Human Mortality from H5N1
As of April 11, 2007

Source WHO Confirmed Human Cases of H5N1

• The thin line represents average mortality of recent cases. The thicker line represents mortality averaged over all cases.
• According to WHO: "Assessment of mortality rates and the time intervals between symptom onset and hospitalization and between symptom onset and death suggests that the illness pattern has not changed substantially during the three years."[1]

H5N1

Influenza A virus subtype H5N1 Genetic structure Infection Human mortality Global spread in 2006 Social impact Pandemic

WHO pandemic phases Low risk New virus Self limiting Person to person Epidemic exists Pandemic exists

Human mortality from H5N1 or the human fatality ratio from H5N1 refer to the ratio of the number of confirmed human deaths resulting from confirmed cases of transmission and infection of H5N1 to the number of those confirmed cases. For example, if there are 100 confirmed cases of humans infected with H5N1 and 10 die, then there is a 10% human fatality ratio (or mortality rate). H5N1 flu is a concern due to the global spread of H5N1 that constitutes a pandemic threat. The majority of H5N1 flu cases have been reported in southeast and east Asia. Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ... April 11 is the 101st day of the year (102nd in leap years) in the Gregorian calendar. ... 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... Image File history File links H5N1_Human_Mortality. ... The World Health Organization (WHO) is a specialized agency of the United Nations (UN) that acts as a coordinating authority on international public health. ... Image File history File links Colorized_transmission_electron_micrograph_of_Avian_influenza_A_H5N1_viruses. ... Genera Influenzavirus A Influenzavirus B Influenzavirus C Isavirus Thogotovirus Influenzavirus A is a genus of a family of viruses called Orthomyxoviridae in virus classification. ... Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ... H5N1 genetic structure refers to the molecular structure of the H5N1 viruss RNA. H5N1 is an Influenza A virus subtype. ... See Epidemiology of WHO-confirmed human cases of avian influenza A(H5N1) infection. ... The global spread of H5N1 in birds is considered a significant pandemic threat. ... Main article: Global spread of H5N1 Notes: Source WHO Confirmed Human Cases of H5N1 [T]he incidence of human cases peaked, in each of the three years in which cases have occurred, during the period roughly corresponding to winter and spring in the northern hemisphere. ... See Influenza pandemic for government preparation for an H5N1 pandemic H5N1 impact is the effect or influence of H5N1 in human society; especially the financial, political, social and personal responses to both actual and predicted deaths in birds, humans, and other animals. ... An influenza pandemic is a large scale epidemic of the influenza virus, such as the 1918 Spanish flu. ... An influenza pandemic is a large scale epidemic of the influenza virus, such as the 1918 Spanish flu. ... Trinomial name Homo sapiens sapiens Linnaeus, 1758 Humans, or human beings, are bipedal primates belonging to the mammalian species Homo sapiens (Latin: wise man or knowing man) in the family Hominidae (the great apes). ... See Epidemiology of WHO-confirmed human cases of avian influenza A(H5N1) infection. ... Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ... The global spread of H5N1 in birds is considered a significant pandemic threat. ... A pandemic (from Greek παν pan all + δήμος demos people) is an epidemic (an outbreak of an infectious disease) that spreads across a large region (example a continent), or even worldwide. ...

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] May 24 is the 144th day of the year (145th in leap years) in the Gregorian calendar. ... For the Manfred Mann album, see 2006 (album). ... The Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, is recognized as the leading United States agency for protecting the public health and safety of people. ... This article is about the state capital of Georgia. ... May 30 is the 150th day of the year in the Gregorian calendar (151st in leap years). ... A pandemic (from Greek παν pan all + δήμος demos people) is an epidemic (an outbreak of an infectious disease) that spreads across a large region (example a continent), or even worldwide. ...

H5N1 vaccines for chickens exist and are 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 quantities sufficient to inoculate a few million people^[5] and might be useful for priming to "boost the immune response to a different H5N1 vaccine tailor-made years later to thwart an emerging pandemic".^[6] 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. H5N1 clinical trials are clinical trials concerning H5N1 vaccine; which is to say they are investigations concerning H5N1 vaccine in humans intended to discover pharmacological effects and identify any adverse reactions. ...

H5N1 cases in humans

Confirmed human cases and mortality rate of avian influenza (H5N1)
As of May 31, 2007

Country	Report dates															edit this table Total
	2003			2004			2005			2006			2007
	cases	deaths		cases	deaths		cases	deaths		cases	deaths		cases	deaths		cases	deaths
Azerbaijan										8	5	63%				8	5	63%
Cambodia							4	4	100%	2	2	100%	1	1	100%	7	7	100%
PR China	1	1	100%				8	5	63%	13	8	62%	2	1	50%	25	15	63%
Djibouti										1	0	0%				1	0	0%
Egypt										18	10	56%	16	4	25%	34	14	41%
Indonesia							19	12	63%	56	46	82%	22	19	86%	98	78	79%
Iraq										3	2	67%				3	2	67%
Laos													2	2	100%	2	2	100%
Nigeria													1	1	100%	1	1	100%
Thailand				17	12	71%	5	2	40%	3	3	100%				25	17	68%
Turkey										12	4	33%				12	4	33%
Vietnam	3	3	100%	29	20	69%	61	19	31%							93	42	45%
Total	4	4	100%	46	32	70%	97	42	43%	116	80	69%	43	27	63%	307	187	61%
Source: World Health Organization Communicable Disease Surveillance & Response (CSR)

See Epidemiology of WHO-confirmed human cases of avian influenza A(H5N1) infection. ... Avian influenza (also known as bird flu, avian flu, influenzavirus A flu, type A flu, or genus A flu) is a flu (influenza) due to a type of influenza virus that is hosted by birds, but may infect several species of mammals. ... Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ... 2007 is a common year starting on Monday of the Gregorian calendar. ... May 31 is the 151st day of the year (152nd in leap years) in the Gregorian calendar. ... 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... Image File history File links Flag_of_Azerbaijan. ... Image File history File links Flag_of_Cambodia. ... Image File history File links Flag_of_the_Peoples_Republic_of_China. ... Anthem YìyÇ’ngjÅ«n JìnxíngqÇ”   (义勇军进行曲/義勇軍進行曲) March of the Volunteers Capital Beijing Largest city Shanghai Official languages Mandarin Chinese1 Government Socialist republic2  -  President Hu Jintao  -  Premier Wen Jiabao Establishment  -  Peoples Republic declared October 1, 1949  Area  -  Total 9,596,960 km² (3rd / 4th4) 3,704,4273 sq... Image File history File links Flag_of_Djibouti. ... Image File history File links Flag_of_Egypt. ... Image File history File links Flag_of_Indonesia. ... Image File history File links Flag_of_Iraq. ... Image File history File links Flag_of_Laos. ... Image File history File links Flag_of_Nigeria. ... Image File history File links Flag_of_Thailand. ... Image File history File links Flag_of_Turkey. ... Image File history File links Flag_of_Vietnam. ... The World Health Organization (WHO) is a specialized agency of the United Nations (UN) that acts as a coordinating authority on international public health. ...

History

A strain of H5N1 killed chickens in 1959 in Scotland and turkeys in 1991 in England.^[7] This strain was "highly pathogenic" (deadly to birds) but caused neither illness nor death in humans.^[8] "The precursor of the H5N1 influenza virus that spread to humans in 1997 was first detected in Guangdong, China, in 1996, when it caused a moderate number of deaths in geese and attracted very little attention." ^[9] In 1997, in Hong Kong, 18 humans were infected and 6 died in the first known case of H5N1 infecting humans. ^[10] H5N1 had evolved from a zero mortality rate to a 33% mortality rate. Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ... This article or section does not adequately cite its references or sources. ... Motto (Latin) No one provokes me with impunity Cha togar mfhearg gun dioladh (Scottish Gaelic)1 Wha daur meddle wi me?(Scots)1 Anthem (Multiple unofficial anthems) Scotlands location in Europe Capital Edinburgh Largest city Glasgow Official languages English, Gaelic, Scots Government Constitutional monarchy  -  Queen Queen Elizabeth II... Motto (French) God and my right Anthem God Save the Queen England() – on the European continent() – in the United Kingdom() Capital (and largest city) London (de facto) Official languages English (de facto) Unified  -  by Athelstan 967 AD  Area  -  Total 130,395 km²  50,346 sq mi  Population  -  2007 estimate 50... Trinomial name Homo sapiens sapiens Linnaeus, 1758 Humans, or human beings, are bipedal primates belonging to the mammalian species Homo sapiens (Latin: wise man or knowing man) in the family Hominidae (the great apes). ... Guangdong, often spelt as Kwangtung, is a province on the south coast of the Peoples Republic of China. ... Other uses: Goose (disambiguation) Genera Anser Branta Chen Cereopsis † see also: Swan, Duck Anatidae Goose (plural geese) is the general English name for a considerable number of birds, belonging to the family Anatidae. ...

The first report, in the current wave of HPAI A(H5N1) outbreaks, was of an outbreak that began December 10, 2003 in the Republic of Korea and continued for fourteen weeks. This strain caused asymptomatic infections in humans and may have died out^[11], like the 1959 strain, so that its low mortality level would have little value for predicting the mortality rate of a pandemic evolving from existing HPAI A(H5N1) strains.^{[12] [13]} The apparently extinct strain that caused human deaths from H5N1 in the Northern part of Vietnam in 2003, 2004 and 2005 also had a much lower case mortality rate than the currently existing strains.^[13] Changes are occurring in H5N1 that are increasing its pathogenicity in mammals.^[14] December 10 is the 344th day (345th in leap years) of the year in the Gregorian calendar, 21 days before the next year. ... 2003 (MMIII) was a common year starting on Wednesday of the Gregorian calendar. ...

In 2005, when a markedly less-lethal strain in Northern Vietnam was responsible for most of the cases reported worldwide, only 42 of 97 people confirmed by the WHO to be infected with H5N1 died -- or 43%. In WHO-confirmed cases in 2006, the case fatality ratio was higher, with 79 deaths among 114 confirmed cases.^[15]-- or 69%. And 33 of the 50 WHO-confirmed cases in 2007 (up to June 15, 2007), have ended in death, or 67%.^[16] The rising total case fatality ratio after the end of 2005 may reflect the widespread circulation in Vietnam of a less-lethal clade in 2005, which was subsequently brought under control. The change was nonetheless interpreted by some as indicating that the virus itself was becoming more deadly over time.^[17] In fact, when less-virulent strains die off, the surviving strains are the more virulent. Such difficulties in interpretation underscore that the global case fatality ratio can serve as but a crude and imperfect summary of the current complex situation with its many contributing factors, and not a clear or reliable predictive tool. If and when an influenza pandemic arises from one of the currently circulating pre-pandemic strains of Asian lineage HPAI A(H5N1), the mortality rates for the resulting human adapted pandemic strain cannot be predicted with any confidence. Who can refer to: WHO, World Health Organization The Who, a British rock band The Guess Who, a Canadian rock band who (pronoun), an English language interrogative pronoun. ... Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ... Who can refer to: WHO, World Health Organization The Who, a British rock band The Guess Who, a Canadian rock band who (pronoun), an English language interrogative pronoun. ... An influenza pandemic is a large scale epidemic of the influenza virus, such as the 1918 Spanish flu. ... Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ... A pandemic (from Greek παν pan all + δήμος demos people) is an epidemic (an outbreak of an infectious disease) that spreads across a large region (example a continent), or even worldwide. ...

Existing pre-pandemic global case fatality ratio

The global case fatality ratio looks only to the official tally of cases confirmed by the WHO. It takes no account of other cases, such as those appearing in press reports. Nor does it reflect any estimate of the global extent of mild, asymptomatic, or other cases which are undiagnosed, unreported by national governments to the WHO, or for any reason cannot be confirmed by the WHO. While the WHO's case count is clearly the most authoritative, these unavoidable limitations result in an unknown number of cases being omitted from it. The problem of overlooked but genuine cases is emphasized by occasional reports in which later serology reveals antibodies to the H5N1 infection in the blood of persons who were never known to have bird flu, and who then are confirmed by the WHO only retroactively as "cases." Press reports of such cases, often poultry handlers, have appeared in various countries. The largest number of asymptomatic cases was recently confirmed among Korean workers who had assisted in massive culls of H5N1-infected poultry.^[18] This relatively benign Korean strain of H5N1 has died out, and the remaining strains of H5N1 have a higher case fatality rate in humans. Who can refer to: WHO, World Health Organization The Who, a British rock band The Guess Who, a Canadian rock band who (pronoun), an English language interrogative pronoun. ... Who can refer to: WHO, World Health Organization The Who, a British rock band The Guess Who, a Canadian rock band who (pronoun), an English language interrogative pronoun. ... Who can refer to: WHO, World Health Organization The Who, a British rock band The Guess Who, a Canadian rock band who (pronoun), an English language interrogative pronoun. ... Who can refer to: WHO, World Health Organization The Who, a British rock band The Guess Who, a Canadian rock band who (pronoun), an English language interrogative pronoun. ... Who can refer to: WHO, World Health Organization The Who, a British rock band The Guess Who, a Canadian rock band who (pronoun), an English language interrogative pronoun. ...

Unconfirmed cases have a potentially huge impact on the case fatality ratio. This mathematical impact is well-understood by epidemiologists, and is easy to see in theory. For example, if for each confirmed case reported by the WHO we assume that there has been another mild and unreported case, the actual global number of cases would be double the current number of WHO-confirmed cases. The fatality ratio for H5N1 infections would then be calculated as the same number of deaths, but divided by a doubled number for total cases, resulting in a hypothetical death ratio of half the currently-reported fatality ratio. Such a result would indicate to epidemiologists that the world was confronting an H5N1 virus that is less-lethal than currently assumed, although possibly one that was more contagious and difficult to track. Who can refer to: WHO, World Health Organization The Who, a British rock band The Guess Who, a Canadian rock band who (pronoun), an English language interrogative pronoun. ...

A case-fatality ratio based on an accurate and all-inclusive count of cases would be invaluable, but unfortunately it is impossible to attain. The ability to diagnose every case of H5N1 as it arises does not exist. A few reported studies have attempted to gather preliminary data on this crucial statistic, by carrying out systematic blood testing of neighbors and contacts of fatal cases in villages where there had been confirmed H5N1 fatalities. This testing failed to turn up any overlooked mild cases. ^{[19] [20]} These methodical studies of contacts provide significant evidence that the high death rate among confirmed cases in the villages where these studies were carried out cannot be simply attributed to a wholesale failure to detect mild cases. Unfortunately, these studies are likely to remain too few and sketchy to define the complex situation worldwide regarding the lethality of the varying H5N1 clades. The testing and reporting necessary for mass serology studies to determine the incidence of overlooked cases for each existing clade and strain of H5N1 worldwide would be prohibitively costly.

Hence the precise allocation of infections by the various H5N1 clades across the spectrum including lethal, serious, mild, and asymptomatic cases is likely to remain 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. Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ...

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 ^[21]. The highly lethal second and third waves of the 1918 Spanish flu evolved through time into a less virulent and more transmissible human form. Although the overall fatality rate for the Spanish Flu was at most 1% to 2% of the population, the lethal waves of the Spanish Flu are not reported to have emerged with anything like the over-50% case fatality ratio observed to date in human H5N1 infection. Unfortunately, a human H5N1 pandemic might emerge with initial lethality resembling that over-50% case fatality now observed in pre-pandemic H5N1 human cases, rather than with the still-high 1-2% seen with the Spanish Flu or with the lower rates seen in the two more recent influenza pandemics.^[22] The Spanish Flu Pandemic, also known as the Great Influenza Pandemic, the 1918 Flu Epidemic, and La Grippe, was an unusually severe and deadly strain of influenza, a viral infectious disease, that killed some 25 million to 40 million people (possibly significantly more) world-wide in 1918 and 1919. ...

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. ^[23][24]

This is consistent with the frequent development of a cytokine storm in the afflicted.^[25] 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. A cytokine storm is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and immune cells. ... A cytokine storm is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and immune cells. ...

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^[26] spouses) of other victims. This observation seemed to suggest that a familial genetic susceptibility might have played a role in the human cases registered to date.^[27]However a systematic study published in July 2007 by researchers at the Harvard School of public health noted no significant familial pattern of infection.^[28]

Planning reports

Governments and other organizations at many levels and in many places have produced "planning" reports that, among other things, have offered speculation on the mortality rate of an eventual H5N1 pandemic. That speculation has varied widely.^[29] One such report stated 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."^[30]. No one knew if "moderately severe" was an accurate guess or not. A report entitled A Killer Flu?^[31] projected that, with an assumed (guessed) contraction rate of just 25%, and with a severity rate as low as that of the two lowest severity flu pandemics of the 1900s, a modern influenza A pandemic would cause 180 thousand deaths in the US, while a pandemic equaling the 1918 Spanish Flu in level of lethality would cause one million deaths in the US. Again, the report offered no evidence that an emerging H5N1 flu pandemic would be between these figures.^[32]

The current avian flu, in humans, is fatal in over 50% of confirmed cases. Yet early projections like those above have assumed that such a lethal avian strain would surely lose genes contributing to its lethality in humans as it made the adaptations necessary for ready transmission in the human population. This optimistic assumption cannot be relied on. As the WHO reported in November 2006, initial outbreaks of an H5N1 pandemic could rival the current lethality of over 50%.^[22] Further information necessary to make an accurate projection of initial lethality of an H5N1 pandemic does not exist, as no data was collected that could show the pre-pandemic virulence in any potential flu strain until after the last pandemic of the 20th Century. There is no basis for assuming that an H5N1 pandemic will emerge with only the far lower 1-2% lethality rate of the Spanish Flu, once assumed to be a worst case scenario. There exists no reliable prediction of the mortality rate of an H5N1 pandemic, and it would be irresponsible to confine planning to only optimistic assumptions out of step with the currently observed case fatality ratio.

Although marred by unrealistically low ranges of assumed mortality, the earlier planning reports nevertheless show convincingly that we are not prepared even for a pandemic as severe as the milder pandemics of the past century.^[33], let alone the much higher case fatality ratios seen more recently.

Predicting pandemic mortality rate

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. Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ... “Aves” redirects here. ... For the current concern about the transmission of an avian flu to humans see Transmission and infection of H5N1. ... A pandemic (from Greek παν pan all + δήμος demos people) is an epidemic (an outbreak of an infectious disease) that spreads across a large region (example a continent), or even worldwide. ... For the current concern about the transmission of an avian flu to humans see Transmission and infection of H5N1. ... Human Flu refers to a subset of Orthomyxoviridae that create influenza in humans and are endemic in humans. ...

One especially important question is whether the H5N1 virus is likely to retain its present high lethality should it acquire an ability to spread easily from person to person, and thus start a pandemic. Should the virus improve its transmissibility by acquiring, through a reassortment event, internal human genes, then the lethality of the virus would most likely be reduced. However, should the virus improve its transmissibility through adaptation as a wholly avian virus, then the present high lethality could be maintained during a pandemic. While many of the current H5N1 strains circulating in birds can generate a dangerous cytokine storm in healthy adult humans, 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.^{[11][34][35][36]} H5N1 genetic structure refers to the molecular structure of the H5N1 viruss RNA. H5N1 is an Influenza A virus subtype. ... A cytokine storm is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and immune cells. ...

If H5N1 mutates so that it can jump from human to human, while maintaining a relatively high level of mortality, how many people could die? Risk communication analysts Peter M. Sandman and Jody Lanard give a round-up of the various estimates:

Worldwide mortality estimates range all the way from 2-7.4 million deaths (the “conservatively low” pandemic influenza calculation of a flu modeling expert at the U.S. Centers for Disease Control and Prevention) to 1000 million deaths (the bird flu pandemic prediction of one Russian virologist). The estimates of most H5N1 experts range less widely but still widely. In an H5N1 pandemic, the experts guess that somewhere between a quarter of us and half of us would get sick, and somewhere between one percent and five percent of those who got sick would die — the young and hale as well as the old and frail. If it's a quarter and one percent, that's 16 million dead; if it's a half and five percent, it's 160 million dead. Either way it's a big number. ^[37]

Perhaps the most extreme maximum has come from renowned virus expert, Robert Webster, who in March 2003 said he believed that H5N1 has the capacity to mutate into a form that could kill a third of the human population.^[38] In March 2006, he is said "Society just can't accept the idea that 50 percent of the population could die. And I think we have to face that possibility".^[39] Robert G. (Rob) Webster (born May 7, 1932), in Balclutha New Zealand, is the virologist who in 1957 was the first to announce a link between human flu and bird flu. ...

Genetic factors

Main article: H5N1 genetic structure

The widespread assumption that future influenza pandemics will be no more lethal than the Spanish Flu finds little basis in genetic analysis of the H5N1 virus.^[40] The H5N1 genes work together in ways we don't yet understand.^[41] Research is continuing. The genetic factors behind why H5N1 is so deadly are only partly understood. Known factors involve the surface antigen encoding gene segments H (hemagglutinin)^[42] and N (neuraminidase) genes (causing it to be H5N1 for example), as well as the matrix M2 gene, and the polymerase genes. H5N1 genetic structure refers to the molecular structure of the H5N1 viruss RNA. H5N1 is an Influenza A virus subtype. ... An antigen is a molecule that stimulates an immune response. ... Hemagglutinin, as depicted in a simplified molecular model. ... Neuraminidase is a glycoside hydrolase enzyme (EC 3. ... Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ...

"In order to cause a pandemic, H5N1 viruses will have to acquire the ability to transmit efficiently from person to person. The H5 hemagglutinin (HA) is found in influenza viruses that typically infect avian species, so efficient person-to-person spread could happen if the H5N1 virus reassorts, or exchanges genes, with circulating human influenza viruses giving rise to a virus with the H5 HA (to which the population is not immune) in a gene constellation that confers the property of transmissibility. Alternatively, efficient person-to-person spread could occur if the H5N1 virus evolves and adapts to more efficient replication and transmissibility in the human population."^[43] Hemagglutinin, as depicted in a simplified molecular model. ...

Neuraminidase which is an antigenic glycoprotein enzyme found on the surface of the influenza viruses. It helps the release of progeny viruses from infected cells. Flu drugs Tamiflu and Relenza work by inhibiting some strains of neuraminidase. They were developed based on N2 and N9. "In the N1 form of the protein, a small segment called the 150-loop is inverted, creating a hollow pocket that does not exist in the N2 and N9 proteins. [...] When the researchers looked at how existing drugs interacted with the N1 protein, they found that, in the presence of neuraminidase inhibitors, the loop changed its conformation to one similar to that in the N2 and N9 proteins."^[44] Neuraminidase is a glycoside hydrolase enzyme (EC 3. ... An antigen is a molecule that stimulates an immune response. ... A glycoprotein is a macromolecule composed of a protein and a carbohydrate (an oligosaccharide). ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... Influenza, commonly known as flu, is an infectious disease of birds and mammals caused by an RNA virus of the family Orthomyxoviridae (the influenza viruses). ... Groups I: dsDNA viruses II: ssDNA viruses III: dsRNA viruses IV: (+)ssRNA viruses V: (-)ssRNA viruses VI: ssRNA-RT viruses VII: dsDNA-RT viruses A virus (from the Latin noun virus, meaning toxin or poison) is a microscopic particle (ranging in size from 20 - 300 nm) that can infect the... Neuraminidase is a glycoside hydrolase enzyme (EC 3. ...

The amino acid substitution (Ser31Asn) in the M2 gene in some H5N1 genotypes is associated with amantadine resistance which increases lethality. However the pathogenicity of H5N1/97 was related to the nonstructural (NS) gene. NS codes for two nonstructural proteins (NS1 and NEP). The NS1 gene of the highly pathogenic avian H5N1 viruses circulating in poultry and waterfowl in Southeast Asia is believed to be responsible for an enhanced proinflammatory cytokine response (especially TNFa) induced by these viruses in human macrophages. 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. This is one gebetic factor in why H5N1 is so deadly. Amantadine, 1-aminoadamantane, is an antiviral drug that was approved by the FDA in 1976 for the treatment of influenza type A in adults. ...

Polymerase encoding gene segments are also implicated in why H5N1 is so deadly. PA codes for the PA protein which is a critical component of the viral polymerase. PB1 codes for the PB1 protein and the PB1-F2 protein. The PB1-F2 likely contributes to viral pathogenicity and might have an important role in determining the severity of pandemic influenza and 75% of H5N1 human virus isolates from Vietnam had a mutation consisting of Lysine at residue 627 in the PB2 protein; which is believed to cause high levels of virulence. Until H5N1, all known avian influenza viruses had a Glu at position 627, while all human influenza viruses had a lysine.

Areas of research

Areas of research to identify the likelihood of rapid or slow evolution to human contagion, or for predicting the greater or lesser likelihood of a rather lethal human-adapted influenza include:

• bird species susceptibility
• bird migration paths
• cell based vaccine development
• adjuvant testing
• human vaccine clinical trials
• bird vaccine testing and use
• computer simulations of pandemic spread patterns (e.g. will grounding flights help?)
• detailed shape and gene code analysis of each of the RNA stands for as many flu virus strains as possible and making them available on a database for study
• wild bird testing for flu viruses
• testing humans for asymptomatic H5N1 infection
• training exercizes in case of a pandemic

Computer simulations and direct gene manipulation have yielded inconclusive results.

Scientific advances

Scientific advances may attenuate probable lethality. The genetic lethality potential of the initial flu pandemic strain is only one important factor in determining the ultimate outcome in number of human lives lost. Another factor that grows potentially more important with the passage of time is human preparation. For example, no flu vaccine specific to H5N1 could be produced when it emerged in Hong Kong in 1997, because it was lethal to eggs. Reverse DNA techniques have since made a vaccine possible, and several H5N1 vaccines have been tested and are in production in at least limited quantities. Vaccine development and production facilities are being ramped up, and possible pre-pandemic vaccines are being produced and studied. If a human pandemic does not emerge in the next few years, its eventual emergence may become almost a non-event if a very-effective pre-pandemic vaccine has prepared the population with sufficient herd immunity to blunt its lethality. Indeed, if there is sufficient immunity to stop it at the source, it will not become pandemic. An influenza pandemic is a large scale epidemic of the influenza virus, such as the 1918 Spanish flu. ... Model of Influenza Virus from NIH The flu vaccine is a vaccine to protect against the highly variable influenza virus. ... Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ... …Herd immunity describes a type of immunity that occurs when the vaccination of the a portion of the population (or herd) provides protection to un-vaccinated individuals. ...

As long as the likelihood of protecting the population continues to rise with the passage of time, that likelihood becomes an increasingly important factor in predicting the loss of lives and the amount of economic dislocation that will ultimately occur. In light of human potential to develop herd immunity via vaccination in advance of a pandemic strain, the time that it allows us to do so before it evolves may become as crucial or more crucial to the measure of damage it causes than its own lethality and contagiousness.

Sources and notes

1. ^ Donald G. McNeil Jr.. "Human Flu Transfers May Exceed Reports", New York Times, June 4, 2006. 
2. ^ "Seven Indonesian Bird Flu Cases Linked to Patients", Bloomberg, May 23, 2006. 
3. ^ WHO confirms human transmission< in Indonesian bird flu cluster.
4. ^ "Avian influenza – situation in Indonesia – update 17", WHO, June 6, 2006. 
5. ^ HHS has enough H5N1 vaccine for 4 million people. CIDRAP (July 5, 2006).
6. ^ Study supports concept of 2-stage H5N1 vaccination. CIDRAP (October 13, 2006).
7. ^ A review of avian influenza in different bird species. Avian Virology, VLA Weybridge, Addlestone, Surrey KT15 3NB, UK.
8. ^ "Situation (poultry) in Asia: need for a long-term response, comparison with previous outbreaks", Disease Outbreak News: Avian influenza A(H5N1), WHO, March 2, 2004. Retrieved on 2006-10-27. 
9. ^ Robert G. Webster, Malik Peiris, Honglin Chen, and Yi Guan (January 2006). H5N1 Outbreaks and Enzootic Influenza. CDC. Retrieved on 2006-10-28.
10. ^ WHO (October 28, 2005). H5N1 avian influenza: timeline.
11. ^ ^{a b} Tan Ee Lyn (February 1, 2007). "Don't ignore less virulent bird flu strains: experts". Scientific American. 
12. ^ "Five Koreans had H5N1 virus but no illness", CIDRAP, September 21, 2006. 
13. ^ ^{a b} WHO (August 18, 2006). Antigenic and genetic characteristics of H5N1 viruses and candidate H5N1 vaccine viruses developed for potential use as pre-pandemic vaccines. Contains latest Evolutionary "Tree of Life" for H5N1
14. ^ Chen H, Deng G, Li Z, Tian G, Li Y, Jiao P, Zhang L, Liu Z, Webster RG, Yu K. (2004). "The evolution of H5N1 influenza viruses in ducks in southern China". Proc. Natl. Acad. Sci. U. S. A. 101 (28): 10452-10457. PubMed.  Full Text
15. ^ Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO. WHO (December 29, 2006).
16. ^ http://www.who.int/csr/disease/avian_influenza/country/cases_table_2007_06_11/en/index.html Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO / 15 June 2007
17. ^ H5N1 Getting Deadlier. based on the article Bird Flu Fatality Rate in Humans Climbs to 64% as Virus Spreads.
18. ^ Five Koreans had H5N1 virus but no illness (21 September 2006). CIDRAP. Retrieved on 2006-08-23.
19. ^ "Mild H5N1 cases weren’t found missed in Cambodian outbreak study", CIDRAP, March 27, 2006. 
20. ^ "Cambodian study suggests mild H5N1 cases are rare", CIDRAP, September 7, 2006. 
21. ^ The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005). NAP. Retrieved on 2006-08-21.
22. ^ ^{a b} CBC CIDRAP WHO PDF
23. ^ Human Avian Influenza A(H5N1) Cases by Age Group and Country.
24. ^ M. Smallman-Raynor and A.D. Cliff (March 4, 2007). "Avian influenza A (H5N1) age distribution in humans [letter]". Emerg Infect Dis. 
25. ^ "Immediate Treatment Needed for Bird Flu Cases, Study Says", New York Times, September 11, 2006. 
26. ^ In the November 2005 Emerging Infectious Diseases Journal article Family Clustering of Avian Influenza A (H5N1) Sonja Olsen et al listed 15 family clusters, in which three included a husband and wife pair. (Only two of these pairs had all four members actually confirmed as H5N1 positive.) The "blood relative theory" is, so far, too weak to be called a theory. It is an observation, with some reasoning that could support it as a hypothesis (the genetic tendency possibility, for instance).
27. ^ I. Nyoman Kandun et al. (November 23, 2006). "Three Indonesian Clusters of H5N1 Virus Infection in 2005". NEJM 355 (21): 2186-2194. 
28. ^ Little Evidence for Genetic Susceptibility to Influenza A (H5N1) from Family Clustering Data -- Virginia E. Pitzer, Sonja J. Olsen, Carl T. Bergstrom, Scott F. Dowell, and Marc Lipsitch http://www.cdc.gov/eid/content/13/7/pdfs/06-1538.pdf
29. ^ http://www.upmc-cbn.org/report_archive/2006/06_June_2006/cbnreport_060206.html CBN Report: Severe Pandemic Planning Assumptions May Be Too Low
30. ^ Pandemic Flu Projection Says More Than Half Million Could Die in U.S.. Senior Journal (June 24, 2005).
31. ^ Healthy Americans Full report PDF.
32. ^ Jennifer Barrett (May 3, 2006). A Dramatic Disconnect. Newsweek. Retrieved on 2006-12-11. estimates two million dead in the US, for example
33. ^ Dr. Martin Meltzer of the Centers for Disease Control, an expert on the societal impact of diseases, warns that “There is no healthcare system anywhere in the world that can cope with even a mild pandemic like the one in 1968” Meltzer MI, Lancet Asia Forum, Singapore, May 2006
34. ^ WHO working group on influenza research at the human and animal interface (November 2, 2006). "Influenza research at the human and animal interface": 15.  (alternate version)
35. ^ Clinical study points to cytokine storm in H5N1 cases. CIDRAP News (September 11, 2006).
36. ^ 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.  Published online.
37. ^ Peter M. Sandman, Jody Lanard (December 4, 2004). Pandemic Influenza Risk Communication: The Teachable Moment. Retrieved on 2006-10-08.
38. ^ Robert Webster, Elizabeth Jane Walker (March-April 2003). "The world is teetering on the edge of a pandemic that could kill a large fraction of the human population". American Scientist 91 (2): 122. Retrieved on 2006-10-08. 
39. ^ "Renowned Bird Flu Expert Warns: Be Prepared", ABC News, March 14, 2006. Retrieved on 2006-10-08. 
40. ^ http://www.informaworld.com/smpp/1150732152-62988796/content~content=a768149644~db=all~order=page Why is the world so poorly prepared for a pandemic of hypervirulent avian influenza?
41. ^ Ferret reassortant study
42. ^ Science Mag
43. ^ plosjournals Subbarao K, Luke C (2007) H5N1 Viruses and Vaccines. PLoS Pathog 3(3): e40 doi:10.1371/journal.ppat.0030040 Published: March 2, 2007
44. ^ Scidev.net News article Bird flu protein's 'pocket' could inspire better drugs published August 16, 2006

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