Bird Flu Protection, Prevention of Asian Influenza H5N1
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.
|Cumulated Human Cases & Deaths from H5N1|
As of November 29, 2006
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." A few isolated cases of suspected human to human transmission exist. with the latest such case in June 2006 (among members of a family in Sumatra). 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."
|Asian Influenza, Bird Flu Virus H5N1|
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.
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 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". 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
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. 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. Some LP strains such as certain Asian H9N2 lineages, adapted to efficient replication in poultry, may cause more prominent signs and also significant mortality. 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.
Poultry Farming Practices
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.
For example, after nearly two years of using mainly culling to control the virus, the Vietnamese government in 2005 adopted a combination of mass poultry vaccination, disinfecting, culling, information campaigns and bans on live poultry in cities.
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."
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 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." 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." 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."
|The Spread of Avian Influenza In the Eastern Hemisphere|
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 newly mutated virus 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. For example, small birds like sparrows, starlings and pigeons can be infected with deadly H5N1 strains and they can carry the virus from chicken house to chicken house causing massive epidemics among the chickens.
Asian Flu & Bird Flu 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. Additionally, vaccination of only humans would not address the possibility or reassortment in pigs, cats, or other mammal hosts.
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 . 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." 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 . 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.
Avian flu virus can last indefinitely 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)
Inactivation of the virus also occurs under the following conditions:
The human incubation period of avian influenza A (H5N1) is 2 to 17 days. 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.
Symptoms of the Flu
- Flu season
- Flu vaccine
- Flu treatment
- Avian flu
- H5N1 flu
- Flu research
- Genome sequencing
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.
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 . 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 Other important mechanisms also exist "in the acquisition of virulence in avian influenza viruses" according to the CDC.
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.
Bird Flu 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 . It is marketed by Roche as Tamiflu. This drug has become a focus for some governments and organizations trying to be seen as making preparations for a possible H5N1 pandemic. In August 2005, Roche agreed to donate three million courses of Tamiflu 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.
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.
As of November 29, 2006
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."
A strain of H5N1 killed chickens in 1959 in Scotland and turkeys in 1991 in England. This strain was "highly pathogenic" (deadly to birds) but caused neither illness nor death in humans. "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." In 1997, in Hong Kong, 18 humans were infected and 6 died in the first known case of H5N1 infecting humans. H5N1 had evolved from a zero mortality rate to a 33% mortality rate.
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 has died out, meaning that its low mortality level is no more relevant than the 1959 strain's low mortality rate in evaluating the mortality rate of existing HPAI A(H5N1) strains. The apparently extinct strain that caused Vietnam's human deaths from H5N1 in 2003, 2004 and 2005 also had a much lower case mortality rate than the currently existing strains. Changes are occurring in H5N1 that are increasing its pathogenicity in mammals.
In 2005, when a markedly less-lethal strain in North 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%. From January 1, 2006 to November 29 2006, the case fatality ratio has been higher, with 76 deaths among 111 WHO-confirmed cases-- or 68%. This has been interpreted by some to mean that the virus itself is becoming more deadly over time. 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 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.
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 , 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.
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. This relatively benign Korean strain of H5N1 has died out, and the remaining strains of H5N1 have a higher case fatality rate in humans.
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.
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. 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.
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 . 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.
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. This is consistent with the frequent development of a cytokine storm in the afflicted. 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.
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. 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.". No one knew if "moderately severe" was an accurate guess or not. A report entitled A Killer Flu? 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.
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%. 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, let alone the much higher case fatality ratios seen more recently.
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.
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.
Influenza A virus subtype H5N1, also known as A(H5N1) or H5N1, is a subtype of the Influenza A virus that can cause illness in humans and many other animal species. A bird-adapted strain of H5N1, called HPAI A(H5N1) for "highly pathogenic avian influenza virus of type A of subtype H5N1", is the causative agent of H5N1 flu, commonly known as "avian influenza" or "bird flu". It is endemic in many bird populations, especially in Southeast Asia. One strain of HPAI A(H5N1) is spreading globally after first appearing in Asia. It is epizootic (an epidemic in nonhumans) and panzootic (affecting animals of many species, especially over a wide area), killing tens of millions of birds and spurring the culling of hundreds of millions of others to stem its spread. Most mentions of "bird flu" and H5N1 in the media refer to this strain.
HPAI A(H5N1) is an avian disease. There is no evidence of efficient human-to-human transmission or of airborne transmission of HPAI A(H5N1) to humans. In almost all cases, those infected with H5N1 had extensive physical contact with infected birds. Still, around 60% of humans known to have been infected with the current Asian strain of HPAI A(H5N1) have died from it, and H5N1 may mutate or reassort into a strain capable of efficient human-to-human transmission. In 2003, world-renowned virologist Robert Webster published an article titled "The world is teetering on the edge of a pandemic that could kill a large fraction of the human population" in American Scientist. He called for adequate resources to fight what he sees as a major world threat to possibly billions of lives. On September 29, 2005, David Nabarro, the newly-appointed Senior United Nations System Coordinator for Avian and Human Influenza, warned the world that an outbreak of avian influenza could kill anywhere between 5 million and 150 million people. Experts have identified key events (creating new clades, infecting new species, spreading to new areas) marking the progression of an avian flu virus towards becoming pandemic, and many of those key events have occurred more rapidly than expected.
Due to the high lethality and virulence of HPAI A(H5N1), its endemic presence, its increasingly large host reservoir, and its significant ongoing mutations, the H5N1 virus is the world's largest current pandemic threat, and billions of dollars are being spent researching H5N1 and preparing for a potential influenza pandemic. At least 12 companies and 17 governments are developing pre-pandemic influenza vaccines in 28 different clinical trials that, if successful, could turn a deadly pandemic infection into a nondeadly one. Full-scale production of a vaccine that could prevent any illness at all from the strain would require at least three months after the virus's emergence to begin, but it is hoped that vaccine production could increase until one billion doses were produced by one year after the initial identification of the virus.
The first known strain of HPAI A(H5N1) (called A/chicken/Scotland/59) killed two flocks of chickens in Scotland in 1959; but that strain was very different from the current highly pathogenic strain of H5N1. The dominant strain of HPAI A(H5N1) in 2004 evolved from 1999 to 2002 creating the Z genotype. It has also been called "Asian lineage HPAI A(H5N1)".
Asian lineage HPAI A(H5N1) is divided into two antigenic clades. "Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections: Map
- Subclade 1, Indonesia
- Subclade 2, Middle East, Europe, and Africa
- Subclade 3, China"
H5N1 isolates are identified like this actual HPAI A(H5N1) example, A/chicken/Nakorn-Patom/Thailand/CU-K2/04(H5N1):
- A stands for the species of influenza (A, B or C).
- chicken is the species the isolate was found in
- Nakorn-Patom/Thailand is the place this specific virus was isolated
- CU-K2 identifies it from other influenza viruses isolated at the same place
- 04 represents the year 2004
- H5 stands for the fifth of several known types of the protein hemagglutinin.
- N1 stands for the first of several known types of the protein neuraminidase.
(Other examples: A/duck/Hong Kong/308/78(H5N3), A/avian/NY/01(H5N2), A/Chicken/Mexico/31381-3/94(H5N2), and A/shoveler/Egypt/03(H5N2)).
As with other avian flu viruses, H5N1 has strains called "highly pathogenic" (HP) and "low-pathogenic" (LP). Avian influenza viruses that cause HPAI are highly virulent, and mortality rates in infected flocks often approach 100%. LPAI viruses have negligible virulence, but these viruses can serve as progenitors to HPAI viruses. The current strain of H5N1 responsible for the deaths of birds across the world is an HPAI strain; all other current strains of H5N1, including a North American strain that causes no disease at all in any species, are LPAI strains. All HPAI strains identified to date have involved H5 and H7 subtypes. The distinction concerns pathogenicity in poultry, not humans. Normally a highly pathogenic avian virus is not highly pathogenic to either humans or non-poultry birds. This current deadly strain of H5N1 is unusual in being deadly to so many species.
Genetic structure and related subtypes
The N in H5N1 stands for "Neuraminidase", as depicted in this ribbon diagram. The N in H5N1 stands for "Neuraminidase", as depicted in this ribbon diagram.
H5N1 is a subtype of the species Influenza A virus of the Influenzavirus A genus of the Orthomyxoviridae family. Like all other influenza A subtypes, the H5N1 subtype is an RNA virus. It has a segmented genome of eight negative sense, single-strands of RNA, abbreviated as PB2, PB1, PA, HA, NP, NA, M and NS.
HA codes for hemagglutinin, an antigenic glycoprotein found on the surface of the influenza viruses and is responsible for binding the virus to the cell that is being infected. NA codes for neuraminidase, an antigenic glycosylated enzyme found on the surface of the influenza viruses. It facilitates the release of progeny viruses from infected cells. The hemagglutinin (HA) and neuraminidase (NA) RNA strands specify the structure of proteins that are most medically relevant as targets for antiviral drugs and antibodies. HA and NA are also used as the basis for the naming of the different subtypes of influenza A viruses. This is where the H and N come from in H5N1.
Influenza A viruses are significant for their potential for disease and death in humans and other animals. Influenza A virus subtypes that have been confirmed in humans, in order of the number of known human pandemic deaths that they have caused, include:
- H1N1, which caused "Spanish flu" and currently causes seasonal human flu
- H2N2, which caused "Asian flu"
- H3N2, which caused "Hong Kong flu" and currently causes seasonal human flu
- H5N1, the world's major current pandemic threat
- H7N7, which has unusual zoonotic potential and killed one person
- H1N2, which is currently endemic in humans and pigs and causes seasonal human flu
- H9N2, which has infected three people
- H7N2, which has infected two people
- H7N3, which has infected two people
- H10N7, which has infected two people
Low pathogenic H5N1
Low pathogenic avian influenza H5N1 (LPAI H5N1) also called "North American" H5N1 commonly occurs in wild birds. In most cases, it causes minor sickness or no noticeable signs of disease in birds. It is not known to affect humans at all. The only concern about it is that it is possible for it to be transmitted to poultry and in poultry mutate into a highly pathogenic strain.
- 1975 – LPAI H5N1 was detected in a wild mallard duck and a wild blue goose in Wisconsin.
- 1981 and 1985 – LPAI H5N1 was detected in ducks by the University of Minnesota conducting a sampling procedure in which sentinel ducks were monitored in cages placed in the wild for a short period of time.
- 1983 – LPAI H5N1 was detected in ring-billed gulls in Pennsylvania.
- 1986 - LPAI H5N1 was detected in a wild mallard duck in Ohio.
- 2005 - LPAI H5N1 was detected in ducks in Manitoba, Canada.
"In the past, there was no requirement for reporting or tracking LPAI H5 or H7 detections in wild birds so states and universities tested wild bird samples independently of USDA. Because of this, the above list of previous detections might not be all inclusive of past LPAI H5N1 detections. However, the World Organization for Animal Health (OIE) recently changed its requirement of reporting detections of avian influenza. Effective in 2006, all confirmed LPAI H5 and H7 AI subtypes must be reported to the OIE because of their potential to mutate into highly pathogenic strains. Therefore, USDA now tracks these detections in wild birds, backyard flocks, commercial flocks and live bird markets."
Properties of H5N1
H5N1 is easily transmissible between birds facilitating a potential global spread of H5N1. While H5N1 undergoes specific mutations and reassorting creating variations which can infect species not previously known to carry the virus, not all of these variant forms can infect humans. H5N1 as an avian virus preferentially binds to a type of galactose receptors that populate the avian respiratory tract from the nose to the lungs and are virtually absent in humans, occurring only in and around the alveoli, structures deep in the lungs where oxygen is passed to the blood. Therefore, the virus is not easily expelled by coughing and sneezing, the usual route of transmission.
H5N1 is mainly spread by domestic poultry, both through the movements of infected birds and poultry products and through the use of infected poultry manure as fertilizer or feed. Humans with H5N1 have typically caught it from chickens, which were in turn infected by other poultry or waterfowl. Migrating waterfowl (wild ducks, geese and swans) carry H5N1, often without becoming sick. Many species of birds and mammals can be infected with HPAI A(H5N1), but the role of animals other than poultry and waterfowl as disease-spreading hosts is unknown.
H5N1 has mutated into a variety of strains with differing pathogenic profiles, some pathogenic to one species but not others, some pathogenic to multiple species. Each specific known genetic variation is traceable to a virus isolate of a specific case of infection. Through antigenic drift, H5N1 has mutated into dozens of highly pathogenic varieties divided into genetic clades which are known from specific isolates, but all currently belonging to genotype Z of avian influenza virus H5N1, now the dominant genotype. H5N1 isolates found in Hong Kong in 1997 and 2001 were not consistently transmitted efficiently among birds and did not cause significant disease in these animals. In 2002 new isolates of H5N1 were appearing within the bird population of Hong Kong. These new isolates caused acute disease, including severe neurological dysfunction and death in ducks. This was the first reported case of lethal influenza virus infection in wild aquatic birds since 1961. Genotype Z emerged in 2002 through reassortment from earlier highly pathogenic genotypes of H5N1 that first infected birds in China in 1996, and first infected humans in Hong Kong in 1997. Genotype Z is endemic in birds in Southeast Asia, has created at least two clades that can infect humans, and is spreading across the globe in bird populations. Mutations are occurring within this genotype that are increasing their pathogenicity. Birds are also able to shed the virus for longer periods of time before their death, increasing the transmissibility of the virus.
Transmission and host range
Influenza A virus, the virus that causes Avian flu. Transmission electron micrograph of negatively stained virus particles in late passage. (Source: Dr. Erskine Palmer, Centers for Disease Control and Prevention Public Health Image Library) Influenza A virus, the virus that causes Avian flu. Transmission electron micrograph of negatively stained virus particles in late passage. (Source: Dr. Erskine Palmer, Centers for Disease Control and Prevention Public Health Image Library)
Infected birds transmit H5N1 through their saliva, nasal secretions, feces and blood. Other animals may become infected with the virus through direct contact with these bodily fluids or through contact with surfaces contaminated with them. H5N1 remains infectious after over 30 days at 0 °C ( 32.0 °F) (over one month at freezing temperature) or 6 days at 37 °C ( 98.6 °F) (one week at human body temperature) so at ordinary temperatures it lasts in the environment for weeks. In arctic temperatures, it doesn't degrade at all.
Because migratory birds are among the carriers of the highly pathogenic H5N1 virus, it is spreading to all parts of the world. H5N1 is different from all previously known highly pathogenic avian flu viruses in its ability to be spread by animals other than poultry.
In October 2004, researchers discovered that H5N1 is far more dangerous than was previously believed. Waterfowl were revealed to be directly spreading the highly pathogenic strain of H5N1 to chickens, crows, pigeons, and other birds, and the virus was increasing its ability to infect mammals as well. From this point on, avian flu experts increasingly referred to containment as a strategy that can delay, but not ultimately prevent, a future avian flu pandemic.
"Since 1997, studies of influenza A (H5N1) indicate that these viruses continue to evolve, with changes in antigenicity and internal gene constellations; an expanded host range in avian species and the ability to infect felids; enhanced pathogenicity in experimentally infected mice and ferrets, in which they cause systemic infections; and increased environmental stability".
The New York Times, in an article on transmission of H5N1 through smuggled birds, reports Wade Hagemeijer of Wetlands International stating, "We believe it is spread by both bird migration and trade, but that trade, particularly illegal trade, is more important".
High mutation rate
Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The segmentation of the influenza genome facilitates genetic recombination by segment reassortment in hosts who are infected with two different influenza viruses at the same time. H5N1 viruses can reassort genes with other strains that co-infect a host organism, such as a pig, bird, or human, and mutate into a form that can pass easily among humans. This is one of many possible paths to a pandemic.
The ability of various influenza strains to show species-selectivity is largely due to variation in the hemagglutinin genes. Genetic mutations in the hemagglutinin gene that cause single amino acid substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors on the surface of host cells. Such mutations in avian H5N1 viruses can change virus strains from being inefficient at infecting human cells to being as efficient in causing human infections as more common human influenza virus types. This doesn't mean that one amino acid substitution can cause a pandemic, but it does mean that one amino acid substitution can cause an avian flu virus that is not pathogenic in humans to become pathogenic in humans.
H3N2 ("swine flu") is endemic in pigs in China, and has been detected in pigs in Vietnam, increasing fears of the emergence of new variant strains. The dominant strain of annual flu virus in January 2006 was H3N2, which is now resistant to the standard antiviral drugs amantadine and rimantadine. The possibility of H5N1 and H3N2 exchanging genes through reassortment is a major concern. If a reassortment in H5N1 occurs, it might remain an H5N1 subtype, or it could shift subtypes, as H2N2 did when it evolved into the Hong Kong Flu strain of H3N2.
Both the H2N2 and H3N2 pandemic strains contained avian flu virus RNA segments. "While the pandemic human influenza viruses of 1957 (H2N2) and 1968 (H3N2) clearly arose through reassortment between human and avian viruses, the influenza virus causing the 'Spanish flu' in 1918 appears to be entirely derived from an avian source".
Humans and H5N1
The earliest infections of humans by H5N1 coincided with an epizootic (an epidemic in nonhumans) of H5N1 influenza in Hong Kong's poultry population. This panzootic (a disease affecting animals of many species, especially over a wide area) outbreak was stopped by the killing of the entire domestic poultry population within the territory.
Symptoms in humans
Avian influenza hemagglutinin bind alpha 2-3 sialic acid receptors while human influenza hemagglutinin bind alpha 2-6 sialic acid receptors. Usually other differences also exist. There is as yet no human form of H5N1, so all humans who have caught it so far have caught avian H5N1.
In general, humans who catch a humanized Influenza A virus (a human flu virus of type A) usually have symptoms that include fever, cough, sore throat, muscle aches, conjunctivitis and, in severe cases, severe breathing problems and pneumonia that may be fatal. The severity of the infection depends to a large part on the state of the infected person's immune system and whether the victim has been exposed to the strain before (in which case they would be partially immune). No one knows if these or other symptoms will be the symptoms of a humanized H5N1 flu.
Highly pathogenic H5N1 avian flu in a human is far worse, killing 50% of humans that catch it. In one case, a boy with H5N1 experienced diarrhea followed rapidly by a coma without developing respiratory or flu-like symptoms. There have been studies of the levels of cytokines in humans infected by the H5N1 flu virus. Of particular concern is elevated levels of tumor necrosis factor alpha, a protein that is associated with tissue destruction at sites of infection and increased production of other cytokines. Flu virus-induced increases in the level of cytokines is also associated with flu symptoms including fever, chills, vomiting and headache. Tissue damage associated with pathogenic flu virus infection can ultimately result in death. The inflammatory cascade triggered by H5N1 has been called a 'cytokine storm' by some, because of what seems to be a positive feedback process of damage to the body resulting from immune system stimulation. H5N1 induces higher levels of cytokines than the more common flu virus types.
Treatment and prevention for humans
There is no highly effective treatment for H5N1 flu, but oseltamivir (commercially marketed by Roche as Tamiflu), can sometimes inhibit the influenza virus from spreading inside the user's body. This drug has become a focus for some governments and organizations trying to be seen as making preparations for a possible H5N1 pandemic. On April 20, 2006, Roche AG announced that a stockpile of three million treatment courses of Tamiflu is waiting at the disposal of the World Health Organization to be used in case of a flu pandemic; separately Roche donated two million courses to the WHO for use in developing nations that may be affected by such a pandemic but lack the ability to purchase large quantities of the drug.
However, WHO expert Hassan al-Bushra has said:
"Even now, we remain unsure about Tamiflu's real effectiveness. As for a vaccine, work cannot start on it until the emergence of a new virus, and we predict it would take six to nine months to develop it. For the moment, we cannot by any means count on a potential vaccine to prevent the spread of a contagious influenza virus, whose various precedents in the past 90 years have been highly pathogenic".
There are several H5N1 vaccines for several of the avian H5N1 varieties, but the continual mutation of H5N1 renders them of limited use to date: while vaccines can sometimes provide cross-protection against related flu strains, the best protection would be from a vaccine specifically produced for any future pandemic flu virus strain. Dr. Daniel Lucey, co-director of the Biohazardous Threats and Emerging Diseases graduate program at Georgetown University has made this point, "There is no H5N1 pandemic so there can be no pandemic vaccine". 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. Vaccine manufacturing companies are being encouraged to increase capacity so that if a pandemic vaccine is needed, facilities will be available for rapid production of large amounts of a vaccine specific to a new pandemic strain.
Animal and lab studies suggest that Relenza (Zanamivir), which is in the same class of drugs as Tamiflu, may also be effective against H5N1, in a study performed on mice in 2000, "zanamivir was shown to be efficacious in treating avian influenza viruses H9N2, H6N1, and H5N1 transmissible to mammals" (Leneva 2001). However another paper, de Jong 2005, suggested that Zazamivir might not provide protection in humans from the current avian strain of H5N1 if "systemic involvement of influenza infection is suspected - as has recently been suggested by some reports on avian H5N1 influenza in humans." While no one knows if zanamivir will be useful or not on a yet to exist pandemic strain of H5N1, it might be useful to stockpile zanamivir as well as oseltamivir in the event of an H5N1 influenza pandemic. Neither oseltamivir nor zanamivir can currently be manufactured in quantities that would be meaningful once efficient human transmission starts.
In September, 2006, a WHO scientist announced that studies had confirmed cases of strains resistant to Tamiflu and Amantadine.
Preparations for pandemic
"The United States is collaborating closely with eight international organizations, including the World Health Organization (WHO), the Food and Agriculture Organization of the United Nations (FAO), the World Organization for Animal Health (OIE), and 88 foreign governments to address the situation through planning, greater monitoring, and full transparency in reporting and investigating avian influenza occurrences. The United States and these international partners have led global efforts to encourage countries to heighten surveillance for outbreaks in poultry and significant numbers of deaths in migratory birds and to rapidly introduce containment measures. The U.S. Agency for International Development (USAID) and the U.S. Department of State, the U.S. Department of Health and Human Services (HHS), and Agriculture (USDA) are coordinating future international response measures on behalf of the White House with departments and agencies across the federal government".
Together steps are being taken to "minimize the risk of further spread in animal populations", "reduce the risk of human infections", and "further support pandemic planning and preparedness".
Ongoing detailed mutually coordinated onsite surveillance and analysis of human and animal H5N1 avian flu outbreaks are being conducted and reported by the USGS National Wildlife Health Center, the Centers for Disease Control and Prevention, the World Health Organization, the European Commission, and others.
Impact on human society
There has been a huge impact of H5N1 on human society; especially the financial, political, social and personal responses to both actual and predicted deaths in birds, humans, and other animals.
Billions of U.S. dollars are being raised and spent to research H5N1 and prepare for a potential avian flu pandemic. Over ten billion dollars have been lost and over two hundred million birds have been killed to try to contain H5N1.
This, like everything else, is subject to political spin; wherein every interest group picks and chooses among the facts to support their favorite cause resulting in a distortion of the overall picture, the motivations of the people involved and the believability of the predictions.
People have reacted by buying less chicken causing poultry sales and prices to fall. Many individuals have stockpiled supplies for a possible flu pandemic. One of the best known experts on H5N1, Dr. Robert Webster, told ABC News he had a three month supply of food and water in his house as he prepared for what he considered a reasonably likely occurrence of a major pandemic.
Much of the content on this page was obtained from the Wikipedia, which is licensed under the GNU Free Documentation License. Other information was obtained from the National Institues of Health Pubmed.org online database.