Influenza A virus

Avian influenza (also known as bird flu) is a type of influenza virulent in birds. It was first identified in Italy in the early 1900s and is now known to exist worldwide.

Infection

The causative agent is the avian influenza (AI) virus. AI viruses all belong to the influenza virus A genus of the Orthomyxoviridae family and are negative-stranded, segmented RNA viruses.

Avian influenza spreads in the air and in manure. Wild fowl often act as resistant carriers, spreading it to more susceptible domestic stocks. It can also be transmitted by contaminated feed, water, equipment and clothing; however, there is no evidence that the virus can survive in well cooked meat.

Cats are also thought to be possible infection vectors for H5N1 strains of avian flu (Kuiken et al, 2004).

The incubation period is 3 to 5 days. Symptoms in animals vary, but virulent strains can cause death within a few days.

Subtypes pathogenic to humans

All Avian Influenza (AI) viruses are type A influenza viruses in the virus family of Orthomyxoviridae and are subdivided into subtypes based on hemagglutinin (H) and neuraminidase (N) protein spikes from the central virus core. There are 16 H types, each with up to 9 N subtypes, yielding a potential for 144 different H and N combinations. In addition, all AI viruses fall into one of 2 pathotypes: low (LPAI) and high (HPAI) pathogenicity, based on how dangerous to poultry.

Of the 16 H types known, only subtypes H5, H7 and H9 are known to be capable of crossing the species barrier from birds to humans. It is feared that if the avian influenza virus undergoes antigenic shift with a human influenza virus, the new subtype created could be both highly contagious and highly lethal in humans. Such a subtype could cause a global influenza pandemic, similar to the Spanish Flu that killed over 20 million people in 1918 (though a variety of sources quote average figures even higher, up to 100 million in some cases). Many health experts are concerned that a virus that mutates to the point where it can cross the species barrier (i.e. from birds to humans) will inevitably mutate to the point where it can be transmitted from human to human. It is at that point that a pandemic becomes likely.

Influenza viruses that infect birds are called “avian influenza viruses.” Only influenza A viruses infect birds. All known subtypes of influenza A virus can infect birds.

However, there are substantial genetic differences between the subtypes that typically infect both people and birds. Within subtypes of avian influenza viruses there also are different strains (described in “Strains”). Avian influenza H5 and H7 viruses can be distinguished as “low pathogenic” and “high pathogenic” forms on the basis of genetic features of the virus and the severity of the illness they cause in poultry; influenza H9 virus has been identified only in a “low pathogenicity” form.

Since 1997 the following types of avian influenza virus has been confirmed to outbreak infecting humans: H5N1, H7N2, H7N3, H7N7, and H9N2.

H5N1

H5N1 avian influenza strain passed from birds to humans in 1997 in Hong Kong. Eighteen people were infected, of whom six died. The outbreak was limited to Hong Kong. All chickens in the territory were slaughtered.

In January 2004, a major new outbreak of H5N1 avian influenza surfaced in Vietnam and Thailand's poultry industry, and within weeks spread to ten countries and regions in Asia, including Indonesia, South Korea, Japan and mainland China. Intensive efforts were undertaken to slaughter chickens, ducks and geese (over 40 million chickens alone were slaughtered in high-infection areas), and the outbreak was contained by March, but the total human death toll in Vietnam and Thailand was 23 people. In February 2004, avian influenza virus was detected in pigs in Vietnam, increasing fears of the emergence of new variant strains.

Fresh outbreaks in poultry were confirmed in Ayutthaya and Pathumthani provinces of Thailand, and Chaohu city in Anhui, China, in July 2004.

In August 2004 avian flu was confirmed in Kampung Pasir, Kelantan, Malaysia. Two chickens were confirmed to be carrying H5N1. As a result Singapore has imposed a ban on the importation of chickens and poultry products. Similarly the EU has imposed a ban on Malaysian poultry products. A cull of all poultry has been ordered by the Malaysian government within a 10km radius of the location of this outbreak.

An outbreak of avian influenza in January 2005 affected 33 out of 64 cities and provinces in Vietnam, leading to the forced killing of nearly 1.2 million poultry. Up to 140 million birds are believed to have died or were killed because of the outbreak.

Vietnam and Thailand have seen several isolated cases where human-to-human transmission of the virus has been suspected. In one case the original carrier, who received the disease from a bird, was held by her mother for roughly 5 days as the young girl died. Shortly afterwards, the mother became ill and perished as well. In March, 2005 it was revealed that two nurses who had cared for avian flu patients have tested positive for the disease.

In May 2005, the occurrence of Avian influenza in pigs in Indonesia was reported ("swine flu"). Along with the continuing pattern of virus circulation in poultry, the occurrence in swine raises the level of concern about the possible evolution of the virus into a strain capable of causing a global human influenza pandemic. Health experts say pigs can carry human influenza viruses, which can combine (i.e. exchange homologous genome sub-units by genetic reassortment.) with the avian virus, swap genes and mutate into a form which can pass easily among humans.

In July 2005, a death in Jakarta was the first confirmed human fatality in Indonesia. The deaths of the man's two children, neither of whom were reported to have had close contact with poultry, further raised concerns of human-to-human transmission (although infection by eating undercooked poultry may be a more likely explanation) [1]. As of July 20, the outbreak had claimed at least 58 human lives — mostly in Vietnam. What concerns health researchers now is that the virus mortality rate in Vietnam has dropped significantly lately, from more than 65% to about 35% in a year. This might be a sign that the virus is able to infect a larger number of people (i.e., the virus is able to spread more easily) and possibly develop into a global pandemic with millions of deaths despite the lower reported percentage of deaths. For example, the mortality rate of 1918 Spanish flu (H1N1) pandemic was less than 5% [2]. Also,in July 2005, it was confirmed H5N1 had appeared in Russia's Novosibirsk region, probably carried by migratory birds [3]. On July 28th, avian influenza was reported to have killed two more people in Vietnam, raising the death toll to 60 [4]. As of July 2005, most human cases of avian influenza in East Asia have been attributed to consumption of diseased poultry. Person-to-person transmission has not been unequivocally confirmed in the outbreaks in East Asia.

In August 2005, scientists said they have successfully tested in people a vaccine that they believe can protect against the strain of avian influenza that is spreading in birds through Asia and Russia. Influenza A(H5N1) virus has infected nearly 100 humans in the past 18 months, killing about half of them. If the virus starts to spread efficiently among humans, experts fear it could trigger a global pandemic that could kill millions. In response, millions of birds throughout Asia have been slaughtered to try to stem the spread of the virus; governments and the World Health Organization have been stockpiling antiviral drugs, and scientists have been scrambling to produce an effective vaccine. Due to the lag time needed to manufacture a vaccine that could prevent deaths from a human influenza pandemic, Dr. Anthony S. Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, announced that the United States will order additional doses of the vaccine that is aimed at containing a human pandemic, should it occur [5].

On August 3, 2005, the United Nations World Health Organization (WHO) said it was following closely reports from China that at least 38 people have died and more than 200 others have been made ill by a swine-borne disease in Sichuan province. Sichuan Province, where infections with Streptococcus suis have been detected in pigs in a concurrent outbreak, has one of the largest pig populations in China. The outbreak in humans has some unusual features and is being closely followed by the WHO. At that time, Chinese authorities say they have found no evidence of human-to-human transmission [6].

Also in early August, an avian outbreak of influenza A(H5N1) was confirmed in Kazakhstan and Mongolia, suggesting further spread of the virus [7]. Later in August, the virus was found in western Russia, marking its appearance in Europe.

H7N2

Following an outbreak of H7N2 among poultry in 2002 44 persons have been found infected in Virginia, United States.

H7N3

In North America, the presence of avian influenza strain H7N3 was confirmed at several poultry farms in British Columbia in February 2004. As of April 2004, 18 farms had been quarantined to halt the spread of the virus. Two cases of humans with avian influenza have been confirmed in that region.

H7N7

In 2003 in Netherlands 89 people were confirmed to have H7N7 influenza virus infection following an outbreak in poultry on several farms. One death has been recorded.

H9N2

The virus type has been documented only in low pathogenic form. Three infections in humans (China and Hong Kong) have been confirmed, all three patients recovered.

Prevention and treatment

Avian influenza in humans can be detected with standard influenza tests. However, these tests have not always proved reliable. In March 2005, the World Health Organization announced that seven Vietnamese who initially tested negative for bird flu were later found to have carried the virus. All seven have since recovered from the disease. Currently (6/05) the most reliable test (microneutralization) requires use of the live virus to interact with antibodies from the patient's blood; because live virus is required, for safety reasons the test can only be done in a level 3 laboratory [8].

Antiviral drugs are sometimes effective in both preventing and treating the disease, but no virus has ever been really cured in medical history. Vaccines, however, take at least four months to produce and must be prepared for each subtype.

Further, as a result of widespread use of the antiviral drug amantadine as a preventive or treatment for chickens in China starting in the late 1990's, some strains of the avian flu virus in Asia have developed drug resistance against amantadine [9]. Chickens in China have received an estimated 2.6 billion doses of amantadine since early 2004. This use of amantadine for poultry goes against international livestock regulations, but China kept it secret until recently, in a manner reminiscent of the secrecy around the early spread of SARS.

Increasing virulence

In July 2004 a group of researchers led by H. Deng of the Harbin Veterinary Research Institute, Harbin, China and Professor Robert Webster of the St Jude Children's Research Hospital, Memphis, Tennessee, reported results of experiments in which mice had been exposed to 21 isolates of confirmed H5N1 strains obtained from ducks in China between 1999 and 2002. They found "a clear temporal pattern of progressively increasing pathogenicity". [10] Results reported by Dr. Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks.

As of July 2005, most human cases of avian influenza in East Asia have been attributed to consumption of diseased poultry. Person-to-person transmission has not been unequivocally confirmed in the outbreaks in East Asia.

In May 2005, the occurrence of Avian influenza in pigs in Indonesia was reported ("swine flu"). Along with the continuing pattern of virus circulation in poultry, the occurrence in swine raises the level of concern about the possible evolution of the virus into a strain capable of causing a global human influenza pandemic. Health experts say pigs can carry human influenza viruses, which can combine (i.e. exchange homologous genome sub-units by genetic reassortment.) with the avian virus, swap genes and mutate into a form which can pass easily among humans.

On August 3, 2005, the United Nations World Health Organization (WHO) said it was following closely reports from China that at least 38 people have died and more than 200 others have been made ill by a swine-borne disease (possible "pig flu" outbreak) in Sichuan province. Sichuan Province, where infections with Streptococcus suis have been detected in pigs in a concurrent outbreak, has one of the largest pig populations in China. The outbreak in humans has some unusual features and is being closely followed by the WHO. At that time, Chinese authorities say they have found no evidence of human-to-human transmission [11].

Symptoms

In humans, it has been found that avian flu causes similar symptoms to other types of flu [12]:

fever
cough
sore throat
muscle aches
conjunctivitis
in severe cases of avian flu, it can cause severe breathing problems and pneumonia, and can be fatal.

In one case, a boy with H5N1 presented to the hospital with diarrhea followed rapidly by a coma without developing flu-like symptoms.[13]

Pandemic threat and preparedness plans

The World Health Organization (WHO) warns that there is a substantial risk of an influenza pandemic within the next few years. One of the strongest candidates is the A(H5N1) subtype of Influenza virus. See "Assessing the pandemic threat" at [14]. WHO published a first edition of the Global Influenza Preparedness Plan in 1999, and updated it in April 2005. See [15] and [16] which define the responsibilities of WHO and national authorities in case of an influenza pandemic. This is the first time a pandemic has been anticipated and is being prepared for.

The aims of such plans are, broadly speaking, the following:

Before a pandemic, attempt to prevent it and prepare for it in case prevention fails.
If a pandemic does occur, to slow its spread and allow societies to function as normally as possible.

Strategies to prevent a pandemic

If avian influenza remains an animal problem with limited human-to-human transmission it is not a pandemic, though it continues to pose a risk.

To prevent the situation from progressing to a pandemic, the following short-term strategies have been put forward:

Culling and vaccinating poultry
Limiting travel in areas where the virus is found

Longer term strategies proposed for regions where highly pathogenic H5N1 is endemic in wild birds have included:

changing local farming practices to increase farm hygiene and reduce contact between livestock and wild birds.
altering farming practices in regions where animals live in close, often unsanitary quarters with people, and changing the practices of open-air "wet markets" where birds are slaughtered in unsanitary conditions near fruits and vegetables. Cock fighting also has played a role in spreading the disease by bringing humans into contact with fowl, and this practice will also continue to contribute to infection if it is not curbed. A challenge to implementing these measures is widespread poverty, frequently in rural areas, coupled with a reliance upon raising fowl for purposes of subsistence farming or income without measures to prevent propagation of the disease.
changing local shopping practices from purchase of live fowl to purchase of slaughtered, pre-packaged fowl.
improving veterinary vaccine availability and cost. [17]

Strategies to slow down a pandemic

Vaccines. A vaccine probably would not be available in the inital stages of population infection [18]. Once a potential virus is identified, it normally takes at least several months before a vaccine becomes widely available, as it must be developed, tested and authorised. The capability to produce vaccines varies widely from country to country; in fact, only 15 countries are listed as "Influenza vaccine manufacturers" according to the World Health Organisation [19]. It is estimated that, in a best scenario situation, 750 million doses could be produced each year, whereas it is likely that each individual would need two doses of the vaccine in order to become inmuno-competent. Distribution to and inside countries would probably be problematic [20]. Several countries, however, have well-developed plans for producing large quantities of vaccine. For example, Canadian health authorities say that they are developing the capacity to produce 32 million doses within four months, enough vaccine to inoculate every person in the country. [21] The United States has also taken steps to produce an avian flu vaccine, which might be ready for mass production by September 2005. [22]
Anti-viral drugs. Several new anti-viral drugs have been developed in recent years. A number of governments are working to stockpile anti-viral drugs but the work is complicated by the constant mutation of the virus, which might become somewhat resistant to some anti-viral drugs, making these drugs less effective.
Non-pharmaceutical means:
- "Social distance". By travelling less, working from home or closing schools there is less opportunity for the virus to spread.
- Respiratory etiquette. Placing one's hand in front of the mouth when coughing or sneezing can somewhat limit the dispersal of droplets. However It has been suggested recently that covering one's mouth and nose with one's hand is not very effective in stopping the spread of germs as these germs are retained in the hand, and are then deposited on doorknobs, on to others through handshakes, etc. Current thinking suggests coughing or sneezing into the crook of one's arm would be preferable to limit germ spread.
- Masks. No mask can provide a perfect barrier but products that meet or exceed the NIOSH N95 standard recommended by the World Health Organization are thought to provide good protection. Other well-fitting masks can be helpful but much less effective. Any mask may be useful to remind the wearer not to touch his face. This can reduce infection due to contact with contaminated surfaces, especially in crowded public places where coughing or sneezing people have no way of washing their hands.
- Hygiene. Frequent handwashing, especially when there has been contact with other people or with potentially contaminated surfaces can be very helpful.

Stages of a pandemic

The World Health Organization (WHO) has developed a global influenza preparedness plan, which defines the stages of a pandemic, outlines WHO's role and makes recommendations for national measures before and during a pandemic.

As of early August 2005, most sources place the current avian influenza epidemic at phase 3. The phases are defined as:

Interpandemic period

Phase 1: No new influenza virus subtypes have been detected in humans. An influenza virus subtype that has caused human infection may be present in animals. If present in animals, the risk of human infection or disease is considered to be low.

Phase 2: No new influenza virus subtypes have been detected in humans. However, a circulating animal influenza virus subtype poses a substantial risk of human disease.

Pandemic alert period

Phase 3: Human infection(s) with a new subtype, but no human-to-human spread, or at most rare instances of spread to a close contact.

Phase 4: Small cluster(s) with limited human-to-human transmission but spread is highly localized, suggesting that the virus is not well adapted to humans.

Phase 5: Larger cluster(s) but human-to-human spread still localized, suggesting that the virus is becoming increasingly better adapted to humans, but may not yet be fully transmissible (substantial pandemic risk).

Pandemic period

Phase 6: Pandemic: increased and sustained transmission in general population.

Notes

The distinction between phase 1 and phase 2 is based on the risk of human infection or disease resulting from circulating strains in animals. The distinction is based on various factors and their relative importance according to current scientific knowledge. Factors may include pathogenicity in animals and humans, occurrence in domesticated animals and livestock or only in wildlife, whether the virus is enzootic or epizootic, geographically localized or widespread, and/or other scientific parameters.

The distinction between phase 3, phase 4 and phase 5 is based on an assessment of the risk of a pandemic. Various factors and their relative importance according to current scientific knowledge may be considered. Factors may include rate of transmission, geographical location and spread, severity of illness, presence of genes from human strains (if derived from an animal strain), and/or other scientific parameters.

The pandemic stage 6 may be marked by two or more waves. For example, the initial wave of the Spanish Influenza pandemic of 1918 killed a few but was mild enough in its effects to receive the dismissive nickname of the "three day flu." But the second wave which hit North America a few months later in the summer of 1918 was lethal. Apparently in the interim the novel H1N1 pandemic strain had added the gene or genes that made the final wave a killer. Perhaps the effects of the lethal second wave would have been even more devastating if the innocuous first wave had not already passed through the population, leaving in its wake at least some immune response to the H1N1 antigens that were present in both waves.

CIDRAP's |Overview of Pandemic Influenzais adapted from HHS National Vaccine Program Office and lists five numbered stages for the pandemic itself. CIDRAP also includes four additional stages, each numbered as zero, that seem to overlap other models' first five stages of a pandemic.

References

Kuiken T et al (2004), Avian H5N1 Influenza in Cats, Science 2004 306: 241 (doi:10.1126/science.1102287)

External links