Transmission and infection of H5N1

Transmission and infection of H5N1 from infected avian sources to humans is a concern due to the global spread of H5N1 that constitutes a pandemic threat.

Infected birds pass on H5N1 through their saliva, nasal secretions, and faeces. 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 openness 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]

On August 22, 2007, a 28-year old Indonesian woman, working as a chicken trader, was the 2nd person to die of bird flu on Bali, raising the death toll in the nation due to the disease to 84 (after 4 days of hospitalization). Tests conducted in two local laboratories positively identified the H5N1 strain of the disease. 194 people, a majority of which are from Indonesia, have died since 2003, according to the World Health Organization. ^[5]

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^[6] 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".^[7] H5N1 pandemic vaccines and technologies to rapidly create them are in the H5N1 clinical trials stage but can not be verified as useful until after there exists a pandemic strain.

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Avian flu in birds

See also: Influenza vaccine#Flu vaccine for nonhumans

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.^[8] 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.^[9] Some LP strains such as certain Asian H9N2 lineages, adapted to efficient replication in poultry, may cause more prominent signs and also significant mortality.^[10][11] 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.^[12][13]

Poultry farming practices

Poultry farming practices have changed due to H5N1:

• 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. ^[14]

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.^[15]

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."^[16]

Dr. Robert Webster explains: "If you use a good vaccine you can prevent the transmission within poultry and to humans. But if they have been using vaccines now [in China] for several years, why is there so much bird flu? There is bad vaccine that stops the disease in the bird but the bird goes on pooping out virus and maintaining it and changing it. And I think this is what is going on in China. It has to be. Either there is not enough vaccine being used or there is substandard vaccine being used. Probably both. It’s not just China. We can’t blame China for substandard vaccines. I think there are substandard vaccines for influenza in poultry all over the world." ^[17] 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." ^[18] 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." ^[19]

Transmission

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. ^[20] 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.^[21]

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 ^[22]. 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." ^[23] 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 ^[24]. 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. ^[25]

Environmental survival

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 0°C (32.0°F) (over one month at freezing temperature)
• 6 days at 37°C (98.6°F) (one week at human body temperature)
• 30 minutes 60°C (140.0°F) (half hour at a temperature that causes first and second degree burns in humans in ten seconds)^[26]

While cooking poultry to 70°C (158°F) kills the H5N1 virus, it is recommended to cook meat to 165°F to kill all foodborne pathogens.^[27]

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 ^[28]

Ordinary levels of chlorine in tap water kill H5N1 in public water systems.^[29]

Incubation

The human incubation period of avian influenza A (H5N1) is 2 to 17 days^[30]. 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.^[31]

Symptoms

See also Pneumonia.

Avian influenza HA bind alpha 2-3 sialic acid receptors while human influenza HA bind alpha 2-6 sialic acid receptors. Usually other differences also exist. There is as yet no human form of H5N1, so all humans who have caught it so far have caught avian H5N1.

Human flu symptoms usually include fever, cough, sore throat, muscle aches, conjunctivitis and, in severe cases, severe breathing problems and pneumonia that may be fatal. The severity of the infection will depend to a large part on the state of the infected person's immune system and if the victim has been exposed to the strain before, and is therefore partially immune. No one knows if these or other symptoms will be the symptoms of a humanized H5N1 flu.

Highly pathogenic H5N1 avian influenza 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. ^[32]

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 ^[33]. 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 ^[34] Other important mechanisms also exist "in the acquisition of virulence in avian influenza viruses" according to the CDC.^[35]

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 ^[25]. 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^[36].

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.^[37]

Research indicates that therapy to block one cytokine to lessen a cytokine storm in a patient may not be clinically beneficial.^[38]

Human mortality rate

Main article: Human mortality from H5N1

Notes and references

See also

• Fujian flu
• Severe acute respiratory syndrome

Further reading

• Epidemiology of WHO-confirmed human cases of avian influenza A(H5N1) infection (pdf).
• WHO Avian influenza resource (updated).
• CDC Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus.
• FAO information on Avian Influenza - Latest news, Disease Card, Maps, Animations.
• Avian Influenza (Bird Flu): Agricultural and Wildlife Considerations. CIDRAP.
• Avian Influenza: Preparing for a Pandemic. American Family Physician.