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Transmission and infection of H5N1

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Transmission and infection of H5N1

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H5N1
WHO pandemic phases
 
  1. Low risk
  2. New virus
  3. Self limiting
  4. Person to person
  5. Epidemic exists
  6. Pandemic exists
Flu

H5N1 flu refers to the transmission and infection of H5N1. H5N1 flu is a concern due to the global spread of H5N1 that constitutes a pandemic threat. This article is about the transmission of the H5N1 virus, infection by that virus, the resulting symptoms of that infection (having or coming down with influenza or more specifically avian flu or even more specifically H5N1 flu which can include pneumonia), and the medical response including treatment.

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

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

H5N1 infections in humans are generally caused by bird to human transmission of the virus. Until May 2006, the WHO estimate of the number of human to human transmission had been "two or three cases". On May 24, 2006, Dr. Julie L. Gerberding, director of the United States Centers for Disease Control and Prevention in Atlanta, estimated that there had been "at least three." On May 30, Maria Cheng, a WHO spokeswoman, said there were "probably about half a dozen," but that no one "has got a solid number."[1] A few isolated cases of suspected human to human transmission exist.[2] with the latest such case in June 2006 (among members of a family in Sumatra).[3] No pandemic strain of H5N1 has yet been found. The key point is that, at present, "the virus is not spreading efficiently or sustainably among humans."[4]

There is also concern, although no definitive proof, that other animals particularly cats may be able to act as a bridge between birds and humans. So far several cats have been confirmed to have died from H5N1 and the fact that cats have regular close contact with both birds and humans means monitoring of H5N1 in cats will need to continue.

Cumulate Human Cases of and Deaths from H5N1
As of October 31, 2006
Image:H5n1 spread (with regression).png
 
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. If this pattern continues, an upsurge in cases could be anticipated starting in late 2006 or early 2007." Avian influenza epidemiology of human H5N1 cases reported to WHO
  • The regression curve for deaths is y = a + ek x, and is shown extended through the end of November, 2006.

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.

Contents

Avian flu in birds

According to Avian Influenza by Timm C. Harder and Ortrud Werner:

Following an incubation period of usually a few days (but rarely up to 21 days), depending upon the characteristics of the isolate, the dose of inoculum, the species, and age of the bird, the clinical presentation of avian influenza in birds is variable and symptoms are fairly unspecific.[7] 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.[8] Some LP strains such as certain Asian H9N2 lineages, adapted to efficient replication in poultry, may cause more prominent signs and also significant mortality.[9][10] 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.[11][12]

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. [13]

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.[14]

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."[15]

Dr. Robert Webster explains: "If you use a good vaccine you can prevent the transmission within poultry and to humans. But if they have been using vaccines now [in China] for several years, why is there so much bird flu? There is bad vaccine that stops the disease in the bird but the bird goes on pooping out virus and maintaining it and changing it. And I think this is what is going on in China. It has to be. Either there is not enough vaccine being used or there is substandard vaccine being used. Probably both. Its not just China. We cant blame China for substandard vaccines. I think there are substandard vaccines for influenza in poultry all over the world." [16] 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." [17] 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." [18]

Transmission by wild birds (waterfowl)

The spread of avian influenza in the eastern hemisphere.
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 virus undergoing mutations could circulate within the domestic and possibly resident bird populations until HPAI arises. This new virus is pathogenic to poultry and possibly to the wild birds that it arose from. Wild birds found to have been infected with HPAI were either sick or dead. This could possibly affect the ability of these birds to carry HPAI for long distances. However, the findings in Qinghai Lake-China, suggest that H5N1 viruses could possibly be transmitted between migratory birds. Additionally, the new outbreaks of HPAI in poultry and wild birds in Russia, Kazakhstan, Western China and Mongolia may indicate that migratory birds probably act as carriers for the transport of HPAI over longer distances. Short distance transmission between farms, villages or contaminated local water bodies is likewise a distinct possibility. The AI virus has adapted to the environment in ways such as: 1) the use of water for survival and to spread 2) has evolved in a reservoir (ducks) strictly tied to water. The water in turn influences movement, social behaviour and migration patterns of water bird species. It is therefore of great importance to know the ecological strategy of influenza virus as well, in order to fully understand this disease and to control outbreaks when they occur. There remains a body of data and analysis missing on the collection and detection of HPAI viruses in wild birds. Finding HPAI viruses in wild birds may be a rare event, but if the contact with susceptible species occurs it can cause an outbreak at the local level or in distant areas. [19]

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 [20]. 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." [21] 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 [22]. 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. [23]

Environmental survival

Avian flu virus can last forever at a temperature dozens of degrees below freezing, as is found in the northern most areas that migratory birds frequent.

Heat kills H5N1 (i.e. inactivates the virus):

  • Over 30 days at 0C (32.0F) (over one month at freezing temperature)
  • 6 days at 37C (98.6F) (one week at human body temperature)
  • 30 minutes 60C (140.0F) (half hour at a temperature that causes first and second degree burns in humans in ten seconds)[24]

Inactivation of the virus also occurs under the following conditions:

  • Acidic pH conditions
    Presence of oxidizing agents such as sodium dodecyl sulfate, lipid solvents, and B-propiolactone
    Exposure to disinfectants: formalin, iodine compounds [25]

Incubation

The human incubation period of avian influenza A (H5N1) is 2 to 17 days[26]. 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.[27]

Symptoms

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. [28]

There have been studies of the levels of cytokines in humans infected by the H5N1 flu virus. Of particular concern is elevated levels of tumor necrosis factor alpha (TNFα), a protein that is associated with tissue destruction at sites of infection and increased production of other cytokines. Flu virus-induced increases in the level of cytokines is also associated with flu symptoms including fever, chills, vomiting and headache. Tissue damage associated with pathogenic flu virus infection can ultimately result in death [29]. The inflammatory cascade triggered by H5N1 has been called a 'cytokine storm' by some, because of what seems to be a positive feedback process of damage to the body resulting from immune system stimulation. H5N1 type flu virus induces higher levels of cytokines than the more common flu virus types such as H1N1 [30] Other important mechanisms also exist "in the acquisition of virulence in avian influenza viruses" according to the CDC.[31]

The NS1 protein of the highly pathogenic avian H5N1 viruses circulating in poultry and waterfowl in Southeast Asia is currently believed to be responsible for the enhanced proinflammatory cytokine response. H5N1 NS1 is characterized by a single amino acid change at position 92. By changing the amino acid from glutamic acid to aspartic acid, researchers were able to abrogate the effect of the H5N1 NS1. This single amino acid change in the NS1 gene greatly increased the pathogenicity of the H5N1 influenza virus.

In short, this one amino acid difference in the NS1 protein produced by the NS RNA molecule of the H5N1 virus is believed to be largely responsible for an increased pathogenicity (on top of the already increased pathogenicity of its hemagglutinin type which allows it to grow in organs other than lungs) that can manifest itself by causing a cytokine storm in a patient's body, often causing pneumonia and death.

Treatment

Neuraminidase inhibitors are a class of drugs that includes zanamivir and oseltamivir, the latter being licensed for prophylaxis treatment in the United Kingdom. Oseltamivir inhibits the influenza virus from spreading inside the user's body [23]. It is marketed by Roche as Tamiflu. This drug has become a focus for some governments and organizations trying to be seen as making preparations for a possible H5N1 pandemic. In August 2005, Roche agreed to donate three million courses of o be deployed by the WHO to contain a pandemic in its region of origin. Although Tamiflu is patented, international law gives governments wide freedom to issue compulsory licenses for life-saving drugs.

A second class of drugs, which include amantadine and rimantadine, target the M2 protein, but are ineffective against H5N1. Unlike zanamivir and oseltamivir, these drugs are inexpensive and widely available and the WHO had initially planned to use them in efforts to combat an H5N1 pandemic. However, the potential of these drugs was considerably lessened when it was discovered that farmers in China have been administering amantadine to poultry with government encouragement and support since the early 1990s, against international livestock regulations; the result has been that the strain of the virus now circulating in South East Asia is largely resistant to these medications and hence significantly more dangerous to humans[32].

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.[33]

Mortality rate

Human Mortality from H5N1
As of October 31, 2006
Image:H5N1 Human Mortality.png
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."[2]

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.[34] "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." [35] In 1997, in Hong Kong, 18 humans were infected and 6 died in the first known case of H5N1 infecting humans. [36] H5N1 had evolved from a zero mortality rate to a 33% mortality rate.

By 2003 H5N1 infection was detected in three flocks in the Republic of Korea. 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.[37] [38] The apparently extinct strain that caused Vietnam's human deaths from H5N1 in 2003, 2004 and 2005 also had a lower case mortality rate than the currently existing strains.[38] Changes are occurring in H5N1 that are increasing its pathogenicity in mammals.[39]

In 2005, 42 of 97 people confirmed by the WHO to be infected with H5N1 died -- or 43%. From January 1, 2006 to October 31, 2006, the case fatality ratio has been higher, with 74 deaths among 109 WHO-confirmed cases [40]-- or 68%. This has been interpreted by some to mean that the virus itself is becoming more deadly over time. [41] The global case fatality ratio is, nonetheless, a crude summary of a complex situation with many contributing factors. In particular, if an influenza pandemic arises from one of the currently circulating strains of Asian lineage HPAI A(H5N1), the mortality rates for the resulting human adapted influenza strain cannot be predicted with any confidence.

H5N1 is currently much better adapted to birds than to other hosts, which is why the disease it causes is called a bird flu. No pandemic strain of H5N1 has yet been found. The precise nature and extent of the genetic alterations that might change one of the currently circulating avian flu strains into a human flu strain cannot be known in advance. While many of the current H5N1 strains circulating in birds can generate a dangerous cytokine storm in healthy adult humans [42][43], 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.[44] 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. [45] [46] 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 [47]. The highly lethal second and third waves of the 1918 Spanish flu evolved through time into toward 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.[48]

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. [49] This is consistent with the frequent development of a cytokine storm in the afflicted.[50] Very few persons over 50 years of age died after suffering a H5N1 attack. Instead, the age-fatality curve of H5N1 influenza attacks in humans resembles that of the 1918 Spanish pandemic flu, and is the opposite of the mortality curve of seasonal flu strains, since seasonal influenza preferentially kills the elderly and does not kill by cytokine storm.

Another factor complicating any attempt to predict lethality of an eventual pandemic strain is that many human victims of the current H5N1 influenza have been blood relatives (but rarely spouses) of other victims. This data suggests that the victims' genetic susceptibility may have played a role in the human cases registered to date.

Mortality rate in planning reports

Governments and other 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."[51]. No one knew if "moderately severe" was an accurate guess or not. A report entitled A Killer Flu?[52] 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[53].

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%.[54] 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.[55], let alone the much higher case fatality ratios seen more recently.

Notes and references

  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.R. Elbers, G. Kock and A. Bouma (2005). "Performance of clinical signs in poultry for the detection of outbreaks during the avian influenza A (H7N7) epidemic in The Netherlands in 2003". Avian Pathol 34.
  8. ^ I. Capua and F. Mutinelli (2001). "Low pathogenicity (LPAI) and highly pathogenic (HPAI) avian influenza in turkeys and chicken". A Colour Atlas and Text on Avian Influenza.
  9. ^ S. Bano S, K. Naeem K, S.A. Malik (2003). "Evaluation of pathogenic potential of avian influenza virus serotype H9N2 in chicken". Avian Dis 47, Suppl.
  10. ^ C Li, K Yu, G TiaG, D Yu, L Liu, B Jing, J Ping, H. Chen (2005). "Evolution of H9N2 influenza viruses from domestic poultry in Mainland China". Virology 340.
  11. ^ D.E. Swayne, D.L. Suarez (2000). "Highly pathogenic avian influenza". Rev Sci Tech 19.
  12. ^ Timm C. Harder and Ortrud Werner. Avian Influenza. Influenza Report.
  13. ^ The Threat of Global Pandemics. Council on Foreign Relations (June 16, 2005). Retrieved on 2006-09-15.
  14. ^ "Vietnam to unveil advanced plan to fight bird flu", Reuters, April 28, 2006.
  15. ^ Robert G. Webster et al (January, 2006). "H5N1 Outbreaks and Enzootic Influenza". Emerging Infectious Diseases. Retrieved on 2006-09-15.
  16. ^ "Expert: Bad vaccines may trigger China bird flu", MSNBC, December 30, 2005. Retrieved on 2006-09-15.
  17. ^ "China H5N1 outbreak puts vaccines under spotlight", Reuters, March 19, 2006. Retrieved on 2006-09-15. This reference is apparently no longer available online via Reuters. It is available as of 21 August, 2006 at [1]
  18. ^ Bird flu vaccine no silver bullet. BBC (February 22, 2006). Retrieved on 2006-09-15.
  19. ^ Wild birds and Avian Influenza. FAO. Retrieved on 2006-09-15.
  20. ^ National Center for Infectious Diseases, Division of Global Migration and Quarantine (March 24, 2005). Interim Guidance about Avian Influenza A (H5N1) for U.S. Citizens Living Abroad. Travel Notices. U.S. Centers for Disease Control and Prevention. Retrieved on 2006-10-27.
  21. ^ Jennifer Schultz. "Bird flu vaccine won't precede pandemic", United Press International, November 28, 2005. Retrieved on 2006-10-27.
  22. ^ Promising research into vaccines includes:
  23. ^ a b Oseltamivir (Tamiflu). National Institutes of Health (January 13, 2000). Revised on January 10, 2001.
  24. ^ Hot Water Burn & Scalding Graph. Retrieved on 2006-09-15.
  25. ^ Avian flu biofacts. CIDRAP.
  26. ^ Full text article online: The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5 (September 29, 2005). "Avian Influenza A (H5N1) Infection in Humans". New England Journal of Medicine 353: 1374-1385.
  27. ^ T Jacob John (November 12, 2005). Bird Flu: Public Health Implications for India. Economic and Political Weekly.
  28. ^ (February 17, 2005) "Fatal Avian Influenza A (H5N1) in a Child Presenting with Diarrhea Followed by Coma". New England Journal of Medicine 352 (7): 686-691.
  29. ^ Robert G. Webster and Elizabeth Jane Walker (2003). "Influenza: The world is teetering on the edge of a pandemic that could kill a large fraction of the human population". American Scientist 91: 122.
  30. ^ M. C. Chan et al (2005). "Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells". Respiratory Research 6.
  31. ^ Martin Hirst, Caroline R. Astell, Malachi Griffith, Shaun M. Coughlin, Michelle Moksa, Thomas Zeng et al (December 2004). "Novel Avian Influenza H7N3 Strain Outbreak, British Columbia". Emerg Infect Dis.
  32. ^ Alan Sipress. "Bird Flu Drug Rendered Useless: Chinese Chickens Given Medication Made for Humans", Washington Post, June 18, 2005.
  33. ^ "WHO sees role for older antivirals in some H5N1 cases", CIDRAP, May 22, 2006.
  34. ^ "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.
  35. ^ Robert G. Webster, Malik Peiris, Honglin Chen, and Yi Guan (January 2006). H5N1 Outbreaks and Enzootic Influenza. CDC. Retrieved on 2006-10-28.
  36. ^ WHO (October 28, 2005). H5N1 avian influenza: timeline.
  37. ^ "Five Koreans had H5N1 virus but no illness", CIDRAP, September 21, 2006.
  38. ^ 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
  39. ^ 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
  40. ^ Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO. WHO (October 31, 2006).
  41. ^ H5N1 Getting Deadlier. based on the article Bird Flu Fatality Rate in Humans Climbs to 64% as Virus Spreads.
  42. ^ Clinical study points to cytokine storm in H5N1 cases. CIDRAP News (September 11, 2006).
  43. ^ 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.
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  48. ^ http://www.cbc.ca/cp/health/061102/x110210.html
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  50. ^ "Immediate Treatment Needed for Bird Flu Cases, Study Says", New York Times, September 11, 2006.
  51. ^ Pandemic Flu Projection Says More Than Half Million Could Die in U.S.. Senior Journal (June 24, 2005).
  52. ^ Healthy Americans Full report PDF.
  53. ^ A Dramatic Disconnect. Newsweek. estimates two million dead in the US, for example
  54. ^ http://www.cbc.ca/cp/health/061102/x110210.html
  55. ^ 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

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