Transmission and infection of H5N1: Difference between revisions
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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 initially denied past outbreaks of [[severe acute respiratory syndrome]] (SARS) and [[HIV]], although there have been some signs of improvement regarding its openess in recent months, particularly with regard to H5N1. |
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 initially denied past outbreaks of [[severe acute respiratory syndrome]] (SARS) and [[HIV]], although there have been some signs of improvement regarding its openess in recent months, particularly with regard to H5N1. |
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[[H5N1]] infections in humans are generally caused by bird to human transmission of the virus. Until May 2006, the WHO estimate of the number of human to human transmission had been "two or three cases". On [[May 24]], [[2006]], Dr. Julie L. Gerberding, director of the United States [[Centers for Disease Control and Prevention]] in [[Atlanta]], estimated that there had been "at least three." On [[May 30]], Maria Cheng, a WHO spokeswoman, said there were "probably about half a dozen," but that no one "has got a solid number."<ref>{{cite news| url=http://www.nytimes.com/2006/06/04/world/asia/04flu.html?ex=1150084800&en=595ebe1cf527875b&ei=5070&emc=eta1 | title=Human Flu Transfers May Exceed Reports | publisher=New York Times | date=[[June 4]] [[2006]] | author=Donald G. McNeil Jr.}}</ref> A few isolated cases of suspected human to human transmission exist<ref> |
[[H5N1]] infections in humans are generally caused by bird to human transmission of the virus. Until May 2006, the WHO estimate of the number of human to human transmission had been "two or three cases". On [[May 24]], [[2006]], Dr. Julie L. Gerberding, director of the United States [[Centers for Disease Control and Prevention]] in [[Atlanta]], estimated that there had been "at least three." On [[May 30]], Maria Cheng, a WHO spokeswoman, said there were "probably about half a dozen," but that no one "has got a solid number."<ref>{{cite news| url=http://www.nytimes.com/2006/06/04/world/asia/04flu.html?ex=1150084800&en=595ebe1cf527875b&ei=5070&emc=eta1 | title=Human Flu Transfers May Exceed Reports | publisher=New York Times | date=[[June 4]] [[2006]] | author=Donald G. McNeil Jr.}}</ref> A few isolated cases of suspected human to human transmission exist.<ref>{{cite news |
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| url=http://www.bloomberg.com/apps/news?pid=10000080&sid=aWESsJvt6CFE&refer=asia |
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| title=Seven Indonesian Bird Flu Cases Linked to Patients |
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| publisher=Bloomberg |
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| date=May 23, 2006 |
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}}</ref> with the latest such case in June 2006 (among members of a family in Sumatra).<ref>{{cite web |
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| url=http://www.foodconsumer.org/777/8/WHO_Confirms_Human_Transmission_In_Indonesian_Bird_Flu_Cluster.shtml |
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| title=WHO confirms human transmission< in Indonesian bird flu cluster |
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}}</ref> No [[pandemic]] strain of H5N1 has yet been found. The key point is that, at present, "the virus is not spreading efficiently or sustainably among humans."<ref>{{cite news|url=http://www.who.int/csr/don/2006_06_06/en/index.html|title=Avian influenza – situation in Indonesia – update 17|publisher=[[WHO]]|date=[[June 6]] [[2006]]}}</ref> |
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There is also concern, although no definitive proof, that other animals — particularly cats — may be able to act as a bridge between birds and humans. So far several cats have been confirmed to have died from H5N1 and the fact that cats have regular close contact with both birds and humans means monitoring of H5N1 in cats will need to continue. |
There is also concern, although no definitive proof, that other animals — particularly cats — may be able to act as a bridge between birds and humans. So far several cats have been confirmed to have died from H5N1 and the fact that cats have regular close contact with both birds and humans means monitoring of H5N1 in cats will need to continue. |
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{{H5N1 case graph}} |
{{H5N1 case graph}} |
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[[H5N1]] vaccines for chickens exists and is sometimes used, although there are many difficulties that make deciding if it helps more or hurts more especially difficult. [[H5N1]] pre-pandemic vaccines exist in quanties sufficient to inoculate a few million people.<ref> |
[[H5N1]] vaccines for chickens exists and is sometimes used, although there are many difficulties that make deciding if it helps more or hurts more especially difficult. [[H5N1]] pre-pandemic vaccines exist in quanties sufficient to inoculate a few million people.<ref>{{cite web |
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| url=http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/jul0506hhsreport.html |
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| publisher=CIDRAP |
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HHS has enough H5N1 vaccine for 4 million people'' published July 5, 2006</ref> [[H5N1]] pandemic vaccines and technologies to rapidly create them are in the [[H5N1 clinical trials]] stage but can not be verified as useful until after there exists a pandemic strain. |
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| title=HHS has enough H5N1 vaccine for 4 million people |
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| date=July 5, 2006 |
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}}</ref> [[H5N1]] pandemic vaccines and technologies to rapidly create them are in the [[H5N1 clinical trials]] stage but can not be verified as useful until after there exists a pandemic strain. |
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==Avian flu in birds== |
==Avian flu in birds== |
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{{See also|Flu_vaccine#Flu vaccine for nonhumans}} |
{{See also|Flu_vaccine#Flu vaccine for nonhumans}} |
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According to ''Avian Influenza'' by Timm C. Harder and Ortrud Werner: |
According to ''Avian Influenza'' by Timm C. Harder and Ortrud Werner: |
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:Following an incubation period of usually a few days (but rarely up to 21 days), depending upon the characteristics of the isolate, the dose of inoculum, the species, and age of the bird, the clinical presentation of avian influenza in birds is variable and symptoms are fairly unspecific |
:Following an incubation period of usually a few days (but rarely up to 21 days), depending upon the characteristics of the isolate, the dose of inoculum, the species, and age of the bird, the clinical presentation of avian influenza in birds is variable and symptoms are fairly unspecific.<ref>{{cite journal |
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| title=Performance of clinical signs in poultry for the detection of outbreaks during the avian influenza A (H7N7) epidemic in The Netherlands in 2003 |
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| author=A.R. Elbers, G. Kock and A. Bouma |
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| journal=Avian Pathol |
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| year=2005 |
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| page=181-7 |
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| volume=34 |
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| url=http://amedeo.com/lit.php?id=16191700 |
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}}</ref> Therefore, a diagnosis solely based on the clinical presentation is impossible. The symptoms following infection with low pathogenic AIV may be as discrete as ruffled feathers, transient reductions in egg production or weight loss combined with a slight respiratory disease.<ref>{{cite journal |
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| author=I. Capua and F. Mutinelli |
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| title=Low pathogenicity (LPAI) and highly pathogenic (HPAI) avian influenza in turkeys and chicken |
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| journal=A Colour Atlas and Text on Avian Influenza |
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| year=2001 |
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| page=13-20 |
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}}</ref> Some LP strains such as certain Asian H9N2 lineages, adapted to efficient replication in poultry, may cause more prominent signs and also significant mortality.<ref>{{cite journal |
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| author=S. Bano S, K. Naeem K, S.A. Malik |
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| title=Evaluation of pathogenic potential of avian influenza virus serotype H9N2 in chicken |
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| url=http://amedeo.com/lit.php?id=14575070 |
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| year=2003 |
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| journal=Avian Dis |
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| volume=47, Suppl |
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| page=17-22 |
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}}</ref><ref>{{cite journal |
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| author=C Li, K Yu, G TiaG, D Yu, L Liu, B Jing, J Ping, H. Chen |
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| title=Evolution of H9N2 influenza viruses from domestic poultry in Mainland China |
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| journal=Virology |
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| year=2005 |
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| volume=340 |
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| page=70-83 |
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| url=http://amedeo.com/lit.php?id=16026813 |
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}}</ref> In its highly pathogenic form, the illness in chickens and turkeys is characterised by a sudden onset of severe symptoms and a mortality that can approach 100% within 48 hours.<ref>{{cite journal |
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| author=D.E. Swayne, D.L. Suarez |
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| title=Highly pathogenic avian influenza |
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| journal=Rev Sci Tech |
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| year=2000 |
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| volume=19 |
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| page=463-8 |
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| url=http://amedeo.com/lit.php?id=10935274 |
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}}</ref><ref>{{cite web |
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| url=http://www.influenzareport.com/ir/ai.htm |
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| title=Avian Influenza |
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| author=Timm C. Harder and Ortrud Werner |
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| publisher=Influenza Report |
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}}</ref> |
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Poultry farming practices have changed due to H5N1: |
Poultry farming practices have changed due to H5N1: |
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*limiting workers contact with [[Cockfight|cock fighting]] |
*limiting workers contact with [[Cockfight|cock fighting]] |
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*reducing purchases of live fowl |
*reducing purchases of live fowl |
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*improving veterinary [[vaccine]] availability and cost. <ref> |
*improving veterinary [[vaccine]] availability and cost. <ref>{{cite web |
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| url=http://www.cfr.org/pub8198/laurie_garrett_anthony_s_fauci_michael_osterholm_rita_colwell/the_threat_of_global_pandemics.php |
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| publisher=Council on Foreign Relations |
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| title=The Threat of Global Pandemics |
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| accessdate=2006-09-15 |
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| date=June 16, 2005 |
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}}</ref> |
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For example, after nearly two years of using mainly culling to control the virus, the [[Vietnam]] government in [[2005]] adopted a combination of mass poultry vaccination, disinfecting, culling, information campaigns and bans on live poultry in cities.<ref> |
For example, after nearly two years of using mainly culling to control the virus, the [[Vietnam]] government in [[2005]] adopted a combination of mass poultry vaccination, disinfecting, culling, information campaigns and bans on live poultry in cities.<ref>{{cite news |
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| url=http://today.reuters.co.uk/news/newsArticle.aspx?type=worldNews&storyID=2006-04-28T080147Z_01_HAN5054_RTRUKOC_0_UK-BIRDFLU-VIETNAM.xml |
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| publisher=Reuters |
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| title=Vietnam to unveil advanced plan to fight bird flu |
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| date=April 28, 2006 |
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}}</ref> |
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Webster ''et al'' write |
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According to the [[CDC]] article ''H5N1 Outbreaks and Enzootic Influenza'' by [[Robert G. Webster]] et. al.:"Transmission of highly pathogenic H5N1 from domestic poultry back to migratory waterfowl in western China has increased the geographic spread. The spread of H5N1 and its likely reintroduction to domestic poultry increase the need for good agricultural vaccines. In fact, the root cause of the continuing H5N1 pandemic threat may be the way the pathogenicity of H5N1 viruses is masked by cocirculating influenza viruses or bad agricultural vaccines."<ref>[http://www.cdc.gov/ncidod/EID/vol12no01/05-1024.htm CDC] ''H5N1 Outbreaks and Enzootic Influenza'' by [[Robert G. Webster]] et. al.</ref> Dr. Robert Webster explains: "If you use a good vaccine you can prevent the transmission within poultry and to humans. But if they have been using vaccines now [in China] for several years, why is there so much bird flu? There is bad vaccine that stops the disease in the bird but the bird goes on pooping out virus and maintaining it and changing it. And I think this is what is going on in China. It has to be. Either there is not enough vaccine being used or there is substandard vaccine being used. Probably both. It’s not just China. We can’t blame China for substandard vaccines. I think there are substandard vaccines for influenza in poultry all over the world." <ref> [http://www.msnbc.msn.com/id/10639567/ MSNBC quoting Reuters quoting Robert G. Webster]</ref> In response to the same concerns, Reuters reports Hong Kong infectious disease expert Lo Wing-lok saying, "The issue of vaccines has to take top priority," and Julie Hall, in charge of the WHO's outbreak response in China, saying China's vaccinations might be masking the virus." <ref> |
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:Transmission of highly pathogenic H5N1 from domestic poultry back to migratory waterfowl in western China has increased the geographic spread. The spread of H5N1 and its likely reintroduction to domestic poultry increase the need for good agricultural vaccines. In fact, the root cause of the continuing H5N1 pandemic threat may be the way the pathogenicity of H5N1 viruses is masked by cocirculating influenza viruses or bad agricultural vaccines."<ref>{{cite journal |
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| url=http://www.cdc.gov/ncidod/EID/vol12no01/05-1024.htm |
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| title=H5N1 Outbreaks and Enzootic Influenza |
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| author=[[Robert G. Webster]] ''et al'' |
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| journal=Emerging Infectious Diseases |
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| date=January, 2006 |
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| accessdate=2006-09-15 |
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}}</ref> |
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Dr. Robert Webster explains: "If you use a good vaccine you can prevent the transmission within poultry and to humans. But if they have been using vaccines now [in China] for several years, why is there so much bird flu? There is bad vaccine that stops the disease in the bird but the bird goes on pooping out virus and maintaining it and changing it. And I think this is what is going on in China. It has to be. Either there is not enough vaccine being used or there is substandard vaccine being used. Probably both. It’s not just China. We can’t blame China for substandard vaccines. I think there are substandard vaccines for influenza in poultry all over the world." <ref>{{cite news |
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| url=http://www.msnbc.msn.com/id/10639567/ |
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| title=Expert: Bad vaccines may trigger China bird flu |
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| date=December 30, 2005 |
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| publisher=MSNBC |
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| accessdate=2006-09-15 |
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}}</ref> In response to the same concerns, Reuters reports Hong Kong infectious disease expert Lo Wing-lok saying, "The issue of vaccines has to take top priority," and Julie Hall, in charge of the WHO's outbreak response in China, saying China's vaccinations might be masking the virus." <ref> |
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{{cite news |
{{cite news |
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| title=China H5N1 outbreak puts vaccines under spotlight |
| title=China H5N1 outbreak puts vaccines under spotlight |
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| publisher=Reuters |
| publisher=Reuters |
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| date=March 19, 2006 |
| date=March 19, 2006 |
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| accessdate=2006-09-15 |
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}} ''This reference is apparently no longer available online via Reuters. It's available as of 21 August, 2006 at [http://bak.flu.org.cn/news/20063196219.htm]''</ref> The BBC reported that Dr Wendy Barclay, a virologist at the University of Reading, UK said: "The Chinese have made a vaccine based on reverse genetics made with H5N1 antigens, and they have been using it. There has been a lot of criticism of what they have done, because they have protected their chickens against death from this virus but the chickens still get infected; and then you get drift - the virus mutates in response to the antibodies - and now we have a situation where we have five or six 'flavours' of H5N1 out there." <ref>[http://news.bbc.co.uk/1/hi/sci/tech/4737276.stm BBC] ''Bird flu vaccine no silver bullet'' 22 February 2006</ref> |
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}} ''This reference is apparently no longer available online via Reuters. It is available as of 21 August, 2006 at [http://bak.flu.org.cn/news/20063196219.htm]''</ref> The BBC reported that Dr Wendy Barclay, a virologist at the University of Reading, UK said: "The Chinese have made a vaccine based on reverse genetics made with H5N1 antigens, and they have been using it. There has been a lot of criticism of what they have done, because they have protected their chickens against death from this virus but the chickens still get infected; and then you get drift - the virus mutates in response to the antibodies - and now we have a situation where we have five or six 'flavours' of H5N1 out there." <ref>{{cite web |
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| url=http://news.bbc.co.uk/1/hi/sci/tech/4737276.stm |
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| title=Bird flu vaccine no silver bullet |
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| publisher=BBC |
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| date=February 22, 2006 |
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| accessdate=2006-09-15 |
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}}</ref> |
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==Transmission by wild birds (waterfowl)== |
==Transmission by wild birds (waterfowl)== |
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According to the [[United Nations]] [[FAO]]: |
According to the [[United Nations]] [[FAO]]: |
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there is no denying the fact that wild water fowl most likely play a role in the avian influenza cycle and could be the initial source for AI viruses, which may be passed on through contact with resident water fowl or domestic poultry, particularly domestic ducks. The virus undergoing mutations could circulate within the domestic and possibly resident bird populations until HPAI arises. This new virus is pathogenic to poultry and possibly to the wild birds that it arose from. Wild birds found to have been infected with HPAI were either sick or dead. This could possibly affect the ability of these birds to carry HPAI for long distances. However, the findings in Qinghai Lake-China, suggest that H5N1 viruses could possibly be transmitted between migratory birds. Additionally, the new outbreaks of HPAI in poultry and wild birds in Russia, Kazakhstan, Western China and Mongolia may indicate that migratory birds probably act as carriers for the transport of HPAI over longer distances. Short distance transmission between farms, villages or contaminated local water bodies is likewise a distinct possibility. The AI virus has adapted to the environment in ways such as: 1) the use of water for survival and to spread 2) has evolved in a reservoir (ducks) strictly tied to water. The water in turn influences movement, social behaviour and migration patterns of water bird species. It is therefore of great importance to know the ecological strategy of influenza virus as well, in order to fully understand this disease and to control outbreaks when they occur. There remains a body of data and analysis missing on the collection and detection of HPAI viruses in wild birds. Finding HPAI viruses in wild birds may be a rare event, but if the contact with susceptible species occurs it can cause an outbreak at the local level or in distant areas. <ref> |
there is no denying the fact that wild water fowl most likely play a role in the avian influenza cycle and could be the initial source for AI viruses, which may be passed on through contact with resident water fowl or domestic poultry, particularly domestic ducks. The virus undergoing mutations could circulate within the domestic and possibly resident bird populations until HPAI arises. This new virus is pathogenic to poultry and possibly to the wild birds that it arose from. Wild birds found to have been infected with HPAI were either sick or dead. This could possibly affect the ability of these birds to carry HPAI for long distances. However, the findings in Qinghai Lake-China, suggest that H5N1 viruses could possibly be transmitted between migratory birds. Additionally, the new outbreaks of HPAI in poultry and wild birds in Russia, Kazakhstan, Western China and Mongolia may indicate that migratory birds probably act as carriers for the transport of HPAI over longer distances. Short distance transmission between farms, villages or contaminated local water bodies is likewise a distinct possibility. The AI virus has adapted to the environment in ways such as: 1) the use of water for survival and to spread 2) has evolved in a reservoir (ducks) strictly tied to water. The water in turn influences movement, social behaviour and migration patterns of water bird species. It is therefore of great importance to know the ecological strategy of influenza virus as well, in order to fully understand this disease and to control outbreaks when they occur. There remains a body of data and analysis missing on the collection and detection of HPAI viruses in wild birds. Finding HPAI viruses in wild birds may be a rare event, but if the contact with susceptible species occurs it can cause an outbreak at the local level or in distant areas. <ref>{{cite web |
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| url=http://www.fao.org/ag/againfo/subjects/en/health/diseases-cards/avian_HPAIrisk.html |
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| publisher=FAO |
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| title=Wild birds and Avian Influenza |
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| accessdate=2006-09-15 |
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}}</ref> |
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==Prevention== |
==Prevention== |
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There are several [[H5N1]] [[vaccine]]s 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]]." <ref>[http://www.upi.com/ConsumerHealthDaily/view.php?StoryID=20051128-054641-9412r Bird flu vaccine won't precede pandemic] by Jennifer Schultz for [[United Press International]] ([[November 28]] [[2005]])</ref> 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 <ref>Promising research into vaccines includes 1)"Avian Influenza: 'Pandemic Vaccine' Appears to Protect Only at High Doses" by Martin Enserink in ''[[Science (journal)|Science]]'', volume 309, page 996, [[12 August]] [[2005]] {{DOI|10.1126/science.309.5737.996b}} 2) [http://www.sciencedaily.com/upi/index.php?feed=Science&article=UPI-1-20060127-15211900-bc-us-fluwrap.xml Science Daily] GlaxoSmithKline in London announced Thursday that it would begin clinical trials of its H5N1 vaccine in April. 3) [http://pittsburghlive.com/x/tribune-review/trib/pittsburgh/s_418036.html Tribune-Review] A promising new bird flu vaccine developed by University of Pittsburgh researchers could provide better protection and be made more quickly than other experimental vaccines.</ref>. 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. |
There are several [[H5N1]] [[vaccine]]s 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]]." <ref>[http://www.upi.com/ConsumerHealthDaily/view.php?StoryID=20051128-054641-9412r Bird flu vaccine won't precede pandemic] by Jennifer Schultz for [[United Press International]] ([[November 28]] [[2005]])</ref> 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 <ref>Promising research into vaccines includes 1)"Avian Influenza: 'Pandemic Vaccine' Appears to Protect Only at High Doses" by Martin Enserink in ''[[Science (journal)|Science]]'', volume 309, page 996, [[12 August]] [[2005]] {{DOI|10.1126/science.309.5737.996b}} 2) [http://www.sciencedaily.com/upi/index.php?feed=Science&article=UPI-1-20060127-15211900-bc-us-fluwrap.xml Science Daily] GlaxoSmithKline in London announced Thursday that it would begin clinical trials of its H5N1 vaccine in April. 3) [http://pittsburghlive.com/x/tribune-review/trib/pittsburgh/s_418036.html Tribune-Review] A promising new bird flu vaccine developed by University of Pittsburgh researchers could provide better protection and be made more quickly than other experimental vaccines.</ref>. 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. |
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It is not likely that use of [[antiviral drug]]s could prevent the evolution of a pandemic flu virus <ref name="tamiflu">Oseltamivir (Tamiflu) |
It is not likely that use of [[antiviral drug]]s could prevent the evolution of a pandemic flu virus <ref name="tamiflu">{{cite web |
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| title=Oseltamivir (Tamiflu) |
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| url=http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500062.html |
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| publisher=[[National Institutes of Health]] |
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| date=January 13, 2000 |
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}} Revised on January 10, 2001. |
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</ref>. |
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==Environmental survival== |
==Environmental survival== |
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Heat kills [[H5N1]] (i.e. inactivates the virus): |
Heat kills [[H5N1]] (i.e. inactivates the virus): |
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*Over 30 days at 0ºC ( |
* Over 30 days at 0ºC (32.0ºF) (over one month at freezing temperature) |
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* 6 days at 37ºC ( |
* 6 days at 37ºC (98.6ºF) (one week at human body temperature) |
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*30 minutes 60ºC (140.0ºF) (half hour at a temperature that causes first and second degree burns in humans in ten seconds) |
* 30 minutes 60ºC (140.0ºF) (half hour at a temperature that causes first and second degree burns in humans in ten seconds)<ref>{{cite web |
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| url=http://www.accuratebuilding.com/services/legal/charts/hot_water_burn_scalding_graph.html |
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| title=Hot Water Burn & Scalding Graph |
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| accessdate=2006-09-15 |
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}}</ref> |
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Inactivation of the virus also occurs under the following conditions: |
Inactivation of the virus also occurs under the following conditions: |
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* |
* [[Acid]]ic [[pH]] conditions |
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* Presence of oxidizing |
* Presence of [[oxidizing agent]]s such as [[sodium dodecyl sulfate]], lipid [[solvent]]s, and [[B-propiolactone]] |
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* Exposure to [[disinfectant]]s: [[formalin]], [[iodine]] compounds <ref>{{cite web |
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* Exposure to disinfectants: formalin, iodine compounds <ref>[http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/biofacts/avflu_human.html Avian flu biofacts from CIDRAP] [http://www.wbuf.noaa.gov/tempfc.htm NOAA] [http://www.accuratebuilding.com/services/legal/charts/hot_water_burn_scalding_graph.html temperature data]</ref> |
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| url=http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/biofacts/avflu_human.html |
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| title=Avian flu biofacts |
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| publisher=CIDRAP |
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}}</ref> |
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==Incubation== |
==Incubation== |
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The human incubation period of avian influenza A (H5N1) is 2 to 17 days<ref name="nejm">Full text article online: "[http://content.nejm.org/cgi/content/full/353/13/1374 Avian Influenza A (H5N1) Infection in Humans]" 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.</ref>. Once infected, the virus can spread by cell-to-cell contact, bypassing receptors. So even if a strain is very hard to initially catch, once infected, it spreads rapidly within a body.<ref> |
The human incubation period of avian influenza A (H5N1) is 2 to 17 days<ref name="nejm">Full text article online: "[http://content.nejm.org/cgi/content/full/353/13/1374 Avian Influenza A (H5N1) Infection in Humans]" 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.</ref>. Once infected, the virus can spread by cell-to-cell contact, bypassing receptors. So even if a strain is very hard to initially catch, once infected, it spreads rapidly within a body.<ref>{{cite web |
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| url=http://www.epw.org.in/showArticles.php?root=2005&leaf=11&filename=9325&filetype=html |
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| title=Bird Flu: Public Health Implications for India |
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| author=T Jacob John |
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| date=November 12, 2005 |
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| publisher=Economic and Political Weekly |
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}}</ref> |
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==Symptoms== |
==Symptoms== |
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Highly pathogenic [[H5N1]] [[avian flu]] in a human is far worse, killing over 50% of humans that catch it. In one case, a boy with H5N1 experienced [[diarrhea]] followed rapidly by a [[coma]] without developing respiratory or flu-like symptoms. <ref>[http://content.nejm.org/cgi/content/short/352/7/686 New England Journal of Medicine] Volume 352:686-691 - February 17, 2005 - Number 7 - ''Fatal Avian Influenza A (H5N1) in a Child Presenting with Diarrhea Followed by Coma''</ref> |
Highly pathogenic [[H5N1]] [[avian flu]] in a human is far worse, killing over 50% of humans that catch it. In one case, a boy with H5N1 experienced [[diarrhea]] followed rapidly by a [[coma]] without developing respiratory or flu-like symptoms. <ref>[http://content.nejm.org/cgi/content/short/352/7/686 New England Journal of Medicine] Volume 352:686-691 - February 17, 2005 - Number 7 - ''Fatal Avian Influenza A (H5N1) in a Child Presenting with Diarrhea Followed by Coma''</ref> |
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There have been studies of the levels of [[cytokine]]s in humans infected by the H5N1 flu virus. Of particular concern is elevated levels of [[Tumor necrosis factor|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 <ref> [http://www.scs.carleton.ca/~soma/biosec/readings/influenza/influenza.html Influenza: The world is teetering on the edge of a pandemic that could kill a large fraction of the human population] by Robert G. Webster and Elizabeth Jane Walker in ''American Scientist'' [[2003]] Volume 91 Page 122.</ref>. The [[Inflammation|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 <ref> |
There have been studies of the levels of [[cytokine]]s in humans infected by the H5N1 flu virus. Of particular concern is elevated levels of [[Tumor necrosis factor|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 <ref> [http://www.scs.carleton.ca/~soma/biosec/readings/influenza/influenza.html Influenza: The world is teetering on the edge of a pandemic that could kill a large fraction of the human population] by Robert G. Webster and Elizabeth Jane Walker in ''American Scientist'' [[2003]] Volume 91 Page 122.</ref>. The [[Inflammation|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 <ref>{{cite journal |
||
| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16283933 |
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| title=Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells |
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| author=M. C. Chan et al |
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| journal=Respiratory Research |
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| year=2005 |
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| volume=6 |
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| page=135 |
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}}</ref> Other important mechanisms also exist "in the acquisition of virulence in [[Influenzavirus A|avian influenza viruses]]" according to the [[CDC]].<ref>{{cite journal |
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| url=http://www.cdc.gov/ncidod/EID/vol10no12/04-0743.htm |
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| title=Novel Avian Influenza H7N3 Strain Outbreak, British Columbia |
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| author=Martin Hirst, Caroline R. Astell, Malachi Griffith, Shaun M. Coughlin, Michelle Moksa, Thomas Zeng ''et al'' |
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| date=December 2004 |
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| journal=Emerg Infect Dis |
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}}</ref> |
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The NS1 [[protein]] of the highly pathogenic avian [[H5N1]] [[virus]]es circulating in [[poultry]] and [[waterfowl]] in Southeast [[Asia]] is currently believed to be responsible for the enhanced proinflammatory [[cytokine]] response. H5N1 NS1 is characterized by a single [[amino acid]] change at position 92. By changing the amino acid from [[glutamic acid]] to [[aspartic acid]], researchers were able to abrogate the effect of the H5N1 NS1. This single amino acid change in the NS1 gene greatly increased the [[pathogenicity]] of the H5N1 influenza virus. |
The NS1 [[protein]] of the highly pathogenic avian [[H5N1]] [[virus]]es circulating in [[poultry]] and [[waterfowl]] in Southeast [[Asia]] is currently believed to be responsible for the enhanced proinflammatory [[cytokine]] response. H5N1 NS1 is characterized by a single [[amino acid]] change at position 92. By changing the amino acid from [[glutamic acid]] to [[aspartic acid]], researchers were able to abrogate the effect of the H5N1 NS1. This single amino acid change in the NS1 gene greatly increased the [[pathogenicity]] of the H5N1 influenza virus. |
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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 <ref name="tamiflu" />. It is marketed by [[Hoffmann-La Roche|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 o 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. |
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 <ref name="tamiflu" />. It is marketed by [[Hoffmann-La Roche|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 o 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. |
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A second class of drugs, which include [[amantadine]] and [[rimantadine]], target the M2 protein, but are ineffective against [[H5N1]]. Unlike zanamivir and oseltamivir, these drugs are inexpensive and widely available and the WHO had initially planned to use them in efforts to combat an [[H5N1]] pandemic. However, the potential of these drugs was considerably lessened when it was discovered that farmers in China have 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 these medications and hence significantly more dangerous to humans<ref> |
A second class of drugs, which include [[amantadine]] and [[rimantadine]], target the M2 protein, but are ineffective against [[H5N1]]. Unlike zanamivir and oseltamivir, these drugs are inexpensive and widely available and the WHO had initially planned to use them in efforts to combat an [[H5N1]] pandemic. However, the potential of these drugs was considerably lessened when it was discovered that farmers in China have 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 these medications and hence significantly more dangerous to humans<ref>{{cite news |
||
| url=http://www.washingtonpost.com/wp-dyn/content/article/2005/06/17/AR2005061701214.html |
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| title=Bird Flu Drug Rendered Useless: Chinese Chickens Given Medication Made for Humans |
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| author=Alan Sipress |
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| publisher=Washington Post |
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|date=June 18, 2005 |
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}}</ref>. |
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:However, recent data suggest that some strains of H5N1 are susceptible to the older drugs. An analysis of more than 600 H5N1 viruses collected in Southeast Asia showed that most samples from China and Indonesia lacked genetic characteristics signaling resistance to amantadine, whereas most samples from Vietnam, Thailand, and Cambodia had those characteristics. The report was published by the Journal of Infectious Diseases. The new WHO guidelines were drawn up by an international group of clinicians with experience treating H5N1 patients, along with other experts, at a meeting in late March. The panel systematically reviewed and graded the evidence for the drugs' effectiveness. Since no results from controlled trials of medication use in H5N1 cases are available, "Overall, the quality of the underlying evidence for all recommendations was very low," the 138-page WHO report states. The evidence includes results of lab and animal studies and indirect evidence from studies of antiviral use in patients with seasonal influenza. The recommendations are classified as "strong" or "weak," depending on the quality of the relevant evidence. The WHO says that if a patient has a confirmed or strongly suspected H5N1 case and NIs are available, "Clinicians should administer oseltamivir treatment (strong recommendation); zanamivir might be used as an alternative (weak recommendation)." Oseltamivir comes in capsule form, whereas zanamivir is taken with an inhaler. The WHO says zanamivir has lower bioavailability outside the respiratory tract than oseltamivir, but it may be active against some strains of oseltamivir-resistant H5N1 virus.<ref> |
:However, recent data suggest that some strains of H5N1 are susceptible to the older drugs. An analysis of more than 600 H5N1 viruses collected in Southeast Asia showed that most samples from China and Indonesia lacked genetic characteristics signaling resistance to amantadine, whereas most samples from Vietnam, Thailand, and Cambodia had those characteristics. The report was published by the Journal of Infectious Diseases. The new WHO guidelines were drawn up by an international group of clinicians with experience treating H5N1 patients, along with other experts, at a meeting in late March. The panel systematically reviewed and graded the evidence for the drugs' effectiveness. Since no results from controlled trials of medication use in H5N1 cases are available, "Overall, the quality of the underlying evidence for all recommendations was very low," the 138-page WHO report states. The evidence includes results of lab and animal studies and indirect evidence from studies of antiviral use in patients with seasonal influenza. The recommendations are classified as "strong" or "weak," depending on the quality of the relevant evidence. The WHO says that if a patient has a confirmed or strongly suspected H5N1 case and NIs are available, "Clinicians should administer oseltamivir treatment (strong recommendation); zanamivir might be used as an alternative (weak recommendation)." Oseltamivir comes in capsule form, whereas zanamivir is taken with an inhaler. The WHO says zanamivir has lower bioavailability outside the respiratory tract than oseltamivir, but it may be active against some strains of oseltamivir-resistant H5N1 virus.<ref> |
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In [[2005]], 42 of 97 people confirmed by the [[WHO]] to be infected with [[H5N1]] died -- or 43%. From [[January 1]] [[2006]] to [[September 14]] [[2006]], the case fatality ratio has been higher, with 66 deaths among 99 [[WHO]]-confirmed cases |
In [[2005]], 42 of 97 people confirmed by the [[WHO]] to be infected with [[H5N1]] died -- or 43%. From [[January 1]] [[2006]] to [[September 14]] [[2006]], the case fatality ratio has been higher, with 66 deaths among 99 [[WHO]]-confirmed cases |
||
<ref>{{cite web |
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<ref>http://www.who.int/csr/disease/avian_influenza/country/cases_table_2006_08_23/en/index.html</ref>-- or 67%. This has been interpreted by some to mean that the virus itself is becoming more deadly over time. <ref>[http://www.dymaxionweb.com/h5n1/archives/2006/05/h5n1_getting_de.html H5N1 Getting Deadlier], based on the article [http://www.bloomberg.com/apps/news?pid=10000080&sid=a7CJ0uPPpg.g Bird Flu Fatality Rate in Humans Climbs to 64% as Virus Spreads]</ref> The global case fatality ratio is, nonetheless, a crude summary of a complex situation with many contributing factors. In particular, if an [[influenza pandemic]] arises from one of the currently circulating strains of [[H5N1|Asian lineage HPAI A(H5N1)]], the mortality rates for the resulting human adapted [[influenza]] strain cannot be predicted with any confidence. |
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| url=http://www.who.int/csr/disease/avian_influenza/country/cases_table_2006_08_23/en/index.html |
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| title=Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO |
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| publisher=WHO |
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| date=August 23, 2006 |
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}}</ref>-- or 67%. This has been interpreted by some to mean that the virus itself is becoming more deadly over time. <ref>{{cite web |
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| url=http://www.dymaxionweb.com/h5n1/archives/2006/05/h5n1_getting_de.html |
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| title=H5N1 Getting Deadlier |
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}} based on the article {{cite web |
|||
| url=http://www.bloomberg.com/apps/news?pid=10000080&sid=a7CJ0uPPpg.g |
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| title=Bird Flu Fatality Rate in Humans Climbs to 64% as Virus Spreads |
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}}</ref> The global case fatality ratio is, nonetheless, a crude summary of a complex situation with many contributing factors. In particular, if an [[influenza pandemic]] arises from one of the currently circulating strains of [[H5N1|Asian lineage HPAI A(H5N1)]], the mortality rates for the resulting human adapted [[influenza]] strain cannot be predicted with any confidence. |
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[[H5N1]] is currently much better adapted to [[bird]]s than to other hosts, which is why the disease it causes is called a [[bird flu]]. No [[pandemic]] strain of H5N1 has yet been found. The precise nature and extent of the genetic alterations that might change one of the currently circulating [[avian flu]] strains into a [[human flu]] strain cannot be known in advance. While many of the current H5N1 strains circulating in birds can generate a dangerous [[cytokine storm]] in healthy adult humans <ref> |
[[H5N1]] is currently much better adapted to [[bird]]s than to other hosts, which is why the disease it causes is called a [[bird flu]]. No [[pandemic]] strain of H5N1 has yet been found. The precise nature and extent of the genetic alterations that might change one of the currently circulating [[avian flu]] strains into a [[human flu]] strain cannot be known in advance. While many of the current H5N1 strains circulating in birds can generate a dangerous [[cytokine storm]] in healthy adult humans <ref>{{cite web |
||
| url=http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/sep1106storm.html |
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| title=Clinical study points to cytokine storm in H5N1 cases |
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| date=September 11, 2006 |
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| publisher=CIDRAP News |
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}}</ref><ref>{{cite journal |
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| url=http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm1477.html |
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| title=Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia |
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| journal=Nature |
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| author=Menno D de Jong ''et al'' |
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| date=September 10, 2006 |
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}} Published online.</ref>, the ultimate pandemic strain might arise from a less-lethal strain, or its current level of lethality might be lost in the adaptation to a human host. |
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A case fatality ratio of over 50% provides a grim backdrop for the fact that the currently circulating H5N1 strains have certain genetic similarities with the [[Spanish Influenza]] pandemic virus. In that pandemic, 50 million to 100 million people worldwide were killed during about a year in [[1918]] and [[1919]] <ref> |
A case fatality ratio of over 50% provides a grim backdrop for the fact that the currently circulating H5N1 strains have certain genetic similarities with the [[Spanish Influenza]] pandemic virus. In that pandemic, 50 million to 100 million people worldwide were killed during about a year in [[1918]] and [[1919]] <ref> |
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| url=http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/mar2706cases.html |
| url=http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/mar2706cases.html |
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| title=Mild H5N1 cases weren’t found missed in Cambodian outbreak study |
| title=Mild H5N1 cases weren’t found missed in Cambodian outbreak study |
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| date= |
| date=March 27, 2006 |
||
| publisher=CIDRAP |
| publisher=CIDRAP |
||
}}</ref> <ref>{{cite news |
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}}</ref> <ref> [http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/sep0706cambodia.html CIDRAP] article ''Cambodian study suggests mild H5N1 cases are rare'' published September 7, 2006</ref> However, the precise allocation of H5N1 infections across the spectrum including lethal, serious, mild, and asymptomatic cases remains unknown in both humans and the hundreds of other species it can infect. Scientists are very concerned about what we do know about [[H5N1]]; but even more concerned about the vast amount of important data that we don't know about H5N1 and its future mutations. |
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| url=http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/sep0706cambodia.html |
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| title=Cambodian study suggests mild H5N1 cases are rare |
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| date=September 7, 2006 |
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| publisher=CIDRAP |
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}}</ref> However, the precise allocation of H5N1 infections across the spectrum including lethal, serious, mild, and asymptomatic cases remains unknown in both humans and the hundreds of other species it can infect. Scientists are very concerned about what we do know about [[H5N1]]; but even more concerned about the vast amount of important data that we don't know about H5N1 and its future mutations. |
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Review of patient ages and outcomes reveals that H5N1 attacks are especially lethal in pre-adults and young adults, while older victims tend to have milder attacks and to survive. |
Review of patient ages and outcomes reveals that H5N1 attacks are especially lethal in pre-adults and young adults, while older victims tend to have milder attacks and to survive. <ref>{{cite web |
||
| url=http://www.wpro.who.int/NR/rdonlyres/299B9BDC-67D8-40AC-81BE-0BC8D38E296A/0/S2_0814.jpg |
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| title=Human Avian Influenza A(H5N1) Cases by Age Group and Country |
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}}</ref> This is consistent with the frequent development of a [[cytokine storm]] in the afflicted.<ref>{{cite news |
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| url=http://www.nytimes.com/2006/09/11/world/11flu.html |
|||
| title=Immediate Treatment Needed for Bird Flu Cases, Study Says |
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| publisher=New York Times |
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| date=September 11, 2006 |
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}}</ref> Very few persons over 50 years of age died after suffering a H5N1 attack. Instead, the age-fatality curve of H5N1 influenza attacks in humans resembles that of the 1918 Spanish pandemic flu, and is the opposite of the mortality curve of seasonal flu strains, since seasonal influenza preferentially kills the elderly and does not kill by [[cytokine storm]]. |
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Another factor complicating any attempt to predict lethality of an eventual pandemic strain is that many human victims of the current H5N1 influenza have been blood relatives (but rarely spouses) of other victims. This data suggests that the victims' genetic susceptibility may have played a role in the human cases registered to date. |
Another factor complicating any attempt to predict lethality of an eventual pandemic strain is that many human victims of the current H5N1 influenza have been blood relatives (but rarely spouses) of other victims. This data suggests that the victims' genetic susceptibility may have played a role in the human cases registered to date. |
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=== Mortality rate in planning reports === |
=== Mortality rate in planning reports === |
||
Governments and other organisations at many levels and in many places have produced "planning" reports that, among other things, offer speculation on the mortality rate of an eventual pandemic. One such report states that "over half a million Americans could die and over 2.3 million could be hospitalized if a moderately severe strain of a pandemic flu virus hits the U.S."<ref> |
Governments and other organisations at many levels and in many places have produced "planning" reports that, among other things, offer speculation on the mortality rate of an eventual pandemic. One such report states that "over half a million Americans could die and over 2.3 million could be hospitalized if a moderately severe strain of a pandemic flu virus hits the U.S."<ref>{{cite web |
||
| publisher=Senior Journal |
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| date=June 24, 2005 |
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| title=Pandemic Flu Projection Says More Than Half Million Could Die in U.S. |
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| url=http://www.seniorjournal.com/Spotlights/FLU2005-06/5-06-24PandemicProjections.htm |
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}}</ref>. No one knows if "moderately severe" is an accurate guess or not. This report entitled ''A Killer Flu?''<ref>{{cite web |
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| url=http://healthyamericans.org/reports/flu/Flu2005.pdf |
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| title=Healthy Americans Full report PDF |
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}}</ref> shows an assumed (guessed) contraction rate of 25% and a severity similar to low severity flu pandemics causing 180 thousand deaths in the US and a 1918 level severity rate causing one million deaths in the US. There is no evidence an H5N1 flu pandemic would be between these figures<ref>{{cite web |
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| url=http://www.msnbc.msn.com/id/12610942/site/newsweek/ |
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| publisher=Newsweek |
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| title=A Dramatic Disconnect |
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}} estimates two million dead in the US, for example</ref> as no data is available reflecting similar virulance in any earlier flu strain as it emerged. The relatively low mortality rate in these and other such reports can not, therefore, be taken as reliable predictions of what the mortality rate of an H5N1 pandemic might be. The low assumed mortality rate does, however, serve the purpose of the reports, which is to show that we are not prepared ''even'' for severity levels that have occurred in the past, let alone the much higher case fatality ratios seen more recently. |
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==Notes and references== |
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==Sources== |
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<div class="references-small"> |
<div class="references-small" style="-moz-column-count:2; column-count:2;"><references/></div> |
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<references/> |
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</div> |
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==See also== |
==See also== |
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Line 145: | Line 325: | ||
{{wikinews|Category:Avian Flu}} |
{{wikinews|Category:Avian Flu}} |
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* |
* {{cite web | url=http://www.who.int/csr/disease/avian_influenza/en/ | title=WHO Avian influenza resource (updated)}} |
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* |
* {{cite web | url=http://www.cdc.gov/flu/avian/gen-info/facts.htm CDC | title=Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus}} |
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* |
* {{cite web | url=http://www.fao.org/ag/avian.html | title=FAO information on Avian Influenza - Latest news, Disease Card, Maps, Animations}} |
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* {{cite web |
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*[http://www.cidrap.umn.edu/cidrap/content/biosecurity/ag-biosec/anim-disease/avianflu.html Avian Influenza (Bird Flu): Agricultural and Wildlife Considerations] |
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| url=http://www.cidrap.umn.edu/cidrap/content/biosecurity/ag-biosec/anim-disease/avianflu.html |
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*[http://www.aafp.org/afp/20060901/783.html American Family Physician: Avian Influenza: Preparing for a Pandemic] |
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| title=Avian Influenza (Bird Flu): Agricultural and Wildlife Considerations |
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| publisher=CIDRAP |
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}} |
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* {{cite web |
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| url=http://www.aafp.org/afp/20060901/783.html |
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| publisher=American Family Physician |
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| title=Avian Influenza: Preparing for a Pandemic |
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}} |
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[[Category:Animal diseases]] |
[[Category:Animal diseases]] |
Revision as of 03:47, 15 September 2006
![]() |
Influenza (flu) |
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H5N1 flu refers to the transmission and infection of H5N1. H5N1 flu is a concern due to the global spread of H5N1 that constitutes a pandemic threat. This article is about the transmission of the H5N1 virus, infection by that virus, the resulting symptoms of that infection (having or coming down with influenza or more specifically avian flu or even more specifically H5N1 flu which can include pneumonia), and the medical response including treatment.
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 is more likely to 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 initially denied past outbreaks of severe acute respiratory syndrome (SARS) and HIV, although there have been some signs of improvement regarding its openess in recent months, particularly with regard to H5N1.
H5N1 infections in humans are generally caused by bird to human transmission of the virus. Until May 2006, the WHO estimate of the number of human to human transmission had been "two or three cases". On May 24, 2006, Dr. Julie L. Gerberding, director of the United States Centers for Disease Control and Prevention in Atlanta, estimated that there had been "at least three." On May 30, Maria Cheng, a WHO spokeswoman, said there were "probably about half a dozen," but that no one "has got a solid number."[1] A few isolated cases of suspected human to human transmission exist.[2] with the latest such case in June 2006 (among members of a family in Sumatra).[3] No pandemic strain of H5N1 has yet been found. The key point is that, at present, "the virus is not spreading efficiently or sustainably among humans."[4]
There is also concern, although no definitive proof, that other animals — particularly cats — may be able to act as a bridge between birds and humans. So far several cats have been confirmed to have died from H5N1 and the fact that cats have regular close contact with both birds and humans means monitoring of H5N1 in cats will need to continue.
![]() Notes:
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H5N1 vaccines for chickens exists and is sometimes used, although there are many difficulties that make deciding if it helps more or hurts more especially difficult. H5N1 pre-pandemic vaccines exist in quanties sufficient to inoculate a few million people.[5] H5N1 pandemic vaccines and technologies to rapidly create them are in the H5N1 clinical trials stage but can not be verified as useful until after there exists a pandemic strain.
Avian flu in birds
According to Avian Influenza by Timm C. Harder and Ortrud Werner:
- Following an incubation period of usually a few days (but rarely up to 21 days), depending upon the characteristics of the isolate, the dose of inoculum, the species, and age of the bird, the clinical presentation of avian influenza in birds is variable and symptoms are fairly unspecific.[6] Therefore, a diagnosis solely based on the clinical presentation is impossible. The symptoms following infection with low pathogenic AIV may be as discrete as ruffled feathers, transient reductions in egg production or weight loss combined with a slight respiratory disease.[7] Some LP strains such as certain Asian H9N2 lineages, adapted to efficient replication in poultry, may cause more prominent signs and also significant mortality.[8][9] In its highly pathogenic form, the illness in chickens and turkeys is characterised by a sudden onset of severe symptoms and a mortality that can approach 100% within 48 hours.[10][11]
Poultry farming practices have changed due to H5N1:
- killing millions of poultry
- vaccinating poultry against bird flu
- vaccinating poultry workers against human flu
- limiting travel in areas where H5N1 is found
- increasing farm hygiene
- reducing contact between livestock and wild birds
- reducing open-air wet markets
- limiting workers contact with cock fighting
- reducing purchases of live fowl
- improving veterinary vaccine availability and cost. [12]
For example, after nearly two years of using mainly culling to control the virus, the Vietnam government in 2005 adopted a combination of mass poultry vaccination, disinfecting, culling, information campaigns and bans on live poultry in cities.[13]
Webster et al write
- Transmission of highly pathogenic H5N1 from domestic poultry back to migratory waterfowl in western China has increased the geographic spread. The spread of H5N1 and its likely reintroduction to domestic poultry increase the need for good agricultural vaccines. In fact, the root cause of the continuing H5N1 pandemic threat may be the way the pathogenicity of H5N1 viruses is masked by cocirculating influenza viruses or bad agricultural vaccines."[14]
Dr. Robert Webster explains: "If you use a good vaccine you can prevent the transmission within poultry and to humans. But if they have been using vaccines now [in China] for several years, why is there so much bird flu? There is bad vaccine that stops the disease in the bird but the bird goes on pooping out virus and maintaining it and changing it. And I think this is what is going on in China. It has to be. Either there is not enough vaccine being used or there is substandard vaccine being used. Probably both. It’s not just China. We can’t blame China for substandard vaccines. I think there are substandard vaccines for influenza in poultry all over the world." [15] In response to the same concerns, Reuters reports Hong Kong infectious disease expert Lo Wing-lok saying, "The issue of vaccines has to take top priority," and Julie Hall, in charge of the WHO's outbreak response in China, saying China's vaccinations might be masking the virus." [16] The BBC reported that Dr Wendy Barclay, a virologist at the University of Reading, UK said: "The Chinese have made a vaccine based on reverse genetics made with H5N1 antigens, and they have been using it. There has been a lot of criticism of what they have done, because they have protected their chickens against death from this virus but the chickens still get infected; and then you get drift - the virus mutates in response to the antibodies - and now we have a situation where we have five or six 'flavours' of H5N1 out there." [17]
Transmission by wild birds (waterfowl)
![](http://upload.wikimedia.org/wikipedia/commons/thumb/9/99/Avian_influenza_spread_map.jpg/300px-Avian_influenza_spread_map.jpg)
According to the United Nations FAO: there is no denying the fact that wild water fowl most likely play a role in the avian influenza cycle and could be the initial source for AI viruses, which may be passed on through contact with resident water fowl or domestic poultry, particularly domestic ducks. The virus undergoing mutations could circulate within the domestic and possibly resident bird populations until HPAI arises. This new virus is pathogenic to poultry and possibly to the wild birds that it arose from. Wild birds found to have been infected with HPAI were either sick or dead. This could possibly affect the ability of these birds to carry HPAI for long distances. However, the findings in Qinghai Lake-China, suggest that H5N1 viruses could possibly be transmitted between migratory birds. Additionally, the new outbreaks of HPAI in poultry and wild birds in Russia, Kazakhstan, Western China and Mongolia may indicate that migratory birds probably act as carriers for the transport of HPAI over longer distances. Short distance transmission between farms, villages or contaminated local water bodies is likewise a distinct possibility. The AI virus has adapted to the environment in ways such as: 1) the use of water for survival and to spread 2) has evolved in a reservoir (ducks) strictly tied to water. The water in turn influences movement, social behaviour and migration patterns of water bird species. It is therefore of great importance to know the ecological strategy of influenza virus as well, in order to fully understand this disease and to control outbreaks when they occur. There remains a body of data and analysis missing on the collection and detection of HPAI viruses in wild birds. Finding HPAI viruses in wild birds may be a rare event, but if the contact with susceptible species occurs it can cause an outbreak at the local level or in distant areas. [18]
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 (a process called reassortment) 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 [19]. 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." [20] 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 [21]. 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 [22].
Environmental survival
Avian flu virus can last forever at a temperature dozens of degrees below freezing, as is found in the northern most areas that migratory birds frequent.
Heat kills H5N1 (i.e. inactivates the virus):
- Over 30 days at 0ºC (32.0ºF) (over one month at freezing temperature)
- 6 days at 37ºC (98.6ºF) (one week at human body temperature)
- 30 minutes 60ºC (140.0ºF) (half hour at a temperature that causes first and second degree burns in humans in ten seconds)[23]
Inactivation of the virus also occurs under the following conditions:
- Acidic pH conditions
- Presence of oxidizing agents such as sodium dodecyl sulfate, lipid solvents, and B-propiolactone
- Exposure to disinfectants: formalin, iodine compounds [24]
Incubation
The human incubation period of avian influenza A (H5N1) is 2 to 17 days[25]. Once infected, the virus can spread by cell-to-cell contact, bypassing receptors. So even if a strain is very hard to initially catch, once infected, it spreads rapidly within a body.[26]
Symptoms
- See also Pneumonia.
Avian influenza HA bind alpha 2-3 sialic acid receptors while human influenza HA bind alpha 2-6 sialic acid receptors. Usually other differences also exist. There is as yet no human form of H5N1, so all humans who have caught it so far have caught avian H5N1.
Human flu symptoms usually include fever, cough, sore throat, muscle aches, conjunctivitis and, in severe cases, severe breathing problems and pneumonia that may be fatal. The severity of the infection will depend to a large part on the state of the infected person's immune system and if the victim has been exposed to the strain before, and is therefore partially immune. No one knows if these or other symptoms will be the symptoms of a humanized H5N1 flu.
Highly pathogenic H5N1 avian flu in a human is far worse, killing over 50% of humans that catch it. In one case, a boy with H5N1 experienced diarrhea followed rapidly by a coma without developing respiratory or flu-like symptoms. [27]
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 [28]. 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 [29] Other important mechanisms also exist "in the acquisition of virulence in avian influenza viruses" according to the CDC.[30]
The NS1 protein of the highly pathogenic avian H5N1 viruses circulating in poultry and waterfowl in Southeast Asia is currently believed to be responsible for the enhanced proinflammatory cytokine response. H5N1 NS1 is characterized by a single amino acid change at position 92. By changing the amino acid from glutamic acid to aspartic acid, researchers were able to abrogate the effect of the H5N1 NS1. This single amino acid change in the NS1 gene greatly increased the pathogenicity of the H5N1 influenza virus.
In short, this one amino acid difference in the NS1 protein produced by the NS RNA molecule of the H5N1 virus is believed to be largely responsible for an increased pathogenicity (on top of the already increased pathogenicity of its hemagglutinin type which allows it to grow in organs other than lungs) that can manifest itself by causing a cytokine storm in a patient's body, often causing pneumonia and death.
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 [22]. 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 o 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, but are ineffective against H5N1. Unlike zanamivir and oseltamivir, these drugs are inexpensive and widely available and the WHO had initially planned to use them in efforts to combat an H5N1 pandemic. However, the potential of these drugs was considerably lessened when it was discovered that farmers in China have 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 these medications and hence significantly more dangerous to humans[31].
- However, recent data suggest that some strains of H5N1 are susceptible to the older drugs. An analysis of more than 600 H5N1 viruses collected in Southeast Asia showed that most samples from China and Indonesia lacked genetic characteristics signaling resistance to amantadine, whereas most samples from Vietnam, Thailand, and Cambodia had those characteristics. The report was published by the Journal of Infectious Diseases. The new WHO guidelines were drawn up by an international group of clinicians with experience treating H5N1 patients, along with other experts, at a meeting in late March. The panel systematically reviewed and graded the evidence for the drugs' effectiveness. Since no results from controlled trials of medication use in H5N1 cases are available, "Overall, the quality of the underlying evidence for all recommendations was very low," the 138-page WHO report states. The evidence includes results of lab and animal studies and indirect evidence from studies of antiviral use in patients with seasonal influenza. The recommendations are classified as "strong" or "weak," depending on the quality of the relevant evidence. The WHO says that if a patient has a confirmed or strongly suspected H5N1 case and NIs are available, "Clinicians should administer oseltamivir treatment (strong recommendation); zanamivir might be used as an alternative (weak recommendation)." Oseltamivir comes in capsule form, whereas zanamivir is taken with an inhaler. The WHO says zanamivir has lower bioavailability outside the respiratory tract than oseltamivir, but it may be active against some strains of oseltamivir-resistant H5N1 virus.[32]
Mortality rate
![]() Source: WHO Confirmed Human Cases of H5N1
|
In 2005, 42 of 97 people confirmed by the WHO to be infected with H5N1 died -- or 43%. From January 1 2006 to September 14 2006, the case fatality ratio has been higher, with 66 deaths among 99 WHO-confirmed cases [33]-- or 67%. This has been interpreted by some to mean that the virus itself is becoming more deadly over time. [34] The global case fatality ratio is, nonetheless, a crude summary of a complex situation with many contributing factors. In particular, if an influenza pandemic arises from one of the currently circulating strains of Asian lineage HPAI A(H5N1), the mortality rates for the resulting human adapted influenza strain cannot be predicted with any confidence.
H5N1 is currently much better adapted to birds than to other hosts, which is why the disease it causes is called a bird flu. No pandemic strain of H5N1 has yet been found. The precise nature and extent of the genetic alterations that might change one of the currently circulating avian flu strains into a human flu strain cannot be known in advance. While many of the current H5N1 strains circulating in birds can generate a dangerous cytokine storm in healthy adult humans [35][36], the ultimate pandemic strain might arise from a less-lethal strain, or its current level of lethality might be lost in the adaptation to a human host.
A case fatality ratio of over 50% provides a grim backdrop for the fact that the currently circulating H5N1 strains have certain genetic similarities with the Spanish Influenza pandemic virus. In that pandemic, 50 million to 100 million people worldwide were killed during about a year in 1918 and 1919 [37]. There is significant evidence that the high death rate among confirmed cases of the H5N1 virus cannot be simply attributed to mild cases being overlooked and thus omitted from the experience base of human H5N1 influenza attacks against which a fatality percentage is figured. [38] [39] However, the precise allocation of H5N1 infections across the spectrum including lethal, serious, mild, and asymptomatic cases remains unknown in both humans and the hundreds of other species it can infect. Scientists are very concerned about what we do know about H5N1; but even more concerned about the vast amount of important data that we don't know about H5N1 and its future mutations.
Review of patient ages and outcomes reveals that H5N1 attacks are especially lethal in pre-adults and young adults, while older victims tend to have milder attacks and to survive. [40] This is consistent with the frequent development of a cytokine storm in the afflicted.[41] Very few persons over 50 years of age died after suffering a H5N1 attack. Instead, the age-fatality curve of H5N1 influenza attacks in humans resembles that of the 1918 Spanish pandemic flu, and is the opposite of the mortality curve of seasonal flu strains, since seasonal influenza preferentially kills the elderly and does not kill by cytokine storm.
Another factor complicating any attempt to predict lethality of an eventual pandemic strain is that many human victims of the current H5N1 influenza have been blood relatives (but rarely spouses) of other victims. This data suggests that the victims' genetic susceptibility may have played a role in the human cases registered to date.
Mortality rate in planning reports
Governments and other organisations at many levels and in many places have produced "planning" reports that, among other things, offer speculation on the mortality rate of an eventual pandemic. One such report states that "over half a million Americans could die and over 2.3 million could be hospitalized if a moderately severe strain of a pandemic flu virus hits the U.S."[42]. No one knows if "moderately severe" is an accurate guess or not. This report entitled A Killer Flu?[43] shows an assumed (guessed) contraction rate of 25% and a severity similar to low severity flu pandemics causing 180 thousand deaths in the US and a 1918 level severity rate causing one million deaths in the US. There is no evidence an H5N1 flu pandemic would be between these figures[44] as no data is available reflecting similar virulance in any earlier flu strain as it emerged. The relatively low mortality rate in these and other such reports can not, therefore, be taken as reliable predictions of what the mortality rate of an H5N1 pandemic might be. The low assumed mortality rate does, however, serve the purpose of the reports, which is to show that we are not prepared even for severity levels that have occurred in the past, let alone the much higher case fatality ratios seen more recently.
Notes and references
- ^ Donald G. McNeil Jr. (June 4 2006). "Human Flu Transfers May Exceed Reports". New York Times.
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(help) - ^ "Seven Indonesian Bird Flu Cases Linked to Patients". Bloomberg. May 23, 2006.
- ^ "WHO confirms human transmission< in Indonesian bird flu cluster".
- ^ "Avian influenza – situation in Indonesia – update 17". WHO. June 6 2006.
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(help) - ^ "HHS has enough H5N1 vaccine for 4 million people". CIDRAP. July 5, 2006.
- ^ A.R. Elbers, G. Kock and A. Bouma (2005). "Performance of clinical signs in poultry for the detection of outbreaks during the avian influenza A (H7N7) epidemic in The Netherlands in 2003". Avian Pathol. 34: 181-7.
- ^ I. Capua and F. Mutinelli (2001). "Low pathogenicity (LPAI) and highly pathogenic (HPAI) avian influenza in turkeys and chicken". A Colour Atlas and Text on Avian Influenza: 13-20.
- ^ S. Bano S, K. Naeem K, S.A. Malik (2003). "Evaluation of pathogenic potential of avian influenza virus serotype H9N2 in chicken". Avian Dis. 47, Suppl: 17-22.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ C Li, K Yu, G TiaG, D Yu, L Liu, B Jing, J Ping, H. Chen (2005). "Evolution of H9N2 influenza viruses from domestic poultry in Mainland China". Virology. 340: 70-83.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ D.E. Swayne, D.L. Suarez (2000). "Highly pathogenic avian influenza". Rev Sci Tech. 19: 463-8.
- ^ Timm C. Harder and Ortrud Werner. "Avian Influenza". Influenza Report.
- ^ "The Threat of Global Pandemics". Council on Foreign Relations. June 16, 2005. Retrieved 2006-09-15.
- ^ "Vietnam to unveil advanced plan to fight bird flu". Reuters. April 28, 2006.
- ^ Robert G. Webster; et al. (January, 2006). "H5N1 Outbreaks and Enzootic Influenza". Emerging Infectious Diseases. Retrieved 2006-09-15.
{{cite journal}}
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(help); Explicit use of et al. in:|author=
(help) - ^ "Expert: Bad vaccines may trigger China bird flu". MSNBC. December 30, 2005. Retrieved 2006-09-15.
- ^
"China H5N1 outbreak puts vaccines under spotlight". Reuters. March 19, 2006.
{{cite news}}
:|access-date=
requires|url=
(help) This reference is apparently no longer available online via Reuters. It is available as of 21 August, 2006 at [1] - ^ "Bird flu vaccine no silver bullet". BBC. February 22, 2006. Retrieved 2006-09-15.
- ^ "Wild birds and Avian Influenza". FAO. Retrieved 2006-09-15.
- ^ Interim Guidance about Avian Influenza A (H5N1) for U.S. Citizens Living Abroad from the U.S. Centers for Disease Control and Prevention. Initial release, March 24, 2005. Updated on November 18, 2005.
- ^ Bird flu vaccine won't precede pandemic by Jennifer Schultz for United Press International (November 28 2005)
- ^ Promising research into vaccines includes 1)"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 2) Science Daily GlaxoSmithKline in London announced Thursday that it would begin clinical trials of its H5N1 vaccine in April. 3) Tribune-Review A promising new bird flu vaccine developed by University of Pittsburgh researchers could provide better protection and be made more quickly than other experimental vaccines.
- ^ a b "Oseltamivir (Tamiflu)". National Institutes of Health. January 13, 2000. Revised on January 10, 2001.
- ^ "Hot Water Burn & Scalding Graph". Retrieved 2006-09-15.
- ^ "Avian flu biofacts". CIDRAP.
- ^ Full text article online: "Avian Influenza A (H5N1) Infection in Humans" 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.
- ^ T Jacob John (November 12, 2005). "Bird Flu: Public Health Implications for India". Economic and Political Weekly.
- ^ New England Journal of Medicine Volume 352:686-691 - February 17, 2005 - Number 7 - Fatal Avian Influenza A (H5N1) in a Child Presenting with Diarrhea Followed by Coma
- ^ Influenza: The world is teetering on the edge of a pandemic that could kill a large fraction of the human population by Robert G. Webster and Elizabeth Jane Walker in American Scientist 2003 Volume 91 Page 122.
- ^ M. C. Chan; et al. (2005). "Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells". Respiratory Research. 6: 135.
{{cite journal}}
: Explicit use of et al. in:|author=
(help) - ^ Martin Hirst, Caroline R. Astell, Malachi Griffith, Shaun M. Coughlin, Michelle Moksa, Thomas Zeng; et al. (December 2004). "Novel Avian Influenza H7N3 Strain Outbreak, British Columbia". Emerg Infect Dis.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - ^ Alan Sipress (June 18, 2005). "Bird Flu Drug Rendered Useless: Chinese Chickens Given Medication Made for Humans". Washington Post.
- ^ "WHO sees role for older antivirals in some H5N1 cases". CIDRAP. May 22, 2006.
- ^ "Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO". WHO. August 23, 2006.
- ^ "H5N1 Getting Deadlier". based on the article "Bird Flu Fatality Rate in Humans Climbs to 64% as Virus Spreads".
- ^ "Clinical study points to cytokine storm in H5N1 cases". CIDRAP News. September 11, 2006.
- ^ Menno D de Jong; et al. (September 10, 2006). "Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia". Nature.
{{cite journal}}
: Explicit use of et al. in:|author=
(help) Published online. - ^ "The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005)". NAP. Retrieved 2006-08-21.
- ^ "Mild H5N1 cases weren't found missed in Cambodian outbreak study". CIDRAP. March 27, 2006.
- ^ "Cambodian study suggests mild H5N1 cases are rare". CIDRAP. September 7, 2006.
- ^ "Human Avian Influenza A(H5N1) Cases by Age Group and Country".
- ^ "Immediate Treatment Needed for Bird Flu Cases, Study Says". New York Times. September 11, 2006.
- ^ "Pandemic Flu Projection Says More Than Half Million Could Die in U.S." Senior Journal. June 24, 2005.
- ^ "Healthy Americans Full report PDF" (PDF).
- ^ "A Dramatic Disconnect". Newsweek. estimates two million dead in the US, for example
See also
Further reading
![](http://upload.wikimedia.org/wikipedia/commons/thumb/2/24/Wikinews-logo.svg/40px-Wikinews-logo.svg.png)
- "WHO Avian influenza resource (updated)".
- CDC "Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus".
{{cite web}}
: Check|url=
value (help) - "FAO information on Avian Influenza - Latest news, Disease Card, Maps, Animations".
- "Avian Influenza (Bird Flu): Agricultural and Wildlife Considerations". CIDRAP.
- "Avian Influenza: Preparing for a Pandemic". American Family Physician.