessened when it was discovered that farmers in China has been administering amantadine to poultry with government encouragement and support since the early 1990s, against international livestock regulations; the result has been that the strain of the virus now circulating in South East Asia is largely resistant to the medication and hence significantly more dangerous to humans^{[31] (http://www.biocrawler.com/encyclopedia/H5N1#endnote_resistance)}. However, the strain of H5N1 spread throughout Northern China, Mongolia, Kazakhstan, Russia and Europe by wild birds in the summer of 2005 is not amantadine resistant.

Global spread 2004/2005

"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." [32] (http://content.nejm.org/cgi/content/full/353/13/1374)

Human and bird cases

January 2004: A major new outbreak of H5N1 surfaced in Vietnam and Thailand's poultry industry, and within weeks spread to ten countries and regions in Asia, including Indonesia, South Korea, Japan and mainland China. Intensive efforts were undertaken to slaughter chickens, ducks and geese (over forty million chickens alone were slaughtered in high-infection areas), and the outbreak was contained by March, but the total human death toll in Vietnam and Thailand was twenty three people.

July 2004: Fresh outbreaks in poultry were confirmed in Ayutthaya and Pathumthani provinces of Thailand, and Chaohu city in Anhui, China.

August 2004: Avian flu was confirmed in Kampung Pasir, Kelantan, Malaysia. Two chickens were confirmed to be carrying H5N1. As a result Singapore has imposed a ban on the importation of chickens and poultry products. Similarly the EU has imposed a ban on Malaysian poultry products. A cull of all poultry has been ordered by the Malaysian government within a 10km radius of the location of this outbreak. These moves appear to have been successful and since then, Singapore has lifted the ban and Malaysia has requested the OIE declare Malaysian poultry bird flu free [33] (http://in.news.yahoo.com/050921/137/608r2.html).

January 2005: An outbreak of avian influenza affected thirty three out of sixty four cities and provinces in Vietnam, leading to the forced killing of nearly 1.2 million poultry. Up to 140 million birds are believed to have died or been killed because of the outbreak.

March 2005: Vietnam and Thailand have seen several isolated cases where human-to-human transmission of the virus has been suspected. In one case a young girl, who received the disease from a bird, was held by her mother for roughly five days until she died. Shortly afterwards, the mother also died. In March 2005, it was revealed that two nurses who had cared for avian flu patients had tested positive for the disease.

July 2005: A death in Jakarta was the first confirmed human fatality in Indonesia. The deaths of the man's two children, neither of whom were reported to have had close contact with poultry, further raised concerns of human-to-human transmission (although infection by eating undercooked poultry may be a more likely explanation) [34] (http://www.washingtonpost.com/wp-dyn/content/article/2005/07/20/AR2005072000879.html). As of July 20, the outbreak had claimed at least fifty eight human lives — mostly in Vietnam. What concerns health researchers now is that the virus mortality rate in Vietnam has dropped significantly lately, from more than 65% to about 35% in a year. This might be a sign that the virus is able to infect a larger number of people (i.e., the virus is able to spread more easily) and possibly develop into a global pandemic with millions of deaths despite the lower reported percentage of deaths. For example, the mortality rate of 1918 Spanish flu (H1N1) pandemic was less than 5% [35] (http://www.boston.com/news/world/asia/articles/2005/04/24/drop_in_virus_mortality_rate_portends_new_danger?pg=2). In July 2005, it was confirmed H5N1 had appeared in Russia's Novosibirsk region, probably carried by migratory birds [36] (http://www.recombinomics.com/News/07290502/H5N1_Russia_Migration_Confirmed.html). On July 28, avian influenza was reported to have killed two more people in Vietnam, raising the death toll to sixty [37] (http://www.washingtonpost.com/wp-dyn/content/article/2005/07/28/AR2005072802341.html). As of July 2005, most human cases of avian influenza in East Asia have been attributed to consumption of diseased poultry. Person-to-person transmission has not been unequivocally confirmed in the outbreaks in East Asia.

August 2005: On August 3 2005, the WHO said it was following closely reports from China that at least 38 people have died and more than 200 others have been made ill by a swine-borne virus in Sichuan Province. Sichuan Province, where infections with Streptococcus suis have been detected in pigs in a concurrent outbreak, has one of the largest pig populations in China. The outbreak in humans has some unusual features and is being closely followed by the WHO. At that time, Chinese authorities say they have found no evidence of human-to-human transmission [38] (http://www.un.org/apps/news/story.asp?NewsID=15279&Cr=pig&Cr1=flu). In early August, an avian outbreak of H5N1 flu was confirmed in Kazakhstan and Mongolia, suggesting further spread of the virus [39] (http://www.flu.org.cn/news/2005831560.htm). Later in August, the virus was found in western Russia, marking its appearance in Europe. As a result, Dutch authorities ordered that free-range chickens would have to be kept indoors.[40] (http://news.bbc.co.uk/1/hi/world/europe/4172182.stm) EU officials chose not to impose a similar policy on member countries.

September 2005: 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 5 to 150 million people. Also, due to a bipartisan effort of the United States Senate, $4 billion dollars was appropriated to develop vaccines and treatments for Avian influenza. [41] (http://www.un.org/News/briefings/docs/2005/050929_Nabarro.doc.htm) In late September 2005, the UN health representative responsible for coordinating a response to an outbreak, David Nabarro, stated that a flu pandemic could happen at any time, and kill from five to 150 million people. He further stated that as the virus had spread to migratory birds, an outbreak could start in Africa or the Middle East, rather than southeast Asia as has been widely assumed. At the same time, agricultural ministers of Association of South East Asian Nations announced a three-year plan to counter the spread of the disease. [42] (http://news.bbc.co.uk/2/hi/asia-pacific/4292426.stm)

October 2005: Romanian officials quarantined Ceamurlia de Jos, a Danube delta village of about 1,200 people, after three dead ducks there tested positive. However, there have been no immediate reports of sickness in the village. The Agriculture Minister said the virus found in the farm-raised ducks came from migrating birds from Russia [43] (http://edition.cnn.com/2005/HEALTH/conditions/10/07/birdflu.romania/). Pending scientific clarification, this is the first time the virus had been detected in Europe. Six villages have been put under quarantine following the deaths of domestic birds and over 6000 birds have been killed. On 13 October 2005 the EU Health Commissioner Markos Kyprianou confirmed that tests on the dead turkeys found on farms in Kiziksa, Turkey, showed that they had died from the H5N1 strain. Even before the test results were available, some 5,000 birds and poultry have been culled in the area. It is believed that the disease had spread from migratory birds that land at the Manyas bird sanctuary (a few miles from the infected farm) on their way to Africa. On 14 October 2005, European health officials confirmed what many had long feared -- the arrival of the H5N1 strain on Europe's doorstep. The European Commission said the bird flu outbreak in Turkey was indeed H5N1, and advised Europe to prepare for a pandemic. It has also been reported in Romania. On 15 October 2005, the British Veterinary Laboratory in Weybridge confirmed that the virus detected in Ciamurlia, Romania is H5N1. On 17 October 2005, a bird flu outbreak occurred in Chios, Greece. The mayor of Chios said a farmer on Oinousses who raised turkeys and chickens noted the previous week that some of his birds had died. Two state veterinarians were sent in to look at nine turkeys. They also took blood samples from some chickens. The mayor said a state lab in Athens confirmed that one of the nine samples proved positive. Authorities have yet to announce what measures they will be taking. The farmer was taken to a hospital for observation. [44] (http://edition.cnn.com/2005/HEALTH/conditions/10/17/birdflu.greece/index.html)

On 19 October 2005, China announced a fresh outbreak of bird flu, saying 2,600 birds have died from the disease in Inner Mongolia. The deaths, at a farm near the region's capital of Hohhot, were due to the H5N1 strain, the Xinhua news agency said.

On 21 October/22 October 2005, the British Government announced that a parrot from South America had died in quarantine from H5N1 . Because the parrot died in quarantine, the United Kingdom is still considered free of avian flu. The staff that had been in contact with the parrots were immediately given anti-viral drugs.

On 26 October 2005, Croatia announced H5N1 strain was found in dead swans [45] (http://www.dw-world.de/dw/article/0,2144,1753925,00.html).

On 31 October 2005, Russia confirmed previously suspected H5N1 bird flu in ten rural communities across Russia. The confirmed outbreak sites are in the central areas of Tula and Tambov, as well as in the Urals province of Chelyabinsk and in Omsk and Altai, in Siberia. [46] (http://en.rian.ru/russia/20051031/41947616.html)

On 31 October 2005, Canada has discovered a strain of H5 avian flu in wild birds and is now checking whether it is the same H5N1 killer strain which has spread to Europe. [47] (http://abcnews.go.com/Health/wireStory?id=1266820)

November 2005: On 11 November 2005, Kuwait has reported positive testing of two birds, one infected with H5N1, and the other with the H5N2 virus, making them the first cases of infection in the Middle East. A flamingo holding the H5N1 virus was found dead by the sea, as the source (http://gulfnews.com/Articles/RegionNF.asp?ArticleID=191926) reports, it was killed by authorities and did not die from the virus, however, it does not report why it was killed. The second bird, a falcon, was found at the Kuwait airport, holding the H5N2 virus.

On 19 November 2005, Wild birds in Manitoba, Canada have tested positive for a low-pathogenic subtype of the H5N1 avian flu virus.

On 20 November 2005, CTV News reported H5N1 strain was found in a farm in the Fraser Valley area of British Columbia, Canada. The Canadian Food Inspection Agency has ordered a precautionary cull of 65,000 birds.

December 29 2005 - "China confirms its third human death from bird flu. That brings the death toll [...] to 74, comprising 14 victims in Thailand, four in Cambodia, 11 in Indonesia, 42 in Vietnam and three in China." [48] (http://today.reuters.co.uk/news/newsArticle.aspx?type=globalNews&storyID=2006-01-03T113657Z_01_FLE341795_RTRUKOC_0_US-BIRDFLU.xml)

January 5 2006 Second Turkish child dies from bird flu. A second Turkish child from the same family died from bird flu on Thursday at a hospital in eastern Turkey where she was being treated, a regional governor said.

Her brother, 14-year-old Mehmet Ali Kocyigit, had already died of the H5N1 strain of bird flu, officials said on Wednesday, confirming the first human death from the disease outside China and southeast Asia.

"We lost Fatma Kocyigit this morning," Niyazi Tanilir, governor in the eastern province of Van, said on the CNN Turk news channel. Newspapers said Fatma was 15-years-old. She died around 6:30 a.m. (0430 GMT). [49] (http://today.reuters.com/news/newsarticle.aspx?type=topNews&storyid=2006-01-05T063816Z_01_MOL141032_RTRUKOC_0_US-BIRDFLU-TURKEY.xml&rpc=22)

Cumulative number of confirmed human cases of H5N1 avian influenza infection Taken from WHO site January 30 2006 edit  (http://www.biocrawler.com/w/index.php?title=Template:H5N1_cases&action=edit)
Country		Date
		2003	2004	2005	2006	Total
Cambodia	cases	0	0	4	0	4
	deaths	0	0	4	0	4
People's Republic of China	cases	0	0	8	2	10
	deaths	0	0	5	2	7
Indonesia	cases	0	0	16	3	19
	deaths	0	0	11	3	14
Thailand	cases	0	17	5	0	22
	deaths	0	12	2	0	14
Turkey	cases	0	0	0	12	12
	deaths	0	0	0	4	4
Iraq	cases	0	0	0	1	1
	deaths	0	0	0	1	1
Vietnam	cases	3	29	61	0	93
	deaths	3	20	19	0	42
Total	cases	3	46	94	18	161
	deaths	3	32	41	10	81
Fatality rate from cases (Morbidity): 53.1% Note: Some infections are unreported, therefore actual morbidity is somewhat lower. Also the mortality rate so far is far under one percent because so few humans catch the disease in the first place.
Sources: Communicable Disease Surveillance & Response (CSR), WHO. [50] (http://www.who.int/csr/disease/avian_influenza/country/en/) "Mortalities from a Flu Pandemic Hard to Predict" by Jon Hamilton. Morning Edition, 16 December 2005. [51] (http://www.npr.org/templates/story/story.php?storyId=5056105)

vi:Tiêu bản:Diễn biến H5N1

Pig cases

In February 2004, avian influenza virus was detected in pigs in Vietnam, increasing fears of the emergence of new variant strains.

In May 2005, the occurrence of Avian influenza in pigs in Indonesia was reported ("swine flu"). Along with the continuing pattern of virus circulation in poultry, the occurrence in swine raises the level of concern about the possible evolution of the virus into a strain capable of causing a global human influenza pandemic. Health experts say pigs can carry human influenza viruses, which can combine (i.e. exchange homologous genome sub-units by genetic reassortment.) with the avian virus, swap genes and mutate into a form which can pass easily among humans.

Tigers, leopards, domestic cats

Variants have been found in a number of domestic cats, leopards and tigers in Thailand, with high lethality. [52] (http://www.recombinomics.com/News/07090502/Qinghai_E627K_Human.html) [53] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16318716&query_hl=1)

"The Thailand Zoo tiger outbreak killed more than 140 tigers, causing health officials to make the decision to cull all the sick tigers in an effort to stop the zoo from becoming a reservoir for H5N1 influenza (ProMED-mail, 2004i; ProMED-mail, 2004w). A study of domestic cats showed H5N1 virus infection by ingestion of infected poultry and also by contact with other infected cats (Kuiken et al., 2004)." [54] (http://www.nap.edu/books/0309095042/html/15.html)

The spread to more and more types and populations of birds and the ability of cats to catch H5N1 from eating this natural prey means the creation of a reservoir for H5N1 in cats where the virus can adopt to mammals is one of the many possible pathways to a pandemic.

Worst case scenario

The worst case scenario for a H5N1 pandemic is somewhere around 150,000,000 human deaths directly due to H5N1 infection (or two to three percent of the world's human population). No one knows what the chances are for this worst case scenario.

"Influenza viruses keep changing. They mutate. And they exchange genetic material with other flu viruses, a process called reassortment. All that’s needed is a mutation or reassortment that produces a new variant of H5N1 — one that’s as deadly as the current strain but as easily transmitted from human to human as lots of other flu strains. Most virologists believe something like this will happen sooner or later, and many believe it will happen soon. When it does, H5N1 will inevitably spread throughout the world. Worldwide mortality estimates range all the way from 2–7.4 million deaths (the “conservatively low” pandemic influenza calculation of a flu modeling expert at the U.S. Centers for Disease Control and Prevention) to 1 billion deaths (the bird flu pandemic prediction of one Russian virologist). The estimates of most H5N1 experts range less widely but still widely. In an H5N1 pandemic, the experts guess that somewhere between a quarter of us and half of us would get sick, and somewhere between one percent and five percent of those who got sick would die — the young and hale as well as the old and frail. If it’s a quarter and one percent, that’s 16 million dead; if it’s a half and five percent, it’s 160 million dead. Either way it’s a big number." Pandemic Influenza Risk (http://www.psandman.com/col/pandemic.htm)

Preparations for a potential epidemic

Main article: Influenza pandemic

"[T]he 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." [55] (http://www.usaid.gov/our_work/global_health/home/News/news_items/ai_activities.html)

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". [56] (http://www.usaid.gov/our_work/global_health/home/News/news_items/ai_activities.html)

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. [57] (http://www.pandemicflu.gov/outbreaks/)

See also

• Antigenic shift
• Avian influenza
• Culture of fear
• Flu vaccine
• Hemagglutinin
• Influenza
• Influenza pandemic
• Neuraminidase
• Pandemic
• Vaccine
• Zoonosis

References

1. ^ ^ ^  Evolution of H5N1 avian influenza viruses in Asia (http://www.cdc.gov/ncidod/EID/vol11no10/05-0644.htm) by The World Health Organization Global Influenza Program Surveillance Network in Emerging Infectious Diseases (2005). See Figure 1 (http://www.cdc.gov/ncidod/EID/vol11no10/05-0644-G1.htm) for a diagramatic representation of the genetic relatedness of Asian H5N1 hemagglutinin genes from various isolates of the virus.
2. ^ ^  "The Threat of Pandemic Influenza: Are We Ready?" Board on Global Health Workshop Summary (2005). See page 118 (http://www.nap.edu/books/0309095042/html/118.html) for a map and page 123 (http://www.nap.edu/books/0309095042/html/123.html#p2000c2099960123001) for a diagram of reassortment of viral genes. The bird culls are described on page 116 (http://www.nap.edu/books/0309095042/html/116.html).
3. ^  PDF format: H5N1 avian influenza: timeline (http://www.who.int/csr/disease/avian_influenza/Timeline_28_10a.pdf) from the World Health Organization (dated 28 October 2005).
4. ^ Mortalities from a Flu Pandemic Hard to Predict (http://www.npr.org/templates/story/story.php?storyId=5056105) by Jon Hamilton of National Public Radio Morning Edition, December 16, 2005.
5. ^  New genotype of avian influenza H5N1 viruses isolated from tree sparrows in China (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16306617) by Z. Kou, F. M. Lei, J. Yu, Z. J. Fan, Z. H. Yin, C. X. Jia, K. J. Xiong, Y. H. Sun, X. W. Zhang, X. M. Wu, X. B. Gao and T. X. Li in Journal of Virology (2005) volume 79, pages 15460-15466.
6. ^  Evolution of the receptor binding phenotype of influenza A (H5) viruses (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16226289&query_hl=1) by A. Gambaryan, A. Tuzikov, G. Pazynina, N. Bovin, A. Balish and A. Klimov in Virology (2005) electronic release on October 11 ahead of print publication.
7. ^  The evolution of H5N1 influenza viruses in ducks in southern China (http://www.pnas.org/cgi/content/abstract/0403212101v1) by H. Chen, G. Deng, Z. Li, G. Tian, Y. Li, P. Jiao, L. Zhang, Z. Liu, R. G. Webster and K. Yu in Proceedings of the National Academy of Sciences of the United States of America (2004) volume 101, pages 10452-10457.
8. ^  Interim Guidance about Avian Influenza A (H5N1) for U.S. Citizens Living Abroad (http://www.cdc.gov/travel/other/avian_flu_ig_americans_abroad_032405.htm) from the U.S. Centers for Disease Control and Prevention. Initial release, March 24, 2005. Updated on November 18, 2005.
9. ^  Bird flu vaccine won't precede pandemic (http://www.upi.com/ConsumerHealthDaily/view.php?StoryID=20051128-054641-9412r) by Jennifer Schultz for United Press International (November 28 2005).
10. ^  "Avian Influenza: 'Pandemic Vaccine' Appears to Protect Only at High Doses" by Martin Enserink in Science, volume 309, page 996, 12 August 2005 DOI:10.1126/science.309.5737.996b (http://dx.doi.org/10.1126/science.309.5737.996b)
11. ^ ^  Oseltamivir (Tamiflu) information (http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500062.html) from United States National Institutes of Health. Webpage content initially developed on January 13, 2000 and revised on January 10, 2001.
12. ^ ^  Full text article online: "Avian Influenza A (H5N1) Infection in Humans (http://content.nejm.org/cgi/content/full/353/13/1374)" by The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5 in New England Journal of Medicine (29 September 2005) Volume 353 pages 1374-1385.
13. ^ Influenza: The world is teetering on the edge of a pandemic that could kill a large fraction of the human population (http://www.scs.carleton.ca/~soma/biosec/readings/influenza/influenza.html) by Robert G. Webster and Elizabeth Jane Walker in American Scientist 2003 Volume 91 Page 122.
14. ^  Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16283933) by M. C. Chan et al in Respiratory Research 2005 Volume 6 page 135.
15. ^  Influenza virus replication (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.3069) in Medical Microbiology, 4th edition edited by Samuel Baron. 1996 Chapter 58. ISBN 0963117211.
16. ^ Bird Flu Drug Rendered Useless: Chinese Chickens Given Medication Made for Humans (http://www.washingtonpost.com/wp-dyn/content/article/2005/06/17/AR2005061701214.html) By Alan Sipress in the Washington Post Saturday, June 18 2005.
17. ^ {Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature. 2005 October 6;437(7060):889-893}
18. ^ {Tumpey TM, Basler CF, Aguilar PV, Zeng H, Solorzano A, Swayne DE, Cox NJ, Katz JM, Taubenberger JK, Palese P, Garcia-Sastre A. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science. 2005 October 7;310(5745):77-80}

• Centers for Disease Control 2005. "Key Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus: May 24 2005." (http://www.cdc.gov/flu/avian/gen-info/facts.htm)
• Horimoto, T. & Kawaoka, Y. 2005. Influenza. In Nature reviews microbiology, 3, 591 – 600.
• Kuiken T et al 2004, Avian H5N1 Influenza in Cats, Science 2004 306: 241 (DOI:10.1126/science.1102287 (http://dx.doi.org/10.1126/science.1102287))

External links and sources

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Official

• WHO Avian influenza resource (updated) (http://www.who.int/csr/disease/avian_influenza/en/)
• CDC Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus (http://www.cdc.gov/flu/avian/gen-info/facts.htm)
• U.S. Agency for International Development (USAID) Avian Influenza Response (http://www.usaid.gov/our_work/global_health/home/News/news_items/avian_influenza.html)
• Global statistics of avian influenza (http://www.info.gov.hk/info/flu/eng/global.htm)
• U.S. Government's avian flu information site (http://www.pandemicflu.gov)
• National Wildlife Health Center (NWHC): Avian Influenza (http://www.nwhc.usgs.gov/research/avian_influenza/avian_influenza_maps.html)
• Official outbreak reports by country (http://www.oie.int/downld/AVIAN%20INFLUENZA/A_AI-Asia.htm)
• Official outbreak reports by week (http://www.oie.int/eng/info/hebdo/a_isum.htm)
• Chart of outbreaks by country (http://www.oie.int/downld/AVIAN%20INFLUENZA/graph%20HPAI%2010112005.pdf)

Technical

• Links and descriptions to abstracts and full texts (http://wildlifedisease.nbii.gov/diseasepublications.jsp?disease=Avian%20Influenza) This bibliography of avian influenza publications was complied through the cooperative effort of the USGS National Wildlife Health Center and the Wildlife Disease Information Node.
• Search for research publications about H5N1: Entez PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi)
• Latest publications on H5N1 (http://www.biojournals.com/h5n1.html)
• Full HTML text of Avian Influenza A (H5N1) Infection in Humans (http://content.nejm.org/cgi/content/full/353/13/1374) by The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5 in the 29 September 2005 New England Journal of Medicine
• Evolutionary "Tree of Life" for H5N1:
  • Here (http://www.nap.edu/books/0309095042/html/79.html) is the phylogenetic tree of the influenza virus hemagglutinin gene segment. Amino acid changes in three lineages (bird, pig, human) of the influenza virus hemagglutinin protein segment HA1.
  • Here (http://www.nap.edu/books/0309095042/html/123.html#p2000c2099960123001) is the tree showing the evolution by reassortment of H5N1 from 1999 to 2004 that created the Z genotype in 2002.
  • Here (http://www.cdc.gov/ncidod/EID/vol11no10/05-0644-G1.htm) is the tree showing evolution by antigenic drift since 2002 that created dozens of highly pathogenic varieties of the Z genotype of avian flu virus H5N1, some of which are increasingly adopted to mammals.
• Evolutionary characterization of the six internal genes of H5N1 human influenza A virus (http://vir.sgmjournals.org/cgi/content/full/81/5/1293)
• Both overview and technical details on influenza viruses with emphasis on the potential H5N1 pandemic (http://sunzi.lib.hku.hk/hkuto/view/B30456721/ft.pdf)

News

• Current status (http://news.google.com/news?q=CDC%20avian%20flu%20threat&hl=en&lr=&sa=N&tab=wn)
• New Scientist Special Report (frequently updated) (http://www.newscientist.com/channel/health/bird-flu)
• Emergency Measures Avian flu is on the rise in Vietnam and is now endemic in much of Asia. Can heightened vigilance keep it at bay? (http://www.time.com/time/asia/magazine/article/0,13673,501050207-1022651,00.html)
• H5N1Drome Avian Flu News from Around the Web (http://www.H5N1drome.com)

General information

• Bird Flu Fears: Is There a Better Way to Develop Drugs? (Center for Economic and Policy Research) October 2005 (PDF) (http://www.cepr.net/publications/intellectual_property_2005_10.pdf)
• Nature Magazine: Avian flu special: The flu pandemic: were we ready!? (http://www.nature.com/nature/journal/v435/n7041/full/435400a.html) - Fictional account of flu epidemic from Nature magazine
• EPIDEMIca: Coverage of the ongoing H5N1 outbreak in China, Vietnam and Thailand (http://www.epidemi.ca)
• A blog on H5N1 (http://crofsblogs.typepad.com/h5n1/)
• On line book available here (http://www.nap.edu/openbook/0309095042/html/R1.html) called "The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005)" by Board on Global Health (BGH) from the INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIESes:H5N1

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