Transmission and infection of 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.

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 improvment 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. A few isolated cases of suspected human to human transmission exist, but there is no proof either way in those cases. Until recently, the WHO estimate of the number of human to human transmission has 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 it noone "has got a solid number."

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.

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 (Elbers 2005). 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 (Capua and Mutinelli 2001). Some LP strains such as certain Asian H9N2 lineages, adapted to efficient replication in poultry, may cause more prominent signs and also significant mortality (Bano 2003, Li 2005). 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 (Swayne and Suarez 2000).

Transmission by wild birds (waterfowl)

The spread of avian influenza in the eastern hemisphere.

According to the United Nations FAO:

Looking at the epidemiological data currently available, 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.

Prevention

The current method of prevention in animal populations is to destroy infected animals, as well as animals suspected of being infected. In southeast Asia, millions of domestic birds have been slaughtered to prevent the spread of the virus.

The probability of a "humanized" form of H5N1 emerging through genetic recombination in the body of a human co-infected with H5N1 and another influenza virus type (a process called reassortment) could be reduced by influenza vaccination of those at risk for infection by H5N1. It is not clear at this point whether vaccine production and immunization could be stepped up sufficiently to meet this demand.

If an outbreak of pandemic flu does occur, its spread might be slowed by increasing hygiene in aircraft, and by examining airline cabin air filters for presence of H5N1 virus.

The American Centers for Disease Control and Prevention advises travelers to areas of Asia where outbreaks of H5N1 have occurred to avoid poultry farms and animals in live food markets . 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 .

Environmental survival

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

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

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

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

Incubation

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

See also Pneumonia.

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

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

Highly pathogenic H5N1 avian flu in a human is far worse, killing over 50% of humans that catch it. In one case, a boy with H5N1 experienced diarrhea followed rapidly by a coma without developing respiratory or flu-like symptoms.

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 .

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 . 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 to the World Health Organization, to 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.

Mortality rate

Human Mortality from H5N1
As of April 11, 2007

Source: WHO Confirmed Human Cases of H5N1 The thin line represents average mortality of recent cases. The thicker line represents mortality averaged over all cases. According to WHO: "Assessment of mortality rates and the time intervals between symptom onset and hospitalization and between symptom onset and death suggests that the illness pattern has not changed substantially during the three years."[1]

In 2005, 41 of 95 people known to be infected with H5N1 died - or 43%. From January 1 2006 to May 19 2006, mortality has been higher, with 47 deaths among 73 cases - or 64%. This has been interpreted by some to mean that the virus itself is becoming more deadly over time. The global mortality rate is, nonetheless, a crude summary of a complex situation with many contributing factors. In particular, if an influenza pandemic arises from the currently circulating 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. Though a new pandemic strain may evolve, the precise nature and extent of the genetic alterations that may 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.

A mortality rate of slightly 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 . There is significant evidence that the high death rate among confirmed cases of the H5N1 virus cannot be simply attributed to mild cases being overlooked and thus omitted from the experience base of human H5N1 influenza attacks against which a fatality percentage is figured. However, the precise allocation of H5N1 infections across the spectrum including lethal, serious, mild, and asymptomatic cases remains unknown in both humans and the hundreds of other species it can infect. Scientists are very concerned about what we do know about H5N1; but even more concerned about the vast amount of important data that we don't know about H5N1 and its future mutations.

Review of patient ages and outcomes reveals that H5N1 attacks are especially lethal in pre-adults and young adults, while older victims tend to have milder attacks and to survive. 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.

Further reading

• 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
• Fowl Play: The Poultry Industry's Central Role in the Bird Flu Crisis -- a 19-page report from a non-govt agency, that claims the H5N1 virus originated in the intensive environment of factory farms, not backyard flocks, and is being spread by the commercial poultry industry, NOT by wild birds.
• Barry Yeoman, Avian Flu: What You Need to Know, O: The Oprah Magazine